title: Association between COVID-19 Risk-Mitigation Behaviors and Specific Mental Disorders in Youth

abstract:
ImportanceAlthough studies of adults show that pre-existing mental disorders increase risk for COVID-19 infection and severity, there is limited information about this association among youth. Mental disorders in general as well as specific types of disorders may influence their ability to comply with risk-mitigation strategies to reduce COVID-19 infection and transmission.

ObjectiveTo examine associations between specific mental disorders and COVID-19 risk-mitigation practices among 314 female and 514 male youth.

DesignYouth compliance (rated as "Never," "Sometimes," "Often," or "Very often/Always") with risk mitigation was reported by parents on the CoRonavIruS Health Impact Survey (CRISIS) in January 2021. Responses were summarized using factor analysis of risk mitigation, and their associations with lifetime mental disorders (assessed via structured diagnostic interviews) were identified with linear regression analyses (adjusted for covariates). All analyses used R Project for Statistical Computing for Mac (v.4.0.5).

SettingThe Healthy Brain Network (HBN) in New York City Participants. 314 female and 514 male youth (ages 5-21)

Main Outcome(s) and Measure(s)COVID-19 risk mitigation behaviors among youth

ResultsA two-factor model was the best-fitting solution. Factor 1 (avoidance behaviors) included avoiding groups, indoor settings, and other peoples homes; avoidance was more likely among youth with any anxiety disorder (p=.01). Factor 2 (hygiene behaviors) included using hand sanitizer, washing hands, and maintaining social distance; practicing hygiene was less likely among youth with ADHD (combined type) (p=.02). Mask wearing, which did not load on either factor, was not associated with any mental health disorder.

Conclusion and RelevanceFindings suggest that education and monitoring of risk-mitigation strategies in certain subgroups of youth may reduce risk of exposure to COVID-19 and other contagious diseases. Additionally, they highlight the need for greater attention to vaccine prioritization for individuals with ADHD.

Key PointsO_ST_ABSQuestionC_ST_ABSAre mental disorders among youth associated with COVID-19 risk-mitigation behaviors?

FindingsBased on the parent CoRonavIruS Health Impact Survey (CRISIS) of 314 females and 514 males aged 5-21, youth with anxiety disorders were more likely to avoid high-risk exposure settings, and those with ADHD (combined type) were less likely to follow hygiene practices. In contrast, mask wearing was not associated with youth mental disorders.

MeaningSpecific types of disorders in youth may interfere with their ability to employ risk-mitigation strategies that may lead to greater susceptibility to COVID-19.


title: Digitizing Non-Invasive Neuromodulation Trials: Scoping Review, Process Mapping, and Recommendations from a Delphi Panel

abstract:
Although relatively costly and non-scalable, non-invasive neuromodulation interventions are treatment alternatives for neuropsychiatric disorders. The recent developments of highly-deployable transcranial electric stimulation (tES) systems, combined with mobile-Health technologies, could be incorporated in digital trials to overcome methodological barriers and increase equity of access. We convened 61 highly-productive specialists and contacted 8 tES companies to assess 71 issues related to tES digitalization readiness, and processes, barriers, advantages, and opportunities for implementing tES digital trials. Delphi-based recommendations (>60% agreement) were provided. Device appraisal showed moderate digitalization readiness, with high safety and possibility of trial implementation, but low connectivity. Panelists recognized the potential of tES for scalability, generalizability, and leverage of digital trials processes; although they reached no consensus about aspects regarding methodological biases. We further propose and discuss a conceptual framework for exploiting shared aspects between mobile-Health tES technologies with digital trials methodology to drive future efforts for digitizing tES trials.

Graphical Abstract. Consensus Roadmap

O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=124 SRC="FIGDIR/small/22271837v1_ufig1.gif" ALT="Figure 1">
View larger version (56K):
org.highwire.dtl.DTLVardef@6dcf65org.highwire.dtl.DTLVardef@14af228org.highwire.dtl.DTLVardef@16043a2org.highwire.dtl.DTLVardef@f85f22_HPS_FORMAT_FIGEXP  M_FIG C_FIG (A) Recruitment process. The study procedure started with defining the components of the research problem by the core research team. After defining the problems, two different sets of participants (the steering committee (SC) including key leaders of the field identified by the core team and the expert panel (EP) as a more diverse group of experts identified based on the number of publications based on a systematic review) were identified and were invited to participate in a Delphi study. The study facilitators (first and last authors) led the communications with the SC to design the initial questionnaire through an iterative approach. (B) Evidence synthesis: To collect the available evidence, companies producing portable tES (ptES) devices were contacted, based on the companies suggested by the SC and EP to provide details about the available devices. For mapping methodological processes of digitizing tES trials, two distinct strategies were performed and embedded into the questionnaire, namely SIPOC (Suppliers, Inputs, Process, Outputs and Customer) and SWOT (Strengths, Weaknesses, Opportunities, and Threats) assessment were performed and embedded into the questionnaire. (C) Consensus development: In the next phase, the questionnaire was validated and finalized via collecting and summarizing opinions. Afterwards, the SC and EP responded to the final questionnaire and results were analyzed providing a list of recommendations for running tES digital trials based on a pre-registered consensus threshold.

category: health informatics


title: Precision recruitment for high-risk participants in a COVID-19 research study

abstract: Studies for developing diagnostics and treatments for infectious diseases usually require observing the onset of infection during the study period. However, when the infection base rate incidence is low, the cohort size required to measure an effect becomes large, and recruitment becomes costly and prolonged. We describe an approach for reducing recruiting time and resources in a COVID-19 study by targeting recruitment to high-risk individuals. Our approach is based on direct and longitudinal connection with research participants and computes individual risk scores from individually permissioned data about socioeconomic and behavioural data, in combination with predicted local prevalence data. When we used these scores to recruit a balanced cohort of participants for a COVID-19 detection study, we obtained a 4-7-fold greater COVID-19 infection incidence compared with similar real-world study cohorts.

category: infectious diseases


title: Features of an aseasonal 2021 RSV epidemic in the UK and Ireland: analysis of the first 10,000 patients

abstract: BronchStart is a prospective cohort study of infants with clinical bronchiolitis attending Emergency Departments in the United Kingdom and Ireland. We found the 2021 summer lower respiratory tract infection peak, although temporally disrupted and with an attenuated disease burden, predominantly affected younger age groups as in previous years.

category: pediatrics


title: Reasons underlying the intention to vaccinate children aged 5-11 against COVID-19: A cross-sectional study of parents in Israel, November 2021

abstract:
BackgroundVaccination is a key tool to mitigate impacts of the COVID-19 pandemic. In Israel, COVID-19 vaccines became available to adults in December 2020 and to 5-11-year-old children in November 2021. Ahead of the vaccine roll-out in children, we aimed to determine whether parents intended to vaccinate their children and describe reasons for their intentions.

MethodsWe recruited parents on social media and collected information on parental socio-demographic characteristics, COVID-19 vaccine history, intention to vaccinate their children against COVID- 19, and reasons for parental decisions, using an anonymous online survey. We identified associations between parental characteristics and intention to vaccinate children using a logistic regression model and described reasons for intentions to vaccinate or not using proportions together with 95% confidence intervals (CI).

Results1837 parents participated. Parental non-vaccination and having experienced major vaccination side effects were strongly associated with non-intention to vaccinate their children (OR 0.09 and 0.18 respectively, p<0.001). Compared with others, parents who were younger, lived in the socio-economically deprived periphery, and belonged to the Arab population had lower intentions to vaccinate their children. Commonly stated reasons for non-intention to vaccinate included vaccine safety and efficacy (53%, 95%CI 50-56) and the belief that COVID-19 was a mild disease (73%, 95%CI 73-79). The most frequently mentioned motives for intending to vaccine children was returning to normal social and educational life (89%, 95%CI 87-91).

ConclusionParental socio-demographic background and their own vaccination experience was associated with intention to vaccinate their children aged 5-11. Intention to vaccinate was mainly for social and economic reasons rather than health, whereas non-intention to vaccinate mainly stemmed from health concerns. Understanding rationales for COVID-19 vaccine rejection or acceptance, as well as parental demographic data, can pave the way for intentional educational campaigns to encourage not only vaccination against COVID-19, but also regular childhood vaccine programming.

HighlightsO_LIParental intention to vaccinate 5-11 children is much lower than vaccine coverage in parental age groups
C_LIO_LIBeing unvaccinated and having experienced side effects following vaccination were the greatest negative predictors in parents of intention to vaccinate their children
C_LIO_LIParents were more likely to accept a COVID-19 vaccine for their children to allow them to return to daily social life and to ensure economic security in the family
C_LIO_LIParents were more likely to reject a COVID-19 vaccination for health reasons such as safety concerns or due the belief that COVID-19 was a mild disease in children
C_LI

category: epidemiology


title: Monocyte, Neutrophil and Whole Blood Transcriptome Dynamics Following Ischemic Stroke

abstract:
BackgroundAfter ischemic stroke (IS), peripheral leukocytes infiltrate the damaged region and modulate the response to injury. Peripheral blood cells display distinctive gene expression signatures post IS and these transcriptional programs reflect changes in immune responses to IS. Dissecting the temporal dynamics of gene expression after IS improves our understanding of immune and clotting responses at the molecular and cellular level that are involved in acute brain injury and may assist with time-targeted, cell-specific therapy.

MethodsThe transcriptomic profiles from peripheral monocytes, neutrophils, and whole blood from 38 ischemic stroke patients and 18 controls were analyzed with RNAseq as a function of time and etiology after stroke. Differential expression analyses were performed at 0-24 h, 24-48 h, and >48 h following stroke.

ResultsUnique patterns of temporal gene expression and pathways were distinguished for monocytes, neutrophils and whole blood with enrichment of interleukin signaling pathways for different timepoints and stroke etiologies. Compared to control subjects, gene expression was generally up-regulated in neutrophils and generally down- regulated in monocytes over all times for cardioembolic, large vessel and small vessel strokes. Self-Organizing Maps identified gene clusters with similar trajectories of gene expression over time for different stroke causes and sample types. Weighted Gene Co- expression Network Analyses identified modules of co-expressed genes that significantly varied with time after stroke and included hub genes of immunoglobulin genes in whole blood.

ConclusionsAltogether, the identified genes and pathways are critical for understanding how the immune and clotting systems change over time after stroke. This study identifies potential time- and cell-specific biomarkers and treatment targets.

category: neurology


title: Zonal Model of Aerosol Persistence in ICUs: Utilization of Time and Space-resolved Sensor Network

abstract:
The COVID-19 pandemic heightened public awareness about airborne particulate matter (PM) due to the spread of infectious diseases via aerosols. The persistence of potentially infectious aerosol in public spaces, particularly medical settings, deserves close investigation; however, approaches for rapidly parameterizing the temporospatial distribution of particles released by an infected individual have not been reported in literature. This paper presents a methodology for mapping the movement of aerosol plumes using a network of low-cost PM sensors in ICUs. Mimicking aerosol generation by a patient, we tracked aerosolized NaCl particles functioning as tracers for potentially infectious aerosols. In positive (closed door) and neutral-pressure (open door) ICUs, an aerosol spike was detected outside the room, with up to 6% or 19% of all PM escaping through the door gaps, respectively. The outside sensors registered no aerosol spike in negative-pressure ICUs. The K-means clustering analysis of temporospatial data suggests three distinct zones: (1) near the aerosol source, (2) room periphery, and (3) immediately outside the room. These zones inform two-phase aerosol plume behavior: dispersion of the original aerosol spike throughout the room, and evacuation phase where "well-mixed" PM decayed uniformly. Decay rates were calculated for 4 ICUs in positive, neutral, and negative mode, with negative modes decaying the fastest. This research demonstrates the methodology for aerosol persistence monitoring in medical settings; however, it is limited by a relatively small data set. Future studies need to evaluate medical settings with high risks of infectious disease, assess risks of airborne disease transmission, and optimize hospital infrastructure.

Significance StatementAirborne infectious diseases, including COVID-19, are a major concern for patients and hospital staff. Here, we develop a systematic methodology for mapping the temporospatial distribution of aerosols in ICUs using a network of low-cost particulate matter (PM) sensors. Our method of analysis provides a perspective on the exfiltration efficiency of ICUs as well as the benefits of rooms that have a negative-pressure mode. Our methods could be extended to other public spaces with a high risk of infectious disease to optimize infrastructure and assess the risk of airborne disease.

category: occupational and environmental health


title: Aerosol Persistence in ICUs: Utilization of Low-cost Sensor Network


title: A multi-analyte serum biomarker panel for early detection of pancreatic adenocarcinoma

abstract:
PurposeWe determined whether a large, multi-analyte panel of circulating biomarkers can improve detection of early-stage pancreatic ductal adenocarcinoma (PDAC).

Experimental DesignWe defined a biologically relevant subspace of blood analytes based on previous identification in premalignant lesions or early-stage PDAC and evaluated each in pilot studies. The 31 analytes that met minimum diagnostic accuracy were measured in serum of 837 subjects (461 healthy, 194 benign pancreatic disease, 182 early stage PDAC). We used machine learning to develop classification algorithms using the relationship between subjects based on their changes across the predictors. Model performance was subsequently evaluated in an independent validation data set from 186 additional subjects.

ResultsA classification model was trained on 669 subjects (358 healthy, 159 benign, 152 early-stage PDAC). Model evaluation on a hold-out test set of 168 subjects (103 healthy, 35 benign, 30 early-stage PDAC) yielded an area under the receiver operating characteristic (ROC) curve (AUC) of 0.920 for classification of PDAC from non-PDAC (benign and healthy controls) and an AUC of 0.944 for PDAC vs. healthy controls. The algorithm was then validated in 146 subsequent cases presenting with pancreatic disease (73 benign pancreatic disease, 73 early and late stage PDAC) as well as 40 healthy control subjects. The validation set yielded an AUC of 0.919 for classification of PDAC from non-PDAC and an AUC of 0.925 for PDAC vs. healthy controls.

ConclusionsIndividually weak serum biomarkers can be combined into a strong classification algorithm to develop a blood test to identify patients who may benefit from further testing.

category: oncology


title: Declines and pronounced state-level variation in tapentadol use in the US

abstract:
BackgroundTapentadol is an opioid approved for the treatment of moderate-to-severe pain in the United States (US). Tapentadol is unique as it is the only Schedule II prescription drug that has dual modes of action as it combines agonist activity at the {micro} opioid receptor with norepinephrine reuptake inhibition. This descriptive study characterized tapentadol use in the US.

MethodsDrug distribution data from 2010 to 2020 were extracted for each state from the Drug Enforcement Administration. Use per state, corrected for population, was analyzed. The percentage of distribution channels (pharmacies, hospitals, and providers), the distributed amount of tapentadol, and the final adjusted quota of tapentadol were obtained. Data on tapentadol use as reported by the Medicare and Medicaid programs for 2010 to 2020 were also analyzed.

ResultsThe distributed amount of tapentadol was 3.5 tons in 2020 and on average, the final adjusted production quota was 207.2% greater than the distributed amount between 2010 and 2020. Distributed tapentadol was 1.3% of all Schedule II opioids distributed in 2020. Tapentadol use decreased by -53.8% between 2012 and 2020 in the US whereas New Hampshire was the only state that had a positive change (+13.1%). There were minor changes in the amounts of tapentadol distributed via various distribution channels (Pharmacies = 98.0%, hospitals = 1.9% in 2020). Tapentadol prescribed by Nurse Practitioners experienced the largest increase of +8.7% among all specialties to 18.0%, the highest percentage of Medicare claims of tapentadol in 2019. Diabetes prevalence was significantly correlated with tapentadol distribution in 2012 (r(50) = .44, p < .01) and 2020 (r(50) = .28, p < .05).

DiscussionThere has been a substantial decline over the past decade in tapentadol distribution and prescribing to Medicaid patients. The unusual tapentadol prescribing pattern in New Hampshire may warrant investigation regarding differing prescribers attitudes towards tapentadol or the employment of tapentadol as part of a step-down therapy for opioid addiction.

category: pain medicine


title: FinnGen: Unique genetic insights from combining isolated population and national health register data

abstract:
Population isolates such as Finland provide benefits in genetic studies because the allelic spectrum of damaging alleles in any gene is often concentrated on a small number of low-frequency variants (0.1% [≤] minor allele frequency < 5%), which survived the founding bottleneck, as opposed to being distributed over a much larger number of ultra--rare variants. While this advantage is well-- established in Mendelian genetics, its value in common disease genetics has been less explored. FinnGen aims to study the genome and national health register data of 500,000 Finns, already reaching 224,737 genotyped and phenotyped participants. Given the relatively high median age of participants (63 years) and dominance of hospital-based recruitment, FinnGen is enriched for many disease endpoints often underrepresented in population-based studies (e.g., rarer immune-mediated diseases and late onset degenerative and ophthalmologic endpoints). We report here a genome-wide association study (GWAS) of 1,932 clinical endpoints defined from nationwide health registries. We identify genome--wide significant associations at 2,491 independent loci. Among these, finemapping implicates 148 putatively causal coding variants associated with 202 endpoints, 104 with low allele frequency (AF<10%) of which 62 were over two-fold enriched in Finland.

We studied a benchmark set of 15 diseases that had previously been investigated in large genome-wide association studies. FinnGen discovery analyses were meta-analysed in Estonian and UK biobanks. We identify 30 novel associations, primarily low-frequency variants strongly enriched, in or specific to, the Finnish population and Uralic language family neighbors in Estonia and Russia.

These findings demonstrate the power of bottlenecked populations to find unique entry points into the biology of common diseases through low-frequency, high impact variants. Such high impact variants have a potential to contribute to medical translation including drug discovery.

category: genetic and genomic medicine


title: SARS-CoV-2 Omicron Variant Infection of Individuals with High Titer Neutralizing Antibodies Post-3rd mRNA Vaccine Dose

abstract:
BackgroundVaccination with COVID-19 mRNA vaccines prevent hospitalization and severe disease caused by wildtype SARS-CoV-2 and several variants, and likely prevented infection when serum neutralizing antibody (NAb) titers were >1:160. Preventing infection limits viral replication resulting in mutation, which can lead to the emergence of additional variants.

MethodsDuring a longitudinal study to evaluate durability of a three-dose mRNA vaccine regimen (2 primary doses and a booster) using a rapid test that semi-quantitatively measures NAbs, the Omicron variant emerged and quickly spread globally. We evaluated NAb levels measured prior to symptomatic breakthrough infection, in groups infected prior to and after the emergence of Omicron.

ResultsDuring the SARS-CoV-2 Delta variant wave, 93% of breakthrough infections in our study occurred when serum NAb titers were <1:80. In contrast, after the emergence of Omicron, study participants with high NAb titers that had received booster vaccine doses became symptomatically infected. NAb titers prior to infection were [≥]1:640 in 64% of the Omicron-infected population, [≥]1:320 (14%), and [≥]1:160 (21%).

DiscussionThese results indicate that high titers of NAbs elicited by currently available mRNA vaccines do not protect against infection with the Omicron variant, and that mild to moderate symptomatic infections did occur in a vaccinated and boosted population, although did not require hospitalization.


title: Evaluation of the role of home rapid antigen testing to determine isolation period after infection with SARS-CoV-2

abstract:
ImportanceRecent CDC COVID-19 isolation guidance for non-immunocompromised individuals with asymptomatic or mild infection allows ending isolation after 5 days if asymptomatic or afebrile with improving symptoms. The role of rapid antigen testing in further characterizing the risk of viral transmission to others is unclear.

ObjectiveUnderstand rates of rapid antigen test (RAT) positivity after day 5 from a positive COVID-19 test and the relationship of this result to symptoms and viral culture.

DesignIn this single center, observational cohort study, ambulatory individuals newly testing SARS-CoV-2 positive completed daily symptom logs, and RAT self-testing starting day 6 until negative. Anterior nasal and oral swabs were collected on a subset for viral culture.

Main Outcomes and MeasuresDay 6 SARS-CoV-2 RAT result, symptoms and viral culture.

Results40 individuals enrolled between January 5 and February 11, 2022 with a mean age of 32 years (range 22 to 57). 23 (58%) were women and 17 (42%) men. All were vaccinated. 33 (83%) were symptomatic. Ten (25%) tested RAT negative on day 6. 61 of 90 (68%) RATs performed on asymptomatic individuals after day 5 were positive. Day 6 viral cultures were positive in 6 (35%) of 17 individuals. A negative RAT or being asymptomatic on day 6 were 100% and 78% predictive respectively for negative culture, while improving symptoms was 69% predictive. A positive RAT was 50% predictive of positive culture.

Conclusion and RelevanceRATs are suboptimal in predicting viral culture results on day 6. Use of routine RATs to guide end of COVID-19 isolation could result in significant numbers of culture negative, potentially non-infectious individuals undergoing prolonged isolation. However, a negative RAT was highly predictive of being culture negative. Complete absence of symptoms was inferior to a negative RAT in predicting a negative culture result, but performed better than improving symptoms. If a positive viral culture is a proxy for infectiousness, these data may help further refine a safer strategy for ending isolation.


title: Different forms of superspreading lead to different outcomes: heterogeneity in infectiousness and contact behavior relevant for the case of SARS-CoV-2

abstract:
Superspreading events play an important role in the spread of SARS-CoV-2 and several other pathogens. Hence, while the basic reproduction number of the original Wuhan SARS-CoV-2 is estimated to be about 3 for Belgium, there is substantial inter-individual variation in the number of secondary cases each infected individual causes. Multiple factors contribute to the occurrence of superspreading events: heterogeneity in infectiousness and susceptibility, variations in contact behavior, and the environment in which transmission takes place. While superspreading has been included in several infectious disease transmission models, our understanding of the effect that these different forms of superspreading have on the spread of pathogens and the effectiveness of control measures remains limited. To disentangle the effects of infectiousness-related heterogeneity on the one hand and contact-related heterogeneity on the other, we implemented both forms of superspreading in an individual-based model describing the transmission and spread of SARS-CoV-2 in the Belgian population. We considered its impact on viral spread as well as on the effectiveness of social distancing. We found that the effects of superspreading driven by heterogeneity in infectiousness are very different from the effects of superspreading driven by heterogeneity in contact behavior. On the one hand, a higher level of infectiousness-related heterogeneity results in less outbreaks occurring following the introduction of one infected individual. Outbreaks were also slower, with a lower peak which occurred at a later point in time, and a lower herd immunity threshold. Finally, the risk of resurgence of an outbreak following a period of lockdown decreased. On the other hand, when contact-related heterogeneity was high, this also led to smaller final sizes, but caused outbreaks to be more explosive in regard to other aspects (such as higher peaks which occurred earlier, and a higher herd immunity threshold). Finally, the risk of resurgence of an outbreak following a period of lockdown increased. Determining the contribution of both source of heterogeneity is therefore important but left to be explored further.

Author summaryTo investigate the effect of different sources of superspreading on disease dynamics, we implemented superspreading driven by heterogeneity in infectiousness and heterogeneity in contact behavior into an individual-based model for the transmission of SARS-CoV-2 in the Belgian population. We compared the impact of both forms of superspreading in a scenario without interventions as well as in a scenario in which a period of strict social distancing (i.e. a lockdown) is followed by a period of partial release. We found that both forms of superspreading have very different effects. On the one hand, increasing the level of infectiousness-related heterogeneity led to less outbreaks being observed following the introduction of one infected individual in the population. Furthermore, final outbreak sizes decreased, and outbreaks became slower, with lower and later peaks, and a lower herd immunity threshold. Finally, the risk for resurgence of an outbreak following a period of lockdown also decreased. On the other hand, when contact-related heterogeneity was high, this also led to smaller final sizes, but caused outbreaks to be more explosive regarding other aspects (such as higher peaks that occurred earlier). The herd immunity threshold also increased, as did the risk of resurgence of outbreaks.


title: Development of a COVID-19 risk-assessment model for participants at an outdoor music festival: Evaluation of the validity and control measure effectiveness

abstract: We developed an environmental exposure model to estimate the Coronavirus Disease 2019 (COVID-19) risk among participants at an outdoor music festival and validated the model using a real cluster outbreak case. Furthermore, we evaluated the extent to which the risk could be reduced by additional infection control measures such as negative proofs of antigen tests on the day of the event, wearing masks, disinfection of environmental surfaces, and vaccination. The total number of already- and newly-infected individuals who participated in the event according to the new model was 47.0 (95% uncertainty interval: 12.5-185.5), which is in good agreement with the reported value (45). Among the additional control measures, vaccination, mask-wearing, and disinfection of surfaces were determined to be effective. Based on the combination of all measures, a 94% risk reduction could be achieved. In addition to setting a benchmark for an acceptable number of newly-infected individuals at the time of an event, the application of this model will enable us to determine whether it is necessary to implement additional measures, limit the number of participants, or refrain from holding an event.


title: SARS-CoV-2 Seroprevalence among health care workers after the first and second pandemic wave

abstract:
BackgroundThe Grand Hopital de Charleroi is a large non-academic Belgian hospital that treated a large number of COVID-19 inpatients. In the context of this pandemic, all professions-combined healthcare workers (HCWs), and not only direct caregivers, are a frontline workforce in contact with suspected and confirmed COVID-19 cases and seem to be a high-risk group for exposure. The aim of our study was to estimate the prevalence of anti-SARS-CoV-2 antibodies in HCWs in our hospital after the first and the second pandemic wave and also to characterize the distribution of this seroprevalence in relation to various criteria.

MethodsAt the end of the two recruitment periods, a total of 4008 serological tests were performed in this single-center cross-sectional study. After completing a questionnaire including demographic and personal data, possible previous COVID-19 diagnostic test results and/or the presence of symptoms potentially related to COVID-19, the study participants underwent blood sampling and serological testing using DiaSorins LIAISON(R) SARS-CoV-2 S1/S2 IgG test for the first phase and LIAISON(R) SARS-CoV-2 TrimericS IgG test for the second phase of this study.

Results302 study participants (10,72%) in the first round of the study and 404 (33,92%) in the second round were positive for SARS-CoV-2-IgG antibodies. The prevalence of seropositivity observed after the second wave was 3,16 times higher than after the first wave. We confirmed that direct, prolonged and repeated contact with patients or their environment was a predominant seroconversion factor, but more unexpectedly, that this was the case for all HCWs and not only caregivers. Finally, the notion of high-risk contact seemed more readily identifiable in ones workplace than in ones private life.

ConclusionOur study confirmed that HCWs are at a significantly higher risk of contracting COVID-19 than the general population, and suggest that repeated contacts with at-risk patients, regardless of the HCWs profession, represent the most important risk factor for seroconversion. (Clinicaltrials.gov number, NCT04723290)


title: Testing Frequency Matters | An Evaluation of the Diagnostic Performance of a SARS-CoV-2 Rapid Antigen Test in United States Correctional Facilities

abstract:
BackgroundThe CDC recommends serial rapid antigen assay collection within congregate facilities for screening and outbreak testing. Though modeling and observational studies from community and long-term care facilities have shown serial collection provides adequate sensitivity and specificity, the diagnostic accuracy of this testing strategy within correctional facilities remains unknown.

MethodsUsing Connecticut Department of Corrections (DOC) data from November 21st 2020 to June 15th 2021, we estimated the accuracy of a rapid assay, BinaxNOW, under three collection strategies, a single test in isolation and two and three serial tests separated by 1-4 day intervals. Diagnostic accuracy metrics were estimated in relation to RT-PCRs collected within one day before the first or after the last included rapid antigen tests in a series.

ResultsOf the 17,669 residents who contributed at least one RT-PCR or rapid antigen during the study period, 3,979 contributed [≥]1 paired rapid antigen test series. In relation to RT-PCR, the three-rapid antigen test strategy had a sensitivity of 89.6% (95% confidence intervals: 86.1-92.6%) and specificity of 97.2% (CI: 95.1-98.3%). The sensitivities for two and one-rapid antigen test strategy were 75.2% and 52.8%, respectively, and the specificities were 98.5% and 99.4%, respectively. The sensitivity was higher among symptomatic residents and when the RT-PCR was collected before the rapid antigen tests.

ConclusionsWe found the serial collection of an antigen test resulted in high diagnostic accuracy. These findings support serial testing within correctional facilities for outbreak investigation, screening, and when rapid detection is required (such as intakes or transfers).


title: Immunogenicity and reactogenicity against the SARS-CoV-2 variants following heterologous primary series involving CoronaVac and ChAdOx1 and BNT162b2 plus heterologous BNT162b2 booster vaccination: An open-label randomized study in healthy Thai adults.

abstract: We evaluated the immunogenicity and reactogenicity of heterologous COVID-19 primary series vaccination schedules. Participants were randomized to one of seven groups that received two-dose homologous BNT162b2 or heterologous combinations of CoronaVac, ChAdOx1 and BNT162b2, with 4 weeks interval. Of 210 participants, median age was 38 (19-60) years, 51% were female. The groups that received BNT162b2 as second dose induced the highest virus-specific IgG response against the ancestral strain [BNT162b2: geometric mean concentration (GMC) 2133-2249, 95%CI 1558 to 3055; ChAdOx1: 851-1201, 95%CI 649 to 1522; CoronaVac: 137-225, 95%CI 103-286 BAU/mL], neutralising antibodies (NAb) against Beta and Delta, and interferon gamma response. All groups induced low to negligible NAb against Omicron. A BNT162b2 booster (3rd dose) following heterologous CoronaVac and ChAdOx1 regimens induced >140-fold increase in NAb titres against Omicron. Our findings indicate that heterologous regimens using BNT162b2 as the second dose may be considered an alternative schedule to maximize immune response.


title: Spike mutations of the SARS-CoV-2 Omicron: more likely to occur in the epitopes

abstract: Almost two years since the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak in 2019, and it is still pandemic over the world. SARS-COV-2 continuing to mutate and evolve, which further exacerbated the spread of the epidemic. Omicron variant, as an emerging mutation recently in South Africa, spreaded fastly to other countries worldwide. However, the gene charicterstic of Omicron and the effect on epitopes are still unclear. In this study, we retrieved 800 SARS-CoV-2 full-length sequences from GISAID database on 14 December 2021 (Alpha 110, Beta 101, Gamma 108, Delta 110, Omicron 107, Lambda 98, Mu 101, GH/490R 65). Overall, 1320 amino acid (AA) sites were mutated in these 800 SARS-CoV-2 sequences. Covariant network analysis showed that the covariant network of Omicron variant was significantly different from other variants. Further, 218 of the 1320 AA sites were occurred in the S gene, including 78 high-frequency mutations (>90%). Notably, we identified 25 unique AA mutations in Omicron, which may affect the transmission and pathogenicity of SARS-CoV-2. Finally, we analyzed the effect of Omicron on epitope peptide. As expected, 64.1% mutations (25/39) of Omicron variants were in epitopes, which was significantly higher than in other variants. These mutations may cause a poor response to vaccines to Omicron variants. In conclusion, Omicron variants, as an emerging mutation, should be alerted for us due that it may lead to poor vaccine response, and more data is needed to evaluate the virulence and vaccines responses to this variants.


title: Proteome reveals antiviral host response and NETosis during acute COVID-19 in high-risk patients

abstract:
SARS-CoV-2 remains an acute threat to human health, endangering hospital capacities worldwide. Many studies have aimed at informing pathophysiologic understanding and identification of disease indicators for risk assessment, monitoring, and therapeutic guidance. While findings start to emerge in the general population, observations in high-risk patients with complex pre-existing conditions are limited.

To this end, we biomedically characterized quantitative proteomics in a hospitalized cohort of COVID-19 patients with mild to severe symptoms suffering from different (co)-morbidities in comparison to both healthy individuals and patients with non-COVID related inflammation. Deep clinical phenotyping enabled the identification of individual disease trajectories in COVID-19 patients. By the use of this specific disease phase assignment, proteome analysis revealed a severity dependent general type-2 centered host response side-by-side with a disease specific antiviral immune reaction in early disease. The identification of phenomena such as neutrophil extracellular trap (NET) formation and a pro-coagulatory response together with the regulation of proteins related to SARS-CoV-2-specific symptoms by unbiased proteome screening both confirms results from targeted approaches and provides novel information for biomarker and therapy development.

Graphical AbstractSars-CoV-2 remains a challenging threat to our health care system with many pathophysiological mechanisms not fully understood, especially in high-risk patients. Therefore, we characterized a cohort of hospitalized COVID-19 patients with multiple comorbidities by quantitative plasma proteomics and deep clinical phenotyping. The individual patients disease progression was determined and the subsequently assigned proteome profiles compared with a healthy and a chronically inflamed control cohort. The identified disease phase and severity specific protein profiles revealed an antiviral immune response together with coagulation activation indicating the formation of NETosis side-by-side with tissue remodeling related to the inflammatory signature.

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category: respiratory medicine


title: Alzheimer's Disease Classification Using Cluster-based Labelling for Graph Neural Network on Tau PET Imaging and Heterogeneous Data

abstract: Graphical neural networks (GNNs) offer the opportunity to provide new insights into the diagnosis, prognosis and contributing factors of Alzheimers disease (AD). However, previous studies using GNNs on AD did not incorporate tau PET neuroimaging features or, more importantly, have applied class labels based only on clinician diagnosis, which can be inconsistent. This study addresses these limitations by applying cluster-based labelling on heterogeneous data, including tau PET neuroimaging data, before applying GNN for classification. The data comprised sociodemographic, medical/family history, cognitive and functional assessments, apolipoprotein E (APoE) {varepsilon}4 allele status, and combined tau PET neuroimaging and MRI data. We identified 5 clusters embedded in a 5-dimensional nonlinear UMAP space. Further projection onto a 3-dimensional UMAP space for visualisation, and using association rule and information gain algorithms, the individual clusters were revealed to have specific feature characteristics, specifically with respect to clinical diagnosis of AD, gender, parental history of AD, age, and underlying neurological risk factors. In particular, there was one cluster comprised mainly of clinician diagnosis of AD. We re-labelled the diagnostic classes based around this AD cluster such that AD cases occurred only within this cluster while those AD cases outside of it were re-labelled as a prodromal stage of AD. A post-hoc analysis supported the re-labelling of these cases given their similar brain tau PET levels, lying between those of the remaining AD and non-AD cases. We then trained a GNN model using the re-labelled data and compared the AD classification performance to that trained using clinician diagnostic labels. We found that GNN with re-labelled data had significantly higher average classification accuracy (p=0.011) and less variability (93.2{+/-}0.03%) than with clinician labelled data (90.06{+/-}0.04%). During model training, the cluster-labelled GNN model also converged faster than that using clinician labels. Overall, our work demonstrates that more objective cluster-based labels are viable for training GNN on heterogeneous data for diagnosing AD and cognitive decline, especially when aided by tau PET neuroimaging data.


title: Sero-surveillance for IgG to SARS-CoV-2 at antenatal care clinics in three Kenyan referral hospitals: repeated cross-sectional surveys 2020-21

abstract:
IntroductionThe high proportion of SARS-CoV-2 infections that have remained undetected presents a challenge to tracking the progress of the pandemic and estimating the extent of population immunity.

MethodsWe used residual blood samples from women attending antenatal care services at three hospitals in Kenya between August 2020 and October 2021and a validated IgG ELISA for SARS-Cov-2 spike protein and adjusted the results for assay sensitivity and specificity. We fitted a two-component mixture model as an alternative to the threshold analysis to estimate of the proportion of individuals with past SARS-CoV-2 infection.

ResultsWe estimated seroprevalence in 2,981 women; 706 in Nairobi, 567 in Busia and 1,708 in Kilifi. By October 2021, 13% of participants were vaccinated (at least one dose) in Nairobi, 2% in Busia. Adjusted seroprevalence rose in all sites; from 50% (95%CI 42-58) in August 2020, to 85% (95%CI 78-92) in October 2021 in Nairobi; from 31% (95%CI 25-37) in May 2021 to 71% (95%CI 64-77) in October 2021 in Busia; and from 1% (95% CI 0-3) in September 2020 to 63% (95% CI 56-69) in October 2021 in Kilifi. Mixture modelling, suggests adjusted cross-sectional prevalence estimates are underestimates; seroprevalence in October 2021 could be 74% in Busia and 72% in Kilifi.

ConclusionsThere has been substantial, unobserved transmission of SARS-CoV-2 in Nairobi, Busia and Kilifi Counties. Due to the length of time since the beginning of the pandemic, repeated cross-sectional surveys are now difficult to interpret without the use of models to account for antibody waning.


title: Burden of Disease from Contaminated Drinking Water in Countries with High Access to Safely Managed Water: A Systematic Review

abstract:
BackgroundThe vast majority of residents of high-income countries (>90%) reportedly have high access to safely managed drinking water, the highest level of service under the Sustainable Development Goal (SDG) framework. Owing perhaps to the widely held perception of near universal access to high-quality water services in these countries, the burden of waterborne disease in these contexts is understudied.

MethodsWe conducted a systematic review of estimates of the disease burden attributed to drinking water in countries where >90% of the population has access to safely managed drinking water per official SDG monitoring. We searched PubMed, Web of Science, and SCOPUS for articles published before September 10, 2021.

FindingsWe identified 24 studies reporting estimates for the disease burden attributable to microbial contaminants. Across these studies, the population-weighted average burden of gastrointestinal illness risks attributed to drinking water was about 3,529 annual cases per 100,000 people. Beyond exposure to infectious agents, we also identified 10 studies reporting disease burden, predominantly, cancer risks, associated with chemical contaminants. Across these studies, the pooled population-weighted average of excess cancer cases attributable to drinking water was 1.8 annual cancer cases per 100,000 people.

InterpretationThese estimates exceed WHO-recommended normative targets for disease burden attributable to drinking water and highlight that there remains important preventable disease burden in these contexts. However, the available literature was scant and limited in geographic scope, disease outcomes, range of microbial and chemical contaminants, and inclusion of subpopulations that could most benefit from water infrastructure investments. These subpopulations include rural, low-income communities; Indigenous or Aboriginal peoples; and populations marginalized due to discrimination by race, ethnicity, or socioeconomic status. Studies quantifying drinking water-associated disease burden in countries with reportedly high access to safe drinking water, with a focus on specific subpopulations and promoting environmental justice, are needed.

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSAlthough the burden of disease associated with unsafe drinking water in low- and middle-income countries has been subject of much research, there is uncertainty about the magnitude and nature of this disease burden in high-income countries and countries where access to safely managed drinking water is >90%. To assess the magnitude of this burden in countries with high levels of access to high quality water, we conducted a systematic review of estimates of the disease burden attributed to drinking water in countries where >90% of the population has access to safely managed drinking water as defined by the WHO/UNICEF Joint Monitoring Programme for Water Supply, Sanitation and Hygiene (JMP). We searched PubMed, Web of Science, and SCOPUS for relevant articles published before September 10, 2021. We searched for articles including "burden of disease" OR "disease burden" OR "gastrointestinal illness" anywhere in the text. From among these articles, we selected those with the terms "drinking water" OR "tap water." From this reduced set, we selected articles reporting on countries with >90% safe water access and including estimates of cases, hospitalizations, or deaths related to drinking water contamination. Additional articles were identified from consultations with subject-matter experts. Only articles in English were recovered, which may have biased our results towards specific countries.

Added value of this studyTo our knowledge, this is the first global review of its kind to identify burden of waterborne disease estimates associated with microbiological contaminants as well as chemical contaminants found in drinking water, specifically in countries with reportedly high access (>90%) to safely managed drinking water. Despite the perception that high quality water is ubiquitous in these countries, we found that burden estimates in these countries exceeded WHO-recommended targets for disease burden attributable to unsafe drinking water. This review also highlighted the gaps in our understanding of waterborne disease burden across and within countries where access to high quality drinking water is common.

Implications of all the available evidenceEven though the levels of access to safely managed drinking water are high in many high-income and some middle-income countries, there remains a potentially important preventable disease burden in these high-income countries. Our review suggests that further burden research expanding the scope of contaminants, disease outcomes, geographic area, and vulnerable subpopulations within countries is necessary. Currently, available evidence is insufficient to support rational decision-making and to prioritize public investment to protect the health of marginalized communities. These groups include rural, low-income communities; Indigenous or Aboriginal peoples; and populations marginalized due to discrimination by race, ethnicity, or socioeconomic status.


title: Open label phase I/II clinical trial and predicted efficacy of SARS-CoV-2 RBD protein vaccines SOBERANA 02 and SOBERANA Plus in children

abstract:
ObjectivesTo evaluate heterologous scheme in children 3-18 y/o using two SARS-CoV-2 r-RBD protein vaccines.

MethodsA phase I/II open-label, adaptive and multicenter trial evaluated the safety and immunogenicity of two doses of SOBERANA02 and a heterologous third dose of SOBERANA Plus in 350 children 3-18 y/o in Havana Cuba. Primary outcomes were safety (in phase I) and safety/immunogenicity (in phase II) measured by anti-RBD IgG ELISA, molecular and live-virus neutralization tests and specific T-cells response. An immunobridging and prediction of efficacy were additional analysis.

ResultsLocal pain was the unique adverse event with >10% frequency, none was serious or severe. Two doses of SOBERANA 02 elicited humoral immune response similar to natural infection; the third dose increased significantly the response in all children, similar to that achieved in vaccinated young adults and higher than in convalescents children. The neutralizing titer was evaluated in a participants subset: all had neutralizing antibodies vs. alpha and delta; 97.9% vs. beta. GMT was 173.8 (CI 95% 131.7; 229.5) vs. alpha, 142 (CI 95% 101.3; 198.9) vs. delta and 24.8 (CI 95% 16.8; 36.6) vs. beta. An efficacy over 90% was estimated.

ConclusionHeterologous scheme was safe and immunogenic in children 3-18 y/o. Trial registry: https://rpcec.sld.cu/trials/RPCEC00000374


title: Immunogenicity and Safety of Booster Dose of S-268019-b or Tozinameran in Japanese Participants: An Interim Report of Phase 2/3, Randomized, Observer-Blinded, Noninferiority Study

abstract:
In this randomized, observer-blinded, phase 2/3 study, S-268019-b (n=101), a recombinant spike protein vaccine, was analyzed for noninferiority versus tozinameran (n=103), when given as a booster [≥]6 months after 2-dose tozinameran regimen in Japanese adults without prior COVID-19 infection. Interim results showed noninferiority of S-268019-b versus tozinameran in co-primary endpoints for neutralizing antibodies on day 29: geometric mean titer (GMT) (124.97 versus 109.70; adjusted-GMT ratio [95% CI], 1.14 [0.94-1.39]; noninferiority P-value, <0.0001) and seroresponse rate (both 100%; noninferiority P-value, 0.0004). Both vaccines elicited anti-spike-protein immunoglobulin G antibodies, and produced T-cell response (n=29/group) and neutralizing antibodies against Delta and Omicron pseudovirus and live virus variants (n=24/group) in subgroups. Most participants reported low-grade reactogenicity on days 1-2, the most frequent being fatigue, fever, myalgia, and injection-site pain. No serious adverse events were reported. In conclusion, S-268019-b was safe and showed robust immunogenicity as a booster, supporting its use as COVID-19 booster vaccine.

JRCT IDjRCT2031210470

HighlightsO_LIThird COVID-19 vaccine dose (booster) enhances immune response
C_LIO_LIInterim phase 2/3 data for booster [≥]6 months after the 2nd dose in Japan are shown
C_LIO_LIS-268019-b was noninferior to tozinameran in inducing neutralizing antibodies
C_LIO_LISera boosted with either vaccines neutralized Delta and Omicron virus variants
C_LIO_LIS-268019-b was safe, and results support its use as a booster in vaccinated adults
C_LI


title: Individualised Profiling of White Matter Organisation in Moderate-to-Severe Traumatic Brain Injury Patients Using TractLearn: A Proof-of-Concept Study

abstract: Approximately 65% of moderate-to-severe traumatic brain injury (m-sTBI) patients present with poor long-term behavioural outcomes, which can significantly impair activities of daily living. Numerous diffusion-weighted MRI studies have linked these poor outcomes to decreased white matter integrity of several commissural tracts, association fibres and projection fibres in the brain. However, these studies focused on group-based analyses, which are unable to deal with the substantial between-patient heterogeneity in m-sTBI. As a result, there is increasing interest in conducting individualised neuroimaging analyses. Here, we generated a detailed subject-specific characterisation of microstructural organisation of white matter tracts in 5 chronic patients with m-sTBI (29 - 49y, 2 females). We developed an imaging analysis framework using fixel-based analysis and TractLearn to determine whether the values of fibre density of white matter tracts at the individual patient level deviate from the healthy control group (n = 12, 8F, Mage=35.7y, age range 25 - 64y). Our individualised analysis confirmed unique white matter profiles, and the heterogeneous nature of m-sTBI to properly characterise the extent of brain abnormality. Future studies incorporating clinical data, as well as utilising larger reference samples and examining the test-retest reliability of the fixel-wise metrics are warranted. This proof-of-concept study suggests that these resulting individual profiles may assist clinicians in planning personalised training programs for chronic m-sTBI patients, which is necessary to achieve optimal behavioural outcomes and improved quality of life.

category: radiology and imaging


title: Human cytomegalovirus strain diversity and dynamics reveal the donor lung as a major contributor after transplantation

abstract:
Mixed human cytomegalovirus (HCMV) strain infections are frequent in lung transplant recipients (LTRs). To date, the influence of the donor (D) and recipient (R) HCMV-serostatus on intra-host HCMV strain composition and replication dynamics after transplantation is only poorly understood.

Here, we investigated ten pre-transplant lungs from HCMV-seropositive donors, and 163 sequential HCMV-DNA positive plasma and bronchoalveolar lavage samples from 50 LTRs with multiviremic episodes post-transplantation. The study cohort included D+R+ (38%), D+R- (36%), and D-R+ (26%) patients. All samples were subjected to quantitative genotyping by short amplicon deep sequencing, and 24 thereof were additionally PacBio long-read sequenced for genotype linkages.

We find that D+R+ patients show a significantly elevated intra-host strain diversity compared to D+R- and D-R+ patients (P=0.0089). Both D+ patient groups display significantly higher replication dynamics than D- patients (P=0.0061). Five out of ten pre-transplant donor lungs were HCMV-DNA positive, whereof in three multiple HCMV strains were detected, indicating that multi-strain transmission via lung transplantation is likely. Using long reads, we show that intra-host haplotypes can share distinctly linked genotypes, which limits overall intra-host diversity in mixed infections. Together, our findings demonstrate donor-derived strains as a main source for increased HCMV strain diversity and dynamics post-transplantation, while a relatively limited number of intra-host strains may facilitate rapid adaptation to changing environments in the host. These results foster targeted strategies to mitigate the potential transmission of the donor strain reservoir with the allograft.

category: transplantation


title: COVID-19 Hospitalisation in Portugal, the first year: Results from hospital discharge data

abstract:
Using Portuguese diagnosis-related groups (DRGs) data we analysed the dynamics of the COVID-19 hospitalisation in Portugal, with the ultimate goal of estimating parameters to be used in COVID-19 mathematical modelling.

After processing the data, corresponding to the period between March 2020 and the end of March 2021, an exploratory analysis was conducted, in which the length of stay (LoS) in hospital care, the time until death (TuD), the number of admissions and mortality count were estimated and described with respect to the age and gender of the patients, but also by region of admission and evolution over time.

The median and mean of LoS was estimated to be 8 and 12.5 days (IQR:4-15) for non-ICU patients and for ICU patients as 18 and 24.3 days (IQR:11-30). The percentage of patients that, during their hospitalisation, required ICU care was determined to be 10.9%. In-hospital mortality of non-ICU patients (22.6%) and of ICU patients (32.8%) were also calculated. In a visual exploratory analysis we observed that they changed with time, age group, gender and region.

Various univariable probability distributions were fitted to the LoS and TuD data, using maximum likelihood estimation (MLE) but also maximum goodness-of-fit estimation (MGE) to obtain the distribution parameters.

AMS Subject Classification62-07,62E07,62F10,62P10


title: The reliability of two prospective cortical biomarkers for pain: EEG peak alpha frequency and TMS corticomotor excitability

abstract: Many pain biomarkers fail to move from discovery to clinical application, attributed to poor reliability and feasible classifications of at-risk individuals. Preliminary evidence has shown that higher pain sensitivity is associated with slow peak alpha frequency (PAF) and depression of corticomotor excitability (CME). The present study evaluated the reliability of these measures, specifically whether, over several days of pain, a) PAF remains stable and b) individuals show two stable and distinct CME responses: facilitation and depression. Seventy-five healthy participants were given an injection of nerve growth factor (NGF) into the right masseter muscle on Day 0 and Day 2, inducing sustained pain. Electroencephalography (EEG) to assess PAF and transcranial magnetic stimulation (TMS) to assess CME were recorded on Day 0, Day 2 and Day 5. PAF reliability was in the excellent range even without standard pre-processing and [~]2 minutes recording length. Moreover, two distinct and stable CME responses were demonstrated: facilitation and depression. These findings support the notion that PAF is a stable trait characteristic, with reliability unaffected by pain, and excellent reliability achievable with minimal pre-processing and [~]2 minutes recording, making it a readily translatable biomarker. Furthermore, the study showed novel evidence of two stable corticomotor adaptations to sustained pain. Overall, the study provides support for the reliability of PAF and CME as prospective cortical biomarkers.


title: Machine Learning Based Reanalysis of Clinical Scores for Distinguishing Between Ischemic and Hemorrhagic Stroke in Low Resource Setting

abstract:
BACKGROUNDIdentification of stroke and classifying them as ischemic and hemorrhagic type using clinical scores alone faces two unaddressed issues. One pertains to over-estimation of performance of scores and the other involves class imbalance nature of stroke data leading to biased accuracy. We conducted a quantitative comparison of existing scores, after correcting them for the above-stated issues. We explored the utility of Machine Learning theory to address overestimation of performance and class imbalance inherent in these clinical scores.

METHODSWe included validation studies of Siriraj (SS), Guys Hospital/Allen (GHS/AS), Greek (GS), and Besson (BS) Scores for stroke classification, from 2001-2021, identified from systematic search on PubMed, ERIC, ScienceDirect, and IEEE-Xplore. From included studies we extracted the reported cross tabulation to identify the listed issues. Further, we mitigated them while recalculating all the performance metrics for a comparative analysis of the performance of SS, GHS/AS, GS, and BS.

RESULTSA total of 21 studies were included. Our calculated sensitivity range (IS-diagnosis) for SS is 40-90% (median 70%[IQR:57-73%], aggregate 71%[SD:15%]) as against reported 43-97% (78%[IQR:65-88%]), for GHS/AS 35-93% (64%[IQR:53-71%], 64%[SD:17%]) against 35-94% (73%[IQR:62-88%]), and for GS 60-74% (64%[IQR:62-69%], 69%[SD:7%]) against 74-94% (89%[IQR:81-92%]). Calculated sensitivity (HS-diagnosis), for SS, GHS/AS, and GS respectively, are 34-86% (59%[IQR:50-79%], 61%[SD:17%]), 20-73% (46%[IQR:34-64%], 44%[SD:17%]), and 11-80% (43%[IQR:27-62%], 51%[SD:35%]) against reported 50-95% (71%[IQR:64-82%]), 33-93% (63%[IQR:39-73%]), and 41-80% (78%[IQR:59-79%]). Calculated accuracy ranges, are 37-86% (67%[IQR:56-75%], 68%[SD:13%]), 40-87% (58%[IQR:47-61%], 59%[SD:14%]), and 38-76% (51%[IQR:45-63%], 61%[SD:19%]) while the weighted accuracy ranges are 37-85% (64%[IQR:54-73%], 66%[SD:12%]), 43-80% (53%[IQR:47-62%], 54%[SD:13%]), and 38-77% (51%[IQR:44-64%], 60%[SD:20%]). Only one study evaluated BS.

CONCLUSIONQuantitative comparison of existing scores indicated significantly lower ranges of performance metrics as compared to the ones reported by the studies. We conclude that published clinical scores for stroke classification over-estimate performance. We recommend inclusion of equivocal predictions while calculating performance metrics for such analysis. Further, the high variability in performance of clinical scores in stroke identification and classification could be improved upon by creating a global data-pool with statistically important attributes. Scores based on Machine Learning from such globally pooled data may perform better and generalise at scale.


title: A Systematic Review and Meta-analysis of Polycystic Ovary Syndrome and Mental Health among Black Asian Minority Ethnic populations

abstract:
BackgroundPolycystic Ovary Syndrome (PCOS) is a chronic and a common gynaecological condition impacting women of reproductive age. Women with PCOS have hormonal, ovulatory and metabolic dysfunction resulting in multiple symptoms. The correlation between hormonal disbalance and the impact on womens mental health (MH) has been researched for decades. However, the prevalence among different ethnicities has not been fully evaluated.

MethodsA systematic methodology was developed, and a protocol was published in PROSPERO (CRD42020210863) and a systematic review of publications between 1st January 1990-30th January 2021 was conducted. Multiple electronic databases were explored using keywords and MeSH terms. The finalised dataset was analysed using statistical methods such as random-effect models, subgroup analysis and sensitivity analysis.

FindingsWe included 30 studies reporting on 3,944 PCOS women. Majority of studies addressed depression anxiety, and common mental health. Studies had fair to poor methodological quality and includes observational studies and Randomised Clinical Trials (RCTs). Overall, 17% (95% CI: 7% to 29%) of women with PCOS have clinical diagnosis of major or severe depression; 33% (95% CI: 26% to 40%) have elevated depressive symptoms or a clinical diagnosis of depression; 41% (95% CI: 28% to 54%) report anxiety symptoms, and 31% (95% CI: 15% to 51%) have a form a common mental health or are takingpsychiatric medication for anxiety and / or depression. The use of various tools to assess mental health symptoms was among the reasons for the substantial heterogeneity across studies.

InterpretationPCOS is associated with an increased risk of mental health disorders including depressive s, anxiety, and other mental health disorders. While BAME populations account for about 20% of most of the samples studied, stratification by ethnicity was rarely attempted which made it difficult to elucidate the MH impact of PCOS on different communities.

FundingNot applicable

PROSPERO registration numberCRD42020210863

category: obstetrics and gynecology


title: Placental transcription profiling in 6-23 weeks' gestation reveals differential transcript usage in early development

abstract: The human placenta is a rapidly developing transient organ that is key to pregnancy success. Early development of the conceptus occurs in a low oxygen environment before oxygenated maternal blood begins to flow into the placenta at [~]10-12 weeks gestation. This process is likely to substantially affect overall placental gene expression. Transcript variability underlying gene expression has yet to be profiled. In this study, accurate transcript expression profiles were identified for 84 human placental chorionic villus tissue samples collected across 6-23 weeks gestation. Differential gene expression (DGE), differential transcript expression (DTE) and differential transcript usage (DTU) between 6-10 weeks and 11-23 weeks gestation groups were assessed. In total, 229 genes had significant DTE yet no significant DGE. Integration of DGE and DTE analyses found that differential expression patterns of individual transcripts were commonly masked upon aggregation to the gene-level. Of the 611 genes that exhibited DTU, 534 had no significant DGE or DTE. The four most significant DTU genes ADAM10, VMP1, GPR126, and ASAH1, were associated with hypoxia-responsive pathways. Transcript usage is a likely regulatory mechanism in early placentation. Identification of functional roles will facilitate new insight in understanding the origins of pregnancy complications.


title: Population-based analysis of radiation-induced gliomas after cranial radiotherapy for childhood cancers

abstract:
BackgroundCranial radiotherapy (RT) is used to treat pediatric central nervous system (CNS) cancers and leukemias. RT carries a risk of secondary CNS malignancies, including radiation-induced gliomas, the epidemiology of which is poorly understood.

MethodsThis retrospective study using SEER registry data (1975-2016) included two cohorts. Cohort 1 included patients diagnosed with Grade III/IV or ungraded glioma as a second malignancy at least 2 years after receiving beam radiation and/or chemotherapy for a first malignancy diagnosed at ages 0-19 years, either a primary CNS tumor treated with RT (1a, n=57) or leukemia with unknown RT treatment (1b, n=20). Cohort 2 included patients with possible missed RIG who received RT for a primary CNS tumor diagnosed at 0-19 and then died of presumed progressive disease more than 5 years after diagnosis, since previous studies have documented many missed RIGs in this group (n=296). Controls (n=10,687) included all other patients ages 0-19 who received RT for a first CNS tumor or leukemia who did not fit inclusion criteria above.

ResultsFor Cohort 1 (likely/definite RIGs), 0.97% of patients receiving cranial RT went on to develop RIG. 3.39% of patients receiving cranial RT for primary CNS tumors fell in Cohort 2 (potential RIGs). Median latency to RIG diagnosis was 11.1 years; latency was significantly shorter for Cohort 1b (median 10.0, range 5.0-16.1) vs. 1a (12.0, 3.6-34.4, p=0.018). Median OS for Cohort 1 was 9.0 months. Receiving surgery, radiation, or chemotherapy were all associated with a non-statistically significant improvement in OS (p 0.1-0.2). 1.8% of brain tumor deaths in the cohort fell in Cohort 1, with an additional 7.9% in Cohort 2.

ConclusionWithin the limitations of a population-based study, 1-4% of patients undergoing cranial RT for pediatric cancers later develop RIG, which is incurable and can occur anywhere from 3-35 years later. 2-10% of pediatric brain tumor deaths are attributable to RIG. Effective treatment of RIG remains unclear and is thus deserving of increased attention in preclinical and clinical studies.


title: Safety and Immunogenicity of a 100 μg mRNA-1273 Vaccine Booster for Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2)

abstract:
ImportanceDue to the emergence of highly transmissible SARS-CoV-2 variants, evaluation of boosters is needed.

ObjectivesEvaluate safety and immunogenicity of 100-{micro}g of mRNA-1273 booster dose in adults.

DesignOpen-label, Phase 2/3 study.

SettingMulticenter study at 8 sites in the U.S.

ParticipantsThe mRNA-1273 100-{micro}g booster was administered to adults who previously received a two dose primary series of 100-{micro}g mRNA-1273 in the phase 3 Coronavirus Efficacy (COVE) trial, at least 6 months earlier.

InterventionLipid nanoparticle containing 100-{micro}g of mRNA encoding the spike glycoprotein of SARS-CoV-2 (Wuhan-HU-1).

Main Outcomes and MeasuresSolicited local and systemic adverse reactions, and unsolicited adverse events were collected after vaccination. Primary immunogenicity objectives were to demonstrate non-inferiority of the neutralizing antibody (nAb) response against SARS-CoV-2 based on the geometric mean titer (GMTs) and the seroresponse rates (SRRs) (booster dose vs. primary series in a historical control group). nAbs against SARS-CoV-2 variants were also evaluated.

ResultsThe 100-{micro}g booster dose had a greater incidence of local and systemic adverse reactions compared to the second dose of mRNA-1273 as well as the 50-{micro}g mRNA-1273 booster in separate studies. The geometric mean titers (GMTs; 95% CI) of SARS-CoV-2 nAbs against the ancestral SARS-CoV-2 at 28 days after the 100-{micro}g booster dose were 4039.5 (3592.7,4541.8) and 1132.0 (1046.7,1224.2) at 28 days after the second dose in the historical control group [GMT ratio=3.6 (3.1,4.2)]. SRRs (95% CI) were 100% (98.6,100) at 28 days after the booster and 98.1% (96.7,99.1) 28 days after the second dose in the historical control group [percentage difference=1.9% (0.4,3.3)]. The GMT ratio (GMR) and SRR difference for the booster as compared to the primary series met the pre-specified non-inferiority criteria. Delta-specific nAbs also increased (GMT fold-rise=233.3) after the 100-{micro}g booster of mRNA-1273.

Conclusions and RelevanceThe 100-{micro}g mRNA-1273 booster induced a robust neutralizing antibody response against SARS-CoV-2, and reactogenicity was higher with the 100-{micro}g booster dose compared to the authorized booster dose level in adults (50-{micro}g). mRNA-1273 100-{micro}g booster dose can be considered when eliciting an antibody response might be challenging such as in moderately or severely immunocompromised hosts.

Trial Registration: NCT04927065

Key PointsQuestion: What is the safety and immunogenicity of a booster dose of 100 {micro}g of mRNA-1273 in adults who previously received the primary series of mRNA-1273?

Findings: In this open-label, Phase 2/3 study, the 100 {micro}g booster dose of mRNA-1273 had a greater incidence of local and systemic adverse reactions compared to a 50 {micro}g booster dose of mRNA- 1273 or after the second dose of mRNA-1273 during the primary series. The 100 {micro}g booster dose of mRNA-1273 induced a robust antibody response against the ancestral SARS-CoV-2 and variants.

Meaning: mRNA-1273 100 {micro}g booster dose might be considered when eliciting an antibody response might be challenging, such as in moderately or severely immunocompromised hosts.


title: Efficacy of LD Bio Aspergillus ICT Lateral flow assay for serodiagnosis of chronic pulmonary aspergillosis

abstract:
BackgroundThe diagnosis of CPA relies on the detection of IgG Aspergillus antibody which is not freely available, especially in resource-poor settings. Point-of-care tests like LDBio Aspergillus ICT lateral flow assay, evaluated in only a few studies, have shown promising results for diagnosis of CPA. However no study has compared the diagnostic performances of LDBio LFA in setting of tuberculosis endemic countries and have compared it with that of IgG Aspergillus.

ObjectivesThis study aimed to evaluate the diagnostic performances of LDBio LFA in CPA and compare it with existing diagnostic algorithm utilising ImmunoCAP IgG Aspergillus.

MethodsSerial patients presenting with respiratory symptoms (cough, hemoptysis, fever etc) for > 4 weeks were screened for eligibility. Relevant investigations including direct microscopy and culture of respiratory secretions, IgG Aspergillus, chest imaging etc were done according to existing algorithm. Serum of all patients were tested by LDBio LFA and IgG Aspergillus (ImmunoCAP Asp IgG) and their diagnostic performances were compared.

ResultsA total of 174 patients were included in the study with [~]66.7% patients having past history of tuberculosis. A diagnosis of CPA was made in 74 (42.5%) of patients. The estimated sensitivity and specificity of LDBio LFA was 67.6% (95% CI: 55.7%-78%) and 81% (95% CI: 71.9%-81%) respectively which increased to 73.3% (95% CI: 60.3%-83.9%) and 83.9% (95% CI: 71.7%-92.4%) respectively in patients with past history of tuberculosis. The sensitivity and specificity of IgG Aspergillus was 82.4% (95% CI: 71.8%-90.3%) and 82% (95% CI: 73.1-89%); 86.7% (95% CI: 75.4%-94.1%) and 80.4% (95% CI: 67.6%-89.8%) in the whole group and those with past history of tuberculosis respectively.

ConclusionsLDBio LFA is a point-of-care test with reasonable sensitivity and specificity. However, further tests may have to be done to rule-in or rule-out the diagnosis of CPA in the appropriate setting.


title: Oxylipin profiling identifies a mechanistic signature of metabolic syndrome: results from two independent cohorts

abstract:
BackgroundMetabolic syndrome (MetS) is a complex condition encompassing a constellation of cardiometabolic abnormalities. Integratively phenotyping the molecular pathways involved in MetS would help to deeply characterize its pathophysiology and to better stratify the risk of cardiometabolic diseases. Oxylipins are a superfamilly of lipid mediators regulating most biological processes involved in cardiometabolic health.

MethodsA high-throughput validated mass spectrometry method allowing the quantitative profiling of over 130 oxylipins was applied to identify and validate the oxylipin signature of MetS in two independent case/control studies involving 476 participants.

ResultsWe have uncovered and validated an oxylipin signature of MetS (coined OxyScore) including 23 oxylipins and having high performances of classification and replicability (cross-validated AUCROC of 89%, 95% CI: 85%-93% and 78%, 95% CI: 72%-85% in the Discovery and Replication studies, respectively). Correlation analysis and comparison with a classification model incorporating both the oxylipins and the MetS criteria showed that the oxylipin signature brings consistent and complementary information supporting its clinical utility. Moreover, the OxyScore provides a unique mechanistic signature of MetS regarding the activation and/or negative feedback regulation of crucial molecular pathways that may help identify patients at higher risk of cardiometabolic diseases.

ConclusionOxylipin profiling identifies a mechanistic signature of metabolic syndrome that may help to enhance MetS phenotyping and ultimately to better predict the risk of cardiometabolic diseases via a better patient stratification.

category: endocrinology


title: The association between plasma chemokines and breast cancer risk and prognosis: A Mendelian randomization study

abstract:
BackgroundDespite the potential role of several chemokines in the migration of cytotoxic immune cells to prohibit breast cancer cell proliferation, a comprehensive view of chemokines and the risk and prognosis of breast cancer is scarce, and little is known about their causal associations.

MethodsWith a two-sample Mendelian randomization (MR) approach, genetic instruments associated with 30 plasma chemokines were created. Their genetic associations with breast cancer risk and survival were extracted from the recent genome-wide association study, with available survival information for 96,661 patients. We further tested the associations between the polygenetic risk score (PRS) for chemokines and breast cancer in the UK Biobank cohort using logistic regression models. The association between chemokine expression in tumors and breast cancer survival was analyzed in the TCGA cohort with Cox regression models.

ResultsPlasma CCL5 was causally associated with the risk of breast cancer in the MR analysis, which was significant in the luminal and HER-2 enriched subtypes and further confirmed using PRS analysis (OR=0.94, 95% CI=0.89-1.00). A potential causal association with breast cancer survival was only found for plasma CCL19, especially for ER-positive patients. In addition, we also found an inverse association between CCL19 expression in tumors and breast cancer overall and relapse-free survival (HR=0.58, 95% CI=0.35-0.95).

ConclusionWe observed an inverse association between genetic predisposition to CCL5 and the risk of breast cancer, while CCL19 was associated with breast cancer survival. These associations suggested the potential of these chemokines as tools for breast cancer prevention and treatment.


title: Field evaluation of a novel, rapid diagnostic assay RLDT, and molecular epidemiology of enterotoxigenic E. coli among Zambian children presenting with diarrhea.

abstract:
BackgroundEnterotoxigenic Escherichia coli (ETEC) is one of the top aetiologic agents of diarrhea in children under the age of 5 in low-middle income countries (LMICs). The lack of point of care diagnostic tools for routine ETEC diagnosis results in limited data regarding the actual burden and epidemiology in the endemic areas. We evaluated performance of the novel Rapid LAMP based Diagnostic Test (RLDT) for detection of ETEC in stool as a point of care diagnostic assay in a resource-limited setting.

MethodsWe conducted a cross-sectional study of 324 randomly selected stool samples from children under 5 presenting with moderate to severe diarrhea (MSD). The samples were collected between November 2012 to September 2013 at selected health facilities in Zambia. The RLDT was evaluated by targeting three ETEC toxin genes [heat labile toxin (LT) and heat stable toxins (STh, and STp)]. Quantitative PCR was used as the "gold standard" to evaluate the diagnostic sensitivity and specificity of RLDT for detection of ETEC. We additionally described the prevalence and seasonality of ETEC.

ResultsThe study included 50.6% of participants that were female. The overall prevalence of ETEC was 19.8% by qPCR and 19.4 % by RLDT. The children between 12 to 59 months had the highest prevalence of 22%. The study determined ETEC toxin distribution was LT (49%), ST (34%) and LT/ST (16%). The sensitivity and specificity of the RLDT compared to qPCR using a Ct 35 as the cutoff, were 90.7% and 97.5% for LT, 85.2% and 99.3% for STh and 100% and 99.7% for STp, respectively.

ConclusionThe results of this study suggest that RLDT is sufficiently sensitive and specific and easy to implement in the endemic countries. Being rapid and simple, the RLDT also presents as an attractive tool for point-of-care testing at the health facilities and laboratories in the resource-limited settings.

Author SummaryETEC is one of the top causes of diarrheal diseases in low and middle income countries. The advancement of molecular diagnosis has made it possible to accurately detect ETEC in endemic areas. However, the complexity, infrastructure and cost implication of these tests has made it a challenge to routinely incorporate them in health facilities in endemic settings. The ETEC RLDT is a simple and cost-effective molecular tool that can be used to screen for ETEC in resource limited settings. Here, we described the performance of the RLDT against a qPCR as the gold standard. Our findings showed that the ETEC RLDT performs comparable to the qPCR and would be a suitable screening tool in health facilities in recourse limited settings.


title: A systematic review about skin lesions in children affected by Coronavirus Disease 2019 (excluding multisystem inflammatory syndrome in children): study protocol.

abstract: COVID-19 disease can give a range of skin manifestations, some of which specific to children and young patients. Given the different nature of the lesions in specific stages of the disease and the fact that they may be the only or predominant symptom of the disease, it is of great importance for the pediatrician and dermatologist to be familiar with COVID-19 skin lesions. The aim of this systematic review, conducted according to the PRISMA statement, is to investigate COVID-19-associated cutaneous involvement in children in terms of type of skin lesions, frequency, and time of onset, with the exclusion of those associated with multisystem inflammatory syndrome in children. A comprehensive literature search will be performed through PubMed between December 2019 and December 2021. The quality of each study will be assessed according to the STROBE tool for observational studies. This systematic review will provide evidence about the dermatological manifestations of COVID-19 disease in children published up to the end of year 2021. Recognizing skin symptoms as potential manifestations of COVID-19 in children is important for a non-delayed diagnosis, with prompt activation of the adequate tracing, isolation, and hygienic measures, and for timely treatment of unlikely but possible serious complications.


title: Financing global health security: estimating the costs of pandemic preparedness in Global Fund eligible countries

abstract:
IntroductionThe Global Fund to Fight AIDS, TB, and Malaria (the Global Fund) pivoted investments to support countries in their response to the COVID-19 pandemic. Recently, the Global Funds Board approved global pandemic preparedness and response as part of their new six-year strategy from 2023-2028.

MethodsPrior research estimated that US$124 billion is required, globally, to build sufficient country-level capacity for health security, with US$76 billion needed over an initial three-year period. Action-based cost estimates generated from that research were coded as directly, indirectly, or unrelated to systems strengthening efforts applicable to HIV, TB, and/or malaria.

ResultsOf approximately US$76 billion needed for country level capacity-building over the next three-year allocation period, we estimate that US$66 billion is needed in Global Fund-eligible countries, and over one-third relates directly or indirectly (US$6 billion and US$21 billion, respectively) to health systems strengthening efforts applicable to HIV, TB, and/or malaria disease programs currently supported by the Global Fund. Among these investments, cost drivers include financing for surveillance and laboratory systems, to combat antimicrobial resistance, and for training, capacity-building, and ongoing support for the healthcare and public health workforce.

ConclusionThis work highlights a potential strategic role for the Global Fund to contribute to health security while remaining aligned with its core mission. It demonstrates the value of action-based costing estimates to inform strategic investment planning in pandemic preparedness.

What is already known on this topicO_LIThe costs, globally, to build country-level public health capacity to address these gaps over the next five years has been previously estimated as US$96-$204 billion, with an estimated US$63-131 billion in investments required over the next three years.
C_LIO_LIResearch conducted prior to the COVID-19 pandemic indicated that over one-third of Global Funds budgets in 10 case-study countries aligned with health security priorities articulated by the Joint External Evaluation, particularly in the areas of laboratory systems, antimicrobial resistance, and workforce development.
C_LI

What this study addsO_LIWe estimate that over 85% of investments needed to build national capacities in health security, globally, over the next three years are in countries eligible for Global Fund support.
C_LIO_LIAreas of investment opportunity aligned with the Global Funds core mandate include financing for surveillance and laboratory systems, combating antimicrobial resistance, and developing and supporting robust healthcare and public health workforces.
C_LI

How this study might affect research, practice or policyO_LIIn aggregate, global-level data highlight areas of opportunity for the Global Fund to expand and further develop its support of global health security in areas aligned with its mandate and programmatic scope.
C_LIO_LISuch investment opportunities have implications not only for existing budgeting and allocation processes, but also for implementation models, partners, programming, and governance structures, should these areas of potential expansion be prioritized.
C_LIO_LIThis work emphasizes a role for targeted, action-based cost estimation to identify gaps and to inform strategic investment decisions in global health.
C_LI

category: public and global health


title: Patients at risk of pulmonary fibrosis Post Covid-19: Epidemiology, pulmonary sequelaes and humoral response

abstract:
BackgroundThe COVID-19 pandemic is one of the greatest public health problems. Our aims were to describe epidemiological characteristics, know the amount of protective antibodies and their permanence after a COVID-19 primary infection in patients with risk of pulmonary fibrosis.

MethodsDescriptive epidemiological and follow-up study of the humoral response in patients at risk of pulmonary fibrosis Post-Covid-19 hospitalized, between March and October 2020, and who were followed up for a one year after hospital discharge.

Results72 patients participated in the study, 52 showed pre-existing chronic comorbidities. COVID-19 clinical severity was rated in 6% mild, 58% as moderate and 36% as severe. After a year of follow-up, the forty percent had pulmonary sequelae, the most frequent (20%) was mild pulmonary fibrosis. Any case of reinfection was detected. All patients presented RBD IgG antibodies and 88% presented IgA antibodies after 8-9 months. The amount of RBD IgG was similar at 4-5 and 8-9 months post-Covid. There was no difference when level of RBD IgG according to the severity of the COVID-19 (p=0.441, p=0.594).

ConclusionsMild pulmonary fibrosis sequelae is exceptional but was detected in a high percentage. The amount of RBD IgG is maintained throughout the convalescent phase and seems to protect against new reinfections despite of emerging viral variants. However, seems not predict the developed or not of pulmonary fibrosis.


title: A rapid review of the effectiveness of alternative education delivery strategies in medical, dental, nursing and pharmacy education during the COVID-19 pandemic

abstract:
BackgroundEducation delivery in higher education institutions was severely affected by the COVID-19 pandemic, with emergency remote teaching developed and adapted promptly for the circumstances. This rapid review investigated the effectiveness of alternative education delivery strategies during the pandemic for medical, dental, nursing and pharmacy students, to help plan and adapt further education provision.

MethodsWe included 23 primary studies in undergraduate education, all published in 2020-2021, no relevant UK-based or postgraduate studies were found. Included studies comprised 10 single cohort descriptive; 11 comparative descriptive; and two RCTs. There was considerable variability in terms of students, type of distance learning, platforms used and outcome measures.

ResultsIn medicine (n=14), self-reported competency and confidence, and demonstrable suturing skills were achieved through participating in remote learning. However, lower levels of knowledge were obtained by students who received virtual or blended learning compared to in-person teaching (low-very low confidence). Using bespoke interactive platforms in undergraduate medical training was superior to standard video (low confidence) or  textbook presentations (very low confidence).

In dentistry (n=2), remote learning led to knowledge gained (low confidence), but self-reported practical and interpersonal skills were lower with remote rather than in-person learning (very low confidence).

In nursing (n=3), remote learning, when compared to in-person, resulted in similar knowledge and self-reported competency levels (very low confidence) pre-COVID, but confidence was higher when learning or assessment was conducted virtually (low confidence).

In pharmacy (n=4), virtual learning was associated with higher skills, but lower knowledge compared to in-person, pre-COVID; self-reported competency and confidence scores were similar between the two groups (very low confidence).

ConclusionsRemote teaching was valued, and learning was achieved, but the comparative effectiveness of virtual versus in-person teaching is less clear. Supplementary alternative or in-person practical sessions may be required post-emergency to address learning needs for some disadvantaged student groups.

category: medical education


title: Elevated Levels of IL-6 in IgA Nephropathy patients are induced by an Epigenetically-Driven Mechanism Triggered by Viral and Bacterial RNA

abstract:
Recently, a several models has been proposed to describe the pathogenesis of Immunoglobulin A nephropathy (IgAN), and among them the multihit and the gut-microbiota. These models explain the pathogenesis of IgAN caused by the production of aberrant IgA, but it is believed further predisposing factors are present, including immunological, genetic, environmental, or nutritional factors that can influence the pathogenesis and that could be useful for development of precision nephrology and personalized therapy.

Newly, the role of IL-6 in pathogenesis is becoming increasingly important. It is essential for glomerular immunoglobulin A deposition and the development of renal pathology in Cd37-deficient mice, even if the reason why levels of IL-6 are elevated in IgAN patients is not well understood. One attainable hypothesis on high levels of IL-6 in IgAN comes out from our recent whole genome DNA methylation screening in IgAN patients, that identified, among others, a hypermethylated region comprising Vault RNA 2-1 (VTRNA2-1), a non-coding RNA also known as precursor of miR-886 (pre-mi-RNA). Consistently, the VTRNA2-1 expression was found down-regulated in IgAN patients.

Here we confirm that VTRNA2-1 is low expressed in IgAN subjects compared to HS and we found that also in transplanted IgAN patients (TP-IgAN), compared to non IgAN transplanted patients (TP), the VTRNA2-1 transcript was expressed at level very low. We found that in IgAN patients with downregulated VTRNA2-1, PKR is overactivated, coherently with the role of the VTRNA2-1 that binds to PKR and inhibits its phosphorylation. The loss of the VTRNA2-1 natural restrain causes, in turn, the activation of CREB by PKR. We found CREB, a classical cAMP-inducible CRE-binding factor interacting with a region of the IL-6 promoter and leading to IL-6 production, overactivated both in IgAN and in TP-IgAN patients. Effectively, in the same patients, we found elevated levels of IL-6 correlating with CREB and PKR phosphorylation.

Since PKR is normally activated by bacterial and viral RNA we hypothesized that these microrganisms can further activate the PKR/CREB/IL-6 pathway leading to an excess of IL-6 production, explaining both the high levels of IL-6, both infection involvement in the disease, both cases of IgAN associated with COVID-19 infection and with COVID-19 RNA-vaccination, and recent data showing microbiota involvment in IgAN.

Effectively, we found that Effectively, we sfound that both the RNA poly(I:C) and the COVID-19 RNA-vaccine stimulation significantly increase the IL-6 levels in IgAN patient PBMCs.

The PKR/CREB/IL-6 pathway may be very important also in the setting of renal transplantation. We found that this pathway is upregulated also in IgAN transplanted patients. Recent studies showed that the cumulative risk of IgA nephropathy recurrence increases after transplant and is associated with a 3.7-fold greater risk of graft loss. Finally, we showed that the IL-6 secretion can be reduced by the PKR inhibitor imoxin.

In conclusion, the discovery of the upregulated VTRNA2-1/PKR/CREB/IL-6 pathway in IgAN patients may provide novel approach to treat the disease and may be useful for development of precision nephrology and personalized therapy, possibly by checking the VTRNA2-1 methylation level in IgAN patients.

category: nephrology


title: Elevated Levels of IL-6 in IgA Nephropathy patients are induced by an Epigenetically Driven Mechanism Triggered by Viral and Bacterial RNA


title: Understanding the comorbidity between posttraumatic stress severity and coronary artery disease using genome-wide information and electronic health records

abstract:
BackgroundThe association between coronary artery disease (CAD) and posttraumatic stress disorder (PTSD) contributes to the high morbidity and mortality observed among affected individuals. To understand the dynamics underlying PTSD-CAD comorbidity, we conducted a genetically-informed causal inference analysis using large-scale genome-wide association (GWA) statistics and follow-up analysis using electronic health records (EHR) and PTSD Checklist (PCL-17 or PCL-6) assessments available from the Million Veteran Program (MVP) and the UK Biobank (UKB), respectively.

MethodsWe used GWA statistics from MVP, UKB, the Psychiatric Genomics Consortium, and the CARDIoGRAMplusC4D Consortium to perform a bidirectional, two-sample Mendelian randomization (MR) analysis to assess cause-effect relationships between CAD and PTSD. We also conducted a pleiotropic meta-analysis to investigate loci with concordant vs. discordant effects between the traits investigated. Leveraging individual-level information derived from MVP and UKB EHRs, we assessed longitudinal changes in the association between CAD and posttraumatic stress severity.

FindingsWe observed a genetic correlation of CAD with PTSD case-control and quantitative outcomes, ranging from 0.18 to 0.32. Our two-sample MR showed a significant bidirectional relationship between CAD and PTSD symptom severity. Genetically-determined PCL-17 total score was associated with increased CAD risk (odds ratio=1.04; 95% confidence interval, 95%CI=1.01-1.06). Conversely, CAD genetic liability was associated with reduced PCL-17 total score (beta=-0.42; 95%CI=-0.04 - -0.81). These estimates were consistent across datasets and were not affected by heterogeneity or horizontal pleiotropy. The pleiotropic meta-analysis between PCL-17 and CAD identified loci with concordant effect enriched for platelet amyloid precursor protein pathway (p=2.97x10-7) and negative regulation of astrocyte activation (p=2.48x10-6) while discordant-effect loci were enriched for biological processed related lipid metabolism (e.g., triglyceride-rich lipoprotein particle clearance, p=1.61x10-10). The EHR-based follow-up analysis highlighted that earlier CAD diagnosis is associated with increased PCL-total score later in life, while lower PCL total score was associated with increased risk of a later CAD diagnosis (Mann-Kendall trend test: MVP tau=0.932, p<2x10-16; UKB tau=0.376, p=0.005)

InterpretationOur results highlight a complicated relationship between PTSD and CAD that may be affected by the long-term consequences of CAD on the mental health of the individuals affected.

FundingThis research was supported by funding from the VA Cooperative Studies Program (CSP, no. CSP575B) and the Veterans Affairs Office of Research and Development MVP (grant nos. MVP000 and VA Merit MVP025).


title: Investigation of Genetic Variants and Causal Biomarkers Associated with Brain Aging

abstract: Delta age is a biomarker of brain aging that captures differences between the chronological age and the predicted biological brain age. Using multimodal data of brain MRI, genomics, and blood-based biomarkers and metabolomics in UK Biobank, this study investigates an explainable and causal basis of high delta age. A visual saliency map of brain regions showed that lower volumes in the fornix and the lower part of the thalamus are key predictors of high delta age. Genome-wide association analysis of the delta age using the SNP array and whole-exome sequencing (WES) data identified novel associated genes related to carcinogenesis, immune response, and neuron survival. Mendelian randomization (MR) for all metabolomic biomarkers and blood-related phenotypes showed that immune-related phenotypes have a causal impact on increasing delta age. Our analysis revealed regions in the brain that are susceptible to the aging process and provided evidence of the causal and genetic connections between immune responses and brain aging.


title: Social connections at work and mental health during the first wave of the COVID-19 pandemic: Evidence from employees in Germany

abstract: Empirical evidence on the social and psychological impact of the COVID-19 pandemic in the workplace and the resulting consequences for the mental health of employees is still sparse. As a result, research on this subject is urgently needed to develop appropriate countermeasures. This study builds on Person-Environment fit theory to investigate social connections at work and mental health during the first wave of the COVID-19 pandemic. It analyses employees needs for social connections and how social connections affect different mental health measures. Survey data were collected in May 2020 in an online survey of employees across Germany and analysed using response surface analysis. Mental health was measured as positive mental health and mental health disorders. Social connections were measured as social support and social interactions. 507 employees participated in the survey and more than one third reported having less social support and social interaction at work than they desired (p < .001). This was associated with a decrease in mental health. In contrast, having more than the desired amount of social support was associated with a decrease and having more than the desired amount of social interaction with an increase in mental health. This study provides important early evidence on the impact of the first wave of the COVID-19 pandemic in the workplace. With it, we aim to stimulate further research in the field and provide early evidence on potential mental health consequences of social distancing measures - while also opening avenues to combat them.

category: health economics