title: Collaborative research methods and best practice with children and young people: Protocol for a mixed-method review of the health and social sciences literature

abstract:
IntroductionChildren and young people have the right to participate in research on matters that affect them, and their contribution improves research quality and insights from findings. Discrete participatory approaches are used across different disciplines. This review will provide a synthesis of existing literature from different disciplines by working with young people and adults experienced in participatory research to develop a broad definition of child and youth led research and to identify best practice.

Methods and AnalysisComprehensive searches will be conducted in eight electronic databases (PsycINFO, Medline, CINAHL, Embase, SocINDEX, ASSIA: Applied Social Sciences Index and Abstracts (Proquest), Social Care Online and SCOPUS). Grey literature reports will also be sourced using Google searching. Eligible studies will be English language primary studies and reviews on collaborative research with children and young people (aged 5-25 years). Qualitative and quantitative data will be integrated in a single qualitative synthesis following the JBI convergent integrated approach. Study quality will be assessed by developed checklists based on existing participation tools co-created with the project steering group and co-creation activities with young people.

Ethics and DisseminationEthical approval is not required as no primary data will be collected. The review will develop guidance on best practice for collaborative research with children and young people, synthesising learnings from a wide variety of disciplines. Dissemination will be via peer-reviewed publications, presentations at academic conferences and lay summaries for various stakeholders. Opportunities for co-creation of outputs will be sought with the young researchers and the project steering committee.

PROSPERO registration number: CRD42021246378

Article SummaryO_ST_ABSStrengths and limitations of the studyC_ST_ABSO_LIFirst systematic review to synthesise findings across different approaches to collaborative research with children and young people
C_LIO_LIResearch focus, questions and analysis framework have been co-designed with young researchers experienced in participatory research
C_LIO_LIMixed method review methodology will enable an in-depth evidence synthesis across a disparate evidence base
C_LIO_LIProvides an interdisciplinary perspective on best practice for collaborative research with children and young people
C_LI

category: health policy


title: Calprotectin and inflammation-associated serum biomarkers determine critical illness in COVID-19

abstract: Little is known on the key contributing factors towards progression into acute respiratory distress syndrome (ARDS) necessitating mechanical ventilation (MV) in COVID-19. We determined serum levels, within 24 hours of diagnosis, of alarmins, as well as pro- and anti-inflammatory molecules in asymptomatic, moderate, severe and intubated patients compared to non-infected comparators. Levels of the pro-inflammatory interleukin (IL)-8, IL-18, matrix metalloproteinase-9, platelet-derived growth factor (PDGF)-B and calprotectin (S100A8/A9) were specific drivers of ARDS. Levels of the anti-inflammatory IL-1ra and IL-33r were increased; IL-38 was increased only in asymptomatic patients, but significantly decreased in the more severe COVID-19 cases. Multivariate ordinal regression showed that pathways of IL-6, IL-33 and calprotectin gave significant probability for worse outcome. These results indicate a dysfunctional response to the presence of alarmins that may be used for prognosis and development of effective treatments.

category: infectious diseases


title: Performance of Various Lateral Flow SARS-CoV-2 Antigen Self Testing Methods in Healthcare Workers: a Multicenter Study.

abstract:
IntroductionRapid antigen detection tests (RDT) are suitable for large-scale testing for SARS-CoV-2 among the population and recent studies have shown that self-testing with RDT in the general population is feasible and yields acceptable sensitivities with high specificity. We aimed to determine the accuracy of two different RDTs, with two different sample collection methods for one of the RDTs among healthcare workers (HCW). Secondary objectives were to determine the accuracy of RDT using a viral load cut-off as proxy of infectiousness and to identify predictors for a false negative RDT.

MethodsCenters that participated were secondary care hospitals, academic teaching hospitals, and long-term care facilities. All HCW that met inclusion criteria were asked to perform a RDT self-test next to a regular SARS-CoV-2 nucleic acid amplification test (NAAT). Three study groups were created. Study group 1; Veritor(tm) System, Becton Dickinson, Franklin Lakes, USA (BD-RDT) with combined oropharyngeal - mid-turbinate nasal sampling, group 2; BD-RDT with mid-turbinate nasal sampling only and group 3; SD Biosensor SARS-CoV-2 Rapid Antigen Test, Roche, Basel, Switzerland (Roche-RDT) with combined oropharyngeal - mid-turbinate nasal sampling. RDT accuracy was calculated using NAAT as reference standard. For samples processed in the cobas(R) 6800/8800 platform (Roche Diagnostics, Basel, Switzerland), established cycle threshold values (Ct-values) could be converted into viral loads. A viral load cut-off of [≥]5.2 log10 SARS-CoV-2 E gene copies/ml was used as proxy of infectiousness. Logistic regression analysis was performed to identify predictors for a false negative RDT.

ResultsIn total, 7,196 HCW were included. Calculated sensitivities were 61.5% (95%CI 56.6%-66.3%), 50.3% (95%CI 42.8%-57.7%) and 74.2% (95%CI 66.4%-80.9%) for study groups 1, 2 and 3, respectively. After application of a viral load cut-off as a proxy for infectiousness for samples processed in the cobas(R) 6800/8800 platform sensitivities increased to 82.2% (95%CI 76.6-86.9%), 61.9% (95%CI 48.8%-73.9%) and 90.2% (95%CI 76.9%-97.3%) for group 1, group 2 and group 3, respectively. Multivariable regression analysis showed that use of Roche-RDT (p <0.01), combined oropharyngeal - mid-turbinate nasal sampling (p <0.05) and the presence of COVID-19 like symptoms at the time of testing (p <0.01) significantly reduced the likeliness of a false-negative RDT result.

ConclusionSARS-CoV-2 RDT has proven able to identify infectious individuals, especially when upper respiratory specimen is collected through combined oropharyngeal - mid-turbinate sampling. Reliability of self-testing with RDT among HCW seems to depend on the type of RDT, the sampling method and the presence of COVID-19 like symptoms at the time of testing.


title: Hybrid immunity from SARS-CoV-2 delta variant surge induced low to undetectable levels of neutralizing antibodies against Omicron variant

abstract: The Omicron variant of SARS-CoV-2 is capable of infecting unvaccinated, vaccinated and previously-infected individuals due to its ability to evade neutralization by antibodies. With three sub-lineages of Omicron emerging in the last four months, there is inadequate information on the quantitative antibody response generated upon natural infection with Omicron variant and whether these antibodies offer cross-protection against other sub-lineages of Omicron variant. We show that both binding and neutralizing antibodies wane by >50% in six months in study participants with hybrid immunity. Omicron infection in a subset of individuals led to a significant increase in binding and neutralizing antibodies to BA.1 and BA.2 sub-lineages of Omicron. The levels of neutralizing antibodies were higher against the Delta variant as compared to the Omicron sub-lineages. These data suggest that Omicron infection elicits neutralizing antibodies that can cross-react with other sub-lineages of Omicron and other variants of concern in people with hybrid immunity.


title: Infection with Omicron variant generates neutralizing antibodies to BA.1 and BA.2 sub-lineages and induces higher levels of cross-neutralizing antibodies to Delta variant


title: A Machine Learning Approach to Differentiate Between COVID-19 and Influenza Infection Using Synthetic Infection and Immune Response Data

abstract: Data analysis is widely used to generate new insights into human disease mechanisms and provide better treatment methods. In this work, we used the mechanistic models of viral infection to generate synthetic data of influenza and COVID-19 patients. We then developed and validated a supervised machine learning model that can distinguish between the two infections. Influenza and COVID-19 are contagious respiratory illnesses that are caused by different pathogenic viruses but appeared with similar initial presentations. While having the same primary signs COVID-19 can produce more severe symptoms, illnesses, and higher mortality. The predictive model performance was externally evaluated by the ROC AUC metric (area under the receiver operating characteristic curve) on 100 virtual patients from each cohort and was able to achieve at least AUC=91% using our multiclass classifier. The current investigation highlighted the ability of machine learning models to accurately identify two different diseases based on major components of viral infection and immune response. The model predicted a dominant role for viral load and productively infected cells through the feature selection process.


title: Tracking the progressive spread of the SARS-CoV-2 Omicron variant in Italy, December 2021 - January 2022

abstract: The SARS-CoV-2 variant of concern Omicron was first detected in Italy in November 2021. Data from three genomic surveys conducted in Italy between December 2021 and January 2022 suggest that Omicron became dominant in less than one month (prevalence on January 3: 78.6%-83.8%) with a doubling time of 2.7-3.1 days. The mean net reproduction number rose from about 1.15 in absence of Omicron to a peak of 1.83 for symptomatic cases and 1.33 for hospitalized cases, while it remained stable for critical cases.


title: Continuing inequalities in COVID-19 mortality in England and Wales, and the changing importance of regional, over local, deprivation

abstract:
BackgroundObservational studies have highlighted that where individuals live is far more important for risk of dying with COVID-19, than for dying of other causes. Deprivation is commonly proposed as explaining such differences. During the period of localised restrictions in late 2020, areas with higher restrictions tended to be more deprived. We explore how this impacted the relationship between deprivation and mortality and see whether local or regional deprivation matters more for inequalities in COVID-19 mortality.

MethodsWe use publicly available population data on deaths due to COVID-19 and all-cause mortality between March 2020 and April 2021 to investigate the scale of spatial inequalities. We use a multiscale approach to simultaneously consider three spatial scales through which processes driving inequalities may act. We go on to explore whether deprivation explains such inequalities.

ResultsAdjusting for population age structure and number of care homes, we find highest regional inequality in October 2020, with a COVID-19 mortality rate ratio of 5.86 (95% CI 3.31 to 19.00) for the median between-region comparison. We find spatial context is most important, and spatial inequalities higher, during periods of low mortality. Almost all unexplained spatial inequality in October 2020 is removed by adjusting for deprivation. During October 2020, one standard deviation increase in regional deprivation was associated with 2.45 times higher local mortality (95% CI, 1.75 to 3.48).

ConclusionsSpatial inequalities are greatest in periods of lowest overall mortality, implying that as mortality declines it does not do so equally. During the prolonged period of low restrictions and low mortality in summer 2020, spatial inequalities strongly increased. Contrary to previous months, we show that the strong spatial patterning during autumn 2020 is almost entirely explained by deprivation. As overall mortality declines, policymakers must be proactive in detecting areas where this is not happening, or risk worsening already strong health inequalities.

Key messages- Spatial inequalities in local mortality are highest in periods of lower overall mortality.
- Spatial inequality in COVID-19 mortality peaked in October 2020, before decreasing strongly in November and over the winter period.
- Deprivation explains almost all inequality during October when inequality was at its highest.
- Regional deprivation was far more strongly associated with local mortality than local deprivation during September to November 2020.
- This is consistent with an overdispersed distribution of secondary infections governed by transmission heterogeneity structured by deprivation.

category: epidemiology


title: Psychological Outcomes of Surgery Trainees in the Era of COVID-19 at a Tertiary Care Hospital of Karachi, Pakistan: A Cross-Sectional Study

abstract:
ObjectivesThe COVID-19 pandemic has resulted in interruptions in training for surgical residents in particular. This has been compounded by burnout and mental health concerns among surgical trainees across the world. We aim to determine the impact of the COVID-19 pandemic on psychological outcomes of surgical trainees in a tertiary-care hospital in Pakistan.

SettingA cross-sectional, online survey-based study was conducted at a private tertiary care hospital of Karachi, Pakistan.

ParticipantsAll the surgery trainees including; residents, fellows and instructors acquiring training at a private tertiary care hospital of Karachi, Pakistan were included in the study.

Outcome measuresThe participants were assessed for their perceptions, and concerns regarding the COVID-19 pandemic, impact on their quality of life and generalized anxiety disorder (GAD).

ResultsA majority (85%) of surgical trainees were concerned regarding contracting COVID-19 infections. Residents were more concerned with fellow residents developing burnout and anxiety as compared to their own psychological concerns. A strong, significant positive correlation (r=0.66, p <0.001) was noted between negative impact on QoL scores and developing GAD in surgical residents. On multivariable analysis, significant associations with GAD remained for family system, and negative impact of COVID-19 on QoL. The increased working hours for junior trainees showed more likelihood of developing GAD as compared to senior trainees.

ConclusionOur investigation on QoL and psychological outcomes of surgical residents showed significant rates of burnout and GAD, which were attributed to concerns with the COVID-19 pandemic. We showed the impact this had on surgical trainees perception regarding their training and concerns with infecting others. This calls for structural interventions to address mental health concerns and provide psychological and educational support to surgical residents.

Strengths and Limitations of the studyO_LIValidated measures were used for evaluating the outcomes
C_LIO_LIThe study results can be generalized to all the surgery resident trainees working at private tertiary care hospitals.
C_LIO_LIThe response rate of trainees was 50%, the authors attempted to mitigate this through regular follow-up emails and reminders for responses.
C_LI

category: psychiatry and clinical psychology


title: Wastewater surveillance for COVID-19 response at multiple geographic scales: Aligning wastewater and clinical results at the census-block level and addressing pervasiveness of qPCR non-detects

abstract:
Wastewater surveillance is a useful complement to clinical testing for managing COVID-19. While good agreement has been found between community-scale wastewater and clinical data, little is known about sub-community relationships between the two data types. Moreover, effects of non-detects in qPCR wastewater data have been largely overlooked. We used data collected from September 2020-June 2021 in Davis, California (USA) to address these gaps. By applying a predictive probability model to spatially disaggregate clinical results, we compared wastewater and clinical data at the community scale, in 16 sampling zones isolating city sub-regions, and in seven zones isolating high-priority building complexes or neighborhoods. We found reasonable agreement between wastewater and clinical data at all scales. Greater activity (i.e., more frequent detections) in clinical data tended to be mirrored in wastewater data. Small, isolated clinical-data spikes were often matched as well. We also developed a method for handling such non-detects using multiple imputation and compared results to (i) single imputation using half the qPCR limit of detection, (ii) single imputation using maximum qPCR cycle number, and (iii) non-detect censoring. Apparent wastewater trends were significantly influenced by non-detect handling. Multiple imputation improved correlation relative to single imputation, though not necessarily relative to censoring.

O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=78 SRC="FIGDIR/small/22269911v1_ufig1.gif" ALT="Figure 1">
View larger version (31K):
org.highwire.dtl.DTLVardef@5a57f5org.highwire.dtl.DTLVardef@144cf73org.highwire.dtl.DTLVardef@8fa56borg.highwire.dtl.DTLVardef@b52587_HPS_FORMAT_FIGEXP  M_FIG C_FIG


title: Integrated multi-omics reveals anaplerotic rewiring in methylmalonyl-CoA mutase deficiency

abstract:
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">
View larger version (23K):
org.highwire.dtl.DTLVardef@1cb2b0org.highwire.dtl.DTLVardef@176cfaorg.highwire.dtl.DTLVardef@1f3cda7org.highwire.dtl.DTLVardef@142ce84_HPS_FORMAT_FIGEXP  M_FIG C_FIG

category: pediatrics


title: Integrated multi-omics reveals anaplerotic insufficiency in methylmalonyl-CoA mutase deficiency


title: Mortality and predictors of Chronic Kidney Diseases (CKD) in selected dialysis centers in Addis Ababa, Ethiopia

abstract:
BackgroundChronic Kidney Disease (CKD) affects 10-15% of the population worldwide. The number of dialysis patients is steadily rising in Ethiopia. Chronic hemodialysis patients experience high rates of mortality; however, data is lacking in Ethiopia. We explored the mortality and its driving factors in selected dialysis center in Addis Ababa

Methodwe retrospectively followed a group of End-Stage Renal Disease patients on hemodialysis from 2016 to2020 in St. Paul Millennium Medical College (SPMMC), Zewditu Memorial Hospital (ZMH), and Menellik II Hospital. We fitted Kaplan Meier analysis to estimate the one and five years survival probability of these patients and Cox Proportional regression analysis to model the predictors of mortality at p value [≤]0.05.

ResultWe analyzed a data of (139) patients under follow up. The mean age ({+/-} SD) of the patients was 36.8 ({+/-}11.95) years. Twenty-four (17%) of the patients died at the end of follow-up. The median survival time was 46.2 months (95% CI: 41.8, 50.5). The one and five-years survival probability of these patients was 64.8% and 18.7%, respectively. Our analysis showed that patients with hypertension (AHR = 4.33; 95% CI: 1.02, 34.56), cardiac complication (AHR = 4.69; 95% CI: 1.32, 16.8), and infection during dialysis (AHR = 3.89; 95% CI: 1.96, 13.8) were more likely to die.

ConclusionThe survival status of hemodialysis patients in three was low. Preventing and treating comorbidities and complication during dialysis would reduce mortality of CKD patients.

category: nephrology


title: Astrocyte biomarker signatures of amyloid-β and tau pathologies in Alzheimer's disease

abstract: Astrocytes can adopt multiple molecular phenotypes in the brain of Alzheimers disease (AD) patients. Here, we studied the associations of cerebrospinal fluid (CSF) glial fibrillary acidic protein (GFAP) and chitinase-3-like protein 1 (YKL-40) levels with brain amyloid-{beta} (A{beta}) and tau pathologies. We assessed 121 individuals across the aging and AD clinical spectrum with positron emission tomography (PET) brain imaging for A{beta} ([18F]AZD4694) and tau ([18F]MK6240), as well as CSF GFAP and YKL-40 measures. We observed that higher CSF GFAP levels were associated with elevated A{beta}-PET but not tau-PET load. By contrast, higher CSF YKL-40 levels were associated with elevated tau-PET but not A{beta}-PET burden. Structural equation modeling revealed that CSF GFAP and YKL-40 mediate the effects of A{beta} and tau, respectively, on hippocampal atrophy, ultimately leading to cognitive impairment. Our results suggest the existence of distinct astrocyte biomarker signatures in response to brain A{beta} and tau accumulation, which may contribute to our understanding of the complex link between reactive astrogliosis heterogeneity and AD progression.

category: neurology


title: Germline TYK2 mutation and cancer risk

abstract: Deucravacitinib, a novel, selective inhibitor of TYK2 is currently under review at the FDA and EMA for treatment of moderate-to-severe plaque psoriasis. It is unclear whether recent safety concerns (i.e. elevated rates of lung cancer and lymphoma) related to similar medications (i.e. other JAK inhibitors) are shared with this novel TYK2 inhibitor. We used a partial loss-of-function variant in TYK2 (rs34536443), previously shown to protect against psoriasis and other autoimmune diseases, to evaluate the potential effect of therapeutic TYK2 inhibition on risk of lung cancer and non-Hodgkin lymphoma. Summary genetic association data on lung cancer risk were obtained from a GWAS meta-analysis of 29,266 cases and 56,450 controls in the Integrative Analysis of Lung Cancer Risk and Etiology (INTEGRAL) consortium. Summary genetic association data on non-Hodgkin lymphoma risk were obtained from a GWAS meta-analysis of 8,489 cases and 374,506 controls in the UK Biobank and InterLymph consortium. In the primary analysis, each copy of the minor allele of rs34536443, representing partial TYK2 inhibition, was associated with an increased risk of lung cancer (OR 1.15, 95% CI 1.07-1.24, P = 1.72 x 10-4) and non-Hodgkin lymphoma (OR 1.18, 95% CI 1.05-1.33, P = 5.25 x 10-3). In secondary analyses, there was weak evidence of an association of rs34536443 with advanced prostate cancer risk (OR 1.08, 95% CI 1.00-1.17, P = 0.04), but little evidence of association with three other common adult cancers examined. Our analyses using an established partial loss-of-function mutation to mimic TYK2 inhibition provide genetic evidence that therapeutic TYK2 inhibition may increase risk of lung cancer and non-Hodgkin lymphoma. These findings, consistent with recent reports from post-marketing trials of similar JAK inhibitors, could have important implications for future safety assessment of Deucravacitinib and other TYK2 inhibitors in development.

category: genetic and genomic medicine


title: Occurrence and transmission potential of asymptomatic and presymptomatic SARS-CoV-2 infections: a living systematic review and meta-analysis

abstract:
BACKGROUNDDebate about the level of asymptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection continues. The amount of evidence is increasing and study designs have changed over time. We updated a living systematic review to address three questions: (1) Amongst people who become infected with SARS-CoV-2, what proportion does not experience symptoms at all during their infection? (2) What is the infectiousness of asymptomatic and presymptomatic, compared with symptomatic, SARS-CoV-2 infection? (3) What proportion of SARS-CoV-2 transmission in a population is accounted for by people who are asymptomatic or presymptomatic?

METHODS AND FINDINGSThe protocol was first published on 1 April 2020 and last updated on 18 June 2021. We searched PubMed, Embase, bioRxiv and medRxiv, aggregated in a database of SARS-CoV-2 literature, most recently on 6 July 2021. Studies of people with PCR-diagnosed SARS-CoV-2, which documented symptom status at the beginning and end of follow-up, or mathematical modelling studies were included. Studies restricted to people already diagnosed, of single individuals or families, or without sufficient follow-up were excluded. One reviewer extracted data and a second verified the extraction, with disagreement resolved by discussion or a third reviewer. Risk of bias in empirical studies was assessed with a bespoke checklist and modelling studies with a published checklist. All data syntheses were done using random effects models. Review question (1): We included 130 studies.

Heterogeneity was high so we did not estimate a mean proportion of asymptomatic infections overall (interquartile range 14-50%, prediction interval 2-90%), or in 84 studies based on screening of defined populations (interquartile range 20-65%, prediction interval 4-94%). In 46 studies based on contact or outbreak investigations, the summary proportion asymptomatic was 19% (95% CI 15-25%, prediction interval 2-70%). (2) The secondary attack rate in contacts of people with asymptomatic infection compared with symptomatic infection was 0.32 (95% CI 0.16-0.64, prediction interval 0.11-0-95, 8 studies). (3) In 13 modelling studies fit to data, the proportion of all SARS-CoV-2 transmission from presymptomatic individuals was higher than from asymptomatic individuals. Limitations of the evidence include high heterogeneity and high risks of selection and information bias in studies that were not designed to measure persistently asymptomatic infection, and limited information about variants of concern or in people who have been vaccinated.

CONCLUSIONSBased on studies published up to July 2021, most SARS-CoV-2 infections were not persistently asymptomatic and asymptomatic infections were less infectious than symptomatic infections. Summary estimates from meta-analysis may be misleading when variability between studies is extreme and prediction intervals should be presented. Future studies should determine the asymptomatic proportion of SARS-CoV-2 infections caused by variants of concern and in people with immunity following vaccination or previous infection. Without prospective longitudinal studies with methods that minimise selection and measurement biases, further updates with the study types included in this living systematic review are unlikely to be able to provide a reliable summary estimate of the proportion of asymptomatic infections caused by SARS-CoV-2.

REVIEW PROTOCOLOpen Science Framework (https://osf.io/9ewys/)

AUTHOR SUMMARYO_ST_ABSWhy was this study done?C_ST_ABS{blacksquare} The proportion of people who will remain asymptomatic throughout the course of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (covid-19), is debated.
{blacksquare}Studies that assess people at just one time point overestimate the proportion of true asymptomatic infection because those who go on to develop covid-19 symptoms will be wrongly classified as asymptomatic, but other types of study might underestimate the proportion if, for example, people with symptoms are more likely to be included in a study population.
{blacksquare}The number of published studies about SARS-CoV-2 is increasing continuously, types of studies are changing and, since 2021, vaccines have become available, and variants of concern have emerged.

What did the researchers do and find?{blacksquare} We updated a living systematic review through 6 July 2021, using automated workflows that speed up the review processes, and allow the review to be updated when relevant new evidence becomes available.
{blacksquare}In 130 studies, we found an interquartile range of 14-50% (prediction interval 2-90%) of people with SARS-CoV-2 infection that was persistently asymptomatic; owing to heterogeneity, we did not estimate a summary proportion.
{blacksquare}Contacts of people with asymptomatic SARS-CoV-2 infection are less likely to become infected than contacts of people with symptomatic infection (risk ratio 0.38, 95% CI 0.16-0.64, prediction interval 0.11-0.95, 8 studies).

What do these findings mean?O_LI{blacksquare} Up to mid-2021, most people with SARS-CoV-2 were not persistently asymptomatic and asymptomatic infection was less infectious than symptomatic infection.
C_LIO_LI{blacksquare} In the presence of high between-study variability, summary estimates from meta-analysis may be misleading and prediction intervals should be presented.
C_LIO_LI{blacksquare} Future studies about asymptomatic SARS-CoV-2 infections caused by variants of concern and in people with immunity following vaccination or previous infection should be specifically designed, using methods to minimise biases in the selection of study participants and in ascertainment, classification and follow-up of symptom status.
C_LI


title: Occurrence and transmission potential of asymptomatic and presymptomatic SARS-CoV-2 infections: update of a living systematic review and meta-analysis


title: Chronic lithium therapy and urine concentrating ability in individuals with bipolar disorder: association between daily dose and resistance to vasopressin and polyuria

abstract:
Background and objectivesChronic lithium treatment in individuals with bipolar disorder can induce nephrogenic diabetes insipidus. However, the prevalence, kinetics and mechanisms of such complication are poorly known. We aimed at evaluating patterns of urine concentrating ability and the correlates of 24-hour urine output in individuals treated with lithium.

Design, setting, participants and measurementsProspective single center observational study of 217 consecutive individuals treated with lithium carbonate and referred to the renal unit. All individuals collected 24-hour urine the day before admission and underwent a desmopressin (DDAVP) concentrating test, fasting plasma vasopressin measurement (copeptin measurement in a subset of individuals, n=119), and measured GFR (mGFR) using urinary 99Tc-DTPA clearance. Maximal urine osmolality (Max Uosm) was defined as the highest level during the DDAVP test.

Results21% of individuals displayed polyuria (> 3l/day), but 55% displayed elevated fasting vasopressin level (> 5 pg/ml). During the DDAVP test, Uosm was significantly lower, and urinary output and free water clearance were significantly higher in the highest treatment duration tertile (> 10 years) whereas no difference was observed between the first two tertiles (< 2.5 years and 2.5-10 years). Among individuals with normal Max Uosm (>600 mOsm/KgH2O) (n=128), 51% displayed elevated vasopressin levels, which was associated with higher lithium daily doses (950 [750- 1200] versus 800 [500- 1000] mg/d, p<0.001), and 100% of patients with lithium daily dose [≥]1400 mg/d had high vasopressin levels. In multivariable analysis, 24-hour urine output was associated with higher lithium daily dose ({beta} 0.49 {+/-} 0.17, p=0.005), female sex ({beta} -359 {+/-} 123, p=0.004), daily osmolar intake ({beta} 2.21 {+/-} 0.24, p<0.001), maximal urine osmolality ({beta} -2.89 {+/-} 0.35, p<0.001) and plasma vasopressin level ({beta} 10.17 {+/-} 4.76, p=0.03), but not with lithium formulation.

ConclusionsHigher lithium daily dose was associated with higher vasopressin levels and higher urine output, independently of other factors. Daily osmolar intake was also associated with higher 24-hour urine output. These results suggest that controlled salt and protein intake and lithium dose might reduce renal resistance to vasopressin in these patients.


title: Identification of thresholds on population density for understanding transmission of COVID-19

abstract:
Pathways of transmission of coronavirus (COVID-19) disease in the human population are still emerging. However, empirical observations suggest that dense human settlements are the most adversely impacted, corroborating a broad consensus that human-to-human transmission is a key mechanism for the rapid spread of this disease. Here, using logistic regression techniques, estimates of threshold levels of population density were computed corresponding to the incidence in the human population. Regions with population densities greater than 3000 person per square mile in the United States have about 95% likelihood to get infected with COVID-19. Since case numbers of COVID-19 dynamically changed each day until November 30, 2020, ca. 4% of US counties were at 50% or higher risk of COVID-19 transmission. While threshold on population density is not the sole indicator for predictability of coronavirus in human population, yet it is one of the key variables on understanding and rethinking human settlement in urban landscapes.

Plane language SummaryPopulation density is certainly one of the key factors influencing the transmission of infectious diseases like COVID-19. It is approximated that in continental United States, population density of 1192 per square mile and higher presents 50% probability of getting infected with COVID-19.

Key PointsO_LIBased on data from the USA, the population density of 1192 persons per square mile represented a 50% or higher probability of risk of transmission of COVID-19.
C_LIO_LIAbout 35 counties in the USA are at very high risk of transmission potential (95% or higher) for COVID-19.
C_LIO_LIAnalysis shows the vulnerability of urban towns to respiratory infectious disease
C_LI


title: Predicting clinical outcomes and hospitalization stay of hospitalized COVID-19 patients by using Deep Learning methods

abstract: Predicting outcomes and other critical clinical events of hospitalized COVID-19 patients may provide a valuable asset to healthcare and a chance to improve patient outcomes. Here, we have analyzed over 10,000 hospitalized COVID-19 patients in the Houston Methodist Hospital at the Texas Medical Center from the beginning of pandemics till April of 2020. This work extends our previous study analyzing longitudinal symptomatics of the hospitalized patients by seeking to understand how standard patient clinical data, like demographics and comorbidities, together with symptom data from early hospitalization can be used to predict the clinical outcomes and hospitalization stay. Deep Learning (DL) classification and regression methods were applied to quantify patient record importance and to perform predictions. The results suggest that patient outcome can be predicted with up to 75% accuracy. However, the prediction of hospitalization stay was more complex indicating deeper optimization of features.


title: Transmission of SARS-CoV-2 Omicron VOC subvariants BA.1 and BA.2: Evidence from Danish Households

abstract:
1The Omicron SARS-CoV-2 variant of concern (VOC lineage B.1.1.529), which became dominant in many countries during early 2022, includes several subvariants with strikingly different genetic characteristics. Several countries, including Denmark, have observed the two Omicron subvariants: BA.1 and BA.2. In Denmark the latter has rapidly replaced the former as the dominant subvariant.

Based on nationwide Danish data, we estimate the transmission dynamics of BA.1 and BA.2 following the spread of Omicron VOC within Danish households in late December 2021 and early January 2022.

Among 8,541 primary household cases, of which 2,122 were BA.2, we identified a total of 5,702 secondary infections among 17,945 potential secondary cases during a 1-7 day follow-up period. The secondary attack rate (SAR) was estimated as 29% and 39% in households infected with Omicron BA.1 and BA.2, respectively.

We found BA.2 to be associated with an increased susceptibility of infection for unvaccinated individuals (Odds Ratio (OR) 2.19; 95%-CI 1.58-3.04), fully vaccinated individuals (OR 2.45; 95%-CI 1.77-3.40) and booster-vaccinated individuals (OR 2.99; 95%-CI 2.11-4.24), compared to BA.1. We also found an increased transmissibility from unvaccinated primary cases in BA.2 households when compared to BA.1 households, with an OR of 2.62 (95%-CI 1.96-3.52). The pattern of increased transmissibility in BA.2 households was not observed for fully vaccinated and booster-vaccinated primary cases, where the OR of transmission was below 1 for BA.2 compared to BA.1.

We conclude that Omicron BA.2 is inherently substantially more transmissible than BA.1, and that it also possesses immune-evasive properties that further reduce the protective effect of vaccination against infection, but do not increase its transmissibility from vaccinated individuals with breakthrough infections.


title: Mapping The Global Landscape Of Chikungunya Rapid Diagnostic Tests: A Scoping Review

abstract:
BackgroundChikungunya virus (CHIKV) is a re-emerging arboviral disease and represents a global health threat because of the unprecedented magnitude of its spread. Diagnostics strategies rely heavily on reverse transcriptase-polymerase chain reaction (RT-PCR) and antibody detection by Enzyme-linked Immunosorbent assay (ELISA). Rapid Diagnostic Tests (RDTs) are available and promise to decentralize testing and increase availability at lower healthcare system levels.

ObjectivesWe aim to identify the extent of research on CHIKV RDTs, map the global availability of CHIKV RDTs, and evaluate the accuracy of CHIKV RDTs for the diagnosis of CHIKV.

Eligibility criteriaWe included studies reporting symptomatic individuals suspected of CHIKV, tested with CHIKV RDTs, against the comparator being a validated laboratory-based RT-PCR or ELISA assay. The primary outcome was the accuracy of the CHIKV RDT when compared with reference assays.

Sources of evidenceMedline, EMBASE, and Scopus were searched from inception to October 13th, 2021. National regulatory agencies (European Medicines Agency, U.S. Food and Drug Administration, and the Brazilian National Health Surveillance Agency) were also searched for registered CHIKV RDTs.

ResultsEighteen studies were included and corresponded to 3722 samples tested with RDTs between 2005-2019. The most development stage of CHIKV RDTs studies was phase I (7/18 studies) and II (7/18 studies). No studies were in phase IV. The countries that manufacturer the most CHIKV RDTs were Brazil (n=17), followed by the USA (n=7), and India (n=6). Neither at EMA nor FDA, registered products were found. Conversely, the ANVISA has approved 23 CHIKV RDTs. Antibody RDTs (n=43) predominated and demonstrated sensitivity between 20% and 100%. The sensitivity of the antigen RDTs ranged from 33.3 to 100%.

ConclusionsThe landscape of CHIKV RDTs is fragmented and needs coordinated efforts to ensure that patients in CHIKV-endemic areas have access to appropriate RDTs. Further research is crucial to determine the impact of such tests on integrated fever case management and prescription practices for acute febrile patients.


title: User acceptability of saliva and gargle samples for identifying COVID-19 positive high-risk workers

abstract: Throughout the COVID-19 pandemic nasopharyngeal or nose/throat swabs (NTS) have been the primary approach for collecting patient samples for the subsequent detection of viral RNA. However, this procedure, if undertaken correctly, can be unpleasant and therefore deters individuals from providing high quality samples. To overcome these limitations other modes of sample collection have been explored. In a cohort of frontline healthcare workers we have compared saliva and gargle samples to gold-standard NTS. 93% of individuals preferred providing saliva or gargle samples, with little sex-dependent variation. Viral titres collected in samples were analysed using standard methods and showed that gargle and saliva were similarly comparable for identifying COVID-19 positive individuals compared to NTS (92% sensitivity; 98% specificity). We suggest that gargle and saliva collection are viable alternatives to NTS swabs and may encourage testing to provide better disease diagnosis and population surveillance.


title: Serum Neutralizing Activity of mRNA-1273 Against the SARS-CoV-2 B.1.1.529 (Omicron) Variant: A Preliminary Report

abstract: The emergence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) B.1.1.529 (Omicron) variant has led to growing concerns of increased transmissibility and escape of both natural and vaccine-induced immunity. In this analysis, sera from adult participants in a phase 2 clinical study (NCT04405076) were tested for neutralizing activity against B.1.1.529 after a 2-dose (100 {micro}g) mRNA-1273 primary vaccination series and after a 50-{micro}g mRNA-1273 booster dose. Results from this preliminary analysis show that 1 month after completing the primary series, mRNA-1273-elicited serum neutralization of B.1.1.529 was below the lower limit of quantification; however, neutralization was observed at 2 weeks after the mRNA-1273 booster dose, although at a reduced level relative to wild-type SARS-CoV-2 (D614G) and lower than that observed against D614G at 1 month after the primary series.


title: Development and External Validation of a Mixed-Effects Deep Learning Model to Diagnose COVID-19 from CT Imaging

abstract:
ObjectivesTo develop and externally geographically validate a mixed-effects deep learning model to diagnose COVID-19 from computed tomography (CT) imaging following best practice guidelines and assess the strengths and weaknesses of deep learning COVID-19 diagnosis.

DesignModel development and external validation with retrospectively collected data from two countries.

SettingHospitals in Moscow, Russia, collected between March 1, 2020, and April 25, 2020. The China Consortium of Chest CT Image Investigation (CC-CCII) collected between January 25, 2020, and March 27, 2020.

Participants1,110 and 796 patients with either COVID-19 or healthy CT volumes from Moscow, Russia, and China, respectively.

Main outcome measuresWe developed a deep learning model with a novel mixed-effects layer to model the relationship between slices in CT imaging. The model was trained on a dataset from hospitals in Moscow, Russia, and externally geographically validated on a dataset from a consortium of Chinese hospitals. Model performance was evaluated in discriminative performance using the area under the receiver operating characteristic (AUROC), sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). In addition, calibration performance was assessed using calibration curves, and clinical benefit was assessed using decision curve analysis. Finally, the models decisions were assessed visually using saliency maps.

ResultsExternal validation on the large Chinese dataset showed excellent performance with an AUROC of 0.936 (95%CI: 0.910, 0.961). Using a probability threshold of 0.5, the sensitivity, specificity, NPV, and PPV were 0.753 (0.647, 0.840), 0.909 (0.869, 0.940), 0.711 (0.606, 0.802), and 0.925 (0.888, 0.953), respectively.

ConclusionsDeep learning can reduce stress on healthcare systems by automatically screening CT imaging for COVID-19. However, deep learning models must be robustly assessed using various performance measures and externally validated in each setting. In addition, best practice guidelines for developing and reporting predictive models are vital for the safe adoption of such models.

StatementsThe authors do not own any of the patient data, and ethics approval was not needed. The lead author affirms that this manuscript is an honest, accurate, and transparent account of the study being reported, that no important aspects of the study have been omitted, and that any discrepancies from the study as planned (and, if relevant, registered) have been explained. Patients and the public were not involved in the study.

FundingThis study was funded by EPSRC studentship (No. 2110275), EPSRC Impact Acceleration Account (IAA) funding, and Amazon Web Services.

SummaryO_ST_ABSWhat is already known on this topicC_ST_ABSO_LIDeep learning can diagnose diseases from imaging data automatically
C_LIO_LIMany studies using deep learning are of poor quality and fail to follow current best practice guidelines for the development and reporting of predictive models
C_LIO_LICurrent methods do not adequately model the relationship between slices in CT volumetric data
C_LI

What this study addsO_LIA novel method to analyse volumetric imaging data composed of slices such as CT images using deep learning
C_LIO_LIModel developed following current best-practice guidelines for the development and reporting of prediction models
C_LI


title: Evaluation of the systemic and mucosal immune response induced by COVID-19 and the BNT162b2 mRNA vaccine for SARS-CoV-2

abstract:
BackgroundCurrently used vaccines to protect from COVID-19 mostly focus on the receptor-binding domain (RBD) of the viral spike protein, and induced neutralizing antibodies have shown to be protective. However, functional relevance of vaccine-generated antibodies are poorly understood on variants-of-concern (VOCs) and mucosal immunity.

MethodsWe compared specific antibody production against the S1 subunit and the RBD of the spike protein, the whole virion of SARS-CoV-2, and monitored neutralizing antibodies in sera and saliva of 104 BNT162b2 vaccinees and 57 individuals with natural SARS-CoV-2 infection. Furthermore, we included a small cohort of 11 individuals which received a heterologous ChAdOx1-S/BNT162b2 prime-boost vaccination.

ResultsVaccinated individuals showed higher S1-IgG antibodies in comparison to COVID-19 patients, followed by a significant decrease 3 months later. Neutralizing antibodies (nAbs) were poorly correlated with initial S1-IgG levels, indicating that these might largely be non-neutralizing. In contrast, RBD IgGAM was strongly correlated to nAbs, suggesting that RBD-IgGAM is a surrogate marker to estimate nAb concentrations after vaccination. The protective effect of vaccine- and infection-induced nAbs was found reduced towards B.1.617.2 and B.1.351 VOCs. NAb titers are significantly higher after third vaccination compared to second vaccination. In contrast to COVID-19 patients, no relevant levels of RBD specific antibodies were detected in saliva samples from vaccinees.

ConclusionsOur data demonstrate that BNT162b2 vaccinated individuals generate relevant neutralizing antibodies, which begin to decrease within three months after immunization and show lower neutralizing potential to VOCs as compared to the original Wuhan virus strain. A third booster vaccination provides a stronger nAb antibody response than the second vaccination. The systemic vaccine does not seem to elicit readily detectable mucosal immunity.


title: Ventricular anatomical complexity and gender differences impact predictions from computational models

abstract:
The aim of this work was to analyze the influence of the gender and anatomical details (trabeculations and false tendons) on the electrophysiology of healthy and infarcted myocardium and their relation to the ventricular tachycardia (VT) inducibility.

To this end, four anatomically normal, human, biventricular geometries (two male, two female), with identifiable trabeculations, were obtained from high-resolution, ex-vivo MRI and represented by detailed and smoothed geometrical models (with and without the trabeculations). Additionally one model was augmented by a scar. The electrophysiology finite element model (FEM) simulations were carried out, using OHara-Rudy human myocyte model, and the comparison of detailed vs smooth, male vs female, as well as normal vs infarcted anatomy was carried out. Finally, the infarcted case was subjected to standard clinical programmed stimulus S1-S4 protocol to identify geometry- and gender-specific VT inducibility.

All female hearts presented action potential prolongation and QRS interval lengthening. Smooth geometries showed different QRS pattern and T wave magnitude in comparison to the corresponding trabeculated geometries. A variety of sustained VTs were obtained in the detailed and smoothed male geometries at different pacing locations, which provide evidence of the geometry-dependent differences regarding the prediction of the locations of reentry channels. In the female phenotype, sustained VTs were induced in both detailed and smooth geometries with RV apex pacing, however no consistent reentry channels were identified.

Anatomical and physiological cardiac features play an important role defining risk in cardiac disease. These are often excluded from electrophysiological simulations. The assumption that the cardiac endocardium is smooth may inaccurately predict different reentry channel locations in tachycardia inducibility studies.

category: cardiovascular medicine


title: Validation of Friedewald, Martin/Hopkins and Sampson Equations in the Low-Density Lipoprotein Cholesterol Estimation with Different Assays

abstract:
BackgroundLow-density lipoprotein cholesterol (LDL-C) is an important biomarker for determining cardiovascular risk and regulating lipid lowering therapy. Therefore, the accurate estimation of LDL-C concentration is essential in cardiovascular disease diagnosis and prognosis. Sampson recently proposed a new formula for the estimation of LDL-C. However, little is known regarding the validation of this formula.

ObjectivesThis study aimed to validate this new formula with other well-known formulas in Turkish population, composed of adults.

MethodsA total of 88,943 participants above 18 years old at Sivas Cumhuriyet University Hospital (Sivas, Turkey) were included to this study. LDL-C was directly measured by homogeneous assays, i.e., Roche, Beckman and Siemens and estimated by Friedewalds, Martin/Hopkins, extended Martin/Hopkins and Sampsons formulas. The accuracies between the estimations obtained by the formulas and the direct measurements were evaluated both in general and separately for the LDL-C, TG and non-HDL-C sublevels. Linear regression analysis was applied and residual error plots were generated between each estimation and direct measurement method. Coefficient of determination (R2) and mean absolute deviations were also calculated.

ResultsThe results showed that the extended Martin/Hopkins approach was the overall most accurate approach for LDL-C estimation. The results also showed that the highest concordances were obtained between the direct assays with the extended Martin/Hopkins formula calculated with the median statistics obtained from our own population. On the other hand, it was observed that the results of the methods may differ in different assays. Although the best performance was obtained by the Sampson formula in patients with "low LDL-C level and hypertriglyceridemia", the extended Martin/Hopkins approach, calculated from the median statistics of our population, gave the most accurate results in patients with "low LDL-C level or hypertriglyceridemia".

ConclusionsIn conclusion, in patients with a low LDL-C level or hypertriglyceridemia, the extended Martin/Hopkins method; in patients with a low LDL-C level and hypertriglyceridemia, the Sampson method may be preferred. The validity of the Martin Hopkins and Sampsons formulas has to be further investigated in different populations.


title: Genome surveillance of SARS-CoV-2 variants and their role in pathogenesis focusing on second wave of COVID-19 in India

abstract: India had witnessed unprecedented surge in SARS-CoV-2 infections and the dire consequences during the second wave of COVID-19, but the detailed report of the epidemiological based spatiotemporal incidences of the disease is missing. Here in, we have applied various statistical methods like correlation, hierarchical clustering to know the pattern of pathogenesis of the circulating VoCs. B.1.617.1 (Kappa) was the predominant VoC during the early phase of second wave. Delta (B.1.617.2) or Delta-like (AY.x) VoC constitutes majority (>90.17) of the cases during the peak of second wave. The correlation plot showed Delta/Delta-like lineage is inversely correlated with other lineages including B.1.617.1 (kappa), B.1.1.7, B.1, B.1.36.29 and B.1.36. Delta/Delta-like surge coincided with second wave whereas all other lineages (B.1.617.1, B.1.36.29, etc.) occurred during the prior phase of the second wave. The spatiotemporal analysis showed that most of the Indian states were affected during the peak of the second wave due to delta surge and fall under the same cluster. The second cluster populated mostly by north-eastern states and islands of India were minimally affected. The presence of signature mutations (T478K, D950N, E156G) along with L452K, D614G and P681R within the spike protein of Delta or Delta-like might cause elevation in host cell attachment, increased transmission and altered antigenicity which in due course of time has replaced the other circulating variants. The timely assessment of new VoCs will provide a rationale for updating the diagnostic, vaccine development by medical industries and decision making by various agencies including government, educational institutions, and corporate industries.


title: Does the use of prediction equations to correct self-reported height and weight improve obesity prevalance estimates? A pooled cross-sectional analysis of Health Survey for England data

abstract:
ObjectiveAdults typically overestimate height and underestimate weight compared with directly measured values, and such misreporting varies by sociodemographic and health-related factors. Using self-reported and interviewer-measured height and weight, collected from the same participants, we aimed to develop a set of prediction equations to correct bias in self-reported height and weight, and assess whether this adjustment improved the accuracy of obesity prevalence estimates relative to those based only on self-report.

DesignPopulation-based cross-sectional study.

Participants38,942 participants aged 16+ (Health Survey for England 2011-16) with non-missing self-reported and interviewer-measured height and weight.

Main outcome measuresComparisons between self-reported, interviewer-measured (gold standard) and corrected (based on prediction equations) body mass index (BMI: kg/m2) including (i) difference between means and obesity prevalence, and (ii) measures of agreement for BMI classification.

ResultsOn average, men overestimated height more than women (1.6 and 1.0cm, respectively; p<0.001), whilst women underestimated weight more than men (2.1 and 1.5kg, respectively; p<0.001). Underestimation of BMI was larger on average for women than for men (1.1 and 1.0kg/m2, respectively; p<0.001). Obesity prevalence based on self-reported BMI was 6.8 and 6.0 percentage points (pp) lower than that estimated using measured BMI for men and women, respectively. Corrected BMI (based on models containing all significant predictors of misreporting of height and weight) lowered underestimation of obesity to 0.8pp in both sexes and improved the sensitivity of being classified as obese over self-reported BMI by 15.0pp for men and 12.2pp for women. Results based on models using age alone as a predictor of misreporting were similar.

ConclusionsCompared with self-reported data, applying prediction equations improved the accuracy of obesity prevalence estimates and increased sensitivity of being classified as obese. Including additional sociodemographic variables does not add enough predictive power to justify the added complexity of including them in prediction equations.

Strengths and limitations of the studyO_LIThe limitations of body mass index (BMI) calculated from self-reported values of height and weight are well known.
C_LIO_LIHealth examination surveys such as the Health Survey for England (HSE) enable study of reporting bias when they collect both self-report and directly measured data on height and weight from the same participants.
C_LIO_LIThis study used HSE 2011-16 data to derive a set of adjustments to self-reported height and weight based on linear regression models that estimated measured values of height and weight from self-reported values of height and weight, with additional corrections for sociodemographic and health-related factors predictive of misreporting.
C_LIO_LICorrected and measured BMI (the gold standard) were compared to quantify by how much obesity prevalence estimates were improved relative to those based on self-report data only.
C_LIO_LIPrediction equations are specific to time, place, target population and methods of data collection. As such, these may not be applicable to surveys with more recent data, or different sociodemographic, health and self-reported anthropometric profiles.
C_LI


title: External control arm analysis: an evaluation of propensity score approaches, G-computation, and doubly debiased machine learning.

abstract:
BackgroundAn external control arm is a cohort of control patients that are collected from data external to a single-arm trial. To provide an unbiased estimation of efficacy, the clinical profiles of patients from single and external arms should be aligned, typically using propensity score approaches. There are alternative approaches to infer efficacy based on comparisons between outcomes of single-arm patients and machine-learning predictions of control patient outcomes. These methods include G-computation and Doubly Debiased Machine Learning (DDML) and their evaluation for ECA analysis is insufficient.

MethodsWe consider both numerical simulations and a trial replication procedure to evaluate the different statistical approaches: propensity score matching, Inverse Probability of Treatment Weighting (IPTW), G-computation, and DDML. The replication study relies on five type 2 diabetes randomized clinical trials granted by the Yale University Open Data Access (YODA) project. From the pool of five trials, observational experiments are artificially built by replacing a control arm from one trial by an arm originating from another trial and containing similarly-treated patients.

ResultsAmong the different statistical approaches, numerical simulations show that DDML has the smallest bias followed by G-computation. Ranking based on mean square error is different with G-computation always being among the lowest-error methods while DDML relative performance improves with increasing sample sizes. For hypothesis testing, DDML controls type-1 error and is conservative whereas G-computation and propensity score approaches can be liberal with type I errors ranging between 5% and 10% in some settings. G-computation is the best method in terms of statistical power, and DDML has comparable power at n = 1000 but its power is inferior to propensity score approaches at n = 250. The replication procedure also indicates that G-computation minimizes mean squared error while DDML has intermediate performances compared to G-computation and propensity score approaches. The confidence intervals of G-computation are the narrowest in lines with its liberal type I error whereas confidence intervals of DDML are the widest that confirms its conservative nature.

ConclusionsFor external control arm analyses, methods based on outcome prediction models can reduce estimation error and increase statistical power compared to propensity score approaches.


title: Wastewater monitoring using a novel, cost-effective PCR-based method that rapidly captures the transition patterns of SARS-CoV-2 variant prevalence (from Delta to Omicron) in the absence of conventional surveillance evidence

abstract:
BackgroundThe magnitude of Omicron SARS-CoV-2 variant of concern (VOC) global spread necessitates reinforcement of surveillance implementation. Conventional VOC surveillance based on genotyping of clinical samples is characterized by certain challenges related to available sequencing capacity, population sampling methodologies, and demands in terms of time, labor, and resources. Wastewater-based SARS-CoV-2 VOC surveillance constitutes a valuable supplementary practice, since it does not require extensive sampling, and provides information on the prevalence of the disease in a timely and cost-effective manner.

MethodsA highly sensitive real-time RT-PCR assay was developed, for targeted Omicron VOC detection and quantification in wastewater samples. The assay exclusively amplifies sequences with the S:{Delta}69/70 deletion, thus its performance is not hampered by the presence of the Delta VOC. The method was incorporated in the analysis of composite daily samples taken from the main Wastewater Treatment Plant (WWTP) of Thessaloniki, Greece from 1 December 2021 to 9 January 2022.

ResultsThe Omicron VOC was detected for the first time in samples from the Thessaloniki WWTP on 19 December 2021. In the following 10-day period, a rapid increase in Omicron sewage viral load was observed with an estimated early doubling time of 1.86 days. The proportion of the total SARS-CoV-2 load attributed to Omicron reached 91.09% on 7 January, revealing a fast Delta-to-Omicron VOC transition pattern. The detection of Omicron in wastewater preceded the outburst of reported (presumable) Omicron cases in the city by approximately 7 days.

ConclusionsThe proposed wastewater-based surveillance approach enables rapid, real-time data acquisition on the Omicron VOC prevalence and transmission dynamics. Timely provision of these results to State authorities can readily influence the decision-making process for targeted public health interventions, including control measures, awareness, and preparedness.


title: Longitudinal DNA Methylation Profiling of the Rectal Mucosa Identifies Cell-specific Signatures of Disease Status, Severity and Clinical Outcomes in Ulcerative Colitis

abstract: In peripheral blood, DNA methylation (DNAm) patterns in inflammatory bowel disease patients reflect inflammatory status rather than disease status. Here, we studied DNAm in diseased rectal mucosa from ulcerative colitis (UC) patients, conducting a cell-type-specific EWAS in epithelial, immune and fibroblast cells to understand DNAm changes across disease states, course, and clinical outcomes. At diagnosis, rectal mucosa in UC exhibited a lower proportion of epithelial cells and fibroblasts, and higher proportion of immune cells, along with 3504, 910, and 2279 altered DNAm sites as detected in our cell-specific EWAS, respectively. While treatment had significant effects on DNAm of immune cells, its effects on fibroblasts and epithelial cells were attenuated. Those requiring colectomy exhibited cell composition and DNAm patterns at follow-up more like disease onset than patients who did not require colectomy. Collectively DNAm and gene expression analysis suggest that targeting epithelial genes involved in barrier function may improve clinical outcomes.

category: gastroenterology


title: Acute upper airway disease in children with the omicron (B.1.1.529) variant of SARS-CoV-2: a report from the National COVID Cohort Collaborative (N3C)

abstract:
BackgroundReports of SARS-CoV-2 causing laryngotracheobronchitis (commonly known as croup) have been limited to small case series. Early reports suggest the Omicron (B.1.1.529) strain of SARS-CoV-2 (the dominant circulating US strain since the week of 12/25/2021) replicates more efficiently in the conducting airways. This may increase the risk of a croup phenotype in children as they have smaller airway calibers.

MethodsDescription of the incidence, change over time, and characteristics of children with SARS-CoV-2 and upper airway infection (UAI) diagnoses within the National COVID Cohort Collaborative (N3C) before and during the rise of the Omicron variant. We compare the demographics, comorbidities, and clinical outcomes of hospitalized SARS-CoV-2 positive children with and without UAI.

ResultsSARS-CoV-2 positive UAI cases increased to the highest number per month (N = 170) in December 2021 as the Omicron variant became dominant. Of 15,806 hospitalized children with SARS-CoV-2, 1.5% (234/15,806) had an UAI diagnosis. Those with UAI were more likely to be male, younger, white, have asthma and develop severe disease as compared to those without UAI.

ConclusionsPediatric acute UAI cases have increased during the Omicron variant surge with many developing severe disease. Improved understanding of this emerging clinical phenotype could aid in therapeutic decision-making and healthcare resource planning.


title: Impact of low relative skeletal muscle mass and power on the development of metabolic syndrome in Japanese women: a 7-year prospective study

abstract: Previous cross-sectional studies indicated that low relative skeletal muscle mass against body weight (appendicular lean mass divided by body weight, ALM/Wt or divided by body mass index, ALM/BMI) was negatively associated with metabolic syndrome (MetS). The aim of this longitudinal study was to investigate the impact of low relative skeletal muscle mass and leg muscle power on the development of MetS in Japanese women in a 7-y prospective study. Subjects were 346 Japanese women aged 26 to 85 years. The reference values for Class I sarcopenia were defined as values one SD below the sex-specific means of the young group. The longitudinal relation between muscle mass or leg power and development of MetS was examined using Kaplan-Meier curves and Cox regression models (average follow-up duration 7 years, range 1 to 10 years). During follow-up, 24 of subjects developed MetS. Both indices of ALM/Wt or ALM/BMI, the incidence of MetS was higher in Class I sarcopenia group than normal muscle mass group even after controlling variables (adjusted hazard ratio [AHR] = 3.22 [95%CI; 1.25-8.27] for ALM/Wt and 3.19 [95%CI; 1.31-7.74] for ALM/BMI). In contrast, for the leg power per body weight, the incidence of MetS was not significantly different between low leg power and normal leg power groups (AHR = 1.23 [95%CI; 0.50-3.04]). Current longitudinal study indicated that low relative skeletal muscle mass but not low leg power was independent risk factors for the development of MetS in Japanese women.

category: public and global health


title: Measurement of subjective and objective indices after progressive resistance training compared with aerobic training in Patients with Haemophilia: a study protocol

abstract:
BackgroundBleeding episodes in mild haemophilia may occur after major injuries or surgical procedures with some people not experiencing bleeding episodes. People suffering from moderate haemophilia bleed once a month, however they rarely experience spontaneous bleeding. Those suffering from severe haemophilia bleed quite often into muscles or joints, and episodes can occur once to twice a week. Bleeding usually occurs spontaneously.

ObjectiveTo investigate the effects of progressive resistance training on quality of life, muscular strength and joint score in patients with haemophilia.

MethodologySixty patients will be enrolled in the study. Thirty patients will be allocated to control group, and thirty to intervention group. Controls will be administered active muscle stretching and aerobic exercises. Intervention group will be given active muscle stretching, and resistance training. Patients will be randomly allocated to each group. Anthropometric data will be measured pre-test to establish a baseline. Study variables include muscular strength, and quality of life. All tests will be measured pre-test and post-test to compare effects of treatment.

ResultsParticipant recruitment commenced in June 2021. The post intervention phase will be completed by August 2020. Data analysis will commence after this. A write-up for publication is expected to be completed after the follow-up phase is finalized in August 2021.

ConclusionsIf resistance training is found to be effective in improving quality of life and muscular strength in participants, it could reduce the frequency of factor therapy given prophylactically, or even as acute treatment, thus directing it towards more severe cases. It will also provide financial relief to organizations supporting the treatment of the hemophilic population.

category: rehabilitation medicine and physical therapy


title: Ready for Impact? A validity and feasibility study of instrumented mouthguards (iMGs)

abstract:
ObjectivesDetermine the validity and feasibility of current Instrumented mouthguards (iMGs) and associated systems.

MethodsPhase 1; Four iMG systems (Football Research Inc [FRI], HitIQ, ORB, Prevent) were compared against dummy headform laboratory criterion standards (25, 50, 75, 100 g). Phase 2; Four iMG systems were evaluated for on-field validity of iMG-triggered events against video-verification to determine true-positives, false-positives and false-negatives (20 {+/-} 9 player matches per iMG). Phase 3; Four iMG systems were evaluated by eighteen rugby players, for perceptions of fit, comfort and function. Phase 4; Three iMG systems (FRI, HitIQ, Prevent) were evaluated for practical feasibility (system usability scale; SUS) by four practitioners.

ResultsPhase 1; Total concordance correlation coefficient was 98.3%, 95.3%, 42.5% and 97.9% for FRI, HitIQ, ORB and Prevent. Phase 2; Different on-field kinematics were observed between iMGs. Positive predictive values were 0.98, 0.90, 0.53 and 0.94 for FRI, HitIQ, ORB and Prevent. Sensitivity values were 0.51, 0.40, 0.71 and 0.75 for FRI, HitIQ, ORB and Prevent. Phase 3; player perceptions of fit, comfort and function were 77%, 6/10, 55% for FRI, 88%, 8/10, 61% for HitIQ, 65%, 5/10, 43% for ORB, and 85%, 8/10, 67% for Prevent. Phase 4; SUS was 51.3-50.6/100, 71.3-78.8/100, and 83.8-80.0/100 for FRI, HitIQ, and Prevent.

ConclusionThis study shows that differences between current iMG systems exist. Sporting organisations can use these findings to ensure accurate head acceleration event data are obtained and system adoption is optimized, to support player welfare initiatives directly related to long-term brain health.

category: sports medicine


title: Medical student residency preferences and motivational factors: a longitudinal, single-institution perspective

abstract:
BackgroundA high proportion of medical school graduates pursue specialties different from those declared at matriculation. While these choices influence the career paths, satisfaction, and potential regret students will experience, they also impact the supply and demand ratio of the shorthanded physician workforce across many specialties. In this study, we investigate how the choice of medical specialty and the factors motivating those choices change between the beginning and end of medical school training.

MethodsA questionnaire was administered annually from 2017 to 2020 to a cohort of medical students at the University of Connecticut to determine longitudinal preferences regarding residency choice, motivational factors influencing residency choice, future career path, and demographic information.

ResultsThe questionnaire respondent totals were as follows: n=76 (Year 1), n=54 (Year 2), n=31 (Year 3), and n=65 (Year 4). Amongst newly matriculated students, 25.0% were interested in primary care, which increased [~]1.4-fold to 35.4% in the final year of medical school. In contrast, 38.2% of matriculated students expressed interest in surgical specialties, which decreased [~]2.5-fold to 15.4% in the final year. Specialty choices in the final year that exhibited the largest absolute change from matriculation were orthopedic surgery (-9.9%), family medicine (+8.1%), radiology (+7.9%), general surgery (-7.2%), and anesthesiology (+6.2%). Newly matriculated students interested in primary care demonstrated no differences in their ranking of motivational factors compared to students interested in surgery, but many of these factors significantly deviated between the two career paths in the final year. Specifically, students interested in surgical specialties were more motivated by the rewards of salary and prestige compared to primary care students, who more highly ranked match confidence and family/location factors.

ConclusionsWe identified how residency choices change from the beginning to the end of medical school, how certain motivational factors change with time, how these results diverge between primary care and surgery specialty choice, and propose a new theory based on risk-reward balance regarding residency choice. Our study promotes awareness of student preferences and may help guide school curricula in developing more student-tailored training approaches. This could foster positive long-term changes regarding career satisfaction and the physician workforce.

category: medical education


title: Spinal cord MRI and MRS Detect Early-stage Alterations and Disease Progression in Friedreich Ataxia

abstract:
BackgroundFriedreich Ataxia (FRDA) is the most common hereditary ataxia. Atrophy of the spinal cord is one of the hallmarks of the disease. Magnetic resonance imaging (MRI) and spectroscopy (MRS) are powerful and non-invasive tools to investigate pathological changes in the spinal cord. A handful of studies have reported cross-sectional alterations in FRDA using MRI and diffusion MRI (dMRI) in FRDA. However, to our knowledge no longitudinal MRI, dMRI or MRS results have been reported in the spinal cord in FRDA.

ObjectiveTo investigate early-stage cross-sectional alterations and longitudinal changes in the cervical spinal cord in FRDA, using a multimodal magnetic resonance (MR) protocol comprising morphometric (anatomical MRI), microstructural (dMRI), and neurochemical (1H MRS) assessments.

DesignWe enrolled 28 early-stage individuals with FRDA and 20 age- and gender-matched controls (cross-sectional study). Disease duration at baseline was 5.5{+/-}4.0 years and Friedreich Ataxia Rating Scale (FARS) total neurological score at baseline was 42.7{+/-}13.6. Twenty-one FRDA participants returned for 1-year follow-up, and 19 of those for 2-year follow-up (cohort study). Each visit consisted in clinical assessments and MR scans. Controls were scanned at baseline only.

ResultsAt baseline, individuals with FRDA had significantly lower spinal cord cross-sectional area (-31%, p=4.10-17), higher eccentricity (+10%, p=5.10-7), lower total N-acetyl-aspartate (-36%, p=6.10-9) and higher myo-inositol (+37%, p=2.10-6) corresponding to a lower ratio tNAA/mIns (-52%, p=2.10-13), lower fractional anisotropy (-24%, p=10-9) as well as higher radial diffusivity (+56%, p=2.10-9), mean diffusivity (+35%, p=10-8) and axial diffusivity (+17%, p=4.10-5) relative to controls.

Longitudinally, spinal cord cross-sectional area decreased by 2.4% per year relative to baseline (p=4.10-4), the ratio tNAA/mIns decreased by 5.8% per year (p=0.03), and fractional anisotropy showed a trend to decrease (-3.2% per year, p=0.08).

Spinal cord cross-sectional area correlated strongly with clinical measures, with the strongest correlation coefficients found between cross-sectional area and Scale for the Assessment and Rating of Ataxia (SARA) (R=-0.55, p=7.10-6) and between cross-sectional area and FARS total neurological score (R=-0.60, p=4.10-7). Less strong but still significant correlations were found for fractional anisotropy and tNAA/mIns.

ConclusionWe report here the first quantitative longitudinal MR results in the spinal cord in FRDA. The largest longitudinal effect size was found for spinal cord cross-sectional area, followed by tNAA/mIns and fractional anisotropy. Our results provide direct evidence that abnormalities in the spinal cord result not solely from hypoplasia, but also from neurodegeneration, and show that disease progression can be monitored non-invasively in the spinal cord.


title: Investigation of air change rate and aerosol behavior during an outbreak of COVID-19 in a geriatric care facility

abstract: We investigated the air change rate (ACR) using the tracer gas method in five areas where the risk of aerosol infection was assumed to be high for an outbreak of an infection among 59 people in a nursing home in Miyagi Prefecture, Japan. The ACRs at the time of the outbreak were estimated to be 4.35, 2.42, 2.04, 4.96, and 6.26 per hour in the general bathroom, special bathroom, shared room, private room, and day room, respectively. In general bathrooms, special bathrooms, shared rooms, and private rooms, the ACR greatly increased by 1.48{square}5.74 times by opening windows. Because the private rooms, where the initial infected patients were thought to have been, were spatially connected to the common recreational day room, the transfer of aerosols from private rooms to the day room may have been the origin of the mass infection. We reproduced the downwind contamination situation using thermo-fluid simulations and found that infectious aerosols could reach the day room in approximately one minute through the corridor. In elderly care facilities, open architectural spaces are advocated to realize a Quality of Life (Q{o}L) and monitor residents; however, management is required to reduce the downwind infection risk from aerosols and ACR.

category: occupational and environmental health


title: The Correlation Between Brain Performance Capacity and COVID-19: A Cross-sectional Survey and Canonical Correlation Analysis

abstract:
ObjectiveTo generate a concept of brain performance capacity (BPC) with sleep, fatigue and mental workload as evaluation indicators and to analyze the correlation between BPC and the impact of COVID-19.

MethodsA cluster sampling method was adopted to randomly select 259 civil air crew members. The measurements of sleep quality, fatigue and mental workload (MWL) were assessed using the Pittsburgh Sleep Quality Index (PSQI), Multidimensional Fatigue Inventory (MFI-20) and NASA Task Load Index. The impact of COVID-19 included 7 dimensions scored on a Likert scale. Canonical correlation analysis (CCA) was conducted to examine the relationship between BPC and COVID-19.

ResultsA total of 259 air crew members participated in the survey. Participants average PSQI score was 7.826 (SD = 3.796), with 49.8% reporting incidents of insomnia, mostly of a minor degree. Participants MFI was an average 56.112 (SD = 10.040), with 100% reporting some incidence of fatigue, mainly severe. The weighted mental workload (MWL) score was an average of 43.084 (SD = 17.543), with reports of mostly a mid-level degree. There was a significant relationship between BPC and COVID-19, with a canonical correlation coefficient of 0.507 (P=0.000), an eigenvalue of 0.364 and a contribution rate of 69.1%. All components of the BPC variable set: PSQI, MFI and MWL contributed greatly to BPC, with absolute canonical loadings of 0.790, 0.606 and 0.667, respectively; the same was true for the COVID-19 variable set, with absolute canonical loadings ranging from 0.608 to 0.951.

ConclusionMultiple indicators to measure BPC and the interrelationship of BPC and COVID-19 should be used in future research to gain a comprehensive understanding of anti-epidemic measures to ensure victory in the battle against the spread of the disease.


title: Low back pain and telecommuting in Japan: influence of work environment quality

abstract:
ObjectivesThis study examined the relationship between frequency of working from home and low back pain (LBP), considering the quality of work environment.

MethodsThe study was based on a cross-sectional internet-based survey. Of 33,302 respondents, data from 12,774 desk workers were retained for analysis. We used a 0-10 numerical rating scale to assess LBP. Work environment was assessed using five subjective questions. Mixed-effects logistic regression nested by city level was used to analyze the relationship between frequency of working from home and LBP, stratified by work environment condition.

ResultsThe prevalence of LBP was 21.0%. Among those reporting a poor work environment, as opposed to almost never working from home, the multivariate odds ratio (OR) of LBP were as follows: working from home less than 1 day per week: OR=1.25, 95% CI: 0.89-1.76, p=0.190); 2-3 days per week: OR=1.58, 95% CI: 1.16-2.16, p=0.004; and 4 or more days per week: OR=1.82, 95% CI: 1.38-2.40, p<0.001. By contrast, among those reporting a good work environment the OR of LBP did not increase as the frequency of working from home increased.

ConclusionsThe relationship between LBP and frequency of working from home was found to vary with the quality of the work environment; more specifically, LBP was associated with frequency of teleworking in a poor work environment. This study suggests that employers should give more support their employees in promoting a good work environment to prevent LBP. (Words: 240/250)


title: Brainstem evoked auditory potentials in tinnitus: a best-evidence synthesis and meta-analysis

abstract:
IntroductionAccumulating evidence suggests a role of the brainstem in tinnitus generation and modulation. Several studies in chronic tinnitus patients have reported latency and amplitude changes of the different peaks of the auditory brainstem response, possibly reflecting neural changes or altered activity. The aim of the systematic review was to assess if alterations within the brainstem of chronic tinnitus patients are reflected in short- and middle-latency auditory evoked potentials (AEPs).

MethodsA systematic review was performed and reported according to the PRISMA guidelines. Studies evaluating short- and middle-latency AEPs in tinnitus patients and controls were included. Two independent reviewers conducted the study selection, data extraction, and risk of bias assessment. Meta-analysis was performed using a multivariate meta-analytic model.

ResultsTwenty-seven cross-sectional studies were included. Multivariate meta-analysis revealed that in tinnitus patients with normal hearing, significantly longer latencies of auditory brainstem response (ABR) waves I (SMD = 0.66 ms, p < 0.001), III (SMD = 0.43 ms p < 0.001), and V (SMD = 0.47 ms, p < 0.01) are present. The results regarding possible changes in middle-latency responses (MLRs) and frequency-following responses (FFRs) were inconclusive.

DiscussionThe discovered changes in short-latency AEPs reflect alterations at brainstem level in tinnitus patients. More specifically, the prolonged ABR latencies could possibly be explained by high frequency sensorineural hearing loss, or other modulating factors such as cochlear synaptopathy or somatosensory tinnitus generators. The question whether middle-latency AEP changes, representing subcortical level of the auditory pathway, are present in tinnitus still remains unanswered. Future studies should identify and correctly deal with confounding factors, such as age, gender and the presence of somatosensory tinnitus components.

category: otolaryngology


title: Dynamics of antibody responses, cellular immunity, and breakthrough infections among Japanese healthcare workers during the 6 months after receiving two doses of BNT162b2 mRNA vaccine

abstract:
IntroductionThe waning of the antibody titre after the first two doses of the Pfizer-BioNTech BNT162b2 mRNA SARS-CoV-2 vaccine was reported. However, knowledge of the dynamics of cellular immunity is scarce. Here, we performed a prospective cohort study to disclose antibody and cellular immunity dynamics and discuss the relationship between immunity and breakthrough infection.

MethodsThe study had a prospective cohort design. Antibody titres against SARS-CoV-2 in serially collected serum samples of 608 Japanese vaccinees after 6 months of vaccination were measured. Simultaneously, T-cell immunity dynamics were assessed using the QuantiFERON SARS-CoV-2 assay. Additionally, participants with suspected breakthrough infection were detected according to the positive conversion of the IgG assay for nucleocapsid proteins of SARS-CoV-2.

ResultsAntibody titres were elevated 3 weeks after vaccination and waned over the remainder of the study period. The QuantiFERON SARS-CoV-2 assay performed on 536 participants demonstrated the similar dynamics. Six participants without predisposing medical conditions demonstrated positive conversion of the IgG assay for nucleocapsid proteins, while five were asymptomatic.

ConclusionWaning of humoral and cellular immunity within 6 months of administration of two doses of BNT162b2 vaccine among Japanese healthcare professionals and the occurrence of asymptomatic breakthrough infection was suspected in approximately 1 of 100 vaccinees.

(UMIN000043340)


title: Liver Echinococcosis Lesion Classification Tool by Deep Learning: development, deployment, and validations

abstract: The endemic of Echinococcosis imposed heavy disease burden in some areas. The sonography for Echinococcosis lesions was essential to disease diagnosis and managements. Especially the biological typing of lesions was key to disease treatments. We used deep-learning tools to help sonographer to classify the lesion types. The model achieved 85%(302/376) accuracy, in contrast to senior sonographer achieved 72%(61/85) accuracy. The accuracy of AI model was higher than senior sonographer (p-value=0.01), could be a feasible method to help sonographer in remote area.


title: N Gene Target Failure (NGTF) for detection of Omicron: a way out for the "stealth" too?

abstract: S-gene target failure (SGTF) is neither specific nor accurate for identification of Omicron lineage of SARS-CoV-2. We observed N-gene target failure (NGTF) in 402 out of 412 SARS-CoV2 positive cases from December to mid-January 2022 using a commercially available assay. This phenomenon was not observed with more than 15,000 cases tested previously. We sequenced the genome of five samples with NGTF and compared these results with six cases where NGTF was not seen. We confirm that cases with NGTF were the Omicron lineage while cases with preserved N-gene amplification belonged to Delta lineage. We discovered that the ERS31-33 deletion (nucleotide 28362-28370del) overlaps with N gene probe used, explaining NGTF. As the  stealth Omicron variant also harbors ERS31-33 deletion, this approach will work for the detection of  stealth Omicron variant as well. We suggest that NGTF can be used as a low cost, rapid screening strategy for detection of Omicron.


title: Limit of Detection for Rapid Antigen Testing of the SARS-CoV-2 Omicron Variant

abstract: There has been debate in the literature about the ability of antigen tests to detect the SARS-CoV-2 Omicron variant including indication on the US Food and Drug administration website that antigen tests may have lower sensitivity for the Omicron variant without provision of data or the potential scale of the issue (see https://www.fda.gov/medical-devices/coronavirus-covid-19-and-medical-devices/sars-cov-2-viral-mutations-impact-covid-19-tests-omicronvariantimpact, accessed 1/27/2022). Here we determined the limit of detection (LoD) for the Omicron variant compared with the WA1 strain used for LoD studies described in the Instructions for Use for all Emergency Use Authorization (EUA)-approved antigen tests. Using live virus (to avoid artifactual findings potentially obtained with gamma-irradiated or heat-killed virus) quantified by plaque forming units (PFU), we examined the analytical sensitivity of three antigen tests widely used in the United States: the Abbott Binax Now, the AccessBio CareStart, and LumiraDx antigen tests. We found that the 95% detection threshold (LoD) for antigen tests was at least as good for Omicron as for the WA1 strain. Furthermore, the relationship of genome copies to plaque forming units for Omicron and WA1 overlap. Therefore, the LoD equivalency also applies if the quantitative comparator is genome copies determined from live virus preparations. Taken together, our data support the continued ability of the antigen tests examined to detect the Omicron variant.


title: Viral Cultures for Assessing Airborne Transmission of SARS-CoV-2: a Systematic Review Protocol

abstract:
This is a protocol for a systematic review that aims to evaluate the role of viral cultures for assessing airborne transmission of SARS-CoV-2. The review will address the following research questions:

Are airborne samples infectious?

If so, what proportion are infectious, and what is the distance and duration of infectiousness in the air?

What is the relationship between infectiousness and airborne PCR cycle threshold (Ct)?

Is there evidence of a chain of transmission that establishes an actual instance of airborne transmission of SARS-CoV-2?

What circumstances might facilitate infectious viruses being airborne over long distances?

We will search LitCovid, medRxiv, Google Scholar, and the WHO Covid-19 database to identify relevant studies. We will include studies reporting airborne transmission attempting viral culture or serial qRT-PCR with or without genomic sequencing. Predictive or modelling studies will be excluded. We will assess the quality of included studies using previously published criteria.

category: intensive care and critical care medicine


title: Three-Dimensional Cephalometric Landmarking and Analysis of Craniomaxillofacial CT scans via Deep Learning

abstract: The increasing use of three-dimensional (3D) imaging by orthodontists and maxillofacial surgeons to assess complex dentofacial deformities and plan orthognathic surgeries implies a critical need for 3D cephalometric analysis. Although promising methods were suggested to localize 3D landmarks automatically, concerns about robustness and generalizability restrain their clinical use. Consequently, highly trained operators remain needed to perform tedious manual landmarking. In this study, we aimed to train and evaluate a deep learning (DL) pipeline based on SpatialConfiguration-Net for automatic localization of 3D cephalometric landmarks on computed tomography (CT) scans. A retrospective sample of consecutive presurgical CT scans was randomly distributed between a training/validation set (n = 160) and a test set (n = 38). The reference data consisted in 33 landmarks, manually localized once by 1 operator (n = 178) or twice by 3 operators (n = 20, test set only). After inference on the test set, one CT scan showed "very low" confidence level predictions; we excluded it from the overall analysis but still assessed and discussed the corresponding results. The model performance was evaluated by comparing the predictions with the reference data; the outcome set included localization accuracy, cephalometric measurements and comparison to manual landmarking reproducibility. On the hold-out test set, the mean localization error was 1.0 {+/-} 1.3mm, while success detection rates for 2.0, 2.5 and 3.0mm were 90.4%, 93.6% and 95.4%, respectively. Mean errors were -0.3 {+/-} 1.3{degrees} and -0.1 {+/-} 0.7mm for angular and linear measurements, respectively. When compared to manual reproducibility, the measurements were within the Bland-Altman 95% limits of agreement for 91.9% and 71.8% of skeletal and dentoalveolar variables, respectively. To conclude, while our DL method still requires improvement, it provided highly accurate 3D landmark localization on a challenging test set, with a reliability for skeletal evaluation on par with what clinicians obtain.

category: dentistry and oral medicine


title: Observed serial intervals of SARS-CoV-2 for the Omicron and Delta varaints in Belgium based on contact tracing data, 19 November to 31 December 2021

abstract: The SARS-CoV-2 Omicron BA.1 variant is rapidly spreading worldwide, possibly outcompeting the Delta strain. We investigated the empirical serial interval for both variants using contact tracing data. Overall, we observed a shorter serial interval for Omicron compared to Delta, suggesting faster transmission. Furthermore, results indicate a relation between the empirical serial interval and the vaccination status for both the Omicron and the Delta variant. Consequently, with the progression of the vaccination campaign, the reasons for and extent of dominance of Omicron over Delta may need further assessment.


title: Bioelectrical Impedance Analysis in the nutritional assessment and prediction of complications in patients undergoing surgery for head and neck malignancies, A pilot observational study

abstract:
BackgroundPatients with head and neck malignancies are especially vulnerable to developing malnutrition, which has a significant impact on morbidity and mortality. Identification of high risk patients is hence critical for optimising outcomes.

ObjectiveIt is hypothesised that bioimpedance analysis (BIA) can provide information on nutritional status and risk of perioperative complications in a timely and accurate manner. The study objectives are; to correlate BIA parameters with Subjective Global Assessment (SGA) scores, and determine the association of BIA parameters with common perioperative complications in patients undergoing head and neck surgery.

MethodThis is a cohort study of 61 patients who were admitted for elective head and neck surgery from 2018-2019. Prior to surgery, patients were evaluated in a preoperative multidisciplinary allied health professional clinic for formal SGA scoring. Bioelectrical impedance analysis was performed using the Bodystat Quadscan 4000. One-way ANOVA and Fisher  s exact test were performed for associations between SGA and BIA parameters and receiver operating characteristic (ROC) curves were plotted for determination of optimal cut-off values of phase angle and Wellness marker in detecting malnutrition and perioperative pneumonia using Youden  s Index (YI).

Results45 males and 16 females with mean {+/-} SD age of 62 {+/-} 1.6 years old were included in the study. Significant differences were observed in Wellness Marker (p=0.004) and phase angle (p=0.006) amongst patients in the 3 SGA categories. BIA parameters (p=0.011 and p=0.032 for Wellness Marker and phase angle respectively) were associated with perioperative pneumonia. No significant differences were observed for other perioperative complications namely surgical site infections, salivary leak/fistula, and flap complications.

ConclusionBioelectrical Impedance Analysis is associated with Subjective Global Assessment and shows promise as a preoperative tool, in conjuction with SGA, to detect malnutrition in patients undergoing surgery for head and neck malignancies and highlight patients at risk of developing perioperative pneumonia.

category: surgery


title: Breakthrough SARS-CoV-2 infections in MS patients on disease modifying therapies

abstract:
BackgroundPatients with Multiple Sclerosis (pwMS) treated with anti-CD20 or fingolimod showed a reduced humoral response to SARS-CoV-2 vaccines. In this study we aimed to monitor the risk of breakthrough SARS-CoV-2 infection in pwMS on different Disease Modifying Therapy (DMT).

MethodsData on number of vaccinated patients and of patients with a breakthrough infection were retrospectively collected in 27 Italian MS centers. We estimated the rate of breakthrough infections and of infection requiring hospitalization per DMT.

Findings19641 vaccinated pwMS were included in the database. After a median follow-up of 8 months, we observed 137 breakthrough infections. As compared to the other DMTs, the rate of breakthrough infections was significantly higher on ocrelizumab (0.57% vs 2.00%, RR=3.55,95%CI=2.74-4.58, p<0.001) and fingolimod (0.58% vs 1.62%, RR=2.65,95%CI=1.75-4.00, p<0.001), while there were no significant differences in any other DMT group. In the ocrelizumab group the hospitalization rate was 16.7% vs 19.4% in the pre-vaccination era (RR=0.86,p=0.74) and it was 3.9% in all the other DMT groups vs 11.9% in the pre-vaccination period (RR=0.33,p=0.02).

InterpretationThe risk of breakthrough SARS-CoV-2 infections is higher in patients treated with ocrelizumab and fingolimod, and the rate of severe infections was significantly reduced in all the DMTs excluding ocrelizumab.