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10.1101/2022.03.22.22272760 | Ventricular and Atrial Pressure-Volume Loops: Analysis of the Effects Induced by Right Centrifugal Pump Assistance | Background and ObjectiveThe main indications for right ventricular assist device (RVAD) support are right heart failure after implantation of a left ventricular assist device (LVAD) or early graft failure following heart transplantation. About 30-40% of patients will need RVAD support after LVAD implantation. Pulmonary hypertension is also an indication for right heart assistance. Several types of RVAD generating pulsatile or continuous flow are available on the market. These assist devices can be connected to the cardiovascular system in different ways. We sought to analyse the effects induced by different RVAD connections when right ventricular elastance is modified using a numerical simulator. The analysis was based on the behaviour of both left and right ventricular and atrial loops in the pressure-volume plane.
MethodsNew modules of the cardiovascular network and a right ventricular centrifugal pump were implemented in CARDIOSIM(C) software simulator platform. The numerical pump model generated continuous flow when connected in series or parallel to the right ventricle. When the RVAD was connected in series (parallel), the pump removed blood from the right ventricle (atrium) and ejected it into the pulmonary artery. In our study, we analysed the effects induced by RVAD support on left/right ventricular/atrial loops when right ventricular elastance slope (EesRIGHT) changed from 0.3 to 0.8 mmHg/ml with the pump connected either in series or parallel. The effect of low and high rotational pump speed was also addressed.
ResultsPercentage changes up to 60% were observed for left ventricular pressure-volume area and external work during in-parallel RVAD support at 4000 rpm with EesRIGHT = 0.3mmHg/ml. The same pump setting and connection type led to percentage variation up to 20% for left ventricular ESV and up to 25% for left ventricular EDV with EesRIGHT = 0.3mmHg/ml. Again the same pump setting and connection generated up to 50% change in left atrial pressure-volume loop area (PVLAL-A) and only 3% change in right atrial pressure-volume loop area (PVLAR-A) when EesRIGHT = 0.3mmHg/ml. Percentage variation was lower when EesRIGHT was increased up to 0.8 mmHg/ml.
ConclusionEarly recognition of right ventricular failure followed by aggressive treatment is desirable to achieve a more favourable outcome. RVAD support remains an option for advanced right ventricular failure although onset of major adverse events may preclude its use. | cardiovascular medicine |
10.1101/2022.03.23.22272829 | The effect of access to safe Water, Sanitation, and Hygiene (WASH) facilities on Child Growth Failure among children 6/59 months in Ecuador applying a random intercept multilevel model using cross-sectional ENSANUT 2018 data. | 1.BackgroundChild Growth Failure - measured as stunting, wasting and underweight - is still an important public health issue affecting 23.1% of children. Typically, literature focused on unproper dietary habits, but living in an unhealthy environment unable to prevent pathogens is another fundamental cause.
ObjectiveTo estimate the association between access to safe water, sanitation, and hygiene (WASH) facilities and risk for Child Growth Failure in under-5 children in Ecuador Design: Cross-sectional multilevel study using the Ecuadorian National Survey on Health and Nutrition (ENSANUT) 2018.
Participants17,688 children 6/59 months residing in 15,382 households.
Main outcome measuresAssociation between the access to safely managed WASH factors and the probability of suffering from: a) stunting, b) underweight and c) wasting; controlling for childs sex, childs age, antenatal care visits, pre-term delivery, assumption of micronutrient during the pregnancy, mothers age, mothers education, mothers height, mothers ethnic group, area and region of residence, the number of people living at home and the family per capita income. The final model is a two-levels random intercept logistic regression focused on the risk of suffering from stunting and underweight. Multilevel logistic models were applied for both the unadjusted and the adjusted estimates. The average marginal effects with the 95% confidence interval and p-value are estimated.
ResultsA safely managed sanitation system showed the strongest protective effect on underweight (-38.1%, 95% CI -16.9% and -59.4%) and stunting (-14.9%, 95% CI -4.7% and -25.1%). Important protective effects against stunting are observed also thanks to safely managed drinking water (-10.9%, 95% CI -0.1% and -21.6%) and applying proper hygiene habits (-9.5%, 95% CI -0.1% and -19.0%). A potential protective effect on underweight was observed also for proper hygiene habits although a wide confidence interval. No effect was observed between safely managed drinking water and the risk of being underweight. Women are characterized by an important lower risk for both stunting and underweight. Stunting is lower after the 24th month of life while no change is observed for underweight. Pre-term deliveries showed a strong growth of the risk for both stunting and underweight, while antenatal care visits significantly reduced the risk of both stunting and underweight as a high mothers education. Genetical (mothers height) and cultural (mothers ethnic group) aspects play an important role with the highest risk for stunting among Indigenous (+32.5%, 95% CI 19.6%-45.4%) and the lowest among Afro-Ecuadorian children (-20.7%, 95% CI 2.0% and -43.4%). Each additional centimetre of the mothers height from the average value (154.2 cm) reduces the risk for the child of suffering from both stunting (-6.1%, 95% CI -5.3% and -6.7%) and underweight (-5.1%, 95% CI -3.7% and -6.5%).
ConclusionsWASH factors play a fundamental role to prevent undernutrition, especially chronic undernutrition (stunting). The study found potential biases due to the use of self-reported cross-sectional data. No data on dietary habits were available for this study which is a potential lack to be considered for the future. | epidemiology |
10.1101/2022.03.23.22272812 | Vaccine Equity in Low- and Middle-Income Countries: A Systematic Review and Meta-analysis | BackgroundEvidence to date has shown that inequality in health, and vaccine coverage in particular, can have ramifications to wider society. However, whilst individual studies have sought to characterise these heterogeneities in immunisation coverage at national level, few have taken a broad and quantitative view of the contributing factors to heterogeneity in vaccine coverage and impact. This systematic review aims to highlight these geographic, demographic, and sociodemographic characteristics through a qualitative and quantitative approach, vital to prioritise and optimise vaccination policies.
MethodsA systematic review of two databases (PubMed and Web of Science) was undertaken using Medical Subject Headings (MeSH) and keywords to identify studies examining factors on vaccine inequality and heterogeneity in vaccine coverage. Inclusion criteria were applied independently by two researchers. Studies including data on key characteristics of interest were further analysed through a meta-analysis to produce a pooled estimate of the risk ratio using a random effects model for that characteristic.
ResultsOne hundred and eight studies were included in this review. We found that inequalities in wealth, education, and geographic access can affect vaccine impact and vaccine dropout. We estimated those living in rural areas were not significantly different in terms of full vaccination status compared to urban areas but noted considerable heterogeneity between countries. We found that females were 3% (95%CI[1%, 5%]) less likely to be fully vaccinated than males. Additionally, we estimated that children whose mothers had no formal education were 28% (95%CI[18%,47%]) less likely to be fully vaccinated than those whose mother had primary level, or above, education. Finally, we found that individuals in the poorest wealth quintile were 27% (95%CI [16%,37%]) less likely to be fully vaccinated than those in the richest.
ConclusionsWe found a nuanced picture of inequality in vaccine coverage and access with wealth disparity dominating, and likely driving, other disparities. This review highlights the complex landscape of inequity and further need to design vaccination strategies targeting missed subgroups to improve and recover vaccination coverage following the COVID-19 pandemic.
RegistrationProspero CRD42021261927 | public and global health |
10.1101/2022.03.23.22272806 | Elevated T-cell exhaustion and urinary tumor DNA levels are associated with BCG failure in patients with non-muscle invasive bladder cancer | BackgroundThe functional status of immune cells within the tumor microenvironment and tumor characteristics may explain Bacillus Calmette-Guerin (BCG)-failure in high-risk non-muscle invasive bladder cancer (NMIBC).
ObjectiveTo characterize molecular correlates of BCG-failure using a multiomics approach.
Design, Setting, and ParticipantsBCG-treated NMIBC patients (n=156) were included. Metachronous tumors were analyzed using RNA-sequencing (n=170) and whole exome sequencing (n=198). Urine samples were analyzed for immune-oncology related proteins (n=190), and tumor-derived DNA (tdDNA; n=192).
Outcome Measurement and Statistical AnalysisPrimary endpoint was BCG-failure. Cox regression, Wilcoxon Rank Sum test, t-test or Fishers exact test were used.
Results and LimitationsBCG caused activation of the immune system regardless of clinical response; however, immune-inhibitory proteins were observed in the urine of BCG-unresponsive patients post-treatment (CD70, PD1, CD5). BCG-failure was associated with post-BCG T-cell exhaustion (p=0.0021). Pre-BCG tumors from patients with post-BCG T-cell exhaustion were characterized by high expression of cell division and immune-related genes. A high post-BCG exhaustion prediction score in pre-BCG tumors was associated with worse post-BCG high-grade recurrence free survival (HGRFS), reflecting BCG-failure (p=0.0084). Pre-BCG tumors of class 2a and 2b were likewise associated with worse post-BCG HGRFS(p=0.0023). Post-BCG exhaustion was observed in patients with high pre-BCG neoantigen load (p=0.023) and mutations in MUC4 (p=0.0007). Finally, absence of post-BCG tdDNA clearance identified patients at high risk of recurrence (p=0.028). The retrospective design, lack of maintenance BCG, and partial overlap in analyses are limitations to the study.
ConclusionsBCG failure may be caused by T-cell exhaustion. Tumor subtype and Pre-BCG tumor characteristics may identify patients at high risk of BCG-failure prior to treatment. Urinary measurements have the potential to be used as a real-time assessment of treatment response.
Patient SummaryA dysfunctional immune response to BCG therapy may explain lack of response to the treatment. | urology |
10.1101/2022.03.22.22272740 | ASSOCIATION BETWEEN NUTRITIONAL STATE AND PHASE ANGLE IN SYMPTOMATIC AND ASYMPTOMATIC HTLV-1 INFECTED PATIENTS | IntroductionThe nutritional status of symptomatic and asymptomatic human T-cell lymphotropic virus type 1 (HTLV-1) infected patients is understudied. The phase angle (PA) has been described in the scientific literature as a prognostic indicator of nutritional status, but this has not been sufficiently discussed in the literature. Therefore, neither the impact of the infection nor the diseases progression is sufficiently known regarding the nutritional status, body condition or composition.
ObjectiveTo compare the nutritional status of symptomatic and asymptomatic adult individuals infected by HTLV-1, using the PA and anthropometric measures as a prognostic indicator in the HTLV-1 infected population.
MethodologyThis was an observational, cross-sectional study with symptomatic and asymptomatic HTLV-1 patients followed up at the Neurology outpatient clinic of the Evandro Chagas National Institute of Infectious Diseases (INI-FIOCRUZ), Brazil, from September 2015 to September 2019. Anthropometric measures and indices (body weight, height, body mass index-BMI, mid-upper arm circumference-MUAC, triceps skinfold - TSF, and mid- arm muscle circumference-MUAC), and bioimpedance (phase angle-PA, percentage of lean mass-%LM, and percentage of fat mass-%FM) were checked to assess the nutritional status. Anthropometric variables were classified according to reference values and compared between groups (symptomatic and asymptomatic). Individuals were considered malnourished when at least one of the nutritional assessment results was outside the reference values. PA was correlated with the nutritional status, and groups of symptomatic and asymptomatic were compared to each other. The R-project(R) program version 3.0.2 was used to analyze the data. Differences were considered significant when the p-value was [≤] 0.05.
ResultsNinety-one patients were evaluated, 33 (36.3%) asymptomatic and 58 (63.7%) symptomatic. The majority were female (61.5%) and the median age was 60 (55-58) years. Symptomatic participants, compared to asymptomatic, had a lower proportion of overweight/obesity (51.7% vs 78.8%; p =0.0171), lower BMI (25.47 {+/-} 5.06 kg/m2 vs 30.08 {+/-} 5.61 kg/m2; p = <0.001), MUAC (29.56 {+/-} 5.13 cm vs 33.22 {+/-} 4.21 cm; p =0.0011), and %FM (30.75% vs 36.60%; p =0.0064), however, had a higher %LM (68.95% vs 63.40%; p =0.0299). All participants presented PA, however there was no difference between symptomatic (5.74{o} {+/-} 1.18) and asymptomatic (6.21{o} {+/-} 1.16).
ConclusionOverweight and obesity were prevalent, especially among asymptomatic participants. Symptomatic participants had lower BMI, MUAC and %FM. Mid-upper arm circumference was considered a good parameter for monitoring the nutritional status of people with HTLV, mainly in situations where weight measurement is not viable. PA was altered in both groups, therefore, it cannot be used as a disease progression indicator, but it does indicate that HTLV infection alone should be a risk of cellular membrane integrity damage. Studies using PA assessment in HTLV-1 carriers are needed.
AUTHORS SUMMARYHTLV is a disease very little explored, and in the scientific field of nutrition it is no different, we found few studies that associate this population and their nutritional status. In academic literature we can find the association of weight, height and BMI, rare studies with bioimpedance assessments.
Until this moment, no study has associated nutritional status with the phase angle, which is being used in several infectious diseases as a prognostic indicator of cell membrane integrity.
In this study, we note that even though the phase angle values are not significant, they show that, regardless of the symptoms, patients who are infected with the HTLV virus are already considered to have damage to the membrane integrity, which makes us emphasize the importance of new studies to a better understanding of factors related to weight gain and probable nutritional deficiencies. | infectious diseases |
10.1101/2022.03.22.22272750 | Acupuncture with or without acupoint application for primary dysmenorrhea: protocol for a systematic review and meta-analysis | IntroductionDysmenorrhea is the most common gynaecological symptom reported by women. Ninety percent of women presenting for primary care experience some menstrual pain. Population surveys suggest that, although prevalence rates vary considerably by geographic al location, complaints of dysmenorrhea are widespread in diverse populations. This study will evaluate the results of randomized controlled trials to determine the efficacy and safety of acupuncture with or without acupoint application for the treatment of dysmenorrhea.
MethodsEight databases, including China National Knowledge Infrastructure, Chinese Scientific Journal Database, Cochrane Central Register of Controlled Trials, Embase, MEDLINE, PubMed, Wanfang Database, and Web of Science, will be searched using English and Chinese search strategies. In addition, manual retrieval of research papers, conference papers, ongoing experiments, and internal reports, among others, will supplement electronic retrieval. All eligible studies published on or before December 12, 2021 will be selected. To enhance the effectiveness of the study, only clinical randomized controlled trials related to the use of acupuncture with or without acupoint application for the treatment of dysmenorrhea will be included.
AnalysisThe Visual Analog Scale will be the primary outcome measure, whereas the McGill pain questionnaire, SF-36 Scale, Self-Rating Anxiety, and Self-Rating Depression scale will be the secondary outcomes. Side effects and adverse events will be included as safety evaluations. To ensure the quality of the systematic evaluation, study selection, data extraction, and quality assessment will be independently performed by two authors, and a third author will resolve any disagreement.
Ethics and disseminationThis systematic review will evaluate the efficacy and safety of acupuncture with or without acupoint application for the treatment of dysmenorrhea. Since all included data will be obtained from published articles, it does not require ethical approval and will be published in a peer-reviewed journal.
INPLASY registration numberINPLASY202230051. | public and global health |
10.1101/2022.03.23.22272828 | Neutrophils in severe COVID-19 are characterized by a hyperactive immature state and maintained CXCR2 expression | Neutrophils are vital in defence against pathogens but excessive neutrophil activity can lead to tissue damage and promote acute respiratory distress syndrome (ARDS). COVID-19 is associated with systemic expansion of immature neutrophils but the functional consequences of this shift to immaturity are not understood. We used flow cytometry to investigate activity and phenotypic diversity of circulating neutrophils in COVID-19. First, we demonstrate hyperactivation of immature CD10- subpopulations in severe disease, with elevated degranulation of secondary granule markers. Partially activated immature neutrophils are detectable three months post symptom onset, indication long term myeloid dysregulation in convalescent COVID-19 patients. Second, we demonstrate that neutrophils from moderately ill patients downregulate the chemokine receptor CXCR2, while neutrophils from severely ill individuals failed to do so, suggesting altered ability for organ trafficking. CD10- and CXCR2hi neutrophil subpopulations were enriched in severe disease and may represent biomarkers for early identification of individuals at high risk of progressing to severe COVID-19. | allergy and immunology |
10.1101/2022.03.23.22272828 | Hyperactive immature state and differential CXCR2 expression of neutrophils in severe COVID-19 | Neutrophils are vital in defence against pathogens but excessive neutrophil activity can lead to tissue damage and promote acute respiratory distress syndrome (ARDS). COVID-19 is associated with systemic expansion of immature neutrophils but the functional consequences of this shift to immaturity are not understood. We used flow cytometry to investigate activity and phenotypic diversity of circulating neutrophils in COVID-19. First, we demonstrate hyperactivation of immature CD10- subpopulations in severe disease, with elevated degranulation of secondary granule markers. Partially activated immature neutrophils are detectable three months post symptom onset, indication long term myeloid dysregulation in convalescent COVID-19 patients. Second, we demonstrate that neutrophils from moderately ill patients downregulate the chemokine receptor CXCR2, while neutrophils from severely ill individuals failed to do so, suggesting altered ability for organ trafficking. CD10- and CXCR2hi neutrophil subpopulations were enriched in severe disease and may represent biomarkers for early identification of individuals at high risk of progressing to severe COVID-19. | allergy and immunology |
10.1101/2022.03.23.22272692 | Adherence to 24h movement recommendations and health indicators in the ABCD study: Cross-sectional and longitudinal associations with cognition, psychosocial health, BMI and brain structure | Adherence to 24h movement guidelines of [≥]60min of physical activity, [≤]2h of screen time, and 9-11h of sleep has been shown to benefit cognition, physical and psychosocial health in children aged 5-13y. However, these findings are largely based on cross-sectional studies or small samples. Here we utilize data from the Adolescent Brain Cognitive Development (ABCD) study of 10000+ children aged 9-11y to examine whether adherence to 24h movement guidelines benefit cognition, BMI, psychosocial health and brain morphometric measures at baseline (T1) and 2 years later (T2). After adjustment for sociodemographic confounders in multivariable linear mixed models, we observed better cognitive scores, fewer behavioural problems, lower adiposity levels and greater gray matter volumes in children who met both sleep and screen time recommendations compared to those who met none. Longitudinal follow up further supports these findings; participants who met both recommendations at T1 and T2 evidenced better outcome measures than those who met none, even after controlling for T1 measures. These findings support consideration of integrated rather than isolated movement recommendations across the day for better cognitive, physical, psychosocial and brain health. | pediatrics |
10.1101/2022.03.22.22272566 | The brain mechanisms of self-identification & self-location in neurosurgical patients using virtual reality and lesion network mapping | Background and ObjectivesThe identification of cognitive biomarkers in preoperative counselling and their monitoring during brain surgery is of growing interest for the safe conduction of resective intracranial procedures with potential impact on the patients personality. The conscious experience of identifying with the body (self-identification) and of where I am in space(self-location) are central for bodily self-consciousness (BSC). In a virtual reality (VR) paradigm using multisensory feedback, illusory self-identification and self-location over a virtual body can be induced, by manipulating the synchrony of visuo-tactile inputs. To date, no studies applied lesion network mapping (LNM) to investigate networks underlying BSC components with VR.
MethodsFifteen neurosurgical patients with intra-axial and extra-axial brain lesions(8 pre-resection, 9 post-resection) performed the visuo-tactile VR paradigm. Patients subjectively rated their self-identification and self-location, after being exposed to synchronous or asynchronous visuo-tactile stimulations. We applied LNM analysis using functional data from 1015 healthy subjects and determined functional connectivity patterns related to each measure.
ResultsIn the post-surgery group, the self-identification network included the right inferior frontal, superior frontal and inferior temporal gyri. The self-location network encompassed the right parahippocampal gyrus, superior temporal gyrus, bilateral cerebellum and brainstem. No clusters survived for the pre-surgery group.
DiscussionOur LNM findings reveal the existence of two distinct networks for self-identification and self-location, including structures playing key roles in self-recognition or self-other distinction as well as in spatial navigation or memory processes, respectively. Such networks should be added to the portfolio of presurgical surveillance of functions related to the sense of self to improve future surgical outcomes.
What is already known on this topicThe development of extra- and intraoperative cognitive biomarkers is of importance for monitoring the personality of patients during cranial surgical procedures, as that may allow for individualized pre-operative counselling and intraoperative decision making. Such guidance may ultimately help to improve neuropsychological outcomes following brain surgery.
Bodily self-consciousness refers to a perceptual form of the sense of self, related to multisensory bodily inputs, which can be disrupted in neurological, psychiatric, or neurosurgical conditions.
What this study addsIn this study, we investigated networks associated with changes in two components bodily self-consciousness (self-identification, self-location) that we manipulated in real-time using multisensory stimulation and virtual reality in neurosurgical patients, who underwent resective surgery for brain tumors or lesions (gliomas, meningiomas, epileptic foci).
Our lesion network mapping findings reveal the existence of two distinct networks of bodily self-consciousness, including structures playing key roles in self-recognition or self-other distinction for self-identification, and in spatial navigation or memory processes for self-location.
How this study might affect research, practice or policyIdeally, such networks should be identified, and their individual anatomical allocation be integrated in the surgical plan, to make them potentially amenable for functional mapping and monitoring during resective brain surgery. Ultimately, that assessment of functions related to the sense of self and personality should help. | neurology |
10.1101/2022.03.22.22272738 | The contribution of white matter pathology, hypoperfusion, lesion load, and stroke recurrence to language deficits following acute subcortical left hemisphere stroke | Aphasia, the loss of language ability following damage to the brain, is among the most disabling and common consequences of stroke. Subcortical stroke, occurring in the basal ganglia, thalamus, and/or deep white matter can result in aphasia, often characterized by word fluency, motor speech output, or sentence generation impairments. The link between greater lesion volume and acute aphasia is well documented, but the independent contributions of lesion location, cortical hypoperfusion, prior stroke, and white matter degeneration (leukoaraiosis) remain unclear, particularly in subcortical aphasia. Thus, we aimed to disentangle the contributions of each factor on language impairments in left hemisphere acute subcortical stroke survivors. Eighty patients with acute left hemisphere subcortical stroke (less than 10 days post-onset) participated. We manually traced acute lesions on diffusion-weighted scans and prior lesions on T2-weighted scans. Leukoaraiosis was rated on T2-weighted scans using the Fazekas et al. (1987) scale. Fluid-attenuated inversion recovery (FLAIR) scans were evaluated for hyperintense vessels in each vascular territory, providing an indirect measure of hypoperfusion in lieu of perfusion-weighted imaging. Compared to subcortical stroke patients without aphasia, patients with aphasia had greater acute and total lesion volume, were older, and had significantly greater damage to the internal capsule (which did not survive controlling for total lesion volume). Patients with aphasia did not differ from non-aphasic patients by other demographic or stroke variables. Age was the only significant predictor of aphasia status in a logistic regression model. Further examination of three participants with severe language impairments suggests that their deficits result from impairment in domain-general, rather than linguistic, processes. Given the variability in language deficits and imaging markers associated with such deficits, it seems likely that subcortical aphasia is a heterogeneous clinical syndrome with distinct causes across individuals. | neurology |
10.1101/2022.03.23.22272815 | Prediction of Uterine Dehiscence via Machine Learning by Using Lower Uterine Segment Thickness and Clinical Features | BackgroundWith the global increase of Cesarean section delivery rates, the long-term effects of Cesarean delivery have started to become more clear. One of the most prominent complications of Cesarean section in recurrent pregnancies is uterine rupture. Assessing the risk of uterine rupture or dehiscence is very important in order to prevent untimely operations and/or maternal and fetal complications.
ObjectiveOur study aims to assess whether machine learning can be used to predict uterine dehiscence or rupture by using patients ultrasonographic findings, clinical findings and demographic data as features. Hence, possible uterine rupture, as well as maternal and fetal complications pertinent to it, could be prevented.
Study DesignThe study was conducted on 317 patients with term (>37 weeks) singleton pregnancy. Demographics, body-mass indices, smoking and drinking habits, clinical features, past pregnancies, number and history of abortions, inter-delivery period, gestation week, number of previous Cesarean operations, fetal presentation, fetal weight, tocography data, trans-abdominal ultrasonographic measurement of lower uterine segment full thickness and myometrium thickness, lower uterine segment findings during Cesarean section were collected and analyzed using machine learning techniques. Logistic Regression, Multilayer Perceptron, Support Vector Machine, Random Forest and Naive Bayes algorithms were used for classification. The dataset was evaluated using 10-fold cross-validation. Correct Classification Rate, F-score, Matthews Correlation Coefficient, Precision-Recall Curve area and Receiver Operating Characteristics area were used as performance metrics.
ResultsAmong the machine learning techniques that has been tested in this study, Naive Bayes algorithm showed the best prediction performance. Among the various combinations of features used for prediction, the essential features of parity, gravida, tocographic contraction, dilation, d&c with the sonographic thickness of lower uterine segment myometrium yielded the best results. The runner-up performance was obtained with the sonographic full thickness of lower uterine segment added to the base features. The base features alone can classify patients with 90.5% accuracy, while adding the myometrium measurement increases the classification performance by 5.1% to 95.6%. Adding the full thickness measurement to the base features raises the classification performance by 4.8% to 95.3% in terms of Correct Classification Rate.
ConclusionNaive Bayes algorithm can correctly classify uterine rupture or dehiscence with a Correct Classification Rate of 0.953, an F-score of 0.952 and a Matthews Correlation Coefficient value of 0.641. This result can be interpreted such that by using clinical features and lower uterine segment ultrasonography findings, machine learning can be used to accurately predict uterine rupture or dehiscence.
Trial registrationClinical Research Ethics Committee of Ankara City Hospital, University of Health Sciences (Approval number: E2-20-108)
Date of registration: 27-01-2021
URL: https://ankarasehir.saglik.gov.tr/TR-348810/2-nolu-etik-kurul.html
e-mail: [email protected]
AJOG at a GlanceA. Why was this study conducted?This study was conducted to:
O_LIDetermine whether machine learning algorithms can be utilized to predict uterine dehiscence and assess the risk of uterine rupture
C_LIO_LIEvaluate the contribution of ultrasonographic measurement of lower uterine segment measurements to the prediction performance of the algorithms
C_LIO_LIFind out which machine learning technique performs the best for predicting uterine dehiscence.
C_LI
B. What are the key findings?O_LIMachine learning methods can be used to accurately predict uterine dehiscence (with up to 95.6% accuracy).
C_LIO_LIUsing lower uterine segment full thickness or myometrium thickness increases the accuracy of Naive Bayes algorithm by 4.8% and 5.1%, respectively.
C_LIO_LINaive Bayes algorithm yields the best prediction performance among the methods tried.
C_LI
C. What does this study add to what is already known?O_LIUltrasonographic lower uterine segment measurements can be used as features in machine learning to increase its prediction performance of uterine dehiscence and hence the risk of uterine rupture.
C_LI | obstetrics and gynecology |
10.1101/2022.03.24.22272870 | Prognostic factors for mortality, ICU and hospital admission due to SARS-CoV-2: A systematic review and meta-analysis of cohort studies in Europe | BackgroundAs mortality from COVID-19 is strongly age-dependent, we aimed to identify population subgroups at an elevated risk for adverse outcomes from COVID-19 using age/gender-adjusted data from European cohort studies with the aim to identify populations that could potentially benefit from booster vaccinations.
MethodsWe performed a systematic literature review and meta-analysis to investigate the role of underlying medical conditions as prognostic factors for adverse outcomes due to SARS-CoV-2, including death, hospitalisation, Intensive Care Unit (ICU) admission, and mechanical ventilation within three separate settings (community, hospital and ICU). Cohort studies that reported at least age and gender-adjusted data from Europe were identified through a search of peer-reviewed articles published until 11th June 2021 in Ovid Medline and Embase. Results are presented as Odds Ratios (ORs) with 95% confidence intervals (95%C.I.) and absolute risk differences (RD) in deaths per 1,000 COVID-19 patients.
FindingsWe included 88 cohort studies with age/gender adjusted data from 6,653,207 SARS-CoV-2 patients from Europe. Hospital-based mortality was associated with high and moderate certainty evidence for solid organ tumours, diabetes mellitus, renal disease, arrhythmia, ischemic heart disease, liver disease, and obesity, while a higher risk, albeit with low certainty, was noted for chronic obstructive pulmonary disease and heart failure. Community-based mortality was associated with a history of heart failure, stroke, diabetes, and end-stage renal disease. Evidence of high/moderate certainty revealed a strong association between hospitalisation for COVID-19 and solid organ transplant recipients, sleep apnoea, diabetes, stroke, and liver disease.
InterpretationThe results confirmed the strong association between specific prognostic factors and mortality and hospital admission. Prioritisation of booster vaccinations and the implementation of non-pharmaceutical protective measures for these populations may contribute to a reduction in COVID-19 mortality, ICU and hospital admissions.
FundingEuropean Centre for Disease Prevention and Control (ECDC) under specific contract No. 10 ECD.11843 within Framework contract ECDC/2019/001 Lot 1B. | infectious diseases |
10.1101/2022.03.24.22272891 | Accuracy of COVID-19 self-tests with unsupervised nasal or nasal plus oropharyngeal self-sampling in symptomatic individuals in the Omicron period | BackgroundPerformances of rapid antigen diagnostic tests (Ag-RDTs) with nasal self-sampling, and oropharyngeal plus nasal (OP-N) self-sampling, in the Omicron period are unknown.
MethodsProspective diagnostic accuracy study among 6,497 symptomatic individuals aged >16 years presenting for SARS-CoV-2 testing at three test-sites. Participants were sampled for RT-PCR (reference test) and received one Ag-RDT to perform unsupervised with either nasal self-sampling (during the emergence of Omicron, and after Omicron share was >90%, phase-1) or with OP-N self-sampling (in a subsequent phase-2; Omicron share >99%). The evaluated tests were Acon Flowflex (Flowflex; phase-1 only), MP Biomedicals (MPBio), and Siemens-Healthineers Clinitest (Clinitest).
FindingsDuring phase-1, 45% of Flowflex, 29% of MPBio, and 35% of Clinitest participants were confirmatory testers (previously tested positive by a self-test at own initiative). Overall sensitivities with nasal self-sampling were 79.0% (95% CI: 74.7-82.8%) for Flowflex, 69.9% (65.1-74.4%) for MPBio, and 70.2% (65.6-74.5%) for Clinitest. Sensitivities were substantially higher in confirmatory testers (93.6%, 83.6%, and 85.7%, respectively) than in those who tested for other reasons (52.4%, 51.5%, and 49.5%, respectively). Sensitivities decreased by 6.1 (p=0.16 by Chi-square test), 7.0 (p=0.60), and 12.8 (p=0.025) percentage points, respectively, when transitioning from 29% to >95% Omicron. During phase-2, 53% of MPBio, and 44% of Clinitest participants were confirmatory testers. Overall sensitivities with OP-N self-sampling were 83.0% (78.8%-86.7%) for MPBio and 77.3% (72.9%-81.2%) for Clinitest. Comparing OP-N to nasal sampling, sensitivities were slightly higher in confirmatory testers (87.4% and 86.1%, respectively), and substantially higher in those testing for other reasons (69.3% and 59.9%, respectively).
InterpretatioSensitivities of three Ag-RDTs with nasal self-sampling decreased during Omicron emergence but was only statistically significant for Clinitest. Sensitivities were substantially influenced by the proportion of confirmatory testers. Addition of oropharyngeal to nasal self-sampling improved sensitivities of MPBio and Clinitest.
FundingDutch Ministry of Health, Welfare, and Sport.
Research into contextO_ST_ABSEvidence before this studyC_ST_ABSSARS-CoV-2 rapid antigen diagnostic tests (Ag-RDTs) require no or minimal equipment, provide a result within 15-30 minutes, and can be used in a range of settings including for self-testing at home. Self-testing may potentially lower the threshold to testing and allows individuals to obtain a test result quickly and at their own convenience, which could support the early detection of infectious cases and reduce community transmission. Real world evidence on the performance of unsupervised nasal and oropharyngeal plus nasal (OP-N) self-sampling in the Omicron variant period is needed to accurately inform end-users and policymakers. Therefore, we conducted a large prospective diagnostic accuracy study of three commercially available Ag-RDTs with self-sampling (the Acon Flowflex test, the MP Biomedicals test, and the Siemens-Healthineers Clinitest) during and after the emergence of Omicron using RT-PCR as the reference standard. Our aims were to evaluate whether the accuracies of Ag-RDTs with nasal self-sampling changed over time with the emergence of Omicron; and to determine whether addition of oropharyngeal to nasal self-sampling with the same swab yielded higher diagnostic accuracies.
What this study addsThe large comprehensive study was conducted in almost 6,500 participants with symptoms when presenting for routine SARS-CoV-2 testing at three public health service COVID-19 test-sites in the Netherlands. During the study, conducted between 21 December 2021 and 10 February 2022, the percentage of the Omicron variant in samples from the national SARS-CoV-2 pathogen surveillance increased from 29% in the first week to 99% in the last week of the study. The period during which the Omicron variant was dominant was divided into a nasal sampling phase (phase-1; Omicron present in >90% of surveillance samples) and an OP-N sampling phase (phase-2; Omicron share was >99%). In phase-1, 45% of Flowflex, 29% of MPBio, and 35% of Clinitest participants visited the test-site because of a positive self-test (confirmatory testers). Overall sensitivities with nasal self-sampling were 79.0% (95% CI: 74.7-82.8%) for the Flowflex, 69.9% (65.1-74.4%) for the MPBio, and 70.2% (65.6-74.5%) for the Clinitest Ag-RDT. Sensitivities were 94%, 84%, and 86%, respectively, for confirmatory testers, and 52%, 52%, and 50%, respectively, for those who had other reasons for getting tested. Sensitivities were 87.0% (79.7-92.4%), 83.1% (72.9-90.7%), and 80.0% (51.9-95.7%), respectively, in the first week, and decreased by 6.1 (p=0.16 by Chi-square test), 7.0 (p=0.60), and 12.8 (p=0.025) percentage points in the final week of the study. In Phase-2, 53% of MPBio and 44% of Clinitest participants were confirmatory testers. Overall sensitivities with OP-N self-sampling were 83.0% (78.8%-86.7%) for MPBio and 77.3% (72.9%-81.2%) for Clinitest. When comparing OP-N to nasal sampling, sensitivities were slightly higher in confirmatory testers (87.4% and 86.1%, respectively), and substantially higher in those testing for other reasons (69.3% and 59.9%).
Implications of all the available evidenceThe sensitivities of three commercially available Ag-RDTs performed with nasal self-sampling decreased during the emergence of Omicron, but this trend was only statistically significant for Clinitest. Addition of oropharyngeal to nasal self-sampling improved the sensitivity of the MPBio and Clinitest, most notably in individuals who visited the test-site for other reasons than to confirm a positive self-test. Based on these findings, the manufacturers of MPBio and Clinitest may consider extending their instructions for use to include combined oropharyngeal and nasal sampling, and other manufacturers may consider evaluating this as well. | infectious diseases |
10.1101/2022.03.23.22272840 | Inverse proportionality between height and duration of epidemic peaks not observed for the COVID-19 epidemic in Japan | The height of the epidemic peaks varied ten-fold, but the duration was almost constant independent of the peak height in the six times COVID-19 epidemics in Japan over the past two years. The observed relation between the peak height and duration contradicts the inverse proportionality, which is the essential conclusion derived from mathematical models for infectious diseases. We found that the peak height was inversely proportional to the number of rhinovirus patients. The literature has revealed the mechanism behind our found power of rhinovirus suppressing COVID-19. We discuss that the critical flaw of current mathematical models originates in the absence of the 0th power term of the number of infected people in the Kermack and McKendrick equation. | infectious diseases |
10.1101/2022.03.23.22272840 | Inverse proportionality between height and duration of epidemic peaks not observed for the COVID-19 epidemic in Japan | The height of the epidemic peaks varied ten-fold, but the duration was almost constant independent of the peak height in the six times COVID-19 epidemics in Japan over the past two years. The observed relation between the peak height and duration contradicts the inverse proportionality, which is the essential conclusion derived from mathematical models for infectious diseases. We found that the peak height was inversely proportional to the number of rhinovirus patients. The literature has revealed the mechanism behind our found power of rhinovirus suppressing COVID-19. We discuss that the critical flaw of current mathematical models originates in the absence of the 0th power term of the number of infected people in the Kermack and McKendrick equation. | infectious diseases |
10.1101/2022.03.23.22272846 | Prediction of CRT Response Using a Lead Placement Score Derived from 4DCT | BackgroundCardiac resynchronization therapy (CRT) is an effective treatment for patients with heart failure; however, 30% of patients do not respond to the treatment. We sought to derive patient-specific left-ventricle (LV) maps of lead placement scores (LPS) that highlight target pacing lead sites for achieving a higher probability of CRT response.
MethodsEighty-two subjects recruited for the ImagingCRT trial were retrospectively analyzed. All 82 subjects had two contrast-enhanced full-cardiac cycle 4DCT scans: a baseline and a 6-month follow-up scan. CRT response was defined as a reduction in CT-derived end-systolic volume [≥]15%. Eight LV features derived from the baseline scans were used to train a support vector machine (SVM) via a bagging approach. An LPS map over the LV was created for each subject as a linear combination of the SVM feature weights and the subjects own feature vector. Performance for distinguishing responders was performed on the original 82 subjects.
ResultsFifty-two (63%) subjects were responders. Subjects with an LPS[≤]Q1 (lower-quartile) had a posttest probability of responding of 14% (3/21), while subjects with an LPS[≥] Q3 (upper-quartile) had a posttest probability of responding of 90% (19/21). Subjects with Q1<LPS<Q3 had a posttest probability of responding that was essentially unchanged from the pretest probability (75% vs 63%, p=0.2). An LPS threshold that maximized the geometric mean of true-negative and true-positive rates identified 26/30 of the non-responders. The AUC of the ROC curve for identifying responders with an LPS threshold was 87%.
ConclusionsAn LPS map was defined using 4DCT-derived features of LV mechanics. The LPS correlated with CRT response, reclassifying 25% of the subjects into low-probability of response, 25% into high-probability of response, and 50% unchanged. These encouraging results highlight the potential utility of 4DCT in guiding patient selection for CRT. The present findings need verification in larger independent data sets and prospective trials.
Clinical PerspectiveCardiac resynchronization therapy (CRT) is a proven treatment for patients with heart failure and dyssynchrony; however, approximately 30% of patients do not respond to the treatment. Additionally, the relatively high non-responder rate poses difficulties for the optimal utilization of medical resources; thus, more accurate patient stratification for CRT remains an unmet need. Despite significant efforts focused on using imaging to guide CRT, the results thus far have been ambiguous. Poor reproducibility of echocardiography coupled with the complexity of cardiac magnetic resonance have likely contributed to the poor overall adoption of these methods for pre-CRT assessment. In this work, we describe a metric called the lead placement score (LPS) that combines multiple 4DCT-derived features of left-ventricular (LV) mechanics into a single number for each possible pacing lead location on the LV; the features included in the LPS map have previously been shown to correlate with CRT response. Using a machine learning classifier, a model was constructed with these features and then used to derive the LPS map for each individual subject. The LPS was found to correlate with the probability of a subject responding to CRT. 4DCT is widely available and provides high-resolution images of the full cardiac cycle. Additionally, recent technological advancements have also dramatically reduced the radiation dose from 4DCT scans. The advantages of 4DCT coupled with the promising results reported in this study, highlight the potential utility of 4DCT in the planning of CRT. | cardiovascular medicine |
10.1101/2022.03.22.22272691 | COVID-19 Vaccine Effectiveness against the Omicron BA.2 variant in England | The BA.1 sub-lineage of the Omicron (B.1.1.529) variant, first detected in the UK in mid-November 2021, rapidly became the dominant strain partly due to reduced vaccine effectiveness. An increase in a second Omicron sub-lineage BA.2 was observed in early January 2022. In this study we use a test-negative case control study design to estimate vaccine effectiveness against symptomatic disease with BA.1 and BA.2 after one or two doses of BNT162b2, ChAdOx1-S or mRNA-1273, and after booster doses of BNT162b2 or mRNA-1273 during a period of co-circulation. Overall, there was no evidence that vaccine effectiveness against symptomatic disease is reduced following infection with the BA.2 sub-lineage as compared to BA.1. Furthermore, similar rates of waning were observed after the second and booster dose for each sub-lineage. These data provide reassuring evidence of the effectiveness of the vaccines currently in use against symptomatic disease caused by BA.2. | epidemiology |
10.1101/2022.03.23.22272849 | Systematic review and meta-analysis of yellow fever vaccine in elderly population | We conducted a systematic review and meta-analysis to assess the risk of serious adverse events in the elderly after yellow fever vaccination compared to the non-elderly population. We searched multiple databases and grey literature and selected research without language and publication date restriction. Studies were analysed in a descriptive way, meta-analysed and expressed in terms of prevalence ratio and risk ratio with a 95% confidence interval, depending on the degree of heterogeneity found. A total of 18 studies were included, of which 10 were meta-analysed. Results obtained through the meta-analysis showed that the risk of serious adverse events after yellow fever vaccination is three times higher for elderlies when compared to non-elderly population and even five times higher for persons >70 years of age. Also, in relation adverse event type a greater risk was for viscerotropic disease associated with yellow fever vaccine up to six times higher when compared to the population under 60 years. The evidence found in this review supports that the vaccine indication in individuals over 60 years of age should be based on a careful analysis of the individual benefit-risk assessment. Results found suggest a higher risk of SAE for individuals over 70 years, especially for viscerotropic and neurotropic disease associated with YFV contraindicating the use of the YFV in this age group. | epidemiology |
10.1101/2022.03.23.22272830 | Estimated Incidence of Respiratory Hospitalizations Attributable to RSV Infections across Age and Socioeconomic Groups | BackgroundSurveillance for respiratory syncytial virus (RSV) likely captures just a fraction of the burden of disease. Understanding the burden of hospitalizations and disparities between populations can help to inform upcoming RSV vaccine programs and to improve surveillance.
MethodsWe obtained monthly age-, ZIP code- and cause-specific hospitalizations in New York, New Jersey, and Washington from the US State Inpatient Databases (2005-2014). We estimated the incidence of respiratory hospitalizations attributable to RSV by age and by socioeconomic status using regression models. We compared the estimated incidence and the recorded incidence (based on ICD9-CM) of RSV hospitalizations to estimate the under-recorded rate in the different sub-populations.
ResultsThe estimated annual incidence of respiratory hospitalizations due to RSV was highest among infants <1 year of age with low socioeconomic status, (2700 per 100,000 people, 95% CrI [2600, 2900]) and were considerable in older adults that are [≥]65 years of age across socioeconomic status, ranging from 130 to 970 per 100,000 people. The incidence of hospitalization recorded as being due to RSV represented a significant undercount, particularly in adults. Only <5% of the estimated RSV hospitalizations were captured for the older adults that are [≥]65 years of age.
ConclusionsRSV causes a considerable burden of hospitalization in young children and in older adults in the U.S, with variation by socioeconomic group. Estimates of the incidence of hospitalizations due to RSV in older adults based on the recorded diagnoses likely represent an underestimate.
Key messagesO_ST_ABSWhat is already known on this topic?C_ST_ABSPrevious study suggested that the incidence of hospitalization for bronchiolitis (often caused by RSV) in infants varies greatly between communities of different socioeconomic levels. However, it is unclear whether these differences are associated with the admission criteria or the risk of RSV infection.
What this study adds?The estimated annual incidence of respiratory hospitalizations due to RSV in infants residing in low socioeconomic areas was about twice as high as the incidence in infants residing in high socioeconomic areas. In older adults, a small fraction of the hospitalizations estimated to be caused by RSV were recorded as such in the inpatient database.
How this study might affect research, practice or policy?With several vaccines and extended half-life monoclonal antibodies against RSV under active development, these estimates can help anticipate the impact of RSV prevention strategies in populations of different demographic characteristics. | epidemiology |
10.1101/2022.03.23.22272836 | Risk factors for SARS-CoV-2 transmission in student residences: a case-ascertained study in Leuven, Belgium from October 2020 until May 2021 | BackgroundStudent residences are at high risk for rapid COVID-transmission due to crowding and frequent close contact.
AimWe aimed to investigate the overall secondary attack rates (SAR) in student residences and to discern risk factors for higher transmission in order to improve the evidence base for screening efforts and preventive measures.
MethodsIn this retrospective case-ascertained study, we analysed data from student residences screened in Leuven, Belgium between October 2020 and May 2021, following detection of a COVID-19 case in the residence. We investigated the impact on the SAR in the living units screened of delay-time until follow-up, shared use of kitchen or sanitary facilities, presence of an external infection source and occurrence of social gatherings attended by the index case.
ResultsWe included 200 residence units, representing 2326 screened residents, of which 68 units showed secondary transmission. The overall SAR was estimated at 0.0813 (95%CI 0.0705-0.0936). Both sharing sanitary facilities (p=0.04) and social gatherings attended by the index case (p=0.033) significantly impacted SAR, which increased from 3% to 13% when both risk factors were present compared to absent.
ConclusionsWe identify risk factors which should be considered when selecting students for screening during an outbreak of COVID-19 in student residences to improve comprehensiveness and proportionality of testing. The identified risk factors improve the evidence base for preventive measures aimed at limiting social gatherings and improving ventilation of shared spaces in outbreak-prone settings. Lastly, they should be considered when designing student accommodation and other shared households. | epidemiology |
10.1101/2022.03.23.22272803 | Development of a Model for Differentiating PDAC from Benign Pancreatic Conditions: A Prospective Case-control Study | Background & aimsPancreatic ductal adenocarcinoma (PDAC) continues to be a devastating disease with late diagnosis and poor overall survival, complicated by clinical presentations similar to benign pancreatic diseases. We aimed to analyse clinical parameters with the goal of developing a prediction model for differentiating suspected PDAC from benign pancreatic conditions.
Methods and resultsWe used a prospectively recruited cohort of patients with pancreatic disease (n=762) enrolled at the Barts Pancreas Tissue Bank between January 1, 2008 and September 21, 2021 to perform a case-control study examining the association of PDAC (n=340) with predictor variables including demographics, comorbidities, lifestyle factors, presenting symptoms and commonly performed blood tests. Using a machine learning approach, candidate PDAC risk-prediction algorithms were trained on 75% of the cohort, using a subset of the predictor variables identified from a preliminary observational association study. Models were assessed on the remaining 25%. Multiple imputed datasets were used for both training and validation to accommodate for unknown data.
Age (over 55), weight loss in hypertensive patients, recent symptom of jaundice, high serum bilirubin, low serum creatinine, high serum alkaline phosphatase, low lymphocyte count and low serum sodium were the most important features when separating putative PDAC cases from less severe pancreatic conditions. A simple logistic regression model had the best performance with an area under the curve (AUC) of 0.88. Setting a probability threshold of 0.17 guided by the maximum F2 score, a sensitivity of 95.6% was reached in the full cohort which could lead to early detection of around 84% of the PDAC patients.
ConclusionThe resultant prediction model significantly outperformed the current UK guidelines for suspected pancreatic cancer referral and could improve detection rates of PDAC in the community. After further work this approach could lead to an easy to understand, utilisable risk score to be applied in the primary and secondary care setting for referring patients to specialist hepato-pancreatico-biliary services. | gastroenterology |
10.1101/2022.03.24.22272866 | Effectiveness of shared medical appointments delivered in primary care for improving health outcomes in patients with long-term conditions: a systematic review of randomised controlled trials | BackgroundShared medical appointments (SMAs) have the potential to address interlinked challenges of limited capacity in primary healthcare and rising prevalence of patients with multiple long-term conditions (LTCs). This review aimed to examine the effectiveness of SMAs compared to one-to-one appointments in primary care at improving health outcomes and reducing demand on healthcare services.
MethodsWe searched for randomised controlled trials (RCTs) of SMAs involving patients with LTCs in primary care across six databases from 2013 and added eligible papers identified from previous relevant reviews. Data were extracted and outcomes narratively synthesised, meta-analysis was undertaken where possible.
ResultsTwenty-three unique trials were included. SMA models varied in terms of components, mode of delivery and target population. Most trials recruited patients with a single LTC, mostly commonly diabetes (n=13), although eight trials selected patients with multiple LTCs. There was substantial heterogeneity in outcome measures which we categorised into health outcomes (biomedical indicators, psychological and well-being measures), behavioural outcomes, and resource use. Meta-analysis showed that participants in SMA groups had lower diastolic blood pressure than those in usual care (d=-0.123, 95%CI = -0.22, -0.03, k=8). No statistically significant differences were found across other outcomes. Where individual studies showed significant differences (patient self-efficacy), these trended in favour of SMAs. Compared with usual care, SMAs had no significant effect on healthcare service use.
ConclusionsSMAs were at least as effective as usual care in terms of health outcomes and did not lead to increased healthcare service use in the short-term. They show some potential in improving self-efficacy which may boost self-care. To strengthen the evidence base, future studies should target standardised behavioural and health outcomes and clearly report SMA components so key behavioural ingredients can be identified. Similarly, transparent approaches to measuring costs would improve comparability between studies.
PROSPEROCRD42020173084 | primary care research |
10.1101/2022.03.23.22272776 | Geospatial analysis reveals distinct hotspots of severe mental illness | BackgroundThe identification of geographic variation in incidence can be an important step in the delineation of disease risk factors, but has mostly been undertaken in upper-income countries. Here, we use Electronic Health Records (EHR) from a middle-income country, Colombia, to characterize geographic variation in major mental disorders.
MethodWe leveraged geolocated EHRs of 16,295 patients at a psychiatric hospital serving the entire state of Caldas, all of whom received a primary diagnosis of bipolar disorder, schizophrenia, or major depressive disorder at their first visit. To identify the relationship between travel time and incidence of mental illness we used a zero-inflated negative binomial regression model. We used spatial scan statistics to identify clusters of patients, stratified by diagnosis and severity: mild (outpatients) or severe (inpatients).
ResultsWe observed a significant association between incidence and travel time for outpatients (N = 11,077, relative risk (RR) = 0.80, 95% confidence interval (0.71, 0.89)), but not inpatients (N = 5,218). We found seven clusters of severe mental illness: the cluster with the most extreme overrepresentation of bipolar disorder (RR = 5.83, p < 0.001) has an average annual incidence of 8.7 inpatients per 10,000 residents, among the highest frequencies worldwide.
ConclusionsThe hospital database reflects the geographic distribution of severe, but not mild, mental illness within Caldas. Each hotspot is a candidate location for further research to identify genetic or environmental risk factors for severe mental illness. Our analyses highlight how existing infrastructure from middle-income countries can be extraordinary resources for population studies. | psychiatry and clinical psychology |
10.1101/2022.03.24.22272835 | Relative Effectiveness of Four Doses Compared to Three Dose of the BNT162b2 Vaccine in Israel | ObjectivesThe rapid spread of the Omicron variant (B.1.1.529) alongside evidence of a relatively rapid waning of the third dose prompted Israel to administer a fourth dose of the BNT162b2 vaccine on January 2022. Thus far, sufficient real-world evidence demonstrating the effectiveness of a fourth dose against infection and severe COVID-19 are lacking. This study examined the short-term effectiveness of a fourth dose compared to three doses over the span of 10 weeks.
DesignA retrospective test-negative case-control study, performing both a matched analysis and an unmatched multiple-tests analysis.
SettingNationally centralized database of Maccabi Healthcare Services (MHS), an Israeli national health fund that covers 2.5 million people.
ParticipantsThe study population included 97,499 MHS members aged 60 or older who were eligible to receive a fourth vaccine dose and performed at least one PCR test during the study period. Of them, 27,876 received the fourth dose and 69,623 received only three doses.
Main outcomes and measuresAnalyses focused on the period from January 10, 2022 (7 days after the fourth dose was first administered to eligible individuals) to March 13, 2022, an Omicron-dominant period in Israel. We evaluated two SARS-CoV-2-related outcomes: (1) breakthrough infection, defined as a positive PCR test performed 7 or more days after inoculation with the BNT162b2 vaccine; and (2) breakthrough infection resulting in a severe disease, defined as COVID-19-related hospitalization or COVID-19 associated mortality.
ResultsA fourth dose provided considerable additional protection against both SARS-CoV-2 infection and severe disease relative to three doses of the vaccine. However, vaccine effectiveness against infection varied over time, peaking during the third week with a VE of 64% (95% CI: 62.0%-65.9%) and declining to 29.2% (95% CI: 17.7%-39.1%) by the end of the 10-week follow-up period. Unlike VE against infection, the relative effectiveness of a fourth dose against severe COVID-19 was maintained at high level (>73%) throughout the 9-week follow-up period. Importantly, severe disease was a relatively rare event, occurring in <1% of both fourth dose and third dose only recipients.
ConclusionsA fourth dose of the BNT162b2 vaccine provided considerable additional protection against both SARS-CoV-2 infection and severe disease relative to three doses of the vaccine. However, effectiveness of the fourth dose against infection wanes sooner than that of the third dose. | public and global health |
10.1101/2022.03.24.22272892 | The modified COVID-19 Yorkshire Rehabilitation Scale (C19-YRSm) patient-reported outcome measure for Long Covid or Post-COVID syndrome | BackgroundThe C19-YRS was the first validated scale reported in the literature for patient assessment and monitoring in Long Covid or Post-COVID syndrome. The 22-item scale contains four subscales measuring symptom severity, functional disability, overall health and additional symptoms.
ObjectivesThis study aimed to modify and refine the scale based on psychometric properties, emerging evidence on additional Long Covid symptoms, and feedback from a working group of patients and healthcare professionals.
MethodsData were collected from 370 patients who completed the C19-YRS scale in a community Long COVID service. The psychometric properties of the Symptom Severity and Functional Disability subscales were assessed using a Rasch Measurement Theory framework, where all individual scale items were assessed for model fit, local dependency, response category functioning and differential item functioning (DIF) by age group and sex. Additionally, the subscales were assessed for targeting, reliability and unidimensionality. The overall health subscale is a single item, and the additional symptoms subscale is not intended to be summed, therefore neither is appropriate for Rasch analyses. Psychometric results and implications were relayed back to the working group for discussion, alongside clinical evidence of emerging and relevant symptoms not covered by the original C19-YRS.
ResultsRasch analysis revealed promising psychometric properties of the symptom severity and functional disability subscales, with both displaying good targeting and reliability, although some individual measurement anomalies were noted. The original 0-10 item response category structure did not operate as intended for both the subscales. Post-hoc rescoring suggested that a 4-point response category structure would be more appropriate for both the subscales, and this aligned with patient feedback. This scoring change was implemented, alongside changes in the item composition of the symptom severity and additional symptoms subscales. The functional disability item set, and the overall health single-item subscale remained unchanged.
ConclusionA modified version of the C19-YRS was developed based on a combination of psychometric evidence, clinical relevance of the content and feedback from the working group (comprising patients and healthcare professionals). Future studies including NIHR funded LOCOMOTION study will undertake large-scale, multi-centre validation of the modified C19-YRS. | rehabilitation medicine and physical therapy |
10.1101/2022.03.24.22272883 | Production of anti-spike antibodies in response to COVID vaccine in lymphoma patients | Patients with hematologic malignancies have poor outcomes from COVID infection and are less likely to mount an antibody response after COVID infection. There is limited data on the efficacy of the COVID vaccines in lymphoma patients, and to suggest the optimal timing of vaccination to elicit immunity in patients receiving immunochemotherapy. This is a retrospective study of adult lymphoma patients who received the COVID vaccine between 12/1/2020 and 11/30/2021. The primary endpoint was a positive anti-COVID spike protein antibody titer following the primary COVID vaccination series. The primary series was defined as 2 doses of the COVID mRNA vaccines or 1 dose of the COVID adenovirus vaccine. Subgroups were compared using Fishers exact test, and unadjusted and adjusted logistic regression models were used for univariate (UVA) and multivariate (MVA) analyses. A total of 243 patients were included in this study; 72 patients (30%) with indolent lymphomas; 56 patients (23%) with Burkitts, diffuse large B-cell lymphoma (DLBCL), and primary mediastinal B-cell lymphoma (PMBL) combined; 55 patients (22%) with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL); and 44 patients (18%) with Hodgkin and T-cell lymphomas (HL/TCL) combined. One-hundred fifty-eight patients (65%) developed anti-COVID spike protein antibodies after completing the primary COVID vaccination series. Thirty-eight of 46 (83%) patients who received an additional primary shot and had resultant levels produced anti-COVID spike protein antibodies. When compared to other lymphoma types, patients with CLL/SLL had a numerically lower seroconversion rate of 51% following the primary series whereas patients with HL/TCL appeared to have a robust antibody response with a seropositivity rate of 77% (p=0.04). Lymphoma patients are capable of mounting a humoral response to the COVID mRNA vaccines. Further studies are required to confirm our findings, including whether T-cell immunity would be of clinical relevance in this patient population. | oncology |
10.1101/2022.03.24.22271703 | International Travel-Related Control Measures to contain The Covid-19 Pandemic: An update to a Cochrane Rapid Review | BackgroundCOVID-19 has proven to be more difficult to manage for many reasons including its high infectivity rate. One of the potential ways to limit its spread is by controlling international travel. The objective of this systematic review is to identify, critically-appraise and summarize evidence on international travel-related control measures.
MethodsThis review is based on the Cochrane review: International travel-related control measures to contain the COVID-19 pandemic and followed the same methods. In brief, we searched for clinical and modelling studies in general health and COVID-19-specific bibliographic databases. The primary outcome categories were (i) cases avoided, (ii) a shift in epidemic development and, (iii) cases detected. Secondary outcomes were other infectious disease transmission outcomes, healthcare utilisation, resource requirements and adverse effects if identified in studies assessing at least one primary outcome.
ResultsWe assessed 66 full-text articles that met with our inclusion criteria. Seventeen new studies (modelling = 9, observational = 8) were identified in the updated search. Most studies were of critical to moderate risk of bias. The added studies did not change the main conclusions of the Cochrane review nor the quality of the evidence (very low to low certainty). However, it did add to the evidence base for most outcomes.
ConclusionsWeak evidence supports the use of international travel-related control measures to limit the spread of COVID-19 via air travel. Real-world studies are required to support these conclusions. | infectious diseases |
10.1101/2022.03.24.22272861 | Intubation and Inhospital mortality in trauma patients with Glasgow Coma Scale Score eight or less. A multicenter cohort study. | BackgroundMost trauma societies recommend intubation of trauma patients with Glasgow coma scale (GCS) [≤] 8, without robust evidence supporting it.
MethodsWe examined the association between intubation and inhopital 30 day mortality in trauma patients arriving with GCS [≤] 8. The data were obtained using the Towards Improved Trauma Care Outcomes (TITCO) registry in India cohort. We compared the outcomes of patients with GCS [≤] 8 who were intubated within one hour after arrival with those who were intubated later or not at all, using multiple analytical approaches to evaluate the consistency of the findings. We also examined the association in multiple subgroups to identify any variability of the effect.
ResultsOf 3476 patients who arrived with a GCS [≤] 8, 1671 (48.1%) were intubated within an hour and 1805 (51.9%) were intubated later or not intubated at all. Overall, 1957 (56.3%) patients died in whole cohort. A total of 947 (56.7%) patients died in intubation group and 1010 (56%) died in non intubation group. In the main analysis, there was no significant association between intubation within an hour and mortality(OR=1.18,[CI,0.76-1.84], p value = 0.467). This result was consistent across multiple sensitivity analysis.
ConclusionIn this observational study of trauma patients with GCS [≤] 8, who present to tertiary care hospitals, intubation within one hour after arrival was not associated with increased or decreased risk of inhospital mortality compared to intubation after one hour or no intubation. Further studies are needed to precisely evaluate the benefit of intubation and thus supporting the recommendations. | emergency medicine |
10.1101/2022.03.23.22272819 | Vaccine Adverse Event Reporting System (VAERS): Evaluation of 31 Years of Reports and Pandemics' Impact | BackgroundVaccine adverse event reporting system (VAERS) was established in the United States (U.S.) as an early warning system with a main purpose of collecting postmarketing adverse events following immunizations (AEFIs) reports to monitor the vaccine safety and to mitigate the risks from vaccines. During the coronavirus diseases 2019 (COVID-19) pandemic, VAERS got more attention as its important role in monitoring the safety of the vaccines. Thus, the aim of this study was to investigate VAERS patterns, reported AEFIs, adverse events of special interest (AESIs), impact of different pandemics since its inception, and surveillance rate of serious vs nonserious AEFIs.
MethodsThis was an observational study using VARES data from 2/7/1990 to 12/11/2021. Patterns of reports over years were first described, followed by a comparison of reports statistics per year. Furthermore, a comparison of incidents (death, ER visits, etc.) statistics over years, in addition to statistics of each vaccine were calculated. Moreover, each incidents statistics for each vaccine were calculated and top vaccines were reported. Finally, survival analysis utilizing cox regression was done, in addition to AESIs distribution stratified by age groups and gender. All analyses were conducted using R (Version 1.4.1717) and Excel for Microsoft 365.
ResultsThere were 1,396,280 domestic and 346,210 non-domestic reports during 1990-2021, including 228 vaccines. For both domestic and non-domestic reports, year of 2021 had the highest reporting rate (48.52% and 70.33%), in addition a notable changes in AEFIs patterns were recorded during 1991, 1998, 2000, 2006, 2009, 2011, and 2017. AEFIs were as follow: deaths (1.00% and 4.08%), ER or doctor visits (13.37% and 2.27%), hospitalizations (5.84% and 27.78%), lethal threat (1.42% and 4.38%), and disabilities (1.4% and 7.96%). Pyrexia was the top reported symptom during the past 31 years, except for 2021 where headache was the top one. COVID-19 vaccines namely Moderna, Pfizer-Biontech, and Janssen were the top 3 reported vaccines with headache, pyrexia, and fatigue as the top associated AEFIs. Followed by Zoster, Seasonal Influenza, Pneumococcal, and Human papillomavirus vaccines. Myocarditis or Pericarditis were the top reported AESIs (26.95% and 25.84%). Male (HR:1.15, 1.14 - 1.16) for domestic (HR:1.23, 1.22 -1.25) for nondomestic have a higher probability of having serious AEFIs. In addition, age group [≤] 5 years old in domestic and >84 years old in nondomestic have a higher probability of having AEFIs compared to other age groups.
ConclusionsThe large data available in VARES make it a useful tool for detecting and monitoring vaccine AEFIs. However, its usability relies on understating the limitations of this surveillance system, the impact of governmental regulations, availability of vaccines, and public health recommendations on the reporting rate. | epidemiology |
10.1101/2022.03.24.22272909 | Assessing Direct and Spillover Effects of Intervention Packages in Network-Randomized Studies | Intervention packages may result in a greater public health impact than single interventions. Understanding the separate impact of each component in the overall package effectiveness can improve intervention delivery. We propose an approach to evaluate the effects of a time-varying intervention package in a single study. In some network-randomized studies, only a subset of participants in exposed networks receive the intervention themselves. The spillover effect contrasts potential outcomes of persons not exposed themselves under intervention in the network versus no intervention in a control network. We estimated effects of components of the intervention package in HIV Prevention Trials Network 037, a Phase III network-randomized HIV prevention trial among people who inject drugs and their risk networks using Marginal Structural Models to adjust for time-varying confounding. The index participant in an intervention network received a peer education intervention initially at baseline, then boosters at 6 and 12 months. All participants were followed to ascertain HIV risk behaviors. There were 560 participants with at least one follow-up visit, 48% of whom randomized to the intervention, and 1,598 participant-visits were observed. The spillover effect of the boosters in the presence of initial peer education training was a 39% rate reduction (95% confidence interval (CI) = -57%, -13%). These methods will be useful for evaluation of intervention packages in studies with network features. | epidemiology |
10.1101/2022.03.24.22272909 | Assessing Direct and Spillover Effects of Intervention Packages in Network-Randomized Studies | Intervention packages may result in a greater public health impact than single interventions. Understanding the separate impact of each component in the overall package effectiveness can improve intervention delivery. We propose an approach to evaluate the effects of a time-varying intervention package in a single study. In some network-randomized studies, only a subset of participants in exposed networks receive the intervention themselves. The spillover effect contrasts potential outcomes of persons not exposed themselves under intervention in the network versus no intervention in a control network. We estimated effects of components of the intervention package in HIV Prevention Trials Network 037, a Phase III network-randomized HIV prevention trial among people who inject drugs and their risk networks using Marginal Structural Models to adjust for time-varying confounding. The index participant in an intervention network received a peer education intervention initially at baseline, then boosters at 6 and 12 months. All participants were followed to ascertain HIV risk behaviors. There were 560 participants with at least one follow-up visit, 48% of whom randomized to the intervention, and 1,598 participant-visits were observed. The spillover effect of the boosters in the presence of initial peer education training was a 39% rate reduction (95% confidence interval (CI) = -57%, -13%). These methods will be useful for evaluation of intervention packages in studies with network features. | epidemiology |
10.1101/2022.03.24.22272875 | Informal Sector Employment and the Health Outcomes of Older Workers in India | A large proportion of the older population in India constitutes an undeniable share of workforce after the retirement age. This stresses the need to understand the implications of working at older ages on health outcomes. The main objective of this study is to examine the variations in health outcomes by formal/informal sector of employment of older workers using the Longitudinal Ageing Study in India. Using binary logistic regression models with interaction terms, the results of this study affirm that type of work does play a significant role in determining health outcomes even after controlling socio-economic, demographic, life-style behaviour, and work characteristics. The risk of Poor Cognitive Functioning (PCF) is high among informal workers, while formal workers suffer greatly from Chronic Health Conditions (CHC) and Functional Limitations (FL). The presence of CHC among informal workers is more damaging because it elevates their FL, whereas for formal workers presence of FL is unfavourable because it deteriorates their cognitive functioning. Therefore, present study underscores the relevance of policies focusing on providing health and healthcare benefits by respective economic activity and socio-economic position of older workers. | public and global health |
10.1101/2022.03.25.22271716 | Stairway visual contrast enhancement to reduce fall-related events | Falls on stairs occur frequently and pose a significant health and financial risk. Laboratory research has found that fall frequency can be reduced through contrast enhancement of the stairs by applying vinyl striping to the first and last steps faces, and all the steps top edges. Here we sought to determine if such step contrast enhancement can reduce the probability of fall-related events such as loss of balance, slips, trips, and falls in public university staircases. Cameras were used to capture stair users ascent and descent on contrast enhanced ( striped) and control stairways. Observed age group, observed gender, traverse direction (ascent, descent), fall-related events, and walking speed (m/s) were recorded. Fall-related events were reduced for the striped stairway compared to the control stairway (odds ratio = 2.87, average marginal effect = 0.002, p = .023) when controlling for observed gender, age category, and traverse direction. These results suggest contrast enhancement of first and last steps face and all steps edges may reduce fall- related events in public settings. Adding contrast enhancement to public stairways is a simple and cost-effective way to reduce the loss of balance, slips, and trips that could lead to catastrophic falls on stairs as well as the health and financial burden associated with such falls.
PRECISContrast enhancement of stairway features may be a simple and cost-effective way to reduce falls on stairs. We show that monochrome striping on the first and last steps faces and black stripes on steps top edges reduce the probability of fall-related events in public stairways. | rehabilitation medicine and physical therapy |
10.1101/2022.03.24.22272884 | COVID-19 outcomes associated with clinical and demographic characteristics in patients hospitalized with severe and critical disease in Peshawar | BackgroundAs a novel disease, understanding the relationship between the clinical and demographic characteristics of coronavirus disease 2019 (COVID-19) patients and their outcome is critical. We investigated this relationship in hospitalized patients in a tertiary healthcare setting.
Aims/objectivesTo study COVID-19 severity and outcomes in relation to clinical and demographic characteristics of in admitted patients
MethodologyIn this cross-sectional study, medical records for 1087 COVID-19 patients were reviewed to extract symptoms, comorbidities, demographic characteristics, and outcomes data. Statistical analyses included the post-stratification chi-square test, independent sample t-test, multivariate logistic regression, and time-to-event analysis.
ResultsThe majority of the study participants were >50 years old (67%) and male (59%) and had the following symptoms: fever (96%), cough (95%), shortness of breath (73%), loss of taste (77%), and loss of smell (77%). Regarding worst outcome, multivariate regression analysis showed that these characteristics were statistically significant: shortness of breath (adjusted odds ratio [aOR] 31.3; 95% CI, 11.87-82.53; p < 0.001), intensive care unit (ICU) admission (aOR 28.3; 95% CI,9.0-89.6; p < 0.001), diabetes mellitus (aOR 5.1; 95% CI;3.2-8.2; p < 0.001), ischemic heart disease (aOR 3.4; 95% CI,1.6-7; p = 0.001), nausea and vomiting (aOR 3.3; 95% CI, 1.7-6.6; p = 0.001), and prolonged hospital stay (aOR 1.04; 95% CI, 1.02-1.08; p = 0.001), while patients with rhinorrhea were significantly protected (aOR 0.3; 95% CI, 0.2-0.5; p < 0.001). A Kaplan-Meier curve showed that the symptoms of shortness of breath, ICU admission, fever, nausea and vomiting, and diarrhea increased the risk of mortality.
ConclusionIncreasing age, certain comorbidities and symptoms, and direct admission to the ICU increased the risk of worse outcomes. Further research is needed to determine risk factors that may increase disease severity and devise a proper risk-scoring system to initiate timely management. | respiratory medicine |
10.1101/2022.03.24.22272917 | Birth history is associated with whole-blood and T-cell methylation patterns in relapse onset multiple sclerosis | BackgroundPregnancy in women with multiple sclerosis (MS) is associated with a reduction of long-term disability progression. The mechanism that drives this effect is unknown, but converging evidence suggests a role for epigenetic mechanisms altering immune and/or central nervous system function.
ObjectivesWe aimed to identify whole blood and immune cell-specific DNA methylation patterns associated with parity in relapse-onset multiple sclerosis.
MethodsWe compared whole-blood methylation patterns between 96 matched pairs of nulligravida and parous females with MS (n=192). Parity was defined as at least one term or pre-term birth, and nulligravida was defined as no prior pregnancies. Methylation was measured with Illumina EPIC arrays, and data was pre-processed and statistically analysed using the ChAMP package. Cell-type proportions were estimated using the EpiDISH package, and cell-specific analysis conducted using linear regression. Gene-set enrichment analysis (GSEA) was performed with ToppGene API and GOmeth. Methylation age was calculated with the methyAge package. Methylation age acceleration (MAA) was calculated by regressing methylation age on chronological age. FDR<0.05 was used to assess significance.
ResultsThe median time from last pregnancy to blood collection was 16.66 years (range = 1.45 - 44.42 years). We identified 903 differentially methylated positions (DMPs) in whole blood; 365 were hypomethylated and 528 were hypermethylated in parous women. We further identified two differentially methylated regions (DMRs) in CRYGN on Chromosome 7 and an intergenic region on Chromosome 15. There were four and eight cell type specific DMPs in CD4+ and CD8+ cells, respectively. Differentially methylated genes were enriched in neuronal plasticity pathways. Parity was associated with reduced MAA by a mean of 1.44 to 2.27 years using the PhenoAge (p = 0.002) and GrimAge (p = 0.005) algorithms.
ConclusionWhole-blood methylation patterns are associated with birth history in females with relapse-onset multiple sclerosis. We found enrichment of differentially methylated genes encoding neuronal processes and reduced MAA in parous women. These methylation changes could mediate the long-term benefit of pregnancy for disease progression in multiple sclerosis. | neurology |
10.1101/2022.03.24.22272764 | Environmental risks and occupational health hazards of bidi workers and their communities in India: protocol for systematic scoping review | BackgroundTobacco consumption is a leading preventable cause of disease and premature deaths. In India bidis are the most common form of smoking tobacco product. Bidi manufacturing is an agro-forest based cottage industry and is generally rolled at home. These workers are exposed to nicotine, tar and other particles through skin leading to occupational health risks in not only themselves but also in their families and communities. There are concerns on environmental risks of bidi manufacturing in home too.
AimTo assess the environmental risks and occupational health hazards of bidi workers and their communities in India.
MethodWe will conduct a scoping review to identify, map and analyse evidence around environmental risks and occupational health hazards in bidi workers and their families and communities. We will search in seven electronic databases (PubMed, EMBASE+EMBASE Classic, CINAHL, Environment complete-EBSCO, GreenFILE-EBSCO, Web of Science and WHO-IRIS). Screening will be done independently by at least two reviewers, with disagreements resolve by consensus. We will extract data for the included studies using a standardised data extraction in an independent fashion, with disagreements resolved by consensus. We will conduct a narrative synthesis. | occupational and environmental health |
10.1101/2022.03.24.22272867 | Effects of genetic liability to Alzheimers disease on circulating metabolites across the life course | ObjectiveAlzheimers disease (AD) has several known genetic determinants, yet the mechanisms through which they lead to disease onset remain poorly understood. This study aims to estimate the effects of genetic liability to AD on plasma metabolites measured at seven different stages across the life course.
MethodsGenetic and metabolomic data from 5,648 offspring from the Avon Longitudinal Study of Parents and Children birth cohort were used. Linear regression models examined the association between higher AD liability, as measured by a genetic risk score (GRS), and plasma metabolites measured at 8, 16, 18 and 25 years of age. Two hundred twenty-nine metabolites were studied, most relating to lipid/lipoprotein traits. Two-sample Mendelian randomization was performed using summary statistics from age-stratified genome-wide association studies (GWAS) of the same metabolites for 118,466 participants from the UK Biobank, to examine the persistence of any AD liability effects into late adulthood.
ResultsThe GRS including the APOE4 isoform demonstrated the strongest positive associations for cholesterol-related traits per doubling of genetic liability to AD, e.g., for low-density lipoprotein cholesterol (LDL-C) at age 25yrs (0.12 SD; 95% CI 0.09, 0.14), with similar magnitudes of association across age groups in ALSPAC. In the UK Biobank, the effect of AD liability decreased with age tertile for several lipid traits (e.g., LDL-C, youngest: 0.15 SD; 95% CI 0.07, 0.23, intermediate: 0.13 SD; 95% CI 0.07, 0.20, oldest: 0.10 SD; 95% CI 0.05, 0.16). Across both cohorts, the effect of AD liability on high-density lipoprotein cholesterol (HDL-C) attenuated as age increased. Fatty acid metabolites also demonstrated positive associations in both cohorts, though smaller in magnitude compared with lipid traits. Sensitivity analyses indicated that these effects were driven by the APOE4 isoform.
ConclusionsThese results support a profound influence of the APOE4 isoform on circulating lipids and fatty acids from early life to later adulthood. Such lipid and fatty acid traits may be implicated in early AD pathogenesis and warrant further investigation as potential targets for preventing the onset of AD. | genetic and genomic medicine |
10.1101/2022.03.24.22272867 | Effects of genetic liability to Alzheimers disease on circulating metabolites across the life course | ObjectiveAlzheimers disease (AD) has several known genetic determinants, yet the mechanisms through which they lead to disease onset remain poorly understood. This study aims to estimate the effects of genetic liability to AD on plasma metabolites measured at seven different stages across the life course.
MethodsGenetic and metabolomic data from 5,648 offspring from the Avon Longitudinal Study of Parents and Children birth cohort were used. Linear regression models examined the association between higher AD liability, as measured by a genetic risk score (GRS), and plasma metabolites measured at 8, 16, 18 and 25 years of age. Two hundred twenty-nine metabolites were studied, most relating to lipid/lipoprotein traits. Two-sample Mendelian randomization was performed using summary statistics from age-stratified genome-wide association studies (GWAS) of the same metabolites for 118,466 participants from the UK Biobank, to examine the persistence of any AD liability effects into late adulthood.
ResultsThe GRS including the APOE4 isoform demonstrated the strongest positive associations for cholesterol-related traits per doubling of genetic liability to AD, e.g., for low-density lipoprotein cholesterol (LDL-C) at age 25yrs (0.12 SD; 95% CI 0.09, 0.14), with similar magnitudes of association across age groups in ALSPAC. In the UK Biobank, the effect of AD liability decreased with age tertile for several lipid traits (e.g., LDL-C, youngest: 0.15 SD; 95% CI 0.07, 0.23, intermediate: 0.13 SD; 95% CI 0.07, 0.20, oldest: 0.10 SD; 95% CI 0.05, 0.16). Across both cohorts, the effect of AD liability on high-density lipoprotein cholesterol (HDL-C) attenuated as age increased. Fatty acid metabolites also demonstrated positive associations in both cohorts, though smaller in magnitude compared with lipid traits. Sensitivity analyses indicated that these effects were driven by the APOE4 isoform.
ConclusionsThese results support a profound influence of the APOE4 isoform on circulating lipids and fatty acids from early life to later adulthood. Such lipid and fatty acid traits may be implicated in early AD pathogenesis and warrant further investigation as potential targets for preventing the onset of AD. | genetic and genomic medicine |
10.1101/2022.03.24.22272867 | Effects of genetic liability to Alzheimers disease on circulating metabolites across the life course | ObjectiveAlzheimers disease (AD) has several known genetic determinants, yet the mechanisms through which they lead to disease onset remain poorly understood. This study aims to estimate the effects of genetic liability to AD on plasma metabolites measured at seven different stages across the life course.
MethodsGenetic and metabolomic data from 5,648 offspring from the Avon Longitudinal Study of Parents and Children birth cohort were used. Linear regression models examined the association between higher AD liability, as measured by a genetic risk score (GRS), and plasma metabolites measured at 8, 16, 18 and 25 years of age. Two hundred twenty-nine metabolites were studied, most relating to lipid/lipoprotein traits. Two-sample Mendelian randomization was performed using summary statistics from age-stratified genome-wide association studies (GWAS) of the same metabolites for 118,466 participants from the UK Biobank, to examine the persistence of any AD liability effects into late adulthood.
ResultsThe GRS including the APOE4 isoform demonstrated the strongest positive associations for cholesterol-related traits per doubling of genetic liability to AD, e.g., for low-density lipoprotein cholesterol (LDL-C) at age 25yrs (0.12 SD; 95% CI 0.09, 0.14), with similar magnitudes of association across age groups in ALSPAC. In the UK Biobank, the effect of AD liability decreased with age tertile for several lipid traits (e.g., LDL-C, youngest: 0.15 SD; 95% CI 0.07, 0.23, intermediate: 0.13 SD; 95% CI 0.07, 0.20, oldest: 0.10 SD; 95% CI 0.05, 0.16). Across both cohorts, the effect of AD liability on high-density lipoprotein cholesterol (HDL-C) attenuated as age increased. Fatty acid metabolites also demonstrated positive associations in both cohorts, though smaller in magnitude compared with lipid traits. Sensitivity analyses indicated that these effects were driven by the APOE4 isoform.
ConclusionsThese results support a profound influence of the APOE4 isoform on circulating lipids and fatty acids from early life to later adulthood. Such lipid and fatty acid traits may be implicated in early AD pathogenesis and warrant further investigation as potential targets for preventing the onset of AD. | genetic and genomic medicine |
10.1101/2022.03.24.22272882 | A mixed methods study of community-based health insurance enrollment trends and underlying challenges in two districts of northeast Ethiopia: a proxy for its sustainability | BackgroundCommunity-based health insurance initiatives in low- and middle-income countries are plagued by persistently low coverage due to their voluntary orientation. In Ethiopia, the schemes membership growth has not been well investigated so far. This study sought to examine the schemes enrollment trend over a five-year period, and to explore the various challenges that underpin membership growth from the perspectives of various key stakeholders.
MethodsThe study employed a mixed methods case study in two districts of northeast Ethiopia: Tehulederie and Kallu. Quantitative data was collected by reviewing the databases of schemes. Key informant interviews and in-depth interviews were conducted face-to-face with 19 key stakeholders and nine community members, respectively. Study participants were purposely selected using the maximum variation technique. Interviews were audio recorded, transcribed verbatim, and translated into English. Thematic analysis was employed with both deductive and inductive coding approaches.
ResultsEnrollment in the two districts has shown an inconsistent trend over the study period (2017 to 2021). The scheme in Tehulederie has a relatively better enrollment trend, particularly in terms of membership retention, which could be due to the strong foundation laid by a rigorous public awareness campaign and technical support during the pilot phase. The challenges contributing to the observed level of performance have been summarized under four main themes that include quality of health care, claims reimbursement for insurance holders, governance practices, and community awareness and acceptability.
ConclusionsThe scheme experienced negative growth ratios in both districts with inconsistent trends, showing that the scheme is not functionally viable. It will regress unless relevant stakeholders at all levels of government demonstrate political will and commitment to its implementation, as well as advocate for the community. Interventions should target on the highlighted challenges in order to boost membership growth and ensure the viability of the community-based health insurance. | health economics |
10.1101/2022.03.24.22272880 | Strengthening health service delivery and governance through institutionalizing "Urban Health Atlas" - a geo-referenced Information Communication and Technology tool: lessons learned from an implementation research in three cities in Bangladesh | IntroductionUrban health governance in Bangladesh is complex as multiple actors are involved and no comprehensive data are currently available on infrastructure, services, or performance either in public and private sectors of the healthcare system. The Urban Health Atlas (UHA) - a novel and interactive geo-referenced, web-based visualization tool was developed in Bangladesh to provide geospatial and service information to decision makers involved in urban health service planning and governance. Our objective was to study the opportunities for institutionalization of the UHA into government health systems responsible for urban healthcare delivery and document the facilitators and barriers to its uptake.
MethodsThis mixed-methods implementation research was carried out during 2017-2019 in three cities in Bangladesh: Dhaka, Dinajpur and Jashore. During the intervention period, six hands-on trainings on UHA were provided to 67 urban health managers across three study sites. Both in-depth and key informant interviews were conducted to understand user experience and document stakeholder perceptions of institutionalizing UHA.
ResultsCapacity building on UHA enhanced understanding of health managers around its utility for service delivery planning, decision making and oversight. Uptake of UHA was challenged by inadequate ICT infrastructure, shortage of human resources and general lack of ICT skill among the managers. Motivating key decision makers and stakeholders about the potential of UHA and engaging them from the inception helped the institutionalization process.
ConclusionWhile uptake of UHA by government health managers appears possible with dedicated capacity building initiatives, its use and regular update are challenged by multiple factors at the implementation level. A clear understanding of context, actors and system readiness is foundational in determining whether the institutionalization of health ICTs is timely, realistic or relevant. | health systems and quality improvement |
10.1101/2022.03.24.22272904 | Booster dose of BNT162b2 in a CoronaVac primary vaccination protocol improves neutralization of SARS-CoV-2 Omicron variant | The emergence of the new SARS-CoV-2 Omicron variant, which is known to accumulate a huge number of mutations when compared to other variants, brought to light the concern about vaccine escape, especially from the neutralization by antibodies induced by vaccination. In this scenario, we evaluated the impact on antibody neutralization induction, against Omicron variant, by a booster dose of BNT162b2 mRNA vaccine after the CoronaVac primary vaccination scheme. The percentage of seroconverted individuals 30 and 60 days after CoronaVac scheme was 17% and 10%, respectively. After booster dose administration, the seroconvertion rate increased to 76.6%. The neutralization mean titer against Omicron in the CoronaVac protocol decreased over time, but after the booster dose, the mean titer increased 43.1 times, indicating a positive impact of this vaccine combination in the serological immune response. | infectious diseases |
10.1101/2022.03.24.22272919 | Vaccine Effectiveness Against Hospitalization Among Adolescent and Pediatric SARS-CoV-2 Cases in Ontario, Canada | BackgroundVaccines to prevent SARS-CoV-2 infection and severe outcomes were approved in 2021 for adolescent and subsequently pediatric populations. With the emergence of variants of concern, it is important to continue to assess vaccine effectiveness against both infection and severe disease manifestations.
MethodsUsing an age and time-matched nested case-control design, we estimated the vaccine effectiveness of SARS-CoV-2 vaccination at preventing hospitalization among adolescent and pediatric patients infected with SARS-CoV-2. We linked SARS-CoV-2 cases ages 4 to 17 years in Ontarios reportable diseases database to SARS-CoV-2 vaccination records. We included 1,441 incident SARS-CoV-2 cases occurring between May 28, 2021 and January 10, 2022. We used multivariable logistic regression to estimate the effectiveness of one and two mRNA vaccine doses against hospitalization among adolescent and pediatric SARS-CoV-2 cases. We quantified and mitigated the impact of unmeasured confounding by calculating an E-value and by applying instrumental variable methods.
ResultsWe included n=131 hospitalized SARS-CoV-2 cases and n=1,310 non-hospitalized SARS-CoV-2 cases. One vaccine dose was shown to be 37% effective against hospitalization among SARS-CoV-2 cases (adjusted odds ratio [aOR] = 0.63 [95% CI: 0.33, 1.13]). In contrast, two doses were 59% (aOR = 0.41 [95% CI: 0.21, 0.77]) effective at preventing hospitalization among SARS-CoV-2 cases.
ConclusionsEven with immune evasion by SARS-CoV-2 variants, two vaccine doses continue to provide protection against hospitalization among adolescent and pediatric patients, even when the vaccines do not prevent infection. SARS-CoV-2 vaccines remain a safe and effective intervention to prevent severe outcomes. | infectious diseases |
10.1101/2022.03.24.22272901 | Impact of Vaccination, Prior Infection, and Therapy on Delta and Omicron Variants | We studied 249,070 patients who were tested for SARS-CoV-2 in the Cleveland Clinic Health System between October 1, 2021 and January 31, 2022. We found that vaccination, especially with recent boosting, was more effective than prior infection and monoclonal antibody therapy against both the delta and omicron variants. Vaccination and prior infection were much less effective against infection with the omicron variant than with the delta variant, but the opposite was true of death after infection. Boosting greatly increased the effectiveness of the two mRNA vaccines against both infection and death, although its effects waned markedly after 6 months. In addition, monoclonal antibody therapy was notably less effective at preventing death from the omicron variant than from the delta variant. Finally, the relatively low mortality of the omicron variant was due to both the reduced lethality of this variant and the increased population immunity acquired from booster vaccination and previous infection. | infectious diseases |
10.1101/2022.03.25.22272920 | Species-specific bacterial detector for fast pathogen diagnosis of severe pneumonia patients in the intensive care unit | Rapid diagnosis of pathogens is the cornerstone of appropriate therapy and is also a great challenge to be overcome. Although NGS and some other PCR-based pathogen detection methods were applied to improve the speed and accuracy of clinical diagnosis, it was still a long way from the clinical needs of rapid and accurate diagnostic therapy in the intensive care unit (ICU). In this study, we aimed at developing a new rapid diagnostic tool, Species-Specific Bacterial Detector (SSBD), to evaluate the existence and quantification of 10 most usual pathogenic bacteria in ICU in 4 hours. Briefly, the species-specific genome fragments of each bacterium were identified by our algorithm using 1791 microbe genomes from 232 species and then used to combine with CRISPR/Cas12 to establish diagnosis tools. Based on the tests of 77 samples, SSBD demonstrated 100% sensitivity and 87% specificity compared with conventional culture test (CCT). Later on, an interventional random-grouped study was applied to evaluate the clinical benefits of SSBD. Briefly, SSBD demonstrated more accurate and faster diagnosis results and led to earlier antibiotics adjustment than CCT. Based on the results acquired by SSBD, cultivation results could deviate from the real pathogenic situation with polymicrobial infections. In addition, nosocomial infections were found widely in ICU, which should deserve more attention. | intensive care and critical care medicine |
10.1101/2022.03.24.22272860 | Association of genetically-predicted lipid traits and lipid-modifying targets with the risk of heart failure | AimsTo assess the association of lipid traits and lipid-modification via licensed or investigational targets with heart failure (HF) risk using 2-sample Mendelian randomization (MR) study.
Methods and resultsGenetic variants obtained from genome-wide association studies (GWASs) in UK Biobank as instrumental variables to investigate the association of lipid traits (low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglyceride (TG), apolipoprotein B (ApoB) and apolipoprotein AI (ApoAI)) and lipid-modifying effect of eight licensed or investigational drug targets with HF risk by using the inverse-variance weighted method. In this study, we observed that genetically-predicted levels of LDL-C, TG, LDL-C and ApoB were significantly related to HF risk, which were mainly mediated by CHD. Further MR analyses identified PCSK9, CETP and LPL, but not HMGCR, as potential targets to prevent HF. The genetic proxy of LDL-C and ApoB increase modified by PCSK9 showed similar evidence in increasing risk of HF (PLDL-C=1.27*10-4; PApoB=1.94*10-4); CETP played a role in HF risk via modifying all investigational lipid traits with the strongest evidence though ApoB (P=5.87*10-6); LPL exerted effects on HF via modifying most lipid traits with the strongest evidence observed via modifying TG (P=3.73*10-12).
ConclusionsThis 2-sample MR study provided genetic evidence of the associations between lipid traits and HF risk, which were mostly mediated by CHD. Besides, drug target MR studies indicated that PCSK9 inhibition, CETP inhibition and LPL activation, but not statins, were effective in reducing HF risk. | epidemiology |
10.1101/2022.03.25.22272946 | Understanding the role of mask-wearing during COVID-19 on the island of Ireland | BackgroundNon-pharmaceutical interventions (NPI) play a key role in managing epidemics, yet it is challenging to evaluate their impacts on disease spread and outcomes.
MethodsTo estimate the effect of a mask-wearing intervention to mitigate the spread of SARS-CoV-2 on the island of Ireland, we focused on the potential for interindividual infectious contact over time as the outcome. This is difficult to measure directly; in a companion paper we estimated it using a multi-strain epidemiological model. We used data on mask-wearing and mobility in both Northern Ireland (NI) and the Republic of Ireland (ROI) to predict independently the estimated infectious contact over time. We made counterfactual predictions of infectious contact rates and hospitalisations under a hypothetical intervention where 90% of the population were wearing masks during early 2020, when in reality few people were wearing masks in public; this was mandated in both jurisdictions on 10th August 2020.
ResultsThere were 1601 hospitalisations with COVID-19 in NI between 12th March and 10th August 2020, and 1521 in ROI between 3rd April and 10th August 2020. Under the counterfactual mask-wearing scenario, we estimated 512 (95% CI 400, 730) hospitalisations in NI, and 344 (95% CI 266, 526) in ROI, during the same periods.
ConclusionsWe have estimated a large effect of population mask-wearing on COVID-19 hospitalisations. This could be partly due to other factors that were also changing over time. | epidemiology |
10.1101/2022.03.24.22272898 | Modestly protective cytomegalovirus vaccination of young children effectively prevents congenital infection at the population level | A vaccine to prevent congenital cytomegalovirus infection (cCMV) is a public health priority. cCMV results from maternal primary or non-primary CMV infection (reinfection or reactivation of chronic infection) during pregnancy. Young children are a major source of transmission to pregnant women because they shed CMV at high viral loads for prolonged periods. CMV vaccines evaluated in clinical trials so far have demonstrated only approximately 50% efficacy against maternal primary infection. None of these have been approved, as higher levels of vaccine-induced immunity are assumed to be required to substantially reduce cCMV prevalence. Here, we designed a mathematical model to capture the relationship between viral shedding by young children and maternal CMV infections during pregnancy. Using this model, we were able to quantify the efficacy of CMV immunity following infection to protect against reinfection and viral shedding. There was a 35% reduction in the risk of infection to a seropositive person (reinfection) versus a seronegative person (primary infection), given the same exposure. Viral shedding following reinfection was only 25% the quantity of that following primary infection. We also found that a vaccine that confers the equivalent of infection-induced immunity, when given to young children, markedly reduces both CMV transmission to pregnant women and rates of cCMV. Thus, we predict that vaccine candidates that have already been shown to be only modestly protective may in fact be highly effective at preventing cCMV by interrupting child-to-mother transmission. | epidemiology |
10.1101/2022.03.24.22272854 | Vaccine effectiveness with BNT162b2 (Comirnaty, Pfizer-BioNTech) vaccine against reported SARS-CoV-2 Delta and Omicron infection among adolescents, Norway, August 2021 to January 2022 | BackgroundCOVID-19 vaccination was recommended for adolescents in Norway since August 2021. In this population-based cohort study, we estimated the BNT162b2 vaccine effectiveness against any PCR-confirmed (symptomatic or not) SARS-CoV-2 infections caused by the Delta and Omicron variant among adolescents (12-17-years-old) in Norway from August 2021 to January 2022.
MethodsUsing Cox proportional hazard models, we estimated the BNT162b2 vaccine effectiveness against any Delta and Omicron infections. Vaccine status was included as a time-varying covariate and models were adjusted for age, sex, comorbidities, county of residence, country of birth, and living conditions. Data were obtained from the National Preparedness registry for COVID-19, which contains individual-level data from national health and administrative registries.
FindingsVaccine effectiveness against Delta infection peaked at 68% (95%CI: 64-71%) and 62% (95%CI: 57- 66%) in days 21-48 after the first dose among 12-15-year-olds and 16-17-year-olds respectively. Among 16-17-year-olds that received two doses, vaccine effectiveness peaked at 93% (95%CI: 90-95%) in days 35-62 and declined to 84% (95%CI: 76-89%) in 63 days or more after the second dose. For both age-groups, we found no protection against Omicron infection after receiving one dose. Among 16-17-year-olds, vaccine effectiveness against Omicron infection peaked at 53% (95%CI: 43-62%) in 7-34 days after the second dose and decreased to 23% (95%CI: 3-40%) in 63 days or more after vaccination. Vaccine effectiveness decreased with time since vaccination for both variants, but waning was observed to occur faster for Omicron.
InterpretationOur results suggest reduced protection from BNT162b2 vaccination against any SARS-CoV-2 infection caused by the Omicron variant compared to the Delta. In addition, waning immunity was observed to occur faster for Omicron. The impact of vaccination among adolescents on reducing infection and thus transmission is limited during omicron dominance.
FundingNo funding was received.
Research in context
Evidence before this studyBNT162b2 (Comirnaty, Pfizer-BioNTech) and mRNA-1273 (Spikevax, Moderna) vaccines have been approved for use in adolescents, based on results from randomized placebo-controlled trials demonstrating comparable immunogenicity and safety profile as in young adults. In addition, observational studies from Israel, the USA and England have reported high protection of BNT162b2 vaccines against SARS-CoV-2 Delta infection among adolescents. These studies also reported decrease in effectiveness with time since last vaccine dose. Evidence on the effect of an extended interval between doses, longer time since vaccination and the effect against different variants is limited. When we first planned this study in early February 2022, no data were available regarding vaccine effectiveness against SARS-CoV-2 Omicron infection among adolescents. To our knowledge when we completed this study and before submitting this article, only one study from England reported results in a preprint on vaccine effectiveness against symptomatic SARS-CoV-2 Omicron infection among adolescents. We searched for studies that evaluated vaccine efficacy or effectiveness after vaccination of adolescents during 2021-2022 in PubMed, medRxiv, bioRxiv, SSRN. We searched for studies with several variations of the primary key search terms "COVID-19", "SARS-CoV-2", and "vaccine" (including names of specific vaccines, as BNT162b2), "vaccine effectiveness", "adolescents", "children".
Added value of this studyThe rapid increase in the incidence of SARS-CoV-2 infection caused by the Omicron variant in highly vaccinated populations has raised concerns about the effectiveness of current vaccines in adults but also adolescents. In this population-based cohort study, we showed that the vaccine effectiveness against Omicron is lower than against Delta infections among adolescents, including symptomatic and asymptomatic infections. We should note that evidence suggests higher rates of asymptomatic carriage for Omicron than other variants of concern. Vaccine effectiveness that includes asymptomatic cases, as in the study from England, is expected to be lower than when including symptomatic cases only. We found that one and two doses of BNT162b2 among adolescents protected well against Delta. Vaccination provided high protection against Delta infections (>91%) among Norwegian 16-17-year-olds 7-62 days after the second dose. We found no protection against Omicron SARS-CoV-2 infection after one vaccine dose, and moderate effectiveness after two doses (peaked at 53%) among the 16-17-year-olds. Moreover, waning immunity was observed to occur faster for Omicron.
Implications of all the available evidenceBased on the available evidence, the vaccine effectiveness among adolescents is similar to that reported among adults, also with an extended period of 8-12 weeks between doses which was used in Norway. Protection is significantly lower against Omicron than Delta infections and immunity wanes faster against Omicron. The impact of vaccination among adolescents on reducing infection and thus transmission is limited during omicron dominance. Policies should take into account the impact of vaccination campaigns among adolescents and their primary objective. Vaccine effectiveness should be re-evaluated when other variants appear as they might have different outcomes as shown between Delta and Omicron infections. | epidemiology |
10.1101/2022.03.25.22272950 | THE IMPACT OF ROUTINES ON EMOTIONAL AND BEHAVIOURAL DIFFICULTIES IN CHILDREN AND ON PARENTAL ANXIETY DURING COVID-19 | Aims and hypothesisWe hypothesised that there would be an association between maintaining a routine during lockdown and both lower emotional and behavioural difficulties in children and lower parental anxiety. We also hypothesised that children of keyworker parents would have fewer emotional and behavioural symptoms due to having maintained more normal routines.
BackgroundThe Covid-19 pandemic and related public health measures have impacted on mental health of children.
MethodsWe used data from the Avon Longitudinal Study of Parents and Children (ALSPAC) to explore associations between maintaining a routine, and emotional and behavioural difficulties in children, using linear regression models. We included measures of parental anxiety. We separately explored associations with having a keyworker parent. We used the Carey Infant Temperament Questionnaire and the Revised Rutter Parent Scale for Preschool Children to establish levels of emotional and behavioural difficulties.
Results289 parents completed questionnaires about their 411 children. Keeping a routine was associated with emotional and behavioural difficulty scores 5.0 points lower (95% CI -10.0 to - 0.1), p=0.045 than not keeping a routine. Parents who reported keeping a routine had anxiety scores 4.3 points lower (95% CI -7.5 to -1.1), p=0.009 than those who did not. Children of keyworkers tended to have lower emotional and behavioural difficulty scores (-3.1 (95%CI -6.26 to 0.08), p=0.056) than children of non-keyworkers. All models were adjusted for relevant potential confounders.
ConclusionMaintaining a routine may be beneficial for both child emotional wellbeing and parental anxiety, although it is also possible that lower parental anxiety levels made maintaining a routine easier. Being the child of a keyworker parent during lockdown may have been protective for child emotional wellbeing. | psychiatry and clinical psychology |
10.1101/2022.03.24.22272864 | Impact assessment of mobility restriction, testing, and vaccination on the COVID-19 pandemic in India | BackgroundBefore the availability of vaccines, countries largely relied on mobility restriction and testing to mitigate the COVID-19 pandemic. Our aim is to assess the combined impact of mobility restriction, testing, and vaccination on the COVID-19 pandemic in India.
MethodsWe conducted a multiple regression analysis to assess the impact of mobility, testing, and vaccination on COVID-19 incidence between April 28, 2021 to November 24, 2021 using data from Our World in Data and Google Mobility Report. The 7-day moving average was applied to offset the daily fluctuations in the mobility and testing. Each independent variable was lagged to construct a temporal relationship, and waning vaccination efficacy was taken into consideration. We performed additional analysis for three time periods between March 28, 2020 to November 24, 2021 (1st: March 28, 2020 [~] October 7, 2020, 2nd: October 8, 2020 [~] April 27, 2021, 3rd: April 28, 2021 [~] November 24, 2021) to examine potential heterogeneity over time.
ResultsMobility (0.041, 95% CI: 0.033 to 0.048), testing (-0.008, 95% CI: -0.015 to -0.001), and vaccination (quadratic term: 0.004, 95% CI: 0.003 to 0.005, linear term: -0.130, 95% CI: -0.161 to -0.099) were all associated with COVID-19 incidence. For vaccination rate, the decrease of number of cases demonstrated a U-shaped curve, while mobility showed a positive association and testing showed an inverse association with COVID-19 incidence. Mobility restriction was effective during all three periods - March 28, 2020 to November 24, 2021 (0.009, 0.048, and 0.026 respectively). Testing was effective during the second and third period - October 8, 2020 to November 24, 2021 (-0.036, and -0.006 respectively).
ConclusionMobility restriction and testing were effective even in the presence of vaccination. This shows the positive value of mobility restrictions, testing, and vaccination from the health system perspective on COVID-19 prevention and control, especially with continual emergence of variants in India and globally. At the same time, this health system gain must be balanced with the challenges in the delivery of non-COVID health services and broader socio-economic impact in deciding the prolonged continuance of mobility restriction. | public and global health |
10.1101/2022.03.24.22272916 | Altered Cerebral Blood Flow in Older Adults with Alzheimer's Disease: A Systematic Review | The prevalence of Alzheimers disease is projected to reach 13 million in the U.S. by 2050. Although major efforts have been made to avoid this outcome, so far there are no treatments that can stop or reverse the progressive cognitive decline that defines Alzheimers disease. The utilization of preventative treatment before significant cognitive decline has occurred may ultimately be the solution, necessitating a reliable biomarker of preclinical/prodromal disease stages to determine which older adults are most at risk. Quantitative cerebral blood flow is a promising potential early biomarker for Alzheimers disease, but the spatiotemporal patterns of altered cerebral blood flow in Alzheimers disease are not fully understood. The current systematic review compiles the findings of 29 original studies that compared quantitative cerebral blood flow in older adults with mild cognitive impairment or Alzheimers disease to that of cognitively normal older adults and/or assessed the relationship between cerebral blood flow and objective cognitive function. Individuals with Alzheimers disease had relatively decreased cerebral blood flow in all brain regions investigated, especially the temporoparietal and posterior cingulate, while individuals with mild cognitive impairment had less consistent results, with relatively increased cerebral blood flow reported in the temporal lobe and thalamus. Most papers reported a positive correlation between cerebral blood flow and cognitive function. This review highlights the need for more studies comparing cerebral blood flow between cognitively normal individuals and those with mild cognitive impairment, as well as the importance of including potential confounding factors in these analyses. | radiology and imaging |
10.1101/2022.03.24.22272914 | T1/T2 Ratio Imaging Improves Cortical Lesion Contrast in Multiple Sclerosis on 3T MRI | BackgroundCortical demyelinated lesions are prevalent in multiple sclerosis (MS) and associated with disability; their presence on MRI has recently been incorporated into MS diagnostic criteria. Presently, advanced and ultra-high-field MRI -- not routinely available in clinical practice -- are the most sensitive methods for detection of cortical lesions, and approaches utilizing MRI sequences obtainable in routine clinical practice remain an unmet need.
ObjectiveTo assess the sensitivity of the ratio of T1-weighted and T2-weighted (T1/T2) signal intensity for focal cortical lesions in comparison to other established, sensitive, advanced and high-field imaging methods.
Methods3-tesla (3T) and 7-tesla (7T) MRI collected from 10 adults with MS participating in a natural history study at the National Institutes of Health were included in the study. T1/T2 images were calculated by dividing 3T T1w images by 3T T2w fluid-attenuated inversion recovery (FLAIR) images for each participant. Cortical lesions were identified using 7T T2*w and T1w images and corresponding voxels were assessed on registered 3T images. For each participant, ratios derived from the median signal intensity of nonlesional tissue in the cortical region of the lesion and the median lesional voxel intensity were computed. These values were compared across 3T imaging sequences, including the calculated T1/T2 image, as well as T1w, T2w, and Inversion Recovery Susceptibility Weighted Imaging with Enhanced T2 weighting (IR-SWIET) images.
Results614 cortical lesions were identified on 7T images. 3T T1/T2 images demonstrated a larger contrast between median nonlesional cortical signal intensity and median cortical lesion signal intensity (median ratio = 1.29, range 1.19 - 1.38) when compared to T1w (1.01, 0.97 - 1.10, p<0.002), T2w (1.17, 1.07 - 1.26, p<0.002), and IR-SWIET (1.21, 1.01 - 1.29, p<0.03).
ConclusionT1/T2 images are sensitive to cortical lesions. Approaches incorporating T1/T2 could improve the accessibility of cortical lesion detection in research settings and clinical practice. | neurology |
10.1101/2022.03.24.22272865 | Spatial Cluster Modeling of Rodent Infestations and Leptospirosis Risks in SE Asian Urban Areas | Urban areas in the Southeast Asia Region are characterized by rainfall, river networks, and rodent infestations. Combinations of these adverse conditions will lead to the increasing risk of leptospirosis as usually contained in rodents. Then this study aims to assess the spatial pattern of rodent infestations and estimate the potential leptospirosis risks using environmental variables including distance to the river and rainfall in a city in SE Asia. The spatial modeling of rodent infestations was developed based on GIS and interpolation analysis. Meanwhile, the cluster modeling of rodent infestations was developed using the K-means clustering method. The results revealed the rodent infestations represented by two rodent species were Rattus rattus and Rattus norvegicus. R. rattus has a higher abundance than R. norvegicus. In contrast, R. norvegicus has wider distribution areas than R. rattus. Regarding the distribution areas, both species overlapped in the Southern parts of the city. R. rattus and R. norvegicus showed a distinct cluster characterized by a high rodent population with affinity for the nearest river, and this indicates the urban inhabitants near the river have more leptospirosis risk. The model of leptospirosis risks estimated an urban area of 35.182 km2 or 17.56% having leptospirosis potential. | occupational and environmental health |
10.1101/2022.03.24.22272873 | A screening tool enhances home-based identification of adolescents (aged 10-14) living with HIV in Zambia and South Africa: HPTN 071 (PopART) Study | IntroductionThe HPTN071 (PopART) for Youth (P-ART-Y) study evaluated the acceptability and uptake of a community-level combination HIV prevention package including universal testing and treatment (UTT) among young people in Zambia and South Africa (SA). We determined whether a four-question primary care level screening tool, validated for use in clinical settings, could enhance community (door-to-door) identification of undiagnosed HIV-positive younger adolescents (aged 10-14) who are frequently left out of HIV interventions.
MethodCommunity HIV-care Providers (CHiPs) contacted and consented adolescents in their homes and offered them participation in the PopART intervention. CHiPs used a four question-screening tool, which included: history of hospital admission; recurring skin problems; poor health in last 3 months; and death of at least one parent. A "yes" response to one or more questions was classified as being "at risk" of being HIV-positive. The data were captured through an electronic data capturing device from August 2016 to December 2017. Proportions of adolescents who were deemed "at risk" were calculated and the association of screening "at risk" with age, sex and community was tested using a chi-squared test. The adjusted odds ratio (OR) comparing the odds of testing HIV-positive if "at risk" with the odds of testing positive if "not at risk" was estimated using logistic regression.
ResultsIn our 14 study sites, 33,283 adolescents aged 10-14 in Zambia and 8,610 in SA participated in the study. About 1.3% (427/33,710) and 1.2% (106/8,610) self-reported to be HIV positive. Excluding the self-reported HIV-positive, we classified 11.3% (3,746/33,283) of adolescents in Zambia and 17.5% (1,491/8,504) in SA as "at risk". In Zambia and SA, the "at risk" adolescents were 4.6 and nearly 16.7 times more likely to test HIV-positive compared to the "not at risk", respectively (both p<0.001). Using the screening tool, one-third of HIV-positive adolescents could be diagnosed using just a tenth of the number of HIV tests compared to universal testing.
ConclusionThe screening tool may be of some value where UTT is not possible and limited resources must be prioritised toward adolescents who are more likely to be living with HIV. Further, the tool is of greater value in settings where there are more adolescents living with HIV who are undiagnosed. However, given our goal is to identify and treat all ALHIV, as well as link all HIV uninfected young people to prevention services, this screening tool should not be a substitute for UTT in community settings.
Clinical Trial NumberNCT01900977 | hiv aids |
10.1101/2022.03.24.22272879 | Incidence and Predictors of Antiretroviral Treatment Failure among Children in Public Health Facilities of Kolfe Keranyo Sub-City, Addis Ababa, Ethiopia: Institution-based retrospective cohort study | BackgroundHuman immunodeficiency virus (HIV) infection is a public health concern globally. The numbers of people living with HIV worldwide in 2018 was estimated at 37.9 million; from those, 1.7 million are children. Globally, 62% of the 37.9 million people were receiving Antiretroviral treatment (ART); 53% had achieved viral suppression. This study aimed to assess the incidence and predictors of Antiretroviral treatment failure among children in Kolfe Keranyo sub-city, Addis Ababa, Ethiopia.
MethodsAn institution-based retrospective cohort study was conducted among 250 children who were enrolled to first-line Antiretroviral treatment from January 2013 to May 2020 in Kolfe Keranyo sub-city. Data was collected by using data extraction checklist and data were extracted by reviewing childrens medical chart and electronic database. Kaplan-Meier method was used to estimate the probability of treatment failure. During bivariable analysis variables with p-value < 0.25 were taken for multivariable Cox regression analysis to assess predictors of treatment failure. Statistically significant association was declared at p-value < 0.05 with 95% confidence interval.
ResultThe overall treatment failure rate within the follow-up period was 17.2%. This study also found that the overall incidence density rate was 3.45% (95% CI: 2.57-4.67) per 1000 person-month observation. Infant prophylaxis for PMTCT (AHR: 3.59, 95% CI: 1.65-7,82), drug substitution (AHR: 0.18, 95% CI: 0.09-0.37), AZT/3TC/NVP based regimen (AHR: 2.27, 95% CI: 1.14-4.25), and more than 3 episodes of poor ART adherence (AHR: 2.27, 95% CI: 1.17-4.38) were found to be predictors of treatment failure among children.
ConclusionHigh proportion of treatment failure was found among children on first-line ART in Kolfe Keranyo sub-city, Addis Ababa. Infant prophylaxis for PMTCT, drug substitution, initial regimen, and poor ART adherence were found to be predictors of first-line ART treatment failure. Close follow-up of children on medication adherence and effective trainings to health care professionals need to be considered. | hiv aids |
10.1101/2022.03.18.22272356 | Optimized infection control practices augment the robust protective effect of vaccination for ESRD patients during a hemodialysis facility SARS-CoV-2 outbreak | BackgroundWhile dialysis patients are at greater risk of serious SARS-CoV-2 complications, stringent infection prevention measures can help mitigate the risk of infection and transmission within dialysis facilities. We describe an outbreak of 14 cases diagnosed in a 13-day period in the second quarter of 2021 in a hospital-based ESRD facility, and our coordinated use of epidemiology, viral genome sequencing, and infection control practices to quickly end the cycle of transmission.
MethodsSymptomatic patients and staff members were diagnosed via RT-PCR tests. Facility-wide screening was conducted using rapid SARS-CoV-2 antigen tests. SARS-CoV-2 genome sequences were obtained from residual diagnostic PCR specimens.
ResultsOf the 106 patients who received dialysis in the facility, 10 were diagnosed with SARS-CoV-2 infection, as was one patient support person. Of three positive staff members, two were unvaccinated and had provided care for six and four of the affected patients, respectively. Sequencing demonstrated that all the cases in the cluster shared an identical B.1.1.7./Alpha substrain. Attack rates were greatest among unvaccinated patients and staff. Vaccine effectiveness was 88% among patients.
ConclusionsPrompt recognition of an infection cluster and rapid intervention efforts successfully ended the outbreak. Alongside consistent adherence to core infection prevention measures, vaccination was highly effective in reducing disease incidence and morbidity in this vulnerable population. | infectious diseases |
10.1101/2022.03.18.22272356 | Optimized infection control practices augment the robust protective effect of vaccination for ESRD patients during a hemodialysis facility SARS-CoV-2 outbreak | BackgroundWhile dialysis patients are at greater risk of serious SARS-CoV-2 complications, stringent infection prevention measures can help mitigate the risk of infection and transmission within dialysis facilities. We describe an outbreak of 14 cases diagnosed in a 13-day period in the second quarter of 2021 in a hospital-based ESRD facility, and our coordinated use of epidemiology, viral genome sequencing, and infection control practices to quickly end the cycle of transmission.
MethodsSymptomatic patients and staff members were diagnosed via RT-PCR tests. Facility-wide screening was conducted using rapid SARS-CoV-2 antigen tests. SARS-CoV-2 genome sequences were obtained from residual diagnostic PCR specimens.
ResultsOf the 106 patients who received dialysis in the facility, 10 were diagnosed with SARS-CoV-2 infection, as was one patient support person. Of three positive staff members, two were unvaccinated and had provided care for six and four of the affected patients, respectively. Sequencing demonstrated that all the cases in the cluster shared an identical B.1.1.7./Alpha substrain. Attack rates were greatest among unvaccinated patients and staff. Vaccine effectiveness was 88% among patients.
ConclusionsPrompt recognition of an infection cluster and rapid intervention efforts successfully ended the outbreak. Alongside consistent adherence to core infection prevention measures, vaccination was highly effective in reducing disease incidence and morbidity in this vulnerable population. | infectious diseases |
10.1101/2022.03.25.22272949 | Risk factors and preventive interventions for post Covid-19 condition: systematic reviews | BackgroundThe Covid-19 outbreak has presented many challenges to governments and healthcare systems, including observations of symptoms that persist beyond acute infection labelled as post Covid-19 condition.
ObjectivesTo systematically identify and synthesize evidence around pre-existing and clinical risk factors for post Covid-19 condition (occurring [≥]12 weeks after positive test/symptom onset) (KQ1), and interventions during the acute and post-acute phases of the illness that could potentially prevent post Covid-19 condition (KQ2).
MethodsWe searched Medline and Embase (Jan 2021-Aug 12 2021 [KQ1], and Jan 2020-Jul 28, 2021 [KQ2]), Clinicaltrials.gov, organizational websites, and reference lists of included studies and relevant systematic reviews. Two investigators independently reviewed abstracts and full-text articles against a priori inclusion criteria, and disagreements were resolved through discussion or by consulting a third reviewer. One investigator abstracted data and assessed risk of bias using design-specific criteria, and a second investigator checked data abstraction and assessments for completeness and accuracy. Meta-analysis was performed when there was sufficient clinical and methodological similarity in an exposure-outcome comparison, based on prespecified variables. We assessed the certainty of evidence using the Grading of Recommendations, Assessment, Development and Evaluation approach (GRADE). A relative effect/association of 0.75-1.49 was considered as "little-to-no", whereas 0.50-0.74/1.5-1.99 was "small-to-moderate" and <0.50/ [≥]2.00 was "large" for fewer/benefit or more/harm, respectively
ResultsFrom 4,672 (KQ1) and 3,781 (KQ2) citations we included 17 and 18 studies, though 4 studies were included for both KQs. We found small-to-moderate associations between female sex and higher non-recovery, fatigue, and dyspnea (moderate certainty). Severe or critical acute-phase Covid-19 severity (versus not) has probably (moderate certainty) a large association with increased cognitive impairment, a small-to-moderate association with more non-recovery, and a little-to-no association with dyspnea. There may be (low certainty) large associations between hospitalization during the acute illness and increased non-recovery, increased dyspnea, and reduced return to work. There may be small-to-moderate associations between several other risk factors and post Covid-19 condition outcomes, including age [≥]60 versus <60 (functional incapacity), non-White people (lower return to work), children age >6 versus <2 years (non-recovery), having [≥]1 versus no comorbidities (non-recovery), chronic pulmonary disease (fatigue), rheumatologic disorder (depression/anxiety), and chronic obstructive pulmonary disease or hypertension (cognitive impairment). Several other risk factors had low certainty for little-to-no association with one or more outcomes (e.g. diabetes, cardiovascular disease) or very low certainty. Interventions to prevent post Covid-19 condition included medications (standard and traditional/ayurvedic), stem cell therapy, rehabilitation or similar therapies, and screening/referrals at either acute phase (symptom onset to 4 weeks) or early post-acute phase (4-8 week), with short (12-16 weeks) or longer (>16 weeks) follow-up for outcomes. We are very uncertain about the effects of preventive interventions, mainly due to risk of bias, inconsistency/lack of consistency (single studies), and in some cases imprecision.
ConclusionsGuidelines in relation to surveillance, screening services, and other services such as access to sickness and disability benefits, might need to focus on females and those with previously severe Covid-19 illness. Interventions targeting fatigue, dyspnea, and cognitive impairment (especially in those who had severe Covid-19) may be good to prioritize for development and evaluation to provide evidence on their effects. Inputs from patients and primary care providers should be taken into account when developing new care pathways and some tailoring to individual needs will likely be paramount. Continuous assessment of the rapidly emerging evidence is important to better shape our understanding as the body of evidence grows. Sufficiently powered prospective trials of preventive interventions are warranted.
PROSPERO registrationCRD42021270354 | infectious diseases |
10.1101/2022.03.24.22272872 | The scope and needs related to training, research, and mentorship among early-career addiction medicine professionals: an online global survey followed by expert group discussions | Addiction medicine is a developing field, with many young professionals opting for a career in this area. However, globally, early-career professionals often face challenges in this field, such as lack of competency-based training due to a shortage of trainers, low availability of institutions with appropriate infrastructure, and limited resources for adequate training, particularly in developing countries. On the other hand, in developed countries, early career professionals may struggle with mentorship, limited job opportunities, and challenges with establishing a suitable research area.
The International Society of Addiction Medicine (ISAM) New Professionals Exploration, Training & Education (NExT) committee, a global platform for early-career addiction medicine professionals (ECAMPs), conducted an online survey using a modified Delphi-based approach among ECAMPs across 56 countries to assess and understand the need and scope for standardized training, research opportunities, and mentorship. The survey was conducted in 2 phases. A total of 110 respondents participated in Phase I (online key informant survey), and 28 respondents participated in Phase II (online expert group discussions on the three themes identified in Phase I). Most participants agreed with the lack of standardized training, structured mentorship programmes, research funding, and research opportunities in addiction medicine for ECAMPs. There is a need for standardized training programmes, improving research opportunities, and effective mentorship programmes to promote the next generation of addiction medicine professionals and further development to the entire field. The efforts of ISAM-NExT are well-received and give a template of how this gap can be addressed. | addiction medicine |
10.1101/2022.03.25.22272928 | A comparison of the genes and genesets identified by EWAS and GWAS of fourteen complex traits | Identifying the genes, properties of these genes and pathways to understand the underlying biology of complex traits responsible for differential health states in the population is a common goal of epigenome-wide and genome-wide association studies (EWAS and GWAS). GWAS identify genetic variants that effect the trait of interest or variants that are in linkage disequilibrium with the true causal variants. EWAS identify variation in DNA methylation, a complex molecular phenotype, associated with the trait of interest. Therefore, while GWAS in principle will only detect variants within or near causal genes, EWAS can also detect genes that confound the association between a trait and a DNA methylation site, or are reverse causal. Here we systematically compare association EWAS and GWAS results of 14 complex traits (N > 4500). A small fraction of detected genomic regions were shared by both EWAS and GWAS (0-9%). We evaluated if the genes or gene ontology terms flagged by GWAS and EWAS overlapped, and after a multiple testing correction, found substantial overlap for diastolic blood pressure (gene overlap P = 5.2x10-6, term overlap P = 0.001). We superimposed our empirical findings against simulated models of varying genetic and epigenetic architectures and observed that in a majority of cases EWAS and GWAS are likely capturing distinct genesets, implying that genes identified by EWAS are not generally causally upstream of the trait. Overall our results indicate that EWAS and GWAS are capturing different aspects of the biology of complex traits. | epidemiology |
10.1101/2022.03.25.22272942 | Estimating time-dependent infectious contact: a multi-strain epidemiological model of SARS-CoV-2 on the island of Ireland | Mathematical modelling plays a key role in understanding and predicting the epidemiological dynamics of infectious diseases. We construct a flexible discrete-time model that incorporates multiple viral strains with different transmissibilities to estimate the changing infectious contact that generates new infections. Using a Bayesian approach, we fit the model to longitudinal data on hospitalisation with COVID-19 from the Republic of Ireland and Northern Ireland during the first year of the pandemic. We describe the estimated change in infectious contact in the context of government-mandated non-pharmaceutical interventions in the two jurisdictions on the island of Ireland. We take advantage of the fitted model to conduct counterfactual analyses exploring the impact of lockdown timing and introducing a novel, more transmissible variant. We found substantial differences in infectious contact between the two jurisdictions during periods of varied restriction easing and December holidays. Our counterfactual analyses reveal that implementing lockdowns earlier would have decreased subsequent hospitalisation substantially in most, but not all cases, and that an introduction of a more transmissible variant - without necessarily being more severe - can cause a large impact on the health care burden. | epidemiology |
10.1101/2022.03.25.22272942 | Estimating time-dependent infectious contact: a multi-strain epidemiological model of SARS-CoV-2 on the island of Ireland | Mathematical modelling plays a key role in understanding and predicting the epidemiological dynamics of infectious diseases. We construct a flexible discrete-time model that incorporates multiple viral strains with different transmissibilities to estimate the changing infectious contact that generates new infections. Using a Bayesian approach, we fit the model to longitudinal data on hospitalisation with COVID-19 from the Republic of Ireland and Northern Ireland during the first year of the pandemic. We describe the estimated change in infectious contact in the context of government-mandated non-pharmaceutical interventions in the two jurisdictions on the island of Ireland. We take advantage of the fitted model to conduct counterfactual analyses exploring the impact of lockdown timing and introducing a novel, more transmissible variant. We found substantial differences in infectious contact between the two jurisdictions during periods of varied restriction easing and December holidays. Our counterfactual analyses reveal that implementing lockdowns earlier would have decreased subsequent hospitalisation substantially in most, but not all cases, and that an introduction of a more transmissible variant - without necessarily being more severe - can cause a large impact on the health care burden. | epidemiology |
10.1101/2022.03.24.22272899 | Tracking population mental health before and across stages of the COVID-19 pandemic in young adults | The SARS-CoV-2 (COVID-19) pandemic has been associated with worsening mental health. Longitudinal studies have monitored changes in mental health from pre-pandemic levels, identifying critical points for mental health as COVID-19 restrictions evolve. Here we highlight changes in depression and anxiety in the UK from pre-pandemic across four pandemic occasions: April and June 2020, January, and July 2021 - corresponding to changes in COVID-19 restrictions. Data were from >5,000 27-29-year-olds from the Avon Longitudinal Study of Parents and Children (ALSPAC). We found that anxiety almost doubled throughout the pandemic compared to pre-pandemic levels and remained high until July 2021 when COVID-19 restrictions were fully lifted. Depression was lower than pre-pandemic levels in April 2020 but increased as the pandemic evolved until July 2021. Women, those with existing mental/physical health conditions and those with economic hardship were most at risk of sustained poorer mental health across the pandemic. Our results highlight the importance of longitudinal studies for tracking mental health during the COVID-19 pandemic and across virus suppression policy changes. | psychiatry and clinical psychology |
10.1101/2022.03.25.22272947 | The effect of galvanic vestibular stimulation on postural balance in Parkinsons Disease: A systematic review and meta-analysis | People with Parkinsons disease (PD) experience postural imbalance, leading to considerably increased risk of falls. Galvanic Vestibular Stimulation (GVS) is postulated to modulate postural balance in humans and improve it in PD. This systematic review and meta-analysis investigate the effects of GVS on postural balance in PD.
Six separate databases and research registers were searched for cross-over design trials that evaluated the effects of GVS on postural balance in PD. We used standardized mean difference (Hedges g) as a measure of effect size in all studies.
We screened 223 studies, evaluated 14, of which five qualified for the meta-analysis. Among n = 40 patients in five studies (range n= 5 to 13), using a fixed effects model we found an effect size estimate of g = 0.43 (p < 0.001, 95% CI [0.29,0.57]). However, the test for residual heterogeneity was significant (p < 0.001), thus we used a random effects model and found a pooled effect size estimate of 0.62 (p > 0.05, 95% CI [- 0.17, 1.41], I2 = 96.21%). Eggers test was not significant and thus trim and funnel plot indicated no bias. To reduce heterogeneity, we performed sensitivity analysis and by removing one outlier study (n = 7 patients), we found an effect size estimate of 0.16 (p < 0.05, 95% CI [0.01, 0.31], I2 = 0%).
Our meta-analysis found GVS has a favourable effect on postural balance in PD patients, but due to limited literature and inconsistent methodologies, this favourable effect must be interpreted with caution. | neurology |
10.1101/2022.03.24.22272911 | Metabolic associations with stroke, dementia, and imaging markers of cerebral small vessel disease: a comprehensive metabolomics study | BackgroundCerebral small vessel disease is a major cause of ischemic stroke and vascular dementia, which are among the leading causes of death and disability worldwide. Metabolomics can help identify novel risk factors to better understand pathogenesis, predict disease progression and severity, and identify therapeutic targets.
MethodsWe analyzed metabolomics profiles from 118,021 UK Biobank participants with baseline metabolomics measurements (baseline surveys, 2006-2010; latest follow-up, March 2022). We examined cross-sectional associations of 325 metabolites with clinical diagnoses of stroke and dementia and MRI markers of small vessel disease. We also evaluated relationships between metabolites and future risk of stroke and dementia and performed Mendelian randomization to ascertain causal relationships.
ResultsAmong 118,021 participants (54% women; mean recruitment age, 56.5 years), 2,477 stroke and 1,785 dementia events were recorded (median follow-up, 13.1 years). In cross-sectional analyses, lower levels of apolipoproteins, free cholesterol, cholesteryl esters, fatty acids, lipoprotein particle concentrations, phospholipids, and triglycerides were associated with increased white matter microstructural damage on diffusion tensor MRI. Lower levels of amino acids and fatty acids and higher levels of ketone bodies were associated with increased risk of dementia. In longitudinal analyses, lipoprotein subclasses of very large HDL were associated with increased risk of stroke, and acetate, 3-hydroxybutyrate, and relative lipoprotein lipid concentrations were associated with increased risk of dementia. Mendelian randomization analyses identified strong evidence supporting causal relationships for many associations.
Conclusionsbiomarker profiling platform and experimentation In this large-scale metabolomics study, we found multiple metabolites associated with stroke, dementia, and MRI markers of small vessel disease. Further studies may help develop personalized prediction models for patients at increased risk of stroke and dementia and provide insights into mechanistic pathways and future treatment approaches.
Key PointsO_ST_ABSQuestionC_ST_ABSAre metabolites associated with stroke, dementia, and MRI markers of cerebral small vessel disease?
FindingsIn an analysis of individual-participant data from 118,021 participants, we identified 289 metabolites that were significantly associated with stroke, dementia, and MRI markers of small vessel disease.
MeaningMetabolic markers were associated with risk of stroke, dementia, and MRI markers of small vessel disease, which could be used to develop personalized prediction models and novel treatment approaches for patients at increased risk of vascular-related conditions. | neurology |
10.1101/2022.03.23.22272850 | Enhanced Recovery After Surgery reduced length of stay after colorectal surgery in a small rural hospital in Ontario | BackgroundEnhanced Recovery After Surgery (ERAS) programs include preoperative, intraoperative and postoperative clinical pathways to improve quality of patient care while reducing length of stay and readmission. This study assessed the feasibility and outcomes of an ERAS protocol for colorectal surgery implemented over two-years in a small, resource-challenged rural hospital.
Study designA prospective cohort study used retrospectively matched controls to assess the effect of ERAS on LOS in patients undergoing colorectal surgery in a small rural hospital in northern Ontario, Canada. ERAS patients were matched to two patients in the control group based on diagnosis, age and gender. Patients had open or laparoscopic colorectal surgeries, with those in the intervention group treated per ERAS protocol and given instructions on pre- and post-operative self-care.
ResultsMost ERAS patients reported adherence to ERAS protocols prior to surgery. Approximately one quarter of patients chose not to complete the postoperative survey. Of those who completed the survey, adherence to protocol was strongest for chewing gum in the days after surgery. Most patients were sitting in a chair for their afternoon meal by the first day and most were walking down the hallway by the second day. The control and ERAS patient groups did not differ significantly (p[≥]0.07) in age ([Formula]years, sd=13.1), gender (52% male), nor in the Canadian Classification of Health Interventions 5-character code. The control group significantly higher (p<0.001) malignant neoplasm of colon (C18, 69% vs 35%), and significantly lower malignant neoplasm of rectum (C20, 0% vs 5%), relative to the ERAS group. The control group had an average ln-transformed LOS that was significantly longer (exponentiated as 1.7 days) than ERAS patients (t-test, p<0.001).
ConclusionThis study found that ERAS could be implemented in a small rural hospital and provided evidence for a reduced LOS of approximately two days. | gastroenterology |
10.1101/2022.03.24.22272863 | International comparison of the impact of the pandemic and vaccination measures adopted on children and adolescent population | BackgroundThe objectives of this study were to compare the cumulative incidence, hospitalizations and mortality, by country and age group, in child and young people (CYP) from the beginning of the pandemic to January 2022, and to describe the differences and similarities and justification in the measures adopted in relation to CYP vaccination against SARS-CoV-2.
MethodsA descriptive quantitative summary of the available data on the impact of the COVID-19 on children and adolescents (<18y) from 7 countries (Chile, Colombia, Paraguay, Nigeria, Ghana, Spain) or regions (Kocaeli, Turkey), based on official published data was performed. Outcome measures were: available data on incidence, admission to hospital and to intensive care units (ICU), and deaths, by country or region; vaccination plans, including age, type of vaccine and official justification about the proposal.
ResultsAll countries analyzed data showed variable incidence rate, and relatively low ICU hospitalizations and deaths. Vaccines used and age at starting were also variable, i.e. starting at 3-5y in some Latin American countries, while in other countries proposal starts at 15y old. Almost all justifications were based on the idea to promote collective protection, and that vaccination is important as it -directly and indirectly-protect the rest of the population.
ConclusionsThe results reinforce the idea of the urgent need to prioritize globally and equitably distribution of vaccines in the population at greatest risk, and to apply the precautionary principle in CYP before deciding to massively vaccinate it.
What is knownThe child population has less severe infections and seems to transmit the infection less than the adult population.
Published data from the Randomized Clinical Trials (RCT) of vaccines in minors presented short follow-up than in the adult population and basically studied the incidence of infection as the main endpoint
What this study addsMortality in the child population due to COVID-19 since the start of the pandemic has been low in all the countries analyzed
The vaccines used as well as the vaccination guidelines shows high variability in these countries
The results of the study reinforce the need to establish global and equitable mechanisms for the distribution of vaccines and prioritize the population at greatest risk, such as older people.
In the child population, it is necessary to apply the precautionary principle before establishing massive vaccination plans | pediatrics |
10.1101/2022.03.24.22272878 | A Qualitative Study Regarding Messages of the COVID-19 Vaccine from Vaccinated Healthcare Providers and Healthy Adults | 1.BackgroundTo promote the vaccination against COVID-19, person-to-person communication from vaccinated people will play an important role. The objectives of this study are to identify what messages were shared by vaccinated people, and the relationship between these messages and their background.
MethodsThis study was an exploratory and prospective basis with individual interviews. The participants were healthcare providers and healthy adults who were recruited at a vaccination site in Chuo-City, Tokyo. The online interviews were conducted using a semi-structured interview. Based on the Health Belief Model (HBM), the participants were asked about their perspectives on vaccines and what they talked about after their vaccination. The interviews were categorized into each item of the HBM and analyzed using NVivo software.
ResultsDuring August to October 2021, five healthcare providers and seven healthy adults were enrolled in the study. One healthy adult could not be contacted resulting in a total of 11 participants interviewed. Both the healthcare providers and the healthy adults mainly talked about side effects after their vaccination, and to ease the other persons concerns based on their experience. Meanwhile, there were differences in the recommendations for vaccination between the two groups. The healthcare providers were strongly aware of the severity of COVID-19 infection and recommended vaccination to others as a useful measure to suppress becoming severely ill. On the other hand, the healthy adults recommended the vaccine with varying degree depending on their expectations and concerns about the vaccine and external factors such as living with a family member.
ConclusionBoth the healthcare providers and healthy adults shared similar messages to ease the vaccination concerns of others. However, their vaccine recommendation level was varied, which may be influenced not only by expectations and concerns toward the vaccine, but also by external factors such as family members living together. | public and global health |
10.1101/2022.03.23.22272852 | Does contrast-enhancement improve visualisation of lenticulostriate arteries in cerebral small vessel disease using time-of-flight magnetic resonance angiography at 7 Tesla? | Background And Purpose7 Tesla-field-strength (7T) Magnetic Resonance Imaging (MRI) allows the small perforating arteries in the brain to be visualised, and this modality may allow visualisation of the arterial pathology in cerebral small vessel disease (cSVD). Most studies have used standard Time-of-Flight (ToF) Magnetic Resonance Angiography (MRA). Whether the use of contrast enhancement improves perforating artery visualisation at 7T remains unclear.
Materials And MethodsIn a prospective study, we compared standard ToF MRA with contrast-enhanced (CE) ToF MRA at 7T for the visualisation of the lenticulostriate arteries (LSAs). Ten patients with symptomatic lacunar stroke were recruited (mean age, SD, 64{+/-}9.9 years). Visualisation was assessed using a visual rating scale administered by two independent expert readers and length of the LSAs visible.
ResultsVisualisation of the LSAs was improved with CE ToF MRA. The mean Visibility and Sharpness Score was higher for CE ToF MRA over standard ToF MRA (2.55{+/-}0.64 vs 1.75{+/-}0.68; P=0.0008). The mean length of LSA visualised was significantly longer with CE ToF MRA compared to standard ToF MRA (24.4{+/-}4.5 vs 21.9{+/-}4.0 mm; P=0.01).
ConclusionCE ToF MRA offers improved visualisation of the LSAs over standard ToF MRA. The addition of contrast may improve the ability to visualise cerebral small vessel disease arterial pathology. | radiology and imaging |
10.1101/2022.03.25.22272936 | Multilevel Correlates of Abdominal Obesity in Adolescents and Youth Living with HIV in peri-urban Cape Town, South Africa. | BackgroundChronic non-communicable disease comorbidities are a major problem faced by people living with HIV (PLHIV). Obesity is an important factor contributing to such comorbidities and PLHIV face an elevated risk of obesity. However, there is data paucity on the intersection of obesity and HIV in adolescents and youth living with HIV (AYLHIV) in sub-Saharan Africa. We therefore aimed to investigate the prevalence of abdominal obesity and associated multilevel factors in AYLHIV in peri-urban Cape Town, South Africa.
MethodsWe conducted a cross-sectional study enrolling AYLHIV aged 15 - 24 years attending primary healthcare facilities in peri-urban Cape Town in 2019. All measures, except for physical examination measures, were obtained via self-report using a self-administered electronic form. Our outcome of interest was abdominal obesity (waist-to-height ratio [≥] 0.5). We collected individual-level data and data on community, built and food environment factors. Data was summarized using descriptive statistics, stratified by sex. Multilevel logistic regression was conducted to investigate factors associated with abdominal obesity, adjusted for sex and age.
FindingsA total of 87 participants were interviewed, 76% were female and the median age was 20.7 (IQR 18.9-23.0) years. More than two fifths had abdominal obesity (41%; 95% CI: 31.0-51.7%), compared to published rates for young people in the general population (13.7-22.1%). In multilevel models, skipping breakfast (aOR= 5.42; 95% CI: 1.32 - 22.25) was associated with higher odds of abdominal obesity, while daily wholegrain consumption (aOR= 0.20; 95% CI: 0.05 - 0.71) and weekly physical activity (aOR = 0.24; 95% CI: 0.06 - 0.92) were associated with lower odds of abdominal obesity. Higher anticipated stigma was associated with reduced odds of obesity (aOR= 0.58; 95% CI: 0.33 - 1.00). Land-use mix diversity (aOR= 0.52; 95% CI: 0.27 - 0.97), access to recreational places (aOR= 0.37; 95% CI: 0.18 - 0.74), higher perceived pedestrian and traffic safety (aOR= 0.20; 95% CI: 0.05 - 0.80) and having a non-fast-food restaurant within walking distance (aOR= 0.30; 95% CI: 0.10 - 0.93) were associated with reduced odds of abdominal obesity. The main limitations of the study were low statistical power and possible reporting bias from self-report measures.
ConclusionsOur findings demonstrate a high prevalence of abdominal obesity and highlight multilevel correlates of obesity in AYLHIV in South Africa. An intersectoral approach to obesity prevention, intervening at multiple levels is necessary to intervene at this critical life stage. | public and global health |
10.1101/2022.03.21.22272700 | The Impact on Staff of Providing Non-Invasive Advanced Respiratory Support During the Covid-19 Pandemic A Qualitative Study in an Acute Hospital | ObjectivesTo explore the experiences of healthcare workers of providing Non-Invasive Advanced Respiratory Support (NARS) to critically unwell patients with covid-19.
DesignA qualitative study drawing on a social constructionist perspective using thematic analysis of semi-structured interviews.
SettingA single acute UK NHS Trust across two hospital sites.
ParticipantsMultidisciplinary team members in acute, respiratory and palliative medicine.
Results21 nurses, doctors (juniors and consultants) and physiotherapists described the provision of NARS to critically unwell covid-19 patients as extremely challenging. The main themes were of feeling ill prepared and unsupported, a need to balance complex moral actions, a sense of duty to patients and their families. The impact on staff was profound and findings are discussed via a lens of moral injury. Injurious events included staff feeling they had acted in a way that caused harm, failed to prevent harm or had been let down by seniors or the Trust. Participants identified factors that mitigated adverse impact.
ConclusionsAlthough many of the issues described by participants are likely immutable components of healthcare in a pandemic there were several important protective factors that emerged from the data. Experience, debriefing and breaks from covid-19 wards were valuable to participants and successfully achieving a peaceful death for the patient was often viewed as compensation for a difficult journey. These protective factors may provide modelling for future education and support services to help prevent moral injury - or aide in its recovery.
Registrationregistered on the Open Science Framework 10.17605/OSF.IO/XB8YH
Strengths and LimitationsO_LISingle Centre Study
C_LIO_LIThe lead author had pre-existing relationships with study participants
C_LIO_LIThe lead author, under strict supervision, practiced a reflexivity based approach to data collection and analysis with objectivity benchmarking from the second author.
C_LI | palliative medicine |
10.1101/2022.03.25.22272926 | Patterns of presentations of children to emergency departments across Europe and the impact of the COVID-19 pandemic: retrospective observational multinational study. | BackgroundTo investigate the impact of the COVID-19 pandemic and infection prevention measures on children visiting emergency departments across Europe.
MethodsRoutine health data were extracted retrospectively from electronic patient records of children aged <16 years, presenting to 38 emergency departments (ED) in 16 European countries for the period January 2018 - May 2020, using predefined and standardized data domains. Observed and predicted numbers of ED attendances were calculated for the period February 2020 to May 2020. Poisson models and incidence rate ratios (IRR) were used to compare age groups, diagnoses and outcomes.
FindingsReductions in pediatric ED attendances, hospital admissions and high triage urgencies were seen in all participating sites. ED attendances were relatively higher in countries with lower SARS-CoV-2 prevalence (incidence rate ratio (IRR) 2{middle dot}62, 95% CI 2{middle dot}19 to 3{middle dot}13) and in children aged >12 months (12-<24 months IRR 0{middle dot}89, 95% CI 0{middle dot}86 to 0{middle dot}92; 2-<5years IRR 0{middle dot}84, 95% CI 0{middle dot}82 to 0{middle dot}87; 5-<12 years IRR 0{middle dot}74, 95% CI 0{middle dot}72 to 0{middle dot}76; 12-<16 years IRR 0{middle dot}74, 95% CI 0{middle dot}71 to 0{middle dot}77; vs. age <12 months as reference group). The impact on pediatric intensive care admissions (IRR 1{middle dot}30, 95% CI 1{middle dot}16 to 1{middle dot}45) was not as great as the impact on general admissions. Lower triage urgencies were reduced more than higher triage urgencies (urgent triage IRR 1{middle dot}10, 95% CI 1{middle dot}08 to 1{middle dot}12; emergent and very urgent triage IRR 1{middle dot}53, 95% CI 1{middle dot}49 to 1{middle dot}57; vs. non-urgent triage category). Reductions were highest and sustained throughout the study period for children with communicable infectious diseases.
InterpretationReductions in ED attendances were seen across Europe during the first COVID-19 lockdown period. More severely ill children continued to attend hospital more frequently compared to those with minor injuries and illnesses, although absolute numbers fell.
FundingRGN was supported by National Institute of Health Research, award number ACL-2018-021-007.
Trial registryISRCTN91495258 | epidemiology |
10.1101/2022.03.26.22272974 | Deterioration of patients with mental disorders in Denmark coinciding with the invasion of Ukraine | The Russian invasion of Ukraine on February 24, 2022 has led to a humanitarian crisis of immense proportions. In turn, this will, inevitably, also lead to a mental health crisis among those affected by the war - either directly or by proxy. The mental health impact of the war in Ukraine is also likely to affect people beyond the borders of the countries directly involved. Here, we investigated whether Danish patients with mental disorders seem to be affected by the war in Ukraine. Specifically, we searched the Electronic Patient Record system of the Psychiatric Services of the Central Denmark Region in the period from January 1, 2022 to March 8, 2022 for clinical notes containing the word *ukrain* (*irrespective of letters and symbols prior to- or following ukrain). We then manually assessed (read) 100 randomly drawn notes containing *ukrain* to determine whether they described worsening of the mental health/symptoms of the patients that was likely attributable to the war in Ukraine. We identified a total of 16,341 adult patients (57% women, mean age 40 years, SD=18) who were registered with at least one clinical note in the Electronic Patient Record system of the Psychiatric Services of the Central Denmark Region in the period from January 1, 2022 to March 8, 2022. During this period, 567,647 clinical notes were entered into the electronic patient record system. Among these, 502 notes from 369 unique patients contained *ukrain* with a sharp rise in incidence following the Russian invasion of Ukraine on February 24, 2022. Among the 100 randomly drawn clinical notes containing *ukrain* (stemming from 94 unique patients), 62 notes from 58 unique patients described worsening of the mental health/symptoms of the patients that seemed attributable to the war in Ukraine. Although causal inference is challenging in this regard, the results of this study suggest that even individuals remotely distanced from the war in Ukraine may be psychologically affected by it - serving as an early warning sign of the potential width of the negative mental health impact from the war, which will, inevitably, hit the Ukrainian population the hardest. | psychiatry and clinical psychology |
10.1101/2022.03.25.22272965 | Machine Learning Enabled Non-invasive Diagnosis of Nonalcoholic Fatty Liver Disease and Assessment of Abdominal Fat from MRI Data | Nonalcoholic fatty liver disease (NAFLD) is the most rapidly growing contributor to chronic liver disease worldwide with high disease burden and suffers from limitations in diagnosis. Inspired by recent advances in machine learning digital diagnostics, we explored the efficacy of training a neural network to classify high risk NAFLD vs. non-NAFLD patients in the UK Biobank dataset based on proton density fat fraction (PDFF). We compared the performance of several ResNet-derived architectures in the context of whole abdomen MRI, segmented liver and abdomen excluding liver (sans-liver). Non-local ResNet trained on whole abdomen MRI images yielded the highest precision (0.88 for NAFLD) and F1 (0.89 for NAFLD). Furthermore, our work on a second, larger cohort explored multi-task learning and the relationship among PDFF, visceral adipose tissue (VAT) and abdominal subcutaneous adipose tissue (ASAT). Interestingly, multi-task learning experiments found a decline in performance for PDFF when combined with VAT and ASAT. We address this deterioration using Multi-gate Mixture-of-Experts (MMoE) approaches. Our work opens the possibility for using a non-invasive deep learning-based diagnostic for NAFLD, and directly enables clinical and genomic research using a larger cohort of potential NAFLD patients in the UK Biobank study. | radiology and imaging |
10.1101/2022.03.25.22272967 | Plasma cell-free DNA as a prognostic biomarker in small cell lung cancer patients | BackgroundLack of biomarkers for treatment selection and monitoring in small-cell lung cancer (SCLC) patients with the limited therapeutic options, result in poor outcomes. Therefore, new prognostic biomarkers are needed to improve their management. The prognostic value of cell-free DNA (cfDNA) and circulating tumor cells (CTCs) have been less explored in SCLC.
MethodsWe quantified cfDNA in 46 SCLC patients at different times during therapy. Moreover, CTCs were analyzed in 21 patients before therapy onset using CellSearch(R) system. Both biomarkers were associated with patients outcomes and a prognostic model was developed.
ResultsHigh cfDNA levels before therapy were associated with shorter progression-free survival and overall survival. Furthermore, changes in cfDNA levels between baseline and 3 weeks and cfDNA levels at progression disease were also associated with patients outcomes. Multivariate analyses confirmed the independence of cfDNA levels as a prognostic biomarker. Finally, the three-risk category prognostic model developed included ECOG Performance Status, gender and baseline cfDNA levels was associated with a higher risk of progression and death.
ConclusionsWe confirmed the prognostic utility of cfDNA in SCLC patients before and during therapy. Our novel risk prognostic model in clinical practice will allow to identify patients who could benefit with actual therapies. | oncology |
10.1101/2022.03.26.22272977 | RNAseq analysis reveals prominent and distinct expressed variants that are related to disease severity in SARS-CoV-2 infected patients with mild-to-severe disease | BackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to be a significant public health challenge globally. SARS-CoV-2 is a novel virus, and the understanding of what constitutes expressed RNAseq variants in healthy, convalescent, severe, moderate and to those admitted at the Intensive Care Unit (ICU) is yet to be presented. We set to characterize the different expressed RNAseq variants in healthy, severe, moderate, ICU, and convalescent individuals.
Materials and methodsThe bulk RNA sequencing data with identifier PRJNA639275 was download from Sequence Reads Archive (SRA). The individuals were divided into: (i) healthy, n=34, severe, n=16, ICU, n=8, moderate, n=8, and convalescent, n=2. Fastqc version 0.11.9 and Cutadapt version 3.7 was used to asses the reads quality and to perform adapter trimming respectively. STAR was using to align reads to the reference genome and GATK best practice was followed to call variants using rnavar pipeline, part of the nf-core pipelines.
ResultsOur analysis demonstrated that convalescent, moderate, severe and those admitted to the ICU are characterized by different sets of unique RNAseq variants. The data shows that the individuals who recover from SARS-CoV-2 infection have the same set of expressed variants as in the healthy controls. We showed that the healthy and SARS-CoV-2 infected individuals display different sets of expressed varinats which is characteristic of the patient phenotype.
ConclusionThe individuals with severe, moderate, those admitted at the ICU, and convalescent individuals display a unique set of variants. The findings in this study will inform the test kit development and SARS-CoV-2 patients classification to enhance management and control of SARS-CoV-2 infection in our population. | health informatics |
10.1101/2022.03.23.22272771 | Dynamics of humoral and cellular immune responses after homologous and heterologous SARS-CoV-2 vaccination with ChAdOx1 nCoV-19 and BNT162b2 | Vaccines are the most important means to overcome the SARS-CoV-2 pandemic. They induce specific antibody and T-cell responses but it remains open how well vaccine-induced immunity is preserved over time following homologous and heterologous immunization regimens. Here, we compared the dynamics of humoral and cellular immune responses up to 5 months after homologous or heterologous vaccination with either ChAdOx1-nCoV-19 (ChAd) or BNT162b2 (BNT) or both. Antibody responses significantly waned after vaccination, irrespective of the regimen. The capacity to neutralize SARS-CoV-2 - including variants of concern such as Delta or Omicron - was superior after heterologous compared to homologous BNT vaccination, both of which resulted in longer-lasting humoral immunity than homologous ChAd immunization. T-cell responses showed less waning irrespective of the vaccination regimen. These findings demonstrate that heterologous vaccination with ChAd and BNT is a potent approach to induce long-term humoral and cellular immune protection.
Research in contextO_ST_ABSEvidence before this studyC_ST_ABSDue to some rare severe side effects after the administration of the adenoviral vaccine, ChAdOx1 nCoV-19, many countries recommended a heterologous vaccination scheme including mRNA vaccines like BNT162b2 for the second dose. We performed a PubMed search (with no restrictions on time span) using the search terms "SARS-CoV-2" and "heterologous vaccination" and obtained 247 results. Only a fraction of manuscripts included direct comparisons of patient cohorts that received either a heterologous or a homologous vaccination regimen. Of those, the vast majority investigated only short-term immunogenicity after vaccination. Thus, little is known about the long-term maintenance of immunity by heterologous compared to homologous vaccination.
Added value of this studyWe add a very comprehensive and comparative study investigating heterologous and homologous vaccination regimens early and late after vaccination. Key features include the number of patients (n = 473), the number of vaccination cohorts (n= 3), the fact that samples were derived from three independent study centers and comparative analyses were performed at two independent study centers, as well as in-depth investigation of humoral and T cellular immunity.
Implications of all the available evidenceThe recent data creates a line of evidence that heterologous vaccination, compared to homologous vaccination regimens, results in at least non-inferior maintenance of humoral and cellular immunity. The enhanced understanding of immunity induced by individual vaccination regimens is crucial for further recommendations regarding the necessity, timing and choice of additional vaccinations and public health policies. | infectious diseases |
10.1101/2022.03.26.22272766 | Analysis of humoral immunity against emerging SARS-CoV-2 variants: a population-based prevalence study in Yokohama, Japan | BackgroundLittle is known about the population prevalence of antibodies against emerging immune escape variants of SARS-CoV-2.
MethodsA population-based prevalence study was conducted in Yokohama City, the most populous municipality of Japan. Quantitative measurements of immunoglobulin G against SARS-CoV-2 spike protein (SP-IgG) and qualitative measurements of neutralization antibodies against the Omicron BA.1 and BA.2 variants were performed.
ResultsOf 6,000 randomly selected residents aged 20-74, 1,277 participated in the study during a period from January 30 to February 28, 2022. Of them, 3% had prior diagnosis of COVID-19, 96% received at least two-doses of SARS-CoV-2 vaccines, and 94% were positive for SP-IgG. The positive rates of neutralizing antibodies were 28% to Omicron BA.1 and BA.2 variants in a random sample of 10% of participants (n=123) and 100% to BA.1 and BA.2 among participants who received the third vaccination at least 7 days before (n=66).
ConclusionsIn this population-based prevalence study in Japan, most had SP-IgG antibodies but the overall neutralizing antibody positive rate was 28% against the Omicron BA.1 and BA.2 variants. The population-level insufficient humoral immunity against the Omicron variants may explain the outbreak of COVID-19 during this period in Japan. | infectious diseases |
10.1101/2022.03.26.22272984 | Monitoring of the SARS-CoV-2 Omicron BA.1/BA.2 variant transition in the Swedish population reveals higher viral quantity in BA.2 cases | Throughout the SARS-CoV-2 pandemic, multiple waves of variants of concern have swept across populations, leading to a chain of new and yet more contagious lineages dominating COVID-19 cases. Here, we tracked the remarkably rapid shift from Omicron BA.1 to BA.2 sub-variant dominance in the Swedish population during January-March 2022. By analysis of 174,933 clinical nasopharyngeal swab samples using a custom variant-typing RT-PCR assay, we uncover nearly two-fold higher levels of viral RNA in cases with Omicron BA.2. Importantly, increased viral load in the upper pharynx upon BA.2 infection may provide part of the explanation why Omicron BA.2 is more transmissible and currently outcompetes the BA.1 variant across populations. | infectious diseases |
10.1101/2022.03.26.22272972 | Damaging missense variants in IGF1R implicate a role for IGF-1 resistance in the aetiology of type 2 diabetes | Type 2 diabetes (T2D) is a chronic metabolic disorder with a significant genetic component. While large-scale population studies have identified hundreds of common genetic variants associated with T2D susceptibility, the role of rare (minor allele frequency < 0.1%) protein coding variation is less clear. To this end, we performed a gene burden analysis of 18,691 genes in 418,436 (n=32,374 T2D cases) individuals sequenced by the UK Biobank (UKBB) study to assess the impact of rare genetic variants on T2D risk. Our analysis identified T2D associations at exome-wide significance (P < 6.9x10-7) with rare, damaging variants within previously identified genes including GCK, GIGYF1, HNF1A, and TNRC6B. In addition, individuals with rare, damaging missense variants in the genes ZEB2 (N=31 carriers; OR=5.5 [95% CI=2.5-12.0]; p=6.4x10-7), MLXIPL (N=245; OR=2.3 [1.6-3.2]; p=3.2x10-7), and IGF1R (N=394; OR=2.4 [1.8-3.2]; p=1.3x10-10) have higher risk of T2D. Carriers of damaging missense variants within IGF1R were also shorter (-2.2cm [-1.8-2.7]; p=1.2x10-19) and had higher circulating protein levels of insulin-like growth factor-1 (IGF-1; 2.3 nmol/L [1.7-2.9] p=2.8x10-14), indicating relative IGF-1 resistance. A likely causal role of IGF-1 resistance on T2D was further supported by Mendelian randomisation analyses using common variants. Our results increase our understanding of the genetic architecture of T2D and highlight a potential therapeutic benefit of targeting the Growth Hormone/IGF-1 axis. | endocrinology |
10.1101/2022.03.23.22272167 | Epidemiologic Assessment of Pediatric Inflammatory Bowel Disease Presentation in NYC During COVID-19 | SARS-nCoV2 may have increased capacity to generate autoimmune disease; multiple reports suggest increased risk of Type 1 Diabetes, and case reports suggest other autoimmune linkages. Inflammatory Bowel Disease (IBD) pathogenesis appears to be a mix of genetic susceptibility, microbial populations, and immune triggers such as infections. Given the perceived role of infection in pathogenesis, decreased incidence of all infections during the pandemic secondary to non-pharmaceutical interventions should decrease IBD incidence rates. The aim of this study was to evaluate the association between the Covid-19 pandemic and IBD presentation in NYC using data from new diagnoses at a consortium of institutions.
Using EMR systems all diagnoses at 4 collaborating institutions were retrieved from 2015-2021. We fit time series model (ARIMA) to the quarterly number of cases of each disease for January 2016-March 2020 and forecast the subsequent 21 months. We not only did not observe a decline in pediatric IBD secondary to absent viral illness but noted a statistically significant increase in Crohns Disease approximately 6 months after the initial 2020 COVID wave in NYC, and trends suggesting increases overall in IBD diagnoses above the existing trend towards increased disease presentation that pre-dated the pandemic. This data suggests that there may be a linkage between SARS-nCoV2 infection rates and subsequent pediatric IBD presentation, warranting further evaluation in the aftermath of the Omicron wave. | gastroenterology |
10.1101/2022.03.23.22272703 | Service-user experiences of an integrated psychological intervention for depression or anxiety and tobacco smoking in IAPT: A qualitative investigation into mechanisms of change in quitting smoking | BackgroundHigh smoking prevalence leads to increased morbidity and mortality in individuals with depression/anxiety. Integrated interventions targeting both smoking and mood have been found to be more effective than those targeting smoking alone, but the mechanisms of change of these integrated interventions have not been investigated.
AimsThis qualitative study aimed to investigate participants subjective experiences of the mechanisms underlying change in smoking behaviour following an integrated CBT-based intervention for smoking cessation and depression/anxiety.
MethodsThis study was embedded within an ongoing randomised controlled acceptability and feasibility trial (http://www.isrctn.com/ISRCTN99531779). Semi-structured interviews were conducted with 15 IAPT service users and data were analysed using thematic analysis.
ResultsFive themes were identified: (1) acquiring an increased awareness of smoking patterns, (2) developing individualised strategies, (3) practitioner style as "supportive but not lecture-y" (4) importance of regular sessions, and (5) having the opportunity to access intervention at "the right time".
ConclusionsThese findings further our understanding of the mechanisms of change towards smoking cessation in this integrated intervention and highlight the need to emphasise and embed these components in manualised interventions to optimise therapeutic benefits and reduce smoking prevalence in people with depression/anxiety.
Relevance statementThis study qualitatively investigated mechanisms underlying change in smoking behaviour following an integrated intervention for depression/anxiety and smoking cessation. Research shows interventions integrating smoking cessation and mood management are more effective than smoking cessation interventions alone; however further investigation is needed to understand mechanisms of change for integrated interventions. The current results identified key factors that were important for participants in the integrated intervention to reduce smoking. An improved understanding of mechanisms underlying change in smoking behaviour helps to identify therapist characteristics and treatment components that improve therapeutic outcomes which future research could investigate using a randomised controlled trial design. | psychiatry and clinical psychology |
10.1101/2022.03.23.22269760 | Infection Prevention and Control practices; an exploratory qualitative study of experiences of health care providers and support staff at the University Teaching Hospital, Lusaka, Zambia | BackgroundInfection Prevention and Control is a public health concern to abate Hospital Acquired Infections. Hospital Acquired Infections are known to complicate clinical care, increase length of stay in hospitals and particularly have disturbing effects on patients recovery as well as devastating effects on health care facilities, especially in low resource settings. However, with effective infection prevention practices, the Microorganisms can be eradicated through proper hand hygiene practices of the health workers and proper waste management and disposal/adequate environmental sanitation.
We explored the experiences of health care providers and support staffing infection prevention practices in selected clinical areas at the University Teaching Hospital, in Lusaka.
Material and MethodsThis was a qualitative study that used an exploratory research design. The exploratory design allowed the participants to give in-depth narratives from their work environments as well as enabled the researcher to observe their Infection Prevention Practices. The observations provided an opportunity to make varied conclusions on compliance to infection prevention practices. The researcher collected data using an interview guide from the thirty (30) study respondents. Observations were conducted in their work environments to strengthen the conclusions made. Audio recordings were transcribed verbatim and then imported into Nvivo Version 11 for data management and analysis. Thematic analysis guided the conclusions made in the study.
ResultsThree main themes emerged from the data analyzed: These were existing guidelines on selected Infection Prevention and Control guidelines; Knowledge and use of the Infection Prevention and Control guidelines, and compliance to Infection Prevention and Control guidelines by health care providers and support staff. The participants demonstrated good understanding of the benefits of observing standard IPC guidelines in the workplace, barriers to compliance were reported in almost all the sites. Staff turnover, limitations in infrastructural, and heavy clinical workloads led to lapses in compliance with Infection Prevention Practices.
ConclusionThe study recommends the setting up of an effective and efficient Infection Prevention and Control Committee at the University Teaching Hospital. The committee should oversee the proper functioning of all safety and occupational Health activities and compliance to all infection prevention and control guidelines in the clinical areas and hospital environment by ensuring effective hand hygiene practices using elbow-operated taps and proper medical waste disposal starting with the use of foot-operated bins and compliance to all existing infection prevention guidelines in all clinical areas within the hospital.. | public and global health |
10.1101/2022.03.23.22270017 | Serological Response to Three, Four and Five Doses of SARS-CoV-2 Vaccine in Kidney Transplant Recipients | Mortality from COVID-19 among kidney transplant recipients (KTR) is high, and their response to three vaccinations against SARS-CoV-2 is strongly impaired.
We retrospectively analyzed serological response of up to five doses of SARS-CoV-2 vaccine in KTR from December 27, 2020, until December 31, 2021. Particularly, the influence of different dose adjustment regimens for mycophenolic acid (MPA) on serological response to fourth vaccination was analyzed.
In total, 4.277 vaccinations against SARS-CoV-2 in 1.478 patients were analyzed. Serological response was 19.5% after 1.203 basic immunizations, and increased to 29.4%, 55.6%, and 57.5% in response to 603 third, 250 fourth and 40 fifth vaccinations, resulting in a cumulative response rate of 88.7%.
In patients with calcineurin inhibitor and MPA maintenance immunosuppression, pausing MPA and adding 5 mg prednisolone equivalent before the fourth vaccination increased serological response rate to 75% in comparison to no dose adjustment (52%) or dose reduction (46%). Belatacept-treated patients had a response rate of 8.7% (4/46) after three vaccinations and 12.5% (3/25) after four vaccinations.
Except for belatacept-treated patients, repeated SARS-CoV-2 vaccination of up to five times effectively induces serological response in kidney transplant recipients. It can be enhanced by pausing MPA at the time of vaccination. | nephrology |
10.1101/2022.03.23.22272674 | Nature prescriptions: a scoping review with a nested meta-analysis | Background"Nature prescriptions" are gaining popularity as a form of social prescribing and in response to calls for sustainable healthcare. Our review and meta-analysis appraised evidence of effectiveness of nature prescriptions on various health outcomes. In doing so, we sought to determine the factors that are critical for the success of nature prescriptions, based on Social Cognitive Theory.
MethodsThis is a scoping review with a nested meta-analysis for a subset of outcomes. Five databases were searched up to July 25, 2021. Randomised and non-randomised controlled studies featuring a nature prescription (i.e. an instruction or organised programme, by a health or social provider, to promote spending time in nature) are included. All health outcomes are eligible, but only key pre-specified outcomes are qualified for meta-analysis. Two reviewers independently conducted all steps of study selection; one reviewer conducted data collection and risk of bias assessment. Summary data was extracted from published reports for analysis. Random-effect models for meta-analysis were conducted using Review Manager 5.4.1.
FindingsWe identified 86 unique studies (116 reports), of which 26 studies contributed data to meta-analysis. Compared to control, nature prescription programmes resulted in a greater reduction in systolic blood pressure (MD = -4{middle dot}9mmHg [-9{middle dot}6 to -0{middle dot}1], I2=65%) and diastolic blood pressure (MD = -3{middle dot}6mmHg [-7{middle dot}4 to 0{middle dot}1], I2=67%). They also had a moderate-to-large effect on depression scores (SMD=0{middle dot}5 [0{middle dot}2 to 0{middle dot}8], I2=79%) and anxiety score (SMD=0{middle dot}6 [0{middle dot}1 to 1{middle dot}2], I2=90%). Lastly, they resulted in a greater increase in daily step counts (MD = 900 steps [790-1010], I2=0%), but did not improve weekly time of moderate physical activities (MD = 25{middle dot}9 minutes [-10{middle dot}3 to 62{middle dot}1], I2=53%). Most studies have moderate to high risk of bias, principally due to non-blinding nature of the interventions, small sample size and lack of analysis plan to rule out risks of bias.
InterpretationNature prescription programmes may provide cardiometabolic and mental health benefits and increase physical activity. Effective nature prescription programmes can select from a range of natural settings, activities and might be implemented via social and community channels, besides health providers. The Social Cognition Theory is useful in designing future nature prescription programmes.
FundingThis work was supported by the Hort Frontiers Green Cities Fund, part of the Hort Frontiers strategic partnership initiative developed by Hort Innovation, with co-investment from the University of Wollongong (UOW) Faculty of Social Sciences, the UOW Global Challenges initiative and contributions from the Australian Government (project number #GC15005). T.A-B. was supported by a National Health and Medical Research Council Boosting Dementia Research Leader Fellowship (#1140317). X.F. was supported by a National Health and Medical Research Council Career Development Fellowship (#1148792).
O_TEXTBOXPanel: Research in context
Evidence before this studyExtensive evidence indicates contact with nature is associated with social, mental and physical health. However, little evidence exists on the effectiveness of nature prescriptions, which involve a health provider (e.g. general practitioner) recommending a patient to spend a fixed amount of time a week in a natural setting (e.g. a park). Other studies have attempted to evaluate the benefits of food prescription or green prescription programmes, which do not necessarily involve nature exposure. Only one systematic review on nature prescriptions has been conducted to date, which is a qualitative review without meta-analysis. The review concluded that the evidence (studies up to June 2019) was too sparse to discern any clear evidence of health impacts. There was insufficient information to assess the risk of bias or quality of evidence in the review. Moreover, the review included only nature prescriptions dispensed in outpatient settings, which left out prescription programmes implemented by other institutions, such as welfare centres, social services, universities or workplaces.
Added value of this studyOur review is the first to provide comprehensive appraisal including meta-analysis of the effectiveness of nature prescription programs on multiple health outcomes. The scoping review identified a range of promising nature-based interventions that were dispensed outside the clinic setting and did not self-label as a nature prescription, but would be effective as one. The nested meta-analyses on key outcomes demonstrated positive benefits on blood pressure, symptoms of depression and anxiety, and physical activity levels.
Implications of all the available evidenceOur findings suggest that an effective nature prescription programme can select from a range of natural settings, activities and can be implemented via social and community channels, in addition to health providers. In addition, we also demonstrated that the Social Cognition Theory framework is useful in designing future nature prescription programmes.
C_TEXTBOX | occupational and environmental health |
10.1101/2022.03.24.22271670 | Study Protocol for a Phase III Randomised Controlled Trial of Sailuotong (SLT) for Vascular Dementia and Alzheimers Disease with Cerebrovascular Disease | BackgroundVascular dementia (VaD) accounts for 15-20% of all dementia cases. It is a syndrome of acquired cognitive impairment with a complex pathophysiological basis. A novel herbal formulation (Sailuotong; SLT) consisting of Panax ginseng, Ginkgo biloba and Crocus sativus extracts was developed to treat VaD. Preclinical animal studies found significant improvements in memory and in pathogenic biochemical parameters. Appropriate safety of SLT was shown in acute and chronic toxicity studies, and early clinical trials of SLT demonstrated enhancements in cognition in VaD patients. A fully powered study with a long intervention period is needed to confirm the efficacy and safety of this novel intervention.
MethodsA rigorous phase III clinical trial was developed with the aim of recruiting 238 patients diagnosed with mild to moderate probable VaD, or VaD mixed with Alzheimers disease (where cerebrovascular disease is the clinical dominant contributor to dementia, abbreviated as CVD+AD). Using a permuted block strategy, participants will be randomly allocated to receive SLT (120 mg bd) or placebo capsules for an intervention period of 52 weeks and will be followed-up for an additional 13 weeks. The primary outcome measures are the Vascular Dementia Assessment Scale-cognitive subscale and Alzheimers Disease Cooperative Study-Activities of Daily Living scale. Secondary outcome measures include the Clinicians Interview Based Impression of Change-Plus, CLOX, EXIT-25, Neuropsychiatric Inventory-Clinician rating scale, and Dementia Quality of Life questionnaire. Safety is assessed through adverse event reports and liver, renal, and coagulation studies.
DiscussionPrimary and secondary outcome measures will be compared between treatment and placebo groups, using intention to treat and per protocol analyses. We hypothesise that a 52-week treatment of SLT will be clinically effective and well tolerated in participants with VaD or AD+CVD. This project will provide vital efficacy and safety data for this novel treatment approach to VaD.
Trial registrationAustralian New Zealand Clinical Trials Registry (ANZCTR), ACTRN 12616000057482. Registered on 20 January 2016. https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=369471&isReview=true | geriatric medicine |
10.1101/2022.03.24.22272090 | Machine Learning techniques for the diagnosis of Schizophrenia based on Event Related Potentials | AntecedentThe diagnosis of schizophrenia could be enhanced with objective neurophysiological biomarkers, such as the event related potential features in conjunction with machine learning procedures. A previous work extracted features from event related responses to three oddball paradigms (auditory and visual P300, and mismatch negativity) for the discrimination of schizophrenic patients. They used several classifiers: Naive Bayes, Support Vector Machine, Decision Tree, Adaboost and Random Forest. The best accuracy was obtained with Random Forest (84.7%).
ObjectiveThe aim of this study was to examine the efficacy of Multiple Kernel Learning classifiers and Boruta feature selection method exploring different features for single-subject classification between schizophrenia patients and healthy controls.
MethodsA cohort of 54 schizophrenic subjects and 54 healthy control subjects were studied. Three sets of features related to the event related potentials signal were calculated: Peak related features, Peak to Peak related features and Signal related features. The Boruta feature selection algorithm was used to evaluate its impact on classification accuracy. A Multiple Kernel Learning algorithm was applied to address schizophrenia detection.
ResultsWe obtained a classification accuracy of 83% using Multiple Kernel Learning classifier with the whole dataset. This result in accuracy triangulates previous work and shows that the differences between schizophrenic patients and controls are robust even when different classifiers are used. Appling the Boruta feature selection algorithm a classification accuracy of 86% was yielded. The variables that contributed most to the classification were mainly related to the latency and amplitude of the auditory P300.
ConclusionThis study showed that Multiple Kernel Learning can be useful in distinguishing between schizophrenic patients and controls. Moreover, the combination with the Boruta algorithm provides an improvement in classification accuracy and computational cost. | health informatics |
10.1101/2022.03.24.22272871 | Detection and prevalence of SARS-CoV-2 co-infections during the Omicron variant circulation, France, December 2021 - February 2022 | In Dec 2021-Feb 2022, an intense and unprecedented co-circulation of SARS-CoV-2 variants with high genetic diversity raised the question of possible co-infections between variants and how to detect them. Using 11 mixes of Delta:Omicron isolates at different ratios, we evaluated the performance of 4 different sets of primers used for whole-genome sequencing and we developed an unbiased bioinformatics method which can detect all co-infections irrespective of the SARS-CoV-2 lineages involved. Applied on 21,387 samples collected between weeks 49-2021 and 08-2022 from random genomic surveillance in France, we detected 53 co-infections between different lineages. The prevalence of Delta and Omicron (BA.1) co-infections and Omicron lineages BA.1 and BA.2 co-infections were estimated at 0.18% and 0.26%, respectively. Among 6,242 hospitalized patients, the intensive care unit (ICU) admission rates were 1.64%, 4.81% and 15.38% in Omicron, Delta and Delta/Omicron patients, respectively. No BA.1/BA.2 co-infections were reported among ICU admitted patients. Although SARS-CoV-2 co-infections were rare in this study, their proper detection is crucial to evaluate their clinical impact and the risk of the emergence of potential recombinants. | infectious diseases |
10.1101/2022.03.24.22272768 | Local CCL18 and CCL21 expand lung fibrovascular niches and recruit lymphocytes, leading to tertiary lymphoid structure formation in prolonged COVID-19 | Post-acute lung sequelae of COVID-19 are challenging many survivors across the world, yet the mechanisms behind are poorly understood. Our results delineate an inflammatory cascade of events occurring along disease progression within fibrovascular niches. It is initiated by endothelial dysfunction, followed by heme scavenging of CD163+ macrophages and production of CCL18. This chemokine synergizes with local CCL21 upregulation to influence the stromal composition favoring endothelial to mesenchymal transition. The local immune response is further modulated via recruitment of CCR7+ T cells into the expanding fibrovascular niche and imprinting an exhausted, T follicular helper-like phenotype in these cells. Eventually, this culminates in the formation of tertiary lymphoid structures, further perpetuating chronic inflammation. Thus, our work presents misdirected immune-stromal interaction mechanisms promoting a self-sustained and non-resolving local immune response that extends beyond active viral infection and leads to profound tissue repurposing and chronic inflammation. | allergy and immunology |
10.1101/2022.03.23.22272791 | Validation of AI-based software for objectification of conjunctival provocation test results in routine examinations and clinical studies | Abstracts1. BackgroundProvocation tests are widely used in allergology to objectively reveal patients sensitivity to specific allergens. The objective quantification of an allergic reaction is a crucial characteristic of the tests. Due to the absence of objective quantitative measurements the conjunctival provocation test (CPT) is a less frequently used method despite its sensitivity and simplicity. We developed a new method AllergoEye based on AI for quantitative evaluation of conjunctival allergic reactions and validated it in a clinical study.
2. MethodsAllergoEye was implemented as a two component system. The first component is based on an Android smartphone camera for imaging the patients eye and the second one is PC based for image analysis and quantification. For AllergoEye validation an open-label, prospective, monocentric study was carried out on 41 patients. Standardized CPT was performed with sequential titration of grass allergen in 4 dilutions with the reaction evaluated by subjective/qualitative symptom scores and by quantitative AllergoEye scores.
3. ResultsAllergoEye demonstrated high sensitivity (98%) and specificity (90%) as compared with human-estimated allergic reaction. Tuning cut-off threshold allowed to increase the specificity of AllergoEye to 97%, where correlation between detected sensitivity to allergen and sIgE CAP-class becomes obvious. Strikingly, such correlation was not found with sensitivity to allergen detected by subjective and qualitative symptom scores.
4. ConclusionClinical validation demonstrated that AllergoEye is a sensitive and efficient instrument for objective measurement of allergic reactions in CPT for clinical studies as well as for routine therapy control. | allergy and immunology |
10.1101/2022.03.23.22272791 | Validation of AI-based software for objectification of conjunctival provocation test results in routine examinations and clinical studies | Abstracts1. BackgroundProvocation tests are widely used in allergology to objectively reveal patients sensitivity to specific allergens. The objective quantification of an allergic reaction is a crucial characteristic of the tests. Due to the absence of objective quantitative measurements the conjunctival provocation test (CPT) is a less frequently used method despite its sensitivity and simplicity. We developed a new method AllergoEye based on AI for quantitative evaluation of conjunctival allergic reactions and validated it in a clinical study.
2. MethodsAllergoEye was implemented as a two component system. The first component is based on an Android smartphone camera for imaging the patients eye and the second one is PC based for image analysis and quantification. For AllergoEye validation an open-label, prospective, monocentric study was carried out on 41 patients. Standardized CPT was performed with sequential titration of grass allergen in 4 dilutions with the reaction evaluated by subjective/qualitative symptom scores and by quantitative AllergoEye scores.
3. ResultsAllergoEye demonstrated high sensitivity (98%) and specificity (90%) as compared with human-estimated allergic reaction. Tuning cut-off threshold allowed to increase the specificity of AllergoEye to 97%, where correlation between detected sensitivity to allergen and sIgE CAP-class becomes obvious. Strikingly, such correlation was not found with sensitivity to allergen detected by subjective and qualitative symptom scores.
4. ConclusionClinical validation demonstrated that AllergoEye is a sensitive and efficient instrument for objective measurement of allergic reactions in CPT for clinical studies as well as for routine therapy control. | allergy and immunology |
10.1101/2022.03.24.22272915 | Inconsistent directions of change in case severity across successive SARS-CoV-2 variant waves suggests an unpredictable future | ObjectiveTo determine how the severity of successively dominant SARS-CoV-2 variants has changed over the course of the COVID-19 pandemic.
DesignProspective cohort analysis.
SettingCommunity- and hospital- sequenced COVID-19 cases in the NHS Greater Glasgow and Clyde (NHS GG&C) Health Board (1.2 million people).
ParticipantsAll sequenced non-nosocomial adult COVID-19 cases in NHS GG&C identified to be infected with the relevant SARS-CoV-2 lineage during the following analysis periods. B.1.177/Alpha analysis: 1st November 2020 - 30th January 2021 (n = 1640). Alpha/Delta analysis: 1st April - 30th June 2021 (n = 5552). AY.4.2 Delta/non-AY.4.2 Delta analysis: 1st July - 31st October 2021 (n = 9613). Non-AY.4.2 Delta/Omicron analysis: 1st - 31st December 2021 (n = 3858).
Main outcome measuresAdmission to hospital, admission to ICU, or death within 28 days of first positive COVID-19 test
ResultsIn the B.1.177/Alpha analysis, 300 of 807 (37.2%) B.1.177 cases were recorded as hospitalised or having a more severe outcome, compared to 232 of 833 (27.9%) Alpha cases. After adjusting for the following covariates: age, sex, time of positive test, comorbidities and partial postcode, the cumulative odds ratio was 1.51 (95% central credible interval 1.08-2.11) for Alpha versus B.1.177. In the Alpha/Delta analysis, 113 of 2104 (5.4%) Alpha cases were recorded as hospitalised or having a more severe outcome, compared to 230 of 3448 (6.7%) Delta cases. After adjusting for the above covariates plus number of vaccine doses and reinfection, the cumulative odds ratio was 2.09 (95% central credible interval 1.42-3.08) for Delta versus Alpha. In the non-AY.4.2 Delta/AY.4.2 Delta analysis, 845 of 8644 (9.8%) non-AY.4.2 Delta cases were recorded as hospitalised or having a more severe outcome, compared to 101 of 969 (10.4%) AY.4.2 Delta cases. After adjusting for the previously stated covariates, the cumulative odds ratio was 0.99 (95% central credible interval 0.76-1.27) for AY.4.2 Delta versus non-AY.4.2 Delta. In the non-AY.4.2 Delta/Omicron analysis, 30 of 1164 (2.6%) non-AY.4.2 Delta cases were recorded as hospitalised or having a more severe outcome, compared to 26 of 2694 (1.0%) Omicron cases. After adjusting for the previously listed covariates, the median cumulative odds ratio was 0.49 (95% central credible interval 0.22-1.06) for Omicron versus non-AY.4.2 Delta.
ConclusionsThe direction of change in disease severity between successively emerging SARS-CoV-2 variants of concern was inconsistent. This heterogeneity in virulence between variants, coupled with independent evolutionary emergence, demonstrates that severity associated with future SARS-CoV-2 variants is inherently unpredictable. | epidemiology |
10.1101/2022.03.24.22272915 | Inconsistent directions of change in case severity across successive SARS-CoV-2 variant waves suggests an unpredictable future | ObjectiveTo determine how the severity of successively dominant SARS-CoV-2 variants has changed over the course of the COVID-19 pandemic.
DesignProspective cohort analysis.
SettingCommunity- and hospital- sequenced COVID-19 cases in the NHS Greater Glasgow and Clyde (NHS GG&C) Health Board (1.2 million people).
ParticipantsAll sequenced non-nosocomial adult COVID-19 cases in NHS GG&C identified to be infected with the relevant SARS-CoV-2 lineage during the following analysis periods. B.1.177/Alpha analysis: 1st November 2020 - 30th January 2021 (n = 1640). Alpha/Delta analysis: 1st April - 30th June 2021 (n = 5552). AY.4.2 Delta/non-AY.4.2 Delta analysis: 1st July - 31st October 2021 (n = 9613). Non-AY.4.2 Delta/Omicron analysis: 1st - 31st December 2021 (n = 3858).
Main outcome measuresAdmission to hospital, admission to ICU, or death within 28 days of first positive COVID-19 test
ResultsIn the B.1.177/Alpha analysis, 300 of 807 (37.2%) B.1.177 cases were recorded as hospitalised or having a more severe outcome, compared to 232 of 833 (27.9%) Alpha cases. After adjusting for the following covariates: age, sex, time of positive test, comorbidities and partial postcode, the cumulative odds ratio was 1.51 (95% central credible interval 1.08-2.11) for Alpha versus B.1.177. In the Alpha/Delta analysis, 113 of 2104 (5.4%) Alpha cases were recorded as hospitalised or having a more severe outcome, compared to 230 of 3448 (6.7%) Delta cases. After adjusting for the above covariates plus number of vaccine doses and reinfection, the cumulative odds ratio was 2.09 (95% central credible interval 1.42-3.08) for Delta versus Alpha. In the non-AY.4.2 Delta/AY.4.2 Delta analysis, 845 of 8644 (9.8%) non-AY.4.2 Delta cases were recorded as hospitalised or having a more severe outcome, compared to 101 of 969 (10.4%) AY.4.2 Delta cases. After adjusting for the previously stated covariates, the cumulative odds ratio was 0.99 (95% central credible interval 0.76-1.27) for AY.4.2 Delta versus non-AY.4.2 Delta. In the non-AY.4.2 Delta/Omicron analysis, 30 of 1164 (2.6%) non-AY.4.2 Delta cases were recorded as hospitalised or having a more severe outcome, compared to 26 of 2694 (1.0%) Omicron cases. After adjusting for the previously listed covariates, the median cumulative odds ratio was 0.49 (95% central credible interval 0.22-1.06) for Omicron versus non-AY.4.2 Delta.
ConclusionsThe direction of change in disease severity between successively emerging SARS-CoV-2 variants of concern was inconsistent. This heterogeneity in virulence between variants, coupled with independent evolutionary emergence, demonstrates that severity associated with future SARS-CoV-2 variants is inherently unpredictable. | epidemiology |
10.1101/2022.03.24.22272373 | Blood-derived DNA methylation clusters associate with adverse social exposures and endophenotypes of stress-related psychiatric illness in a trauma-exposed cohort of women | Adverse social exposures (ASEs) such as low income, low educational attainment, and childhood/adult trauma exposure are associated with variability in brain region measurements of grey matter volume (GMV), surface area (SA), and cortical thickness (CT). These CNS morphometries are associated with stress-related psychiatric illnesses and represent endophenotypes of stress-related psychiatric illness development. Epigenetic mechanisms, such as 5-methyl-cytosine (5mC), may contribute to the biological embedding of the environment but are understudied and not well understood. How 5mC relates to CNS endophenotypes of psychiatric illness is also unclear.
In 97 female, African American, trauma-exposed participants from the Grady Trauma Project, we examined the associations of childhood trauma burden (CTQ), adult trauma burden, low income and low education with blood-derived 5mC clusters and variability in brain region measurements in the amygdala, hippocampus and frontal cortex subregions. To elucidate whether peripheral 5mC indexes CNS endophenotypes of psychiatric illness, we tested whether 73 brain/blood correlated 5mC clusters, defined by networks of correlated 5mC probes measured on Illuminas HumanMethylation Epic Beadchip, mediated the relationship between ASEs and brain measurements.
CTQ was negatively associated with rostral middle frontal gyrus (RMFG) SA ({beta} = - 0.231, p = 0.041). Low income and low education were also associated with SA or CT in a number of brain regions. Seven 5mC clusters were associated with CTQ (pmin = 0.002), two with low education (pmin = 0.010), and three with low income (pmin = 0.007). Two clusters fully mediated the relation between CTQ and RMFG SA, accounting for 47% and 35% of variability respectively. These clusters were enriched for probes falling in DNA regulatory regions, as well as signal transduction and immune signaling gene ontology functions. Methylome-network analyses showed enrichment of macrophage migration (p = 9x10-8), T cell receptor complex (p = 6x10-6), and chemokine-mediated signaling (p = 7x10-4) pathway enrichment in association with CTQ.
Our results support prior work highlighting brain region variability associated with ASEs, while informing a peripheral inflammation-based epigenetic mechanism of biological embedding of such exposures. These findings could also serve to potentiate increased investigation of understudied populations at elevated risk for stress-related psychiatric illness development. | psychiatry and clinical psychology |
10.1101/2022.03.25.22272820 | Closed-loop stimulation of lateral cervical spinal cord in upper-limb amputees to enable sensory discrimination | Modern myoelectric prosthetic hands have multiple independently controllable degrees of freedom, but require constant visual attention to use effectively. As we know from motor control of our native limbs, somatosensory feedback is essential to control our movements and provides information not available through vision alone. Similarly, stimulation of the nervous system can potentially provide artificial somatosensory feedback to reduce the reliance on visual cues to efficiently operate prosthetic devices. We have shown previously that epidural stimulation of the lateral cervical spinal cord can evoke tactile sensations perceived as emanating from the missing arm and hand in people with upper-limb amputation. In this study, two subjects with upper-limb amputation used this somatotopically-matched tactile feedback to discriminate object size and compliance while controlling a prosthetic hand. With less than 30 minutes of training each day, both subjects were able to use artificial somatosensory feedback to perform a subset of the discrimination tasks at a success level well above chance. Subject 1 was consistently more adept at determining object size (74% accuracy; chance: 33%) while Subject 2 achieved a higher accuracy level in determining object compliance (60% accuracy; chance 33%). In each subject, discrimination of the other object property was only slightly above or at chance level suggesting that the task design and stimulation encoding scheme are important determinants of which object property could be reliably identified. Our observations suggest that artificial somatosensory feedback provided via spinal cord stimulation can be readily used to infer information about the real-world with minimal training, but that task design is critical and that performance improvements may not generalize across tasks. | rehabilitation medicine and physical therapy |
10.1101/2022.03.25.22272940 | Price and Tax Elasticity of Alcohol Consumption: Evidence from Seven Indian States | In this paper, we develop a novel methodology for constructing price indices of India Made Foreign Liquor (IMFL), which account for incompatible state-level taxation structure and policies across seven states in India. We use this price index to compute price and tax elasticity of IMFL in the seven states. We find that a 1% increase in price leads to only a 0.057% decline in consumption while a 1% increase in tax reduces alcohol consumption by 0.14%. We extend our estimates to show that a 10% increase in taxes will lead to an 8.4% increase in tax revenue. Our results are the most updated estimates of alcohol consumption elasticities, which overcomes several challenges such as varying manufacturing costs across states and varying tax across types of products within states, which other papers do not. | health economics |
10.1101/2022.03.25.22272953 | Impact of supplementary air filtration on airborne particulate matter in a UK hospital ward | BackgroundDuring the COVID-19 pandemic, aerosol spread of SARS-CoV-2 has been a major problem in healthcare facilities, resulting in increased use of supplementary HEPA filtration to mitigate transmission. We report here a natural experiment that occurred when an air filtration unit (AFU) on an inpatient ward for older people was accidentally switched off.
AimTo assess aerosol transport within the ward and determine whether the AFU reduced particulate matter (PM) levels in the air.
MethodsTime-series PM, CO2, temperature and humidity data (at 1 minute intervals) was collected from multiple sensors around the ward over two days in August 2021. During this period, the AFU was accidentally switched off for approximately 7 hours, allowing the impact of the intervention on particulates (PM1-PM10) to be assessed using a Mann-Whitney test. Pearson correlation analysis of the PM and CO2 signals was also undertaken to evaluate the movement of airborne particulates around the ward.
FindingsThe AFU greatly reduced PM counts of all sizes throughout the ward space (p<0.001 for all sensors), with PM signals positively correlated with indoor CO2 levels (r = 0.343 - 0.817; all p<0.001). Aerosol particle counts tended to rise and fall simultaneously throughout the ward space when the AFU was off, with PM signals from multiple locations highly correlated (e.g. r = 0.343 - 0.868 (all p<0.001) for PM1).
ConclusionAerosols freely migrated between the various sub-compartments of the ward, suggesting that social distancing measures alone cannot prevent nosocomial transmission of SARS-CoV-2. The AFU greatly reduced PM levels throughout the ward space.
Practical implicationsO_LIAerosols can freely migrate throughout whole wards, suggesting that social distancing measures alone are not enough to prevent SARS-CoV-2 transmission.
C_LIO_LIAppropriately sized supplementary room air filtration, if utilised correctly, can greatly reduce aerosol levels throughout ward spaces.
C_LIO_LIAir filtration devices are often placed in rooms without any consideration given to their performance. It is therefore important to commission air filtration devices using PM and CO2 sensors before they are utilised in order to demonstrate that they are effective throughout entire ward spaces.
C_LI | infectious diseases |
10.1101/2022.03.26.22272979 | Impact of the Russian invasion of Ukraine onthe COVID-19 pandemic dynamics | Full-scale invasion of Ukraine by Russian troops, which began on February 24, 2022, caused an unprecedented number of refugees, which in the ongoing COVID-19 pandemic could increase the number of patients. The recent pandemic dynamics in Ukraine, Poland, Germany and in the whole world was compared with the previous epidemic waves simulated with the use of the generalized SIR-model and corresponding parameter identification procedure. Since before the war the estimation of the number of infectious persons per capita in Ukraine 3.6 times exceeded the global figure, the increase of the number the new cases and the pandemic duration is expected. From the beginning of March 2022 the increase of the averaged number of new cases in Germany and worldwide is visible. | epidemiology |