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10.1101/2022.03.07.22271554 | Predicting pneumothorax after lung biopsy from pre-operative imaging using a deep convolutional neural network | BackgroundPneumothorax remains one of the most common complications after computed tomography (CT)-guided lung biopsies. Radiographic features including bullae and nodule size are possible markers for post-biopsy pneumothorax. We determine whether a convolutional neural network (CNN) can accurately predict a pneumothorax after lung biopsy based on pre-operative imaging alone.
MethodsWith institutional review board approval, we retrospectively evaluated 3,822 patients who underwent a CT-guided lung biopsy between 2011 to 2019. Two image sets were created with CT scout images (1300 patients, 650 pneumothoraces) and chest x-rays (CXR) taken within three months pre-procedure (884 patients, 140 pneumothoraces). Using pre-operative images, CNNs of varying layer depths were trained using transfer learning to predict the development of a pneumothorax post-biopsy. Performance against models were compared using sensitivity analysis and the McNemars test.
ResultsThe CNN models trained with CT scout images performed near chance. However, the models performed better with CXR radiographs taken within three months pre-biopsy. For the anterior-posterior view, sensitivity was 0.40, specificity was 0.89, PPV was 0.43, and NPV was 0.87 (AUC = 0.67). For the lateral view, sensitivity was 0.40, specificity was 0.80, PPV was 0.32, and NPV was 0.86 (AUC = 0.65). Increasing CNN layers did not affect performance (p > 0.05).
ConclusionChest radiographs taken within three months of lung biopsy may provide important radiographic information for CNNs to assess pneumothorax risk in patients prior to CT-guided lung biopsies. However, more baseline and standardized CXRs before biopsies are necessary to create a robust model for clinical application. | radiology and imaging |
10.1101/2022.03.07.22270395 | Effect of a Pilates exercise program on the flexion-relaxation rate in women with chronic low back pain | PurposeTo evaluate the effect of a Pilates exercise program (PEP) on FRR and FRR asymmetry of the erector spinae (ES) muscle during standing maximal trunk flexion/extension in women with chronic low-back pain (LBP). A secondary goal was to investigate the effect of PEP on full trunk flexion ROM (TFRoM), pain intensity and functional capacity and analyse their relationship with the FRR.
Material and methodsThirty women with chronic LPB were randomly assigned to either PEP (EG, n=15) or control group (CG=15). EG followed an 8-week PEP while no specific intervention was carried out on the controls. Before and after this period all variables were recorded.
ResultsFRR did not show any significant changes between or within groups (p>0.05). EG showed a significant statistical difference in the FRR asymmetry pre- and post-intervention (p{square} 0.05). Full TFRoM did not show any significant changes between or within groups (p>0.05). EG showed a significant decrease of 30% on pain intensity and a significant increase of 13.4 % in functional capacity (P{square}0.001) from pre to post-intervention.
ConclusionsAn 8-week PEP does not affect FRR nor full trunk ROM, however yields improvements in pain intensity and functional capacity.Professionals should be aware of the negative effect on FRR asymmetry. | rehabilitation medicine and physical therapy |
10.1101/2022.03.07.22272045 | Factors Associated With Post-craniotomy Headache After Microvascular Decompression in Hemifacial Spasm? A Retrospective Study | ObjectivePatients who undergo microvascular decompression (MVD) often experience post-craniotomy headache (PCH), while the PCH is always neglected. This study is aimed to describe the natural course and risk factors of PCH.
MethodsThe severity and duration of PCH in 87 patients who undergo MVD were recorded. Factors related to the severity and duration of PCH were analyzed.
ResultsMost patients (63.2%) had at least one assessment of moderate to severe PCH. Almost all patients (92%) would gradually decrease to disappear within 7 days. A small number of patients (25.5%) had PCH at the incision, and other patients had PCH inside the head. Younger age and gas in the prepontine cistern were the salient features of patients in the severe group. Younger, higher SAS, gas in the prepontine cistern area, and postoperative fever were independent risk factors that affect the duration of PCH.
ConclusionsPCH is the most common and self-limiting complication after MVD among patients with HFS. Young age, temperature > 38{degrees}C after MVD within 24h, and gas around the TN are associated may predict the severity and duration of PCH.
SignificanceThis is the first study to describe the severity, duration, location, and risk factors of PCH. | neurology |
10.1101/2022.03.07.22272014 | The clinical need for clustered AChR cell-based assay testing of seronegative MG | Trial eligibility in myasthenia gravis (MG) remains largely dependent on a positive autoantibody serostatus. This significantly hinders seronegative MG (SNMG) patients from receiving potentially beneficial new treatments. In a subset of SNMG patients, acetylcholine receptor (AChR) autoantibodies are detectable by a clustered AChR cell-based assay (CBA). Of 99 SNMG patients from two academic U.S. centers, 18 (18.2%) tested positive by this assay. Autoantibody positivity was further validated in 17/18 patients. In a complementary experiment, circulating AChR-specific B cells were identified in a CBA-positive SNMG patient. These findings corroborate the clinical need for clustered AChR CBA testing when evaluating SNMG patients. | neurology |
10.1101/2022.03.07.22271999 | Machine Learning for Real-Time Aggregated Prediction of Hospital Admission for Emergency Patients | Machine learning for hospital operations is under-studied. We present a prediction pipeline that uses live electronic health-records for patients in a UK teaching hospitals emergency department (ED) to generate short-term, probabilistic forecasts of emergency admissions. A set of XGBoost classifiers applied to 109,465 ED visits yielded AUROCs from 0.82 to 0.90 depending on elapsed visit-time at the point of prediction. Patient-level probabilities of admission were aggregated to forecast the number of admissions among current ED patients and, incorporating patients yet to arrive, total emergency admissions within specified time-windows. The pipeline gave a mean absolute error (MAE) of 4.0 admissions (mean percentage error of 17%) versus 6.5 (32%) for a benchmark metric. Models developed with 104,504 later visits during the Covid-19 pandemic gave AUROCs of 0.68-0.90 and MAE of 4.2 (30%) versus a 4.9 (33%) benchmark. We discuss how we surmounted challenges of designing and implementing models for real-time use, including temporal framing, data preparation, and changing operational conditions. | health systems and quality improvement |
10.1101/2022.03.07.22272001 | Gaps in mobility data and implications for modelling epidemic spread: a scoping review and simulation study | Reliable estimates of human mobility are important for understanding the spatial spread of infectious diseases and the effective targeting of control measures. However, when modelling infectious disease dynamics, data on human mobility at an appropriate temporal or spatial resolution are not always available, leading to the common use of model-derived mobility proxies. In this study we reviewed the different data sources and mobility models that have been used to characterise human movement in Africa. We then conducted a simulation study to better understand the implications of using human mobility proxies when predicting the spatial spread and dynamics of infectious diseases.
We found major gaps in the availability of empirical measures of human mobility in Africa, leading to mobility proxies being used in place of data. Empirical data on subnational mobility were only available for 17/54 countries, and in most instances, these data characterised long-term movement patterns, which were unsuitable for modelling the spread of pathogens with short generation times (time between infection of a case and their infector). Results from our simulation study demonstrated that using mobility proxies can have a substantial impact on the predicted epidemic dynamics, with complex and non-intuitive biases. In particular, the predicted times and order of epidemic invasion, and the time of epidemic peak in different locations can be underestimated or overestimated, depending on the types of proxies used and the country of interest.
Our work underscores the need for regularly updated empirical measures of population movement within and between countries to aid the prevention and control of infectious disease outbreaks. At the same time, there is a need to establish an evidence base to help understand which types of mobility data are most appropriate for describing the spread of emerging infectious diseases in different settings. | infectious diseases |
10.1101/2022.03.09.22271896 | Quantifying the vaccine-induced humoral immune response to spike-receptor binding domain as a surrogate for neutralization testing following mRNA-1273 (Spikevax) vaccination against COVID-19 | BackgroundThere is a need for automated, high throughput assays to quantify immune response after vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This study assessed the combined utility of the Roche assays, Elecsys(R) Anti-SARS-CoV-2 S (ACOV2S) and Elecsys Anti-SARS-CoV-2 (ACOV2N) using samples from the 2019-nCoV vaccine (mRNA-1273, Spikevax) phase 2 trial (NCT04405076).
MethodsSamples from 593 healthy participants in two age cohorts (18-54 years and [≥]55 years), who received two injections with either placebo (n=198) or mRNA-1273 at a dose of either 50 g (n=197) or 100 g (n=198), were collected at Days 1 (first vaccination), 15, 29 (second vaccination), 43 and 57. ACOV2S results were used to assess the humoral response to vaccination in different clinical trial subgroups and were compared to a live virus microneutralization assay. Sample panels from patients with evidence of previous or concomitant infection (as identified using ACOV2N) or with an inconsistent antibody response pattern were analyzed separately.
ResultsReceptor-binding domain (RBD)-specific antibodies were readily detectable by ACOV2S for the vast majority of participants (174/189 [50 g dose group] and 178/192 [100 g]) at the first time point of assessment, with non-converters predominantly older in age. Complete seroconversion for all participants was observed at the subsequent timepoint (Day 29) and before administration of the second dose of vaccine. Two weeks after the first vaccine dose (Day 15), geometric mean concentration (GMC) of antibody levels were 1.37-fold higher in the 100 g compared with the 50 g dose group; this difference reduced to 1.09-fold two weeks after the second dose (Day 43). In both the 50 g and 100 g dose groups, a more pronounced response was observed in the younger versus the older age group on Day 15 (2.49-fold and 3.94-fold higher GMC, respectively) and Day 43 (1.35-fold and 1.50-fold higher GMC). Few subjects had a previous or concomitant natural SARS-CoV-2-infection (n=8). Vaccination of pre-infected individuals boosted the immune response to very high ACOV2S results compared to infection-naive vaccine recipients. ACOV2S measurements were strongly correlated with those from the live microneutralization assay (Pearsons r=0.779; p<0.0001) and good qualitative agreement was achieved (100% positive and 91.8% negative percentage agreement; 90.0% positive and 100% negative predictive value).
ConclusionThe results from this study confirmed that ACOV2S is a highly valuable assay for the tracking of vaccine-related immune responses. Combined application with ACOV2N enables serologic monitoring for breakthrough infection or stratification of previous natively-infected individuals. The adaptive measuring range and high resolution of ACOV2S allows for the early identification of seroconversion as well as for resolution of very high titers and detection of longitudinal differences between age and dose groups. Additionally, good correlation of ACOV2S with live virus microneutralization indicates the utility of ACOV2S as a reliable estimate of neutralization capacity in routine diagnostic settings. | infectious diseases |
10.1101/2022.03.07.22272028 | Short-term drop in antibody titer after the third dose of SARS-CoV-2 BNT162b2 vaccine in adults | Little is known about the longevity of antibodies after a third dose of BNT162b2 (BioNTech/Pfizer). Therefore, the serum antibody levels were evaluated after the third dose of BNT162b2 which dropped significantly within 11 weeks from 4155.59 {+/-} 2373.65 BAU/ml to 2389.10 {+/-} 1433.90 BAU/ml, p-value <0.001 but remained higher than after the second dose.
These data underline the positive effect of third dose of BNT162b2 but shows a rapid and significant drop of antibodies within a short span of time.
Trial RegistrationThis trial was prospectively registered in the German Clinical Trial Register (DRKS00021270). | infectious diseases |
10.1101/2022.03.09.22271977 | Ultrastructural characterisation of young and aged dental enamel by atomic force microscopy | Recent advances in atomic force microscopy (AFM) have allowed the characterisation of dental-associated biomaterials and biological surfaces with high-resolution and minimal sample preparation. In this context, the topography of dental enamel - the hardest mineralised tissue in the body - has been explored with AFM-based approaches at the micro-scale. With age, teeth are known to suffer changes that can impact their structural stability and function; however, changes in enamel structure because of ageing have not yet been explored with nanoscale resolution. Therefore, the aim of this exploratory work was to optimise an approach to characterise the ultrastructure of dental enamel and determine potential differences in topography, hydroxyapatite (HA) crystal size, and surface roughness at the nanoscale associated to ageing. For this, a total of six teeth were collected from human donors from which enamel specimens were prepared. By employing AC mode imaging, HA crystals were characterised in both transversal and longitudinal orientation with high-resolution in environmental conditions. Sound superficial enamel displayed the presence of a pellicle-like coating on its surface, that was not observable on cleaned specimens. Acidetching exposed crystals that were imaged and morphologically characterised in highresolution at the nanoscale in both the external and internal regions of enamel in older and younger specimens. Our results demonstrated important individual variations in HA crystal width and roughness parameters across the analysed specimens; however, an increase in surface roughness and decrease in HA width was observed for the pooled older external enamel group compared to younger specimens. Overall, high-resolution AFM was an effective approach for the qualitative and quantitative characterisation of human dental enamel ultrastructure at the nanometre range. Future work should focus on exploring the ageing of dental enamel with increased sample sizes to compensate for individual differences as well as other potential confounding factors such as behavioural habits and mechanical forces. | dentistry and oral medicine |
10.1101/2022.03.07.22272040 | Extending non-targeted exposure discovery of environmental chemical exposures during pregnancy and their association with pregnancy complications, a cross-sectional study | BackgroundNon-targeted Analysis (NTA) methods can identify novel exposures in a variety of biological matrices, however, few have been assessed for relationships with pregnancy complications.
ObjectivesThis study characterizes levels of nine exogenous and endogenous chemicals including linear and branched isomers perfluorooctane sulfonate (PFOS); perfluorohexane sulfonate (PFHxS); monoethylhexyl phthalate; 4-nitrophenol; and tetraethylene glycol; the fatty acids: tridecanedioic acid and octadecanedioic acid, and the bile acid: deoxycholic acid. These chemicals were identified, selected, and confirmed in prior NTA steps and we evaluate their relationship with pregnancy complications in a diverse pregnancy cohort in San Francisco.
MethodsMatched maternal and cord serum samples were collected from 302 pregnant people at delivery from the Chemicals in Our Bodies cohort in San Francisco. Chemicals were identified via NTA and quantified using targeted approaches. We calculate distributions and Spearman correlation coefficients testing the relationship of chemicals within and between the maternal and cord blood matrices. Among the maternal samples we used logistic regression to calculate the odds of gestational diabetes mellitus (GDM) and hypertensive disorders of pregnancy associated with prenatal chemical exposures.
ResultsWe detected linear PFOS, PFHxS, tridecanedioic acid, and deoxycholic acid in at least 97% of maternal samples. We observed strong correlations between cord and maternal levels of PFHxS (coefficient = 0.9), linear PFOS (0.8), and branched PFOS (0.8). In maternal samples, branched PFOS was correlated with linear PFOS (0.8) and PFHxS (0.6). We found Linear PFOS and branched PFOS were positively associated with increased odds of GDM [OR (95%CI): 1.60 (0.94, 2.73) and 1.56 (1.00, 2.44) respectively] and tridecanedioic acid was positively associated with hypertensive disorders of pregnancy [1.71 (0.79, 3.82)].
DiscussionChemicals measured in this study were identified through NTA and targeted quantification. We identified endogenous and exogenous chemicals some of which have seldom been quantified in pregnant people. | endocrinology |
10.1101/2022.03.07.22272040 | Extending non-targeted exposure discovery of environmental chemical exposures during pregnancy and their association with pregnancy complications, a cross-sectional study | BackgroundNon-targeted Analysis (NTA) methods can identify novel exposures in a variety of biological matrices, however, few have been assessed for relationships with pregnancy complications.
ObjectivesThis study characterizes levels of nine exogenous and endogenous chemicals including linear and branched isomers perfluorooctane sulfonate (PFOS); perfluorohexane sulfonate (PFHxS); monoethylhexyl phthalate; 4-nitrophenol; and tetraethylene glycol; the fatty acids: tridecanedioic acid and octadecanedioic acid, and the bile acid: deoxycholic acid. These chemicals were identified, selected, and confirmed in prior NTA steps and we evaluate their relationship with pregnancy complications in a diverse pregnancy cohort in San Francisco.
MethodsMatched maternal and cord serum samples were collected from 302 pregnant people at delivery from the Chemicals in Our Bodies cohort in San Francisco. Chemicals were identified via NTA and quantified using targeted approaches. We calculate distributions and Spearman correlation coefficients testing the relationship of chemicals within and between the maternal and cord blood matrices. Among the maternal samples we used logistic regression to calculate the odds of gestational diabetes mellitus (GDM) and hypertensive disorders of pregnancy associated with prenatal chemical exposures.
ResultsWe detected linear PFOS, PFHxS, tridecanedioic acid, and deoxycholic acid in at least 97% of maternal samples. We observed strong correlations between cord and maternal levels of PFHxS (coefficient = 0.9), linear PFOS (0.8), and branched PFOS (0.8). In maternal samples, branched PFOS was correlated with linear PFOS (0.8) and PFHxS (0.6). We found Linear PFOS and branched PFOS were positively associated with increased odds of GDM [OR (95%CI): 1.60 (0.94, 2.73) and 1.56 (1.00, 2.44) respectively] and tridecanedioic acid was positively associated with hypertensive disorders of pregnancy [1.71 (0.79, 3.82)].
DiscussionChemicals measured in this study were identified through NTA and targeted quantification. We identified endogenous and exogenous chemicals some of which have seldom been quantified in pregnant people. | endocrinology |
10.1101/2022.03.08.22270920 | SARS-CoV-2 genomic surveillance enables the identification of Delta/Omicron co-infections in Argentina. | Molecular surveillance of SARS-CoV-2 is crucial to early detect new variants and lineages. In addition, detection of coinfections with more than one SARS-CoV-2 lineage have been sporadically reported. In this work, surveillance of SARS-CoV-2 variants was performed on 2067 RNA samples (Ct>30) obtained during December 2021 and January 2022 from Cordoba province, Argentina, by real time RT-PCR specific for VOC/VOI relevant mutations (TaqMan SARS-CoV-2 Mutation Panel, Applied Biosystems). The following distribution of variants was obtained: Omicron (54.9%), Delta (44.2%) and Lambda (0.8%). Three samples (0.1%), obtained the last week of December, presented a profile compatible with a Delta/Omicron co-infection. One of them was sequenced by NGS-Illumina, obtaining reads for both VOCs. One of the studied patients presented severe symptoms, although he was not vaccinated and presented risk factors (older than 60 years, arterial hypertension). We describe for the first time in Argentina, the identification of cases of co-infection with two SARS-CoV-2 lineages, VOCs Delta and Omicron, during the third COVID-19 wave in the country (a high viral circulation period), when Delta and Omicron co-circulated. Our findings highlight the importance of continuing with molecular surveillance and co-detection studies of VOC/VOIs, in order to elucidate possible recombination events and the emergence of new variants. | epidemiology |
10.1101/2022.03.07.22271997 | Bioinfo-pharmacology: the example of therapeutic hypothermia | Computer-aided drug discovery (CADD) is a widely used method for drug discovery with many successes. Meanwhile, CADD has the limitation of analyzing multi-level scores such as docking results of multiple proteins with multiple drugs. We propose a method of PageRank to solve the problem. This method can make a comprehensive ranking based on multi-level scores. Then we take an example of therapeutic hypothermia (TH). Three levels of TH data were used in the article: the log2 foldchange (logFC) of proteins, the relative expression values of mRNA, and the docking scores of proteins and molecules. After calculation, we get the comprehensive drug rank and drug combination rank of each group of TH, which means we can generate the rank of drug directly from bioinformatics. Based on this method, we raised the concept of bioinfo-pharmacology. Given the high rationality and compatibility of bioinfo-pharmacology, it can effectively enhance popular drug discovery techniques such as the docking or pharmacophore model. Besides, it could advance the application of precision medicine.
Keyword: computer-aided drug discovery (CADD); precision medicine; Therapeutic hypothermia; di-erential gene expression; virtual screening; | pharmacology and therapeutics |
10.1101/2022.03.07.22271997 | Bioinfo-pharmacology: the example of therapeutic hypothermia | Computer-aided drug discovery (CADD) is a widely used method for drug discovery with many successes. Meanwhile, CADD has the limitation of analyzing multi-level scores such as docking results of multiple proteins with multiple drugs. We propose a method of PageRank to solve the problem. This method can make a comprehensive ranking based on multi-level scores. Then we take an example of therapeutic hypothermia (TH). Three levels of TH data were used in the article: the log2 foldchange (logFC) of proteins, the relative expression values of mRNA, and the docking scores of proteins and molecules. After calculation, we get the comprehensive drug rank and drug combination rank of each group of TH, which means we can generate the rank of drug directly from bioinformatics. Based on this method, we raised the concept of bioinfo-pharmacology. Given the high rationality and compatibility of bioinfo-pharmacology, it can effectively enhance popular drug discovery techniques such as the docking or pharmacophore model. Besides, it could advance the application of precision medicine.
Keyword: computer-aided drug discovery (CADD); precision medicine; Therapeutic hypothermia; di-erential gene expression; virtual screening; | pharmacology and therapeutics |
10.1101/2022.03.07.22272004 | Phase Recognition in Contrast-Enhanced CT Scans based on Deep Learning and Random Sampling | PurposeA fully automated system for interpreting abdominal computed tomography (CT) scans with multiple phases of contrast enhancement requires an accurate classification of the phases. Current approaches to classify the CT phases are commonly based on 3D convolutional neural network (CNN) approaches with high computational complexity and high latency. This work aims at developing and validating a precise, fast multi-phase classifier to recognize three main types of contrast phases in abdominal CT scans.
MethodsWe propose in this study a novel method that uses a random sampling mechanism on top of deep CNNs for the phase recognition of abdominal CT scans of four different phases: non-contrast, arterial, venous, and others. The CNNs work as a slice-wise phase prediction, while the random sampling selects input slices for the CNN models. Afterward, majority voting synthesizes the slice-wise results of the CNNs, to provide the final prediction at scan level.
ResultsOur classifier was trained on 271,426 slices from 830 phase-annotated CT scans, and when combined with majority voting on 30% of slices randomly chosen from each scan, achieved a mean F1-score of 92.09% on our internal test set of 358 scans. The proposed method was also evaluated on 2 external test sets: CTPAC-CCRCC (N = 242) and LiTS (N = 131), which were annotated by our experts. Although a drop in performance has been observed, the model performance remained at a high level of accuracy with a mean F1-score of 76.79% and 86.94% on CTPAC-CCRCC and LiTS datasets, respectively. Our experimental results also showed that the proposed method significantly outperformed the state-of-the-art 3D approaches while requiring less computation time for inference.
ConclusionsIn comparison to state-of-the-art classification methods, the proposed approach shows better accuracy with significantly reduced latency. Our study demonstrates the potential of a precise, fast multi-phase classifier based on a 2D deep learning approach combined with a random sampling method for contrast phase recognition, providing a valuable tool for extracting multi-phase abdomen studies from low veracity, real-world data. | radiology and imaging |
10.1101/2022.03.02.22271746 | Higher levels of myelin are associated with higher resistance against tau pathology in Alzheimer's disease | In Alzheimers disease (AD), pathologic tau gradually progresses from initially circumscribed predilection regions to closely connected cortical regions. The pattern of tau-deposition is of critical importance for the clinical expression of AD, but the factors that underlie region-dependent susceptibility and resistance to tau pathology remain elusive. Motivated by brain-autopsy findings suggesting late thinly myelinated regions are the first to develop tau pathology, we investigated whether the level of myelination in fiber-tracts and cortex is predictive of region-specific tau accumulation. To address this hypothesis, we combined MRI-derived template of normative myelin distribution with tau-PET imaging from two independent samples of AD-biomarker characterized participants. We found that higher myelinated cortical regions show lower tau-PET uptake in spatially corresponding areas and regions connected by highly myelinated fiber-tracts show lower rates of tau spreading. These findings were independent of amyloid-PET levels. Together, our findings suggest that higher myelination is an important resistance factor against tau pathology in AD. | neurology |
10.1101/2022.03.09.22271989 | Automated detection of axonal injury along white matter tracts in acute severe head trauma | New techniques for individualized assessment of white matter integrity are needed to detect traumatic axonal injury (TAI) and predict outcomes in critically ill patients with acute severe traumatic brain injury (TBI). Diffusion MRI tractography has the potential to quantify white matter microstructure in vivo and has been used to characterize tract-specific changes in TBI. However, tractography is not routinely used in the clinical setting to assess the extent of TAI, in part because focal lesions reduce the robustness of automated methods. In the present study, we propose an automated pipeline for individualized assessment of white matter damage in patients with acute severe TBI that is based on tractography reconstructions and multivariate analysis of along-tract diffusion metrics. We used the Mahalanobis distance to test for a deviation of diffusion metrics along 40 white matter tracts in 18 patients with acute severe TBI as compared to 33 healthy subjects. The automated pipeline successfully reconstructed white matter tracts in all patients with a successful FreeSurfer anatomical segmentation (17 of 18 patients), including 13 with focal lesions. In these 17 patients, a mean of 37.5 +/- 2.1 tracts were reconstructed without the need for manual intervention and a mean of 2.47 +/- 2.1 needed to be reinitialized upon visual inspection. The pipeline detected at least one injured tract in all patients (mean: 12.6, SD: 7.6). The number and neuroanatomic location of disrupted tracts varied across patients and levels of consciousness. The pre-motor, parietal, and temporal sections of the corpus callosum were the structures most frequently injured (in 10, 9, and 8 patients respectively), consistent with histological studies of TAI. Multivariate measures of TAI did not show a significant association with behavioral measures of consciousness, or subscales measuring basic language and motor function. In summary, we provide proof- of-principle evidence that an automated tractography pipeline can be used to detect and quantify TAI in patients with acute severe head trauma and could therefore assist in the clinical assessment of TAI. | neurology |
10.1101/2022.03.01.22271693 | The Acoustic Dissection of Cough: Diving into Machine Listening-based COVID-19 Analysis and Detection | PurposeThe coronavirus disease 2019 (COVID-19) has caused a crisis worldwide. Amounts of efforts have been made to prevent and control COVID-19s transmission, from early screenings to vaccinations and treatments. Recently, due to the spring up of many automatic disease recognition applications based on machine listening techniques, it would be fast and cheap to detect COVID-19 from recordings of cough, a key symptom of COVID-19. To date, knowledge on the acoustic characteristics of COVID-19 cough sounds is limited, but would be essential for structuring effective and robust machine learning models. The present study aims to explore acoustic features for distinguishing COVID-19 positive individuals from COVID-19 negative ones based on their cough sounds.
MethodsWith the theory of computational paralinguistics, we analyse the acoustic correlates of COVID-19 cough sounds based on the COMPARE feature set, i. e., a standardised set of 6,373 acoustic higher-level features. Furthermore, we train automatic COVID-19 detection models with machine learning methods and explore the latent features by evaluating the contribution of all features to the COVID-19 status predictions.
ResultsThe experimental results demonstrate that a set of acoustic parameters of cough sounds, e. g., statistical functionals of the root mean square energy and Mel-frequency cepstral coefficients, are relevant for the differentiation between COVID-19 positive and COVID-19 negative cough samples. Our automatic COVID-19 detection model performs significantly above chance level, i. e., at an unweighted average recall (UAR) of 0.632, on a data set consisting of 1,411 cough samples (COVID-19 positive/negative: 210/1,201).
ConclusionsBased on the acoustic correlates analysis on the COMPARE feature set and the feature analysis in the effective COVID-19 detection model, we find that the machine learning method to a certain extent relies on acoustic features showing higher effects in conventional group difference testing. | health informatics |
10.1101/2022.03.09.22270872 | Disparities in Knowledge, Attitude and Practices on Mental Health among Healthcare Workers and Community members in Meru County, Kenya | BackgroundMental health (MH) remains a neglected priority in many low and middle-income countries. Currently, there is inadequate data on the prevalence of mental health in Kenya. This is compounded by huge inequity in the distribution of skilled human resources for mental health services. Inadequate knowledge about mental health and negative attitudes towards people with mental health disorders is widespread among the general public.
MethodsThis was a descriptive cross-sectional survey that utilised mixed methods for data collection. A total of 535 community members and 109 healthcare workers (HCWs) were targeted for the study. All cadres of healthcare workers in the selected health facilities who voluntarily consented to participate were recruited through simple random sampling. Data were collected using household surveys, Key Informant Interviews (KIIS) with facility in-charges; Focus Group Discussions (FGD) with community members particularly community Health Volunteers (CHVs) and youth; and In-depth Interviews (IDI) with community gate keepers such as religious leaders, Religious leader, Chiefs/sub-Chiefs, and traditional leaders. Data analysis included simple univariate frequencies of questions chosen to reflect the key concepts on mental health. Descriptive statistics were used to determine frequencies and percentages for the different variables under study. For qualitative data, thematic analysis was applied to generate themes through deductive and inductive methods. Triangulation of qualitative and quantitative data was conducted.
ResultsApproximately 39.1% of respondents reported to have had a family member with mental illness and 68% of HCWs reported to have diagnosed a patient with mental illness. 64% of respondents cited causes of mental disorders as witchcraft; generational curses in some families; genetic factors; drug and substance abuse especially marijuana; social and economic/financial pressures; and injuries from accidents. 93.3% of the HCWs reported to have referred patients to a mental health facility. Only 29.4% of the HCWs reported having counselling services in the facilities for patients with mental health needs. Majority (90.8% HCWs and 62.3% community members) reported that it is convenient for patients with MH needs and illness from the community to access the health care facilities and that MH services were available and mainly offered at the Meru Teaching and Referral Hospital (81.7% HCWs and 53.8% community members). Majority of HCWs (89.9%) reported that MH services were affordable to community members. On the contrary, only 44.4% of community members reported that MH services are affordable. The HCWs reported that the drugs were given for free at the health facilities while community members reported that sometimes stock-outs in drugs for MH existed in which case they would purchase drugs from pharmacies. Majority (96.4% HCWs and 62.5% community members) reported that patients with mental health1 needs and illness2 are treated with respect in the facilities. Aside from health facilities, community members also seek mental health services from: religious leaders; traditional healers including the Religious leader who were approached for cleansing if one believed that the mental health issues were a curse for committing certain offenses. It was also evident that some families did not seek any kind of help for their relatives with mental health illness and needs, with some even detaining them.
ConclusionThis study adds to the global knowledge on mental health among healthcare workers and community members providing vital data at service delivery level from an African developing country perspective. There is evidence of high burden of MH in the county with very few facilities offering MH services for patients. The existence of myths and misconceptions around the causes of MH is evident and needs to be addressed. There are also evident disparities in the perception of HCWs and Community members in MH with regards to availability and affordability of MH services and access to MH drugs. Communities still seek MH services from traditionalists and some people still neglect MH cases. Sustained poor mental health of individuals, families, the communities including healthcare workers has an enormous contribution towards negative health seeking behavior as well as social capital, an important determinant of health not just in Kenya but in many rural settings across the world. With this therefore, there is need to build the capacity of health care workers and create awareness to the community members as well as strengthen health systems to tackle MH. | health systems and quality improvement |
10.1101/2022.03.08.22271816 | Aerosolized Ad5-nCoV booster vaccination elicited potent immune response against the SARS-CoV-2 Omicron variant after inactivated COVID-19 vaccine priming | The SARS-CoV-2 Omicron variant has become the dominant SARS-CoV-2 variant around the world and exhibits immune escape to current COVID-19 vaccines to some extent due to its numerous spike mutations. Here, we evaluated the immune responses to booster vaccination with intramuscular adenovirus-vectored vaccine (Ad5-nCoV), aerosolized Ad5-nCoV, a recombinant protein subunit vaccine (ZF2001) or homologous inactivated vaccine (CoronaVac) in those who received two doses of inactivated COVID-19 vaccines 6 months prior. We found that the Ad5-nCoV booster induced potent neutralizing activity against the wild-type virus and Omicron variant, while aerosolized Ad5-nCoV generated the greatest neutralizing antibody responses against the Omicron variant at day 28 after booster vaccination, at 14.1-fold that of CoronaVac, 5.6-fold that of ZF2001 and 2.0-fold that of intramuscular Ad5-nCoV. Similarly, the aerosolized Ad5-nCoV booster produced the greatest IFN{gamma} T-cell response at day 14 after booster vaccination. The IFN{gamma} T-cell response to aerosolized Ad5-nCoV was 12.8-fold for CoronaVac, 16.5-fold for ZF2001, and 5.0-fold for intramuscular Ad5-nCoV. Aerosolized Ad5-nCoV booster also produced the greatest spike-specific B cell response. Our findings suggest that inactivated vaccine recipients should consider adenovirus-vectored vaccine boosters in China and that aerosolized Ad5-nCoV may provide a more efficient alternative in response to the spread of the Omicron variant. | infectious diseases |
10.1101/2022.03.08.22272080 | Exposures associated with sporadic Cryptosporidium infection in industrialised countries: a systematic review | Transmission of Cryptosporidium can occur via contaminated food or water, contact with animals or other people. Exposures are often identified from outbreak investigations, but sources for sporadic disease and pathways to infection are still unclear. The aim of this review is to consolidate the literature to describe exposures associated with human cryptosporidiosis in industrialised countries.
Methods followed the recommendations made in the Cochrane Handbook for Systematic Reviews of Interventions. Three steps were used to identify the literature including electronic database searching using PubMed, Scopus and Web Of Science; reference list trawling; and an exploration of the grey literature. Quality was assessed using the Newcastle-Ottawa Scale. Screening of results was undertaken by two reviewers and data extracted using a standardised form. A narrative summary presented. Papers were included if they reported on sporadic cases and were published between 2008 and 2018. Exposures were grouped into pathways.
After full-text screening, eight articles (comprising 11 studies) were included, and seven (comprising 10 studies) were suitable for further synthesis. None of the identified grey literature was included. Four studies described case-control methods, two were case-case studies and one cross-sectional. Study year ranged from 1999 to 2017 and the studies were conducted in five, large countries in three continents: Europe (UK and the Netherlands), North America (USA, Canada), and Australia.
Included papers investigated water and animal exposures most frequently. Recreational water was not a major source of sporadic illness in this review. The person-to-person pathway represented the most consistent finding, with all three studies reporting on contact with a symptomatic individual demonstrating correlations between exposure and disease. This applied particularly to the home environment, which is increasingly understood to be a significant setting for spread of Cryptosporidium infection. Further work on this would help support public health messaging on preventing spread of disease at home.
Systematic review registration: PROSPERO number CRD42017056589. | epidemiology |
10.1101/2022.03.08.22271980 | Self-injury, suicidal ideation and -attempt and eating disorders in young people following the initial and second COVID-19 lockdown | BackgroundThe initial COVID-19 lockdowns have had negative effect on different mental health measures, especially in young women. However, the impact on self-injury, suicidality and eating disorder (ED) are less elucidated and remains inconsistent. We compare self-reported self-injury, suicide ideation and -attempt and symptoms of EDs from before through different pandemic periods until spring 2021.
MethodsYoung participants in the Danish National Birth Cohort reported these measures in an 18-year follow-up in 2015-2021 and in a COVID-19 survey in spring 2021 when participants were aged 19-24 years. Changes in measures from pre to post lockdown were estimated with longitudinal data (N=7,597) and with repeated cross-sectional data (N=24,625) by linear regression.
FindingsIn the longitudinal comparisons 14% of women and 7% of men reported self-injury pre lockdown, which decreased 6%-points (95% CI:-7%;-5%) for women and 3%-points (95% CI:-4%;-2%) for men during lockdown. For suicide ideation, the pre lockdown proportions were 25% and 18% for women and men respectively, and decreased 7%-points (95% CI:-8%;-6%) for women and 3%-points (95% CI:-5%;-1%) for men. For suicide attempt no change was observed. Pre lockdown 15% and 3% of women and men, respectively, had symptoms of EDs, which decreased 2%-points (95% CI:-3%;-1%) for women. We observed no changes in proportions of self-injury, suicide ideation or EDs in the repeated cross-sectional data.
InterpretationOur findings provide no support for increase in self-injury, suicidality and EDs following the lockdowns, and if anything, indicate a reduction in self-injury and suicide ideation as well as EDs in women. | epidemiology |
10.1101/2022.03.08.22272082 | Community Engagement to support COVID-19 Vaccine Uptake: A living systematic review protocol | BackgroundWidespread vaccination against Coronavirus Disease 2019 (COVID-19) is one of the most effective ways to control, and ideally, end the global COVID-19 pandemic. Vaccine hesitancy and vaccine rates vary widely across countries and populations and are influenced by complex socio-cultural, political, economic, and psychological factors. Community engagement is an integral strategy within immunisation campaigns and has been shown to improve vaccine acceptance. As evidence on community engagement to support COVID-19 vaccine uptake is emerging, this review aims to lessen the knowledge-to-practice gap by providing regular evidence on current best-practice.
MethodologyA living systematic review will be conducted which includes an initial systematic review and bi-monthly review updates. Searching and screening for the review and subsequent updates will be done in four streams: a systematic search of six databases, grey literature review, preprint review, and citizen sourcing. All articles will be collated into Covidence, where screening will be done by a minimum of two reviewers at title/abstract and full-text. Data will be extracted across pre-defined data extraction tables, and synthesis will occur using the convergent integrated approach. Updates to the review resulting from the subsequent bi-monthly searches will be shared in an open-access platform. The protocol has been registered with PROSPERO: CRD42022301996.
DiscussionGiven the variation in vaccination rates across different contexts and the recognition that high vaccination coverage is required to reduce COVID-19 transmission and to stop the emergence of new variants, it is imperative the global community implements strategies that will improve uptake and that this work is widely shared and contextualised. Community engagement to promote vaccine uptake is highly encouraged, and recent studies highlight its potential to influence vaccine rates, particularly across populations that are marginalised. The high-priority research needed on this topic, and the rapidly changing evidence base, supports the conduct of a living systematic review. | public and global health |
10.1101/2022.03.08.22272068 | The prevalence of female genital mutilation: a systematic review and meta-analysis of national, regional, facility and school-based studies. | BackgroundFemale Genital Mutilation/Cutting (FGM/C) is a non-medical procedure entailing the modification of the external female genitalia. The Sustainable Development Goals aim to end FGM/C by 2030. This systematic review aimed to examine FGM/C prevalence and types, by World Health Organization (WHO) region and country.
Methods and FindingsA systematic search using MeSH headings and keywords from inception to March 2, 2020 was undertaken in MEDLINE, PsycINFO, Web of Science, and Embase to identify studies presenting FGM/C prevalence. Abstract and full-text screening, quality assessment, and data extraction were undertaken by two reviewers. Only nationally representative studies were included in the meta-analysis. Pooled FGM/C prevalence was estimated by meta-analysis using random effects models. FGM/C prevalence and types were presented separately by women aged 15-49 and girls aged 0-14. 3,205 articles were identified. 135 met the inclusion criteria and 28 were included in the meta-analysis. Across 27 countries, the pooled prevalence estimate of FGM/C in women aged 15-49 was 40% (95% CI: 26-55%; I2 =100%), and 15% (95% CI: 10-21%; I2 =100%) in girls aged 0-14 across 34 countries. The country with the highest FGM/C prevalence in women was Guinea (97%) and the lowest, Uganda (0{middle dot}3%). The highest prevalence in girls was in Mali (77%), and the lowest in Ghana (0%). The most common category of FGM/C was "flesh removed" at 69% (women) and 70% (girls). Limitations include that studies had heterogeneous terminology and relied on recall.
ConclusionsThere is large variation in FGM/C prevalence, and the lower prevalence in the current generation of girls is encouraging. However, considerable policy and community-level interventions are required to meet the SDG. Future research should consider collecting data on the 15-19 age group in order to accurately assess generational differences in FGM prevalence. The study protocol is available: https://osf.io/ema9j/.
FundingNone | sexual and reproductive health |
10.1101/2022.03.08.22272005 | impaired bed mobility in prediagnostic and de novo Parkinson's disease | BackgroundWearable technology research suggests that nocturnal movements are disturbed in early Parkinsons disease (PD). In this study, we investigate if patients also already experience impaired bed mobility before PD diagnosis. Furthermore, we explore its association with motor and nonmotor features and its value for phenoconversion and disease progression prediction.
MethodsPPMI data were downloaded for de novo PD subjects, subjects at-risk for developing a synucleinopathy (with isolated REM sleep behavior disorder, hyposmia or a pathogenic mutation) and controls. Impaired bed mobility was assessed with the MDS-UPDRS part 2 item 9. A frequency analysis was performed. Multivariable logistic regression analyses were used to investigate the association with other PD variables. Cox proportional-hazards models were used to test if difficulties with turning in bed could predict phenoconversion. Linear mixed models were used to evaluate if difficulties with turning in bed could predict disease progression.
ResultsOf the at-risk subjects, 9.2-12.5% experienced difficulties with turning in bed vs. 25.0% of de novo PD subjects and 2.5% of controls. Impaired turning ability was associated with MDS-UPDRS motorscore (axial signs in the at-risk group, bradykinesia in the de novo PD group) and SCOPA-AUT score (gastrointestinal symptoms). In addition, difficulties with turning in bed were a significant predictor for phenoconversion in the at-risk group and for development of motor complications in the de novo PD group.
ConclusionOur findings suggest that difficulties with turning in bed can be helpful as clinical symptom for a prodromal PD screening and for motor complication prediction in early PD.
HighlightsO_LISubjective difficulties with turning in bed are a prodromal PD symptom.
C_LIO_LIImpaired bed mobility predicts synucleinopathy phenoconversion in at-risk groups.
C_LIO_LIImpaired bed mobility predicts development of motor complications in de novo PD.
C_LI | neurology |
10.1101/2022.03.08.22272044 | A non-coding single nucleotide polymorphism at 8q24 drives IDH1-mutant glioma formation | Establishing causal links between inherited polymorphisms and cancer risk is challenging. Here, we focus on the single nucleotide polymorphism rs55705857 (A>G), which confers a 6-fold increased risk of IDH-mutant low-grade glioma (LGG) and is amongst the highest genetic associations with cancer. By fine-mapping the locus, we reveal that rs55705857 itself is the causal variant and is associated with molecular pathways that drive LGG. Mechanistically, we show that rs55705857 resides within a brain-specific enhancer, where the risk allele disrupts OCT2/4 binding, allowing increased interaction with the Myc promoter and increased Myc expression. To functionally test rs55705857, we generated an IDH1R132H-driven LGG mouse model and show that mutating the highly conserved, orthologous mouse rs55705857 locus dramatically accelerated tumor development from 463 to 172 days and increased penetrance from 30% to 75%. Overall, our work generates new LGG models and reveals mechanisms of the heritable predisposition to lethal glioma in [~]40% of LGG-patients. | oncology |
10.1101/2022.03.08.22272071 | Donor whole blood DNA methylation is not a strong predictor of acute graft versus host disease in unrelated donor allogeneic haematopoietic cell transplantation | Allogeneic hematopoietic cell transplantation (HCT) is used to treat many blood-based disorders and malignancies. While this is an effective treatment, it can result in serious adverse events, such as the development of acute graft-versus-host disease (aGVHD). This study aimed to develop a donor-specific epigenetic classifier that could be used in donor selection in HCT to reduce the incidence of aGVHD.
The discovery cohort of the study consisted of 288 donors from a population receiving HLA-A, -B, -C and -DRB1 matched unrelated donor HCT with T cell replete peripheral blood stem cell grafts for treatment of acute leukaemia or myelodysplastic syndromes after myeloablative conditioning. Donors were selected based on recipient aGVHD outcome; this cohort consisted of 144 cases with aGVHD grades III-IV and 144 controls with no aGVHD that survived at least 100 days post-HCT matched for sex, age, disease and GVHD prophylaxis.
Genome-wide DNA methylation was assessed using the Infinium Methylation EPIC BeadChip (Illumina), measuring CpG methylation at >850,000 sites across the genome. Following quality control, pre-processing and exploratory analyses, we applied a machine learning algorithm (Random Forest) to identify CpG sites predictive of aGVHD. Receiver operating characteristic (ROC) curve analysis of these sites resulted in a classifier with an encouraging area under the ROC curve (AUC) of 0.91.
To test this classifier, we used an independent validation cohort (n=288) selected using the same criteria as the discovery cohort. Different attempts to validate the classifier using the independent validation cohort failed with the AUC falling to 0.51. These results indicate that donor DNA methylation may not be a suitable predictor of aGVHD in an HCT setting involving unrelated donors, despite the initial promising results in the discovery cohort.
Our work highlights the importance of independent validation of machine learning classifiers, particularly when developing classifiers intended for clinical use. | genetic and genomic medicine |
10.1101/2022.03.08.22272089 | Sex differences in functional network topology over the course of aging in 37543 UK Biobank participants | Aging is a major risk factor for cardiovascular and neurodegenerative disorders, with considerable societal and economic implications. Healthy aging is accompanied by changes in connectivity between and within resting-state functional networks, however, there is no consensus on the impact of sex on these age-related alterations. Here, in a large cross-sectional sample of 37543 UK Biobank participants, we show that multilayer measures that capture the interaction between positive and negative connections provide crucial information on the impact of sex on age-related changes in network topology, being closely related to cognitive, structural, and cardiovascular risk factors that have been shown to differ between men and women. We also provide additional insights into the genetic influences on multilayer connectivity changes that occur during aging. Our findings indicate that multilayer measures contain previously unknown information on the relationship between sex and age, opening up new avenues for research into functional brain connectivity in aging. | geriatric medicine |
10.1101/2022.03.08.22271951 | Analysis of the metabolic syndrome and its association with cART in HIV positive individuals receiving various cART regimens with review of literature. | ContextMany endocrine and metabolic disorders are seen in patients with HIV infection. Various comorbidities have been reported at a higher rate in HIV positive individuals, some at an earlier age. Since metabolic syndrome and its determinants are slowly developing, studies are needed in this regard.
AimsThe study aimed to analyze various parameters associated with the metabolic syndrome in HIV positive individuals and stratify subjects based on their treatment regimens, and present a brief comparison based on the same.
Settings and DesignA cross sectional study involving 155 participants was conducted at a tertiary care centre in Western India.
Materials and MethodsDetailed history and clinical examination was carried out. Routine investigations were done and parameters of interest to the study were then analysed based on AHA/NHLBI definitions.
Statistical Analysis usedUnivariate analysis of all parameters. Multiple logistic regression for statistically significant parameters.
Results and ConclusionDeranged HDL cholesterol was the most common component of the metabolic syndrome seen amongst all participants (53.8%) which was significantly higher in the treatment naive group (P = 0.001). The difference between the incidence of metabolic syndrome between the ART naive group and patients receiving ART was not significant. Males had a significantly higher prevalence of metabolic syndrome than females (26.3%>12.4%, P = 0.026). There was a significant difference in the incidence between the Zidovudine and Tenofovir treatment groups(P=0.02). Patients on the TLE (Tenofovir, Lamivudine, and Efavirenz) regimen had the lowest prevalence (4.2%) of metabolic syndrome. | hiv aids |
10.1101/2022.03.08.22272034 | The origin, epidemiology and phylodynamics of HIV-1 CRF47_BF | CRF47_BF is a circulating recombinant form (CRF) of the human immunodeficiency virus type 1 (HIV-1), the etiological agent of AIDS. CRF47_BF represents one of 19 CRFx_BFs and has a geographic focus in Spain, where it was first identified in 2010. Since its discovery, CRF47_BF has expanded considerably in Spain, predominantly through heterosexual contact ([~]56% of the infections). Little is known, however, about the origin and diversity of this CRF or its epidemiological correlates, as very few samples have been available so far. This study conducts a phylogenetic analysis with representatives of all CRFx_BF sequence types along with HIV-1 M Group subtypes to place the CRF47_BF sequences in a definitive phylogenetic context. The CRFx_BF sequences cluster into a single, not well supported, clade that includes their dominant parent subtypes (subtype B and subtype F). This clade also includes subtype D and excludes subsubtype F2. The CRF47_BF sequences all share a most recent common ancestor. Further analysis of this clade couples CRF47_BF protease-reverse transcriptase sequences and epidemiological data from an additional 87 samples collected throughout Spain, coupled with additional CRF47_BF database sequences from Brazil and Spain to investigate the origin and phylodynamics of CRF47_BF. The Spanish region with the highest proportion of CRF47_BF samples in the data set was the Basque Country (43.7%) with Navarre next highest at 19.5%. We include in our analysis epidemiological data on host sex, mode of transmission, time of collection, and geographic region. The phylodynamic analysis indicates that CRF47_BF originated in Brazil around 1993-1994 and spread to Spain from Brazil in approximately 1999-2000. The virus spread rapidly throughout Spain with increasing population sizes prior to 2010 and again between 2010 and 2017 with population declines to 2019 and a steady state through 2020. Three strongly supported clusters associated with Spanish regions (Basque Country, Navarre, and Aragon), together comprising 60.8% of the Spanish samples, were identified, one of which was also associated with transmission among men who have sex with men. The expansion in Spain of CRF47_BF, together with that of other CRFs and subtype variants of South American origin, previously reported, reflects the increasing relationship between the South American and European HIV-1 epidemics. | hiv aids |
10.1101/2022.03.07.22272060 | A Genomic Snapshot of Enterococcus faecalis within Public Hospital Environments in South Africa | Enterococci are among the most common opportunistic hospital pathogens. This study used whole-genome sequencing (WGS) and bioinformatics to determine the antibiotic resistome, genetic support, clones and phylogenetic relationship of Enterococcus faecalis isolated from hospital environments in South Africa. Isolates were recovered from 11 frequently touched sites by patients and healthcare workers in different wards at 4 levels of healthcare (A, B, C and D) in Durban, South Africa. Following microbial identification and antibiotic susceptibility tests. Of the 245 E. faecalis isolates identified, 38 were subjected to WGS on the Illumina MiSeq platform. The tet(M) (31/38, 82%) and erm(C) (16/38, 42%) genes were the most common antibiotic resistome found in isolates originating from the different hospital environments which corroborated with their antibiotic resistance phenotypes. The isolates harboured mobile genetic elements consisting of plasmids (n=11) and prophages (n=14), that were mostly clone-specific. Of note, a large number insertion sequence (IS) families were found with the IS3 (55%), IS5 (42%), IS1595 (40%) and Tn3 Transposon been the most predominate. Microbial typing using WGS data revealed 15 clones with 6 major sequence types (ST) belonging to ST16 (n =7), ST40 (n = 6), ST21 (n =5), ST126 (n = 3), ST23 (n =3) and ST386 (n=3). Phylogenomic analysis showed that the major clones were mostly conserved within specific hospital environments. However, further metadata insights revealed the complex intra-clonal spread of these E. faecalis major clones between the sampling sites within each specific hospital setting. The results of these genomic analyses will offer insights into E. faecalis in the hospital environments relevant in the design of optimal infection prevention strategies in hospital settings. | infectious diseases |
10.1101/2022.03.08.22272062 | Safety and immunogenicity of a hybrid-type vaccine booster in BBIBP-CorV recipients: a randomized controlled phase 2 trial | The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants with immune escape ability raises the urgent need for developing cross-neutralizing vaccines against the virus. NVSI-06-08 is a potential broad-spectrum recombinant COVID-19 vaccine that integrates the antigens from multiple SARS-CoV-2 strains into a single immunogen. Here, we evaluated the safety and immunogenicity of NVSI-06-08 as a heterologous booster dose in adults previously vaccinated with the inactivated vaccine BBIBP-CorV in a randomized, double-blind, controlled, phase 2 trial conducted in the United Arab Emirates (NCT05069129). Three groups of healthy adults over 18 years of age (600 participants per group) who had administered two doses of BBIBP-CorV 4-6-month, 7-9-month and >9-month earlier, respectively, were vaccinated with either a homologous booster of BBIBP-CorV or a heterologous booster of NVSI-06-08. The primary outcome was immunogenicity and safety of booster vaccinations. The exploratory outcome was cross-reactive immunogenicity against multiple SARS-CoV-2 variants of concerns (VOCs). The incidence of adverse reactions was low in both booster vaccinations, and the overall safety profile of heterologous boost was quite similar to that of homologous boost. Heterologous NVSI-06-08 booster was immunogenically superior to homologous booster of BBIBP-CorV. Both Neutralizing and IgG antibodies elicited by NVSI-06-08 booster were significantly higher than by the booster of BBIBP-CorV against not only SARS-CoV-2 prototype strain but also multiple VOCs. Especially, the neutralizing activity induced by NVSI-06-08 booster against the immune-evasive Beta variant was no less than that against the prototype strain, and a considerable level of neutralizing antibodies against Omicron (GMT: 367.67; 95%CI, 295.50-457.47) was induced by heterologous booster, which was substantially higher than that boosted by BBIBP-CorV (GMT: 45.03; 95%CI, 36.37-55.74). Our findings showed that NVSI-06-08 was safe and immunogenic as a booster dose following two doses of BBIBP-CorV, which was immunogenically superior to homologous boost with another dose of BBIBP-CorV. Our study also indicated that the design of hybrid antigen may provide an effective strategy for broad-spectrum vaccine developments. | infectious diseases |
10.1101/2022.03.08.22271905 | Impact of SARS-CoV-2 vaccination of children ages 5-11 years on COVID-19 disease burden and resilience to new variants in the United States, November 2021-March 2022: a multi-model study | BackgroundSARS-CoV-2 vaccination of persons aged 12 years and older has reduced disease burden in the United States. The COVID-19 Scenario Modeling Hub convened multiple modeling teams in September 2021 to project the impact of expanding vaccine administration to children 5-11 years old on anticipated COVID-19 burden and resilience against variant strains.
MethodsNine modeling teams contributed state- and national-level projections for weekly counts of cases, hospitalizations, and deaths in the United States for the period September 12, 2021 to March 12, 2022. Four scenarios covered all combinations of: 1) presence vs. absence of vaccination of children ages 5-11 years starting on November 1, 2021; and 2) continued dominance of the Delta variant vs. emergence of a hypothetical more transmissible variant on November 15, 2021. Individual team projections were combined using linear pooling. The effect of childhood vaccination on overall and age-specific outcomes was estimated by meta-analysis approaches.
FindingsAbsent a new variant, COVID-19 cases, hospitalizations, and deaths among all ages were projected to decrease nationally through mid-March 2022. Under a set of specific assumptions, models projected that vaccination of children 5-11 years old was associated with reductions in all-age cumulative cases (7.2%, mean incidence ratio [IR] 0.928, 95% confidence interval [CI] 0.880-0.977), hospitalizations (8.7%, mean IR 0.913, 95% CI 0.834-0.992), and deaths (9.2%, mean IR 0.908, 95% CI 0.797-1.020) compared with scenarios where children were not vaccinated. This projected effect of vaccinating children 5-11 years old increased in the presence of a more transmissible variant, assuming no change in vaccine effectiveness by variant. Larger relative reductions in cumulative cases, hospitalizations, and deaths were observed for children than for the entire U.S. population. Substantial state-level variation was projected in epidemic trajectories, vaccine benefits, and variant impacts.
ConclusionsResults from this multi-model aggregation study suggest that, under a specific set of scenario assumptions, expanding vaccination to children 5-11 years old would provide measurable direct benefits to this age group and indirect benefits to the all-age U.S. population, including resilience to more transmissible variants. | epidemiology |
10.1101/2022.03.08.22271856 | Trends and factors associated with initiation of HIV treatment and uptake of viral load testing among PLHIV in Jamaica | IntroductionJamaica did not achieve the UNAIDS 90-90-90 targets in 2020. This study aims to examine trends and factors associated with uptake of HIV treatment and viral load testing among people living with HIV (PLHIV) in Jamaica, to make recommendations for improving patient management and outcomes.
MethodsThis secondary analysis uses patient-level data from the National Treatment Service Information System. The baseline sample is PLHIV initiating anti-retroviral treatment (ART) between January 2015-December 2019. Descriptive statistics are used to summarize demographic and clinical variables. Multivariable logistic regression is used to assess factors associated with ART initiation (31+ days vs. same day) and viral load testing uptake (viral load test vs. no test), using categorical variables for age group, gender and regional health authority. Adjusted odds ratios and 95% confidence intervals are reported.
ResultsSame day ART initiation increased by 72% over 5 years. The coverage of 1st viral load test was 90% but declined to 79% for the 2nd test. Testing occurred mostly after 0-6 months on ART (n=3047, 55%) and uptake was highest in the South-East Region (n=2885, 53%). Those virally suppressed were significantly more likely to have same day ART initiation compared to those non-suppressed (aOR=1.58, CI=1.43-1.75). Males were significantly more likely to have same day ART initiation (aOR=1.46, CI=1.32-1.62) but no first viral load test (aOR=1.55, CI=1.27-1.90) compared to females.
ConclusionThe goal of immediate ART initiation is increasingly being met and is significantly associated with viral suppression at the first viral load test. Males were less likely to have a viral load test after ART initiation. A qualitative assessment should be conducted to understand important challenges faced to access routine viral load testing, followed by implementation of differentiated service care models, targeting males. | epidemiology |
10.1101/2022.03.08.22272025 | Integrated single-cell RNA sequencing analysis reveals alterations of ageing human lung endothelium heterogeneity in idiopathic pulmonary fibrosis | Increasing age is the main risk factor for chronic lung diseases (CLD) including idiopathic pulmonary fibrosis (IPF). Halting or reversing progression of IPF remains an unmet clinical need due to limited knowledge of underlying mechanisms. In particular, the contribution of the endothelium to ageing in human lung under physiological conditions and in IPF remains insufficiently understood. In this study, we analysed heterogeneity of endothelium in physiologically ageing human lung and its alterations in IPF. We conducted a comprehensive in silico analysis of scRNAseq profiles of human lung tissues from older healthy donors and age-matched IPF patients (n=9 for each group) by integrating datasets from two independent cohorts. We generated a single-cell map of the ageing human lung and identified 17 subpopulations of ageing endothelium (12 for blood and 5 for lymphatic vessels, including 4 "de-differentiated"), with distinct transcriptional profiles, specific gene expression signatures and percentage contributions, revealing previously underappreciated extent of heterogeneity. In IPF lung, the balance of different endothelial sub-types was significantly altered both in terms of cell numbers and gene expression patterns, identifying disease-relevant subpopulations and transcriptional changes associated with specific signalling pathways and cellular processes. These findings reveal a previously unrecognised phenomenon of ageing human lung endothelium re-programming towards an "IPF endothelium" state, suggesting potential avenues for therapeutic management or biomarker discovery for diagnostics or prognostics of IPF. Our study creates a conceptual framework for appreciating the heterogeneity of ageing endothelium and its alterations in CLDs and diseases associated with fibrosis in other organs, including lymphoedema and cancer. | respiratory medicine |
10.1101/2022.03.09.22271906 | Idetification of CACNA1B (p.K567R) mutation responsible for familiar AVNRT | Atrioventricular nodal reentry tachycardia (AVNRT) is the most common form of paroxysmal supraventricular tachycardia (PSVT). The exact cause of AVNRT has not yet been found. However, an increasing number of reports suggest that AVNRT is hereditary, but no precise pathogenic gene has been found so far. In our study, we found that a point mutation of CACNA1B (p.K567R) which encoded the 1 subunit of N-type calcium channel (Cav 2.2), was cosegregated with AVNRT in one family. Previous research showed that overexpression and point mutations of human CACNA1B in zebrafish embryos may be related to abnormal heart rate. Telemetric ECG recordings showed that rats with a CACNA1B point mutation displayed sporadic supraventricular tachycardia and altered QRS complex morphology. In addition, the CACNA1B (p.K567R) rats presented a double path phenomenon and AVNRT induction by intracardiac electrophysiological examination. Indexes of heart rate variance in CACNA1B mutation rats showed an in cardiac sympathetic activity and an imbalance of cardiac sympathetic and parasympathetic activity. Single-cell RNA sequencing indicated that the number of neurons in the superior cervical ganglion (SCG) of mutant rats was higher than in wild-type (WT) rats, accompanied by an increased expression of CACNA1B. Functional enrichment in SCG proteomics suggests that point mutant rats have abnormalities in synaptic function and ion transport, which could lead to the release of neurotransmitters. This could affect the cardiac autonomic neural activity and lead to an imbalance in sympathetic and parasympathetic activity and the subsequent occurrence of AVNRT. Our findings indicate that CACNA1B (p.K567R) is the pathogenic gene of AVNRT in familial AVNRT and confirm that CACNA1B is the first definitive AVNRT pathogenic gene that has been discovered. | pathology |
10.1101/2022.03.08.22271796 | Derivation and external validation of clinical prediction rules identifying children at risk of linear growth faltering (stunting) presenting for diarrheal care | BackgroundNearly 150 million children under-5 years of age were stunted in 2020. We aimed to develop a clinical prediction rule (CPR) to identify children likely to experience additional stunting following acute diarrhea, to enable targeted approaches to prevent this irreversible outcome.
MethodologyWe used clinical and demographic data from the Global Enteric Multicenter Study (GEMS) study to build predictive models of linear growth faltering (decrease of [≥]0.5 or [≥]1.0 in height-for-age z-score [HAZ] at 60 day follow-up) in children [≤]59 months presenting with moderate-to-severe diarrhea (MSD), and community controls, in Africa and Asia. We screened variables using random forests, and assessed predictive performance with random forest regression and logistic regression using 5-fold cross-validation. We used the Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) study to A) re-derive, and B) externally validate our GEMS-derived CPR.
ResultsOf 7639 children in GEMS, 1744 (22.8%) experienced severe growth faltering ([≥]0.5 decrease in HAZ). In MAL-ED, we analyzed 5683 diarrhea episodes from 1322 children, of which 961(16.9%) episodes experienced severe growth faltering. Top predictors of growth faltering in GEMS were: age, HAZ at enrollment, respiratory rate, temperature, and number of people living in the household. The maximum AUC was 0.75 (95% CI: 0.75, 0.75) with 20 predictors, while 2 predictors yielded an AUC of 0.71 (95% CI: 0.71, 0.72). Results were similar in the MAL-ED re-derivation. A 2-variable CPR derived from children 0-23 months in GEMS had an AUC=0.63 (95% CI 0.62, 0.65), and AUC=0.68 (95% CI: 0.63, 0.74) when externally validated in MAL-ED.
ConclusionsOur findings indicate that use of prediction rules could help identify children at risk of poor outcomes after an episode of diarrheal illness. | public and global health |
10.1101/2022.03.08.22272086 | The Adaptive Olfactory Measure of Threshold (ArOMa-T): A rapid test of olfactory function | PurposeMany widely-used psychophysical tests of olfaction have limitations that can create barriers to adoption outside research settings. For example, tests that measure the ability to identify odors may confound sensory performance with memory recall, verbal ability, and past experience with the odor. Conversely, threshold-based tests typically avoid these issues, but are labor intensive. Additionally, many commercially available olfactory tests are slow and may require a trained administrator, making them impractical for use in a short wellness visit or other broad clinical assessment.
MethodsWe tested the performance of the Adaptive Olfactory Measure of Threshold (ArOMa-T) - a novel odor detection threshold test that employs an adaptive Bayesian algorithm paired with a disposable odor-delivery card - in a non-clinical sample of individuals (n=534) at the 2021 Twins Day Festival in Twinsburg, OH.
ResultsParticipants successfully completed the test in under 3 min with a false alarm rate of 9.6% and a test-retest reliability of 0.61. Odor detection thresholds differed by sex ([~]3.2-fold) and between the youngest and oldest age groups ([~]8.7-fold), consistent with prior work. In an exploratory analysis, we failed to observe evidence of detection threshold differences between participants who reported a history of COVID-19 and matched controls who did not. We also found evidence for broad-sense heritability of odor detection thresholds.
ConclusionTogether, these data indicate the ArOMa-T can determine odor detection thresholds. The ArOMa-T may be particularly valuable in clinical or field settings where rapid and portable assessment of olfactory function is needed. | otolaryngology |
10.1101/2022.03.08.22272086 | The Adaptive Olfactory Measure of Threshold (ArOMa-T): A rapid test of olfactory function | PurposeMany widely-used psychophysical tests of olfaction have limitations that can create barriers to adoption outside research settings. For example, tests that measure the ability to identify odors may confound sensory performance with memory recall, verbal ability, and past experience with the odor. Conversely, threshold-based tests typically avoid these issues, but are labor intensive. Additionally, many commercially available olfactory tests are slow and may require a trained administrator, making them impractical for use in a short wellness visit or other broad clinical assessment.
MethodsWe tested the performance of the Adaptive Olfactory Measure of Threshold (ArOMa-T) - a novel odor detection threshold test that employs an adaptive Bayesian algorithm paired with a disposable odor-delivery card - in a non-clinical sample of individuals (n=534) at the 2021 Twins Day Festival in Twinsburg, OH.
ResultsParticipants successfully completed the test in under 3 min with a false alarm rate of 9.6% and a test-retest reliability of 0.61. Odor detection thresholds differed by sex ([~]3.2-fold) and between the youngest and oldest age groups ([~]8.7-fold), consistent with prior work. In an exploratory analysis, we failed to observe evidence of detection threshold differences between participants who reported a history of COVID-19 and matched controls who did not. We also found evidence for broad-sense heritability of odor detection thresholds.
ConclusionTogether, these data indicate the ArOMa-T can determine odor detection thresholds. The ArOMa-T may be particularly valuable in clinical or field settings where rapid and portable assessment of olfactory function is needed. | otolaryngology |
10.1101/2022.03.08.22272093 | Chromosomal microarray analyses from 5,778 patients with neurodevelopmental disorders and congenital anomalies in Brazil | Chromosomal microarray analysis (CMA) has been recommended and practiced routinely since 2010 in USA and Europe as the first-tier cytogenetic test for patients with unexplained neurodevelopmental delay/intellectual disability, autism spectrum disorders, and/or multiple congenital anomalies. However, in Brazil, the use of CMA is still limited, due to its high cost and complexity of the combination of private and public health systems. Although the country has one of the world largest single payer public healthcare system, nearly all patients referred for CMA come from the private sector. This reflects on the small number of CMA studies in Brazilian cohorts. This study is by far the largest Brazilian cohort (n=5,788) studied by CMA and results from a joint collaboration formed by the University of Sao Paulo and three private genetic diagnostic centers to investigate the genetic bases of neurodevelopmental disorders and congenital abnormalities. It is common practice to investigate the inheritance of VUS; however, our results indicate an extremely low cost-benefit of this approach, and strongly suggest that in cases of limited budget, investigation of the parents of VUS carriers using CMA should not be prioritized. Another aspect discussed is the classification of variants of low penetrance, once CNV classification is mostly designed to Mendelian or highly-penetrant variants. | genetic and genomic medicine |
10.1101/2022.03.08.22272114 | The Construction of Multi-ethnic Polygenic Risk Score using Transfer Learning | As most existing genome-wide association studies (GWAS) were conducted in European ancestry cohorts and as the existing PRS models have limited transferability across ancestry groups, PRS research on non-European ancestry groups is negatively impacted. Here we propose a novel PRS method using transfer learning techniques. Our approach, TL-PRS, uses gradient descent to fine-tune the baseline PRS model from an ancestry group with large sample GWAS to the dataset of target ancestry. In our application of constructing PRS for the six quantitative and two dichotomous traits for 10,285 South Asian and 8,168 African ancestry individuals in UK Biobank, TL-PRS achieved up to 42% average relative improvement compared to the existing methods. Our approach increases the transferability of PRSs across ancestries and thereby helps reduce existing inequities in genetics research. | genetic and genomic medicine |
10.1101/2022.03.08.22272111 | Risk Perceptions and Private Protective Behaviors: Evidence from COVID-19 Pandemic | We analyze data from a survey we administered during the COVID-19 pandemic to investigate the relationship between peoples subjective beliefs about risks and their private protective behaviors. On average, people substantially overestimate the absolute level of risk associated with economic activity, but have correct signals about their relative risk. Subjective risk beliefs are predictive of changes in economic activities independently of government policies. Government mandates restricting economic behavior, in turn, attenuate the relationship between subjective risk beliefs and protective behaviors. | health policy |
10.1101/2022.03.09.22271972 | Pharmaceutical Payments to Japanese Board-certified Infectious Disease Specialists: A Four-year Retrospective Analysis of Payments from 92 Pharmaceutical Companies between 2016 and 2019 | ObjectiveConflict of interest with pharmaceutical companies is one of the most contentious issues in infectious diseases. However, there is a lack of whole picture of detailed payments in Japan.
Study Design and SettingThis retrospective study assessed financial relationships between pharmaceutical companies and all infectious disease specialists board-certified by the Japanese Association for Infectious Disease, using publicly disclosed payment data from 92 pharmaceutical companies. Descriptive analyses were conducted for the payments. Payment trends were examined by the generalized estimating equations.
ResultsOf 1614 board-certified infection disease specialists, 1,055 (65.4%) received a total of $17,784,070 payments, corresponding to 21,680 cases between 2016 and 2019. The mean{+/-}SD and median (interquartile range: IQR) were $16,857{+/-}$45,010 and $3,183 ($938{square}$11,250) in payments. All board executive members of Japanese Association of Infectious Disease received higher payments averaging $163,792. There were no significant changes in payments per specialist (annual change rate: -1.4% [95% CI: -4.7{square}2.3%], p=0.48) and prevalence of specialists with payments (annual change rate: -1.4% [95% CI: -3.1%{square}0.2%], p=0.093) over the four years.
ConclusionThere were substantial financial relationships between pharmaceutical companies and board-certified infectious disease specialists in Japan. Such personal payments must be restricted to a certain level to avoid potential conflict of interest. | health policy |
10.1101/2022.03.08.22272037 | Impact of Epstein-Barr virus co-infection on natural acquired Plasmodium vivax antibody response | BackgroundThe simultaneous infection of Plasmodium falciparum and Epstein-Barr virus (EBV) could promote the development of the aggressive endemic Burkitts Lymphoma (eBL) in children living in P. falciparum holoendemic areas. While it is well-established that eBL is not related to other human malaria parasites, the impact of EBV infection on the generation of human malaria immunity remains largely unexplored. Considering that this highly prevalent herpesvirus establishes a lifelong persistent infection on B-cells with possible influence on malaria immunity, we hypothesized that EBV co-infection could have impact on the naturally acquired antibody responses to P. vivax, the most widespread human malaria parasite.
Methodology/Principal FindingsThe study design involved three cross-sectional surveys at six-month intervals (baseline, 6 and 12 months) among long-term P. vivax exposed adults living in the Amazon rainforest. The approach focused on a group of malaria-exposed individuals whose EBV-DNA (amplification of balf-5 gene) was persistently detected in the peripheral blood (PersVDNA, n=27), and an age-matched malaria-exposed group whose EBV-DNA could never be detected during the follow-up (NegVDNA, n=29). During the follow-up period, the serological detection of EBV antibodies to lytic/ latent viral antigens showed that IgG antibodies to viral capsid antigen (VCA-p18) were significantly different between groups (PersVDNA > NegVDNA). A panel of blood-stage P. vivax antigens covering a wide range of immunogenicity confirmed that in general PersVDNA group showed low levels of antibodies as compared with NegVDNA. Interestingly, more significant differences were observed to a novel DBPII immunogen, named DEKnull-2, which has been associated with long-term neutralizing antibody response. Differences between groups were less pronounced with blood-stage antigens (such as MSP1-19) whose levels can fluctuate according to malaria transmission.
Conclusions/SignificanceIn a proof-of-concept study we provide evidence that a persistent detection of EBV DNA in peripheral blood of adults in a P. vivax semi-immune population may impact the long-term immune response to major malaria vaccine candidates.
Author SummaryIn the Amazon rain forest, both Plasmodium vivax and Epstein-Barr virus (EBV) infections are common, yet the Burkitts lymphoma (BL) is rare, despite an association between endemic BL with chronic P. falciparum exposure. Nevertheless, the influence of EBV infection on malaria immunity remains undetermined. Here, we investigated for the first time whether continuous detection of EBV DNA in the peripheral blood of adults exposed to P. vivax could impact the antibody response to blood-stage malaria vaccine candidates. The methodological approach involved 12-month follow-up among P. vivax-exposed Amazonian classified as persistent EBV-DNA carriers (PersVDNA) and an age-matched group with no viral DNA detection (NegVDNA); groups were further differentiated based on profile of viral antibodies (mainly IgG VCA-p18). Collectively, our findings demonstrated that antibody levels against P. vivax antigens were in general lower in the PersVDNA group as compared with NegVDNA. More significant differences were observed to a novel vaccine candidate (DEKnull-2) whose antibody response were previously associated with broadly neutralizing P. vivax antibodies. Differences between groups were less pronounced with P. vivax antigens associated with seasonal changes in the antibody responses. In this conceptual study, we provide evidence that long-term detection of EBV in peripheral blood may impact immune response to major malaria vaccine candidates. | infectious diseases |
10.1101/2022.03.09.22272125 | Performance evaluation of a non-invasive one-step multiplex RT-qPCR assay for detection of SARS-CoV-2 direct from human saliva | Polymerase chain reaction (PCR) has proven to be the gold-standard for SARS-CoV-2 detection in clinical settings. The most common approaches rely on nasopharyngeal specimens obtained from swabs, followed by RNA extraction, reverse transcription and quantitative PCR. Although swab-based PCR is sensitive, swabbing is invasive and unpleasant to administer, reducing patient compliance for regular testing and resulting in an increased risk of improper sample collection. To overcome these obstacles, we developed a non-invasive one-step RT-qPCR assay performed directly on saliva specimens. The University of Nottingham Asymptomatic Testing Service (UoNATS) protocol simplifies sample collection and bypasses the need for RNA extraction, additives, or extraneous processing steps, thus helping to encourage more regular testing and reducing processing time and costs. We have evaluated the assay against the performance criteria specified by the UK regulatory bodies and attained accreditation (BS EN ISO/IEC 17025:2017) for SARS-CoV-2 diagnostic testing by the United Kingdom Accreditation Service (UKAS). We observed a sensitivity of 1 viral copy per microlitre of saliva and demonstrated a concordance of >99.4% between our results and those of other accredited testing facilities. We concluded that saliva is a stable medium with surprising longevity, and allows for a highly precise, repeatable, and robust testing method. | infectious diseases |
10.1101/2022.03.09.22271788 | Comparison of influenza and COVID-19-associated hospitalizations among children < 18 years old in the United States - FluSurv-NET (October-April 2017-2021) and COVID-NET (October 2020-September 2021) | BackgroundInfluenza virus and SARS-CoV-2 are significant causes of respiratory illness in children.
MethodsInfluenza and COVID-19-associated hospitalizations among children <18 years old were analyzed from FluSurv-NET and COVID-NET, two population-based surveillance systems with similar catchment areas and methodology. The annual COVID-19-associated hospitalization rate per 100 000 during the ongoing COVID-19 pandemic (October 1, 2020-September 30, 2021) was compared to influenza-associated hospitalization rates during the 2017-18 through 2019-20 influenza seasons. In-hospital outcomes, including intensive care unit (ICU) admission and death, were compared.
ResultsAmong children <18 years old, the COVID-19-associated hospitalization rate (48.2) was higher than influenza-associated hospitalization rates: 2017-18 (33.5), 2018-19 (33.8), and 2019-20 (41.7). The COVID-19-associated hospitalization rate was higher among adolescents 12-17 years old (COVID-19: 59.9; influenza range: 12.2-14.1), but similar or lower among children 5-11 (COVID-19: 25.0; influenza range: 24.3-31.7) and 0-4 (COVID-19: 66.8; influenza range: 70.9-91.5) years old. Among children <18 years old, a higher proportion with COVID-19 required ICU admission compared with influenza (26.4% vs 21.6%; p<0.01). Pediatric deaths were uncommon during both COVID-19- and influenza-associated hospitalizations (0.7% vs 0.5%; p=0.28).
ConclusionsIn the setting of extensive mitigation measures during the COVID-19 pandemic, the annual COVID-19-associated hospitalization rate during 2020-2021 was higher among adolescents and similar or lower among children <12 years old compared with influenza during the three seasons before the COVID-19 pandemic. COVID-19 adds substantially to the existing burden of pediatric hospitalizations and severe outcomes caused by influenza and other respiratory viruses.
SummaryAnnual hospitalization rates and proportions of hospitalized children experiencing severe outcomes were as high or higher for COVID-19 during October 2020-September 2021 compared with influenza during the three seasons before the COVID-19 pandemic, based on U.S. population-based surveillance data. | infectious diseases |
10.1101/2022.03.08.22272101 | Not all mosquitoes are created equal: incriminating mosquitoes as vectors of arboviruses | The globalization of mosquito-borne arboviral diseases has placed more than half of the human population at risk. Understanding arbovirus ecology, including the role individual mosquito species play in virus transmission cycles, is critical for limiting disease. Canonical virus-vector groupings, such as Aedes- or Culex-associated flaviviruses, have historically been defined using phylogenetic associations, virus isolation in the field, and mosquito feeding patterns. These associations less frequently rely on vector competence, which quantifies the intrinsic ability of a mosquito to become infected with and transmit a virus during a subsequent blood feed. Herein, we quantitatively synthesize data from 80 laboratory vector competence studies of 115 mosquito-virus pairings of Australian mosquito species and viruses of public health concern to further substantiate existing canonical vector-virus groupings, uncover new associations, and quantify variation within these groupings. Our synthesis reinforces current canonical vector-virus groupings but reveals substantial variation within them. While Aedes species were generally the most competent vectors of canonical "Aedes-associated flaviviruses" (such as dengue, Zika, and yellow fever viruses), there are some notable exceptions; for example, Aedes notoscriptus is an incompetent vector of dengue viruses. Culex spp. were the most competent vectors of many traditionally Culex-associated flaviviruses including West Nile, Japanese encephalitis and Murray Valley encephalitis viruses, although some Aedes spp. are also moderately competent vectors of these viruses. Conversely, many mosquito genera were associated with the transmission of the arthritogenic alphaviruses, Ross River, Barmah Forest, and chikungunya viruses. We also confirm that vector competence is impacted by multiple barriers to infection and transmission within the mesenteron and salivary glands of the mosquito. Although these barriers represent important bottlenecks, species that were susceptible to infection with a virus were often likely to transmit it. Importantly, this synthesis provides essential information on what species need to be targeted in mosquito control programs.
Author summaryThere are over 3,500 species of mosquitoes in the world, but only a small proportion are considered important vectors of arboviruses. Vector competence, the physiological ability of a mosquito to become infected with and transmit arboviruses, is used in combination with virus detection in field populations and analysis of vertebrate host feeding patterns to incriminate mosquito species in virus transmission cycles. Here, we quantified the vector competence of Australian mosquitoes for endemic and exotic viruses of public health concern by analyzing 80 laboratory studies of 115 mosquito-virus pairings. We found that Australia has species that could serve as efficient vectors for each virus tested and it is these species that should be targeted in control programs. We also corroborate previously identified virus-mosquito associations at the mosquito genus level but show that there is considerable variation in vector competence between species within a genus. We also confirmed that vector competence is influenced by infection barriers within the mosquito and the experimental protocols employed. The framework we developed could be used to synthesize vector competence experiments in other regions or expanded to a world-wide overview. | infectious diseases |
10.1101/2022.03.09.22272138 | Risks for death after admission to pedaitric intensive care (PICU) - a comparison with the general population | Objective/AimThe aim of the study was to investigate the mortality rate in children after admission to a Pediatric Intensive Care Unit (PICU), compared to the matched general Swedish population.
DesignSingle-center, retrospective cohort study.
SettingRegistry study of hospital registers, a national population register and Statistics Sweden.
PatientsChildren admitted to a tertiary PICU in Sweden in 2008-2016.
InterventionsNone
Main ResultsIn total, 6,487 admissions (4,682 patients) were included in the study. During the study period 444 patients died. Median follow-up time for the entire PICU cohort was 7.2 years (IQR 5.0-9.9 years). Patients were divided into four different age groups (0-28 d, > 28 d -1 yr, > 1-4 yr, and > 4 yr) and four different risk stratification groups [Predicted Death Rate (PDR) intervals: 0-10%, > 10-25%, > 25-50%, and > 50%] at admission. Readmission was seen in 929 (19.8%) patients. The Standardized Mortality Ratios (SMRs) were calculated using the matched Swedish population as a reference group. The SMR for the entire study group was 49.8 (95% CI: 44.8-55.4). For patients with repeated PICU admissions SMR was 108.0 (95% CI: 91.9-126.9), and after four years 33.9 (95% CI: 23.9-48.0). Patients with a single admission had a SMR of 35.2 (95% CI: 30.5-40.6), and after four years 11.0 (95% CI: 7.0-17.6). The highest SMRs were seen in readmitted children with oncology/hematology (SMR=358) and neurologic (SMR=192) diagnosis. Children aged >1-4 years showed the highest SMR (325). In PDR group 0-10% children with repeated PICU admissions (n=798), had a SMR of 100.
ConclusionSMRs were greatly elevated up to four years after PICU admission, declining from over 100 to 33 for patients with repeated PICU admissions, and from 35 to 11 for patients with a single PICU admission, compared to the matched Swedish population. | intensive care and critical care medicine |
10.1101/2022.03.08.22271329 | Genetic overlap between mood instability and alcohol-related phenotypes suggests shared biological underpinnings | Alcohol use disorder (AUD) is a pervasive and devastating mental illness with high comorbidity rates with other mental disorders. We aimed to characterize the shared vs. unique polygenicity of AUD, alcohol consumption (AC) and mood instability (MOOD), a relevant transdiagnostic factor, using large genome-wide association studies (GWASs) data. We hypothesize that cross-analyzing these phenotypes would shed light on their unique and shared polygenicity, increase our knowledge regarding the genetic basis of the comorbidity between AUD and mood disorders, and boost discovery for jointly-associated loci. Summary statistics for MOOD, AC and AUD GWASs (Ns =363,705; 200,680 and 200,004; respectively) were analysed to characterize the cross-phenotype associations between MOOD and AC, MOOD and AUD and AC and AUD, respectively. To do so, we used a newly-established pipeline that combines (i) the bivariate causal mixture model (MiXeR) to quantify the cross-phenotype polygenic overlap and (ii) the conjunctional false discovery rate (conjFDR) to discover specific jointly-associated genomic loci. These loci were functionally characterized and mapped to genes and biological functions. We also performed validation in independent samples and phenotypic analyses. MOOD was highly polygenic (10,400 single nucleotide polymorphisms, SNPs) compared to AC and AUD (4,900 SNPs, SD =600 and 4,300 SNPs, SD =2,000; respectively). The polygenic overlap of MOOD and AC was much larger than that of MOOD and AUD (98% vs. 49%) and genetic correlation was opposite (-0.2 vs. 0.23), which was confirmed in independent samples. MOOD&AUD causal SNPs were significantly enriched for brain genes, conversely to MOOD&AC. Among 38 loci identified in the joint analysis, sixteen were novel for MOOD, AC and AUD. Similarly distinct patterns were evidenced for SNP localization, function and previous GWAS associations outside of the phenotypes that were currently studied. MOOD, AC and AUD were also strongly associated at the phenotypic level. Overall, using multilevel polygenic quantification, joint loci discovery and functional annotation methods, we evidenced that the polygenic overlap between MOOD and AC/AUD implicated shared biological underpinnings but clearly distinct functional patterns between MOOD&AC and MOOD&AUD. Using the MOOD endophenotype, the current study suggests new mechanisms for the comorbidity of AUD with mood disorders. | addiction medicine |
10.1101/2022.03.08.22272041 | Impacts of COVID-19 on glycemia and risk of diabetic ketoacidosis | BackgroundReports indicate that COVID-19 may impact pancreatic function and increase type 2 diabetes (T2D) risk, although real-world COVID-19 impacts on HbA1c and T2D are unknown. We tested whether COVID-19 increased HbA1c, risk of T2D, or diabetic ketoacidosis (DKA).
MethodsWe compared pre- and post-COVID-19 HbA1c, and risk of developing T2D in a large real-world clinical cohort of 8,755 COVID-19(+) patients and a matched control cohort of 11,998 COVID-19(-) patients. We investigated if DKA risk was modified in COVID-19(+) patients with type 1 diabetes (T1D) (N=704) or T2D (N=22,904), or by race and sex.
FindingsWe observed a statistically significant, albeit clinically insignificant, HbA1c increase post-COVID-19 (all patients {Delta}HbA1c=0.06%, P<.001; with T2D {Delta}HbA1c=0.1%; P<.001), and no increase among COVID-19(-) patients (P>.05). COVID-19(+) patients were 40% more likely to be diagnosed with T2D compared to COVID-19(-) patients (P<.001) and 28% more likely to be diagnosed with T2D for the same HbA1c change as COVID-19(-) patients (P<.001). COVID-19(+) patients with T2D on insulin were 34% more likely to develop DKA compared to COVID-19(-) patients on insulin (P<.05), and COVID-19(+) Black patients with T2D displayed disproportionately increased DKA risk (HR:1.63, P=.007). There was no significant difference in DKA risk between COVID-19(+) and COVID-19(-) patients with T1D.
InterpretationDKA risk is increased in T2D patients on insulin and in Black patients with T2D after COVID-19 infection.T2D risk is greater in COVID-19(+) patients for the same HbA1c increase in COVID-19(-) patients, indicating that T2D risk attributed to COVID-19 may be due to increased recognition during COVID-19 management.
FundingNo funding to report. | endocrinology |
10.1101/2022.03.08.22272110 | Epidemiology and genomic analysis of Klebsiella oxytoca from a single hospital network in Australia | Infections caused by Klebsiella oxytoca are the second most common cause of Klebsiella infections in humans. Most studies to date have focused on K. oxytoca outbreaks and few have examined the broader clinical context of K. oxytoca. Here, we collected all clinical isolates identified as K. oxytoca in a hospital microbiological diagnostic lab across a 15-month period (n=239). The majority of isolates were sensitive to antimicrobials, however 22 isolates were resistant to third-generation cephalosporins (3GCR), of which five were also carbapenem resistant. Whole genome sequencing of a subset of 92 isolates (all invasive, 3GCR and non-urinary isolates collected >48h after admission) showed those identified as K. oxytoca by the clinical laboratory actually encompassed four distinct species (K. oxytoca, Klebsiella michiganensis, Klebsiella grimontii and Klebsiella pasteurii), referred to as the K. oxytoca species complex (KoSC). There was significant diversity within the population, with only 10/67 multi-locus sequence types (STs) represented by more than one isolate. Strain transmission was rare, with only a single likely event identified. Six isolates had either extended spectrum beta-lactamase (blaSHV-12 and/or blaCTX-M-9) or carbapenemase (blaIMP-4) genes. One pair of K. michiganensis and K. pasteurii genomes carried an identical blaIMP-4 IncL/M plasmid, indicative of plasmid transmission. Whilst antimicrobial resistance was rare, the resistance plasmids were similar to those found in other Enterobacterales, demonstrating that KoSC has access to the same plasmid reservoir and thus there is potential for multi-drug resistance. Further genomic studies are required to improve our understanding of the KoSC population and facilitate investigation into the attributes of successful nosocomial isolates. | epidemiology |
10.1101/2022.03.09.22271973 | Symptoms of depression and anxiety among Vietnamese immigrants in Japan during the COVID-19 pandemic | ObjectiveWe aimed to examine the mental health status and related factors among Vietnamese immigrants in Japan during the coronavirus disease 2019 (COVID-19) pandemic.
DesignOnline cross-sectional survey administered from September 21 to October 21, 2021
SettingOnline survey of Vietnamese immigrants in Japan
ParticipantsThe inclusion criteria for participation were 1) Vietnamese citizenship or Japanese citizenship in those of Vietnamese descent, current residence in Japan, and 2) age [≥]18 years.
Main OutcomesPatient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder 7-item (GAD-7) scores were considered the main outcome measures. Multivariable logistic regression was used to identify factors related to symptoms of depression and anxiety, and the chosen variables were entered simultaneously in the survey.
ResultsAmong 621 participants (age: 26.0{+/-}4.8 years; male: 347 [55.9%]) who completed the questionnaire, 73.7% reported a decrease in income when compared with the period before the COVID-19 pandemic, and 60.4% reported being recently affected by poor socioeconomic status. Moderate-to-severe symptoms of depression (PHQ-9 score [≥]10 points) and mild-to-severe symptoms of anxiety (GAD-7 [≥]5 points) were observed in 203 (32.7%) and 285 (45.9%) individuals, respectively. Factors related to depressive symptoms were age (odds ratio [OR]=0.94, p=0.043), medical or psychiatric co-morbidity (OR=2.46, p<0.001), and low socioeconomic status (OR=2.47, p<0.001). Factors related to anxiety symptoms were being single (OR=1.72, p=0.044), medical or psychiatric co-morbidity (OR=2.52, p<0.001), low socioeconomic status (OR=2.72, p<0.001), and absence of a partner with whom to discuss ones health (OR=1.66, p=0.013).
ConclusionsThe current findings demonstrate that, when compared with Japanese citizens, Vietnamese immigrants experienced a decrease in income, worsening working conditions, and poor mental health status during the COVID-19 pandemic. These findings highlight the potential contribution of low socioeconomic status and social isolation to poor mental health status.
Strengths and limitations of this studyO_LIVietnamese immigrants, who are the second largest immigrant group in Japan, were studied. No previous assessment of their mental health during the COVID-19 pandemic has been carried out.
C_LIO_LIThis study provided a non-contact approach to prevent infection using online surveys. Therefore, we received a wide range of responses from areas with low COVID-19 infection rate area to high COVID-19 infection rate area in Japan.
C_LIO_LIThe survey may not be a complete representation of all Vietnamese immigrants living in Japan, as some elderly Vietnamese immigrants may not have been able to participate due to the online format.
C_LI | psychiatry and clinical psychology |
10.1101/2022.03.09.22271973 | Symptoms of depression and anxiety among Vietnamese immigrants in Japan during the COVID-19 pandemic: a cross-sectional web-based study | ObjectiveWe aimed to examine the mental health status and related factors among Vietnamese immigrants in Japan during the coronavirus disease 2019 (COVID-19) pandemic.
DesignOnline cross-sectional survey administered from September 21 to October 21, 2021
SettingOnline survey of Vietnamese immigrants in Japan
ParticipantsThe inclusion criteria for participation were 1) Vietnamese citizenship or Japanese citizenship in those of Vietnamese descent, current residence in Japan, and 2) age [≥]18 years.
Main OutcomesPatient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder 7-item (GAD-7) scores were considered the main outcome measures. Multivariable logistic regression was used to identify factors related to symptoms of depression and anxiety, and the chosen variables were entered simultaneously in the survey.
ResultsAmong 621 participants (age: 26.0{+/-}4.8 years; male: 347 [55.9%]) who completed the questionnaire, 73.7% reported a decrease in income when compared with the period before the COVID-19 pandemic, and 60.4% reported being recently affected by poor socioeconomic status. Moderate-to-severe symptoms of depression (PHQ-9 score [≥]10 points) and mild-to-severe symptoms of anxiety (GAD-7 [≥]5 points) were observed in 203 (32.7%) and 285 (45.9%) individuals, respectively. Factors related to depressive symptoms were age (odds ratio [OR]=0.94, p=0.043), medical or psychiatric co-morbidity (OR=2.46, p<0.001), and low socioeconomic status (OR=2.47, p<0.001). Factors related to anxiety symptoms were being single (OR=1.72, p=0.044), medical or psychiatric co-morbidity (OR=2.52, p<0.001), low socioeconomic status (OR=2.72, p<0.001), and absence of a partner with whom to discuss ones health (OR=1.66, p=0.013).
ConclusionsThe current findings demonstrate that, when compared with Japanese citizens, Vietnamese immigrants experienced a decrease in income, worsening working conditions, and poor mental health status during the COVID-19 pandemic. These findings highlight the potential contribution of low socioeconomic status and social isolation to poor mental health status.
Strengths and limitations of this studyO_LIVietnamese immigrants, who are the second largest immigrant group in Japan, were studied. No previous assessment of their mental health during the COVID-19 pandemic has been carried out.
C_LIO_LIThis study provided a non-contact approach to prevent infection using online surveys. Therefore, we received a wide range of responses from areas with low COVID-19 infection rate area to high COVID-19 infection rate area in Japan.
C_LIO_LIThe survey may not be a complete representation of all Vietnamese immigrants living in Japan, as some elderly Vietnamese immigrants may not have been able to participate due to the online format.
C_LI | psychiatry and clinical psychology |
10.1101/2022.03.09.22272128 | Protocol for a multi-site case control study evaluating child and adolescent mental health service transformation in England using the i-THRIVE model | The National i-THRIVE Programme seeks to evaluate the impact of the NHS England-funded whole system transformation on child and adolescent mental health services (CAMHS). This article reports on the design for a model of implementation that has been applied in CAMHS across over 70 areas in England using the THRIVE needs-based principles of care. The implementation protocol in which this model, i-THRIVE (implementing-THRIVE), will be used to evaluate the effectiveness of the THRIVE intervention is reported, together with the evaluation protocol for the process of implementation. To evaluate the effectiveness of i-THRIVE to improve care for children and young peoples mental health, a case-control design will be conducted. N = 10 CAMHS sites that adopt the i-THRIVE model from the start of the NHS England-funded CAMHS transformation will be compared to N = 10 comparator sites that choose to use different transformation approaches within the same timeframe. Sites will be matched on population size, urbanicity, funding, level of deprivation and expected prevalence of mental health care needs. To evaluate the process of implementation, a mixed-methods approach will be conducted to explore the moderating effects of context, fidelity, dose, pathway structure and reach on clinical and service level outcomes. This study addresses a unique opportunity to inform the ongoing national transformation of CAMHS with evidence about a popular new model for delivering children and young peoples mental health care, as well as a new implementation approach to support whole system transformation. If the outcomes reflect benefit from i-THRIVE, this study has the potential to guide significant improvements in CAMHS by providing a more integrated, needs-led service model that increases access and involvement of patients with services and in the care they receive. | psychiatry and clinical psychology |
10.1101/2022.03.09.22272127 | Cultural adaptation of the person-centered maternity care scale at governmental health facilities in Cambodia | BackgroundIn Cambodia, the importance of valuing womens childbirth experiences in improving quality of care has been understudied. This is largely because of absence of reliable Khmer tools for measuring womens intrapartum care experiences. Generally, cross-cultural development of those tools often involves translation from a source language into a target language. Yet, few earlier studies considered Cambodian cultural context. Thus, we developed the Cambodian version of the Person-Centered Maternity Care (PCMC) scale, by culturally adapting its original to Cambodian context for ensuring cultural equivalence and content validity.
MethodsThree rounds of cognitive interviewing with 20 early postpartum women were conducted at two governmental health facilities in Cambodia. Cognitive interviewing was composed of structured questionnaire pretesting and qualitative probing. The issues identified in the process of transcribing and translating audio-recorded cognitive interviews were iteratively discussed among study team members, and further analyzed.
ResultsA total of 14 issues related to cultural adaptations were identified in the 31 translated questions for the Cambodian version of the PCMC scale. Our study identified three key findings: (i) discrepancies between the WHO recommendations on intrapartum care and Cambodian field realities; (ii) discrepancies in recognition on PCMC between national experts and local women; and (iii) challenges in correctly collecting and interpreting less-educated womens views on intrapartum care.
ConclusionNot only womens verbal data but also their non-verbal data and cultural contexts should be comprehensively counted, when reflecting Cambodian womens intrapartum practice realities in the translated version. This is the first study that attempted to develop the tool for measuring Cambodian womens experiences during childbirth, by addressing cross-cultural issues. | sexual and reproductive health |
10.1101/2022.03.08.22272112 | Blood transcriptomic biomarkers of alcohol consumption and cardiovascular disease risk factors: the Framingham Heart Study | BackgroundThe relations of alcohol consumption and gene expression remain to be elucidated in large study samples.
ObjectivesTo study the relationship between alcohol consumption, gene expression, and cardiovascular disease (CVD) risk factors.
MethodsWe performed cross-sectional association analysis of whole blood derived gene expression levels with alcohol consumption in 5,531 Framingham Heart Study (FHS) participants (mean age 55 years; 54% women) by splitting the sample into a discovery sample and a replication sample (2:1 ratio) using independent pedigrees. We also examined the cross-sectional association of alcohol-associated genes with three CVD risk factors: obesity, hypertension, and diabetes. Linear mixed models or generalized estimation equations were used to quantify associations accounting for familial relationship and multiple covariates.
ResultsWe identified 25 alcohol-associated genes (false discovery rate < 0.05 in the discovery sample and Bonferroni corrected P < 0.05 in the replication sample). We further showed cross-sectional associations of 16 alcohol-associated genes with obesity, nine genes with hypertension, and eight genes with diabetes (all P < 0.002). For example, we observed decrease in expression of PROK2 ({beta} = -0.0018; 95%CI: -0.0021, -0.0007; P = 6.5e-5) and PAX5 ({beta} = -0.0014; 95%CI: -0.0021, -0.0007; P = 6.5e-5) per 1 g/day increase in alcohol consumption. Consistent with our previous observation on the inverse association of alcohol consumption with obesity and positive association of alcohol consumption with hypertension, we found that PROK2 was positively associated with obesity (OR = 1.42; 95%CI: 1.17, 1.72; P = 4.5e-4) and PAX5 was negatively associated with hypertension (OR = 0.73; 95%CI: 0.59, 0.89; P = 1.6e-3). We also observed that alcohol consumption was positively associated with expression of ABCA13 ({beta} = 0.0012; 95%CI: 0.0007, 0.0017; P = 1.3e-6) and ABCA13 was positively associated with diabetes (OR = 2.57; 95%CI: 1.73, 3.84; P = 3.5e-06); this finding, however, was inconsistent with our observation on the inverse association between alcohol consumption and diabetes.
ConclusionsWe observed that alcohol consumption was associated with whole blood expression levels of 25 genes in middle aged to older adults in the FHS. In addition, complex relationships may exist between alcohol-associated genes and CVD risk factors. | nutrition |
10.1101/2022.03.09.22271599 | Evaluation of systemic immune response in patients with inflammatory complications of large joint replacements | We studied the features of systemic immunity in patients with inflammatory complications of their knee replacements and used the factor analysis to find immune characteristics associated with the progress of the pathological condition. The components indicative of changes related to the development of cell and humoral immune response in patients were isolated. Our findings present prospects for the development of new diagnostic techniques ensuring higher precision in searching for adequate surgical methods. | orthopedics |
10.1101/2022.03.09.22272129 | Multiple Sclerosis: Exploring the Limits of Genetic and Environmental Susceptibility | OBJECTIVETo explore the nature of genetic and environmental susceptibility to multiple sclerosis (MS) and to define the limits of this nature based on the statistical uncertainties regarding the various epidemiological observations that have been made.
BACKGROUNDCertain parameters of MS-epidemiology can be directly observed (e.g., the risk of MS-recurrence in siblings and twins of an MS proband, the proportion of women among MS patients, the population-prevalence of MS, and the time-dependent changes in the sex-ratio). By contrast, other parameters can only be inferred from the observable parameters (e.g., the proportion of the population that is genetically susceptible, the proportion of women among susceptible individuals, the probability that a susceptible individual will experience an environment sufficient to cause MS given their genotype, and if they do, the probability that they will ultimately develop the disease).
DESIGN/METHODSThe "genetically-susceptible" subset (G) of the population (Z) is defined to include everyone with any non-zero life-time chance of developing MS. For the observed parameters, plausible ranges are assigned values such that they include either the 95% confidence intervals or the estimated parameter-ranges for each observation. By contrast, for the non-observed parameters, the ranges are assigned such that they cover any plausible value for each parameter. Using both a Cross-sectional Model and a Longitudinal Model, together with established parameter relationships, we explore iteratively trillions of potential parameter combinations and determine those combinations (solutions) that are constrained by the observed parameter ranges.
RESULTSUsing both Models, under all circumstances, genetic-susceptibitly is limited to to less than 52% of the population. If solutions are excluded, in which susceptible women either comprise less than 18% of susceptible individuals or have a penetrance more than 20 times that in susceptible men, then both Models agree that genetic-susceptibility is limited to less than 12% of the population. Consequently, a large number (and likely the large majority) of individuals have no chance whatsoever of developing MS, regardless of their environmental exposure. Also, although the penetrance of MS in susceptible women is greater than it is in men and, for most solutions, susceptible men outnumber susceptible women. As expected, the probability that susceptible individuals will develop MS increases with an increased likelihood of individuals experiencing a sufficient environmental exposure. Nevertheless, as this probability approaches 1, these response-curves plateau at <64% for women and at <23% for men. Finally, under current environmental conditions are such that more than 68% of susceptible individuals are experiencing an environment sufficient to cause MS given their particular genotype.
CONCLUSIONSThe development of clinical MS (in an individual) requires both that they have the appropriate genotype (which is quite rare in the population) and that they have an environmental exposure sufficient to cause MS given their particular genotype (which is currently quite common among susceptible individuals). Nevertheless, even when the necessary genetic and environmental factors, required for MS pathogenesis, co-occur for an individual, this is still insufficient for that person to develop MS. Rather, disease pathogenesis, even in this circumstance, involves an important element of chance.
Author SummaryCertain parameters of MS-epidemiology can be directly observed. These parameters include the risk of MS recurrence in siblings and twins of an MS proband, the proportion of women among MS patients, the population-prevalence of MS, and the time-dependent changes in the sex-ratio. By contrast, there are other parameters of MS-epidemiology, which cant be observed, but which must be inferred based on the values of the observable parameters. These parameters include the proportion of the general population (Z) that is genetically susceptible to MS, the proportion of women among susceptible individuals, the probability that a susceptible individual will experience an environment sufficient to cause MS, and if they do, the likelihood that they will actually develop the MS. We define the subset (G) - i.e., the genetically-susceptible subset - to include everyone in (Z) who has any non-zero chance of developing MS over their life-time. For the observed parameters, plausible ranges are assigned values such that they include either the 95% confidence intervals or the estimated parameter-ranges for each observation. By contrast, for the non-observed parameters, the ranges are assigned such that they cover any plausible value for each parameter. Then, using both a Cross-sectional Model and a Longitudinal Model, together with established parameter relationships, we explore iteratively trillions of potential parameter combinations and determine those combinations (solutions) that are constrained by the observed parameter values. The Cross-sectional Model requires two assumptions, commonly made in studies of monozygotic twins, to establish certain relationships between the observed and non-observed parameters. By contrast, the Longitudinal Model makes neither of these assumptions but, rather, this Model utilizes the observed changes in the female-to-male (F:M) sex-ratio, which have taken place over the past 4-5 decades, to determine the response curves for susceptible individuals, relating their probability of developing MS to their probability of experiencing an environment sufficient to cause MS. Using both of these analytic Models, under all circumstances, genetic-susceptibitly is limited to to less than 52% of the population. If solutions are excluded, in which susceptible women either comprise less than 18% of susceptible individuals or have a penetrance greater than 20 times that in susceptible men, then both Models agree that genetic-susceptibility is limited to less than 12% of the population. Consequently, a large number (and likely the large majority) of individuals have no chance whatsoever of developing MS, regardless of their environmental experiences. Also, the penetrance of MS in susceptible women is considerably greater than it is in men although, for most solutions, susceptible men outnumber susceptible women. As expected, MS-probability increases with an greater likelihood of a sufficient environmental exposure although these response-curves plateau at <64% for women and at <27% for men. Finally, the current environmental conditions are such that more than 68% of susceptible individuals, at present, are experiencing an environment sufficient to cause MS given their particular genotype. Consequently, the development of clinical MS (in an individual) requires both that they have the appropriate genotype (which is quite rare in the population) and that they have an environmental exposure sufficient to cause MS given their individual genotype (which is currently quite common among susceptible individuals). Nevertheless, even when the necessary genetic and environmental factors, required for MS pathogenesis, co-occur for an individual, this is still insufficient for that person to develop MS. Rather, disease pathogenesis, even in this circumstance, involves an important element of chance. | genetic and genomic medicine |
10.1101/2022.03.09.22272139 | Longitudinal associations between perceived stress and anhedonia during psychotherapy | BackgroundChronic stress alters reward sensitivity and contributes to the emergence of anhedonia. In clinical samples, the perception of stress is a strong predictor of anhedonia. While there is substantial evidence demonstrating psychotherapy reduces perceived stress, little is known regarding the effects of treatment-related decreases in perceived stress on anhedonia.
MethodsThe current study investigated reciprocal relations between perceived stress and anhedonia using a cross-lagged panel model approach in a 15-week clinical trial examining the effects of Behavioral Activation Treatment for Anhedonia (BATA), a novel psychotherapy to treat anhedonia, compared to a Mindfulness-Based Cognitive Therapy (MBCT) comparison intervention (ClinicalTrials.gov Identifiers NCT02874534 and NCT04036136).
ResultsTreatment completers (n=72) experienced significant reductions in anhedonia (M=-8.94, SD=5.66) on the Snaith-Hamilton Pleasure Scale (t(71)=13.39, p<.0001), and significant reductions in perceived stress (M=-3.71, SD=3.88) on the Perceived Stress Scale (t(71)=8.11, p<.0001) following treatment. Across all treatment-seeking participants (n=87), a longitudinal autoregressive cross-lagged model revealed significant paths showing that higher levels of perceived stress at treatment Week 1 predicted reductions in anhedonia at treatment Week 4.
ConclusionsLongitudinal models illustrated that individuals with relatively high perceived stress at the start of treatment were likely to report relatively lower anhedonia a few weeks into treatment. At mid-treatment, individuals with low perceived stress were more likely to report lower anhedonia towards the end of treatment. Early treatment components are thought to reduce perceived stress, allowing for mid-to-late treatment components to exert their direct effects on anhedonia. The findings presented here demonstrate the importance of including stress-reducing components in cognitive-behavioral-based anhedonia treatments. | psychiatry and clinical psychology |
10.1101/2022.03.02.22271425 | Polygenic risk vectors (PRV) improve genetic risk stratification for cardio-metabolic diseases | 1.Accurate disease risk stratification can lead to more precise and personalized prevention and treatment of diseases. As an important component to disease risk, genetic risk factors can be utilized as an early and stable predictor for disease onset. Recently, the polygenic risk score (PRS) method has combined the effects from hundreds to millions of single nucleotide polymorphisms (SNPs) into a score that can be used for genetic risk stratification. However, current PRS approaches only utilize the additive associations between SNPs and disease risk in a one-dimensional score. Here, we show that leveraging multiple types of genetic effects in multi-dimensional risk vectors, or a polygenic risk vector (PRV), can improve the stratification of cardio-metabolic diseases risks. Using data from UK Biobank (UKBB) and Electronic Medical Records and Genomics (eMERGE) Network biobank linked electronic health records (EHR) as development and evaluation data, we found that the combined effects between the additive PRS and the dominant PRS outperformed either one in terms of disease risk stratification, especially for the individuals in the high-risk group. Our results demonstrate that disease risks are likely to be influenced by multiple types of genetic effects, and PRV could utilize these effects for better risk stratification while retaining the simplicity of the PRS method. | genetic and genomic medicine |
10.1101/2022.03.08.22272076 | Avey: An Accurate AI Algorithm for Self-Diagnosis | ObjectivesTo present our AI-based symptom checker, rigorously measure its accuracy, and compare it against existing popular symptom checkers and seasoned primary care physicians.
DesignVignettes study.
Setting400 gold-standard primary care vignettes.
Intervention/ComparatorWe utilized 7 standard accuracy metrics for evaluating the performance of 6 symptom checkers. To this end, we developed and peer-reviewed 400 vignettes, each approved by at least 5 out of 7 independent and experienced general practitioners. To the best of our knowledge, this yielded the largest benchmark vignette suite in the field thus far. To establish a frame of reference and interpret the results of symptom checkers accordingly, we further directly compared the best-performing symptom checker against 3 primary care physicians with an average experience of 16.6 years.
Primary Outcome MeasuresWe thoroughly studied the diagnostic accuracies of symptom checkers and physicians from 7 standard angles, including: (a) M1, M3, and M5 as measures of a symptom checkers or a physicians ability to return a vignettes main diagnosis at the top, among the first 3 diseases, or among the first 5 diseases of their differential diagnosis, respectively (b) recall as a measure of the percentage of relevant diseases that are returned in a symptom checkers or a physicians differential diagnosis, (c) precision as a measure of the percentage of diseases in a symptom checkers or a physicians differential diagnosis that are relevant, (d) F1-measure as a trade-off measure between recall and precision, and (e) Normalized Discounted Cumulative Gain or NDCG as a measure of ranking quality of a symptom checkers or a physicians differential diagnosis.
ResultsOur AI-based symptom checker, namely, Avey significantly outperformed 5 popular symptom checkers, namely, Ada, WebMD, K Health, Buoy, and Babylon by averages of 24.5%, 175.5%, 142.8%, 159.6%, 2968.1% using M1; 22.4%, 114.5%, 123.8%, 118.2%, 3392% using M3; 18.1%, 79.2%, 116.8%, 125%, 3114.2% using M5; 25.2%, 65.6%, 109.4%, 154%, 3545% using recall; 8.7%, 88.9%, 66.4%, 88.9%, 2084% using F1-measure; and 21.2%, 93.4%, 113.3%, 136.4%, 3091.6% using NDCG, respectively. Under precision, Ada outperformed Avey by an average of 0.9%, while Avey surpassed WebMD, K Health, Buoy, and Babylon by averages of 103.2%, 40.9%, 49.6%, and 1148.5%, respectively. To the contrary of symptom checkers, physicians outperformed Avey by averages of 37.1% and 1.2% using precision and F1-measure, while Avey exceeded them by averages of 10.2%, 20.4%, 23.4%, 56.4%, and 25.1% using M1, M3, M5, recall, and NDCG, respectively. To facilitate the reproducibility of our study and support future related studies, we made all our gold-standard vignettes publicly and freely available. Moreover, we posted online all the results of the symptoms checkers and physicians (i.e., 45 sets of experiments) to establish a standard of full transparency and enable verifying and cross validating our results.
ConclusionsAvey tremendously outperformed the considered symptom checkers. In addition, it compared favourably to physicians, whereby it underperformed them under some accuracy metrics (e.g., precision and F1-measure), but outperformed them under some others (e.g., M1, M3, M5, recall, and NDCG). We will continue evolving Aveys AI model. Furthermore, we will study its usability with real patients, examine how they respond to its suggestions, and measure its impact on their subsequent choices for care, among others. | health informatics |
10.1101/2022.03.01.22271507 | Immunogenicity and safety of a recombinant adenovirus type-5 COVID 19 vaccine in adults: data from a randomised, double-blind, placebo-controlled, single-dose, phase 3 trial in Russia | BackgroundTo determine the immunogenicity, efficacy, reactogenicity, and safety of a single dose of recombinant adenovirus type-5 vectored COVID-19 vaccine (Ad5-nCoV, 5 x 1010 viral particles per 0.5 mL dose), we conducted a single-dose, randomised, double-blind, placebo-controlled, parallel group (3:1 Ad5-nCoV:placebo), phase 3 trial (Prometheus).
MethodsFrom 11-September-2020 to 05-May-2021, across six sites in the Russian Federation, 496 participants were injected with either placebo or Ad5-nCoV expressing the full-length spike (S) protein from the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
ResultsSeroconversion (the primary endpoint) rates of 78.5% (95% CI: 73.9; 82.6) against receptor binding domain (RBD), 90.6% (95% CI: 87.2; 93.4) against S protein and 59% (95% CI: 53.3; 64.6) against neutralising SARS-CoV2 antibodies 28 days post-vaccination. Geometric mean titres (GMTs) were also elevated for antibodies against the RBD (405.32 [95% CI: 361.58; 454.46]) and S protein (678.86 [95% CI: 607.44; 754.40]) compared to the GMT of neutralising antibodies against SARS-CoV-2 (16.73 [95% CI: 15.36; 18.22]). Using an IFN-{gamma} ELISpot assay after stimulating the cells with full-length S protein we showed that the Ad5-nCoV vaccine induced the most robust cellular immune response on Days 14 and 28. Up to Day 28, the primary and all secondary endpoints of the Ad5-nCoV vaccine were statistically superior to the placebo ([p] <0.001). Systemic reactions were reported in 113 of 496 (22.8%) participants (Ad5-nCoV, 26.9%; Placebo, 10.5%), and local reactions were reported in 108 (21.8%) participants (Ad5-nCoV, 28.5%; Placebo, 1.6%). These were generally mild and resolved within 7 days after vaccination. Of the six serious adverse events reported, none of the events were vaccine related. There were no deaths or premature withdrawals.
ConclusionA single-dose of Ad5-nCoV vaccine induced a marked specific humoral and cellular immune response with a favourable safety profile.
Trial RegistrationClinicalTrials.gov: NCT04540419 | infectious diseases |
10.1101/2022.03.01.22271679 | Trajectories of gene expression, seasonal influenza, and within-host seasonal immunity: transfer value to covid-19 | As a novel approach we will combine trajectories or longitudinal studies of gene expression with information on annual influenza epidemics. Seasonality of gene expression in immune cells from blood could be a consequence of within-host seasonal immunity interacting with the seasonal pandemics of influenza (flu) in temperate regions and, thus, with potential valuable analogy transfer to the proposed seasonal development of covid-19.
Here we operationalized within-host immunity as genes with both a significant seasonal term and a significant flu term in the sine-cosine model. Information on gene expression was based on microarray using RNase buffered blood samples collected randomly from a population-based cohort of Norwegian middle-aged women in 2003-2006, The Norwegian Women and Cancer (NOWAC) study. The unique discovery (N=425) and replication (N=432) design were based on identical sampling and preprocessing. Data on proportion of sick leaves due to flu, and the flu intensities per week was obtained from the National Institute of Public Health, giving a semi-ecological analysis.
The discovery analysis found 2942 (48.1%) significant genes in a generalized seasonal model over four years. For 1051 within-host genes both the seasonal and the flu term were significant. These genes followed closely the flu intensities. The trajectories showed slightly more genes with a maximum in early winter than in late summer. Moving the flu intensity forward in time indicated a better fit 3-4 weeks before the observed influenza. In the replication analyses, 369 genes (35.1% of 1051) were significant. Exclusion of genes with unknown functions and with more than a season in difference reduced the number of genes in the discovery dataset to 305, illustrating the variability in the measurements and the problem in assessing weak biological relationships. Thus, we found for the first time a clear seasonality in gene expression with marked responses to the annual seasonal influenza in a unique discovery - replication design. Hypothetically, this could support the within-host seasonal immunity concept. | infectious diseases |
10.1101/2022.03.11.22272072 | Temporal trends, socio-economic inequalities in obesity and responses by federal government, Nepal: a systematic review of observational studies, policies, strategies and plans, 2005-2019 | BackgroundObesity has risen to epidemic proportions in low-income countries such as Nepal whose achievements in reducing maternal and child-undernourishment is well known. However, scientific evidence concerning recent transition towards obesity and corresponding responses by the state remains scanty. This review purported to assess the trends and disparities in obesity prevalence among women and children, and to analyse the governmental policies and programmes.
MethodsWe searched PubMed and Google Scholar for articles published between January 1, 2005 and April 10, 2019, and websites of Demographic and Health Survey, Non-Communicable Diseases Risk Factor Survey, and Micronutrient Status Survey. We extracted data on the prevalence of obesity and overweight from the selected studies and synthesised narratively. Overweight and obesity prevalence data from the latest available nationwide surveys were disaggregated by gender, geographical location and household wealth quintile. We retrieved the federal governmental policies, strategies and plans from the websites of Ministry of Health and Population and the National Nutrition and Food Security Secretariat, National Planning Commission.
ResultsTwenty studies that reported prevalence of overweight and/or obesity, with data from 79,082 men and women aged 15 years or more and 11,866 children under five years, were included. Obesity or overweight among men and women increased from 20.0% in 2004 to 36.1% in 2016 while obesity alone rose from 5.3% to 7.5%. Prevalence of childhood obesity or overweight remained very low, although doubled between 2006 and 2016, from 0.6% to 1.2%. Prevalences of overweight and obesity were much higher among women, inhabitants of urban areas and central provinces, and the affluent. Governmental policies, strategies and plans on nutrition were primarily designed to control undernutrition, with some direct and indirect implications for preventing obesity.
ConclusionsPrevalence of overweight and obesity increased substantially between 2005 and 2019, disproportionately affecting socio-economic and geographical groups in Nepal. Governmental efforts to contain the obesity epidemic should be reinforced by actions that are more specifically targeted to addressing obesogenic environments.
Systematic review registrationPROSPERO CRD42019132332 | public and global health |
10.1101/2022.03.09.22271804 | High-throughput discovery of SLC6A1 variants affecting GABA transport in neurological disorders | SLC6A1 encodes the neuronal GABA transporter GAT-1. Pathogenic variants in SLC6A1 lead to haploinsufficiency and are associated with epilepsy, autism and schizophrenia. Most variants observed in patients are rare missense mutations whose functional impact and pathogenicity remain unknown. We quantified GABA uptake of 182 SLC6A1 variants using plasmid expression constructs in SLC6A1-deficient HEK293T cells. Cells were incubated with deuterated GABA, then analyzed by mass spectrometry to assess transporter activity. Of the 102 variants with partial or complete loss of transporter function compared to wildtype, only 24 (23.5%) had previously been classified as Pathogenic or Likely pathogenic in the ClinVar database. This suggests an increase in the number of SLC6A1 variants that are likely pathogenic, implying a 40% increased diagnostic yield for SLC6A1 haploinsufficiency. SLC6A1 variants associated with Schizophrenia did not lead to complete loss of function, suggesting either an association between hypomorphic variants and Schizophrenia or an alternative mechanism of pathogenesis. | neurology |
10.1101/2022.03.10.22271799 | Assessment of Androgen Receptor splice variant-7 as a biomarker of clinical response in castration-sensitive prostate cancer | BackgroundTherapies targeting the androgen receptor (AR) have improved the outcome for patients with castration-sensitive prostate cancer (CSPC). Expression of the constitutively active AR splice variant-7 (AR-V7) has shown clinical utility as a predictive biomarker of AR-targeted therapy resistance in castration-resistant prostate cancer (CRPC), but its importance as predictive biomarker in CSPC remains understudied.
MethodsWe explored multiple approaches to quantify AR-V7 mRNA and protein in prostate cancer cell lines and patient-derived xenograft (PDX) models, in both publicly available and independent institutional clinical cohorts, to identify reliable approaches for detecting AR-V7 mRNA and protein, and its association with clinical outcome.
ResultsIn publicly available benign prostate, CSPC and CRPC cohorts, AR-V7 mRNA was much less abundant when detected using reads across splice boundaries than when considering isoform-specific exonic reads. The RM7 AR-V7 antibody had increased sensitivity and specificity for AR-V7 protein detection by immunohistochemistry (IHC) in CRPC cohorts and identified AR-V7 protein reactivity very rarely in CSPC cohorts, when compared to the EPR15656 AR-V7 antibody. Using multiple CRPC PDX models, we demonstrated that AR-V7 expression was exquisitely sensitive to hormonal manipulation. In CSPC cohorts, AR-V7 protein quantification by either assay did not associate with time to development of castration-resistance or overall survival, and intense neoadjuvant androgen-deprivation therapy did not lead to significant detectable AR-V7 mRNA or staining following treatment, and neither pre- nor post-treatment AR-V7 levels associated with the volume of residual disease after therapy.
ConclusionThis study demonstrates that further analytical validation and clinical qualification is required before AR-V7 can be considered for clinical use in CSPC as a predictive biomarker. | oncology |
10.1101/2022.03.09.22271087 | Unified classification and risk-stratification in Acute Myeloid Leukemia | Clinical recommendations for AML classification and risk-stratification remain heavily reliant on cytogenetic findings at diagnosis, which are present in <50% of patients. Using comprehensive molecular profiling data from 3,653 patients we characterize and validate 16 molecular classes describing 100% of AML patients. Each class represents diverse biological AML subgroups, and is associated with distinct clinical presentation, likelihood of response to induction chemotherapy, risk of relapse and death over time. Secondary AML-2, emerges as the second largest class (24%), associates with high-risk disease, poor prognosis irrespective of flow MRD negativity, and derives significant benefit from transplantation. Guided by class membership we derive a 3-tier risk-stratification score that re-stratifies 26% of patients as compared to standard of care. This results in a unified framework for disease classification and risk-stratification in AML that relies on information from cytogenetics and 32 genes. Last, we develop an open-access patient-tailored clinical decision support tool. | hematology |
10.1101/2022.03.09.22272066 | Seroneutralization of Omicron BA.1 and BA.2 in patients receiving anti-SARS-CoV-2 monoclonal antibodies. | The SARS-CoV-2 Omicron BA.1 variant has been supplanted in many countries by the BA.2 sub-lineage. BA.2 differs from BA.1 by about 21 mutations in its spike. Human anti-spike monoclonal antibodies (mAbs) are used for prevention or treatment of COVID-19. However, the capacity of therapeutic mAbs to neutralize BA.1 and BA.2 remains poorly characterized. Here, we first compared the sensitivity of BA.1 and BA.2 to neutralization by 9 therapeutic mAbs. In contrast to BA.1, BA.2 was sensitive to Cilgavimab, partly inhibited by Imdevimab and resistant to Adintrevimab and Sotrovimab. Two combinations of mAbs, Ronapreve (Casirivimab + Imdevimab) and Evusheld (Cilgavimab + Tixagevimab), are indicated as a pre-exposure prophylaxis in immunocompromised persons at risk of severe disease. We analyzed sera from 29 such individuals, up to one month after administration of Ronapreve and/or Evusheld. After treatment, all individuals displayed elevated antibody levels in their sera and neutralized Delta with high titers. Ronapreve recipients did not neutralize BA.1 and weakly impaired BA.2. With Evusheld, neutralization of BA.1 and BA.2 was detected in 19 and 29 out of 29 patients, respectively. As compared to Delta, titers were more severely decreased against BA.1 (344-fold) than BA.2 (9-fold). We further report 4 breakthrough Omicron infections among the 29 participants. Therefore, BA.1 and BA.2 exhibit noticeable differences in their sensitivity to therapeutic mAbs. Anti-Omicron activity of Ronapreve, and to a lesser extent that of Evusheld, is reduced in patients sera, a phenomenon associated with decreased clinical efficacy. | infectious diseases |
10.1101/2022.03.09.22271543 | SHERLOCK4HAT: a CRISPR-based tool kit for diagnosis of Human African Trypanosomiasis | Elimination of Human African Trypanosomiasis (HAT) requires highly specific and sensitive tools for both diagnostic at point of care and epidemiological surveys. We have adapted SHERLOCK (Specific High-sensitivity Enzymatic Reporter unLOCKing) for the detection of trypanosome nucleic acids. Our SHERLOCK4HAT diagnostic tool kit, using 7SLRNA, TgSGP and SRA targets, distinguishes between Trypanosoma brucei (T. b.) brucei, T. b. gambiense (g) and T. b. rhodesiense (r) without cross-reactivity and with sensitivity between 0.01 and 0.1 parasite/{micro}L. SHERLOCK4HAT can accurately detect a trypanosome infection in cryo-banked patient buffy coats, with 85.1% sensitivity and 98.4% specificity for gHAT, and 100% sensitivity and 94.1% specificity for rHAT. Our SHERLOCK4HAT diagnostic showed 85.6% correlation with a reference standard qPCR in gHAT patients, 96.2% correlation in rHAT patients, discriminates between r/gHAT with 100% accuracy and is compatible with lateral flow assay readout for use at the point of care. | infectious diseases |
10.1101/2022.03.09.22271910 | Plasma metabolites associated with cognitive function across race/ethnicities affirming the importance of healthy nutrition | INTRODUCTIONWe studied the replication and generalization of previously identified metabolites potentially associated with global cognitive function in multiple race/ethnicities and assessed the contribution of diet to these associations.
METHODSWe tested metabolite-cognitive function associations in U.S.A. Hispanic/Latino adults (n= 2,222) from the Community Health Study/ Study of Latinos (HCHS/SOL) and in European (n=1,365) and African (n=478) Americans from the Atherosclerosis Risk In Communities (ARIC) Study. We applied Mendelian Randomization (MR) analyses to assess causal associations between the metabolites and cognitive function and between Mediterranean diet and cognitive function.
RESULTSSix metabolites were consistently associated with lower global cognitive function across all studies. Of these, four were sugar related (e.g., ribitol). MR analyses provided weak evidence for a potential causal effect of ribitol on cognitive function and bi-directional effects of cognitive performance on diet.
DISCUSSIONSeveral diet-related metabolites were associated with global cognitive function across studies with different race/ethnicities. | epidemiology |
10.1101/2022.03.10.22271805 | SARS-CoV-2 seroconversion in response to infection and vaccination: A time series local study in Brazil | The investigation of antibodies raised against different SARS-CoV-2 antigens can help to determine the extent of previous SARS-CoV-2 infections in the population and track the humoral response to vaccination. Therefore, serological surveys can provide key information to better manage the pandemic and/or to implement the most effective vaccination program. Here we describe a time series anti-Nucleocapsid, anti-Spike IgG serological survey analysis in the city of Matinhos, PR, Brazil during the year of 2021. Seroconversion rates to the Nucleocapsid antigen was not influenced by gender or age. Comparison of the serological data with official COVID-19 cases in the city suggest that case sub notification is higher than 47%. Furthermore, by applying serological data, the corrected infection fatality rate was estimated to be lower than 2.4 % in contrast with the official estimative of 3.6 %. The rates of IgG reactive to Spike antigen resembled the curve of the fraction the population that had taken the second vaccine dose. Up to 82% of Spike seroconversion was detected in the end of 2021 confirming the effective of the COVID-19 vaccination program in the city. This SARS-CoV-2 serological study unraveled the SARS-CoV-2 infection rates and the response to vaccination in the city of Matinhos. It is likely that the numbers reported here may be similar in other cities in Brazil. | epidemiology |
10.1101/2022.03.09.22271220 | Pharmacokinetics of favipiravir in adults with mild COVID-19 in Thailand | We assessed the pharmacokinetics of favipiravir (FPV) in adults with symptomatic SARS-CoV-2 infection without pneumonia in Thailand. FPV dosing was 1800 mg twice-daily on day 1, then 800 mg twice-daily for 14 days. Eight subjects (7 female), median (range) age 39 (19-53) years and BMI 27.9 (18.0-33.6) were included. Inter-subject variability was high but all achieved minimum plasma concentrations (Cmin) above EC50 (9.7 mg/L). FPV was well tolerated; 1 subject stopped prematurely due to rash. | pharmacology and therapeutics |
10.1101/2022.03.09.22271883 | Development of medical device software for the screening and assessment of depression severity using data collected from a wristband-type wearable device: SWIFT study protocol | IntroductionFew biomarkers can be clinically used to diagnose and assess the severity of depression. However, a decrease in activity and sleep efficiency can be observed in depressed patients, and recent technological developments have made it possible to measure these changes. In addition, physiological changes, such as heart rate variability, can be used to distinguish depressed patients from normal persons; these parameters can be used to improve diagnostic accuracy. The proposed research will explore and construct machine learning models capable of detecting depressive episodes and assessing their severity using data collected from wristband-type wearable devices.
MethodsPatients with depressive symptoms and healthy subjects will wear a wristband-type wearable device for 7 days; data on triaxial acceleration, pulse rate, skin temperature, and ultraviolet light will be collected. On the seventh day of wearing, the severity of depressive episodes will be assessed using SCID-5, HAMD, and other scales. Data for up to five 7-day periods of device wearing will be collected from each subject. Using wearable device data associated with clinical symptoms as supervisory data, we will explore and build a machine learning model capable of identifying the presence or absence of depressive episodes and predicting the HAMD scores for an unknown data set.
DiscussionOur machine learning model could improve the clinical diagnosis and management of depression through the use of a wearable medical device.
Trial RegistrationjRCT1031210478, Japan Registry of Clinical Trials (jRCT) | psychiatry and clinical psychology |
10.1101/2022.03.09.22271844 | Using remotely delivered Spring Forest Qigong to reduce neuropathic pain in adults with spinal cord injury: Protocol of a quasi-experimental clinical trial | BackgroundAbout 50% of Americans living with spinal cord injury (SCI) suffer from long-term debilitating neuropathic pain, interfering with quality of daily life. Neuropathic pain is refractory to many available treatments -some carrying a risk for opioid addiction- highlighting an urgent need for new treatments. In this study, we will test our hypothesis that Spring Forest Qigong will reduce SCI-related neuropathic pain by improving body awareness. We will determine whether remotely delivered Qigong is feasible and whether it reduces neuropathic pain (primary outcome). We will also determine whether it reduces spasms frequency and/or severity, improves functional performance, mood, or body awareness (secondary outcomes).
MethodsIn this quasi-experimental study, adults with SCI will practice Qigong at home with a 45min video, at least 3x/week for 12 weeks. The Qigong practice includes movements with guided breathing and is individualized based on functional abilities, i.e., the participants will do kinesthetic imagery of Qigong movements with guided breathing, for movements that they are unable to perform actively. The primary clinical outcome [boxh]the highest, average, and lowest neuropathic pain ratings perceived in the prior week[boxh] will be recorded weekly throughout the study period. The secondary outcomes will be collected at 4 time points: at baseline, midway during the Qigong intervention (6 weeks), after the Qigong intervention (12 weeks), and after the 6-week follow-up. The data will be analyzed with a repeated measure ANOVA and with Tukey post-hoc tests.
DiscussionSuccessful outcomes will provide promising evidence for remotely delivered Qigong for neuropathic pain and spasm reduction in individuals living with SCI.
Clinical Trial registration number: ClinicalTrials.gov: NCT04917107
HIGHLIGHTSO_LISpinal cord injury-related neuropathic pain is notoriously difficult to treat.
C_LIO_LIQigong is a mind and body approach, accessible for adults with spinal cord injury.
C_LIO_LIWe will investigate the feasibility of a remotely delivered Qigong intervention.
C_LI | rehabilitation medicine and physical therapy |
10.1101/2022.03.11.22271887 | Different Covid-19 Outcomes Among Systemic Rheumatic Diseases: A Nation-wide Cohort Study | BackgroundNationwide data at a country level on Covid-19 in unvaccinated patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS), psoriatic arthritis (PsA), systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) are scarce.
MethodsBy interlinking data from national electronic registries, covering nearly 99% of the Greek population (approximately 11,000,000), between March 2020 and February 2021, when vaccination became available, we recorded confirmed infections and Covid-19-associated hospitalizations and deaths in essentially all adult patients with RA, AS, PsA, SLE, and SSc under treatment (n=74,970, median age of 67.5, 51.2, 58.1, 56.2, 62.2 years, respectively) and in individually matched (1:5) on age, sex, and region of domicile random comparators from the general population.
ResultsBinary logistic regression analysis after adjusting for age, sex and biologic agents, revealed that RA, PsA, SLE and SSc, but not AS patients, had significantly higher risk of infection (by 43%, 25%, 20% and 49%, respectively), and hospitalization for Covid-19 (by 81%, 56%, 94%, and 111%, respectively), possibly due, at least in part, to increased testing and lower threshold for admission. Patients with RA and SSc had indeed higher Covid-19 associated mortality rates [OR:1.86 (95% CI 1.37 to 2.52) and OR:2.90 (95% CI 0.97 to 8.67), respectively] compared to the general population. Each additional year of age increased the risk of hospitalization for Covid-19 by 3% (OR 1.030, 95% CI: 1.028 to 1.034) and the risk of Covid-19 related death by 8% (OR 1.08, 95% CI: 1.07 to 1.09), independently of gender, systemic rheumatic disease, and biologic agents. A further analysis using AS patients as the reference category, adjusting again for age, sex and use of biologic agents showed that patients with SSc had increased mortality (OR: 6.90, 95% CI: 1.41 to 33.72), followed by SLE (OR: 4.05 95% CI: 0.96 to 17.12) and RA patients (OR: 3.65, 95% CI: 1.06 to 12.54), whereas PsA patients had comparable mortality risk with AS patients.
ConclusionComparing to the general population, Covid-19 may have a more severe impact in real-world patients with systemic rheumatic disease. Covid-19 related mortality is increased in subgroups of patients with specific rheumatic diseases, especially in older ones, underscoring the need for priority vaccination policies and access to targeted treatments. | rheumatology |
10.1101/2022.03.04.22271934 | Prevention of SARS-CoV-2 airborne transmission in a workplace based on CO2 sensor network | We measured the compartmental air change per hour (ACH) using a CO2 sensor network in an office space where a cluster of COVID-19 infections attributed to aerosol transmission occurred. Generalized linear mixed models and dynamic time warping were used for a time series data analysis, and the results indicated that the ventilation conditions were poor at the time of the cluster outbreak, and that the low ACH in the room likely contributed to the outbreak. In addition, the adverse effects of inappropriate partitions and the effectiveness of ventilation improvements were investigated in detail. ACH of less than 2 /h was considered a main contributor for the formation of the COVID-19 cluster in the studied facility.
Practical ImplicationsA systematic method for measuring and evaluating indoor ventilation to prevent the spread of infectious diseases caused by aerosols is presented. Ventilation bias caused by ventilation pathways and inappropriate use of plastic sheeting can be detected by a CO2 sensor network and time series data analysis. Estimated ventilation rate will be a good index to suppress the formation of the COVID-19 cluster. | occupational and environmental health |
10.1101/2022.03.09.22272113 | Evidence for SARS-CoV-2 Delta and Omicron co-infections and recombination | Between November 2021 and February 2022, SARS-CoV-2 Delta and Omicron variants co-circulated in the United States, allowing for co-infections and possible recombination events. We sequenced 29,719 positive samples during this period and analyzed the presence and fraction of reads supporting mutations specific to either the Delta or Omicron variant. We identified 18 co-infections, one of which displayed evidence of a low Delta-Omicron recombinant viral population. We also identified two independent cases of infection by a Delta-Omicron recombinant virus, where 100% of the viral RNA came from one clonal recombinant. In the three cases, the 5-end of the viral genome was from the Delta genome, and the 3-end from Omicron including the majority of the spike protein gene, though the breakpoints were different. Delta-Omicron recombinant viruses were rare, and there is currently no evidence that Delta-Omicron recombinant viruses are more transmissible between hosts compared to the circulating Omicron lineages. | infectious diseases |
10.1101/2022.03.09.22272113 | Evidence for SARS-CoV-2 Delta and Omicron co-infections and recombination | Between November 2021 and February 2022, SARS-CoV-2 Delta and Omicron variants co-circulated in the United States, allowing for co-infections and possible recombination events. We sequenced 29,719 positive samples during this period and analyzed the presence and fraction of reads supporting mutations specific to either the Delta or Omicron variant. We identified 18 co-infections, one of which displayed evidence of a low Delta-Omicron recombinant viral population. We also identified two independent cases of infection by a Delta-Omicron recombinant virus, where 100% of the viral RNA came from one clonal recombinant. In the three cases, the 5-end of the viral genome was from the Delta genome, and the 3-end from Omicron including the majority of the spike protein gene, though the breakpoints were different. Delta-Omicron recombinant viruses were rare, and there is currently no evidence that Delta-Omicron recombinant viruses are more transmissible between hosts compared to the circulating Omicron lineages. | infectious diseases |
10.1101/2022.03.10.22272197 | Blood group O and post-COVID-19 syndrome | ObjectiveThe ABO blood group system modulates the inflammatory response and has been involved in COVID-19. O-group protects against SARS-CoV-2 infection, but there are no data regarding post-COVID-19 syndrome (PCS). Our aim was to assess this possible association.
Subjects and methodsCase-control study in a community setting, with subjects who had experienced mild COVID-19. Cases were PCS+, controls were PCS-, and the exposure variable, O-group. Epidemiological data (age, sex, BMI, smoking, comorbidities), laboratory parameters (inflammatory markers, IgG antibodies, blood type) and clinical data were collected. Composite inflammatory indices were developed. Multivariate analyses were performed.
ResultsWe analyzed 121 subjects (56.2% women), mean age 45.7 {+/-} 16 years. Blood group frequencies were 43.3%, 7.7%, 5.7%, and 43.3% for A, B, AB and O, respectively. Thirty-six patients were PCS+. There were no significant differences between cases and controls. Compared to non-O, a higher prevalence of PCS (p=0.036), number of symptoms (p=0.017) and myalgia (p=0.030) were noted in O-group. Concerning inflammatory markers, PCS+ and PCS-showed no differences in A, B, and AB groups. In contrast, O-group PCS+ patients had significantly higher lymphocyte count, higher levels of fibrinogen and CRP, and higher percentages of 3 composite indices, than PCS-subjects. The O-group showed a 4-fold increased risk of PCS compared to non-O (adjusted OR=4.20 [95%CI, 1.2-14]; p=0.023).
ConclusionAn increased risk of PCS has shown to be associated with O-group, after controlling for confounders. In O-group subjects with PCS, slightly albeit significant, raised levels of fibrinogen, CRP, and lymphocyte count, have been demonstrated. | infectious diseases |
10.1101/2022.03.10.22272197 | Blood group O and post-COVID-19 syndrome | ObjectiveThe ABO blood group system modulates the inflammatory response and has been involved in COVID-19. O-group protects against SARS-CoV-2 infection, but there are no data regarding post-COVID-19 syndrome (PCS). Our aim was to assess this possible association.
Subjects and methodsCase-control study in a community setting, with subjects who had experienced mild COVID-19. Cases were PCS+, controls were PCS-, and the exposure variable, O-group. Epidemiological data (age, sex, BMI, smoking, comorbidities), laboratory parameters (inflammatory markers, IgG antibodies, blood type) and clinical data were collected. Composite inflammatory indices were developed. Multivariate analyses were performed.
ResultsWe analyzed 121 subjects (56.2% women), mean age 45.7 {+/-} 16 years. Blood group frequencies were 43.3%, 7.7%, 5.7%, and 43.3% for A, B, AB and O, respectively. Thirty-six patients were PCS+. There were no significant differences between cases and controls. Compared to non-O, a higher prevalence of PCS (p=0.036), number of symptoms (p=0.017) and myalgia (p=0.030) were noted in O-group. Concerning inflammatory markers, PCS+ and PCS-showed no differences in A, B, and AB groups. In contrast, O-group PCS+ patients had significantly higher lymphocyte count, higher levels of fibrinogen and CRP, and higher percentages of 3 composite indices, than PCS-subjects. The O-group showed a 4-fold increased risk of PCS compared to non-O (adjusted OR=4.20 [95%CI, 1.2-14]; p=0.023).
ConclusionAn increased risk of PCS has shown to be associated with O-group, after controlling for confounders. In O-group subjects with PCS, slightly albeit significant, raised levels of fibrinogen, CRP, and lymphocyte count, have been demonstrated. | infectious diseases |
10.1101/2022.03.10.22272197 | Blood group O and post-COVID-19 syndrome | ObjectiveThe ABO blood group system modulates the inflammatory response and has been involved in COVID-19. O-group protects against SARS-CoV-2 infection, but there are no data regarding post-COVID-19 syndrome (PCS). Our aim was to assess this possible association.
Subjects and methodsCase-control study in a community setting, with subjects who had experienced mild COVID-19. Cases were PCS+, controls were PCS-, and the exposure variable, O-group. Epidemiological data (age, sex, BMI, smoking, comorbidities), laboratory parameters (inflammatory markers, IgG antibodies, blood type) and clinical data were collected. Composite inflammatory indices were developed. Multivariate analyses were performed.
ResultsWe analyzed 121 subjects (56.2% women), mean age 45.7 {+/-} 16 years. Blood group frequencies were 43.3%, 7.7%, 5.7%, and 43.3% for A, B, AB and O, respectively. Thirty-six patients were PCS+. There were no significant differences between cases and controls. Compared to non-O, a higher prevalence of PCS (p=0.036), number of symptoms (p=0.017) and myalgia (p=0.030) were noted in O-group. Concerning inflammatory markers, PCS+ and PCS-showed no differences in A, B, and AB groups. In contrast, O-group PCS+ patients had significantly higher lymphocyte count, higher levels of fibrinogen and CRP, and higher percentages of 3 composite indices, than PCS-subjects. The O-group showed a 4-fold increased risk of PCS compared to non-O (adjusted OR=4.20 [95%CI, 1.2-14]; p=0.023).
ConclusionAn increased risk of PCS has shown to be associated with O-group, after controlling for confounders. In O-group subjects with PCS, slightly albeit significant, raised levels of fibrinogen, CRP, and lymphocyte count, have been demonstrated. | infectious diseases |
10.1101/2022.03.10.22271815 | Current epidemiological situation of COVID-19 in the Republic of Belarus: characteristics of the epidemic process, sanitary and anti-epidemic measures | This is an analysis of the features of the COVID-19 pandemic the population of the Republic of Belarus from February 2020 to January 2022, the characteristics of sanitary and anti-epidemic measures carried out in the country, assessment of study the safety (tolerance) of the vaccines used the epidemiological efficacy of the vaccination.
A retrospective analysis of COVID-19 cases in the Republic of Belarus from the beginning of registration (February 28, 2020) to January, 3, 2022 was performed. Vaccine safety (tolerance) and efficacy were assessed in an observational study. Safety (tolerance) was assessed by presence/absence of adverse reactions: general (fever, malaise, headache, muscle pain, runny nose, nausea, vomiting, sore throat, etc) and local ones (redness, swelling, soreness at the injection place).
The COVID-19 pandemic in the Republic of Belarus is characterized by successive development stages: from no cases in early 2020 to detected cases where most individuals had no history of contact with COVID-19 patients; periods of rising and falling incidence
Vaccines against COVID-19 (Gam-COVID-Vac (Russia), inactivated vaccine against SARS-CoV-2 (Vero Cell) Sinopharm / BIBP (China) demonstrated a high safety profile in mass vaccination of the population of the Republic of Belarus. | epidemiology |
10.1101/2022.03.09.22272163 | FHIR Profiliferation: A Data Science Approach | Profiling is a mechanism for shaping Fast Healthcare Interoperability Resources (FHIR) for particular use cases. "Profiliferation" (profile + proliferation) is a coinage referring to the explosive growth in the number of FHIR profiles over the past few years. By reviewing a broad sample of almost 3000 FHIR profiles from 125 implementation guides, it was determined that just two items, Observation and Extension, accounted for half the profiles. FHIRs 80/20 rule was determined to be closer to 65/35, revealing that FHIR is more dependent on profiling than initially intended. Use of the Observation resource was inconsistent, hinting that the resource is either poorly designed, or that users lack proper guidance. Better management of reusable items and certain changes in FHIR and profiling practices could improve the consistency of FHIR artifacts and reduce unnecessary and potentially incompatible profiles. | health informatics |
10.1101/2022.03.09.22271922 | Comparing People-Like-Me and linear mixed model predictions of functional recovery following knee arthroplasty | ObjectivePrediction models can be useful tools for monitoring patient status and personalizing treatment in health care. The goal of this study was to compare the relative strengths and weaknesses of two different approaches for predicting functional recovery after knee arthroplasty: a neighbors-based "people-like-me" (PLM) approach and a linear mixed model (LMM) approach.
Materials and MethodsWe used two distinct datasets to train and then test PLM and LMM prediction approaches for functional recovery following knee arthroplasty. We used Timed Up and Go (TUG)--a commonly used test of mobility--to operationalize physical function. Both approaches used patient characteristics and baseline postoperative TUG values to predict TUG recovery from days 1-425 following surgery. We compared the accuracy and precision of PLM and LMM predictions in the testing dataset.
ResultsA total of 317 patient records with 1379 TUG observations were used to train PLM and LMM approaches, and 456 patient records with 1244 TUG observations were used to test the predictions. The approaches performed similarly in terms of mean squared error and bias, but the PLM approach provided more accurate and precise estimates of prediction uncertainty.
Discussion and ConclusionOverall, the PLM approach more accurately and precisely predicted TUG recovery following knee arthroplasty. These results suggest PLM predictions may be more clinically useful for monitoring recovery and personalizing care following knee arthroplasty. However, clinicians and organizations seeking to use predictions in practice should consider additional factors (e.g., resource requirements) when selecting a prediction approach. | health informatics |
10.1101/2022.03.09.22271297 | Possible Role of P-selectin Adhesion in Long-COVID: A Comparative Analysis of a Long-COVID Case Versus an Asymptomatic Post-COVID Case | BackgroundLong-term outcomes of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are now recognized as an emerging public health challenge - a condition termed Long-COVID. The pathophysiology of Long-COVID remains to be established. Functional P-selectin activity, implicated in COVID-19 sequalae, was measured between two convalescent COVID-19 subjects, one with (Long-COVID subject) and another without Long-COVID symptoms.
MethodsFlow adhesion of whole blood or isolated white blood cells to P-selectin (FA-WB-Psel and FA-WBC-Psel) was measured using a standardized microfluidics clinical assay; impedance aggregometry with a collagen agonist was measured using model 590 Chrono-Log impedance aggregometer; standard laboratory assays were performed to evaluate changes in blood chemistries.
ResultsFor both subjects, hemoglobin, WBC, platelet counts, electrolytes and ferritin were within normal reference ranges, with FA-WB-Psel significantly elevated compared to healthy controls (p< 0.01). In vitro treatment of whole blood samples with crizanlizumab (anti-p-selectin monoclonal antibody) within the clinical dose range (10 g/ml) mL) inhibited FA-WB-Psel only in samples from asymptomatic post-COVID subject, with the Long-COVID subject sample requiring close to 5-fold elevated dose to achieve a response. Pronounced inhibition of P-selectin adhesion of isolated leukocytes was observed for both subjects in autologous platelet-poor plasma and buffer. Impedance aggregometry showed greater baseline platelet aggregation to collagen in the Long-COVID sample, although both samples responded similarly to aspirin-induced platelet inhibition.
ConclusionsPresented results suggest that elevated platelet activation in Long-COVID subject may be associated with increased P-Selectin activity. The results are discussed in terms of possible use on P-selectin inhibition therapies in treating Long-COVID. | infectious diseases |
10.1101/2022.03.10.22272100 | Bebtelovimab, alone or together with bamlanivimab and etesevimab, as a broadly neutralizing monoclonal antibody treatment for mild to moderate, ambulatory COVID-19 | BACKGROUNDBebtelovimab is a potent, fully human IgG1 monoclonal antibody (mAb) targeting the S-protein of SARS-CoV-2, with broad neutralizing activity to all currently known SARS-CoV-2 variants of concern, including omicron variant lineages. Specialized developmental approaches accelerated the initiation of a clinical trial designed to evaluate the efficacy and safety of bebtelovimab alone (BEB) or together with bamlanivimab (BAM) and etesevimab (ETE) delivered via slow intravenous push for the treatment of mild-to-moderate COVID-19.
METHODSThis portion of the phase 2, BLAZE-4 trial (J2X-MC-PYAH; NCT04634409) enrolled 714 patients (between May and July 2021) with mild-to-moderate COVID-19 within 3 days ([≤]3 days) of laboratory diagnosis of SARS-CoV-2 infection. Patients at low risk for severe COVID-19 were randomized 1:1:1 (double-blinded) to placebo, BEB 175 mg, or BEB 175 mg+BAM 700 mg+ETE 1400 mg (BEB+BAM+ETE). Patients at high risk for progression to severe COVID-19 were randomized 2:1 (open-label) to BEB or BEB+BAM+ETE, and a subsequent treatment arm enrolled patients to BEB+BAM+ETE using Centers for Disease Control and Prevention (CDC) updated criteria for High-risk. All treatments were administered intravenously over [≥]30 seconds (open-label BEB) or [≥]6.5 minutes (all other treatment arms). For the placebo-controlled patients (termed Low-risk), the primary endpoint was the proportion of patients with persistently high viral load (PHVL) (log viral load >5.27) on Day 7. For the open-label patients (termed High-risk), the primary endpoint was safety. In nonclinical studies, SARS-CoV-2 isolates were tested using an endpoint neutralization assay to measure BEBs inhibitory concentration greater than 99% (IC99).
RESULTSBaseline viral sequencing data were available from 611 patients; 90.2% (n=551) aligned with a variant of interest or concern (WHO designation), with the majority infected with delta (49.8%) or alpha (28.6%) variants. Among the Low-risk patients, PHVL occurred in 19.8% of patients treated with placebo, as compared to 12.7% (p=0.132) of patients treated with BEB+BAM+ETE and 12.0% (p=0.097) of patients treated with BEB, a 36% and 40% relative risk reduction, respectively. Viral load-area under the curve analysis from baseline to Day 11 showed statistically signficant reductions for patients treated with BEB (p=0.006) and BEB+BAM+ETE (p=0.043) compared to patients who received placebo. Time to sustained symptom resolution was reduced by a median of 2 days for patients treated with BEB (6 days; p=0.003) and 1 day for patients treated with BEB+BAM+ETE (7 days; p=0.289) compared to placebo (8 days). The incidence of COVID-19-related hospitalization or all-cause deaths by day 29 were similar across treatment arms, as expected given the patients risk status (the Low risk cohorts had a Low risk of hospitalization, and High risk cohorts received only active therapy without placebo). Overall, safety results were consistent with previous studies investigating mAbs targeting SARS-CoV-2. The proportion of patients with treatment emergent adverse events (AEs) were 9.7% in Low-risk (n=37/380) and 14.7% in High-risk (n=48/326) patients treated with BEB or BEB+BAM+ETE; majority of AEs were considered mild or moderate in severity. Serious AEs were reported in 2.1% of High-risk patients (n=7/326), including one death (a cerebrovascular accident); 1 serious AE was reported among Low-risk patients. In an in vitro neutralization assay, BEB neutralized the omicron isolate (BA.1) with <2.44ng/ml estimated IC99.
CONCLUSIONSIn patients with mild-to-moderate COVID-19, treatment with BEB or BEB+BAM+ETE was associated with greater viral clearance, a reduction in time to sustained symptom resolution, and safety results consistent with mAbs that target SARS-CoV-2. Integration of clinical findings with in vitro neutralization of emerging viral variants offered a pragmatic framework for investigating the efficacy of a new antiviral mAb agent, as demonstrated by bebtelovimab. | infectious diseases |
10.1101/2022.03.09.22270766 | Rare Variants in Inborn Errors of Immunity Genes Associated with Covid-19 Severity | Covid-19 is a contagious disease caused by SARS-CoV-2, a novel severe acute respiratory syndrome coronavirus. Common variants and networks underlying host genetic mechanisms have been extensively studied to identify disease-associated genetic factors. However, there are few studies about the rare variants, typically inborn errors of immunity, in understanding the host genetics behind Covid-19 infection, especially in the Chinese population. To fill this gap, we investigate likely-deleterious missense and high-confidence predicted loss-of-function variants by (a) performing gene- and pathway-level association analyses, (b) examining known genes involved in type I interferon signaling and others previously reported in Covid-19 disease, and (c) identifying candidate genes with accumulating mutations and their potential protein-protein interactions with known genes. Based on our analyses, several putative genes and pathways are uncovered and worth further investigation, for example, genes IL12RB1, TBK1, and TLR3, and pathways Tuberculosis (hsa:05152), Primary Immunodeficiency (hsa:05340), and Influenza A (hsa:05164). These regions generally play an essential role in regulating antiviral innate immunity responses to foreign pathogens and in responding to many inflammatory diseases. We believe that to some extent, as an acute inflammatory disease, Covid-19 is also affected by these inborn errors of immunity. We hope that the identification of these rare genetic factors will provide new insights into the genetic architecture of Covid-19. | infectious diseases |
10.1101/2022.03.10.22271924 | Novel Application of a Multistate Model to Evaluate the Opioid Use Disorder Care Cascade: A Retrospective Cohort Study | BackgroundEvaluating the opioid use disorder (OUD) care cascade can improve OUD treatment retention and care.
ObjectivesTo identify risk and protective factors for retention among patients in OUD treatment.
MethodsWe conducted a retrospective cohort study among patients diagnosed with OUD using data from the Rhode Island (RI) All-Payer Claims Database from 2011 to 2019. Patients who initiated treatment (Stage 2) were classified into sub-stages of retention (Stage 3) corresponding to multistate modeling states capturing early retention (sub-stage 1), short and long-term retention (sub-stage 2), and short and long-term disengagement (sub-stage 3). The association of baseline characteristics with state transitions were evaluated.
ResultsA cohort of 6,939 RI residents diagnosed with OUD included 41% aged 40 to 60 years, 57.6% male, and 70.8% Medicaid beneficiaries. In sub-stage 1, cannabis (Relative risk ratios (RRR) = 1.16; 95% confidence interval (CI) = 1.04,1.29) and cocaine use disorders (RRR=1.15; 95% CI=1.05,1.25) increased early disengagement risk after engagement. Medicaid beneficiaries were less likely to experience early disengagement (RRR=0.81; 95% CI =0.76,0.87). In sub-stage 2, alcohol (RRR=1.29; 95% CI=1.13,1.47) or cocaine use disorders (RRR=1.18; 95% CI=1.01,1.40) increased risk of disengagement among patients in the retention states. In sub-stage 3, tobacco (RRR=1.10; 95% CI=1.01,1.21) and alcohol (RRR=1.14; 95% CI=1.03,1.27) use disorders were associated with re-engagement from disengaged states.
ConclusionThe multistate model applied to a cohort of patients initiating medication for OUD led to the identification of factors associated with treatment engagement and retention. These results may guide strategies to sustain treatment among OUD patients. | addiction medicine |
10.1101/2022.03.10.22272024 | Prevalence and Predictors of Depression, Anxiety and Stress among Elderly in the aftermath of COVID-19: A Quantitative Study from Central India | BackgroundElderly persons have been more prone to depression, anxiety and stress during COVID-19 pandemic. They need more care and support towards mental health during these difficult times.
MethodologyThis was a cross-sectional and quantitative study conducted in the state of Madhya Pradesh, during the month of March 2021 to August 2021. Participants were recruited from a population aged more than 60 years, those who were able to read and write Hindi/English or having at least one family member; reporting to a tertiary care teaching hospital during the second wave of COVID-19 in India. Those who were confirmed COVID-19 cases & undergoing treatment, with diagnosed mental health disorders and who didnt give consent were excluded. A semi-structured questionnaire along with DASS-21 scale was completed by participants online.
ResultsOut of 690 subjects, 7.25% had mild and moderate depression, 0.58% had severe and extremely severe depression. Mild and moderate anxiety symptoms were reported by 9.56%, 2.46% reported severe and extremely severe anxiety. Mild and moderate stress was reported by 4.78%, while 0.42% were severely and extremely stressed. A positive statistical association was found between alcohol addiction and depression (p=0.028). The elderly subjects had a nap the day time were significantly less depressed during COVID-19 pandemic (p=0.033). It was found that older the subjects, more were they anxious during the pandemic (p=0.042). An association was found between alcohol addiction and stress (p=0.043).
ConclusionsDepressive symptoms in participants were positively correlated with alcohol addiction. Females reported higher level of stress. There is a felt need to formulate psychological interventions for elderly to improve their mental health and psychological resilience. We need to tackle and fight the stigma, fear and anxiety related to the COVID-19, which is greater than disease itself.
Key messageO_ST_ABSWhat is already knownC_ST_ABSPsychological problems like anxiety, depressive symptoms, fearfulness, a state of uncertainty and stress are common in all age groups; furthermore older adults are more prone to develop mental health issues in wake of stressful situations.
What this study adds toAbout one fourth of elderly developed anxiety, depression and stress during the COVID-19 pandemic.
Effect on practice and policyThere is a need for proactive identification through screening of elderly for mental health issues following unprecedented stress like COVID-19 pandemic. | psychiatry and clinical psychology |
10.1101/2022.03.09.22272160 | Cross-sector Decision Landscape in Response to COVID-19: A Qualitative Analysis of North Carolina Decision-Makers | ContextThe COVID-19 pandemic response has demonstrated the interconnectedness of individuals, organizations, and other entities jointly contributing to the production of community health. This response has involved stakeholders from numerous sectors who have been faced with new decisions, objectives, and constraints.
ObjectiveWe aimed to examine the cross-sector organizational decision landscape that formed in response to the COVID-19 pandemic.
DesignWe applied a systems approach to the qualitative analysis of semi-structured interviews on the cross-sector, organizational response to the COVID-19 pandemic. We analyzed transcribed interviews using conventional content analysis to synthesize key themes.
SettingSemi-structured interviews were conducted via secure, video-conferencing platform between October 2020 and January 2021.
ParticipantsForty-four state and local decision-makers representing organizations from nine sectors in North Carolina participated.
Main Outcome MeasuresWe defined the decision landscape as including decision-maker roles, key decisions, and inter-relationships involved in producing community health.
ResultsDecision-maker roles were characterized by underlying tensions between balancing organizational mission with employee/community health and navigating organizational versus individual responsibility for reducing transmission. Key Decisions fell into several broad categories, including how to translate public health guidance into practice; when to institute, and subsequently loosen, public health restrictions; and how to address downstream social and economic impacts of public health restrictions. Lastly, given limited and changing information, as well as limited resources and expertise, the COVID-19 response required cross-sector collaboration, which was commonly coordinated by local health departments.
ConclusionsBy documenting the local, cross-sector decision landscape that formed in response to COVID-19, we illuminate the impacts different organizations may have on information/misinformation, prevention behaviors, and, ultimately, health. Public health researchers and practitioners must understand, and work within, this complex decision landscape when responding to COVID-19 and future community health challenges. | public and global health |
10.1101/2022.03.09.22272143 | Knowledge, attitudes, and positions of religious leaders towards female genital mutilation: A cross-sectional study from the Kurdistan Region of Iraq | BackgroundUnderstanding the perspectives of the key players in the community regarding female genital cutting (FGC) is very important for directing preventive programs. Religious leaders help shape community behaviors, which is highly pertinent in the case of FGC as it is frequently perceived to be a religious requirement. This study assesses religious leaders knowledge, attitudes, and positions towards FGC in the Kurdistan Region of Iraq.
MethodsThis cross-sectional study was conducted in the Kurdistan Region of Iraq. It included a purposive sample of 147 local religious leaders (khateebs) representing the three governorates of Erbil, Sulaimaniyah, and Duhok. A self-administered questionnaire was used to collect data about the religious leaders knowledge, attitude, and position towards FGC.
ResultsThe participants identified reduction of the sexual desire of women as the main benefit (37%) and risk (24%) of FGC. Cultural tradition and religious requirements were the main reasons for practicing FGC. About 59% of the religious leaders stated that people ask for their advice on FGC. Around 14% of the participants supported performing FGC, compared to 39.1% who opposed it. Religious (73.9%) and cultural (26.1%) rationales were the main reasons given for supporting FGC. Being a cultural practice and having harmful effects (53.5%) and lack of clear religious evidence (46.6%) were the main reasons for being against FGC. Around 52% of the participants recommended banning FGC by law, while 43.5% did not support banning it. A statistically significant association (P=0.015) was found between religious leaders residence and their position on performing FGC. More than 46% of those residing in Duhok were against performing FGC, compared to lower proportions in Erbil (38.8%) and Sulaimaniyah (30%).
ConclusionA conclusive decision concerning FGC banning needs to be made by religious authorities to advise people to avoid the practice. Health awareness activities incorporating FGC risks should be carried out to enlighten religious leaders at different levels of religious positions. Further research exploring perspectives of religious authorities concerning religious leaders inconclusive judgments about FGC is deemed necessary. | public and global health |
10.1101/2022.03.10.22272081 | Interstitial lung damage following COVID-19 hospitalisation: an interim analysis of the UKILD Post-COVID study. | IntroductionShared characteristics between COVID-19 and pulmonary fibrosis, including symptoms, genetic architecture, and circulating biomarkers, suggests interstitial lung disease (ILD) development may be associated with SARS-CoV-2 infection.
MethodsThe UKILD Post-COVID study planned interim analysis was designed to stratify risk groups and estimate the prevalence of Post-COVID Interstitial Lung Damage (ILDam) using the Post-HOSPitalisation COVID-19 (PHOSP-COVID) Study. Demographics, radiological patterns and missing data were assessed descriptively. Bayes binomial regression was used to estimate the risk ratio of persistent lung damage >10% involvement in linked, clinically indicated CT scans. Indexing thresholds of percent predicted DLco, chest X-ray findings and severity of admission were used to generate risk strata. Number of cases within strata were used to estimate the amount of suspected Post-COVID ILDam.
ResultsA total 3702 people were included in the UKILD interim cohort, 2406 completed an early follow-up research visit within 240 days of discharge and 1296 had follow-up through routine clinical review. We linked the cohort to 87 clinically indicated CTs with visually scored radiological patterns (median 119 days; interquartile range 83 to 155, max 240), of which 74 people had ILDam. ILDam was associated with abnormal chest X-ray (RR 1.21 95%CrI 1.05; 1.40), percent predicted DLco<80% (RR 1.25 95%CrI 1.00; 1.56) and severe admission (RR 1.27 95%CrI 1.07; 1.55). A risk index based on these features suggested 6.9% of the interim cohort had moderate to very-high risk of Post-COVID ILDam. Comparable radiological patterns were observed in repeat scans >90 days in a subset of participants.
ConclusionThese interim data highlight that ILDam was not uncommon in clinically indicated thoracic CT up to 8 months following SARS-CoV-2 hospitalisation. Whether the ILDam will progress to ILD is currently unknown, however health services should radiologically and physiologically monitor individuals who have Post-COVID ILDam risk factors. | respiratory medicine |
10.1101/2022.03.10.22272081 | Interstitial lung damage following COVID-19 hospitalisation: an interim analysis of the UKILD Post-COVID study. | IntroductionShared characteristics between COVID-19 and pulmonary fibrosis, including symptoms, genetic architecture, and circulating biomarkers, suggests interstitial lung disease (ILD) development may be associated with SARS-CoV-2 infection.
MethodsThe UKILD Post-COVID study planned interim analysis was designed to stratify risk groups and estimate the prevalence of Post-COVID Interstitial Lung Damage (ILDam) using the Post-HOSPitalisation COVID-19 (PHOSP-COVID) Study. Demographics, radiological patterns and missing data were assessed descriptively. Bayes binomial regression was used to estimate the risk ratio of persistent lung damage >10% involvement in linked, clinically indicated CT scans. Indexing thresholds of percent predicted DLco, chest X-ray findings and severity of admission were used to generate risk strata. Number of cases within strata were used to estimate the amount of suspected Post-COVID ILDam.
ResultsA total 3702 people were included in the UKILD interim cohort, 2406 completed an early follow-up research visit within 240 days of discharge and 1296 had follow-up through routine clinical review. We linked the cohort to 87 clinically indicated CTs with visually scored radiological patterns (median 119 days; interquartile range 83 to 155, max 240), of which 74 people had ILDam. ILDam was associated with abnormal chest X-ray (RR 1.21 95%CrI 1.05; 1.40), percent predicted DLco<80% (RR 1.25 95%CrI 1.00; 1.56) and severe admission (RR 1.27 95%CrI 1.07; 1.55). A risk index based on these features suggested 6.9% of the interim cohort had moderate to very-high risk of Post-COVID ILDam. Comparable radiological patterns were observed in repeat scans >90 days in a subset of participants.
ConclusionThese interim data highlight that ILDam was not uncommon in clinically indicated thoracic CT up to 8 months following SARS-CoV-2 hospitalisation. Whether the ILDam will progress to ILD is currently unknown, however health services should radiologically and physiologically monitor individuals who have Post-COVID ILDam risk factors. | respiratory medicine |
10.1101/2022.03.09.22272152 | Afucosylation of HLA-specific IgG1 as a potential predictor of antibody pathogenicity in kidney transplantation | Antibody-mediated rejection (AMR) is the leading cause of graft failure. While donor-specific antibodies (DSA) are associated with a higher risk of AMR, not all patients with DSA develop rejection suggesting that the characteristics of alloantibodies that determine their pathogenicity remain undefined. Using human leukocyte antigen (HLA)-A2-specific antibodies as a model, we applied systems serology tools to investigate qualitative features of immunoglobulin G (IgG) alloantibodies including Fc-glycosylation patterns and Fc{gamma}R binding properties. The levels of afucosylation of anti-A2 antibodies were elevated in all seropositive patients and were significantly higher in AMR patients, suggesting potential cytotoxicity via Fc{gamma}RIII-mediated mechanisms. Afucosylation of both glycoengineered monoclonal and naturally glycovariant polyclonal serum IgG specific to HLA-A2 exhibited potentiated binding to, slower dissociation from, and enhanced signaling through Fc{gamma}RIII, a receptor widely expressed on innate effector cells. Collectively, these results suggest that afucosylated DSA may be a biomarker of AMR and could contribute to its pathogenesis.
O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=62 SRC="FIGDIR/small/22272152v1_ufig1.gif" ALT="Figure 1">
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[email protected]@12e1532org.highwire.dtl.DTLVardef@71938eorg.highwire.dtl.DTLVardef@8e8847_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical Abstract.C_FLOATNO Potential influence of HLA-A2-specific IgG1 afucosylation, Fc{gamma}RIIIa binding and activation on ADCC and graft rejection.Illustration created with https://BioRender.com.
C_FIG | transplantation |
10.1101/2022.03.11.22272021 | Clinical improvement of DM1 patients reflected by reversal of disease-induced gene expression in blood | Myotonic dystrophy type 1 (DM1) is an incurable multisystem disease caused by a CTG-repeat expansion in the DM1 protein kinase (DMPK) gene. The OPTIMISTIC clinical trial demonstrated positive and heterogenous effects of cognitive behavioral therapy (CBT) on the capacity for activity and social participations in DM1 patients. Here, we performed mRNA sequencing of full blood for 27 patients of the OPTIMISTIC cohort before and after the CBT intervention. We identified 608 genes for which their expression was significantly associated with the disease causing CTG-repeat expansion, as well as 1176 genes significantly associated with the average clinical response towards the intervention. Remarkably, all 97 genes significantly associated with both returned to more normal levels in patients who benefited most from CBT. This trend was consistent with the difference observed between DM1 patients and controls in an earlier study of blood mRNA expression levels, singling these genes out as candidate biomarkers for therapy response. Together these results highlight the ability to find disease relevant information in full blood of DM1 patients, opening new avenues to monitor therapy effects. | neurology |
10.1101/2022.03.09.22271551 | The development of the Supplemental Nutrition Assistance Program enrollment accessibility (SNAP-Access) score | BackgroundThe Supplemental Nutrition Assistance Program (SNAP) is a federally funded public benefit providing critical food assistance to millions of Americans. However, it is typically administered by states, creating potential variation in accessibility and transparency of information about enrollment for people with disabilities.
ObjectiveTo create a method to assess the accessibility and transparency of information about the disability-inclusive process and practices of SNAP enrollment
MethodsData was collected from SNAP landing and enrollment webpages from all 50 U.S. states, the District of Columbia, and New York City from June-August 2021. Based on key principles of universal design and accessibility, scores were determined for each SNAP program across three areas: flexibility in the enrollment process (6 points), efficiency of finding information about enrollment on SNAP websites (6 points), and the accessibility of SNAP webpages (6 points). Total scores were the sum of these sub-categories (18 points maximum).
ResultsOf the 52 SNAP programs assessed, mean scores were 10.66 (SD=2.51) for the total score, 2.67 (SD=0.91) for flexibility in the enrollment process, 3.32 (SD=1.19) for efficiency of finding information about enrollment on SNAP websites, and 4.67 (SD=1.72) for the accessibility of SNAP webpage. A total of 0 SNAP programs received the maximum score (6 points) on flexibility, 2 programs the maximum on efficiency, and 31 programs the maximum on accessibility.
ConclusionsWe found differences in the accessibility, flexibility, and efficiency of SNAP program enrollment information available on SNAP websites and outline much room for improvement across all three of these areas. | health policy |
10.1101/2022.03.09.22272170 | SARS-CoV-2 Omicron disease burden in Australia following border reopening: a modelling analysis | BackgroundCountries with high COVID-19 vaccination rates have seen the SARS-CoV-2 Omicron variant result in rapidly increasing case numbers. This study evaluated the impact on the health system which may occur following introduction of the Omicron variant into Western Australia following state border reopening. We aimed to understand the effect of high vaccine coverage levels on the population health burden in the context of lower vaccine effectiveness against the Omicron variant, the impact of a third dose booster regime, and ongoing waning of vaccine-induced immunity. Originally scheduled for 5th February 2022, the Western Australian border was opened on 3rd March 2022, we also aimed to determine the impact of delaying border reopening on the COVID-19 health burden and whether the West Australian health system would be able to manage the resulting peak demand.
MethodsAn agent-based model was used to evaluate changes in the COVID-19 health burden resulting from different border openings, at monthly intervals. We assumed immunity was derived from vaccination with the BNT162b2 Pfizer BioNTech vaccine and waned at observed rates from the UK. The model was calibrated against outbreaks in two other Australian states, Queensland and South Australia, both of which were in a similar situation to Western Australia with negligible COVID-19 transmission prior to Omicrons introduction. Age-specific infections generated by the model, together with recent UK data, permitted resulting outbreak health burden to be quantified, in particular peak ICU demand.
ResultsOverall population immunity in Western Australia is shown to peak and then plateau for a period of 5 months, between February and June 2022, resulting in a similar health burden if the border is reopened prior to June 2022. For an opening date of 5th March 2022, hospitalisations are predicated to peak at 510 beds, 51 of which will be in ICU, with a total of 383 deaths. If the border reopened on 5th June 2022, hospitalisations are expected to peak with 750 beds required, 75 of which would be in ICU, and a total of 478 deaths. With a total surge capacity of 52 fully staffed ICU beds, West Australian hospitals are predicted to have adequate ICU capacity for future COVID-19 demands if border reopening occurs prior to May 2022.
ConclusionsOur results show that with extremely high SARS-CoV-2 vaccination rates in Western Australian, and documented vaccine-induced vaccine waning rates, the overall population immunity in Western Australia will be at its highest in the period of February 2022 to June 2022. Opening the Western Australian border prior to the end this period will result in the lowest health burden in comparison to opening in June 2022 or later. With a border reopening of 3rd March 2022 announced by the Western Australian government, our data for a 5th March 2022 opening date may be used to predict the progression of this resulting outbreak. These data show expected peak demand of 510 hospital beds, 51 of which will be in ICU, with a total of 383 deaths. With a surge capacity of 52 ICU beds, it is expected that the Western Australian hospital system will be able to handle the additional load during the peak of the wave. | infectious diseases |
10.1101/2022.03.09.22272170 | SARS-CoV-2 Omicron disease burden in Australia following border reopening: a modelling analysis | BackgroundCountries with high COVID-19 vaccination rates have seen the SARS-CoV-2 Omicron variant result in rapidly increasing case numbers. This study evaluated the impact on the health system which may occur following introduction of the Omicron variant into Western Australia following state border reopening. We aimed to understand the effect of high vaccine coverage levels on the population health burden in the context of lower vaccine effectiveness against the Omicron variant, the impact of a third dose booster regime, and ongoing waning of vaccine-induced immunity. Originally scheduled for 5th February 2022, the Western Australian border was opened on 3rd March 2022, we also aimed to determine the impact of delaying border reopening on the COVID-19 health burden and whether the West Australian health system would be able to manage the resulting peak demand.
MethodsAn agent-based model was used to evaluate changes in the COVID-19 health burden resulting from different border openings, at monthly intervals. We assumed immunity was derived from vaccination with the BNT162b2 Pfizer BioNTech vaccine and waned at observed rates from the UK. The model was calibrated against outbreaks in two other Australian states, Queensland and South Australia, both of which were in a similar situation to Western Australia with negligible COVID-19 transmission prior to Omicrons introduction. Age-specific infections generated by the model, together with recent UK data, permitted resulting outbreak health burden to be quantified, in particular peak ICU demand.
ResultsOverall population immunity in Western Australia is shown to peak and then plateau for a period of 5 months, between February and June 2022, resulting in a similar health burden if the border is reopened prior to June 2022. For an opening date of 5th March 2022, hospitalisations are predicated to peak at 510 beds, 51 of which will be in ICU, with a total of 383 deaths. If the border reopened on 5th June 2022, hospitalisations are expected to peak with 750 beds required, 75 of which would be in ICU, and a total of 478 deaths. With a total surge capacity of 52 fully staffed ICU beds, West Australian hospitals are predicted to have adequate ICU capacity for future COVID-19 demands if border reopening occurs prior to May 2022.
ConclusionsOur results show that with extremely high SARS-CoV-2 vaccination rates in Western Australian, and documented vaccine-induced vaccine waning rates, the overall population immunity in Western Australia will be at its highest in the period of February 2022 to June 2022. Opening the Western Australian border prior to the end this period will result in the lowest health burden in comparison to opening in June 2022 or later. With a border reopening of 3rd March 2022 announced by the Western Australian government, our data for a 5th March 2022 opening date may be used to predict the progression of this resulting outbreak. These data show expected peak demand of 510 hospital beds, 51 of which will be in ICU, with a total of 383 deaths. With a surge capacity of 52 ICU beds, it is expected that the Western Australian hospital system will be able to handle the additional load during the peak of the wave. | infectious diseases |
10.1101/2022.03.11.22271682 | The impact of introduction of the 10-valent pneumococcal conjugate vaccine (PCV10) on pneumococcal carriage in Nigeria | BackgroundPneumococcal Conjugate Vaccines (PCVs) reduce the burden of pneumococcal disease by reducing nasopharyngeal acquisition and transmission of serotypes in the vaccines (vaccine-serotypes). Following introduction of the 10-valent PCV (PCV10) in Nigeria, we assessed the population-level impact of PCV introduction on pneumococcal carriage.
MethodsWe conducted annual cross-sectional carriage and vaccination coverage surveys between 2016 and 2020 in rural and urban sites in Nigeria. We recruited a random sample of residents and used WHO-recommended laboratory methods to identify pneumococcal serotypes. We modelled prevalence ratios for the change in annual carriage prevalence using log-binomial regression, and explored the association between vaccination coverage in children <5 years and changes in the population-level vaccine-serotype carriage.
FindingsWe enrolled 4,684 and 3,653 participants for the carriage surveys and 2,135 and 1,106 children for the coverage surveys in the rural and urban sites, respectively. Carriage prevalence of vaccine-serotypes declined steadily with increasing levels of PCV10 coverage among children aged <5 years. From 2016 to 2020, coverage with three doses of PCV10 increased from 7% to 59% and from 15% to 81% in the rural and urban sites, respectively. Prevalence ratios for the annual change in vaccine-serotype carriage in participants aged <5 years and [≥]5 years were 0.84 (95% CI:0.79-0.89) and 0.86 (95%CI:0.80-0.89) in the rural, and 0.69 (95% CI:0.62-0.77), and 0.83 (95% CI:0.74-0.93) in the urban sites.
ConclusionsWe found significant reduction in vaccine-serotype carriage at a population level following a steady increase in PCV10 coverage, indicating direct and indirect vaccine effects. | infectious diseases |
10.1101/2022.03.09.22270839 | Safety of praziquantel in persons with and without schistosomiasis: systematic review and meta-analysis | Millions of praziquantel doses have been delivered in schistosomiasis endemic populations through preventive chemotherapy. However, no comprehensive assessment of short and long-term safety has been conducted. This systematic review assessed safety of praziquantel in persons with and without schistosome infections who received praziquantel treatment.
MethodsWe identified relevant studies (published, unpublished, in press or preprint) that assessed safety of praziquantel without language restriction. We searched MEDLINE, EMBASE, CINAHL, and LILACS from 1978 to 31st October 2021, using well-formulated and piloted search strategy. We also searched the Cochrane Infectious Diseases Group Specialized Register, CENTRAL (The Cochrane Library 2021), mRCT, Google Scholar, Hinari and Africa Journals Online. References of relevant studies were checked and experts were contacted for additional studies. One author searched and managed the search output. Two authors selected studies, extracted data and assessed quality of the included studies for risk of bias. Activities at all stages were checked independently by a third reviewer. Discrepancies were resolved through discussion among the authors. Data were analysed with RevMan v5.4 and STATA v17. Binary outcomes were reported as risk ratio using random-effects model and continuous outcomes as mean difference, all presented with their 95% confidence intervals. P-value was set at 0.05. Heterogeneity was assessed using I2-static and where possible sensitivity analysis was conducted. When pooling of data was not possible, we presented data in a narrative synthesis and as tables.
Main resultsThe search retrieved 3202 studies of which 134 met the inclusion criteria; 94 (70.1%) were conducted in Africa, 17 (12.7%) in Asia, 15 (11.2%) in the Americas (14 from Brazil), 4 (3.0%) in the Middle East and 3 (2.2%) in Europe. Praziquantel mostly resulted in mild-to-moderate and transient adverse events, however, majority of the included studies had design issues, including very short follow-up times (mostly few hours) for assessing incidence of adverse events. Less than <10% of the studies reported severe or serious adverse events. The subgroup analyses of twenty studies comparing school age children (SAC) and adults, and involved over one million participants found no difference in the nature of adverse events, but SAC experienced higher incidence than adults: headache (RR 3.07, 95% CI 2.32 to 4.06, twenty studies, I2 = 98%, p < 0.00001), dizziness (RR 1.80, 95% CI 1.36 to 2.37, p = 0.0001), vomiting (RR 2.43, 95% CI 1.87 to 3.14, I2 = 98%; p < 0.00001), four time for abdominal pain (RR 3.97, 95% CI 3.09 to 5.10, I2 = 96%, p < 0.00001), nausea (RR 1.67, 95% CI 1.32 to 2.12, I2 = 97%, p < 0.0001), general discomfort (RR 1.32, 95% CI 1.03 to 1.68, I2 = 97%, p < 0.00001), fever (RR 4.78, 95% CI 3.04 to 7.52, I2 = 98%, p < 0.00001), diarrhoea (RR 1.41, 95% CI 1.12 to 1.78, I2 = 92%, p < 0.00001), itching (RR 2.42, 95% CI 1.58 to 3.70, I2 = 93%, p <0.0001) and breathing difficulty (RR 2.46, 95% CI 1.41 to 4.29, I2 = 92%, p = 0.002). There was no statistically significant difference in incidence of swelling. Some of the studies that assessed safety in pregnant women reported serious events including miscarriages, foetal deaths and congenital anomalies, but the evidence is incoclusive given the limited numbers. Some studies reported praziquantel-related visual adverse events, but evidence is limited and remains inconclusive. There was paucity of data on long term adverse events, and events in co-morbidity, polypharmacy, co-infection with taeniasis. Generally, adverse events research in this area lacked methodological rigour.
ConclusionsThe evidence generated from this review involving millions of people and millions of doses from different geographic locations with mostly mild-to-moderate and transient adverse events shows praziquantel is safe. However, given that the primary studies included in the review had design issues, including over 95% assessing adverse events over very short follow-up times, means serious long-term adverse events would have been missed. Also, the fact that some pregnant women who received praziquantel experienced serious events including miscarriages, foetal deaths and congenital anomalies calls for caution in the inclusion of pregnant women, particularly in their first trimester, in preventive chemotherapy campaigns. Additionally, the studies that reported severe visual adverse events raise safety concerns. Praziquantel is now offered repeatedly in endemic communities and the fact that in some settings up to 90% of those without infection could be offered the drug and the fact that there was no study that compared safety between infected and non-infected recipients, warrants further research. Evidence on safety in pregnant women and their foetuses, co-morbidity, polypharmacy, co-infection with taeniasis, as well as co-administration with drugs used in other preventive chemotherapy programmes, remain inconclusive and further research with long follow-up that should include blood chemistry analysis to provide additional evidence on long term safety, is warranted. This systematic review has exposed the lack of methodological rigour in adverse events studies and recommends future research should use robust and standardized design, methods, conduct and reporting. | infectious diseases |