Risk factors for early childhood growth faltering in rural Cambodia IntroductionInadequate nutrition in early life and exposure to sanitation-related enteric pathogens have been linked to poor growth outcomes in children. Despite rapid development in Cambodia, high prevalence of growth faltering and stunting continue to persist. This study aimed to assess nutrition and WASH variables and their association with nutritional status of children under 24 months in rural Cambodia.

MethodsWe conducted surveys in 491 villages across 55 rural communes in Cambodia in September 2016 to measure associations between child, household, and community-level risk factors for stunting and length-for-age z-score (LAZ). A primary survey measured child-level variables, including anthropometric measures and risk factors for growth faltering and stunting, for 4,036 children under 24 months of age from 3,877 households (approximately 8 households per village). For LAZ, we calculated bivariate and adjusted associations (as mean differences) with 95% confidence intervals using generalised estimating equations (GEEs) to fit linear regression models with robust standard errors. For stunting, we calculated unadjusted and adjusted prevalence ratios (PRs) with 95% confidence intervals using GEEs to fit Poisson regression models with robust standard errors. For all models assessing effects of household-level variables, we used GEEs to account for clustering at the village level.

ResultsAfter adjustment for potential confounding, presence of water and soap at a households handwashing station was found to be significantly associated (p<0.05) with increased LAZ (adjusted mean difference in LAZ +0.10, 95% CI: 0.03, 0.16), and household use of an improved drinking water source was associated with less stunting in children compared to households that did not use an improved source of drinking water (aPR 0.81, 95% CI: 0.66, 0.98); breastfeeding was associated with a lower LAZ score (-0.16, 95% CI: -0.27, -0.05). No other feeding practices (i.e., dietary diversity, meal frequency, minimum acceptable diet) or sanitation variables (i.e., households safe disposal of child stools, household-level sanitation, community-level sanitation) were associated with LAZ scores or stunting in children under 24 months of age. In an age-stratified analysis, children under 12 months of age were longer (LAZ +0.12, 95% CI: 0.02, 0.21) if there was presence of water and soap at the household handwashing station; at the community level, higher prevalence of shared sanitation (percentage of households in a village who report to use shared sanitation facilities) was negatively associated with child length (LAZ - 0.36, 95% CI: -0.66, -0.07).
Comparative analyses of FDA EUA-approved rapid antigen tests and RT-PCR for COVID-19 quarantine and surveillance-based isolation BackgroundRapid antigen (RA) tests are being increasingly employed to detect SARS-CoV-2 infections in quarantine and surveillance. Prior research has focused on RT-PCR testing, a single RA test, or generic diagnostic characteristics of RA tests in assessing testing strategies.

MethodsFor 18 RA tests with emergency use authorization from the United States of America FDA and an RT-PCR test, we conducted a comparative analysis of the post-quarantine transmission, the effective reproduction number during serial testing, and the false-positive rates. To quantify the extent of transmission, we developed an analytical mathematical framework informed by COVID-19 infectiousness, test specificity, and temporal diagnostic sensitivity data.

ResultsWe demonstrate that the relative effectiveness of RA and RT-PCR tests in reducing post-quarantine transmission depends on the quarantine duration and the turnaround time of testing results. For quarantines of two days or shorter, conducting a RA test on exit from quarantine reduces onward transmission more than a single RT-PCR test (with a 24-h delay) conducted upon exit. Applied to a complementary approach of performing serial testing at a specified frequency paired with isolation of positives, we have shown that RA tests outperform RT-PCR with a 24-h delay. The results from our modeling framework are consistent with quarantine and serial testing data collected from a remote industry setting.

ConclusionsThese RA test-specific results are an important component of the tool set for policy decision-making, and demonstrate that judicious selection of an appropriate RA test can supply a viable alternative to RT-PCR in efforts to control the spread of disease.

Plain language summaryPrevious research has determined optimal timing for testing in quarantine and the utility of different frequencies of testing for disease surveillance using RT-PCR and generalized rapid antigen tests.

However, these strategies can depend on the specific rapid antigen test used. By examining 18 rapid antigen tests, we demonstrate that a single rapid antigen test performs better than RT-PCR when quarantines are two days or less in duration. In the context of disease surveillance, the ability of a rapid antigen test to provide results quickly counteracts its lower sensitivity with potentially more false positives. These analytical results based on highly controlled test validation were consistent with real-world data obtained from quarantine and serial testing in an industrial setting.
DNR orders in SARS-CoV-2 patients: a retrospective validation study in a Swiss COVID-19 Center BackgroundThe worldwide pandemic situation forced many hospitals to adapt COVID-19 management strategies. In this scenario, the Swiss Academy of Medical Sciences (SAMW/ASSM) organized national guidelines based on expert opinion to identify Do-Not-Resuscitate (DNR) patients, to reduce futile ICU admission and resource misuse. However, the practical impact of this standardized national protocol has not been yet evaluated. In our specialized COVID-19 Center, we investigated characteristics and mortality of DNR patients identified according to national standardized protocol, comparing them to non-DNR patients.

MethodsThis was a pilot retrospective validation study, evaluating consecutive hospital admitted COVID-19 patients. Primary outcome was 30-days survival of DNR patients in comparison to the control group. Secondary outcomes reported quality of treatment of deceased patients, especially of agitation/sedation and dyspnea, using respectively the Richmond Agitation-Sedation Scale - Palliative care (RASS-PAL) for sedation and agitation (+4/-5) and the modified Borg Scale for dyspnea (1-10).

ResultsFrom March 16 to April 1, 2020, 213 consecutive patients were triaged; at 30-days follow-up, 9 patients (22.5%) died in the DNR group, 4 (2.2%) in the control group. The higher mortality rate in the DNR group was further confirmed by Log-Rank Mantel-Cox (23.104, p < 0.0001). In the DNR-group deceased patients, end-of-life support was performed with oxygen (100%), opioids (100%) and sedatives (89%); the mean RASS-PAL improved from 2.2 to -1.8 (p < 0.0001) and the Borg scale improved from 5.7 to 4.7 (p = 0.581).

ConclusionA national standardized protocol identified patients at higher risk of short-term death. Although the legal status of DNRs varies from country to country, the implementation of national standardized protocol could be the way to guarantee a better treatment of COVID-19 patients in a pandemic situation with limited resources. Hair loss in females and thromboembolism in males are significantly enriched in post-acute sequelae of COVID (PASC) relative to recent medical history After one year of the COVID-19 pandemic, over 130 million individuals worldwide have been infected with the novel coronavirus, yet the post-acute sequelae of COVID-19 (PASC), also referred to as the  long COVID syndrome, remains mostly uncharacterized. We leveraged machine-augmented curation of the physician notes from electronic health records (EHRs) across the multi-state Mayo Clinic health system to retrospectively contrast the occurrence of symptoms and diseases in COVID-19 patients in the post-COVID period relative to the pre-COVID period (n=6,413). Through comparison of the frequency of 10,039 signs and symptoms before and after diagnosis, we identified an increase in hypertensive chronic kidney disease (OR 47.3, 95% CI 23.9-93.6, p=3.50x10-9), thromboembolism (OR 3.84, 95% CI 3.22-4.57, p=1.18x10-4), and hair loss (OR 2.44, 95% CI 2.15-2.76, p=8.46x10-3) in COVID-19 patients three to six months after diagnosis. The sequelae associated with long COVID were notably different among male vs female patients and patients above vs under 55 years old, with the hair loss enrichment found primarily in females and the thromboembolism enrichment in males. These findings compel targeted investigations into what may be persistent dermatologic, cardiovascular, and coagulopathic phenotypes following SARS-CoV-2 infection. Uncovering Survivorship Bias in Longitudinal Mental Health Surveys During the COVID-19 Pandemic AimsMarkedly elevated adverse mental health symptoms were widely observed early in the coronavirus disease 2019 (COVID-19) pandemic. Unlike the U.S., where cross-sectional data indicate anxiety and depression symptoms have remained elevated, such symptoms reportedly declined in the U.K., according to analysis of repeated measures from a largescale longitudinal study. However, nearly 40% of U.K. respondents (those who did not complete multiple follow-up surveys) were excluded from analysis, suggesting that survivorship bias might partially explain this discrepancy. We therefore sought to assess survivorship bias among participants in our longitudinal survey study as part of The COVID-19 Outbreak Public Evaluation (COPE) Initiative.

MethodsSurvivorship bias was assessed 4,039 U.S. respondents who completed surveys including the assessment of mental health as part of The COPE Initiative in April 2020 and were invited to complete follow-up surveys. Participants completed validated screening instruments for symptoms of anxiety, depression, and insomnia. Survivorship bias was assessed for (1) demographic differences in follow-up survey participation, (2) differences in initial adverse mental health symptom prevalences adjusted for demographic factors, and (3) differences in follow-up survey participation based on mental health experiences adjusted for demographic factors.

ResultsAdjusting for demographics, individuals who completed only one or two out of four surveys had higher prevalences of anxiety and depression symptoms in April 2020 (e.g., one-survey versus four-survey, anxiety symptoms, adjusted prevalence ratio [aPR]: 1.30, 95% confidence interval [CI]: 1.08-1.55, P=0.0045; depression symptoms, aPR: 1.43, 95% CI: 1.17-1.75, P=0.00052). Moreover, individuals who experienced incident anxiety or depression symptoms had higher odds of not completing follow-up surveys (adjusted odds ratio [aOR]: 1.68, 95% CI: 1.22-2.31, P=0.0015, aOR: 1.56, 95% CI: 1.15-2.12, P=0.0046, respectively).

ConclusionsOur findings revealed significant survivorship bias among longitudinal survey respondents, indicating that restricting analytic samples to only respondents who provide repeated assessments in longitudinal survey studies could lead to overly optimistic interpretations of mental health trends over time. Cross-sectional or planned missing data designs may provide more accurate estimates of population-level adverse mental health symptom prevalences than longitudinal surveys. Remote exposure to secondhand tobacco smoke is associated with lower exercise capacity through effects on oxygen pulse, a proxy of cardiac stroke volume BackgroundPast exposure to secondhand tobacco smoke (SHS) is associated with exercise limitation. Pulmonary factors including air trapping contribute to this limitation but the contribution of cardiovascular factors is unclear.

ObjectiveTo determine contribution of cardiovascular mechanisms to SHS-associated exercise limitation.

MethodsWe examined the cardiovascular responses to maximum effort exercise in 245 never-smokers with remote, prolonged occupational exposure to SHS and no known history of cardiovascular disease. We estimated the contribution of oxygen-pulse (proxy for cardiac stroke volume) and changes in systolic (SBP) and diastolic blood pressures (DBP) and heart rate (HR) towards exercise capacity, and examined whether the association of SHS with exercise capacity was mediated through these variables.

ResultsAt peak exercise (highest workload completed [WattsPeak]=156{+/-}46 watts [135{+/-}33 %predicted]), oxygen consumption (VO2Peak) and oxygen-pulse (O2-PulsePeak) were 1,557{+/-}476 mL/min (100{+/-}24 %predicted) and 11.0{+/-}3.0 mL/beat (116{+/-}25 %predicted), respectively, with 29% and 3% participants not achieving their predicted normal range. Oxygen saturation at peak exercise was 98{+/-}1% and remained >93% in all participants. Sixty-six percent showed hypertensive response to exercise. In models adjusted for covariates, WattsPeak was associated directly with O2-PulsePeak, HRPeak, and SBPPeak and inversely with SHS, air trapping (RV/TLC), and rise of SBP over workload (all P<0.01). Moreover, SHS exposure association with WattsPeak was substantially (41%) mediated through its effect on O2-PulsePeak (P<0.038). Although not statistically significant, a considerable proportion (36%) of air trapping effect on WattsPeak seemed to be mediated through O2-PulsePeak (P=0.078). The likelihood of having baseline respiratory symptoms (modified Medical Research Council score [&ge;]1) was associated with steeper rise in SBP over workload (P<0.01).

ConclusionIn a never-smoker population with remote exposure to SHS, abnormal escalation of afterload and an SHS-associated reduction in cardiac output contributed to lower exercise capacity.

Key messagesO_ST_ABSWhat is the key question?C_ST_ABSWhat are the cardiovascular health effects of past exposure to secondhand tobacco smoke in never-smokers? How do pulmonary and cardiovascular systems interact in this setting?

What is the bottom line?Healthy never-smokers with history of remote past exposure to secondhand tobacco smoke have an abnormal cardiovascular response to exercise, which is characterized by a stroke volume and thus an exercise capacity that are reduced proportional to their years of exposure to secondhand tobacco smoke.

Why read on?The abnormal cardiovascular response to exercise in this population reveals the presence of an occult or subclinical pathology that impairs the cardiopulmonary functional reserve and reduces the efficiency of bodys oxygen delivery machinery, which could be disadvantageous during the times of increased cardiopulmonary output demands as in physiological distress or disease. PREVALENCE THRESHOLD THAT SHOULD BE APPLIED IN SCHISTOSOMIASIS MASS DRUG ADMINISTRATION PRGROGRAMMES: SYSTEMATIC REVIEW AND META-ANALYSIS BackgroundThe WHO-recommended prevalence thresholds for deciding schistosomiasis mass drug administration (MDA) are based on anecdotal evidence and may mislead. This study systematically synthesized evidence to generate a single optimal  global prevalence threshold that should guide schistosomiasis MDA programmes worldwide.

MethodsWe searched several databases from 1978 to 31st October 2021 without language restriction. Two reviewers selected studies, extracted data, and assessed risk of bias using relevant risk of bias tools, and resolved disagreements through discussion. The review followed best practices protocols and guidelines. Data were analysed and presented as prevalence reduction (PR) and relative risk (RR) for dichotomous outcomes or mean difference for continuous outcomes, each presented with their 95% confidence intervals (CI). Meta-regression of observations on prevalence rates and intensity of infection were performed to assess the effect of repeat MDA over time. Sensitivity analysis was performed to test the robustness of the results to the risk of bias components. The overall level of evidence was graded using GRADE.

FindingsOf the 1,232 studies retrieved, 38 met our inclusion criteria and 34 were included in the meta-analysis. No direct relation was observed between prevalence and intensity of infection. Praziquantel reduced prevalence of S. mansoni in school age children (SAC) at 12 months (RR 0.56, 95% CI 0.46 to 0.69; 14 studies, n=86,073); 24 months (RR 0.46; 95% CI 0.32 to 0.66; 14 studies; n=83,721); 36 months (RR 0.44, 95% CI 0.33 to 0.58; 7 studies, n=70,933) and 48 months (RR 0.25, 95% CI 0.11 to 0.59; 5 studies; n=27,483). Similarly for S. haematobium, there were reductions in prevalence in school age children (SAC) at 12 months (RR 0.38, 95% CI 0.28 to 0.52; 8 studies, n=37,868); at 24 months (RR 0.30; 95% CI 0.30[boxh]0.52; 7 studies; n=37,107); and 36 months (RR 0.39, 95% CI 0.21 to 0.71; 5 studies, n=28,146). There was no significant reduction in prevalence at 48 months (2 studies, n=10,954). Further analyses were performed from a series of prevalence thresholds created from the data at 5%, 10%, 15%, 20%, 30% and [&ge;]40% and the results showed differences in the effect of MDA when each threshold was applied in the regression model. For annual MDA involving SAC, school-based treatment (SBT) appeared to perform better than community-wide treatment (CWT) in terms of prevalence reduction; but this could be subject to the frequency of treatment and retreatment applied in SAC compared to CWT. Using the optimal prevalence threshold of 10%, the model suggested it will take over 10 years to bring the prevalence of schistosomiasis to 1% for S. haematobium and up to 15 years for S. mansoni with repeated annual MDA.

InterpretationThis systematic review and meta-analysis provides evidence that 10% prevalence is the optimum that should be used as the  standard global threshold for implementing MDA in endemic countries.

FundingThis work was commissioned and supported by the World Health Organization, Geneva, Switzerland as part of evidence-based schistosomiasis guideline development.

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSCurrently, the prevalence thresholds used in implementing mass drug administration within the preventive chemotherapy strategy for schistosomiasis control are based on anecdotal evidence and unreliable. We identified relevant studies regardless of language or publication status (published, unpublished, in press, and ongoing). We searched PubMed, CINAHL and LILACS from 1978 to 31st October 2021 without language restriction. We also searched the Cochrane Infectious Diseases Group Specialized Register, CENTRAL (The Cochrane Library 2021), mRCT, Hinari, the WHO Library Database, Africa Journals Online and Google Scholar. Experts in the field of schistosomiasis were contacted, preprint repositories were searched and the reference lists of articles were reviewed for additional or unpublished data. This study was commissioned by the WHO to provide systematically synthesized evidence to inform on a single global prevalence threshold that should be applied by endemic countries when deciding MDA campaigns for the prevention and control of schistosomiasis.

Added value of this studyThis is the first systematic review and meta-analysis commissioned by the WHO to determine a single prevalence threshold that should be employed by endemic countries for the implementation of global schistosomiasis mass drug administration. This study pooled data involving thousands of participants across thousands of villages from all endemic settings, making it unique in terms of statistical power and generalizability of the main findings and conclusions. The study used PICOS (P-population, I-intervention, C-comparator, O-outcomes and S-study) to formulate an appropriate review question, clear objectives, stringent inclusion and exclusion criteria as well as rigorous quality assessment and data synthesis, following strictly best practices for preparing and reporting systematic reviews. The search has been very comprehensive including all relevant electronic databases and non-electronic sources, done in close collaboration with experienced information specialist. The review process ensured meticulous attention to details, making the necessary effort to minimize bias, carrying out aspects of the review independently by the reviewers and addressing disagreements through discussions between the reviewers. Given the geographical variations, and differences in the levels of baseline endemicities, diagnostic criteria, age groups treated and follow-up times across studies, this necessitated robust sub-group analyses to detect any sub-group effects. We ran meta-regression analyses to identify any potentially useful trends, and tested the robustness of effect estimates from sensitivity analyses. We have assembled world-class experts from diverse backgrounds and geographical locations, including epidemiologists, evidence synthesis specialists, economists, allied health professionals, statisticians, biomedical scientists, clinicians and non-medical experts to produce this innovative, demand-driven, policy- and context-relevant systematic review and meta-analysis that will help guide policy and practice in the global control of schistosomiasis.

Implications of all the available evidenceOur review provides evidence that 10% baseline prevalence is the minimum optimal threshold that should be used to decide the implementation of MDA programmes in schistosomiasis endemic countries. Praziquantel is effective in reducing the prevalence of schistosomiasis at 12 months, but incremental benefit of repeated annual treatment appears to be minimal after 12 months. Effectiveness depends on several factors, which are difficult to disentangle, however, the rate at which prevalence decreases does not appear to be influenced by baseline intensity of infection and treatment approach (whether whole community or school-based). From exploratory analysis, intensity of infection appears to be more stable than prevalence for assessing outcome of MDA. Therefore, further research is needed to determine an optimal intensity threshold and compare it with prevalence threshold. In terms of policy, the difficulty in achieving elimination with mass drug administration alone means that integration of non-pharmacological interventions such access to clean water, improved sanitation, hygiene education (WASH) and snail control to complement MDA if elimination is to be achieved.

This systematic review was registered in PROSPERO CRD422020221548. Factors affecting first return to work following arthroscopic rotator cuff repair: A retrospective observational study in an occupational medicine clinic and single-surgeon practice BackgroundReturn to work (RTW) following arthroscopic rotator cuff repair (aRCR) within New South Wales (NSW), Australia, under compensable schemes has not been reported.

AimsDetermine factors affecting RTW status and time in patients treated with aRCR under state-based compensation schemes, compared to those outside such schemes.

MethodsPatients undergoing aRCR by one surgeon with minimum 1-year follow-up were grouped into those under (CP) or outside (non-CP) workers or vehicle accident compensation schemes, matched by age and gender. RTW status and time were assessed using chi-square analysis and multivariable linear regression.

ResultsOf 1054 available patients, 90 CP patients were identified with 29 consented and matched to non-CP (N=29). A higher proportion of CP patients (17.2 vs 0%, P<0.001) never returned to work and a lower proportion resumed pre-injury duties at first RTW (3 vs 52%, P<0.01). Median time to first RTW did not differ between CP and non-CP groups (5.1 vs 4.4, P=0.86). Smoking (P=0.007) and post-injury activity level (P=0.004) were significantly associated with longer time to first RTW, whereas compensation status was not.

ConclusionsCP patients undergoing aRCR in NSW are at risk of not returning to work. For those that return, there is no significant difference compared to non-CP in time to first RTW. Particularly, patient and management factors associated with extended time to first RTW have been identified. Interventions aimed at modifiable factors such as smoking cessation and increasing preoperative activity may improve future outcomes.

What is already known about this subjectO_LIWork-related injury and disease present a significant financial burden to the Australian economy ($AUD61.8billion per annum), with shoulder conditions due to body stressing accounting for 7% of this total cost (>$AUD4.2billion)
C_LIO_LIPatients receiving compensation appear to have poorer outcomes and take longer to return to work than their non-compensated counterparts, but the degree to which this occurs is variably reported in the literature
C_LIO_LIThe effect of modifiable factors on return to work status and time remain unclear, and have not previously been reported for the Australian population under the New South Wales workers compensation scheme
C_LI

What this study addsO_LIPatients receiving arthroscopic rotator cuff repair under a compensable scheme in New South Wales are at increased risk of not returning to work compared to patients presenting outside of a compensable scheme and patients in equivalent schemes internationally
C_LIO_LIPatients reporting a longer duration of symptoms and smokers are at increased risk of extended time to first return to work
C_LI

What impact this may have on practice or policyO_LIThe study has identified smoking and pre-surgery activity levels as key targets for intervention in patients receiving arthroscopic rotator cuff repair under a workers compensation scheme in New South Wales
C_LIO_LIBy further investigating whether interventions designed to modify these factors are able to favourably affect patient outcomes, there is potential to return patients to their preoperative level of work sooner
C_LI HIV-infected patients on combined antiretroviral treatment had similar level of arterial stiffness to the patients with ST-segment elevation myocardial infarction. PurposeThe cardiovascular disease has become very common among HIV-infected patients. The aim was to compare the arterial stiffness and the endothelial dysfunction in HIV-infected patients to non-HIV-infected patients in week 4 after ST-segment elevation myocardial infarction (STEMI).

MethodsThe arterial stiffness was calculated by Endo-PAT 2000(ITAMAR(R)) and the endothelial function by Peripheral Arterial Tonometry(PAT(R)). The correct endothelial function was defined for natural logarithm of reactive hyperaemia index (lnRHI)>0.51. Arterial stiffness was assessed as the AI and corrected for heart rate of 75 bpm (AI@75).

ResultsSixty-three patients were recruited to this study, n=34 patients with HIV infection (n=18 on cART) and n=29 HIV-negative patients after recent STEMI. No statistically significant differences for AI and AI@75 were found in STEMI and in HIV on cART group. We observed p<0.05 for AI and AI@75 for patients without cART compared to STEMI and on cART patients. The observed lnRHI results were significantly different p<0.05 in STEMI and on cART patients. We get similar endothelial dysfunction p>0.05 for patients without cART compared to STEMI and on cART patients.

ConclusionsAssessing cardiovascular risk also with non-invasive methods among HIV-infected patients is very important especially in HIV-patients on cART. Endothelial dysfunction is connected with HIV infection and can be similar for STEMI and HIV-infected without cART. Detection of Somatic Copy Number Deletion of CDKN2A Gene for Clinical Practices Based on Discovery of A Base-Resolution Common Deletion Region BackgroundCDKN2A is most frequently inactivated by somatic copy number deletion (SCND) in human cancers. An accurate method to detect CDKN2A SCND is absent.

MethodsTo look for the pattern of CDKN2A SCND in cancer cells, interstitial base-resolution deletion/fusion coordinates for CDKN2A were extracted from published articles and our whole genome sequencing (WGS) datasets. A multiplex PCR assay was setup to quantify CDKN2A copy number and confirmed with WGS and loss of heterozygosity (LOH) assays using gastric carcinoma (GC) samples from two sets of patients (n=156 and 140), respectively.

ResultsWe characterized a 5.1-kb common deletion region (CDR) from the CDKN2A/P16INK4A promoter to intron-2 in >90% (83/92) of cancer cell lines and 100% (18/18) of GC samples by WGS. The CDR includes exon-2 that is shared by P16INK4A and P14ARF genes. Then, a highly reproducible and quantitative assay, P16-Light, targeted to the CDR was setup with a lower limit of detection at 20%. P16-Light was further compared with WGS (gold standard) and LOH assay by denaturing high performance liquid chromatography. The positive rate of CDKN2A SCND by P16-Light was more than two times of that by WGS in GCs from a patients cohort (25.6% vs. 10.9%), and was significantly correlated with each other (p<0.028). While CDKN2A SCND was significantly associated with GC distant metastasis (p=0.023), such association was not observed for CDKN2A LOH.

ConclusionBased on our finding that there is a 5.1-kb CDR within the CDKN2A gene, a vary convenient P16-Light assay was setup to detect CDKN2A SCND for routine clinical applications. PENet: Continuous-Valued Pulmonary Edema Severity Prediction On Chest X-ray Using Siamese Convolutional Networks For physicians to take rapid clinical decisions for patients with congestive heart failure, the assessment of pulmonary edema severity in chest radiographs is vital. While deep learning has been promising in detecting the presence or absence, or even discrete grades of severity, of such edema, prediction of the continuous-valued severity yet remains a challenge. Here, we propose PENet, a deep learning framework to assess the continuous spectrum of pulmonary edema severity from chest X-rays. We present different modes of implementing this network, and demonstrate that our best model outperforms that of earlier work (mean area under the curve of 0.91 over 0.87, for nine comparisons), while saving training data and computation. Tracking deaths from hitherto undetected infections can be an indicator of latent sars-cov-2 cases BackgroundWith countries across the world facing repeated epidemic waves, it becomes critical to monitor, mitigate and prevent subsequent waves. Common indicators like active case numbers can flatter to deceive in the presence of systemic inefficiencies like insufficient testing or contact tracing. Test positivity rates are sensitive to testing strategies and cannot estimate the extent of undetected cases. Reproductive numbers estimated from logarithms of new incidences are inaccurate in dynamic scenarios and not sensitive enough to capture changes in efficiencies. Systemic fatigue results in lower testing, inefficient tracing and quarantining thereby precipitating the onset of the epidemic wave.

MethodsWe propose a novel indicator for detecting the slippage of test-trace efficiency based on the numbers of deaths/hospitalizations resulting from known and hitherto unknown infections. This can also be used to forecast an epidemic wave that is advanced or exacerbated due to drop in efficiency.

ResultsUsing a modified SEIRD epidemic simulator we show that (i) Ratio of deaths/hospitalizations from an undetected infection to total deaths converges to a measure of systemic test-trace inefficiency. (ii) This index forecasts the slippage in efficiency earlier than other known metrics. (iii) Mitigation triggered by this index helps reduce peak active caseload and eventual deaths.

ConclusionsDeaths/hospitalizations accurately track the systemic inefficiencies and detect latent cases. Based on these results we make a strong case that administrations use this metric in the ensemble of indicators. Further hospitals may need to be mandated to distinctly register deaths/hospitalizations due to previously undetected infections.

Key MessagesO_LIDeaths or Hospitalizations are unmissable events in an epidemic and this paper proposes a metric Dratio based on these numbers to monitor the inefficiencies in test-track-trace performance.
C_LIO_LIThe ratio of deaths(or hospitalizations) resulting from undetected infections to total deaths (or hospitalizations) detect the onset of laxity in regulations earlier than other conventional metrics like daily increase in active cases, daily deaths or even reproductive number estimates.
C_LIO_LIMitigation by tracking the Dratio reduces or truncates the epidemic wave intensity or delays it sufficiently.
C_LI The energy balance theory: an unsatisfactory model of body composition fluctuations Differential weight and fat losses under isocaloric diets of distinct macronutrient composition are well-documented findings in obesity research.1-6 Such data are considered a result of inadequate methodology as it disagree with the energy balance theory.7 A recent mathematical analysis of this paradigm has found, however, serious analytical contradictions in its foundations.8 As an alternative, a mass balance model was proposed to explain the aforesaid body composition alterations. Here, we expand on this observation by contrasting both models. We show that mass balance explains a wide range of fending experiments including those concurring with the energy balance principle. The latter, however, is less flexible and results in poor forecasts in settings consistent with mass balance. The energy balance theory is thus an unsatisfactory model of body composition changes. Consequently, by shifting to a mass balance paradigm of obesity a much deeper understanding of this disease may follow in the near future. Early prediction of preeclampsia in pregnancy with circulating cell-free RNA Liquid biopsies that measure circulating cell-free RNA (cfRNA) offer an unprecedented opportunity to noninvasively study the development of pregnancy-related complications and to bridge gaps in clinical care. Here, we used 404 blood samples from 199 pregnant mothers to identify and validate cfRNA transcriptomic changes that are associated with preeclampsia (PE), a multi-organ syndrome which is the second largest cause of maternal death globally. We find that changes in cfRNA gene expression between normotensive (NT) and preeclamptic mothers are striking and stable early in gestation, well before the onset of symptoms. These changes are enriched for genes specific to neuromuscular, endothelial, and immune cell types and tissues that reflect important aspects of PE physiology and suggest new hypotheses for disease progression. This enabled identification and independent validation of a panel of 18 genes whose measurement between 5-16 weeks of gestation can form the basis of a liquid biopsy test that would identify mothers at risk of PE well before the clinical symptoms manifest themselves. Finally, we demonstrate that cfRNA changes reflect the multifactorial nature of PE and provide a means to non-invasively monitor maternal organ health. Tests based on these observations could help predict and manage who is at risk for PE, an important and until now unachieved objective for obstetric care. Meta-analytic findings on reading in children with cochlear implants This meta-analysis study aims to quantify the group differences in reading skills between children with cochlear implants and their hearing peers and between children with cochlear implants and children with hearing aids (aged between 3 to 18 years old). Of the 5,642 articles screened, 47 articles met predetermined inclusion criteria (published between 2002 and 2019). The robust variance estimation based meta-analysis models were used to synthesize all the effect sizes. Children with cochlear implants scored significantly lower than their hearing peers in phonological awareness (g = - 1.62, p < .001), vocabulary (g = -1.50, p < .001), decoding (g = -1.24, p < .001), and reading comprehension (g = -1.39, p < .001), but not for fluency (g = -.67, p = .054). Compared to children with hearing aids, children with cochlear implants scored significantly lower in phonological awareness (g = -.30, p = .028). The percentage of unilateral cochlear implant negatively impacts the group difference between children with cochlear implants and their hearing peers. Findings from this study confirm a positive shift in reading outcomes for profoundly deaf children due to cochlear implantation. Some children with cochlear implants may need additional supports in educational settings. PBPK-led guidance for cystic fibrosis patients taking elexacaftor-tezacaftor-ivacaftor with nirmatrelvir-ritonavir for the treatment of COVID-19 BackgroundCystic fibrosis transmembrane conductance regulator (CFTR) modulating therapies including elexacaftor, tezacaftor, and ivacaftor (ETI) are primarily eliminated through cytochrome P450 (CYP) 3A-mediated metabolism. This creates a therapeutic challenge to the treatment of COVID-19 with nirmatrelvir-ritonavir in people with cystic fibrosis (pwCF) due to the potential for significant drug-drug interactions (DDI). However, pwCF are more at risk of serious illness following COVID-19 infection and hence it is important to manage the DDI risk and provide treatment options.

MethodsCYP3A-mediated DDI of ETI was evaluated using a physiologically based pharmacokinetic (PBPK) modeling approach. Modeling was performed incorporating physiological information and drug dependent parameters of ETI to predict the effect of ritonavir (the CYP3A4 inhibiting component of the combination) on pharmacokinetics of ETI. The ETI models were verified using independent clinical pharmacokinetic and DDI data of ETI with a range of CYP3A modulators.

ResultsWhen ritonavir was administered on day 1 through 5, the predicted AUC ratio of ivacaftor (the most sensitive CYP3A substrate) on day 6 was 9.31, indicating that its metabolism was strongly inhibited. Based on the predicted DDI, the dose of ETI should be reduced when co-administered with nirmatrelvir-ritonavir to elexacaftor 200mg-tezacaftor 100mg-ivacaftor 150mg on days 1 and 5, with resumption of full dose ETI on day 9, considering the residual inhibitory effect of ritonavir as a mechanism-based inhibitor.

ConclusionsCoadministration of nirmatrelvir-ritonavir requires a significant reduction in the ETI dosing frequency with delayed resumption of full dose due to the mechanism-based inhibition with ritonavir. Spatial Allocation of Scarce COVID-19 Vaccines The COVID-19 Vaccines Global Access (COVAX) is an initiative led by the World Health Organization (WHO) and other partners that aims for an equitable access of COVID-19 vaccines. Despite a potential heterogeneous disease burden across space, countries receiving allotments of vaccines via COVAX may want to follow WHOs allocation rule and distribute vaccines to their jurisdictions based on the jurisdictions relative population size. Utilizing economic-epidemiological modeling, we benchmark the performance of this ad hoc allocation rule by comparing it to the rule that minimizes the economic damages and expenditures over time, including a penalty cost representing the social costs of deviating from the ad hoc allocation. Under different levels of vaccine scarcity and different demographic characteristics, we consider scenarios where length of immunity and compliance to travel restrictions vary, and consider the robustness of the rules when assumptions regarding these factors are incorrect. The benefits from deviating are especially high when immunity is permanent, when there is compliance to travel restrictions, when the supply of vaccine is low, and when there is heterogeneity in demographic characteristics. Interestingly, a lack of compliance to travel restrictions pushes the optimal allocations of vaccine towards the ad hoc and improves the relative robustness of the ad hoc rule, as the mixing of the populations reduces the spatial heterogeneity in disease burden.

JEL ClassificationC61, H12, H84, I18, Q54 What delirium detection tools are used in routine clinical practice in the United Kingdom? Survey results from 91% of acute healthcare organisations. PurposeOur aim was to collect information on delirium assessment processes and pathways in non-intensive care settings in the United Kingdom (UK).

MethodsWe sent a Freedom of Information request to 169 UK National Health Service (NHS) hospitals, trusts and health boards (units) in July 2020 to obtain data on usage of delirium assessment tools in clinical practice and delirium pathways or guidelines.

ResultsWe received responses from 154/169 units (91% response rate). Of these, 146/154 (95%) units reported use of formal delirium assessment processes and 131/154 (85%) units had guidelines or pathways in place. The 4  As Test (4AT) was the most widely used tool, with 117/146 (80%) units reporting use. The Confusion Assessment Method was used in 65/146 (45%) units, and the Single Question to identify Delirium (SQiD) in 52/146 (36%) units.

ConclusionsOur findings show that the 4AT is the most commonly used tool in the UK, with 80% of units reporting use. This study adds to our knowledge of real-world uptake of delirium detection methods at scale. Future studies should evaluate real-world implementation of delirium assessment tools further via (i) tool completion rates and (ii) rates of positive scores against the expected prevalence delirium in the clinical population concerned.

KEY SUMMARY POINTSO_ST_ABSAimC_ST_ABSTo seek information on delirium assessment processes and pathways in non-intensive clinical care settings in the United Kingdom (UK), and to assess usage of specific delirium assessment tools: the 4  As Test (4AT), Confusion Assessment Method and Single Question to identify Delirium (SQiD).

FindingsIn total, 95% of National Health Service (NHS) units (hospitals, trusts and health boards) reported use of formal delirium assessment processes and 85% of units had guidelines or pathways in place. The 4AT was the most widely used tool, with 80% of units reporting use; the Confusion Assessment Method was reportedly used in 45% of units and the SQiD in 36% of units.

MessageThis study shows real-world, large-scale uptake of delirium detection methods and delirium guidelines in UK hospitals, which contributes to ongoing efforts to improve delirium care. Decoding hand and wrist movement intention from chronic stroke survivors with hemiparesis using a user-friendly, wearable EMG-based neural interface Prosthetics and orthotics have been recognized for decades as a potential means to restore hand function and independence to individuals living with impairment due to stroke. However, 75% of stroke survivors, caregivers, and health care professionals (HCP) believe current practices are insufficient, specifically calling out the upper extremity as an area where innovation is needed to develop highly usable prosthetics/orthotics for the stroke population. A promising method for controlling upper limb technologies is to infer movement intent non-invasively from surface electromyography (EMG) activity. While this approach has garnered significant attention in the literature, existing technologies are often limited to research settings and struggle to meet stated user needs. To address these limitations, we have developed the NeuroLife(R) EMG System, which consists of a wearable forearm sleeve with 150 embedded electrodes and associated hardware and software to record and decode surface EMG. Here, we demonstrate accurate decoding of 12 functional hand, wrist, and forearm movements, including multiple types of grasps from participants with varying levels of chronic impairment from stroke, with an overall accuracy of 77.1{+/-}5.6%. Importantly, we demonstrate the ability to decode a subset of 3 fundamental movements in individuals with severe hand impairment at 85.4{+/-}6.4% accuracy, highlighting the potential as a control mechanism for assistive technologies. Feedback from stroke survivors who tested the system indicates that the sleeves design meets various user needs, including being comfortable, portable, and lightweight. The sleeve is in a form factor such that it can be used at home without an expert technician and can be worn for multiple hours without discomfort. Taken together, the NeuroLife EMG System represents a platform technology to record and decode high-definition EMG for the eventual real-time control of assistive devices in a form factor designed to meet user needs. Short Practical Regimen of Acupuncture for Melasma: A Prospective Cohort Study in a Tertiary Hospital in Thailand BackgroundMelasma is a common skin pigmentation disorder. Acupuncture shows benefits for patients with melasma, although no standardized method or optimal number of sessions have been determined.

ObjectiveTo comparatively assess clinical outcomes of melasma between five vs ten standard acupuncture sessions.

MethodsWe performed a prospective observational cohort study in all melasma patients at the Acupuncture Clinic, King Chulalongkorn Memorial Hospital, Bangkok, Thailand. All patients were treated with standard acupuncture procedure twice a week and were evaluated after the fifth and the tenth sessions of acupuncture, with a follow-up one week after the last session. Participants were divided into two treatment groups: Groups A and B received five and ten acupuncture sessions respectively. Melasma outcomes were assessed by using the Melanin Index (MI), Melasma Area and Severity Index (MASI), patient-reported improvement scores and acupuncture-related adverse events.

ResultsOf 113 participants, 67 received five sessions of acupuncture treatment while 39 received ten sessions. 7 participants did not finish treatment. After five sessions of acupuncture in Group A, the mean MI decreased by 28.7 (95%CI -38.5 to -18.8), whereas the median MASI decreased by 3.4 (-6.9, -1.2) points. After ten sessions of acupuncture in Group B, the mean MI decreased by 31.3 (95%CI -45.0 to -17.6), whereas the median MASI decreased by 5.4 (-9.9, - 3.0) points. The first five sessions of acupuncture had a higher effect on the change in magnitude than the last five sessions, although there was no statistically significant difference. However, ten-session of acupuncture, had not reached the peak benefit on melasma yet. Further studies should be done with a higher number of sessions to determine the optimal rounds of treatment. Twenty-nine participants reported minor side effects, mostly consisting of persistent pain and small hematoma. Group B had RR of having adverse events 1.8 times (95% CI 1.0-3.4) compared to group A.

ConclusionAcupuncture has a potential dose-response effect on clinical and patient-reported melasma outcomes with minor side effects. Integrated multi-omics reveals anaplerotic insufficiency in methylmalonyl-CoA mutase deficiency Multi-layered omics approaches can help define relationships between genetic factors, biochemical processes and phenotypes thus extending research of inherited diseases beyond identifying their monogenic cause 1. We implemented a multi-layered omics approach for the inherited metabolic disorder methylmalonic aciduria (MMA). We performed whole genome sequencing, transcriptomic sequencing, and mass spectrometry-based proteotyping from matched primary fibroblast samples of 230 individuals (210 affected, 20 controls) and related the molecular data to 105 phenotypic features. Integrative analysis identified a molecular diagnosis for 84% (177/210) of affected individuals, the majority (148) of whom had pathogenic variants in methylmalonyl-CoA mutase (MMUT). Untargeted analysis of all three omics layers revealed dysregulation of the TCA cycle and surrounding metabolic pathways, a finding that was further corroborated by multi-organ metabolomics of a hemizygous Mmut mouse model. Integration of phenotypic disease severity indicated downregulation of oxoglutarate dehydrogenase and upregulation of glutamate dehydrogenase, two proteins involved in glutamine anaplerosis of the TCA cycle. The relevance of disturbances in this pathway was supported by metabolomics and isotope tracing studies which showed decreased glutamine-derived anaplerosis in MMA. We further identified MMUT to physically interact with both, oxoglutarate dehydrogenase complex components and glutamate dehydrogenase providing evidence for a multi-protein metabolon that orchestrates TCA cycle anaplerosis. This study emphasizes the utility of a multi-modal omics approach to investigate metabolic diseases and highlights glutamine anaplerosis as a potential therapeutic intervention point in MMA.

Take home messageCombination of integrative multi-omics technologies with clinical and biochemical features leads to an increased diagnostic rate compared to genome sequencing alone and identifies anaplerotic rewiring as a targetable feature of the rare inborn error of metabolism methylmalonic aciduria.

Graphical abstract

O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=100 SRC="FIGDIR/small/22269972v2_ufig1.gif" ALT="Figure 1">
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org.highwire.dtl.DTLVardef@1cb2b0org.highwire.dtl.DTLVardef@176cfaorg.highwire.dtl.DTLVardef@1f3cda7org.highwire.dtl.DTLVardef@142ce84_HPS_FORMAT_FIGEXP  M_FIG C_FIG Airway management, procedural data, and mortality records of patients undergoing surgery for mucormycosis associated with coronavirus disease (COVID-19) In India, the second wave of coronavirus disease (COVID -19) was associated with a distinct surge in cases of invasive fungal infection with mucormycosis. This disease was seen typically in the sinonasal form in COVID-19 patients. Uncontrolled diabetes, steroid use in COVID-19 treatment, etc. were some of the postulated risk factors for the association of COVID 19 and Mucormycosis. The management plan of these cases included surgical debridement, systemic antifungal therapy, sugar control, and management of antifungal related systemic adverse effects. In this retrospective case record review, we aimed to evaluate the airway management plan, demographics, and overall outcomes in patients undergoing surgical resection for COVID-19 associated mucormycosis. Forty-one (71.9 %) patients had a diagnosis of sino-nasal mucormycosis, fourteen (24.6%) had a diagnosis of rhino-orbital mucormycosis, and 2 patients (3.5%) were diagnosed with palatal mucormycosis. Total 44 (77.19 %) patients had co-morbidities. The most common co-morbidity was Diabetes Mellitus 42 (73.6%), followed by hypertension 21 (36.84%) and Acute kidney injury 14 (28.07%). We used the intubation difficulty scale score to assess intubating conditions. Intubation was easy to slightly difficult in 53 out of 57 patients. In our study, mortality occurred in 7 (12.28 %) patients. The median mortality time was 60 (range, 27-74) days. The median time to hospital discharge was 53.5 (range,10-85) days. Managing COVID-19 on its own is challenging and additional mucormycosis can lead to increased morbidity and mortality. Despite challenges and risks, timely and meticulous interventions can reduce complications. Best practices for multi-ancestry, meta-analytic transcriptome-wide association studies: lessons from the Global Biobank Meta-analysis Initiative SUMMARYThe Global Biobank Meta-analysis Initiative (GBMI), through its genetic and demographic diversity, provides a valuable opportunity to study population-wide and ancestry-specific genetic associations. However, with multiple ascertainment strategies and multi-ethnic study populations across biobanks, the GBMI provides a distinct set of challenges in implementing statistical genetics methods. Transcriptome-wide association studies (TWAS) are a popular tool to boost detection power for and provide biological context to genetic associations by integrating single nucleotide polymorphism to trait (SNP-trait) associations from genome-wide association studies (GWAS) with SNP-based predictive models of gene expression. TWAS presents unique challenges beyond GWAS, especially in a multi-biobank and meta-analytic setting like the GBMI. In this work, we present the GBMI TWAS pipeline, outlining practical considerations for ancestry and tissue specificity and meta-analytic strategies, as well as open challenges at every step of the framework. Our work provides a strong foundation for adding tissue-specific gene expression context to biobank-linked genetic association studies, allowing for ancestry-aware discovery to accelerate genomic medicine. Pausing methotrexate improves immunogenicity of COVID-19 vaccination in elderly patients with rheumatic diseases ObjectiveTo study the effect of methotrexate (MTX) and its discontinuation on the humoral immune response after COVID-19 vaccination in patients with autoimmune rheumatic diseases (AIRD).

MethodsNeutralising SARS-CoV-2 antibodies were measured after second vaccination in 64 rheumatic patients on methotrexate therapy, 31 of whom temporarily paused medication without a fixed regimen. The control group consisted of 21 AIRD patients without immunosuppressive medication.

ResultsMTX patients showed a significantly lower median antibody response compared to AIRD patients without immunosuppressive therapy (p< 0.001). Young age (<60 years) and MTX-hold after vaccination were found to be the main factors influencing antibody response after vaccination, while BMI or MTX dose demonstrated no effect. For patients taking MTX, age correlated negatively with immune response (r=-0.49; p<0.001) and all patients with antibody levels (14 %) below the cut-off were older than 60 years. Patients who held MTX during at least one vaccination showed significantly higher median neutralising antibody levels after second vaccination, compared to patients who continued MTX therapy during both vaccinations (68.82 %, 92.73 %, p=<0.001). This effect was particularly pronounced in patients older than 60 years (p=0.0016). The impact of the time period after vaccination was greater than of the time before vaccination with the critical cut-off being 10 days.

ConclusionMTX reduces the immunogenicity of SARS-CoV-2 vaccination in an age-dependent manner. Our data further suggest that holding MTX for at least 10 days after vaccination significantly improves the antibody response in patients over 60 years of age. Complementary frailty and mortality prediction models on older patients as a tool for assessing palliative care needs BackgroundPalliative care (PC) has demonstrated benefits for life-limiting illnesses. Cancer patients have mainly accessed these services, but there is growing consensus about the importance of promoting access for patients with non-malignant disease. Bad survival prognosis and patients frailty are usual dimensions to decide PC inclusion.

ObjectivesThe main aim of this work is to design and evaluate three quantitative models based on machine learning approaches to predict frailty and mortality on older patients in the context of supporting PC decision making: one-year mortality, survival regression and one-year frailty classification.

MethodsThe dataset used in this study is composed of 39,310 hospital admissions for 19,753 older patients (age >= 65) from January 1st, 2011 to December 30th, 2018. All prediction models were based on Gradient Boosting Machines. From the initial pool of variables at hospital admission, 20 were selected by a recursive feature elimination algorithm based on the random forests GINI importance criterion. Besides, we run an independent grid search to find the best hyperparameters in each model. The evaluation was performed by 10-fold cross-validation and area under the receiver operating characteristic curve and mean absolute error were reported. The Cox proportional-hazards model was used to compare our proposed approach with classical survival methods.

ResultsThe one-year mortality model achieved an AUC ROC of 0.87 {+/-} 0.01; the mortality regression model achieved an MAE of 329.97 {+/-} 5.24 days. The one-year frailty classification reported an AUC ROC of 0.9 {+/-} 0.01. The Spearmans correlation between the admission frailty index and the survival time was -0.1, while the point-biserial correlation between one-year frailty index and survival time was -0.16.

ConclusionsOne-year mortality model performance is at a state-of-the-art level. Frailty Index used in this study behaves coherently with other works in the literature. One-year frailty classifier demonstrated that frailty status within the year could be predicted accurately. To our knowledge, this is the first study predicting one-year frailty status based on a frailty index. We found mortality and frailty as two weakly correlated and complementary PC needs assessment criteria. Predictive models are available online at http://demoiapc.upv.es.