title: Risk factors for hospitalization, disease severity and mortality in children and adolescents with COVID-19: Results from a nationwide German registry

abstract:
ObjectiveTo characterize the clinical features of children and adolescents hospitalized with SARS-CoV-2 infections and to explore predictors for disease severity.

DesignNationwide prospective observational cohort study.

SettingData collected from 169 out of 351 childrens hospitals in Germany between March 18, 2020 and April 30, 2021 and comparison with the Statutory Notification System.

Participants1,501 children and adolescents up to 19 years of age with laboratory confirmed SARS-CoV-2 infections who were admitted to childrens hospitals and subsequently reported to the COVID-19 registry of the German Pediatric Infectious Disease Society (DGPI).

Main outcome measuresAdmission to intensive care, in-hospital.

ResultsAs compared to the information in the statutory notification system, up to 30% of all children and adolescents hospitalized in Germany during the study period were reported to the DGPI registry. Median age was three years (IQR, 0-12), with 36% of reported cases being infants. Although roughly half of patients in the registry were not admitted to the hospital due to their SARS-CoV-2 infection, 72% showed infection-related symptoms during hospitalization. Preexisting comorbidities were present in 28%, most commonly respiratory disorders, followed by neurological, neuromuscular, and cardiovascular diseases. Median length of hospitalization was five days (IQR 3-10). Only 20% of patients received a SARS-CoV-2-related therapy. Infants were less likely to require therapy as compared to older children. Overall, 111 children and adolescents were admitted to intensive care units (ICU). In a fully adjusted model, patient age, trisomy 21, coinfections and primary immunodeficiencies (PID) were significantly associated with intensive care treatment. In a bivariate analysis, pulmonary hypertension, cyanotic heart disease, status post (s/p) cardiac surgery, fatty liver disease, epilepsy and neuromuscular impairment were statistically significant risk factors for ICU admission.

ConclusionOverall, a small proportion of children and adolescents was hospitalized in Germany during the first year of the pandemic. The majority of patients within our registry was not admitted due to COVID-19 suggesting an overestimation of the disease burden even in hospitalized children. Nevertheless, a large proportion of children and adolescents with confirmed COVID-19 reported in Germany could be captured. This allowed for detailed assessment of overall disease severity and underlying risk factors in our cohort. The main risk factors for COVID-19 disease associated intensive care treatment were older patient age, trisomy 21, PIDs and coinfection at the time of hospitalization.

Trial registrationRegistry of hospitalized pediatric patients with SARS-CoV-2 infection (COVID-19), DRKS00021506


title: Environmental Influences on Childhood Asthma Prevalence in Philadelphia

abstract:
BackgroundIn 2019, the American Lung Association found that, for the second year in a row, the Philadelphia metro has worsened the surrounding areas air quality, due to worsening ozone smog. This spike in unhealthy air quality in Philadelphia has affected the health of the citys population. Unhealthy air quality can be exacerbated by asbestos, which has been found in many Philadelphia elementary schools. Although asbestos usage is now highly regulated, it can still be found in consumer products and construction material today. Among the many factors contributing to asthma onset and other lung diseases, air pollution and dangerous air particles such as asbestos are important contributors. Children in these asbestos infected schools became exposed and ultimately sick which led to their schools eventual closure. Due to childrens immature and more vulnerable airways, this exposure may have led to increasing cases of respiratory distress.

MethodsThis research study analyzed publicly available asbestos data from Asbestos Hazard Emergency Response Act (AHERA) reports from four Philadelphia elementary schools (Laura H. Carnell, James J. Sullivan, Clara Barton, and Thomas M. Peirce) from 2016-2018 to further understand the influence of asbestos particles on asthma in children. Secondary data analysis determined the levels of asbestos contamination in each elementary school and the severity of the condition for each school. This was compared to childrens asthma prevalence during the selected time period.

ResultsAsbestos was mainly found in the 2-6 inch pipe insulation and tiles within each school. Between 0.06 and 1.18% asbestos damage was found in 2-6inch pipe insulation in schools closed for asbestos abatement. An r2 of 0.9997 was found when comparing the 206inch pipe damage percentage and the newly friable material found in each school. Thomas M. Pierce Elementary was determined to be the highest concern according to the analysis of the AHERA reports.

ConclusionChildren exposed to asbestos in elementary schools, and with a predisposition to asthma, were more likely to suffer from respiratory distress, due to the multiple contributing environmental factors.

category: occupational and environmental health


title: Fitness barriers to spread of colistin-resistant Klebsiella pneumoniae overcome by establishing niche in patient population with elevated colistin use

abstract:
There is an urgent need to improve our understanding of how new antibiotic resistant organisms emerge and spread. A high-priority resistance threat is the ST258 lineage of carbapenem-resistant Klebsiella pneumoniae. Here, we studied resistance to the last-line drug colistin among ST258 by tracking its evolution across 21 U.S. hospitals over the course of a year. Phylogenetic analysis supported a significant fitness cost being associated with resistance, as resistance emergence was common but resistance variants were rarely transmitted. Furthermore, several resistance variants that were transmitted had acquired secondary variants that reverted the strain to susceptible. The exceptions to the general pattern of instability associated with resistance were two large clusters of resistant strains in one sublineage (clade IIB) present across Southern California hospitals. Quantification of transmission fitness in the healthcare environment indicated that, while resistant isolates from other clades were less fit than their susceptible counterparts, clade IIB resistant isolates were more fit, despite having similar resistance variants. Additional analyses supported the increased fitness of colistin-resistant clade IIB isolates being driven by a lineage-defining variant that increased clade IIBs association with patient subpopulations with enhanced colistin exposure. These results show that a favorable genetic background and sustained selective pressure led to the emergence and spread of a colistin-resistant ST258 sublineage across a regional healthcare network. These findings highlight the utility of integrating pathogen genomic and corresponding clinical data from regional healthcare networks to detect emerging antibiotic resistance threats and understand the clinical practices and patient populations that drive their spread.

Significance StatementSelective pressure in hospitals leads to frequent antibiotic resistance evolution. However, emergent resistance alleles are often not transmitted to other individuals because of fitness costs associated with resistance. Due to the difficulty of studying pathogen fitness in humans, our understanding of how resistant organisms circumvent these costs is limited. We integrate genomic and clinical data to understand the evolutionary trajectories leading to transmissible resistance for the last-line antibiotic colistin. While colistin resistance is generally associated with a fitness cost that hinders transmission, this cost was mitigated in a sublineage that had previously acquired mutations increasing its association with patient populations more likely to receive colistin, suggesting a key role for historical contingency in the emergence and spread of stable resistance.

category: infectious diseases


title: Fitness barriers to spread of colistin resistance overcome by first establishing niche in patients with enhanced colistin exposure


title: Early Prediction of In-Hospital Death of COVID-19 Patients: A Machine-Learning Model Based on Age, Blood Analyses, and Chest X-Ray Score

abstract:
BackgroundTo develop and validate an early-warning model to predict in-hospital mortality on admission of COVID-19 patients at an emergency department (ED).

MethodsIn total, 2782 patients were enrolled between March 2020 and December 2020, including 2106 patients (first wave) and 676 patients (second wave) in the COVID-19 outbreak in Italy. The first-wave patients were divided into two groups with 1474 patients used to train the model, and 632 to validate it. The 676 patients in the second wave were used to test the model. Age, 17 blood analytes and Brescia chest X-ray score were the variables processed using a Random Forests classification algorithm to build and validate the model. ROC analysis was used to assess the model performances. A web-based death-risk calculator was implemented and integrated within the Laboratory Information System of the hospital.

ResultsThe final score was constructed by age (the most powerful predictor), blood analytes (the strongest predictors were lactate dehydrogenase, D-dimer, Neutrophil/Lymphocyte ratio, C-reactive protein, Lymphocyte %, Ferritin std and Monocyte %), and Brescia chest X-ray score. The areas under the receiver operating characteristic curve obtained for the three groups (training, validating and testing) were 0.98, 0.83 and 0.78, respectively.

ConclusionsThe model predicts in-hospital mortality on the basis of data that can be obtained in a short time, directly at the ED on admission. It functions as a web-based calculator, providing a risk score which is easy to interpret. It can be used in the triage process to support the decision on patient allocation.


title: Cross-neutralizing activity against SARS-CoV-2 variants in COVID-19 patients: Comparison of four waves of the pandemic in Japan

abstract: In March 2021, Japan is facing a 4th wave of SARS-CoV-2 infection. To prevent further spread of infection, sera cross-neutralizing activity of patients previously infected with conventional SARS-CoV-2 against novel variants is important but is not firmly established. We investigated the neutralizing potency of 81 COVID-19 patients sera from 4 waves of pandemic against SARS-CoV-2 variants using their authentic viruses. Most sera had neutralizing activity against all variants, showing similar activity against B.1.1.7 and D614G, but lower activity especially against B.1.351. In the 4th wave, sera-neutralizing activity against B.1.1.7 was significantly higher than that against any other variants, including D614G. The cross-neutralizing activity of convalescent sera was effective against all variants but was potentially weaker for B.1.351.


title: Convalescent Plasma in Critically ill Patients with COVID-19

abstract:
BACKGROUNDThe evidence for benefit of convalescent plasma for critically ill patients with Covid-19 is inconsistent. We hypothesized that convalescent plasma would improve outcomes for critically ill adult patients with Covid-19.

METHODSIn an ongoing adaptive platform trial, critically ill patients with confirmed Covid-19, defined as receiving intensive care-level organ support, were randomized to open-label convalescent plasma or not (i.e., control group). The primary end point was organ support-free days (i.e., days alive and free of ICU-based organ support) up to day 21. The primary analysis was a Bayesian cumulative logistic model with predefined criteria for superiority or futility. An odds ratio greater than 1 represented improved survival, more organ support-free days, or both.

RESULTSThe convalescent plasma intervention was stopped after pre-specified criteria for futility were met. At that time, 1084 participants had been randomized to convalescent plasma and 916 to no convalescent plasma (control). The median organ support-free days were 0 (interquartile range, -1 to 16) for the convalescent plasma group and 3 (interquartile range, -1 to 16) days for the control group. The median adjusted odds ratio (OR) was 0.97 (95% credible interval 0.83 to 1.15) and posterior probability of futility (OR < 1.2) was 99.4% for convalescent plasma compared to control. In-hospital mortality was 37.3% (401/1075) in convalescent plasma group, and 38.4% (347/904) in controls. The observed treatment effects were consistent across primary and secondary outcomes.

CONCLUSIONSIn critically ill adults with confirmed Covid-19, treatment with convalescent plasma, did not improve clinical outcomes.

Clinicaltrials.gov: NCT02735707

category: intensive care and critical care medicine


title: Topology identifies emerging adaptive mutations in SARS-CoV-2

abstract: The COVID-19 pandemic has initiated an unprecedented worldwide effort to characterize its evolution through the mapping of mutations of the coronavirus SARS-CoV-2. The early identification of mutations that could confer adaptive advantages to the virus, such as higher infectivity or immune evasion, is of paramount importance. However, the large number of currently available genomes precludes the efficient use of phylogeny-based methods. Here we establish a fast and scalable early warning system based on Topological Data Analysis for the identification and surveillance of emerging adaptive mutations in large genomic datasets. Analyzing millions of SARS-CoV-2 genomes from GISAID, we demonstrate that topologically salient mutations are linked with an increase in infectivity or immune escape. We report on emerging potentially adaptive mutations as of January 2022, and pinpoint mutations in Variants of Concern that are likely due to convergent evolution. Our approach can improve the surveillance of mutations of concern, guide experimental studies, and aid vaccine development.

category: epidemiology


title: Topological data analysis identifies emerging adaptive mutations in SARS-CoV-2


title: Association of leucocyte telomere length with frailty: a large-scale cross-sectional analysis in UK Biobank

abstract:
BackgroundLeucocyte telomere length (LTL), a potential marker of biological age, has been associated with risk of many diseases. We investigated whether LTL is associated with risk of frailty, a multidimensional syndrome of decline that affects multiple systems and predisposes to adverse health outcomes.

MethodsIn a cross-sectional analysis, we studied 441,781 UK Biobank participants (aged 40-70 years), with complete data on LTL and frailty indicators. We defined frailty as the presence of at least three of five indicators: weaker grip strength, slower walking pace, weight loss in the past year, lower physical activity, and exhaustion in the past two weeks. We evaluated association of LTL with frailty using adjusted (chronological age, sex, deprivation, smoking, alcohol intake, body mass index, multimorbidity) multinomial and ordinal regression models. We used Mendelian randomisation (MR), using 131 genetic variants associated with LTL, to assess if the association of LTL with frailty was causal.

FindingsFrail participants (4{middle dot}6%) were older (median age difference (95% CI): 3 (2{middle dot}5; 3{middle dot}5) years), more likely to be female (61%), and had shorter LTL (-0{middle dot}13SD vs 0{middle dot}03SD) than non-frail. In adjusted analyses, both age and LTL were associated with frailty (OR=1{middle dot}03 (95%CI: 1{middle dot}02-1{middle dot}04) per year of older chronological age; 1{middle dot}10 (1{middle dot}08; 1{middle dot}11) per SD shorter LTL). Within each age group (40-49, 50-59, 60-69 years) the prevalence of frailty was about 33% higher in participants with shorter (-2SD) versus longer telomeres (+2SD). MR analysis showed an association of LTL with frailty that was directionally consistent with the observational association, but not statistically significant.

InterpretationInter-individual variation in LTL is associated with the risk of frailty independently of chronological age and other risk factors. Our findings provide evidence for an additional biological determinant of frailty.

FundingThe UK Medical Research Council, the Biotechnology and Biological Sciences Research Council and the British Heart Foundation (MRC grant: MR/M012816/1) funded our measurements of LTL in UK Biobank. The funders had no role in study design; the collection, analysis, and interpretation of data; the writing of the report; and the decision to submit the paper for publication.

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSTelomere length has been proposed as a biomarker of biological age. Shorter leucocyte telomere length (LTL) is associated with higher incidence of several age-associated diseases, spanning multiple body systems, and with lower life expectancy. However, the association of shorter LTL with frailty, a multidimensional syndrome of decline across multiple systems, is inconclusive. We searched PubMed using the terms "telomere length AND frailty" in the title, abstract, or text with no language restrictions. This search identified 50 papers published before 30 November, 2020. Of these, three systematic reviews and/ or meta-analyses of modest size (five to nine studies, with total n<10,000) and 11 original research articles reported on associations between telomere length and frailty. These small-scale studies, primarily in older individuals, do not support an independent association between shorter LTL and higher risk of frailty.

Added value of this studyOur large-scale population-based study, involving over 441,000 participants, provides strong evidence that shorter LTL is associated with higher risk of both pre-frailty and frailty even after adjustment for chronological age and other established determinants of frailty, namely, age, sex, alcohol intake, smoking, obesity, deprivation and multimorbidity. Within each age group (40-49, 50-59, 60-69 years) the prevalence of frailty was about 33% higher in participants with shorter (-2SD) versus longer telomeres (+2SD). Part of the association of shorter LTL with higher risk of frailty may be due to the association in aggregate of LTL with diseases. Findings using genetic variants associated with LTL as instruments were directionally consistent with the observational association, but not statistically significant.

Implications of all the available evidenceShorter LTL is associated with frailty independent of chronological age and several other risk factors. The observation that risk of frailty associated with shorter LTL is proportionately similar across the age range of 40-70 years suggests that shorter LTL acts through a mechanism beyond just accelerating the impact of chronological ageing on risk of frailty.


title: Deaths involving COVID-19 by disability status: a retrospective analysis of 29 million adults during the first two waves of the Coronavirus pandemic in England

abstract:
ObjectivesTo assess the association between self-reported disability and deaths involving COVID-19 among adults in England.

DesignCohort study of >29 million adults using data from the Office for National Statistics Public Health Data Asset.

SettingPeople living in private households or communal establishments (including care homes) in England.

Participants29,293,845 adults (47% male) aged 30-100 years (mean age = 56) present at the 2011 Census who were alive on 24 January 2020. The main exposure was self-reported disability from the 2011 Census.

Main outcome measuresDeath involving COVID-19, occurring between 24 January 2020 and 28 February 2021. We estimated the age-standardised mortality rate per 100,000 person-years at-risk, stratified by sex, disability status, and wave of the pandemic. We calculated hazard ratios (HRs) for disabled people compared with non-disabled people, adjusted for geographical factors, socio-demographic characteristics, and pre-pandemic health conditions.

ResultsDisabled people made up 17% of the study population, including 7% who were  more-disabled and 10%  less-disabled. From 24 January 2020 to 28 February 2021, 105,213 people died from causes involving COVID-19 in England, 58% of whom were disabled. Age-adjusted analyses showed that, compared to non-disabled people, mortality involving COVID-19 was higher among both more-disabled people (HR=3.05, 95% CI: 2.98 to 3.11 in males; 3.48, 3.41 to 3.56 in females) and less-disabled people (HR=1.88, 95% CI: 1.84 to 1.92 in males; 2.03, 1.98 to 2.08 in females). Among people aged 30-69, HRs reached 8.47 (8.01 to 8.95) among more-disabled females and 5.42 (5.18 to 5.68) for more-disabled males. Sequential adjustment for residence type, geography, socio-demographics, and health conditions partly explained the associations, indicating that a combination of these factors contributed towards the increased risk.

ConclusionDisabled people in England had markedly increased risk of mortality involving COVID-19 compared to non-disabled people and should be prioritised within the pandemic response.


title: Safety, Immunogenicity, and Efficacy of a COVID-19 Vaccine (NVX-CoV2373) Co-administered With Seasonal Influenza Vaccines

abstract:
BackgroundThe safety and immunogenicity profile of COVID-19 vaccines when administered concomitantly with seasonal influenza vaccines has not yet been reported.

MethodsA sub-study on influenza vaccine co-administration was conducted as part of the phase 3 randomized trial of the safety and efficacy of NVX-CoV2373. The first [~]400 participants meeting main study entry criteria and with no contraindications to influenza vaccination were invited to join the sub-study. After randomization in a 1:1 ratio to receive NVX-CoV2373 (n=217) or placebo (n=214), sub-study participants received an age-appropriate, licensed, open-label influenza vaccine with dose 1 of NVX-CoV2373. Reactogenicity was evaluated via electronic diary for 7 days post-vaccination in addition to monitoring for unsolicited adverse events (AEs), medically-attended AEs (MAAEs), and serious AEs (SAEs). Influenza haemagglutination inhibition and SARS-CoV-2 anti-spike IgG assays were performed. Vaccine efficacy against PCR-confirmed, symptomatic COVID-19 was assessed. Comparisons were made between sub-study and main study participants.

FindingsSub-study participants were younger, more racially diverse, and had fewer comorbid conditions than main study participants. Reactogenicity events more common in the co-administration group included tenderness (70.1% vs 57.6%) or pain (39.7% vs 29.3%) at injection site, fatigue (27.7% vs 19.4%), and muscle pain (28.3% vs 21.4%). Rates of unsolicited AEs, MAAEs, and SAEs were low and balanced between the two groups. Co-administration resulted in no change to influenza vaccine immune response, while a reduction in antibody responses to the NVX-CoV2373 vaccine was noted. Vaccine efficacy in the sub-study was 87.5% (95% CI: -0.2, 98.4) while efficacy in the main study was 89.8% (95% CI: 79.7, 95.5).

InterpretationThis is the first study to demonstrate the safety, immunogenicity, and efficacy profile of a COVID-19 vaccine when co-administered with seasonal influenza vaccines. The results suggest concomitant vaccination may be a viable immunisation strategy.

FundingThis study was funded by Novavax, Inc.

Research in ContextO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed for research articles published from December 2019 until 1 April 2021 with no language restrictions for the terms "SARS-CoV-2", "COVID-19", "vaccine", "co-administration", and "immunogenicity". There were no peer-reviewed publications describing the simultaneous use of any SARS-CoV-2 vaccine and another vaccine. Several vaccine manufacturers had recent publications on phase 3 trials results (Pfizer/BioNTech, Moderna, AstraZeneca, Janssen, and the Gamaleya Research Institute of Epidemiology and Microbiology). Neither these publications nor their clinical trials protocols (when publicly available) described co-administration and they often had trial criteria specifically excluding those with recent or planned vaccination with any licenced vaccine near or at the time of any study injection.

Added value of this studyImmune interference and safety are always a concern when two vaccines are administered at the same time. This is the first study to demonstrate the safety and immunogenicity profile and clinical vaccine efficacy of a COVID-19 vaccine when co-administered with a seasonal influenza vaccine.

Implications of all the available evidenceThis study provides much needed information to help guide national immunisation policy decision making on the critical issue of concomitant use of COVID-19 vaccines with influenza vaccines.

category: allergy and immunology


title: CD16ahigh NK cell infiltration and spatial relationships with T cells and macrophages can predict improved progression-free survival in high grade ovarian cancer

abstract:
BackgroundHigh grade serous cancer (HGSC) remains a highly fatal malignancy with less than 50% of patients surviving 5 years after diagnosis. Despite its high mutational burden, HGSC is relatively refractory to checkpoint immunotherapy, suggesting that additional features of the cancer and its interactions with the immune system remain to be understood. Natural killer (NK) cells may contribute to HGSC control, but the role(s) of this population or its subsets in this disease are poorly understood.

MethodsWe used a TMA containing duplicate treatment-naive tumors from 1145 patients with HGSC and a custom staining panel to simultaneously measure macrophages, T cells and NK cells, separating NK cells based on CD16a expression. Using pathologist-validated digital pathology, machine learning, computational analysis and Pearsons correlations, we quantitated infiltrating immune cell density, co-infiltration and co-localization with spatial resolution to tumor region. We compared the prognostic value of innate, general, and adaptive immune cell "neighborhoods" to define characteristics of HGSC tumors predictive for progression-free survival and used flow cytometry to define additional features of the CD16adim NK cell subset.

ResultsNK cells were observed in >95% of tumor cores. Intrastromal localization of CD16alow and CD16ahigh NK cells was associated with shorter and longer progression-free survival, respectively. CD16ahigh NK cells most frequently co-localized with T cells and macrophages; their proximity was termed an "adaptive" neighborhood. We find that tumors with more area represented by adaptive immune cell neighborhoods corresponded to superior progression free survival. In contrast, CD16alow NK cells did not co-infiltrate with other immune cell types, and expressed the ectonucleotidases, CD39 and CD73, which have been previously associated with poor prognosis in patients with HGSC.

ConclusionsProgression-free survival for patients with HGSC may be predicted by the subset of NK cells within the tumor infiltrate (i.e. CD16ahigh vs. CD16alow). NK cell subtypes were associated predictable co-infiltrating and co-localizing leukocyte subsets, suggesting that their presence and activity may influence, or be influenced by the tumor microenvironment. Our data suggest that immunotherapeutic strategies for HGSC should consider the constitution of NK cell subsets and may benefit from mobilizing and activating CD16high NK cells.

category: oncology


title: Support needs and barriers to accessing support: Baseline results of a mixed-methods national survey of people bereaved during the COVID-19 pandemic

abstract:
BackgroundThe COVID-19 pandemic is a mass bereavement event which has profoundly disrupted grief experiences. Understanding support needs and access to support among people bereaved at this time is crucial to ensuring appropriate bereavement support infrastructure.

AimTo investigate grief experiences, support needs and use of formal and informal bereavement support among people bereaved during the pandemic.

DesignBaseline results from a longitudinal survey. Support needs and experiences of accessing support are reported using descriptive statistics and thematic analysis of free-text data.

Setting/Participants711 adults bereaved in the UK between March-December 2020, recruited via media, social media, national associations and community/charitable organisations.

ResultsHigh-level needs for emotional support were identified. Most participants had not sought support from bereavement services (59%, n=422) or their GP (60%, n=428). Of participants who had sought such support, over half experienced difficulties accessing bereavement services (56%, n=149)/GP support (52%, n=135). 51% reported high/severe vulnerability in grief; among these, 74% were not accessing bereavement or mental-health services. Barriers included limited availability, lack of appropriate support, discomfort asking for help, and not knowing how to access services. 39% (n=279) experienced difficulties getting support from family/friends, including relational challenges, little face-to-face contact, and disrupted collective mourning. The perceived uniqueness of pandemic bereavement and wider societal strains exacerbated their isolation.

ConclusionsPeople bereaved during the pandemic have high levels of support needs alongside difficulties accessing support. We recommend increased provision and tailoring of bereavement services, improved information on support options, and social/educational initiatives to bolster informal support and ameliorate isolation.

Key statementsO_ST_ABSWhat is already known about the topic?C_ST_ABS- Features of pandemic bereavement, such as traumatic death experiences, exacerbate family distress and add to the complexity of grief.
- In pre-pandemic times most people mainly relied on the informal support of friends and family to cope with their bereavement, but an estimated 40% required more formal therapeutic support from bereavement or mental health services.
- Bereaved people experience difficulties getting the support that they need from bereavement services and their social networks.

What this paper adds- Participants had high level needs for emotional support, especially dealing with/expressing feelings, with 51% experiencing high or severe vulnerability in grief; however, 74% of this group were not accessing formal bereavement service or mental health support.
- Most participants had not tried to access bereavement services, for reasons such as lack of appropriate support, discomfort in asking for help and uncertainty of how to access services; of the 41% who tried, 56% experienced difficulties such as long waiting lists or ineligibility.
- A substantial proportion of people (39%) reported difficulties accessing support from friends and family; reduced in-person contact affected the perceived quality of support and disrupted collective mourning practices, whilst the wider social difficulties of the pandemic compounded feelings of isolation.

Implications for policy and practice- Further investment in the provision of tailored bereavement support is needed to meet the diverse needs and backgrounds of bereaved people, including support that is culturally and crisis/context competent, and group-based support for those with shared experiences and characteristics.
- To raise awareness of support options, information on grief and bereavement services should be provided proactively following a death and made available in online and community settings, with GPs and other primary care providers better resourced to signpost to appropriate support.
- Following compassionate communities approaches, expanded provision of informal community-based support and activities could help with isolation, whilst longer-term educational and societal initiatives are needed to bolster community support for people experiencing death, dying and bereavement.

category: public and global health


title: Reopening International Borders without Quarantine: Contact Tracing Integrated Policy against COVID-19

abstract: With the COVID-19 vaccination widely implemented in most countries, propelled by the need to revive the tourism economy, there is a growing prospect for relieving the social distancing regulation and reopening borders in tourism-oriented countries and regions. The need incentivizes stakeholders to develop border control strategies that fully evaluate health risks if mandatory quarantines are lifted. In this study, we have employed a computational approach to investigate the contact tracing integrated policy in different border reopening scenarios in Hong Kong, China. Built on a modified SEIR epidemic model with a 30% vaccination coverage, the results suggest that scenarios with digital contact tracing and quick isolation intervention can reduce the infectious population by 92.11% compared to those without contact tracing. By further restricting the inbound population with a 10,000 daily quota and applying moderate-to-strong community non-pharmacological interventions (NPIs), the average daily confirmed cases in the forecast period of 60 days can be well controlled at around 9 per day (95% CI: 7-12). Two main policy recommendations are drawn from the study. First, digital contact tracing would be an effective countermeasure for reducing local virus spread, especially when it is applied along with a moderate level of vaccination coverage. Second, implementing a daily quota on inbound travelers and restrictive community NPIs would further keep the local infection under control. This study offers scientific evidence and prospective guidance for developing and instituting plans to lift mandatory border control policies in preparing for the global economic recovery.


title: The prevalence, incidence, prognosis and risk factors for depression and anxiety in a UK cohort during the COVID-19 pandemic

abstract:
BackgroundThe COVID-19 pandemic had profound immediate impacts on population mental health. However, in whom the effects may be prolonged is less clear.

AimsTo investigate the prevalence, incidence, prognosis, and risk factors for depression and anxiety reported in a UK cohort over three distinct periods in the pandemic in 2020.

MethodAn online survey was distributed to a UK community cohort (n=3097) at three points: April (baseline), July-September (T2) and November-December (T3). Participants completed validated measures of depression and anxiety on each occasion and we prospectively explored the role of socio-demographic factors and psychological factors (loneliness, positive mood, perceived risk of and worry about COVID-19) as risk factors.

ResultsDepression (PHQ-9 means - baseline: 7.69, T2: 5.53, T3: 6.06) and anxiety scores (GAD-7 means -baseline: 6.59, T2: 4.60, T3: 4.98) were considerably greater than pre-pandemic population norms. Women reported greater depression and anxiety than men. Being younger, having prior mental health disorders, more negative life events due to COVID-19, as well as greater loneliness and lower positive mood at baseline were significant predictors of poorer mental health outcomes.

ConclusionThe negative impact of the COVID-19 pandemic on mental health has persisted to some degree. Younger people and individuals with prior mental health disorders were at greatest risk. Easing of restrictions might bring the opportunity for a return to social interaction, which could mitigate the risk factors of loneliness and positive mood.

category: psychiatry and clinical psychology


title: IMPACT OF COVID-19 PANDEMIC ON SICKNESS ABSENCE FOR MENTAL ILL HEALTH IN NATIONAL HEALTH SERVICE STAFF

abstract:
ObjectiveTo explore the patterns of sickness absence in National Health Service (NHS) staff attributable to mental ill health during the first wave of the Covid-19 epidemic in March - July 2020

DesignCase-referent analysis of a secondary data set

SettingNHS Trusts in England

ParticipantsPseudonymised data on 959,356 employees who were continuously employed by NHS trusts during 1 January 2019 to 31 July 2020

Main Outcome MeasuresTrends in the burden of sickness absence due to mental ill health from 2019 to 2020 according to demographic, regional and occupational characteristics.

ResultsOver the study period, 164,202 new sickness absence episodes for mental ill health were recorded in 12.5% (119,525) of the study sample. There was a spike of sickness absence for mental ill health in March-April 2020 (899,730 days lost) compared with 519,807 days in March-April 2019; the surge was driven by an increase in new episodes of long-term absence and had diminished by May/June 2020. The increase was greatest in those aged >60 years (227%) and among employees of Asian and Black ethnic origin (109%-136%). Among doctors and dentists the number of days absent declined by 12.7%. The biggest increase was in London (122%) and the smallest in the East Midlands (43.7%); the variation between regions reflected the rates of Covid-19 sickness absence during the same period.

ConclusionAlthough the Covid-19 epidemic led to an increase in sickness absence attributed to mental ill health in NHS staff, this had substantially declined by May/June 2020, corresponding with the decrease in pressures at work as the first wave of the epidemic subsided.

Article SummaryStrengths and limitations of this study

O_LILarge study population
C_LIO_LIStudy population were not self-selected
C_LIO_LIJob exposure matrix allowed adjustment for occupational exposure
C_LIO_LIData did not extend to the start of the second wave in September 2020
C_LI


title: Impact of long-term care facility size on preparedness and adherence to infection prevention and control guidance for the mitigation of COVID-19

abstract:
AimTo evaluate the preparedness and adherence of Brazilian long-term care facilities (LTCFs) to the World Health Organization (WHO) infection prevention and control (IPC) guidance and examine the association of LTCF size with adherence to recommendations.

MethodsWe conducted a cross-sectional study of LTCF managers for 12 consecutive weeks from May 5, 2020. We developed and pre-tested a 46-item questionnaire based on WHO IPC guidance that included multiple-choice and dichotomous questions as well as an open-ended question on the main difficulties encountered by the facility in tackling the pandemic. Using a global adherence score based on the adoption of 20 recommendations, we classified preparedness as (1) excellent for LTCFs following [≥]14 recommendations, (2) good for those following 10-13 recommendations, and (3) poor for those following <10 recommendations. LTCF size was established as small, medium, and large according to a 2-step cluster analysis of the number of residents as a continuous variable. We used descriptive statistics and chi-square tests at a 5% significance level.

ResultsOf 362 facilities included in the study, 308 (85.1%) adhered to 14 or more recommendations; 3 were classified as poorly adherent. Regarding LTCF size, we found a lower adherence to screening visitors for COVID-19 signs and symptoms (p=0.037) and to isolating patients until they have 2 negative laboratory tests (p=0.032) in larger facilities than in medium and small facilities.

ConclusionsPreparedness for mitigating COVID-19 in Brazilian LTCFs was considered excellent for most of the proposed recommendations, regardless of LTCF size. Difficulties and problems with infrastructure and/or resident care were much less commonly reported than those related to maintenance of a sufficient stock of materials, workforce management, and financial distress.

category: geriatric medicine


title: Subcutaneous REGEN-COV Antibody Combination in Early SARS-CoV-2 Infection

abstract:
ImportanceEasy-to-administer antiviral treatments may be used to prevent progression from asymptomatic infection to COVID-19 and to reduce viral carriage.

ObjectiveEvaluate the efficacy and safety of subcutaneous casirivimab and imdevimab antibody combination (REGEN-COV) to prevent progression from early asymptomatic SARS-CoV-2 infection to COVID-19.

DesignRandomized, double-blind, placebo-controlled, phase 3 study that enrolled asymptomatic close contacts living with a SARS-CoV-2-infected household member (index case). Participants who were SARS-CoV-2 RT-qPCR-positive at baseline were included in the analysis reported here.

SettingMulticenter trial conducted at 112 sites in the United States, Romania, and Moldova.

ParticipantsAsymptomatic individuals [≥]12 years of age were eligible if identified within 96 hours of collection of the index cases positive SARS-CoV-2 test sample.

InterventionsA total of 314 asymptomatic, SARS-CoV-2 RT-qPCR-positive individuals living with an infected household contact were randomized 1:1 to receive a single dose of subcutaneous REGEN-COV 1200mg (n=158) or placebo (n=156).

Main Outcome(s) and Measure(s)The primary endpoint was the proportion of participants who developed symptomatic COVID-19 during the 28-day efficacy assessment period. The key secondary efficacy endpoints were the number of weeks of symptomatic SARS-CoV-2 infection and the number of weeks of high viral load (>4 log10 copies/mL). Safety was assessed in all treated participants.

ResultsSubcutaneous REGEN-COV 1200mg significantly prevented progression from asymptomatic to symptomatic disease compared with placebo (31.5% relative risk reduction; 29/100 [29.0%] vs 44/104 [42.3%], respectively; P=.0380). REGEN-COV reduced the overall population burden of high-viral load weeks (39.7% reduction vs placebo; 48 vs 82 total weeks; P=.0010) and of symptomatic weeks (45.3% reduction vs placebo; 89.6 vs 170.3 total weeks; P=.0273), the latter corresponding to an approximately 5.6-day reduction in symptom duration per symptomatic participant. Six placebo-treated participants had a COVID-19-related hospitalization or ER visit versus none for those receiving REGEN-COV. The proportion of participants receiving placebo who had [≥]1 treatment-emergent adverse events was 48.1% compared with 33.5% for those receiving REGEN-COV, including events related (39.7% vs 25.8%, respectively) or not related (16.0% vs 11.0%, respectively) to COVID-19.

Conclusions and RelevanceSubcutaneous REGEN-COV 1200mg prevented progression from asymptomatic SARS-CoV-2 infection to COVID-19, reduced the duration of high viral load and symptoms, and was well tolerated.

Trial RegistrationClinicalTrials.gov Identifier, NCT04452318

KEY POINTSO_ST_ABSQuestionC_ST_ABSCan treatment with the anti-SARS-CoV-2 antibody combination REGEN-COV prevent COVID-19 and reduce viral load when given to recently exposed and asymptomatic individuals?

FindingsIn this randomized, double-blind, phase 3 trial, subcutaneously administered REGEN-COV 1200 mg significantly reduced progression of asymptomatic SARS-CoV-2 infection to symptomatic infection (ie, COVID-19) by 31.5% compared with placebo. REGEN-COV also reduced the overall population burden of high viral load weeks (39.7% reduction vs placebo; 48 vs 82 total weeks; P=.0010).

MeaningIn the current pandemic, utilization of subcutaneous REGEN-COV prevents progression of early asymptomatic infection to COVID-19 and reduces viral carriage.


title: Subcutaneous REGEN-COV Antibody Combination in Early Asymptomatic SARS-CoV-2 Infection: A Randomized Clinical Trial


title: The findings of Antimicrobial Resistance Surveillance in Bangladesh (2016-2020)

abstract:
Surveillance is one of the effective tools to address antimicrobial resistance. In Bangladesh a countrywide antimicrobial resistance surveillance has been ongoing since 2016. The main objective of this surveillance is to formulate the guideline for clinicians and to assist policy makers to know the gravity of the AMR problem in Bangladesh.

It is a case-based surveillance conducted by Institute of Epidemiology, Disease Control & Research (IEDCR) in nine sentinel sites where five types of clinical cases were selected according to case definition, and ten types of bacteria were identified from six types of preselected specimens. All the laboratory works were performed following the standard operating procedure supplied by the AMR surveillance Reference laboratory at IEDCR. Total 19,263 samples were processed during the period of March 2017 to March 2020 among which wound swab yielded highest growth (57%). E. coli was the highest (1717) isolated organism among the ten priority pathogens which showed highest sensitivity (91%) to Imipenem. Imipenem also showed higher sensitivity to most of the organisms. Third generation cephalosporin was found to be less sensitive to Escherichia coli (37%) and Klebsiella pneumoniae (28%); nevertheless, Salmonella species showed higher sensitivity (97%) to it. Acinetobacter calcoaceticus-baumannii complex isolated from ICU patients showed alarming resistance to all of the antibiotics including highest sensitive antibiotic Imipenem (29%). Salmonella species isolated from blood showed higher susceptibility to most of the antibiotics except ciprofloxacin (7%). Alarmingly, only 36% of the Staphylococcus aureus isolates showed susceptibility to cefoxitin indicates high prevalence of MRSA infection.

The result of the surveillance representing the whole country is surely alarming as many of the bacteria are resistant to the commonly used as well as reserve groups of antibiotics. Concerted effort should be taken from all concerned authorities to curb the problem immediately.


title: Chronic fatigue and post-exertional malaise in people living with long COVID

abstract:
PurposePeople living with long COVID describe a high symptom burden, and a more detailed assessment of chronic fatigue and post-exertional malaise (PEM) may inform the development of rehabilitation recommendations. The aims of this study were to use validated questionnaires to measure the severity of fatigue and compare this with normative data and thresholds for clinical relevance in other diseases; measure and describe the impact of PEM; and assess symptoms of dysfunctional breathing, self-reported physical activity/sitting time, and health-related quality of life.

MethodsThis was an observational study involving an online survey for adults living with long COVID (data collection from February-April, 2021) following a confirmed or suspected SARS-CoV-2 infection. Questionnaires included the Functional Assessment of Chronic Illness Therapy-Fatigue Scale (FACIT-F) and DePaul Symptom Questionnaire-Post-Exertional Malaise.

ResultsAfter data cleaning, n=213 participants were included in the analysis. Participants primarily identified as women (85.5%), aged 40-59 (78.4%), who had been experiencing long COVID symptoms for [≥]6 months (72.3%). The total FACIT-F score was 18{+/-}10 (where the score can range from 0-52, and a lower score indicates more severe fatigue), and 71.4% were experiencing chronic fatigue. Post-exertional symptom exacerbation affected most participants, and 58.7% met the scoring thresholds used in people living with myalgic encephalomyelitis/chronic fatigue syndrome. PEM occurred alongside a reduced capacity to work, be physically active, and function both physically and socially.

ConclusionLong COVID is characterized by chronic fatigue that is clinically relevant and is at least as severe as fatigue in several other clinical conditions, including cancer. PEM appears to be a common and significant challenge for the majority of this patient group. Patients, researchers, and allied health professionals are seeking information on safe rehabilitation for people living with long COVID, particularly regarding exercise. Fatigue and post-exertional symptom exacerbation must be monitored and reported in studies involving interventions for people with long COVID.


title: Estimating the Burden of SARS-CoV-2 among the Rohingya Refugees

abstract:
BackgroundSince the emergence of the COVID-19 pandemic, substantial concern has surrounded its impact among the Rohingya refugees living in the Kutupalong-Balukhali refugee camps in Bangladesh. Early modeling work projected a massive outbreak was likely after an introduction of the SARS-CoV-2 virus into the camps. Despite this, only 317 laboratory-confirmed cases and 10 deaths were reported through October 2020. While these official numbers portray a situation where the virus has been largely controlled, other sources contradict this, suggesting the low reported numbers to be a result of limited care seeking and testing, highlighting a population not willing to seek care or be tested. SARS-CoV-2 seroprevalence estimates from similar a timeframe in India (57%) and Bangladesh (74%) further sow doubt that transmission had been controlled. Here we explore multiple data sources to understand the plausibility of a much larger SARS-CoV-2 outbreak among the Rohingya refugees.

MethodsWe used a mixed approach to analyze SARS-CoV-2 transmission using multiple available datasets. Using data from reported testing, cases, and deaths from the World Health Organization (WHO) and from WHOs Emergency Warning, Alert, and Response System, we characterized the probabilities of care seeking, testing, and being positive if tested. Unofficial death data, including reported pre-death symptoms, come from a community-based mortality survey conducted by the International Organization for Migration (IOM),) in addition to community health worker reported deaths. We developed a probabilistic inference framework, drawing on these data sources, to explore three scenarios of what might have happened among the Rohingya refugees.

ResultsAmong the 144 survey-identified deaths, 48 were consistent with suspected COVID-19. These deaths were consistent with viral exposures during Ramadan, a period of increased social contacts, and coincided with a spike in reported cases and testing positivity in June 2020. The age profile of suspected COVID-19 deaths mirrored that expected. Through the probability framework, we find that under each scenario, a substantial outbreak likely occurred, though the cumulative size and timing vary considerably. In conjunction with the reported and suspected deaths, the data suggest a large outbreak could have occurred early during spring 2020. Furthermore, while many mild and asymptomatic infections likely occurred, death data analyzed suggest there may have been significant unreported mortality.

ConclusionsWith the high population density, inability to home isolate adequately, and limited personal protective equipment, infection prevention and control in the Rohingya population is extremely challenging. Despite the low reported numbers of cases and deaths, our results suggest an early large-scale outbreak is consistent with multiple sources of data, particularly when accounting for limited care seeking behavior and low infection severity among this young population. While the currently available data do not allow us to estimate the precise incidence, these results indicate substantial unrecognized SARS-CoV-2 transmission may have occurred in these camps. However, until serological testing provides more conclusive evidence, we are only able to speculate about the extent of transmission among the Rohingya.


title: Cervical Cancer Screening in South Florida Veteran Population 2014-2020: Cytology and High-Risk HPV Correlation and HPV Epidemiology

abstract:
ObjectiveThis project aims to use our robust womens health patient data to analyze the correlation between cytology and Hr-HPV testing, study performance of Hr-HPV testing for detecting cytology lesions, and examine epidemiologic measures of HPV infections in the womens veteran population.

MethodsWe collected patient data from 2014 to 2020 from our computerized patient record system. We performed HPV assays using the ROCHE 4800 system. The COBAS HPV assay detects HPV 16, HPV 18, and 12 other HPV types (31, 33, 35, 39, 45, 51, 56, 58, 59, 66, and 68). We organized cytology results and Hr-HPV assays with Microsoft Access and Microsoft Excel for analysis.

ResultsA total of 9437 cervical specimens were co-tested. High-grade cytology lesions (HSIL or higher and ASC-H) were overwhelmingly positive for Hr-HPV (94.1% and 87.2%, respectively). Low-grade cytology lesions (LSIL and ASC-US) were positive for Hr-HPV in lower percentages (72.6% and 54.9%, respectively). Hr-HPV testing had a sensitivity of 91.3%, a specificity of 93.1%, a positive predictive value of 16.4%, and a negative predictive value of 99.8% for detecting high-grade cytology lesions. Hr-HPV testing had a lower performance for detecting low-grade cytology lesions. Ten (10) cases had high-grade cytology and negative Hr-HPV test. Nine out of ten (9/10) of these patients showed no dysplasia (6) or low-grade dysplasia (3) on subsequent biopsy. Overall, 14.4% of tests were positive for Hr-HPV. The highest positive Hr-HPV test rates were in the second and eighth decades of life, 25.1% and 22.0%, respectively. In women over age 30, HPV types 16 and 18 were present in 11.7% and 6.4% of tests, respectively. Other HPV types were present in 82.3% of tests.

ConclusionsHr-HPV testing has high performance for detecting high-grade cytology lesions. We believe our findings are in accordance with recent studies and guidelines that recommend primary Hr-HPV testing as the preferred screening method. The percentage of positive Hr-HPV tests and rates for age and HPV types 16 and 18 in our womens veteran population suggest similar HPV prevalence to that of the general US population.

category: pathology


title: Patient Outcomes and Lessons-Learned from Treating Patients with Severe COVID-19 at a Long-Term Acute Care Hospital

abstract:
ObjectiveTo describe characteristics, clinical management, and patient outcomes during and after acute COVID-19 phase in a long-term acute care hospital in the Northeastern United States.

MethodsA single-center retrospective analysis of electronic medical records of patients treated for COVID-19-related impairments, from March 19, 2020 through August 14, 2020, was conducted to evaluate patient outcomes in response to the facilitys holistic treatment approach.

Results118 admissions were discharged by the data cut-off. Mean patient age was 63 years, 64.1% were male, and 29.9% of patients tested-positive for SARS-CoV-2 infection at admission. The mean (SD) length-of-stay at was 25.5 (13.0) days and there was a positive correlation between patient age and length-of-stay. Of the 51 patients non-ambulatory at admission, 83.3% were ambulatory at discharge. Gait increased 217.4 feet from admission to discharge, a greater increase than the reference cohort of 146.3 feet. 93.8% (15/16) of patients mechanically ventilated at admission were weaned before discharge (mean 11.3 days). 74.7% (56/75) of patients admitted with a restricted diet were discharged on a regular diet.

ConclusionThe majority of patients treated at a long-term acute care hospital for severe COVID-19 and related complications improved significantly through coordinated care and rehabilitation.

category: rehabilitation medicine and physical therapy


title: A qualitative study exploring the experience of the Medical Intern Programme: Supportive transition for international doctors working in the NHS

abstract:
BackgroundThe UK is experiencing a shortage of doctors. Consequently, the Medical Intern Programme, a unique two year programme consisting of an observership, four clinical rotations at the level of a foundation doctor within an NHS Trust and a postgraduate diploma from a university in the north of England, was set up to enhance the NHS workforce by facilitating the entry of international medical graduates into UK medicine via a supported transitional programme. We aimed to explore the experiences of the doctors enrolled on the Medical Intern Programme.

MethodsSemi-structured interviews were conducted via the telephone with seven doctors enrolled on the programme. The interview guide was informed by the research questions and data were analysed using a thematic analysis.

ResultsWe identified four themes that were important in the experiences of the doctors: preparing to work in the UK, feeling supported, weighing up the pros and cons of the programme and comparisons between countries.

ConclusionsThe Medical Intern Programme successfully facilitated international doctors transition to the UK and working in the NHS. Support needs to be provided at the organisational, team and individual level including a period of observing and shadowing to enable the doctors to understand the systems and multidisciplinary team working in the NHS.

category: medical education


title: Urine test predicts kidney injury and death in COVID-19

abstract:
BackgroundKidney injury is common in COVID-19 infection, but serum creatinine (SCr) is not a sensitive or specific marker of kidney injury. We hypothesized that molecular markers of tubular injury could diagnose COVID-19 associated kidney damage and predict its clinical course.

MethodsThis is a prospective cohort study of 444 consecutive COVID-19 patients (43.9% females, 20.5% African American, 54.1% Latinx) in Columbia Universitys Emergency Department at the peak of the New York pandemic (March-April 2020). Urine and blood were collected simultaneously at admission (median time of day 0, IQR 0-2 days) and within 1 day of a positive SARS-CoV-2 test in 70% of patients. Biomarker assays were blinded to clinical data.

ResultsUrinary NGAL (uNGAL) was strongly associated with AKI diagnosis (267{+/-}301 vs. 96{+/-}139 ng/mL, P=1.6x10-10). uNGAL >150ng/mL had 80% specificity and 75% sensitivity to diagnose AKIN stage 2 or higher. uNGAL quantitatively predicted the duration of AKI and outcomes, including death, dialysis, shock, and longer hospital stay. The risk of death increased 73% per standard deviation of uNGAL [OR (95%CI): 1.73 (1.29-2.33), P=2.8x10-4] and was independent of baseline SCr, co-morbidities, and proteinuria [adjusted OR (95%CI): 1.51 (1.10-2.11), P=1.2x10-2]. Proteinuria and uKIM-1 also indicated tubular injury but were not diagnostic of AKI. Typically, distal nephron segments transcribe NGAL, but in COVID-19 biopsies with widespread acute tubular injury (ATI), NGAL expression overlapped KIM-1 in proximal tubules.

ConclusionuNGAL predicted diagnosis, duration, and severity of AKI and ATI, as well as hospital stay, dialysis, shock, and death in patients with acute COVID-19.

category: nephrology


title: Quarantine and testing strategies to reduce transmission risk from imported SARS-CoV-2 infections: a global modelling study

abstract:
BackgroundMany countries require incoming air travellers to quarantine on arrival and/or undergo testing to limit importation of SARS-CoV-2.

MethodsWe developed mathematical models of SARS-CoV-2 viral load trajectories over the course of infection to assess the effectiveness of quarantine and testing strategies. We consider the utility of pre and post-flight Polymerase Chain Reaction (PCR) and lateral flow testing (LFT) to reduce transmission risk from infected arrivals and to reduce the duration of, or replace, quarantine. We also estimate the effect of each strategy relative to domestic incidence, and limits of achievable risk reduction, for 99 countries where flight data and case numbers are estimated.

ResultsWe find that LFTs immediately pre-flight are more effective than PCR tests 3 days before departure in decreasing the number of departing infectious travellers. Pre-flight LFTs and post-flight quarantines, with tests to release, may prevent the majority of transmission from infectious arrivals while reducing the required duration of quarantine; a pre-flight LFT followed by 5 days in quarantine with a test to release would reduce the expected number of secondary cases generated by an infected traveller compared to symptomatic self-isolation alone, Rs, by 85% (95% UI: 74%, 96%) for PCR and 85% (95% UI: 70%, 96%) for LFT, even assuming imperfect adherence to quarantine (28% of individuals) and self-isolation following a positive test (86%). Under the same adherence assumptions, 5 days of daily LFT testing would reduce Rs by 91% (95% UI: 75%, 98%).

ConclusionsStrategies aimed at reducing the risk of imported cases should be considered with respect to: domestic incidence, transmission, and susceptibility; measures in place to support quarantining travellers; and incidence of new variants of concern in travellers origin countries. Daily testing with LFTs for 5 days is comparable to 5 days of quarantine with a test on exit or 14 days with no test.


title: Maternal cigarette smoking and cleft lip and palate: A systematic review and meta-analysis

abstract:
ObjectivesA systematic review and meta-analysis to determine the association between active maternal smoking and cleft lip and palate etiology.

Data SourcesMedline, Embase, Web of Science and the Cochrane database from inception to November 2020.

Study selectionObservational studies of cigarette smoking habits in pregnant women. Outcomes included cleft lip and/or palate, cleft lip {+/-} palate and cleft palate only.

Data analysisPublication bias analyses were performed and the Newcastle Ottawa scales were used to assess study quality. Fixed or random effect models were used in the meta-analysis, dependent on risk of statistical heterogeneity.

ResultsForty-five studies were eligible for inclusion of which 11 were cohort and 34 were case-control studies. Sixteen studies were of sufficient standard for inclusion in the meta-analysis. The summary odds ratio for the association between smoking and cleft lip and/or palate was 1.42 (95%CI 1.27 to 1.59) with a population attributable fraction of 4% (95%CI 3% - 5%). There was limited evidence to show a dose-response effect of smoking.

ConclusionsThis review reports a moderate association between maternal smoking and orofacial cleft but the overall quality of the conventional observational studies included was poor. There is a need for high quality and novel research strategies to further define the role of smoking in the etiology of cleft lip and palate.


title: Coupling freedom from disease principles and early warning from wastewater surveillance to improve health security

abstract: Infectious disease surveillance is vitally important to maintaining health security, but these efforts are challenged by the pace at which new pathogens emerge. Wastewater surveillance can rapidly obtain population-level estimates of disease transmission, and we leverage freedom from disease principles to make use of non-detection of SARS-CoV-2 in wastewater to estimate the probability that a community is free from SARS-CoV-2 transmission. From wastewater surveillance of 24 treatment plants across upstate New York beginning in May 2020, we observed a reliable limit of detection of 0.3--0.5 cases per 10,000 population. No COVID-19 cases were reported 40% of the time following a non-detection of SARS-CoV-2 in wastewater, and cases were less than 1 daily case per 10,000 population 97% of the time following non-detection. Trends in the intensity of SARS-CoV-2 in wastewater correlate with trends in COVID-19 incidence and test positivity ({rho}>0.5), with the greatest correlation observed for active cases and a three-day lead time between wastewater sample date and clinical test date. Wastewater surveillance can cost-effectively demonstrate the geographic extent of the transmission of emerging pathogens, confirming that transmission is absent or under control and alerting of an increase in transmission. If a statewide wastewater surveillance platform had been in place prior to the onset of the COVID-19 pandemic, policymakers would have been able to complement the representative nature of wastewater samples to individual testing, likely resulting in more precise public health interventions and policies.


title: Natural language inference for clinical registry curation

abstract: Clinical registries - structured databases of demographic, diagnosis, and treatment information for patients with specific diseases or phenotypes - play vital roles in high-quality retrospective studies, operational planning, and assessment of patient eligibility for research, including clinical trials. However, registries are extremely time and resource intensive to curate. Natural language processing (NLP) can help, but standard NLP methods require specially annotated training sets or the construction of separate models for each of dozens or hundreds of different registry fields, rendering them insufficient for registry curation at scale. Natural language inference (NLI), a specific branch of NLP focused on logical relationships between statements, presents a possible solution, but NLI methods are largely unexplored in the clinical domain outside the realm of conference shared tasks and computer science benchmarks. Here we convert registry curation into an NLI problem, applying five state-of-the-art, pretrained, deep learning based NLI models to clinical, laboratory, and pathology notes to infer information about 43 different breast oncology registry fields. We evaluate the models inferences against a manually curated, 7439 patient breast oncology research database. The NLI models show considerable variation in performance, both within and across registry fields. One model, ALBERT, outperforms the others (BART, RoBERTa, XLNet, and ELECTRA) on 22 out of 43 fields. A detailed error analysis reveals that incorrect inferences primarily arise through models misinterpretations of temporality--they interpret historical findings as current and vice versa--as well as confusion based on subtle terminology and abbreviation variants common in clinical notes. However, modern NLI methods show promise for increasing the efficiency of registry curation, even when used "out of the box" with no additional training.

category: health informatics


title: The NICE COVID-19 search strategy for Ovid MEDLINE and Embase: developing and maintaining a strategy to support rapid guidelines

abstract: Introduction The United Kingdom's (UK) National Institute for Health and Care Excellence (NICE) needs access to evidence on COVID-19 to develop rapid guidelines for healthcare professionals. This paper reports on how the NICE COVID-19 search strategy for identifying references in Ovid MEDLINE and Embase has been developed and maintained. Methods Each free-text line from the June 2020 version of the NICE COVID-19 search strategy was categorised as Critical, High, Medium, Low or Zero priority, according to the number of results and their relevance to NICE. Five search options were devised and tested by combining them with a search for drug treatments. The two prioritised options were compared to the COVID-19 Limit available in Ovid. New subject headings were tested and added. The selected option was refined to make the strategy simpler to use. Results The updated strategy combines free-text terms, categorised as Critical, High and Medium priority for NICE, with appropriate subject headings. Discussion The paper describes the challenges of maintaining a search strategy during the COVID-19 pandemic, as terminology continues to evolve. Conclusions A search strategy for identifying COVID-19 references, within the remit of NICE, has been developed. The recommended strategy could be considered for validation at an appropriate point in the pandemic. It is hoped that understanding how NICE has maintained its COVID-19 strategy will encourage further discussion on the challenges.


title: A pilot feasibility study on SARS-CoV-2 detection method based on nasopharyngeal lavage fluid

abstract:
ObjectiveNose and nasopharyngeal swab is the preferred and worldwide accepted method to detect the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) within the nose and nasopharynx. This method may be linked with possible difficulties, such as patients discomfort or complications. This paper shows a pilot study of SARS-CoV-2 detection with nasal and nasopharyngeal lavage fluids.

MethodsNasal lavage fluid was collected from patients who were submitted to SARS-CoV-2 screening test, due to a preceding positive rapid antigen test. A control group was enrolled among healthcare professionals whose nasopharyngeal swab tested negative. Nasal lavages were performed using isotonic saline solution injected through a nasal fossa. Both lavage fluid and traditional nasopharyngeal swab were analyzed by real-time PCR and antigenic test.

ResultsA total of 49 positive subjects were enrolled in the study. Results of the analysis on lavages and nasopharyngeal swabs were concordant for 48 cases, regardless of the antigenic and molecular test performed. RT-PCR resulted weakly positive at swab in one case and negative at lavage fluid. Among the control group (44 subjects) nasopharyngeal swab and lavage fluid analyses returned a negative result. Sensitivity of the molecular test based on nasal lavage fluid, compared to traditional nasal swab, was 97.7%, specificity was 100%, and accuracy was 98.9%, with high agreement (Cohens k, 0.978).

ConclusionNasal and nasopharyngeal lavages resulted to be highly reliable and well tolerated. A larger series is needed in order to confirm these results. This approach may potentially represent a valid alternative to the traditional swab method in selected cases.


title: A pan-European study of SARS-CoV-2 variants in wastewater under the EU Sewage Sentinel System

abstract: Wastewater based surveillance employing qPCR has already shown its utility for monitoring SARS-CoV-2 at community level, and consequently the European Commission has recommended the implementation of an EU Sewage Sentinel System. However, using sequencing for the determination of genomic variants in wastewater is not fully established yet. Therefore, we focused on the sequencing analysis of SARS-CoV-2 RNA in wastewater samples collected across 20 European countries including 54 municipalities. Our results provide unprecedented insight into the abundance and the profile of the mutations associated with the variants of concerns: B.1.1.7, P.1, B.1.351 and B.1.617.2, which were present in various wastewater samples. This study shows that integrating genomic and wastewater-based epidemiology (WBE) can support the identification of variants circulating in a city at community level.


title: Ketamine for the multivariate effect of PTSD: Systematic review and meta-analysis

abstract: The aim of this systematic review and meta-analysis was to examine the efficacy, anti-effect of ketamine (intervention) for post-traumatic stress disorder (PTSD) patients during analgesia proceeding and mental illness treatment methods, in comparison with control (midazolam, opioid, saline or placebo). The bibliographic databases Cochrane, Embase, Pubmed and Web of Science were searched from inception to 23 May 2021 for randomized controlled trials, case-control and cohort studies included. For continuous and dichotomous outcomes, respectively, we calculated the mean difference using the inverse-variance method and the risk ratio with the Mantel-Haenszel method. In all, ten trials with 705 patients were included. Confirmed by meta-analysis, ketamine didnt increase the prevalence of PTSD by a risk ratio (95 % CI) of 0.86 (0.61 to 1.20), p = 0.38 in 3 trials with 503 patients. Evidence of a difference was found in the PTSD-scales taken between ketamine and control during short durations (months), with a mean difference (95 % CI) of 2.45 (1.33 to 3.58), p < 0.001 in three trials with 65 patients. Another evidence is shown in chronic PTSD (years), with a mean difference (95 % CI) of -3.66 (-7.05 to -0.27), p = 0.03 in three trials with 91 patients. Sub-group analysis underlined the increased benefit of ketamine administration for those in whom the procedure was more than one week in the chronic PTSD group. The adoption of ketamine for the short duration of PTSD is in avoidance, but for chronic PTSD is recommended and, in the opinion of the authors, should be considered as a new therapy in view of its potential to ameliorate arousal, avoidance and dissociative symptoms, neuroticism after trauma needing more animal research and clinical trials.

category: pharmacology and therapeutics


title: Targeted vaccination and the speed of SARS-CoV-2 adaptation

abstract: The limited supply of vaccines against SARS-CoV-2 raises the question of targeted vaccination. Older and more sensitive hosts should be vaccinated first to minimize the disease burden. But what are the evolutionary consequences of targeted vaccination? We clarify the consequences of different vaccination strategies through the analysis of the speed of viral adaptation measured as the rate of change of the frequency of vaccine-escape mutations. We show that a vaccine-escape mutant is expected to spread faster if vaccination targets individuals which are likely to be involved in a higher number of contacts. We also discuss the pros and cons of dose-sparing strategies. Because delaying the second dose increases the proportion of the population vaccinated with a single dose, this strategy can both speed-up the spread of the vaccine-escape mutant and reduce the cumulated number of deaths. Hence, slowing down viral adaptation may not always be the optimal vaccination strategy. We contend that a careful assessment of the consequences of alternative vaccination strategies on both (i) the speed of adaptation and (ii) the mortality is required to determine which individuals should be vaccinated first.


title: SIGMA METRICS ASSESSMENT AS QUALITY IMPROVEMENT METHODOLOGY IN A CLINICAL CHEMISTRY LABORATORY

abstract:
BackgroundThe concept of sigma metrics & lean six sigma is well known in the field of healthcare. However not many labs utilize the six sigma metrics for maintenance of high quality laboratory performance. A minimum value of 3 {sigma} is desired in any clinical laboratory & values of {sigma}[≥] 6 are regarded as gold standard for obtaining high quality lab reports.

Aims &ObjectivesTo calculate bias, cv & sigma metrics from the IQC & EQC data in order to ascertain extent of quality management in our lab.

Materials &MethodsAn extensive study of sample processing and quality practices was carried out in the Central Laboratory of Department of Biochemistry; PGIMER &Dr. RML Hospital, New Delhi; from Feb 2020 to July 2020. The IQC used(both level I & level II) were from Biorad Laboratories India (lyphochek assayed chemistry control) & the EQC used was from Randox Laboratories, UK. All the controls were run on Beckman Coulter clinical chemistry analyser AU 680. Total 14 clinical parameters were analysed & subsequently; Mean, S.D., CV, bias & {sigma} were calculated through their respective formulas.

ResultsSigma level was more than 6 for both levels of IQC was observed for Amylase. It indicates world class performance. Total bilirubin, AST, Triglyceride & HDL depicted {sigma} values between 3.1 - 6 for both L1 & L2. Iron showed {sigma} value of 5.5 in L1 whereas it was 3.78 in L2.

ConclusionSigma metrics in clinical laboratory is an essential technique to ascertain poor assay performance, along with assessment of the efficiency of existing laboratory process.


title: Phase 1 Trial of Cyclosporine for Hospitalized Patients with COVID-19

abstract: Coronavirus Disease 2019 (COVID-19) remains a global health emergency with limited treatment options, lagging vaccine rates and inadequate healthcare resources in the face of an ongoing calamity. The disease is characterized by immune dysregulation and cytokine storm. Cyclosporine A (CSA) is a calcineurin inhibitor that modulates cytokine production and may have direct antiviral properties against coronaviruses. To test whether a short course of treatment was safe in COVID-19 patients, we treated 10 hospitalized, oxygen requiring, non-critically ill patients with CSA at a starting dose of 9mg/kg/day. Five patients experienced adverse events, none were serious, and transaminitis was most common. No subject enrolled in this trial required intensive care unit (ICU)-level care and all patients were discharged alive from the hospital. Further, CSA treatment was associated with significant reductions in serum cytokines and chemokines important in COVID-19 hyper-inflammation, including CXCL10. In conclusion, short courses of CSA appear safe and feasible in COVID-19 patients requiring oxygen and therefore, may be a useful adjunct in resource-poor or resource-limited health care settings.


title: SARS-CoV-2 shedding, infectivity and evolution in an immunocompromised adult patient

abstract: This report describes a persistent SARS-CoV-2 infection of at least 218 days in a male, in his 40s who had undergone a prior autologous hematopoietic stem cell transplant due to a diffuse large B-cell lymphoma. He did not manifest a humoral immune response to the virus. Whole-genome sequencing and viral cultures confirmed a continual infection with a replication-positive virus that had undergone genetic variation for at least 196 days following symptom onset.


title: NHS CHECK: protocol for a cohort study investigating the psychosocial impact of the COVID-19 pandemic on healthcare workers

abstract:
IntroductionThe COVID-19 pandemic has had profound effects on the working lives of healthcare workers (HCWs), but the extent to which their well-being and mental health have been affected remains unclear. This longitudinal cohort study aims to recruit a cohort of NHS healthcare workers, conducting surveys at regular intervals to provide evidence about the prevalence of symptoms of mental disorders, investigate associated factors such as occupational contexts and support interventions available.

Methods and AnalysisAll staff, students, and volunteers working in each of the 18 participating NHS Trusts in England will be sent emails inviting them to complete a survey at baseline, with email invitations for the follow up surveys being sent 6 and 12 months later. Opening in late April 2020, the baseline survey collects data on demographics, occupational and organisational factors, experiences of COVID-19, a number of validated measures of symptoms of poor mental health (e.g. depression, anxiety, post-traumatic stress disorder; PTSD), and measures of constructs such as resilience and moral injury. These regular surveys will be complemented by in-depth psychiatric interviews with a select sample of healthcare workers. Qualitative interviews will also be conducted, to gain deeper understanding of the support programmes used or desired by staff, and facilitators and barriers to accessing such programmes.

Ethics and DisseminationEthical approval for the study was granted by the Health Research Authority (reference: 20/HRA/210, IRAS: 282686) and local Trust Research and Development approval. Cohort data are being collected via Qualtrics online survey software, are pseudonymised and held on secure University servers. Participants are aware that they can withdraw from the study at any time, and there is signposting to support services for any participant who feels they need it. Only those consenting to be contacted about further research will be invited to participate in the psychiatric and qualitative interview components of the study. Findings will be rapidly shared with NHS Trusts to enable better support of staff during the pandemic, and via academic publications in due course.

Strengths and limitations of this studyO_LIThe longitudinal cohort design addresses the lack of long-term data on this population, and the current predominance of cross-sectional evidence available.
C_LIO_LIThe availability of Trust HR data means we will be able to calculate response rates, and weight the data appropriately.
C_LIO_LIThe diagnostic interview component of the study will allow us to establish the true prevalence of mental disorders, which can be inflated by the measures used in most mental health and wellbeing cohort studies.
C_LIO_LIThe qualitative interviews will give deeper insight into the support programmes that HCWs find most helpful, and provide ideas for Trusts to improve their offer to staff.
C_LIO_LIThe three components of the study give breadth and depth lacking in much of the mental health and wellbeing research currently available, but there is a risk of over-burdening already stretched HCWs.
C_LI


title: The 5-months impact of tozinameran (BNT162b2) mRNA vaccine on kidney transplant and chronic dialysis patients

abstract:
BackgroundDetermining the humoral immunogenicity of tozinameran (BNT162b2) vaccine in patients requiring chronic renal replacement therapy, and its impact on COVID-19 morbidity several months after vaccination, will guide risk assessment and subsequent changes in vaccination policy.

MethodsIn a prospective post-vaccination cohort study with up to 5 months follow-up we studied outpatient dialysis and kidney transplant patients and respective healthcare teams. Outcomes were anti S1/S2 antibody response to vaccine or infection and infection rate during followup.

Results175 dialysis patients (40% women, 65{+/-}15 years), 252 kidney transplant patients (33% women, 54{+/-}14 years) and 71 controls (65% women, 44{+/-}14 years) were followed. Three months or longer after vaccination we detected anti S1/S2 IgG antibodies in 80% of dialysis patients, 44% of transplant recipients and 100% of controls, whereas respective rates after infection were 94%, 75% and 100%. Predictors of non-response were older age, diabetes, history of cancer, lower lymphocyte count and lower vitamin-D levels. Factors associated with lower titers in dialysis patients were modality (hemodialysis vs peritoneal) and high serum ferritin levels. In transplant patients, hypertension and higher calcineurin or mTOR inhibitor drug levels were linked with diminished antibody response. Vaccination associated with fewer subsequent infections (HR=0.23, p<0.05). Moreover, higher antibody titers associated with fewer events, HR 0.41 for each unit increased in log10titer (p<0.05).

ConclusionsDialysis patients, and more so kidney transplant recipients, mounted reduced antibody response to COVID-19 mRNA vaccination, and lesser humoral response associated with more infections. Measures to identify and protect non-responsive patients are urgently required.

SignificanceReports on the humoral immunogenicity of SARS-CoV-2 mRNA vaccines in patients with end stage renal disease are scarce, and association with subsequent COVID-19 morbidity is unknown. In this cohort study that included 175 patients treated with dialysis, 252 kidney transplant recipients and 71 control volunteers, the proportion achieving an antibody response was time- and group-dependent, reaching 80%, 44% and 100% at 3 months post prime inoculation. Personal history of vaccination, positive antibody responses and antibody titers associated with significantly lower risk of COVID-19 infection. Thus, in patients with end stage renal disease, SARS-CoV-2 antibody testing may be warranted after vaccination, to identify non-responders at higher risk for disease.


title: Impact of tozinameran (BNT162b2) mRNA vaccine on kidney transplant and chronic dialysis patients: 3-5 months followup


title: Similar Rates of AKI during the First Two Waves of COVID-19 in Northern Italy: a single-center study

abstract:
IntroductionTwo waves of COVID-19 cases have overwhelmed most European countries during 2020. It is unclear if the incidence of acute kidney injury (AKI) has changed during the COVID-19 outbreaks. This study aims to evaluate the differences in incidence, risk factors and outcome of AKI in patients with SARS-CoV-2 infection during the first and second wave of COVID-19.

MethodWe reviewed the health medical records of 792 consecutive patients with COVID-19 hospitalized at the University Hospital of Modena, Italy, from February 25 to December 14, 2020.

ResultsAKI was diagnosed in 122 (15.4%) patients. Incidence of AKI remained steady rate during wave-1 (15.9%) and wave-2 (14.7%) (P=0.89). AKI patients were older (P=<0.001) and had a more severe respiratory impairment (PO2/FO2) (P=[≤]0.001) than their non-AKI counterparts. AKI led to a longer hospital stay (P=0.001), complicated with a higher rate of ICU admission. COVID-19-related AKI was associate with 59.7% of deaths during wave-1 and 70.6% during wave-2. At the end of the period of observation, 24% (wave-1) and 46.7% (wave-2) of survivors were discharged with a not fully recovered kidney function. Risk factors for AKI in patients with COVID-19 were diuretics (HR=5.3; 95%CI, 1.2-23.3; P=0.025) and cardiovascular disease (HR, 2.23; 95%CI, 1.05-5.1; P=0.036).

ConclusionThe incidence of AKI (about 15%) remained unchanged during 2020, regardless of the trend of COVID-19. AKI occurred in patients with severe COVID-19 symptoms and was associated with a higher incidence of deaths than non-AKI patients. The risk factors of COVID-19-related AKI were diuretic therapy and cardiovascular disease.


title: Humoral Response to BNT162b2 mRNA Covid19 Vaccine in Peritoneal and Hemodialysis Patients: a Comparative Study

abstract:
IntroductionGeneralized immunization against COVID19 has become the cornerstone in prevention of severe acute respiratory syndrome associated with this pandemic. Maintenance dialysis patients (MDP) are at higher risk of both exposure and mortality from the disease. Efficacy and security of BNT162b2 vaccine is well documented for the general population, but not in MDP, particularly in peritoneal dialysis (PD) patients. This study aims to compare humoral response between hemodialysis (HD) and PD patients.

Materials and MethodsObservational prospective study including MDP on HD or PD program from a Portuguese middle-sized Nephrology Center, who received BNT162b2 vaccine. Specific anti-Spike IgG was measured as arbitrary units per milliliter (AU/mL) on two separate occasions: 3 weeks after the first dose and 3 weeks after the second. The two modality groups were compared both for absolute value and number of non-responders (NR) after both inoculations. Demographic data was also compared.

ResultsOf 73 patients enrolled, 67 were eligible for the final study: 42 HD and 25 PD patients. PD group developed significantly higher antibody titers in both inoculations: first dose with Med 5.44 vs 0.99 (p<0.01) and second dose with Med 170.43 vs 65.81 (p<0.01). HD status was associated with NR after the first dose (Phi=0.383; p<0.01), but not after the second (p=0.08). Age, Charlson comorbidity index and dialysis vintage were lower in the PD group (p<0.01; p=0.02; p<0.01, respectively).

ConclusionThis study demonstrated a better humoral response to immunization with BNT162b2 in PD patients, when compared to HD patients, after each of the two recommended inoculations. Both groups showed substantial humoral response after just one dose of the vaccine. Older age and higher comorbidity burden may explain the relative immunogenicity deficit, probably in a superior degree comparing with age matched healthy population.

What is already known about this subjectO_LIMaintenance hemodialysis patients have lower humoral response to BNT162b2 mRNA COVID19 vaccine when compared to the general population;
C_LIO_LIMaintenance dialysis patients are at high risk of exposure to COVID19 in addition to a more severe course of the disease;
C_LI

What this study addsO_LIMaintenance peritoneal dialysis patients have better humoral response with BNT162b2 when compared to those on hemodialysis;
C_LIO_LIThere is a substantial humoral response after a single dose of the vaccine for both hemodialysis (50%) and peritoneal dialysis (88%) patients.
C_LI

What impact this may have on clinical practice or policyO_LIProtocols for follow-up measures, including extra inoculations, might have to be considered for hemodialysis patients;
C_LIO_LIPeritoneal dialysis patients should be promptly immunized in all centers, rejecting constraints regarding lower effectiveness or yield.
C_LI


title: Validation of motor and functional scales for the evaluation of adult patients with 5q spinal muscular atrophy

abstract:
ObjectiveTo assess in adult spinal muscular atrophy (SMA) patients the construct validity and responsiveness of several outcome measures.

MethodsPatients older than 15 years and followed-up at least for 6 months, between October 2015 and August 2020, with one motor function scale (Hammersmith Functional Motor Scale Expanded, HFMSE; Revised Upper Limb module, RULM) in five referral centers were included. Bedside functional scales (Egen Klassification, EK2; Revised Amyotrophic Lateral Sclerosis Functional Rating Scale, ALSFRS-R) were also collected when available. Correlations and regression models were performed to evaluate the construct validity. The monthly slopes of change were used to calculate their responsiveness.

ResultsThe study included 79 SMA patients, followed up for a mean of 16 months. All scales showed strong or very strong correlations with each other. A floor effect in motor function scales was found in weakest patients (HFMSE < 5 and RULM<10), and a ceiling effect in stronger patients (with HFMSE >55 and RULM > 35), when compared with other scales. ALSFRS-R (B=0.72) showed a strong discriminating ability between walkers, sitters, and non-sitters, and HFMSE (B=0.86) between walkers and sitters. The responsiveness was overall low, although in treated patients a moderate responsiveness was found for ALSFRS-R and HFMSE in walkers (0.69 and 0.61 respectively), and for EK2 in sitters (0.65) and non-sitters (0.60).

ConclusionsThis study shows the validity in SMA adult patients of commonly used scales. Overall, bedside functional scales showed some advantages over motor function scales, although all scales showed low responsiveness in untreated patients.

category: neurology


title: Factors associated with COVID-19 susceptibility and severity in patients with multiple sclerosis: A systematic review

abstract:
BackgroundWe conducted this systematic review to identify factors associated with coronavirus disease (COVID-19) susceptibility and outcomes among people with multiple sclerosis (MS).

MethodsAvailable studies from PubMed, Scopus, EMBASE, Web of Science, and gray literature including reference list and conference abstracts were searched from December 1, 2019, through April 12, 2021. We included cross-sectional, case-control, and cohort studies that reported risk factors of contracting COVID-19 or its outcome in patients with MS on univariate or multivariate regression analyses.

ResultsOut of the initial 2719 records and 1553 conference abstracts, a total of 20 studies were included. Factors associated with COVID-19 susceptibility were reported in 11 studies and risk factors for infection outcomes were discussed in 10. History of contact with an infected is strongly suggested as a risk factor for COVID-19 susceptibility. Other factors that could be associated with contracting infection are younger age, relapsing course, and anti-CD20 agents. The evidence suggests that increasing age, greater MS severity, treatment with anti-CD20 agents, previous use of corticosteroids, and specific comorbidities (obesity and coronary artery disease) could be independently associated with worse infection outcomes. Male sex is likely to be a risk factor for more severe disease. The black or African American race was reported as a possible risk factor.

ConclusionDue to a paucity of research and methodological issues, no risk factors for COVID-19 susceptibility and outcomes neither be confirmed nor excluded. Further large studies are needed to address factors associated with COVID-19 susceptibility and severity.


title: Brain imaging before and after COVID-19 in UK Biobank

abstract: There is strong evidence for brain-related abnormalities in COVID-191-13. It remains unknown however whether the impact of SARS-CoV-2 infection can be detected in milder cases, and whether this can reveal possible mechanisms contributing to brain pathology. Here, we investigated brain changes in 785 UK Biobank participants (aged 51-81) imaged twice, including 401 cases who tested positive for infection with SARS-CoV-2 between their two scans, with 141 days on average separating their diagnosis and second scan, and 384 controls. The availability of pre-infection imaging data reduces the likelihood of pre-existing risk factors being misinterpreted as disease effects. We identified significant longitudinal effects when comparing the two groups, including: (i) greater reduction in grey matter thickness and tissue-contrast in the orbitofrontal cortex and parahippocampal gyrus, (ii) greater changes in markers of tissue damage in regions functionally-connected to the primary olfactory cortex, and (iii) greater reduction in global brain size. The infected participants also showed on average larger cognitive decline between the two timepoints. Importantly, these imaging and cognitive longitudinal effects were still seen after excluding the 15 cases who had been hospitalised. These mainly limbic brain imaging results may be the in vivo hallmarks of a degenerative spread of the disease via olfactory pathways, of neuroinflammatory events, or of the loss of sensory input due to anosmia. Whether this deleterious impact can be partially reversed, or whether these effects will persist in the long term, remains to be investigated with additional follow up.


title: SARS-CoV-2 is associated with changes in brain structure in UK Biobank


title: Optimized Decision Support For Selection of Transoral Robotic Surgery or (Chemo)radiation: Quantified Pre-therapy Risk Stratification for Patient-reported and Clinician-graded Swallowing Impairment and Toxicity

abstract:
PurposeTo develop a decision-making tool to choose the optimal treatment for oropharyngeal squamous cell cancer (OPSCC) patients who are eligible for primary transoral robotic surgery (TORS) and primary (chemo)radiation therapy with comparable locoregional control and survival.

MethodsDecision tree models were constructed to study two decision-making scenarios, 1) TORS vs. definitive radiation therapy (RT), and 2) TORS vs. definitive chemo(radiation) therapy (CRT) based on well-established objective and subjective swallowing-function instruments, MD Anderson Dysphagia Inventory (MDADI), MD Anderson Symptom Inventory-Head and Neck Module (MDASI-HN), and clinician-rated Dynamic Imaging Grade of Swallowing Toxicity (DIGEST) that measure swallowing-related toxicity pre-therapy, 3-6 months (short-term), and 18-24 months (long-term) after therapy for five treatment cohorts (RT, CRT, TORS, TORS with adjuvant RT, and TORS with adjuvant CRT). The optimal treatment was sought as a function of postoperative extranodal extension (ENE) and/or positive margin (PM) that can trigger the adjuvant therapy. 2D heatmaps were constructed indicating the thresholds of postoperative events likelihoods required for TORS or definitive therapy to become the optimal treatment. Additionally, a risk calculation model was developed to quantify the risk associated with TORS in the settings that estimation of postoperative complications likelihoods may not be available.

ResultsUnder the first scenario and for short-term measures, MDADI and MDASI instruments indicate the superiority of definitive therapy to TORS at all times, while DIGEST required a maximum of 40% likelihood for both ENE and PM events to indicate TORS as the optimal treatment. For 18-24 months measures, MDASI indicated TORS as the optimal treatment; however, MDADI- and DIGEST-based long-term measures indicated threshold likelihoods of 90% and 25%, respectively, for TORS to remain the optimal treatment. For short-term outcomes, TORS resulted in higher toxicity even when the likelihood associated with postoperative tumor resection margin (TM) are extremely low. For higher probability of postoperative TM, all instruments indicated high risk associated with TORS (>83%). For long-term swallowing-related toxicity, TORS remained the optimal therapy independent from the probability of postoperative TM based on MDASI instrument. However, MDADI-based measure assigned a high risk to TORS (>86%) when postoperative TM is extremely likely. DIGEST-based measures indicated a very high risk associated with TORS independent from the postoperative TM likelihood (>91%).

Under the second scenario (TORS vs. definitive CRT), Both MDASI- and MDADI-based short-term measures indicated TORS as the optimal therapy independent from postoperative ENE/PM events. However, according to the DIGEST-based measure, definitive RT remained the optimal therapy when the probability of postoperative ENE and PM events exceed 80%. In this case, TORS was the optimal therapy if both events were not relatively likely (<55%). The same result was observed for MDADI and MDASI instruments for long-term measures indicating TORS as the optimal therapy independent from postoperative PM or ENE events. However, the DIGEST measure indicated that TORS is the optimal therapy only if the likelihood of both events are very low (<20%). When the postoperative TM is very unlikely (<10%), all instruments indicated TORS as the optimal therapy based on short-term outcomes. However, when the postoperative TM is extremely likely (>90%), DIGEST-based measures demonstrated the superiority of definitive CRT once the likelihood of postoperative ENE or PM is, at least, 60%. Long-term measures indicated higher sensitivity to postoperative TM likelihood with both MDADI- and DIGEST-based measures indicating a moderately high risk (> 60%) with TORS causing higher clinician-rated swallowing toxicity compared to definitive CRT when postoperative TM is extremely likely.

ConclusionThe current study using decision modeling shows proof of concept that in the absence of reliable estimation of postoperative ENE/PM events concurrent with significant postoperative positive margins (i.e., more than 2mm) that can trigger adjuvant therapy, the overall toxicity level incurred by OPSCC patients undergoing TORS may become more severe compared to patients receiving non-surgical treatments thus advocating definitive (C)RT protocols. The results further demonstrated that, when available, the likelihoods of postoperative events triggering postoperative adjuvant therapy must be incorporated when choosing the optimal treatment plan for eligible patients.


title: Sex-specific transcriptional differences and loss of gene imprinting in pancreatic neuroendocrine tumors

abstract: Pancreatic neuroendocrine tumors (PNETs) occur more frequently in men and are associated with higher mortality in males; however, the molecular basis for these sexual dimorphisms is unclear. Here, we demonstrate that PNETs are associated with the emergence of unique sex-specific transcriptomic differences that are not observed in non-neoplastic pancreatic islet tissues. We also show that while widespread sex-specific differences are present in the DNA methylation landscapes of control pancreatic islets, they are erased in PNETs. This includes a loss of imprinting with regards to many genes. These results implicate an emergence of sex-associated genetic and epigenetic dysregulations in PNETs.