title: Analysis of whole exome sequencing in severe mental illness hints at selection of brain development and immune related genes

abstract: Evolutionary trends may underlie some aspects of the risk for common, non-communicable disorders, including psychiatric disease. We analyzed whole exome sequencing data from 80 unique individuals from India coming from families with two or more individuals with severe mental illness. We used Population Branch Statistics (PBS) to identify variants and genes under positive selection and identified 75 genes as candidates for positive selection. Of these, 20 were previously associated with Schizophrenia, Alzheimers disease and cognitive abilities in genome wide association studies. We then checked whether any of these 75 genes were involved in common biological pathways or related to specific cellular or molecular functions. We found that immune related pathways and functions related to innate immunity such as antigen binding were over-represented. We also evaluated for the presence of Neanderthal introgressed segments in these genes and found Neanderthal introgression in a single gene out of the 75 candidate genes. However, the introgression pattern indicates the region is unlikely to be the source for selection. Our findings hint at how selection pressures in individuals from families with a history of severe mental illness may diverge from the general population. Further, it also provides insights into the genetic architecture of severe mental illness, such as schizophrenia and its link to immune factors.


title: Methodological proposal to explore and design future health innovation policies and opportunities for Responsible Research and Innovation (RRI)

abstract: Responsible Research and Innovation (RRI) seeks to align the research results with the needs of society to respond to current and future problems, also encompassing financial instruments, innovative public policies, and the distribution of resources. These policies should prioritize research in those areas with the greatest impact on society, and particularly in health research, this impact should be focused on responding to clinical problems of the population rather than economic impact. A methodology is proposed that uses information from open sources to identify discrepancies between the results of the most translational research of a region and its health needs, in order to provide useful information for the formulation of innovation policies.

category: health policy


title: Different responses to neoadjuvant chemotherapy in urothelial carcinoma molecular subtypes

abstract: For muscle-invasive bladder cancer (MIBC), there are no tissue biomarkers in clinical use that identify patients sensitive or resistant to neoadjuvant chemotherapy. The present study investigates how molecular subtypes impact pathological response and survival in 149 patients receiving preoperative cisplatin-based chemotherapy. Tumor classification was performed by transcriptomic profiling and by a 13-marker immunostaining panel. Furthermore, we explored differential gene expression and chemotherapy response beyond molecular subtypes. Tumors with Genomically Unstable (GU) and Urothelial-like (Uro) subtypes had higher proportions of pathological response and superior survival outcomes as compared to the Basal-Squamous (Ba/Sq) subtype following neoadjuvant chemotherapy and radical cystectomy. Based on our findings, we suggest that urothelial cancer of the luminal-like GU- and Uro-subtypes are more responsive to cisplatin-based chemotherapy. We also found the gene coding for osteopontin (SPP1) to display a subtype-dependent effect on chemotherapy response, confirmed at the protein level by immunohistochemistry. Combined analyses of second-generation, subtype-specific biomarkers may be an additional way forward to develop a more precision-based treatment approach for neoadjuvant chemotherapy in MIBC.

category: oncology


title: Validity and Reliability of a Behavior Assessment Questionnaire for Children with Obesity

abstract:
The 10-item Behavior Assessment Questionnaire (BAQ) was developed to assess parent-report of child screen time, physical activity, and food consumption during the past 3 months in children with obesity. Response options were on a 5-point scale, converted to 0-100, with higher scores indicating healthier behavior. To evaluate, two convenience samples of parents of children 5-18 years completed the questionnaire: a cohort presenting to an obesity program (n=83) and a cohort of community events attenders and hospital employee parents (n=147). Scores had a normal distribution without floor or ceiling effects. Cronbachs alpha for the 10-item scale was .71. Factor analysis yielded three component factors with Cronbachs alpha of .66, .75, and .59 for the Screen Time, Physical Activity, and Food Consumption dimensions respectively. Scores of the obesity group (49.02 [SD 14.52]) were lower than scores of the community group (55.44 [SD 13.55]), p=.001. The BAQ demonstrated reliability and validity for use as an index of lifestyle behaviors.

Key MessagesO_LIA short, easily administered questionnaire, completed by parents, about obesity-associated lifestyle behaviors of children demonstrates reliability and validity
C_LIO_LIThis questionnaire could help pediatric providers assess behaviors in order to provide more targeted lifestyle counseling for children to reduce obesity risk.
C_LI

category: pediatrics


title: Trajectories of child emotional and behavioural difficulties before and during the COVID-19 pandemic in a longitudinal UK cohort

abstract:
ImportanceCOVID-19 public health mitigation measures are likely to have detrimental effects on emotional and behavioural problems in children. However, longitudinal studies with pre-pandemic data are scarce.

ObjectiveTo explore trajectories of childrens emotional and behavioural difficulties during the COVID-19 pandemic.

Design and settingData were from children from the third generation of a birth cohort study; the Avon Longitudinal Study of Parents and Children - Generation 2 (ALSPAC-G2) in the southwest of England.

ParticipantsThe study population comprised of 708 children (median age at COVID-19 data collection was 4.4 years, SD=2.9, IQR= [2.2 to 6.9]), whose parents provided previous pre-pandemic surveys and a survey between 26 May and 5 July 2020 that focused on information about the COVID-19 pandemic as restrictions from the first lockdown in the UK were eased.

ExposuresWe employed multi-level mixed effects modelling with random intercepts and slopes to examine whether childrens trajectories of emotional and behavioural difficulties (a combined total difficulties score) during the pandemic differ from expected pre-pandemic trajectories.

Main outcomesChildren had up to seven measurements of emotional and behavioural difficulties from infancy to late childhood, using developmentally appropriate scales such as the Emotionality Activity Sociability Temperament Survey in infancy and Strengths and Difficulties Questionnaire in childhood.

ResultsThe observed normative pattern of childrens emotional and behavioural difficulties pre-pandemic, was characterised by an increase in scores during infancy peaking around the age of 2, and then declining throughout the rest of childhood. Pre-pandemic, the decline in difficulties scores after age 2 was 0.6 points per month; but was approximately one third of that in post-pandemic trajectories (there was a difference in mean rate of decline after age 2 of 0.2 points per month in pre vs during pandemic trajectories [95 % CI: 0.10 to 0.30, p <0.001]). This lower decline in scores over the years translated to older children having pandemic difficulty scores higher than would be expected from pre-pandemic trajectories (for example, an estimated 10.0 point (equivalent of 0.8 standard deviations) higher score (95% CI: 5.0 to 15.0) by age 8.5 years). Results remained similar although somewhat attenuated after adjusting for maternal anxiety and age.

Conclusion and relevanceThe COVID-19 pandemic may be associated with greater persistence of emotional and behavioural difficulties after the age 2. Emotional difficulties in childhood predict later mental health problems. Further evidence and monitoring of emotional and behavioural difficulties are required to fully understand the potential role of the pandemic on young children.

Key FindingsO_ST_ABSQuestionC_ST_ABSHow has the COVID-19 pandemic influenced emotional difficulties in young children?

FindingsUsing repeated longitudinal data from before and during the pandemic we provide evidence that emotional difficulty scores of primary school aged children are higher by an estimated 10.0 points (0.8 standard deviations) (95% CI: 5.0 to 15.0) by age 8.5 years than would be expected based on pre pandemic data.

MeaningThe level of difference in emotional difficulties found in the current study has been linked to increased likelihood of mental health problems in adolescence and adulthood. Therefore, this increase in difficulties needs careful monitoring and support.

category: psychiatry and clinical psychology


title: What is known from the existing literature about the available treatments for pelvic floor dysfunction among female athletes? A scoping review protocol

abstract:
BackgroundPelvic floor dysfunction (PFD) is a term used to describe a variety of symptoms, signs and conditions involving different impairments on the pelvic floor muscles.

The existing literature suggests that some sports may lead to a higher risk of developing PFD, in particular among female athletes. Despite a recent scoping review highlighted a great number of studies dealing with epidemiologic data on this topic, no study has been conducted to map the available treatments.

In this framework, the aim of the present scoping review will be to map and summarize the literature to identify the available evidence concerning the treatments for PFD among female athletes.

Inclusion criteriaStudies considering female athletes practicing sports at any performance level with any type of PFD will be eligible for inclusion. Any treatment options (i.e. preventive, conservative, surgery) reported by each study and any context will be considered.

MethodsThis scoping review will be performed in accordance with the Joanna Briggs Institute methodology. MEDLINE, Cochrane Central, Scopus, CINAHLComplete, Embase, PEDro and SPORTDiscus database will be searched from inception to May 2021. Additional records will be identified through searching in grey literature and the reference lists of all relevant studies. No study design, publication type, data and language restrictions will be applied.

Two reviewers will independently screen all abstracts and full-text studies for inclusion. A data collection form will be developed by the research team to extract the characteristics of the studies included. A tabular and accompanying narrative summary of the information will be provided.

ConclusionsThis will be the first scoping review to provide a comprehensive overview of the topic. The results will add meaningful information for clinicians in the management of PFD among female athletes. Furthermore, any knowledge gaps of the topic will be identified. The results of this research will be published in a peer-reviewed journal and will be presented at relevant (inter)national scientific events.

category: rehabilitation medicine and physical therapy


title: Neocortical Localization and Thalamocortical Modulation of Neuronal Hyperexcitability in Fragile X Syndrome

abstract: Fragile X Syndrome (FXS) is a monogenetic form of intellectual disability and autism in which well-established knockout (KO) animal models point to neuronal hyperexcitability and abnormal gamma-frequency physiology as a basis for key disorder features. Translating these findings into patients may identify tractable treatment targets. Using source modeling of resting-state electroencephalography data, we report novel findings in FXS, including 1) increases in localized gamma activity, 2) pervasive changes of theta/alpha activity, indicative of disrupted thalamocortical modulation coupled with elevated gamma power, 3) stepwise moderation of these abnormalities based on female sex, and 4) relationship of this physiology to intellectual disability and neuropsychiatric symptoms. Our observations extend findings in Fmr1-/- KO mice to patients with FXS and raise a novel role for disrupted thalamocortical modulation in local hyperexcitability. This systems-level mechanism has received limited preclinical attention but has significant implications for understanding fundamental disease mechanisms.

category: neurology


title: A year of genomic surveillance reveals how the SARS-CoV-2 pandemic unfolded in Africa

abstract: The progression of the SARS-CoV-2 pandemic in Africa has so far been heterogeneous and the full impact is not yet well understood. Here, we describe the genomic epidemiology using a dataset of 8746 genomes from 33 African countries and two overseas territories. We show that the epidemics in most countries were initiated by importations, predominantly from Europe, which diminished following the early introduction of international travel restrictions. As the pandemic progressed, ongoing transmission in many countries and increasing mobility led to the emergence and spread within the continent of many variants of concern and interest, such as B.1.351, B.1.525, A.23.1 and C.1.1. Although distorted by low sampling numbers and blind-spots, the findings highlight that Africa must not be left behind in the global pandemic response, otherwise it could become a breeding ground for new variants.

category: genetic and genomic medicine


title: Predicting pulmonary function from the analysis of voice: a machine learning approach

abstract:
Providing proper timely treatment of asthma, self-monitoring can play a vital role in disease control. Existing methods (such as peak flow meter, smart spirometer) requires special equipment and are not always used by the patient. Using voice recording as surrogate measures of lung function can be used to assess asthma, which has good potential to self-monitor asthma and could be integrated into telehealth platforms. This study aims to apply machine learning approach to predict lung functions from recorded voice for asthma patients.

A threshold-based mechanism was designed to separate speech and breathing from recordings (323 recordings from 26 participants) and features extracted from these were combined with biological attributes and lung function (percentage predicted forced expiratory volume in 1 second, FEV1%). Three predictive models were developed: (a) regression models to predict lung function, (b) multi-class classification models to predict the severity, and (c) binary classification models to predict abnormality. Random Forest (RF), Support Vector Machine (SVM), and Linear Regression (LR) algorithms were implemented to develop these predictive models. Training and test samples were separated (70%:30% using balanced portioning). Features were normalised and 10-fold cross-validation used to measure the models training performances on the training samples. Models were then run on the test samples to measure the final performances.

The RF based regression model performed better with lowest root mean square error = 10.86, and mean absolute score = 11.47, as compared to other models. In predicting the severity of lung function, the SVM based model performed better with 73.20% accuracy. The RF based model performed better in binary classification models for predicting abnormality of lung function (accuracy = 0.85, F1-score = 0.84, and area under the receiver operating characteristic curve = 0.88).

The proposed machine learning approach can predict lung function (in terms of FEV1%), from the recorded voice files, better than other published approaches. These models can be extended to predict both the severity and abnormality of lung function with reasonable accuracies. This technique could be used to develop future telehealth solutions including smartphone-based applications which have potential to aid decision making and self-monitoring in asthma.

category: health informatics


title: Construction and Validation of the Ohio Children's Opportunity Index

abstract:
ObjectiveTo describe the development of an area-level measure of childrens opportunity, the Ohio Childrens Opportunity Index (OCOI).

Data Sources/Study SettingSecondary data were collected from US census based-American Community Survey (ACS), US Environmental Protection Agency, US Housing and Urban Development, Ohio Vital Statistics, US Department of Agriculture-Economic Research Service, Ohio State University Center for Urban and Regional Analysis, Ohio Incident Based Reporting System, IPUMS National Historical Geographic Information System, and Ohio Department of Medicaid.

Study DesignOCOI domains were selected based on existing literature, which included family stability, infant health, childrens health, access, education, housing, environment and criminal justice domains. The composite index was developed using an equal weighting approach. Validation analyses were conducted between OCOI and health and race-related outcomes.

Data Collection/Extraction MethodsData were aggregated at the census tract level.

Principal FindingsComposite OCOI scores ranged from 0-100 with an average value of 74.82 (SD, 17.00), was negatively skewed. Census tracts in the major metropolitan cities across Ohio represented 76% of the total census tracts in the least advantaged OCOI septile. OCOI served as a significant predictor of health and race-related outcomes. The average life expectancy at birth of children born in the most advantaged septile was approximately nine years more than those born in the least advantaged septile. Increases in OCOI were associated with decreases in proportion of Black (48 points lower in the most advantaged vs least advantaged septile), p<0.001) and Minority populations (54 points lower in most advantaged vs least advantaged septile, p<0.001).

ConclusionAs the first opportunity index developed for children in Ohio, the OCOI is a valuable resource for policy reform, especially related to health equity. Health care providers can use it to obtain more holistic views on their patients and implement interventions that can tackle barriers to childhood development.


title: Background rates of five thrombosis with thrombocytopenia syndromes of special interest for COVID-19 vaccine safety surveillance: incidence between 2017 and 2019 and patient profiles from 20.6 million people in six European countries

abstract:
BackgroundThrombosis with thrombocytopenia syndrome (TTS) has been reported among individuals vaccinated with adenovirus-vectored COVID-19 vaccines. In this study we describe the background incidence of TTS in 6 European countries.

MethodsElectronic medical records from France, Netherlands, Italy, Germany, Spain, and the United Kingdom informed the study. Incidence rates of cerebral venous sinus thrombosis (CVST), splanchnic vein thrombosis (SVT), deep vein thrombosis (DVT), pulmonary embolism (PE), and stroke, all with concurrent thrombocytopenia, were estimated among the general population between 2017 to 2019. A range of additional adverse events of special interest for COVID-19 vaccinations were also studied in a similar manner.

FindingsA total of 25,432,658 individuals were included. Background rates ranged from 1.0 (0.7 to 1.4) to 8.5 (7.4 to 9.9) per 100,000 person-years for DVT with thrombocytopenia, from 0.5 (0.3 to 0.6) to 20.8 (18.9 to 22.8) for PE with thrombocytopenia, from 0.1 (0.0 to 0.1) to 2.5 (2.2 to 2.7) for SVT with thrombocytopenia, and from 0.2 (0.0 to 0.4) to 30.9 (28.6 to 33.3) for stroke with thrombocytopenia. CVST with thrombocytopenia was only identified in one database, with incidence rate of 0.1 (0.1 to 0.2) per 100,000 person-years. The incidence of TTS increased with age, with those affected typically having more comorbidities and greater medication use than the general population. TTS was also more often seen in men than women. A sizeable proportion of those affected were seen to have been taking antithrombotic and anticoagulant therapies prior to their TTS event.

InterpretationAlthough rates vary across databases, TTS has consistently been seen to be a very rare event among the general population. While still very rare, rates of TTS are typically higher among older individuals, and those affected were also seen to generally be male and have more comorbidities and greater medication use than the general population.

FundingThis study was funded by the European Medicines Agency (EMA/2017/09/PE Lot 3).

category: hematology


title: Background rates of five thrombosis with thrombocytopenia syndromes of special interest for COVID-19 vaccine safety surveillance: incidence between 2017 and 2019 and patient profiles from 25.4 million people in six European countries


title: Establishment of an evaluation panel for the decentralized technical evaluation of the sensitivity of 31 rapid detection tests for SARS-CoV-2 diagnostics

abstract:
BackgroundThe detection of SARS-CoV-2 with rapid diagnostic tests has become an important tool to identify infected people and break infection chains. These rapid diagnostic tests are usually based on antigen detection in a lateral flow approach.

Aims & MethodsWhile for PCR diagnostics the validation of a PCR assay is well established, for antigen tests e.g. rapid diagnostic tests there is no common validation strategy. Here we present the establishment of a panel of 50 pooled clinical specimens that cover a SARS-CoV-2 concentration range from approximately 1.1 x 109 to 420 genome copies per mL of specimen. The panel was used to evaluate 31 rapid diagnostic tests in up to 6 laboratories.

ResultsOur results show that there is significant variation in the detection limits and the clinical sensitivity of different rapid diagnostic tests. We conclude that the best rapid diagnostic tests can be applied to reliably identify infectious individuals who are presenting with SARS-CoV-2 loads correlated to 106 genome copies per mL of specimen. Infected individuals displaying SARS-CoV-2 genome loads corresponding to less than 106 genome copies per mL will be identified by only some rapid diagnostics tests, while many tests miss these viral loads to a large extent.

ConclusionsSensitive RDTs can be applied to identify infectious individuals with high viral loads, but not to identify infected individuals.

category: infectious diseases


title: The Impact of Universal Transport Media and Viral Transport Media Liquid Samples on a SARS-CoV-2 Rapid Antigen Test

abstract: The impact of universal transport media (UTM) and viral transport media (VTM) liquid samples on the performance of the Healgen Scientific Rapid COVID-19 Antigen Test was investigated. Twelve different UTM/VTM liquid samples were added at different dilutions to the extraction buffer, and 2 of 12 generated false-positive results. To understand the cause of these false-positive results, the effect of extraction buffer dilution on sample pH, surfactant concentration, and ionic strength were investigated. The most important factor in UTM/VTM liquid sample dilution of the extraction buffer was ionic strength as measured by conductivity. Dilutions with conductivity below [~]17 mS/cm can induce a false-positive result. It was also noted that the ionic strength of UTM/VTMs can vary, and those with low ionic strength can be problematic. To rule out the effect of other common components found in UTMs/VTMs, several materials were mixed with extraction buffer and tested at high concentrations. None was shown to produce false-positive results.


title: Significant and sustained decrease in non-SARS-CoV-2 respiratory viral infections during COVID-19 public health interventions.

abstract: Public health interventions to decrease the spread of SARS-CoV-2 were largely implemented in the United States during spring 2020. This study evaluates the additional effects of these interventions on non-SARS-CoV-2 respiratory viral infections from a single healthcare system in the San Francisco Bay Area. The results of a respiratory pathogen multiplex polymerase chain reaction panel intended for inpatient admissions were analyzed by month between 2019 and 2020. We found major decreases in the proportion and diversity of non-SARS-CoV-2 respiratory viral illnesses in all months following masking and shelter-in-place ordinances. These findings suggest real-world effectiveness of nonpharmaceutical interventions on droplet-transmitted respiratory infections.


title: An evidence-based data science perspective on the prediction of heart failure readmissions

abstract: The prevention of unplanned 30-day readmissions of patients discharged with a diagnosis of heart failure (HF) remains a profound challenge among hospital enterprises. Despite the many models and indices developed to predict which HF patients will readmit for any unplanned cause within 30 days, predictive success has been meager. Using simulations of HF readmission models and the diagnostics most often used to evaluate them (C-statistics, ROC curves), we demonstrate common factors that have contributed to the lack of predictive success among studies. We reveal a greater need for precision and alternative metrics such as partial C-statistics and precision-recall curves and demonstrate via simulations how those tools can be used to better gauge predictive success. We suggest how studies can improve their applicability to hospitals and call for a greater understanding of the uncertainty underlying 30-day all-cause HF readmission. Finally, using insights from sampling theory, we suggest a novel uncertainty-based perspective for predicting readmissions and non-readmissions.

category: cardiovascular medicine


title: An evidence synthesis approach for combining different data sources illustrated using entomological efficacy of insecticides for indoor residual spraying

abstract:
BackgroundProspective malaria public health interventions are initially tested for entomological impact using standardised experimental hut trials. In some cases, data are collated as aggregated counts of potential outcomes from mosquito feeding attempts given the presence of an insecticidal intervention. Comprehensive data i.e. full breakdowns of probable outcomes of mosquito feeding attempts, are more rarely available. Bayesian evidence synthesis is a framework that explicitly combines data sources to enable the joint estimation of parameters and their uncertainties. The aggregated and comprehensive data can be combined using an evidence synthesis approach to enhance our inference about the potential impact of vector control products across different settings over time.

MethodsAggregated and comprehensive data from a meta-analysis of the impact of Actellic(R) 300CS (Syngenta), an indoor residual spray (IRS) product, used on wall surfaces to kill mosquitoes and reduce malaria transmission, were analysed using a series of statistical models to understand the benefits and limitations of each.

ResultsMany more data are available in aggregated format (N = 23 datasets, 5 studies) relative to comprehensive format (N = 3 datasets, 2 studies). The evidence synthesis model was most robust at predicting the probability of mosquitoes dying or surviving and blood-feeding. Generating odds ratios from the correlated Bernoulli random sample indicates that when mortality and blood-feeding are positively correlated, as exhibited in our data, the number of successfully fed mosquitoes will be under-estimated. Analysis of either dataset alone is problematic because aggregated data require an assumption of independence and there are few and variable data in the comprehensive format.

ConclusionsWe developed an approach to combine sources from trials to maximise the inference that can be made from such data. Bayesian evidence synthesis enables inference from multiple datasets simultaneously to give a more informative result and highlight conflicts between sources. Advantages and limitations of these models are discussed.

Key messagesO_LIStatistical models are developed to best infer key mosquito IRS statistics from disparate data sources.
C_LIO_LINaive methods, previously adopted, of combining different data sources can create bias and must be explicitly considered.
C_LIO_LIMosquitoes are highly likely to feed in experimental hut trials using indoor residual spraying of insecticides so the assumption of independence in the probability of mosquitoes dying is reflective of trial data.
C_LIO_LIWe provide code for practitioners to implement this approach themselves in both BUGS and Stan languages running from R.
C_LI

category: epidemiology


title: Inferring the COVID-19 IFR with a simple Bayesian evidence synthesis of seroprevalence study data and imprecise mortality data

abstract:
Estimating the COVID-19 infection fatality rate (IFR) has proven to be particularly challenging -and rather controversial- due to the fact that both the data on deaths and the data on the number of individuals infected are subject to many different biases. We consider a Bayesian evidence synthesis approach which, while simple enough for researchers to understand and use, accounts for many important sources of uncertainty inherent in both the seroprevalence and mortality data. With the understanding that the results of ones evidence synthesis analysis may be largely driven by which studies are included and which are excluded, we conduct two separate parallel analyses based on two lists of eligible studies obtained from two different research teams. The results from both analyses are rather similar. With the first analysis, we estimate the COVID-19 IFR to be 0.31% (95% credible interval of (0.16%, 0.53%)) for a typical community-dwelling population where 9% of the population is aged over 65 years and where the gross-domestic product at purchasing-power parity (GDP at PPP) per capita is $17.8k (the approximate worldwide average). With the second analysis, we obtain 0.32% (95% credible interval of (0.19%, 0.47%)). Our results suggest that, as one might expect, lower IFRs are associated with younger populations (and may also be associated with wealthier populations). For a typical community-dwelling population with the age and wealth of the United States we obtain IFR estimates of 0.43% and 0.41%; and with the age and wealth of the European Union, we obtain IFR estimates of 0.67% and 0.51%. O_QDAbove all, whats needed is humility in the face of an intricately evolving body of evidence. The pandemic could well drift or shift into something that defies our best efforts to model and characterize it.

Siddhartha Mukherjee, The New Yorker

February 22, 2021

C_QD


title: Inferring the COVID-19 infection fatality rate in the community-dwelling population: a simple Bayesian evidence synthesis of seroprevalence study data and imprecise mortality data


title: The evaluation of a novel digital immunochromatographic assay with silver amplification to detect SARS-CoV-2

abstract:
IntroductionRapid antigen tests are convenient for diagnosing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); however, they have lower sensitivities than nucleic acid amplification tests. In this study, we evaluated the diagnostic performance of Quick Chaser(R) Auto SARS-CoV-2, a novel digital immunochromatographic assay that is expected to have higher sensitivity than conventional antigen tests.

MethodsA prospective observational study was conducted between February 8 and March 24, 2021. We simultaneously obtained two nasopharyngeal samples, one for evaluation with the QuickChaser(R) Auto SARS-CoV-2 antigen test and the other for assessment with reverse transcription PCR (RT-PCR), considered the gold-standard reference test. The limit of detection (LOD) of the new antigen test was compared with those of four other commercially available rapid antigen tests.

ResultsA total of 1401 samples were analyzed. SARS-CoV-2 was detected by reference RT-PCR in 83 (5.9%) samples, of which 36 (43.4%) were collected from symptomatic patients. The sensitivity, specificity, positive predictive value, and negative predictive value were 74.7% (95% confidence interval (CI): 64.0-83.6%), 99.8% (95% CI: 99.5-100%), 96.9% (95% CI: 89.2-99.6%), and 98.4% (95% CI: 97.6-99.0%), respectively. When limited to samples with a cycle threshold (Ct) <30 or those from symptomatic patients, the sensitivity increased to 98.3% and 88.9%, respectively. The QuickChaser(R) Auto SARS-CoV-2 detected 34-120 copies/test, which indicated greater sensitivity than the other rapid antigen tests.

ConclusionsQuickChaser(R) Auto SARS-CoV-2 showed sufficient sensitivity and specificity in clinical samples of symptomatic patients. The sensitivity was comparable to RT-PCR in samples with Ct<30.


title: Nanopore Sequencing of SARS-CoV-2: Comparison of Short and Long PCR-tiling Amplicon Protocols

abstract: Surveillance of the SARS-CoV-2 variants including the quickly spreading mutants by rapid and near real-time sequencing of the viral genome provides an important tool for effective health policy decision making in the ongoing COVID-19 pandemic. Here we evaluated PCR-tiling of short ([~]400-bp) and long ([~]2 and [~]2.5-kb) amplicons combined with nanopore sequencing on a MinION device for analysis of the SARS-CoV-2 genome sequences. Analysis of several sequencing runs demonstrated that using the long amplicon schemes outperforms the original protocol based on the 400-bp amplicons. It also illustrated common artefacts and problems associated with this approach, such as uneven genome coverage, variable fraction of discarded sequencing reads, as well as the reads derived from the viral sub-genomic RNAs and/or human and bacterial contamination.


title: Plans to vaccinate children for COVID-19: a survey of US parents

abstract: In a national online survey of 2,074 US parents conducted in March 2021, 49.4% reported plans to vaccinate their child for COVID-19 when available. Lower income and less education were associated with greater parental vaccine hesitancy/resistance, while safety, effectiveness and lack of need were the primary reasons for vaccine hesitancy/resistance.


title: Disentangling heterogeneity of psychosis expression in the general population: sex-specific moderation effects of environmental risk factors on symptom networks

abstract:
BackgroundPsychosis expression in the general population may reflect a behavioral manifestation of the risk for psychotic disorder. It can be conceptualized as an interconnected system of psychotic and affective experiences; a so-called  symptom network. Differences in demographics, as well as exposure to adversities and risk factors, may produce substantial heterogeneity in symptom networks, highlighting potential etiological divergence in psychosis risk.

MethodsTo explore this idea in a data-driven way, we employed a novel recursive partitioning approach in the 2007 English National Survey of Psychiatric Morbidity survey (N = 7,242). We sought to identify  network phenotypes by explaining heterogeneity in symptom networks through potential moderators, including age, sex, ethnicity, deprivation, childhood abuse, separation from parents, bullying, domestic violence, cannabis use, and alcohol.

ResultsSex was the primary source of heterogeneity in symptom networks. Additional heterogeneity was explained by interpersonal trauma (childhood abuse, domestic violence) in women and domestic violence, cannabis use, ethnicity in men. Among women, especially those exposed to early interpersonal trauma, an affective loading within psychosis may have distinct relevance. Men, particularly those from minority ethnic groups, demonstrated a strong network connection between hallucinatory experiences and persecutory ideation.

ConclusionSymptom networks of psychosis expression in the general population are highly heterogeneous. The structure of symptom networks seems to reflect distinct sex-related adversities, etiologies, and mechanisms of symptom-expression. Disentangling the complex interplay of sex, minority ethnic group status, and other risk factors may help optimize early intervention and prevention strategies in psychosis.


title: Exploring real-world concordance of tissue mutation burden (TMB) from blood and tissue in patients with solid tumors

abstract:
PurposeTumor mutational burden (TMB) is an approved biomarker for immunotherapy in metastatic cancer patients. While initially measured from tissue (tTMB), TMB derived from circulating tumor DNA (ctDNA) - also known as blood TMB (bTMB) - is increasingly being used in the clinic. Currently, real-world concordance between tTMB and bTMB is not well understood.

Patients and methodsFrom October 2020 to March 2021, cancer patients who had both tTMB and bTMB results were selected. Patients were classified according to clinical variables and tumor burden, and correlation analyses or tests of independence were performed to explore any associations.

ResultsFrom a total of 38 patients included in our study, 20 patients (52.6%) had non-small cell lung carcinoma and 18 (47.4%) had other cancers. Median bTMB of 9.6 mut/MB was higher than median tTMB of 4.0 mut/Mb, and the distributions of bTMB and tTMB differed significantly (n=38, p < 0.001). bTMB was positively correlated with tTMB in the total study population (Spearman {rho}=0.57, p < 0.001) and a tTMB of 10 mut/Mb correlated with a bTMB of 21.1 mut/Mb. Dividing patients by cancer type or site of tumor biopsy resulted in significantly differing strength and degree of correlation, but dividing patients by concordant and discordant bTMB:tTMB ratio did not reveal any significantly different distributions of clinical variables or tumor burden.

ConclusionbTMB was positively correlated with tTMB, and median bTMB was higher than median tTMB. Cancer type and site of tissue biopsy may influence concordance between tTMB and bTMB. Future studies with more patients may help define the optimal bTMB threshold for receiving immunotherapy, which may be different from the tTMB threshold.


title: Clinical coding of long COVID in English primary care: a federated analysis of 58 million patient records in situ using OpenSAFELY

abstract:
BackgroundLong COVID is a term to describe new or persistent symptoms at least four weeks after onset of acute COVID-19. Clinical codes to describe this phenomenon were released in November 2020 in the UK, but it is not known how these codes have been used in practice.

MethodsWorking on behalf of NHS England, we used OpenSAFELY data encompassing 96% of the English population. We measured the proportion of people with a recorded code for long COVID, overall and by demographic factors, electronic health record software system, and week. We also measured variation in recording amongst practices.

ResultsLong COVID was recorded for 23,273 people. Coding was unevenly distributed amongst practices, with 26.7% of practices having not used the codes at all. Regional variation was high, ranging between 20.3 per 100,000 people for East of England (95% confidence interval 19.3-21.4) and 55.6 in London (95% CI 54.1-57.1). The rate was higher amongst women (52.1, 95% CI 51.3-52.9) compared to men (28.1, 95% CI 27.5-28.7), and higher amongst practices using EMIS software (53.7, 95% CI 52.9-54.4) compared to TPP software (20.9, 95% CI 20.3-21.4).

ConclusionsLong COVID coding in primary care is low compared with early reports of long COVID prevalence. This may reflect under-coding, sub-optimal communication of clinical terms, under-diagnosis, a true low prevalence of long COVID diagnosed by clinicians, or a combination of factors. We recommend increased awareness of diagnostic codes, to facilitate research and planning of services; and surveys of clinicians experiences, to complement ongoing patient surveys.


title: Dysbiosis in pre-cancerous mucosa may drive immune dysfunction: a study of immune system: microbiota interaction in familial adenomatous polyposis

abstract:
ObjectivesFamilial adenomatous polyposis (FAP) is a condition caused by a constitutional pathogenic variant of the adenomatous polyposis coli (APC) gene that results in intestinal adenoma formation and colorectal cancer (CRC), necessitating pre-emptive colectomy. We sought to examine interaction between the mucosal immune system and commensal bacteria in FAP to test for immune dysfunction that might accelerate tumorigenesis.

MethodsColonic biopsies were obtained from macroscopically normal mucosal tissue from 14 healthy donors and 13 patients with FAP during endoscopy or from surgical specimens. Intraepithelial and lamina propria lymphocytes were phenotyped. Intraepithelial microbes were labelled with anti-IgA/IgG and analyzed by flow cytometry.

ResultsProportions of resident memory CD103-expressing CD8+ and {gamma}{delta} T cell receptor+ intraepithelial lymphocytes were dramatically reduced in both left and right colon of patients with FAP compared to healthy controls. In lamina propria, T-cells expressed less CD103 and CD4+ CD103+ cells expressed less CD73 ectonucleotidase. IgA coating of epithelia-associated bacteria, IgA+ peripheral B cells and CD4 T-cell memory responses to commensal bacteria were increased in FAP.

ConclusionsLoss of resident memory T-cells and {gamma}{delta} T-cells in mucosal tissue of patients with FAP accompanies intestinal microbial dysbiosis previously reported in this pre-cancerous state and suggests impaired cellular immunity and tumor surveillance. This may lead to barrier dysfunction, possible loss of regulatory T-cell function and excess IgA antibody secretion. Our data are the first to implicate mucosal immune dysfunction as a contributing factor in this genetically driven disease and identify potentially critical pathways in the etiology of CRC.

category: gastroenterology


title: SARS-CoV-2 RNA and antibody detection in human milk from a prospective multicenter study in Spain

abstract:
BackgroundDuring the COVID-19 pandemic in 2020, breastfeeding in women positive for SARS-CoV-2 was compromised due to contradictory data regarding potential viral transmission. However, growing evidence confirms the relevant role of breast milk in providing passive immunity by generating and transmitting specific antibodies against the virus. Thus, our study aimed to develop and validate a specific protocol to detect SARS-CoV-2 in breast milk matrix as well as to determine the impact of maternal SARS-CoV-2 infection on presence, concentration, and persistence of specific SARS-CoV-2 antibodies.

Study design/MethodsA prospective multicenter longitudinal study in Spain was carried out from April to December 2020. A total of 60 mothers with SARS-CoV-2 infection and/or recovered from COVID-19 were included (n=52 PCR-diagnosed and n=8 seropositive). Data from maternal-infant clinical records and symptomatology were collected. A specific protocol was validated to detect SARS-CoV-2 RNA in breast milk, targeting the N1 region of the nucleocapsid gene and the envelope (E) gene. Presence and levels of SARS-CoV-2 specific immunoglobulins (Igs) -IgA, IgG, and IgM-in breast milk samples from COVID-19 patients and from 13 women before the pandemic were also evaluated.

ResultsAll breast milk samples showed negative results for SARS-CoV-2 RNA presence. We observed high intra- and inter-individual variability in the antibody response to the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein for each of the three isotypes IgA, IgM and IgG. Protease domain (MPro) antibodies were also detected in milk. In general, 82.9 % of the milk samples were positive for at least one of the three antibody isotypes, being 52.86 % of those positive for all three Igs. Positivity rate for IgA was relatively stable over time (65.2 - 87.5 %), whereas it raised continuously for IgG (47.8 % the first ten days to 87.5 % from day 41 up to day 206 post-PCR confirmation).

ConclusionsConsidering the lack of evidence for SARS-CoV-2 transmission through breast milk, our study confirms the safety of breastfeeding practices and highlights the relevance of virus-specific SARS-CoV-2 antibody transfer, that would provide passive immunity to breastfed infants and protect them against COVID-19 disease. This study provides crucial data to support official breastfeeding recommendations based on scientific evidence.


title: COVID-19 wastewater based epidemiology: long-term monitoring of 10 WWTP in France reveals the importance of the sampling context

abstract:
SARS-CoV-2 wastewater-based epidemiology (WBE) has been advancedas a relevant indicator of distribution of COVID-19 in communities, supporting classical testing and tracing epidemiological approaches. An extensive sampling campaign, including ten municipal wastewater treatment plants, has been conducted in different cities of France over a 20-weeks period, encompassing the second peak of COVID-19 outbreak in France. A well-recognised ultrafiltration - RNA extraction - RT-qPCR protocol was used and qualified, showing 5.5 +/-0.5% recovery yield on heat-inactivated SARS-CoV-2. Importantly the whole, solid and liquid, fraction of wastewater was used for virus concentration in this study.

Campaign results showed medium- to strong-correlation between SARS-CoV-2 WBE data and COVID-19 prevalence. To go further, WWTP inlet flow rate and raining statistical relationships were studied and taken into account for each WWTP in order to calculate contextualized SARS-CoV-2 loads. This metric presented improved correlation strengths with COVID-19 prevalence for WWTP particularly submitted and sensitive to rain. Such findings highlighted that SARS-CoV-2 WBE data ultimately require to be contextualised for relevant interpretation.

HighlightsO_LIFirst study monitoring inlet of 10 WWTPs located in France for SARS-CoV-2 RNA quantification over a 20-weeks period encompassing the second peak of COVID-19 outbreak
C_LIO_LIViral recovery yield was 5.5 % +/-0.5% using heat-inactivated SARS-CoV-2
C_LIO_LIMedium to high Spearmans correlation strength was observed between SARS-CoV-2 WBE and COVID-19 prevalence data
C_LIO_LIConsidering sampling context (ei. rain events) improved data consistency and correlation strength
C_LI

Graphical Abstract

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category: occupational and environmental health


title: Pharmacogenomic and drug interaction risk associations with hospital length of stay among Medicare Advantage members with COVID-19

abstract:
ImportanceCOVID-19 has severely impacted older populations and strained healthcare resources, with many patients requiring long periods of hospitalization. Reducing the hospital length of stay (LOS) reduces patient and hospital burden. Given that adverse drug reactions are known to prolong LOS, unmanaged pharmacogenomic risk and drug interactions among COVID-19 patients may be a risk factor for longer hospital stays.

ObjectiveThe objective of this study was to determine if pharmacogenomic and drug interaction risks were associated with longer lengths of stay among high-risk patients hospitalized with COVID-19.

DesignRetrospective cohort study of medical and pharmacy claims

SettingAdministrative database from a large U.S. health insurance company

ParticipantsMedicare Advantage members with a first COVID-19 hospitalization between January 2020 and June 2020, who did not die during the stay.

Exposures(1) Pharmacogenetic interaction probability (PIP) of [≤]25% (low), 26%-50% (moderate), or >50% (high), which indicate the likelihood that one or more clinically actionable gene-drug or gene-drug-drug interactions would be identified with testing; (2) drug-drug interaction (DDI) severity of minimal, minor, moderate, major, or contraindicated, which indicate the severity of an interaction between two or more active medications.

Main Outcomes and MeasuresThe primary outcome was hospital length of stay. Results were stratified by hierarchical condition categories (HCC) counts and chronic conditions.

ResultsA total of 6,025 patients hospitalized with COVID-19 were included in the study. Patients with moderate or high PIP were hospitalized for 9% (CI: 4%-15%; p < 0.001) and 16% longer (CI: 8%-24%; p < 0.001), respectively, compared to those with low PIP, whereas RAF score was not associated with LOS. High PIP was significantly associated with 12%-22% longer lengths of stay compared to low PIP in patients with hypertension, hyperlipidemia, diabetes, or COPD. Finally, among patients with 2 or 3 HCCs, a 10% longer length of stay was observed among patients with moderate or more severe DDI compared to minimal or minor DDI.

Conclusions and RelevanceProactively mitigating pharmacogenomic risk has the potential to reduce length of stay in patients hospitalized with COVID-19 especially those with COPD, diabetes, hyperlipidemia, and hypertension.

Key PointsO_ST_ABSQuestionC_ST_ABSWhat is the impact of unmanaged pharmacogenomic risk among patients hospitalized with COVID-19?

FindingsAmong 6,025 patients hospitalized with COVID-19, those with greater unmanaged pharmacogenomic risk for adverse drug reactions had longer hospital stays than those with lower risk, both within the entire cohort and within groups matched by number and type of chronic conditions.

MeaningPreemptive pharmacogenomic testing may shorten hospital stay by reducing adverse drug reactions among seriously ill patients and more broadly improve patient risk classification, care utilization predictions, and health system performance.

category: health systems and quality improvement


title: Artificial Intelligence Sepsis Prediction Algorithm Learns to Say "I don't know"

abstract: Sepsis is a leading cause of morbidity and mortality worldwide. Early identification of sepsis is important as it allows timely administration of potentially life-saving resuscitation and antimicrobial therapy. We present COMPOSER (COnformal Multidimensional Prediction Of SEpsis Risk), a deep learning model for the early prediction of sepsis, specifically designed to reduce false alarms by detecting unfamiliar patients/situations arising from erroneous data, missingness, distributional shift and data drifts. COMPOSER flags these unfamiliar cases as  indeterminate rather than making spurious predictions. Six patient cohorts (515,720 patients) curated from two healthcare systems in the United States across intensive care units (ICU) and emergency departments (ED) were used to train and externally and temporally validate this model. In a sequential prediction setting, COMPOSER achieved a consistently high area under the curve (AUC) (ICU: 0.925-0.953; ED: 0.938-0.945). Out of over 6 million prediction windows roughly 20% and 8% were identified as  indeterminate amongst non-septic and septic patients, respectively. COMPOSER provided early warning within a clinically actionable timeframe (ICU: 12.2 [3.2 22.8] and ED: 2.1 [0.8 4.5] hours prior to first antibiotics order) across all six cohorts, thus allowing for identification and prioritization of patients at high risk for sepsis.

category: intensive care and critical care medicine


title: Optimizing the spatio-temporal allocation of COVID-19 vaccines: Italy as a case study

abstract:
While SARS-CoV-2 vaccine distribution campaigns are underway across the world, communities face the challenge of a fair and effective distribution of limited supplies. We wonder whether suitable spatial allocation strategies might significantly improve a campaigns efficacy in averting damaging outcomes. To that end, we address the problem of optimal control of COVID-19 vaccinations in a country-wide geographic and epidemiological context characterized by strong spatial heterogeneities in transmission rate and disease history. We seek the vaccine allocation strategies in space and time that minimize the number of infections in a prescribed time horizon. We examine scenarios of unfolding disease transmission across the 107 provinces of Italy, from January to April 2021, generated by a spatially explicit compartmental COVID-19 model tailored to the Italian geographic and epidemiological context. We propose a novel optimal control framework to derive optimal vaccination strategies given the epidemiological projections and constraints on vaccine supply and distribution logistic. Optimal schemes significantly outperform the explored alternative allocation strategies based on incidence, population distribution, or prevalence of susceptibles in each province. Our results suggest that the complex interplay between the mobility network and the spatial heterogeneities imply highly non-trivial prioritization of local vaccination campaigns. The extent of the overall improvements in the objectives grants further inquiry aimed at refining other possibly relevant factors so far neglected. Our work thus provides a proof-of-concept of the potential of optimal control for complex and heterogeneous epidemiological contexts at country, and possibly global, scales.

Author summaryThe development of vaccines has sparked high hopes towards the control of SARS-CoV-2 transmission without resorting to extensive community-wide restrictions. A fundamental unanswered question concerns the best possible allocation of a limited vaccine stock in space and time given a specific goal. We address this through an optimal control framework based on a reliable spatially explicit COVID-19 epidemiological model, where vaccine distribution is optimized under supply and deployment capacity constraints. This tool provides strategies for optimal allocations in different scenarios, yielding important improvements over considered alternatives. By accounting for spatial heterogeneities and human mobility networks, the presented approach complements currently used allocation methods based on criteria such as age or risk.


title: Optimal control of the spatial allocation of COVID-19 vaccines: Italy as a case study


title: Exploring the extracellular transcriptome in seminal plasma for non-invasive prostate cancer diagnosis

abstract: A diagnostic non-invasive biomarker test for prostate cancer at an early stage, with high sensitivity and specificity, would improve diagnostic decision making. Extracellular RNAs present in seminal plasma might contain biomarker potential for the accurate detection of clinically significant prostate cancer. So far, the extracellular messenger RNA (mRNA) profile of seminal plasma has not been interrogated for its biomarker potential in the context of prostate cancer. Here, we investigate the mRNA transcriptome in seminal plasma samples obtained from prostate cancer patients (n=25), patients with benign prostate hyperplasia (n=26) and individuals without prostatic disease (n=6). Seminal plasma harbors a complex mRNA repertoire that reflects prostate as its tissue of origin. The endogenous RNA content is higher in the prostate cancer samples compared to the control samples. Prostate cancer antigen 3 (PCA3), a long non-coding RNA with prostate cancer-specific overexpression, and ATP-binding cassette transporter 1 (ABCA1), known to be involved in the prostate cancer pathogenesis, were more abundant in the prostate cancer group. In addition, twelve high confidence fusion transcripts could be detected in prostate cancer samples, including the bona-fide prostate cancer fusion transcript TMPRSS2-ERG. Our findings provide proof-of-principle that the extracellular transcriptome of seminal plasma can reveal information of an underlying prostate cancer.


title: Pooling of samples for SARS-CoV-2 detection using rapid antigen tests

abstract: While molecular assays, such as RT-PCR, have been widely used throughout the COVID-19 pandemic, the technique is costly and resource intensive. As a means to reduce costs and increase diagnostic efficiency, pooled testing for RT-PCR has been implemented. However, pooling samples for antigen testing has not been evaluated. We propose a pooling strategy for antigen testing that would significantly expand SARS-CoV-2 surveillance, especially for low-to-middle income countries, schools, and workplaces. Our data demonstrate that combining of up to 20 nasal swab specimens per pool can expand surveillance with antigen tests, even if a pool contains only one positive sample.


title: SARS-CoV-2 naïve and recovered individuals show qualitatively different antibody responses following mRNA vaccination

abstract: mRNA-based vaccines effectively induce protective neutralizing antibody responses against SARS-CoV-2, the etiological agent of COVID-19. The specific compositional patterns of these responses remain largely unknown. We found that SARS-CoV-2-naive individuals receiving the first dose of an mRNA vaccine developed a SARS-CoV-2-specific antibody response with a subclass profile comparable to that induced by the natural infection, except IgA2, which did not increase. SARS-CoV-2-naive subjects also mounted a robust virus-specific recall response after receiving the second dose. This response increased all IgG subclasses, but boosted neither IgM nor IgA1 and IgA2 subclasses. In contrast, individuals recovered from COVID-19 mounted peak virus-specific antibody responses upon primary immunization and did not further augment such responses following secondary immunization. Remarkably, compared to SARS-CoV-2-naive subjects, individuals with pre-existing immunity showed increased levels of all virus-specific antibodies but IgG3 following primary vaccination. By dissecting the heterogeneity of mRNA vaccine-induced humoral responses to SARS-CoV-2, our findings indicate that the induction of optimal immune protection may require the development of personalized vaccination programs.


title: Risk of COVID-19 epidemic resurgence with the introduction of vaccination passes

abstract:
BackgroundThe introduction of COVID-19 vaccination passes (VPs) by many countries coincided with the Delta variant fast becoming dominant across Europe. A thorough assessment of their impact on epidemic dynamics is still lacking.

MethodsHere, we propose the VAP-SIRS model that considers possibly lower restrictions for the VP holders than for the rest of the population, imperfect vaccination effectiveness against infection, rates of (re-)vaccination and waning immunity, fraction of never-vaccinated, and the increased transmissibility of the Delta variant.

ResultsSome predicted epidemic scenarios for realistic parameter values yield new COVID-19 infection waves within two years, and high daily case numbers in the endemic state, even without introducing VPs and granting more freedom to their holders. Still, suitable adaptive policies can avoid unfavorable outcomes.

ConclusionsWhile VP holders could initially be allowed more freedom, the lack of full vaccine effectiveness and increased transmissibility will require accelerated (re-)vaccination, wide-spread immunity surveillance, and/or minimal long-term common restrictions.

Plain language summaryAssessing the impact of vaccines, other public health measures, and declining immunity on SARS-CoV-2 control is challenging. This is particularly true in the context of vaccination passes, whereby vaccinated individuals have more freedom of making contacts than unvaccinated ones. Here, we use a mathematical model to simulate various scenarios and investigate the likelihood of containing COVID-19 outbreaks in example European countries. We demonstrate that both Alpha and Delta SARS-CoV-2 variants inevitably lead to recurring outbreaks when measures are lifted for vaccination pass holders. High revaccination rates and a lowered fraction of the unvaccinated population increase the benefit of vaccination passes. These observations are important for policy making, highlighting the need for continued vigilance, even where the epidemic is under control, especially when new variants of concern emerge.


title: Assessing the risk of COVID-19 epidemic resurgence in relation to the Delta variant and to vaccination passes


title: Risk assessment of COVID-19 epidemic resurgence in relation to SARS-CoV-2 variants and vaccination passes


title: Different approaches to quantify years of life lost from COVID-19

abstract: The burden of an epidemic is often characterized by death counts, but this can be misleading as it fails to acknowledge the age of the deceased patients. Years of life lost is therefore widely used as a more relevant metric, however, such calculations in the context of COVID-19 are all biased upwards: patients dying from COVID-19 are typically multimorbid, having far worse life expectation than the general population. These questions are quantitatively investigated using a unique Hungarian dataset that contains individual patient level data on comorbidities for all COVID-19 deaths in the country. To account for the comorbidities of the patients, a parametric survival model using 11 important long-term conditions was used to estimate a more realistic years of life lost. As of 12 May, 2021, Hungary reported a total of 27,837 deaths from COVID-19 in patients above 50 years of age. The usual calculation indicates 10.5 years of life lost for each death, which decreases to 9.2 years per death after adjusting for 11 comorbidities. The expected number of years lost implied by the life table, reflecting the mortality of a developed country just before the pandemic is 11.1 years. The years of life lost due to COVID-19x in Hungary is therefore 12% or 1.3 years per death lower when accounting for the comorbidities and is below its expected value, but how this should be interpreted is still a matter of debate. Further research is warranted on how to optimally integrate this information into epidemiologic risk assessments during a pandemic.


title: Metabolomic profiling in small vessel disease identifies multiple associations with disease severity

abstract:
Cerebral small vessel disease (SVD) is a major cause of vascular cognitive impairment and dementia. There are few treatments, largely reflecting limited understanding of the underlying pathophysiology. Metabolomics can be used to identify novel risk factors in order to better understand pathogenesis and to predict disease progression and severity.

We analysed data from 624 patients with symptomatic cerebral SVD from two prospective cohort studies. Serum samples were collected at baseline and patients underwent MRI scans and cognitive testing at regular intervals with up to 14 years of follow-up. Using ultra-performance liquid chromatography mass spectrometry and nuclear magnetic resonance spectroscopy, we obtained metabolic and lipidomic profiles from 369 annotated metabolites and 54,764 unannotated features and examined their association with respect to disease severity, assessed using MRI SVD markers, cognition, and future risk of all-cause dementia.

Over 100 annotated metabolites were significantly associated with SVD imaging markers, cognition, and progression to dementia. Decreased levels of multiple glycerophospholipids, sphingolipids, and sterol lipids were associated with increased SVD load as evidenced by higher white matter hyperintensities (WMH) volume, lower mean diffusivity normalised peak height (MDNPH), greater brain atrophy, and impaired cognition. Higher levels of several amino acids and nucleotides were associated with higher WMH volume, greater atrophy, and lower MDNPH. Lower baseline levels of carnitines and creatinine were associated with higher annualised change in peak width of skeletonised mean diffusivity (PSMD), and several metabolites, including lower levels of valine, caffeine, and VLDL analytes, were associated with future dementia incidence. Additionally, we identified 1,362 unannotated features associated with lower MDNPH and 2,474 unannotated features associated with increased WMH volume.

Our results show multiple distinct metabolic signatures that are associated with imaging markers of SVD, cognition, and conversion to dementia. Further research should assess causality and the use of metabolomic screening to improve the ability to predict future disease severity and dementia risk in SVD. The metabolomic profiles may also provide novel insights into disease pathogenesis and help identify novel treatment approaches.


title: COVID-19 outbreak rates and infection attack rates associated with the workplace: a descriptive epidemiological study

abstract:
BackgroundA large number of COVID-19 outbreaks/clusters have been reported in a variety of workplace settings since the start of the pandemic. However, information on the rate of outbreak occurrences which helps to identify the type of workplaces that are more likely to experience an outbreak, or infection attack rates which estimates the potential extent of the virus transmission in an outbreak, has not yet been available to inform intervention strategies to limit transmission.

ObjectivesTo link datasets on workplace settings and COVID-19 workplace outbreaks in England in order to: identify the geographical areas and workplace sectors with a high rate of outbreaks; and compare infection attack rates by workplace size and sector.

MethodsWe analysed Public Health England (PHE) HPZone data on COVID-19 outbreaks in workplaces, covering the time period of 18 May - 12 October 2020. The workplaces analysed excluded care homes, hospitals and educational settings. We calculated the workplace outbreak rates by nine English regions, 151 Upper Tier Local Authorities (UTLAs) and twelve industrial sectors, using National Population Database (NPD) data extracted in May 2019 on the total number of the relevant workplaces as the denominator. We also calculated the infection attack rates by enterprise size (small, medium, large) and industrial sector, using PHE Situations of Interest (SOI) data on the number of test-confirmed COVID-19 cases in a workplace outbreak as the numerator, and using NPD data on the number employed in that workplace as the denominator.

ResultsIn total, 1,317 confirmed workplace outbreaks were identified from HPZone data, of which 1,305 were available for estimation of outbreak rates. The average outbreak rate was 66 per 100,000 workplaces. Of the nine geographical regions in England, the North West had the highest workplace outbreak rate (155/100,000 workplaces), based on 351 outbreaks. Of the UTLAs, the highest workplace outbreak rate was Blackburn with Darwen (387/100,000 workplaces). The industrial sector with the highest workplace outbreak rate was manufacturers and packers of food (1,672/100,000), based on 117 outbreaks: this was consistent across seven of the regions. In addition, high outbreak rates in warehouses were observed in the East Midlands and the North West.

In total, 390 outbreaks were identified from SOI data and 264 of them allowed for estimation of attack rates. The overall median attack rate was 3.4% of the employed persons with confirmed COVID-19 at a workplace with an outbreak. Most of these outbreaks (162) had an attack rate less than 6%. However, in a small number of outbreaks (57) the attack rate was over 15%. The attack rates increased as the size of the enterprise decreased. The highest attack rate was for outbreaks in close contact services (median 16.5%), which was followed by outbreaks in restaurants and catering (median 10.2%), and in manufacturers and packers of non-food products (median 6.7%).

ConclusionsOur linked dataset analysis approach allows early identification of geographical regions and industrial sectors with higher rates of COVID-19 workplace outbreaks as well as estimation of attack rates by enterprise size and sector. This can be used to inform interventions to limit transmission of the virus. Our approach to analysing the workplace outbreak data can also be applied to calculation of outbreak rates and attack rates in other types of settings such as care homes, hospitals and educational settings.


title: Acute biliary pancreatitis management during the COVID-19 pandemic

abstract:
ObjectiveTo analyze acute biliary pancreatitis (ABP) management during the COVID-19 pandemic.

MethodsThis was a retrospective cohort study conducted with ABP patients during two discrete periods: a control period from March 16, 2019, through March 15, 2020 (period 1); and a COVID-19 era between March 16, 2020, and March 15, 2021 (period 2).

ResultsA total of 89 patients with ABP were identified, 58 in period 1 and 31 in period 2, which equates to a 46.6% reduction. The mean age of the patients was 62.75{+/-}16.59 years, and 51 (57.3%) of the patients were female. qSOFA and WSES scores are significantly higher in the patients in period 2 (p=0.031, p=0.032). There were no significant differences regarding hematological parameters except lactate. Lactate levels were significantly higher in period 2 (p=0.012). Twenty-two patients (37.9%) in period 1 and six (19.3%) patients in period 2 underwent cholecystectomy (p=0.072). Cholecystectomy was performed laparoscopically in 18 (81.8%) patients in period 1 and in five (83.3%) patients in period 2 (p=0.932). There were no significant differences regarding surgical intervention between the two periods. Three patients were diagnosed COVID-19 in period 2. All of these patients died. The severity of ABP was significantly worse in SARS-CoV-2-positive patients, with over 100% of patients in this group developing severe pancreatitis. Six patients (10.3%) in period 1, 10 (32.2%) patients in period 2 were admitted in ICU (p=0.010). The median length of stay was 5 (1-40) days in period 1 and 4 (2-75) days in period 2 (p= 0.641). The hospital mortality rate was 3.4% and 19.3% in period l and period 2, respectively. Mortality was significantly higher in period 2 (p=0.012).

ConclusionDuring the COVID-19 outbreak, a significant decrease in the number of patients with ABP and increased severity was observed. Additionally, it can be said that SARS-CoV-2 infection has a mortal course in patients with ABP. Analysis and evaluation of ABP patients during the pandemic period is important to draw conclusions that will help confront future health crises.


title: HISTOPATHOLOGICAL AND IMMUNOHISTOCHEMICAL PROGNOSTIC FACTORS IN HIGH-GRADE NON-ENDOMETRIOID CARCINOMAS OF THE ENDOMETRIUM (HG-NECs). IS IT POSSIBLE TO IDENTIFY SUB-GROUPS AT INCREASED RISK?

abstract:
Endometrial cancer is an emerging disease with an increase in prevalence of aggressive histotypes in recent years. In the present study potential histopathological and immunohistochemical prognostic markers are investigated

Consecutive cases of high grade non-endometrioid carcinoma (HG-NEC) of the endometrium were considered. Each surgical specimen has been routinely processed, the most representative block has been selected for immunohistochemistry and tested for ER, PR, ki67, p53, E-cadherin, {beta}-catenin, Bcl-2 and cyclin D1. For each immunomarker the percentage of positive tumor cells were evaluated (%) and dichotomized as low and high according to the distribution in the study population. Follow-up was collected for disease-free survival (DFS) and overall survival (OS).

33 cases were eligible: 19 resulted FIGO I-II, 14 resulted FIGO III-IV. 12 patients suffered a recurrent disease (mean follow-up 24.6 months); 8 patients died of the disease (mean follow-up 26.6 months).

Women with recurrent disease demonstrated a significant higher bcl2% (35.84{+/-}30.96% vs 8.09{+/-}11.56% p=0.0032) while DOD patients had higher ki67% (75{+/-}13.09% vs 58.6{+/-}19.97% p=0.033) and bcl2% of border significance (34.37{+/-}34.99% vs 13{+/-}17.97% p=0.078).

As expected FIGO III-IV had a worse DFS (HR=3.34; 95%CI:1.1-10.99; p=0.034) and OS (HR=5.19; 95%CI: 1.27-21.14 p= 0.0217). Bcl2-high patients (bcl2>10%) demonstrated a significant worse DFS (HR=9.11; 95%CI: 2.6-32.4; p=0.0006) and OS (HR=7.63; 95%CI:1.7-34; p=0.0084); also PR low patients (PR[≤]10%) had a significant worse DFS (HR=3.74; 95%CI:1.2-11.9; p=0,02).

HG-NEC represent an heterogeneous group of endometrial aggressive neoplasms with a worrisome prognosis often at an advanced stage at presentation. Bcl2 and PR may represent promising markers to identify a sub-group of patients having an even worse prognosis requiring a careful and close follow-up.

category: pathology


title: Cost savings from managing hypertension in primary health care clinics in Kuwait

abstract:
BackgroundGeneric medications are one of the most common solutions for bringing down pharmaceutical costs for both patients and health care providers. Efforts to increase uptake of generics include policies to support generic substitution and prescription. The aim of this study is to estimate the total cost of drugs prescribed by physicians in selected primary health care centers for managing hypertension and the potential cost savings from substituting generic drugs for branded ones

Methods and FindingsOne thousand patients with hypertension were randomly selected from the Primary Care Information System database from among patients who sought treatment at three primary health care centers from Al-Jahra governorate in Kuwait from January to December 2018. Generic antihypertensive drugs were substituted for branded ones, and cost savings were calculated by referring to the International Drug Price Indicator Guide. The mean age of 1,000 patients was 57.01 (SD = 11.82) years. Most (57.4%) of the patients were females, and 50.2% were Kuwaitis. The mean number of drugs per prescription was 1.78 (SD = 1.25; range: 1 to 9 drugs). The total number of drugs prescribed was 1,781, with a total cost of KD 10,093 and with a mean of KD 10.09 (SD = 7.34). Only 71 generic drugs had been prescribed, making the generic prescription rate 4.0%. The total number of antihypertensive drugs prescribed was 1,206 (mean: 1.21; SD = 0.46), with a cost of KD 7,678.5 (mean = KD 7.68; SD = 4.06) and with ACE inhibitors as the most prescribed class at 32.19%. Eight hundred ninety antihypertensive drugs were substituted for 774 patients at estimated cost savings of KD 5,675; that is, substituting generic drugs reduced antihypertensive drug cost by 74%.

ConclusionGeneric drug prescription appears to be low among primary care physicians in health care centers in Kuwait, but these centers could see substantial cost savings from substituting generic antihypertensive drugs for branded ones. Active interventions are needed to encourage generic prescription among health practitioners to reduce the overall pharmaceutical expenditures.

category: public and global health


title: 7-Tesla Functional Cardiovascular MR Using Vectorcardiographic Triggering overcoming the magnetohydrodynamic effect

abstract:
ObjectiveUltra-high-field (B0 [≥] 7 Tesla) cardiovascular magnetic resonance (CMR) offers increased resolution. However, ECG gating is impacted by the magneto-hydrodynamic (MHD) effect distorting the ECG trace. We explored the technical feasibility of a 7T MR scanner using ECG trigger learning algorithm to quantitatively assess cardiac volumes and vascular flow.

Methods7T scans performed on 10 healthy volunteers on a whole-body research MRI (Siemens Healthcare, Erlangen, Germany) with 8 channel Tx/32 channel Rx cardiac coil (MRI Tools GmbH, Berlin, Germany). Vectorcardiogram ECG was performed using a learning phase outside of the magnetic field, with a trigger algorithm overcoming severe ECG signal distortions.

Vectorcardiograms were quantitatively analyzed for false negative and false positive events. Cine CMR was performed after 3rd-order B0 shimming using a high-resolution breath-held ECG-retro-gated segmented spoiled gradient echo, and 2D phase contrast flow imaging. Artefacts were assessed using a semi-quantitative scale.

Results7T CMR scans were acquired in all patients (100%) using the VCG learning method. 3,142 R-waves were quantitatively analyzed, yielding sensitivity 97.6%, specificity 98.7%. Mean image quality score was 0.9, sufficient to quantitate both cardiac volumes, ejection fraction (EF), aortic and pulmonary blood flow. Mean LVEF was 56.4%, RVEF 51.4%.

ConclusionReliable cardiac ECG triggering is feasible in healthy volunteers at 7T utilizing a state-of-the-art 3-lead trigger device despite signal distortion from the MHD effect. This provides sufficient image quality for quantitative analysis. Other ultra-high-field imaging applications such as human brain functional MRI with physiologic noise correction may benefit from this method of ECG triggering.

Key pointsO_LIUltra-high field 7 Tesla cardiac MRI is challenging due to the impact of the magneto-hydrodynamic (MHD) effect causing severe distortions in the ECG trace.
C_LIO_LIUsing VCG with a learning phase outside the ultra-high field magnet, the R waves can be adequately detected to perform high quality Cardiac MRI scans, overcoming signal distortion from the MHD effect.
C_LI

category: radiology and imaging


title: Cellular immunity predominates over humoral immunity after the first dose of COVID-19 vaccines in solid organ transplant recipients

abstract: Knowledge on the vaccine-induced cellular and humoral immunity and on immunogenicity of vector-based and mRNA vaccines in solid organ transplant recipients is limited. Therefore, SARS-CoV-2 specific T-cells and antibodies were analyzed in 40 transplant recipients and 70 age-matched controls after the first dose of vector-based or mRNA vaccines. Plasmablasts and SARS-CoV-2 specific CD4 and CD8 T-cells were quantified using flow-cytometry. Specific antibodies were analyzed by ELISA and neutralization assay. SARS-CoV-2 specific antibodies and T-cells were induced in both groups with significantly lower levels in patients. While antibodies were detected in 80% of controls and 5.3% of patients, specific CD4 and/or CD8 T-cells were more frequently found in both controls (84.3%) and patients (23.7%). The two vaccine types showed notable differences, as IgG and neutralizing activity were more pronounced after mRNA vaccination (p<0.0001 each), whereas CD4 and CD8 T-cell levels were higher after vector vaccination (p=0.009; p<0.0001). Plasmablast numbers were significantly higher in controls and correlated with SARS-CoV-2 specific IgG- and CD4 T-cell levels. In conclusion, assessment of antibodies is not sufficient to identify COVID-19-vaccine responders. Together with differences in immunogenicity among vaccines, this necessitates combined analysis of humoral and cellular immunity to reliably assess responders among immunocompetent and immunocompromised individuals.

category: transplantation


title: EVALUATION OF STATISTICAL ILLITERACY IN LATIN AMERICAN CLINICIANS AND OF THE EFFICACY OF A 10-HOUR COURSE

abstract:
IntroductionAll medics require statistical interpretation skills to keep up to date with the scientific advances and evidence-based recommendations of their specific field. However, statistical illiteracy among clinicians is a highly prevalent problem with far-reaching consequences. The few available studies that report statistical literacy improvements after educational interventions do not report for how long these benefits last. We measured for the first-time statistical proficiency among Latin-American clinicians with different levels of training and evaluated the efficacy of a 10-hour course at multiple timepoints.

MethodsUsing an online questionnaire, we evaluated self-perceived statistical proficiency, scientific literature reading habits and statistical literacy (using an adaptation of the Quick Risk Test) across multiple levels of medical training. Separately, we evaluated statistical proficiency among Internal Medicine residents at a tertiary centre in Mexico City immediately before, immediately after and one and two months after a 10-hour statistics course using the same adaptation (allowing for "I dont know" answers) of the Quick Risk Test. Scores across multiple time points were compared using Friedmans Test.

ResultsData from 392 clinicians from 9 Latin American countries were analyzed. Most clinicians (85%) failed our adaptation of the Quick Risk Test (mean score = 2.6/10, IQR:1.4). The 10-hour course significantly improved the scores of the Internal Medicine Residents (n=16) from 3.8/10, IQR:1.8 to 8.3/10, IQR:1.4 (p<0.01). However, scores dropped after one and two months to 7.7/10, IQR:1.6 and 6.1 / 10, IQR:2.2, respectively.

ConclusionsStatistical Illiteracy is highly prevalent among Latin American clinicians. Short-term educational interventions are effective but, their benefits quickly fade away if they are not periodically reinforced. Medical boards and Medical schools need to periodically teach and evaluate statistical proficiency to ameliorate these issues.

category: medical education


title: Thalamic white matter macrostructure and subnuclei volumes in Parkinson's disease depression

abstract:
ObjectiveDepression is a common non-motor feature of Parkinsons disease (PD) which confers significant morbidity and is often challenging to treat. The thalamus is a key component in the basal ganglia - thalamocortical network critical to pathogenesis of PD and depression but the precise thalamic subnuclei involved in PD depression have not yet been identified and may even represent potential therapeutic targets.

MethodsWe performed structural and diffusion weighted imaging on 76 participants with PD to evaluate the relationship between PD depression and grey and white matter thalamic subnuclear changes. We used a thalamic segmentation method to divide the thalamus into its 50 constituent subnuclei (25 each hemisphere). We used fixel based analysis of diffusion weighted imaging data to calculate mean fibre cross section (FC) for white matter tracts connected to each subnucleus and assessed volume and FC at baseline and 14-20 months follow-up. A generalised linear mixed model was used to evaluate the relationship between depression, subnuclei volume and mean FC for each of the 50 thalamic subnuclei, adjusting for age, gender, intracranial volume and time.

ResultsWe found that depression scores in PD were associated with lower right pulvinar anterior (PuA) subnucleus volume. Antidepressant use was associated with higher right PuA volume suggesting a possible protective effect of treatment. After follow-up, depression scores were associated with decreases in white matter tract macrostructure across almost all tracts connected to thalamic subnuclei.

ConclusionWe demonstrate that depression is associated with right thalamic PuA subnucleus volume loss and widespread thalamic white matter macrostructural changes, but that antidepressants may protect against volume loss in PD depression. Our work provides mechanistic insights for depression in PD, suggests possible benefits of actively treating depression, and a potential target for therapeutic intervention to the PuA subnucleus for PD depression.


title: Evaluation of the ratio of the transverse diameter of cerebellum to the transverse diameter of frontal lobe by trans-cerebellar section

abstract:
ObjectiveOn the basis of a prospective study of evaluating the development of frontal lobe in mid-to-late trimester by trans-cerebellar section, it had been found that the transverse frontal diameter had a higher correlation with gestational age than the anteroposterior frontal diameter. In order to provide more valuable information for the prenatal diagnosis of suspected fetal microcephaly, the reference value range of the ratio of the transverse diameter of cerebellum to the transverse diameter of frontal lobe by trans-cerebellar section was further prospectively established.

MethodsA prospective cross-sectional study was conducted on 870 normal fetuses at 21 to 36 weeks of gestation from January 2019 to June 2020. The transverse diameter of cerebellum and the transverse diameter of frontal lobe were measured by trans-cerebellar section, and the ratio of the transverse diameter of cerebellum to the transverse diameter of frontal lobe was calculated, and the correlation was analyzed statistically.

ResultsThe ratio of the transverse diameter of cerebellum to the transverse diameter of frontal lobe increased positively with gestational age which correlation coefficient was 0.413 (P < 0.001). Taking gestational age as the independent variable and the ratio of the transverse diameter of cerebellum to the transverse diameter of frontal lobe as the dependent variable, it showed that there was a linear relationship between the gestational age and the ratio of the transverse diameter of cerebellum to the transverse diameter of frontal lobe. We got a correlation formula that the ratio of the transverse diameter of cerebellum to the transverse diameter of frontal lobe =0.004x (gestational age-21)+0.530.

ConclusionThis study has preliminarily established the normal reference range of the ratio of the transverse diameter of cerebellum to the transverse diameter of frontal lobe by trans-cerebellar section in normal mid-to-late pregnancy fetuses, which can provide valuable information for the prenatal diagnosis of suspected fetal microcephaly.

category: obstetrics and gynecology


title: Aging metrics incorporating cognitive and physical function capture mortality risk: results from three prospective cohort studies

abstract:
BackgroundThe aims of this study were to: 1) describe the proportions of vulnerable persons identified by three existing aging metrics that incorporate cognitive and physical function; 2) examine the associations of the three metrics with mortality; and 3) develop and validate a new simple functional score for mortality prediction.

MethodsThe three aging metrics were the combined presence of cognitive impairment and physical frailty (CI-PF), the frailty index (FI), and the motoric cognitive risk syndrome (MCR). We operationalized them with data from two large cohort studies: the China Health and Retirement Longitudinal Study (CHARLS) and the US National Health and Nutrition Examination Survey (NHANES). Logistic regression models or Cox proportional hazard regression models, and receiver operating characteristic curves were used to examine the associations of the three metrics with mortality. A new functional score was developed and validated in the Rugao Ageing Study (RAS), an independent dataset.

ResultsIn CHARLS, the proportions of vulnerable persons identified by CI-PF, FI, and MCR were 2.2%, 16.6%, and 19.6%, respectively. Each metric predicted mortality after adjustment for age and sex, with some variations in the strength of the associations (CI-PF, odds ratio (OR)=2.87, 95% confidence interval (CI)=1.74, 4.74; FI, OR=1.94, 95% CI=1.50, 2.50; MCR, OR=1.27, 95% CI=1.00, 1.62). CI-PF and FI had additional predictive utility beyond age and sex, as demonstrated by integrated discrimination improvement, and continuous net reclassification improvement (all P <0.001). These results were replicated in NHANES. Furthermore, we developed a new functional score by selecting six self-reported items from CI-PF and FI in CHARLS, and demonstrated that it predicted mortality risk. This functional score was further validated in RAS. To facilitate the quick screening of persons with deteriorations in cognitive and physical function, we introduced a publicly available online tool designed for this new functional score.

ConclusionsDespite the inherent differences in the aging metrics incorporating cognitive and physical function, they consistently capture mortality risk. The findings support the incorporation of cognitive and physical function for risk stratification in both Chinese and US persons, but call for caution when applying them in specific study settings.

category: geriatric medicine


title: Histopathological Image Analysis for Oral Squamous Cell Carcinoma classification using concatenated deep learning models

abstract: Oral squamous cell carcinoma (OSCC) is a subset of head and neck squamous cell carcinoma (HNSCC), the 7th most common cancer worldwide, and accounts for more than 90% of oral malignancies. Early detection of OSCC is essential for effective treatment and reducing the mortality rate. However, the gold standard method of microscopy-based histopathological investigation is often challenging, time-consuming and relies on human expertise. Automated analysis of oral biopsy images can aid the histopathologists in performing a rapid and arguably more accurate diagnosis of OSCC. In this study, we present deep learning (DL) based automated classification of 290 normal and 934 cancerous oral histopathological images published by Tabassum et al (Data in Brief, 2020). We utilized transfer learning approach by adapting three pre-trained DL models to OSCC detection. VGG16, InceptionV3, and Resnet50 were fine-tuned individually and then used in concatenation as feature extractors. The concatenated model outperformed the individual models and achieved 96.66% accuracy (95.16% precision, 98.33% recall, and 95.00% specificity) compared to 89.16% (VGG16), 94.16% (InceptionV3) and 90.83% (ResNet50). These results demonstrate that the concatenated model can effectively replace the use of a single DL architecture.


title: Monitors to Improve Indoor Carbon Dioxide Concentrations in the Hospital: Background, Rationale and Protocol for a Randomized, Sham-controlled, Cross-Over, Open Label Trial

abstract: Coronavirus disease 2019 (COVID-19) has caused considerably morbidity and mortality worldwide, mainly among older adults. Hospital outbreaks contribute to the burden of this disease, despite optimal hand hygiene and personal protective equipment such as masks and face shields. Ventilation with fresh outdoor air has emerged as an important strategy to reduce indoor aerosol transmission of COVID-19. Carbon dioxide (CO2) monitors are increasingly advocated to facilitate ventilation in schools, long-term care facilities, offices and public buildings. Moreover, several health authorities have issued guidelines for target CO2 values in work as well as clinical environments. Given that modern hospitals have superior indoor air quality control systems, it remains however unknown whether feedback from CO2 monitors is needed and/or effective to improve ventilation further. Here, we describe the rationale and protocol for a randomized, sham-controlled, crossover, open label trial of CO2 monitors in double-bed hospital rooms in two acute geriatric wards. Based on pilot data, Aranet4 Home(R) monitors will be used to alert nurses and other staff to raised indoor CO2 concentrations. Practical limitations in implementing CO2 monitors are discussed, and will be surveyed among staff as additional study outcomes. The Monitors to Improve Indoor Carbon Dioxide (CO2) Concentrations in the Hospital (MICH) trial is registered at ClinicalTrials.gov, identifier: NCT04770597.


title: COVID-19 case definitions, diagnostic testing criteria, and surveillance across the pandemic's 25 highest burden countries

abstract:
ObjectiveWe compared suspect, probable, and confirmed case definitions, as well as diagnostic testing criteria, used in the COVID-19 pandemics 25 highest burden countries to aid interpretation of global and national surveillance data.

MethodsWe identified the COVID-19 pandemics 25 countries with the highest disease burden based on the number of cumulative reported cases to the World Health Organization (WHO) as of 1 October 2020. We searched official websites of these countries for suspect, probable, and confirmed case definitions. Given that confirmation of COVID-19 usually requires diagnostic testing, we also searched for diagnostic testing eligibility criteria in these countries. Extracted case definitions and testing criteria were managed in a database and analyzed in Microsoft Excel.

FindingsWe identified suspect, probable, and confirmed case definitions in 96%, 64%, and 100% of countries, respectively. Testing criteria were identified in 100% of countries. 56% of identified countries followed WHO recommendations for using a combination of clinical and epidemiological criteria as part of the suspect case definition. 75% of identified countries followed WHO recommendations on using clinical, epidemiological, and diagnostic criteria for probable cases. 72% of countries followed WHO recommendations on using PCR testing for confirming a case of COVID-19. Finally, 64% of countries used testing eligibility criteria at least as permissive as WHO.

ConclusionThere is marked heterogeneity in who is eligible for testing in countries and how countries define a case of COVID-19. This affects the ability to compare burden, transmission, and response impact estimates derived from case surveillance data across countries.


title: Impact of BNT162b first vaccination on the immune transcriptome of elderly patients infected with the B.1.351 SARS-CoV-2 variant

abstract: Fast-spreading variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) energize the COVID-19 pandemic. The B.1.351 variant carrying the escape mutation E484K in the receptor binding domain is of particular concern due to reduced immunological protection following vaccination. Protection can manifest as early as 10 days following immunization with full protection two weeks following the second dose, but the course is not well-characterized for variants. Here, we investigated the immune transcriptome of six elderly individuals (average age 82 yr.) from an old peoples home, who contracted B.1.351, with four having received the first dose of BNT162b eight to 11 days prior to the onset of COVID-19 symptoms. The patients were hospitalized and received dexamethasone treatment. Immune transcriptomes were established from PBMCs approximately 10 and 35 days after the onset of COVID-19 symptomology. RNA-seq revealed a more intensive immune response in vaccinated patients as compared to unvaccinated ones. Specifically, transcription factors linked to the JAK/STAT pathway, interferon stimulated genes, and genes associated with innate antiviral immunity and COVID-19-SARS-CoV-2 infection were highly enriched in vaccinated patients. This rendered the transcriptomes of the older vaccinated group significantly different than older unvaccinated individuals infected at the same institution and more similar to the immune response of younger unvaccinated individuals (age range 48-62) following B.1.351 infection. All individuals in this study whether vaccinated or not were hospitalized due to B.1.351 infection and one vaccinated patient died illustrating that although an enhanced immune response was documented infection it was insufficient to protect from disease. This highlights the need for maintaining physical distancing and prevention measures throughout the time course of vaccination in older adults.


title: Post-acute COVID-19 syndrome and its prolonged effects: An updated systematic review

abstract:
ObjectiveThis systematic review aimed at estimating the demographics, clinical characteristics, and prevalence of post-acute COVID-19 symptoms in view of published literature that studied prolonged clinical manifestations after recovery from acute COVID-19 infection.

MethodsAfter protocol setting, relevant articles were searched on various databases including PubMed, Medline, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), Embase, and Web of Sciences using MeSH keywords. The data regarding demographic, clinical characteristics, and prevalence of each persisting symptom were carefully studied and tabulated. Data analysis was carried out using Statistical Package for Social Sciences (SPSS) version 26.

ResultsOut of the 153 articles reviewed, 21 articles qualified for the final analysis. The most common persistent clinical manifestations were fatigue (54.11%), dyspnea (24.38%), alopecia (23.21%), hyperhidrosis (23.6%), insomnia (25.98%), anxiety (17.29%), and arthralgia (16.35%). In addition to these symptoms, new onset hypertension, diabetes, neuropsychiatric disorders, and bladder incontinence were also reported.

ConclusionClinical features of post-acute COVID-19 infection can manifest even after 60 days of initial infection. Constitutional symptoms include fatigue, dyspnea, anosmia, and insomnia were the most commonly reported in literature. Multidisciplinary care along with regular follow-up must be a provided to such patients. Curation and modification of guidelines is required for the assessment of discharged hospitalized patients for better management of their post-acute COVID-19 syndrome.


title: Immune Responses to COVID-19 mRNA Vaccines in Patients with Solid Tumors on Active, Immunosuppressive Cancer Therapy

abstract: Vaccines against SARS-CoV-2 have shown high efficacy, but immunocompromised participants were excluded from controlled clinical trials. We compared immune responses to the Pfizer/BioNTech mRNA vaccine in solid tumor patients (n=53) on active cytotoxic anti-cancer therapy to a control cohort (n=50) as an observational study. Using live SARS-CoV-2 assays, neutralizing antibodies were detected in 67% and 80% of cancer patients after the first and second immunizations, respectively, with a 3-fold increase in median titers after the booster. Similar trends were observed in serum antibodies against the receptor-binding domain (RBD) and S2 regions of Spike protein, and in IFN{gamma}+ Spike-specific T cells. Yet the magnitude of each of these responses was diminished relative to the control cohort. We therefore quantified RBD- and Spike S1-specific memory B cell subsets as predictors of anamnestic responses to additional immunizations. After the second vaccination, Spike-specific plasma cell-biased memory B cells were observed in most cancer patients at levels similar to those of the control cohort after the first immunization. We initiated an interventional phase 1 trial of a third booster shot (NCT04936997); primary outcomes were immune responses with a secondary outcome of safety. After a third immunization, the 20 participants demonstrated an increase in antibody responses, with a median 3-fold increase in virus-neutralizing titers. Yet no improvement was observed in T cell responses at 1 week after the booster immunization. There were mild adverse events, primarily injection site myalgia, with no serious adverse events after a month of follow-up. These results suggest that a third vaccination improves humoral immunity against COVID-19 in cancer patients on active chemotherapy with no severe adverse events.