title: Mortality in individuals treated with COVID-19 convalescent plasma varies with the geographic provenance of donors

abstract: Treatment and prevention of coronavirus disease 2019 (COVID-19) have attempted to harness the immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) including the development of successful COVID-19 vaccines and therapeutics (e.g., Remdesivir, convalescent plasma [CP]). Evidence that SARS-CoV-2 exists as quasispecies evolving locally suggests that immunological differences may exist that could impact the effectiveness of antibody-based treatments and vaccines. Regional variants of SARS-CoV-2 were reported in the USA beginning in November 2020 but were likely present earlier. There is available evidence that the effectiveness of CP obtained from donors infected with earlier strains in the pandemic may be reduced when tested for neutralization against newer SARS-Cov-2 variants. Using data from the Expanded Access Program to convalescent plasma, we used a gradient-boosting machine to identify predictors of 30-day morality and a series of regression models to estimate the relative risk of death at 30 days post-transfusion for those receiving near sourced plasma (defined as plasma transported [≤] 150 miles) vs. distantly sourced plasma (> 150 miles). Our results show a lower risk of death at 30 days post-transfusion for near sourced plasma. Additional analyses stratified by disease severity, time to treatment, and donor region further supported these findings. The results of this study suggest that near sourced plasma is superior to distantly sourced plasma, which has implications for interpreting the results of clinical studies and designing effective treatment of COVID-19 patients as additional local variant are likely to emerge.

category: infectious diseases


title: T-cell receptor sequencing identifies prior SARS-CoV-2 infection and correlates with neutralizing antibody titers and disease severity

abstract: Measuring the adaptive immune response to SARS-CoV-2 can enable the assessment of past infection as well as protective immunity and the risk of reinfection. While neutralizing antibody (nAb) titers are one measure of protection, such assays are challenging to perform at a large scale and the longevity of the SARS-CoV-2 nAb response is not fully understood. Here, we apply a T-cell receptor (TCR) sequencing assay that can be performed on a small volume standard blood sample to assess the adaptive T-cell response to SARS-CoV-2 infection. Samples were collected from a cohort of 302 individuals recovered from COVID-19 up to 6 months after infection. Previously published findings in this cohort showed that two commercially available SARS-CoV-2 serologic assays correlate well with nAb testing. We demonstrate that the magnitude of the SARS-CoV-2-specific T-cell response strongly correlates with nAb titer, as well as clinical indicators of disease severity including hospitalization, fever, or difficulty breathing. While the depth and breadth of the T-cell response declines during convalescence, the T-cell signal remains well above background with high sensitivity up to at least 6 months following initial infection. Compared to serology tests detecting binding antibodies to SARS-CoV-2 spike and nucleoprotein, the overall sensitivity of the TCR-based assay across the entire cohort and all timepoints was approximately 5% greater for identifying prior SARS-CoV-2 infection. Notably, the improved performance of T-cell testing compared to serology was most apparent in recovered individuals who were not hospitalized and were sampled beyond 150 days of their initial illness, suggesting that antibody testing may have reduced sensitivity in individuals who experienced less severe COVID-19 illness and at later timepoints. Finally, T-cell testing was able to identify SARS-CoV-2 infection in 68% (55/81) of convalescent samples having nAb titers below the lower limit of detection, as well as 37% (13/35) of samples testing negative by all three antibody assays. These results demonstrate the utility of a TCR-based assay as a scalable, reliable measure of past SARS-CoV-2 infection across a spectrum of disease severity. Additionally, the TCR repertoire may be useful as a surrogate for protective immunity with additive clinical value beyond serologic or nAb testing methods.


title: Weekly SARS-CoV-2 screening of asymptomatic students and staff to guide and evaluate strategies for safer in-person learning

abstract:
BackgroundData suggest that COVID-19 transmission in K-12 schools is uncommon, but few studies have confirmed this using widespread screening of asymptomatic individuals.

ObjectiveTo evaluate the incidence of asymptomatic COVID-19, document the frequency of in-school transmission, and confirm feasibility of widespread asymptomatic screening in schools.

DesignProspective observational study

SettingSingle mid-sized suburban school district including 10 schools and a central office.

ParticipantsDistrict staff and students

InterventionsAsymptomatic screening PCR for SARS-CoV-2

MeasurementsConcurrent with a hybrid model and layered mitigation, weekly pooled testing of staff and secondary students was offered using saliva samples collected at home. Identification of >1 case in a school prompted investigation for possible in-school transmission. Staff and families were surveyed about satisfaction with the screening program.

ResultsFrom weeks 1-18, rates of incident COVID-19 in the surrounding community rose steadily. Weekly staff and student screening identified 0-7 asymptomatic cases/week. In week 7, 5 cases were identified among staff who shared an office setting. Enhancements to mitigation strategies were undertaken. The proportion of survey respondents self-reporting comfort with in-person learning before versus after implementation of screening increased.

LimitationsBecause screening testing was not mandatory, the results from the participating population might not represent the entire school community.

ConclusionsIn this school district with layered mitigation measures, in-school transmission was rare. The program identified a cluster with in-school staff-to-staff transmission and spurred enhancement of safety strategies. A weekly COVID-19 screening program can provide critical data to inform mitigation efforts, and provides school-specific, current data to inform decisions about in-person learning models. Screening provided reassurance and identified asymptomatic cases.

FundingThe Wellesley Education Foundation provided funding for the testing.


title: Older biological age is associated with adverse COVID-19 outcomes: A cohort study in UK Biobank

abstract:
BackgroundOlder chronological age is the most powerful risk factor for adverse coronavirus disease-19 (COVID-19) outcomes. It is uncertain, however, whether older biological age, as assessed by leucocyte telomere length (LTL), is also associated with COVID-19 outcomes.

MethodsWe associated LTL values obtained from participants recruited into UK Biobank (UKB) during 2006-2010 with adverse COVID-19 outcomes recorded by 30 November 2020, defined as a composite of any of the following: hospital admission, need for critical care, respiratory support, or mortality. Using information on 131 LTL-associated genetic variants, we conducted exploratory Mendelian randomisation (MR) analyses in UKB to evaluate whether observational associations might reflect cause-and-effect relationships.

FindingsOf 6,775 participants in UKB who had tested positive for infection with SARS-CoV-2 in the community, there were 914 (13.5%) with adverse COVID-19 outcomes. The odds ratio (OR) for adverse COVID-19 outcomes was 1{middle dot}17 (95% CI 1{middle dot}05-1{middle dot}31; P=0{middle dot}004) per 1-SD shorter usual LTL, after adjustment for chronological age, sex and ethnicity. Similar ORs were observed in analyses that: adjusted for additional risk factors; disaggregated the composite outcome and reduced the scope for selection or collider bias. In MR analyses, the OR for adverse COVID-19 outcomes was directionally concordant but non-significant.

InterpretationShorter LTL, indicative of older biological age, is associated with higher risk of adverse COVID-19 outcomes, independent of several major risk factors for COVID-19 including chronological age. Further data are needed to determine whether this association reflects causality.

FundingUK Medical Research Council, Biotechnology and Biological Sciences Research Council and British Heart Foundation.


title: Limit of detection in different matrices of nineteen commercially available rapid antigen tests for the detection of SARS-CoV-2

abstract: In the context of the coronavirus disease 2019 (COVID-19) pandemic there has been an increase of the use of antigen-detection rapid diagnostic tests (Ag-RDT). The performance of Ag-RDT vary greatly between manufacturers and evaluating their analytical limit of detection (LOD) has become high priority. Here we describe a manufacturer-independent evaluation of the LOD of 19 marketed Ag-RDT using live SARS-CoV-2 spiked in different matrices: direct culture supernatant, a dry swab, and a swab in Amies. Additionally, the LOD using dry swab was investigated after 7 days storage at -80{degrees}C of the SARS-CoV-2 serial dilutions. An LOD of {approx} 5.0 x 102 pfu/ml (1.0 x 106 genome copies/ml) in culture media is defined as acceptable by the World Health Organization. Fourteen of nineteen Ag-RDTs (ActiveXpress, Espline, Excalibur, Innova, Joysbio, Mologic, NowCheck, Orient, PanBio, RespiStrip, Roche, Standard-F, Standard-Q and Sure-Status) exceeded this performance criteria using direct culture supernatant applied to the Ag-RDT. Six Ag-RDT were not compatible with Amies media and a decreased sensitivity of 2 to 20-fold was observed for eleven tests on the stored dilutions at -80{degrees}C for 7 days. Here, we provide analytical sensitivity data to guide appropriate test and sample type selection for use and for future Ag-RDT evaluations.


title: Evaluating the neutralizing ability of a CpG-adjuvanted S-2P subunit vaccine against SARS-CoV-2 Variants of Concern

abstract: Vaccination is currently the best weapon to control the COVID-19 pandemic. However, an alarming number of novel variants termed Variants of Concern (VoC) were found to harbor mutations that diminished the neutralizing capacity of antibodies elicited by the vaccines. We have investigated the neutralizing titers of antibodies from sera of humans and rats immunized with the MVC-COV1901 vaccine against pseudoviruses coated with the wildtype, D614G, B.1.1.7, or B.1.351 spike proteins. Rats vaccinated with two doses of adjuvanted S-2P retained neutralization activities against the B.1.351 variant, albeit with a slight reduction compared to wildtype. Phase 1 vaccinated subjects showed more reduced neutralization abilities against the B.1.351 variant. The study is among the first, to our knowledge, to demonstrate dose-dependent neutralizing responses against VoCs, particularly against B.1.351, from different doses of antigen in a clinical trial for a subunit protein COVID-19 vaccine. The appearance of vaccine escape variants is a growing concern facing many current COVID-19 vaccines and therapeutics. Strategies should be adopted against the ever-changing nature of these variants. The observations of this study grant us valuable insight into preemptive strikes against current and future variants.

category: allergy and immunology


title: A Pilot Study of Train-of-Four and Post-Tetanic Count Monitoring with the TetraGraph Electromyograph Compared to the TwitchView Monitor Electromyograph

abstract:
BackgroundQuantitative twitch monitoring is recommended for avoiding residual neuromuscular blockade. Electromyograph twitch monitors are a form of quantitative twitch monitoring. The TwitchView electromyograph has been previously validated against "gold standard" mechanomyography, and may serve as a comparator for other monitors. We have previously shown that the GE electromyograph monitor overcounted twitches, frequently misinterpreting noise as a twitch. This is a pilot study to evaluate the performance of the TetraGraph electromyograph in comparison to the TwitchView electromyograph.

MethodsTwitchView and TetraGraph electrodes were applied to opposite arms of patients prior to induction of anesthesia. Post-tetanic count, train-of-four count and train-of-four ratio were then measured approximately every 5 minutes during an unrestricted general anesthetic. Measurements were not made for 10 minutes following neuromuscular blocking drugs or reversal agents.

ResultsEight patients were enrolled. The mean baseline train-of-four ratio was 1.02 (SD=0.04) for the TwitchView and 0.99 (SD=0.03) for the TetraGraph (p=0.22). Bland Altman analysis of all of the train-of-four ratio data found that average TwitchView train-of-four values were larger with a bias of 0.10. Train-of-four counts and train-of-four ratios were generally less when measured with TetraGraph than when measured with TwitchView.In 83% (209/253) of data pairs, the result from TetraGraph was less than the result from TwitchView and in 6% (16/253) of data pairs, the result from TetraGraph was greater than the result from TwitchView (p<0.0001). In 11% (28/253) of data pairs, the result from TetraGraph was the same as TwitchView [95%CI 7.35% 16.0%]. Evaluation of individual patient results confirmed the overall results. In some cases there were large discrepancies, such as 4 twitches reported by the TwitchView when the TetraGraph reported a post-tetanic count.

ConclusionsUsers of the TetraGraph electromyograph should be aware that significant underestimation of post-tetanic-count, train-of-four count and train-of-four ratio may occur. This could result in administration of unnecessary reversal agents, excessive doses of reversal agents, or delay in extubation. We are undertaking a comparison of the TetraGraph monitor to mechanomyography to confirm the results of this pilot study.

category: anesthesia


title: Anticoagulation trends in adults aged 65 and over with atrial fibrillation; a cohort study.

abstract:
ObjectiveTo describe patterns of anticogulation prescribing and persistence for those aged [≥]65 years with atrial fibrillation (AF).

MethodsDescriptive cohort study using electronic general practice records of patients in England who attended a flu vaccination aged [≥]65, and were diagnosed with AF between 2008-2018. Patients were stratified by 10 year age group and year of diagnosis. Proportion anticoagulated, type of anticoagulation (direct oral anticoagulant (DOAC) or Warfarin) initiated at diagnosis, and persistence with anticoagulation over time are reported.

Results42,290 patients (49% female), aged 65-74 (n=11,722), 75-84 (n=19,055) and 85+ (n=11,513) at AF diagnosis are included. Prescription of anticoagulation at diagnosis increased over the time period from 55% to 86% in people aged 65-74, from 54% to 86% in people aged 75-84 and from 27% to 75% in people aged 85 and over. No patients were prescribed DOACs as a first anticoagulation agent in 2008, by 201892% of new AF patients were started on DOACs. Survivor function for 5 year persistence for patients taking only a single type of anticoagulant was 0.80 (0.77:0.82) for DOACs and0.71(0.70:0.72) for warfarin, Survivor function for any anticoagulation at 5 years was0.79(0.78:0.81), 0.73(0.72:0.75), 0.58(0.59:0.64) for people aged 65-74, 75-84 and 85+ respectively.

ConclusionsRates of anticoagulation for new AF in those aged [≥]65 have increased from 2008 to 2018, over which time there has been a shift from initiating anticoaguation with warfarin to DOACs. Persistence with anticoagulation is higher in people on DOACs than on warfarin, and in people under the aged of 85.

Key MessagesO_ST_ABSWhat is already known?C_ST_ABSAnticoagulation is a highly effective way of reducing the risk of stroke associated with AF, but is underused, particularly in older people. The introduction of DOACs has been associated with increasing use of anticoagulation in AF.

What does this study add?Our study provides up to date information on anticoagulation for AF in older people who are most at risk of AF related stroke and highlights particular increases in use of anticoagulation in people aged 85 and over.

DOACs are now the major class of anticoagulant prescribed to patients with new AF in UK general practice.

Long term persistence with anticoagulation is higher with DOACs than warfarin, but drops in all age groups over 5 years.

How might this impact on clinical practice?Improved uptake of anticoagulation at all ages removes one of the potential barriers to screening for atrial fibrillation, but new strategies may be needed to enhance longer term persistence with treatment.

category: cardiovascular medicine


title: Lives Saved from Age-Prioritised COVID-19 Vaccination

abstract:
BACKGROUNDThe criteria used to allocate scarce COVID-19 vaccines are hotly contested. While some are pushing just to get vaccines into arms as quickly as possible, others advocate prioritization in terms of risk.

OBJECTIVEOur aim is to use demographic models to show the enormous potential of vaccine risk-prioritization in saving lives.

METHODSWe develop a simple mathematical model that accounts for the age distribution of the population and of COVID-19 mortality. This model considers only the direct live-savings for those who receive the vaccine, and does not account for possible indirect effects of vaccination. We apply this model to the United States, Japan, and Bangladesh.

RESULTSIn the United States, we find age-prioritization would reduce deaths during a vaccine campaign by about 93 percent relative to no vaccine and 85 percent relative to age-neutral vaccine distribution. In countries with younger age structures, such as Bangladesh, the benefits of age-prioritization are even greater.

CONTRIBUTIONFor policy makers, our findings give additional support to risk-prioritized allocation of COVID-19 vaccines. For demographers, our results show how the age-structures of the population and of disease mortality combine into an expression of risk concentration that shows the benefits of prioritized allocation. This measure can also be used to study the effects of prioritizing other dimensions of risk such as underlying health conditions.

category: epidemiology


title: The presence of SARS-CoV-2 RNA in different freshwaters of urban settings determined by RT-qPCR: implications for water safety

abstract: This study is the first focused on the presence of SARS-CoV-2 in different freshwater environments in an urban setting. Groundwater and surface water reservoirs for drinking water as well as water from receiving rivers of the Monterrey Metropolitan Area were sampled repeatedly during a SARS-CoV-2 peak phase between October 2020 and January 2021, and viral RNA was measured by quantitative reverse transcription polymerase chain reaction. Forty-four percent of the groundwater samples had detectable viral loads between 2.6 and 38.3 copies/ml. A significant correlation between viral load and sucralose concentration in groundwater reaffirmed the hypothesis of leaching and infiltrating effluent from surface and/or failing sewage pipes and emphasized the importance of water disinfection. Twelve percent of the surface water dam samples tested positive for viral RNA, with values varying between 3.3 and 3.8 copies/ml. Finally, 13% of the river samples were positive for viral RNA, with concentrations ranging from 2.5 to 7.0 copies/ml. Untreated wastewater samples taken in the same period showed viral loads of up to 3535 copies/ml, demonstrating a dilution effect and/or wastewater facilities efficiency of three orders of magnitude. Variations in the viral loads in the groundwater and surface water over time and at the submetropolitan level generally reflected the reported trends in infection cases for Monterrey. The viral loads in the freshwater environments of Monterrey represent a low risk for recreational activities according to a preliminary risk assessment model. However, this result should not be taken lightly due to uncertainty regarding data and model constraints and the possibility of situations where the infection risk may increase considerably.


title: The presence of SARS-CoV-2 RNA in different freshwater environments in urban settings determined by RT-qPCR: implications for water security


title: Distinct transcriptomic signature of mRNA and microRNA in ulcerative colitis and irritable bowel syndrome

abstract:
BackgroundUlcerative colitis (UC) and irritable bowel syndrome (IBS) are both chronic bowel diseases involving stress. To identify genes differentially expressed in UC and IBS, and to determine whether psychological stress can influence those gene expressions, we conducted this pilot study.

MethodsPatients of UC, irritable bowel syndrome (IBS) and normal controls (NC) (n=5 in each group) were recruited. Perceived stress scale (PSS) was adopted to assess psychological stress level. Sigmoid mucosa samples were collected during colonoscopy. Differentially expressed genes (DEGs) of both mRNA and microRNA (DEG-mRNA and DEG-miRNA) were identified by RNA-Seq and microarray, respectively. Weighted gene co-expression network analysis (WGCNA), gene ontology, and microRNA target analysis were performed to identify regulatory relationships and pathways involved. Pearson correlation was performed to identify the relationship between DEGs and PSS score.

ResultsIn total, 1,770 and 938 DEG-mRNAs, 107 and 3 DEG-miRNAs were identified in UC and IBS (nominal P<0.05), respectively. The transcriptome changes in UC and IBS were highly correlated but transcriptome severity was larger in UC. There were 268 overlapped DEG-mRNAs and 3 overlapped DEG-miRNAs between UC and IBS. Median PSS score was 27.5 (24.7, 40.0) in UC, 27.0 (17.5, 32.5) in IBS and 22.0 (12.0, 28.5) in NC. Five of the UCs DEG-mRNAs were significantly correlated to PSS scores, including SLC4A7, PLCB1, SPATA33, DECR2, RP11-792A8.4. There were no DEGs correlate with PSS scores in IBS. One module enriched for immunological pathways was upregulated in UC. Metabolic pathways were enriched in IBS. Within the UC-related co-expression module, we identified 18 DEG-mRNAs that were also targets of DEG-miRNA.

ConclusionsIntegration of microRNA and mRNA expression profiles identified changes of gene expression in both UC and IBS. Although the two diseases have significant overlapped transcriptomic changes, they have distinct signature. Immunological pathways are involved prominently in UC while metabolic pathways in IBS. Psychological stress is uniquely associated with the transcriptome changes of UC.

category: gastroenterology


title: Primary care clinical management following self-harm during the first wave of COVID-19 in the UK

abstract:
BackgroundA substantial reduction in GP-recorded self-harm occurred during the first wave of COVID-19 but effects on primary care management of self-harm are unknown.

AimTo examine the impact of COVID-19 on clinical management within three months of an episode of self-harm.

Design and settingProspective cohort study using data from the UK Clinical Practice Research Datalink.

MethodWe compared cohorts of patients with an index self-harm episode recorded during a pre-pandemic period (10th March-10th June, 2010-2019) versus the COVID-19 first-wave period (10th March-10th June 2020). Patients were followed up for three months to capture psychotropic medication prescribing, GP/practice nurse consultation and referral to mental health services.

Results48,739 episodes of self-harm were recorded during the pre-pandemic period and 4,238 during the first-wave COVID-19 period. Similar proportions were prescribed psychotropic medication within 3 months in the pre-pandemic (54.0%) and COVID-19 first-wave (54.9%) cohorts. Likelihood of having at least one GP/practice nurse consultation was broadly similar (83.2% vs. 80.3% in the COVID-19 cohort). The proportion of patients referred to mental health services in the COVID-19 cohort (3.4%) was around half of that in the pre-pandemic cohort (6.5%).

ConclusionDespite the challenges experienced by primary healthcare teams during the initial COVID-19 wave, prescribing and consultation patterns following self-harm were broadly similar to pre-pandemic levels. However, the reduced likelihood of referral to mental health services warrants attention. Accessible outpatient and community services for people who have self-harmed are required as the COVID-19 crisis recedes and the population faces new challenges to mental health.

category: primary care research


title: Emotional responses toward COVID-19: A longitudinal assessment of age differences

abstract: The current study investigates the relation between age and emotional responses and coping strategies at two moments during the spread of COVID-19 in Poland, namely the first peak (March-May 2020) and the second pick (October-December 2020). A sample of 414 individuals between the ages of 18 and 81 were asked to rate the intensity of the  shock,  sadness,  anger, and  fear they experienced due to COVID-19 and respond to items from the Brief Cope questionnaire. The present findings demonstrate that anger was consistently less intense among older adults than younger ones. Emotion-focused coping strategies were more commonly used by younger adults than middle-aged or older ones at the first peak of the outbreak; however, this trend had reversed during the second peak of the pandemic, as the older age groups demonstrated a far greater increase in the use of this form of coping. Results indicate a greater ability to use emotional regulation among older adults than younger ones, as the former are less likely to react to a crisis through anger and more able to adapt coping mechanisms to a dynamic environment.

category: psychiatry and clinical psychology


title: COVID 19 Vaccine Perceptions in the New York State Intellectual and Developmental Disabilities Community

abstract:
BackgroundPeople with intellectual and developmental disabilities (IDD) are at disproportionate risk for severe COVID-19 outcomes, particularly those living in congregate care settings. Yet, there is limited data on vaccine perceptions in the disability community.

ObjectiveTo explore COVID-19 vaccine perceptions in individuals with IDD, their family members, and those who work with them, to inform a statewide vaccine information and messaging project.

MethodsA national survey, adapted for the IDD community, was distributed to a convenience sample of IDD organizations throughout New York State, in five languages. Constructs included vaccine intention, reasons for vaccine hesitancy, and trusted sources of vaccine information. Zip code data were used to map respondent location and vaccine preferences.

ResultsOf n= 825 respondents, approximately 75% intended to or had received the vaccine, across roles (i.e., people with disabilities, family members, direct care workers) and racial/ethnic groups. Greater vaccine hesitancy was reported in younger individuals and those making decisions on behalf of a person with IDD. Concerns included side effects and the swiftness of vaccine development. Black and Hispanic participants had heightened concerns about being an "experiment" for the vaccine. Trusted sources of information included healthcare providers and family members. Respondents who intended/got the vaccine were distributed throughout the state.

ConclusionsVaccine preferences in this New York State disability community sample align with national data. Identified concerns suggest the need for community education that addresses misperceptions. Age and race differences in perspectives highlight the need for tailored education, delivered by trusted messengers.

category: public and global health


title: Factors informing healthcare workers' willingness to work during the COVID-19 pandemic

abstract:
ObjectiveThe COVID-19 pandemic represents a substantial challenge to healthcare workers. Exploring the determinants of their willingness to work is crucial to ensuring hospital function during the outbreak. Hence, this study examines the factors affecting the motivation and hesitation of health workers in the face of the COVID-19 pandemic in Poland.

Study DesignAn online, anonymous survey was carried out among Polish healthcare workers during the COVID-19 pandemic.

MethodThe respondents were asked about their demographic characteristics, stress-related factors, and their self-reported motivation and hesitation to work. The responses were gathered during September-December 2020.

Results912 valid responses were obtained. Of these, 22.8% (N = 208) respondents reported being strongly motivated to work while 37.8% (N = 345) expressed strong hesitation. The participants demographic characteristics and their responses to the stress-related questions were assigned to four categories depending on the odds ratios of motivation and hesitation. While some factors were linked to enhanced motivation and reduced hesitation, others solely affected either motivation or hesitation, and yet others had a positive impact on both.

ConclusionOverall, the study indicates that in order to increase hospital workers motivation and decrease their hesitation, they must be made to feel protected by both their hospitals and local and national authorities.


title: Job stress among workers who telecommute during the coronavirus disease (COVID-19) pandemic in Japan: a cross-sectional study

abstract:
ObjectivesThe work system reform and the COVID-19 pandemic in Japan have prompted efforts toward telecommuting in Japan, and there has been little research regarding the stress and health effects of telecommuting. This study aimed to clarify the relationship between telecommuting and job stress among Japanese workers.

Study DesignThis was a cross-sectional study.

MethodsIn December 2020, during the  third wave of the COVID-19 pandemic, an Internet-based nationwide health survey of 33,087 Japanese workers (CORoNaWork study) was conducted. Data for 27,036 individuals was included as 6,051 individuals provided invalid responses. We analysed a sample of 13,468 office workers from this database. We classified participants into four groups according to telecommuting frequency and compared the subscale of the Job Content Questionnaire and subjective job stress among these groups: high-frequency, medium-frequency, and low-frequency telecommuters group and non-telecommuters group. We used a linear mixed model and ordinal logistic regression analysis.

ResultsThere was a significant difference in the score of job control of the JCQ among the four groups after adjusting for multiple confounding factors. The high-frequency telecommuters group had the highest job control score. Regarding the fluctuation score of subjective job stress, the high- and medium-frequency telecommuters groups were significantly lower than those of the non-telecommuters group after adjusting for multiple confounding factors.

ConclusionWe found that high-frequency telecommuting was associated with high job control. This study suggests that the widespread adoption of telecommuting as a countermeasure to the public health challenges associated with the COVID-19 pandemic may also have a positive impact on job stress.


title: Psychosocial impact of the Covid-19 pandemic: Identification of most vulnerable populations.

abstract:
With the aim of analyzing the psychosocial impact of Covid-19 pandemic on society in general and health care workers in particular, we developed a 74-question survey questionnaire which was shared through social media. After analyzing 56,656 responses obtained during the first pandemic peak, the results showed an early and important negative impact on family finances, fear of working with Covid-19 patients and ethical issues related to Covid-19 care among healthcare workers (HCW). We have identified 7 target groups at higher risk of impaired mental health and susceptible to benefiting from an intervention: women, under 42 years of age, people with care burden, socio-economically deprived groups, people with unskilled or unqualified jobs, Covid-19 patients, and HCW working with Covid-19 patients. These results should encourage the active implementation of specific strategies to increase resilience in these groups and to prepare an adequate organizational response.

Summary boxO_ST_ABSWhat is already known?C_ST_ABSO_LIStudies in small cohorts have reported an important impact of the Covid-19 pandemic on the general population at several levels
C_LIO_LIAccording to previous studies in small cohorts, approximately 20% of the population suffered from impaired mental health status due to the pandemic
C_LI

What are the new findings?O_LIWe have studied 56,656 survey questionnaires to assess the impact of the Covid-19 outbreak on health status, family finances, habits, general health and mental health status, and ethics, especially in health care workers
C_LIO_LIWe have identified 7 target groups susceptible to benefitting from an intervention, and which should be taken into account when designing new contention measures against the pandemic
C_LI

What do the new findings imply?O_LIThe design and active implementation of interventions to build individual resilience, especially for the targeted populations described, and preparation of an appropriate organizational response are key
C_LIO_LIThe results obtained in this project could help local and national Governments to design or adjust coping measures against future outbreaks
C_LI


title: Polygenic risk scores lack prognostic value for adults with severe mental illness

abstract: Schizophrenia (SCZ) is the archetypal severe mental illness and one of the most deeply characterized human genetic traits. Like most common diseases SCZ is highly polygenic, and as such its genetic liability can be summarized at the individual level by a polygenic risk score (PRS). Polygenic risk scores are a cornerstone of the precision medicine vision, as it is widely anticipated they will come to serve as biomarkers of disease and poor outcomes in real-world clinical practice. However, to date, few studies have assessed their actual prognostic value relative to current standards-of-care. SCZ is an ideal test case towards this end because the predictive power of the SCZ PRS exceeds that of most other common diseases. Here, we analyzed clinical and genetic data from two multi-ethnic cohorts totaling 8,541 adults with SCZ and related psychotic disorders, assessing whether the SCZ PRS improves poor outcome prediction relative to clinical features captured in a standard psychiatric interview. For all outcomes investigated, the SCZ PRS did not improve the performance of predictive models, an observation that was generally robust to divergent case definitions and ancestral backgrounds of study participants. These findings demonstrate the limited potential of even the most powerful contemporary polygenic risk scores as a tool for individualized outcome prediction.

category: genetic and genomic medicine


title: How to incentivise doctor attendance in Bangladesh: a latent class analysis of a discrete choice experiment

abstract:
ObjectiveTo elicit preferences of doctors over interventions to address doctor absenteeism in rural facilities in Bangladesh, a pervasive form of corruption across the country.

MethodsWe conducted a discrete choice experiment with 308 doctors across four tertiary hospitals in Dhaka, Bangladesh. Four attributes of rural postings were included based on a literature review, qualitative research and a consensus-building workshop with policymakers and key health-system stakeholders: relationship with the community, security measures, attendance-based policies, and incentive payments. Respondents choices were analysed with mixed multinomial logistic and latent class models and were used to simulate the likely uptake of jobs under different policy packages.

ResultsAll attributes significantly impacted doctor choices (p<0.01). Doctors strongly preferred jobs at rural facilities where there was a supportive relationship with the community ({beta}=0.93), considered good attendance in education and training (0.77) or promotion decisions (0.67), with functional security (0.67) and higher incentive payments (0.5 per 10% increase of base salary). Jobs with disciplinary action for poor attendance were disliked by respondents (-.63). Latent class analysis identified three groups of doctors that differed in their uptake of jobs. Scenario modelling identified intervention packages that differentially impacted doctor behaciour and combinations that could feasibly improve doctors attendance.

ConclusionBangladeshi doctors have strong but varied preferences over interventions to overcome absenteeism. Some were unresponsive to intervention but a substantial number appear amenable to change. Designing policy packages that consider these differences and target particular doctors could begin to generate sustainable solutions to doctor absenteeism in rural Bangladesh.

category: health policy


title: Changes in HIV Treatment Differentiated Care Utilization During the COVID-19 Pandemic in Zambia

abstract:
BackgroundDifferentiated service delivery (DSD) models aim to lessen the burden of HIV treatment on patients and providers in part by reducing requirements for facility visits and extending dispensing intervals. With the advent of the COVID-19 pandemic, minimizing patient contact with healthcare facilities and other patients, while maintaining treatment continuity and avoiding loss to care, has become more urgent, resulting in efforts to increase DSD uptake. We assessed the extent to which DSD coverage and antiretroviral treatment (ART) dispensing intervals have changed during the COVID-19 pandemic in Zambia.

MethodsWe used patient data from Zambias electronic medical record system (SmartCare) for 737 health facilities, representing about 3/4 of all ART patients nationally, to compare the numbers and proportional distributions of patients enrolled in DSD models in the six months before and six months after the first case of COVID-19 was diagnosed in Zambia in March 2020. Segmented linear regression was used to determine whether the introduction of COVID-19 into Zambia further accelerated the increase in DSD scale-up.

ResultsBetween September 2019 and August 2020, 181,317 patients aged 15+ (81,520 and 99,797 from September 1, 2019 to March 1, 2020 and from March 1 to August 31, 2020, respectively) enrolled in DSD models in Zambia. Overall participation in all DSD models increased over the study period, but uptake varied by model. The rate of acceleration increased in the second period for home ART delivery (152%), [≤]2-month fast-track (143%), and 3-month MMD (139%). There were significant decelerations in the increase in enrolment for 4-6-month fast-track (-28%) and  other models (-19%).

ConclusionsParticipation in DSD models for stable ART patients in Zambia increased after the advent of COVID-19, but dispensing intervals diminished. Eliminating obstacles to longer dispensing intervals, including those related to supply chain management, should be prioritized to achieve the expected benefits of DSD models and minimize COVID-19 risk.

category: hiv aids


title: Developing machine learning models for predicting intensive care unit resource use during the COVID-19 pandemic

abstract:
ImportanceThe COVID-19 pandemic has put massive strains on hospitals, and tools to guide hospital planners in resource allocation during the ebbs and flows of the pandemic are urgently needed.

ObjectiveWe investigate whether Machine Learning (ML) can be used for predictions of intensive care requirements 5 and 10 days into the future.

DesignRetrospective design where health Records from 34,012 SARS-CoV-2 positive patients was extracted. Random Forest (RF) models were trained to predict risk of ICU admission and use of mechanical ventilation after n days (n = 5, 10).

SettingTwo Danish regions, encompassing approx. 2.5 million citizens.

ParticipantsAll patients from the bi-regional area with a registered positive SARS-CoV-2 test from March 2020 to January 2021.

Main outcomesPrediction of future 5- and 10-day requirements of ICU admission and ventilator use. Mortality was also predicted.

ResultsModels predicted 5-day risk of ICU admission with an area under the receiver operator characteristic curve (ROC-AUC) of 0.986 and 5-day risk of use of ventilation with an ROC-AUC of 0.995. The corresponding 5-day forecasting models predicted the needed ICU capacity with a coefficient of determination (R2) of 0.930 and use of ventilation with an R2 of 0.934. Performance was comparable but slightly reduced for 10-day forecasting models.

ConclusionsRandom Forest-based modelling can be used for accurate 5- and 10-day forecasting predictions of ICU resource requirements.

FundingThe study was funded by grants from the Novo Nordisk Foundation to MS (#NNF20SA0062879 and #NNF19OC0055183) and MN (#NNF20SA0062879).

The foundation took no part in project design, data handling and manuscript preparation.

KEY POINTSO_ST_ABSQuestionC_ST_ABSCan machine learning models (ML) be used for predicting hospital and intensive care unit (ICU) resource requirements, and thus assist in logistics crisis management during the COVID-19 pandemic?

FindingsRetrospective study of the resource use of 34.012 COVID-19 patients during the first and second COVID-19 wave in Denmark. ML models were trained for the purpose of predicting the number of patients needing ICU admission and ventilators 5 and 10 day after their first positive SARS-CoV-2 test. The study demonstrates that ML models can accurately predict intensive care admission requirements with 5-day area under the receiver operator characteristic curve (ROC-AUC) of 0.986 and need for ventilator support with a ROC-AUC of 0.995. 10-day predictions were comparable.

MeaningThe study demonstrates that ML modelled could be a useful tool for hospital planners during crisis management, including the current COVID-19 pandemic.


title: Reduced BNT162b2 mRNA vaccine response in SARS-CoV-2-naive nursing home residents

abstract: The SARS-CoV-2 pandemic impact on nursing home (NH) residents prompted their prioritization for early vaccination. To fill the data gap for vaccine immunogenicity in NH residents, we examined antibody levels after BNT162b2 mRNA vaccine to spike, receptor binding domain (RBD) and for virus neutralization in 149 NH residents and 111 health care worker controls. SARS-CoV-2-naive NH residents mount antibody responses with nearly 4-fold lower median neutralization titers and half the anti-spike level compared to SARS-CoV-2-naive healthcare workers. By contrast, SARS-CoV-2-recovered vaccinated NH residents had neutralization, anti-spike and anti-RBD titers similar to SARS-CoV-2-recovered vaccinated healthcare workers. NH residents blunted antibody responses have important implications regarding the quality and durability of protection afforded by neoantigen vaccines. We urgently need better longitudinal evidence on vaccine effectiveness specific to NH resident populations to inform best practices for NH infection control measures, outbreak prevention and potential indication for a vaccine boost.


title: Vascular Inflammation in Lungs of Patients with Fatal Coronavirus Disease 2019 (COVID-19) Infection: Possible role for the NLRP3 inflammasome

abstract: Hyperinflammation is a key event that occurs with SARS-CoV-2 infection. In the lung, hyperinflammation leads to structural damage to tissue. To date, numerous lung histological studies have shown extensive alveolar damage, but there is scarce documentation of vascular inflammation in postmortem lung tissue. Here we document histopathological features and monitor the NLRP3 inflammasome in fatal cases of disease caused by SARS Cov2 (COVID-19). We posit that inflammasome formation along the vessel wall is a characteristic of lung inflammation that accompanies COVID-19 and that it is a probable candidate that drives amplification of inflammation post infection.


title: Symptoms of COVID-19 in a population-based cohort study

abstract: Accurate diagnosis of potential SARS-CoV-2 infections by symptoms is one strategy for continuing global surveillance, particularly in low-resource communities. We conducted a prospective, population-based cohort study, the Arizona CoVHORT, among Arizona residents to elucidate the symptom profile of laboratory-confirmed COVID-19 participants(16.2%) compared to laboratory-confirmed negative(22.4%) and untested general population participants(61.4%). Among the 1514 study participants, those who were COVID-19 positive were more likely to be Hispanic(33.5%) and more likely to report obesity > 30 kg/m2(34.7%) compared to COVID-19 negative participants(19.2%; 31.0%) and untested CoVHORT participants(13.8%; 23.8%). Of the 245 laboratory-confirmed COVID-19 cases, 15.0% reported having had no symptoms. Of those that did report symptoms, the most commonly-reported first symptoms were sore throat(19.0%), headache(15.5%), cough(12.7%), runny nose/cold-like symptoms(12.1%), and fatigue(12.0%). In adjusted logistic regression models, COVID-19 positive participants were more likely than negative participants to experience loss of taste and smell(OR:35.7; 95% CI 18.4-69.5); bone or nerve pain(OR:17.9; 95% CI 6.7-47.4), vomiting(OR:10.8; 95% CI 3.1-37.5), nausea(OR:10.5; 95% CI 5.5-19.9), and headache(OR:8.4; 95% CI 5.6-12.8). When comparing confirmed COVID-19 cases with confirmed negative or untested participants, the pattern of symptoms that discriminates SARS-CoV-2 infection from those arising from other potential circulating pathogens may differ from general reports of symptoms among cases alone.


title: Non-Alcoholic Fatty Liver Disease (NAFLD) in Children and Adolescents taking Atypical Antipsychotic Medications : A Protocol for a Systematic Review and Meta-Analysis

abstract: Atypical Antipsychotic medications are commonly prescribed to children and adolescents and are associated with important adverse effects including weight gain and metabolic syndrome. Non-Alcoholic Fatty Liver Disease (NAFLD) is not only the most common pediatric liver disease, but can also be associated with serious complications including liver cirrhosis. Given that both NAFLD and Atypical Antipsychotics (AAP) are associated with metabolic syndrome, we aimed to comprehensively examine the association between AAP and NAFLD in children and adolescents. We will conduct a systematic review following the PRISMA guidelines, of English-language literature published between 1950 and 2020, exploring NAFLD in subjects younger than 18 years on AAP.


title: Role of Combining Anticoagulant and Antiplatelet Agents in COVID-19 Treatment: A Rapid Review

abstract:
Although primarily affecting the respiratory system, COVID-19 causes multiple organ damage. One of its grave consequences is a prothrombotic state that manifests as thrombotic, microthrombotic, and thromboembolic events.Therefore, understanding the effect of antiplatelet and anticoagulation therapy in the context of COVID-19 treatment is important. The aim of this rapid review is to highlight the role of thrombosis in COVID-19 and provide new insights on the use of antithrombotic therapy in its management. A rapid systematic review was performed using preferred reporting items for systematic reviews. Papers published in English on antithrombotic agent use and COVID-19 complications were eligible. Results showed that the use of anticoagulants increased survival and reduced thromboembolic events in patients. However, despite the use of anticoagulants, patients still suffered thrombotic events likely due to heparin resistance. Data on antiplatelet use in combination with anticoagulants in the setting of COVID-19 is quite scarce. Current side effects of anticoagulation therapy emphasize the need to update treatment guidelines. In this rapid review, we address a possible modulatory role of antiplatelet and anticoagulant combination against COVID{square}19 pathogenesis. This combination may be an effective form of adjuvant therapy against COVID{square}19 infection. However, further studies are needed to elucidate potential risks and benefits associated with this combination.

It was not appropriate or possible to involve patients or the public in the design, or conduct, or reporting, or dissemination plans of our research


title: Parasite species regulates T cell activation in human malaria

abstract: The biology of Plasmodium vivax is markedly different to that of P. falciparum; how this shapes the immune response to infection remains unclear. To address this shortfall, we inoculated human volunteers with a clonal field isolate of P. vivax and tracked their response through infection and convalescence. High dimensional protein and RNA-seq data show that P. vivax triggers an acute phase response that shares remarkable overlap with that of P. falciparum, suggesting a hardwired emergency myeloid response that does not discriminate parasite species. We then used cytometry by time of flight to analyse the fate and function of innate-like and adaptive T cells; these data show that P. vivax can activate up to one quarter of the entire T cell compartment. Heterogeneous effector memory-like CD4+ T cells dominate this extraordinary response and phenotypic analysis reveals unexpected features of terminal differentiation that are normally associated with cytotoxicity and autoinflammatory disease. In line with this observation, we found that CD4+ T cell activation coincides with collateral tissue damage and liver injury. Finally, comparative analyses demonstrate that P. falciparum drives T cell activation far in excess of P. vivax, which may partially explain why falciparum malaria more frequently causes severe disease.


title: Mapping T cell activation and differentiation at single cell resolution in naive hosts infected with Plasmodium vivax


title: COVID-19 Survivors' Reports of the Timing, Duration, and Health Impacts of Post-Acute Sequelae of SARS-CoV-2 (PASC) Infection

abstract:
IMPORTANCEPost-Acute Sequelae of SARS-CoV-2 Infection (PASC) is a major public health concern. Studies suggest that 1 in 3 infected with SARS-CoV-2 may develop PASC, including those without initial symptoms or with mild COVID-19 disease.1, 2

OBJECTIVETo evaluate the timing, duration, and health impacts of PASC reported by a large group of primarily non-hospitalized COVID-19 survivors.

DESIGN, SETTING, AND PARTICIPANTSA survey of 5,163 COVID-19 survivors reporting symptoms for more than 21 days following SARS-CoV-2 infection. Participants were recruited from Survivor Corps and other online COVID-19 survivor support groups.

MAIN OUTCOMES AND MEASURESParticipants reported demographic information, as well as the timing, duration, health impacts, and other attributes of PASC. The temporal distribution of symptoms, including average time of onset and duration of symptoms were determined, as well as the perceived distress and impact on ability to work.

RESULTSOn average, participants reported 21.4 symptoms and the number of symptoms ranged from 1 to 93. The most common symptoms were fatigue (79.0%), headache (55.3%), shortness of breath (55.3%), difficulty concentrating (53.6%), cough (49.0%), changed sense of taste (44.9%), diarrhea (43.9%), and muscle or body aches (43.5%). The timing of symptom onset varied and was best described as happening in waves. The longest lasting symptoms on average for all participants (in days) were "frequently changing" symptoms (112.0), inability to exercise (106.5), fatigue (101.7), difficulty concentrating (101.1), memory problems (100.8), sadness (99.2), hormone imbalance (99.1), and shortness of breath (96.9). The symptoms that affected ability to work included the relapsing/remitting nature of illness (described by survivors as "changing symptoms"), inability to concentrate, fatigue, and memory problems, among others. Symptoms causing the greatest level of distress (on scale of 1 "none" to 5 "a great deal") were extreme pressure at the base of the head (4.4), syncope (4.3), sharp or sudden chest pain (4.2), brain pressure (4.2), headache (4.2), persistent chest pain or pressure (4.1), and bone pain in extremities (4.1).

CONCLUSIONS AND RELEVANCEPASC is an emerging public health priority characterized by a wide range of changing symptoms, which hinder survivors ability to work. PASC has not been fully characterized and the trajectory of symptoms and long-term outcomes are unknown. There is no treatment for PASC, and survivors report distress in addition to a host of ongoing symptoms. Capturing patient reports of symptoms through open-ended inquiry is a critical first step in accurately and comprehensively characterizing PASC to ensure that medical treatments and management strategies best meet the needs of individual patients and help mitigate health impacts of this new disease.


title: No support for oxytocin modulation of reward-related brain function in autism: evidence from a randomized controlled trial

abstract: Autism spectrum disorder (ASD) is characterized by difficulties in social communication and interaction, which have been related to atypical neural processing of rewards, especially in the social domain. Since intranasal oxytocin has been shown to modulate activation of the brains reward circuit, oxytocin could be a useful tool to ameliorate the processing of social rewards in ASD and thus improve social difficulties. In this randomized, double-blind, placebo-controlled, crossover fMRI study, we examined effects of a 24 IU dose of intranasal oxytocin on reward-related brain function in 37 men with an ASD diagnosis and 37 age- and IQ-matched control participants. Participants performed an incentive delay task that allows the investigation of neural activity associated with the anticipation and receipt of monetary and social rewards. Apart from a specific interaction effect in a single voxel within the left amygdala during the receipt of rewards, oxytocin did not influence neural processes related to the anticipation or consumption of social or monetary rewards in either group. Exploratory analyses suggested that oxytocin may increase ventral striatum sensitivity to monetary, but not social rewards, in individuals with high levels of self-reported anxiety, depression, alexithymia, and autistic traits irrespective of an ASD diagnosis. There were no significant differences in reward-related brain function between the two groups under placebo. Overall, our results do not support the hypothesis that intranasal oxytocin generally enhances activation of reward-related neural circuits in men with and without ASD without intellectual impairment. How and if oxytocin can be beneficial in the treatment of social difficulties in ASD needs to be addressed by examining moderating influences of individual differences and context on reward-related oxytocin effects.


title: Addressing disruptions in childhood routine immunisation services during the COVID-19 pandemic: perspectives and lessons learned from Liberia, Nepal, and Senegal

abstract:
The COVID-19 pandemic has inflicted multifaceted disruptions to routine immunisation from global to local levels, affecting every aspect of vaccine supply, access, and demand. Since March 2020, country programmes have implemented a range of strategies to either continue vaccination services during COVID-19 measures like  lockdown and/or resume services when risks of SARS-CoV-2 transmission could be appropriately mitigated. Through the Exemplars in Global Health partnership in Liberia, Nepal, and Senegal, we conducted interviews with immunisation programme managers and ministry of health leadership to better understand how they have addressed the myriad vaccination challenges posed by the ongoing pandemic. From establishing alternative modes of service delivery to combatting vaccine distrust and rumours via risk communication campaigns, many routine immunisation programmes have demonstrated how to adapt, resume, and/or maintain vital vaccination efforts during the COVID-19 crisis. Yet millions of children remain un- or under-vaccinated worldwide, and the same programmes striving to implement catch-up services for missed doses and postponed mass campaigns will also soon be tasked with COVID-19 vaccine deployment. As laid bare by the current pandemic, the worlds gains against vaccine-preventable diseases are fragile: enshrined by a delicate global ecosystem of logistics, supply, and procurement, the success of routine immunisation ultimately rests upon dedicated programme staff, the resources and support available to them, and then the trust in and demand for vaccines by their recipients. Our collective lessons learned during COVID-19 offer insights in programme adaptation and resilience that, if prioritised, could strengthen equitable, sustainable vaccine delivery for all populations.

Summary boxO_LIKey message 1: As the COVID-19 pandemic affected routine immunisation services worldwide, country programmes have used a range of mitigation strategies to maintain vaccine delivery and/or resume interrupted programming. Interviews with immunisation programme managers and Ministry of Health staff provided key perspectives and lessons learned on how countries have approached routine immunisation services during the COVID-19 crisis.
C_LIO_LIKey message 2: Key themes for mitigating COVID-19s effects on routine immunisation included prioritising continued services with strengthened infection prevention control; identifying alternative locations and approaches to providing vaccine services (e.g., conducting door-to-door vaccination if facility-based services were not possible); engaging in effective communications and mobilisation activities, especially to offset misinformation about COVID-19 and vaccines; setting up systems and strategies for reaching children who missed doses amid periods of disruption; and conducting catch-up campaigns as soon as SARS-CoV-2 transmission risks could be minimised.
C_LIO_LIKey message 3: The ways in which COVID-19 has affected routine immunisation services have varied over time and across settings, underscoring the importance of contextually-tailored mitigation efforts and adaptation given evolving challenges amid an ongoing pandemic. As countries prepare and initiate roll-out COVID-19 vaccines, it will be vital to avoid one-size-fits-all implementation strategies and support the continuance of routine immunisation services through this next phase of COVID-19 response.
C_LI


title: Factors influencing COVID-19 vaccination uptake in an elderly sample in Poland

abstract:
BackgroundsThis research represents an investigation into potential predictors for the uptake of the COVID-19 vaccination in Poland, following the instigation of policies to encourage the over-seventies to be vaccinated.

MethodsIndividuals participated in cross-sectional structured interviews. 1427 respondents were questioned for determining vaccination uptake, revealing attitudes regarding vaccination, where information was sourced from, health status and behavior, demographics and socio-economic profiles.

ResultsSelected predictors for acceptance of the vaccination were: being talked through the importance of the vaccination and potential side-effects by a medical professional; sharing living space with others; having a high ranking occupation; suffering from chronic illnesses; being able to access medical services by driving or walking rather than using public transport or relying on others. Those who opted not to be vaccinated most frequently justify their decision by saying that they were concerned about the efficacy of the vaccine or that they were worried about side-effects.

ConclusionsIt appears that the current nationwide campaign has successfully raised awareness regarding the vaccine, but this research indicates that a more information-based campaign, focusing on evidence of the vaccines efficacy and the non-serious nature of all side-effects, could lead to improved uptake of the COVID-19 vaccine.


title: Determinants of COVID-19 outcomes: A systematic review.

abstract:
BackgroundThe current pandemic, COVID-19, caused by a novel coronavirus SARS-CoV-2, has claimed over a million lives worldwide in a year, warranting the need for more research into the wider determinants of COVID-19 outcomes to support evidence-based policies.

ObjectiveThis study aimed to investigate what factors determined the mortality and length of hospitalisation in individuals with COVID-19.

Data SourceThis is a systematic review with data from four electronic databases: Scopus, Google Scholar, CINAHL and Web of Science.

Eligibility CriteriaStudies were included in this review if they explored determinants of COVID-19 mortality or length of hospitalisation, were written in the English Language, and had available full-text.

Study appraisal and data synthesisThe authors assessed the quality of the included studies with the Newcastle{square}Ottawa Scale and the Agency for Healthcare Research and Quality checklist, depending on their study design. Risk of bias in the included studies was assessed with risk of bias assessment tool for non-randomised studies. A narrative synthesis of the evidence was carried out. The review methods were informed by the Joana Briggs Institute guideline for systematic reviews.

ResultsThe review included 22 studies from nine countries, with participants totalling 239,830. The included studies quality was moderate to high. The identified determinants were categorised into demographic, biological, socioeconomic and lifestyle risk factors, based on the Dahlgren and Whitehead determinant of health model. Increasing age (ORs 1.04-20.6, 95%CIs 1.01-22.68) was the common demographic determinant of COVID-19 mortality while living with diabetes (ORs 0.50-3.2, 95%CIs -0.2-0.74) was one of the most common biological determinants of COVID-19 length of hospitalisation.

Review limitationMeta-analysis was not conducted because of included studies heterogeneity.

ConclusionCOVID-19 outcomes are predicted by multiple determinants, with increasing age and living with diabetes being the most common risk factors. Population-level policies that prioritise interventions for the elderly population and the people living with diabetes may help mitigate the outbreaks impact.

PROSPERO registration numberCRD42021237063.

Strength and limitations of this reviewO_LIThis is the first systematic review synthesising the evidence on determinants of COVID-19 LOS outcome.
C_LIO_LIIt is also the first review to provide a comprehensive investigation of contextual determinants of COVID-19 outcomes, based on the determinants of health model; thus, presenting with crucial gaps in the literature on the determinants of COVID-19 outcomes that require urgent attention.
C_LIO_LIThe review was restricted in conducting meta-analysis due to included studies heterogeneity.
C_LIO_LIThe review focused on only papers published in the English Language; hence, other relevant papers written on other languages could have been omitted.
C_LI


title: Corticosteroids and mortality in patients with severe Covid-19 who have autoantibodies

abstract:
Auto-reactivity in COVID-19 is increasingly being recognized and may identify a group of patients with inflammation severe enough to result in loss of self-tolerance. Corticosteroids are potent anti-inflammatory agents and now the standard of care for patients with severe Covid-19 requiring oxygen support/mechanical ventilation. We studied the outcomes of COVID-19 patients who demonstrated clinically identifiable auto-reactivity and received corticosteroid treatment.

In this retrospective cohort study, we included 51 COVID-19 patients admitted between March 10, 2020 and May 2, 2020 who received corticosteroid treatment and also had serum sample in our institution bio-bank available for ANA and RF ELISA. Twelve patients (23.5%) had positive ANA or RF. Mortality rate among patients with positive autoantibodies was significantly higher than those without (9/12 or 75% versus 13/39 or 33.3%, p= 0.02). The high mortality rate in patients with auto-reactivity warrants further investigation and may be the subgroup where additional immunomodulation is effective.


title: In-person schooling and COVID-19 transmission in Canada's three largest cities

abstract:
In North America and Europe, the Fall 2020 school term has coincided with the beginning of the second wave of the novel coronavirus (COVID-19) pandemic, sparking a heated debate about the role of in-person schooling for community transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This issue has immediate policy relevance for deciding how to operate schools safely as the pandemic unfolds, new variants of SARS-CoV-2 are circulating, and immunization coverage remains low. We contribute to this debate by presenting data on trends in COVID-19 weekly incidence among school-aged children 0-19 years old vis-a-vis other age groups during Fall 2020 in Canadas three largest cities: Montreal, Toronto and Calgary. We interpret these trends in light of the different back-to-school policies and other public health measures implemented in the three cities over the observation period.

KEY POINTSO_LISchool closures are an effective measure to reduce the overall incidence of the novel coronavirus (COVID-19). Nonetheless, there is a general consensus that the decision to close schools to control the spread of COVID-19 should be used as last resort because of the negative impact on childrens development and mental health, and since they are less likely to have severe COVID-19 outcomes than adults.
C_LIO_LIExisting evidence highlights the importance of adopting appropriate mitigation strategies for limiting COVID-19 community spread when returning to in-person schooling. To understand the association between in-person schooling and COVID-19 transmission given different mitigation strategies, especially universal masking and distance learning, we compare how the second wave of COVID-19 has affected school-aged children age 0-19 years old vis-a-vis other age groups in Montreal, Toronto and Calgary during Fall 2020.
C_LIO_LIThe case of Montreal attests to the negative consequences of not implementing recommended migration strategies when reopening schools, even when public health measures such as gatherings restrictions are in place to maintain low levels of community transmission. On the contrary, school measures adopted in Toronto (optional distance learning and masking mandates), have limited the role of COVID-19 transmission among school-aged children for overall community transmission. In Calgary, this effect has been smaller, likely because public health measures to limit COVID-19 community spread were not introduced until early December 2020.
C_LIO_LIOur findings have immediate policy relevance for deciding how to operate schools safely as the pandemic unfolds, new variants of SARS-CoV-2 are circulating, and immunization coverage remains low.
C_LI


title: Long Covid in adults discharged from UK hospitals after Covid-19: A prospective, multicentre cohort study using the ISARIC WHO Clinical Characterisation Protocol.

abstract:
Structured AbstractO_ST_ABSObjectivesC_ST_ABSThe long-term consequences of severe Covid-19 requiring hospital admission are not well characterised. The objective of this study was to establish the long-term effects of Covid-19 following hospitalisation and the impact these may have on patient reported outcome measures.

DesignA multicentre, prospective cohort study with at least 3 months follow-up of participants admitted to hospital between 5th February 2020 and 5th October 2020.

Setting31 hospitals in the United Kingdom.

Participants327 hospitalised participants discharged alive from hospital with confirmed/high likelihood SARS-CoV-2 infection.

Main outcome measures and comparisonsThe primary outcome was self-reported recovery at least ninety days after initial Covid-19 symptom onset. Secondary outcomes included new symptoms, new or increased disability (Washington group short scale), breathlessness (MRC Dyspnoea scale) and quality of life (EQ5D-5L). We compared these outcome measures across age, comorbidity status and in-hospital Covid-19 severity to identify groups at highest risk of developing long-term difficulties. Multilevel logistic and linear regression models were built to adjust for the effects of patient and centre level risk factors on these outcomes.

ResultsIn total 53.7% (443/824) contacted participants responded, yielding 73.8% (327/443) responses with follow-up of 90 days or more from symptom onset. The median time between symptom onset of initial illness and completing the participant questionnaire was 222 days (Interquartile range (IQR) 189 to 269 days). In total, 54.7% (179/327) of participants reported they did not feel fully recovered. Persistent symptoms were reported by 93.3% (305/325) of participants, with fatigue the most common (82.8%, 255/308), followed by breathlessness (53.5%, 175/327). 46.8% (153/327) reported an increase in MRC dyspnoea scale of at least one grade. New or worse disability was reported by 24.2% (79/327) of participants. Overall (EQ5D-5L) summary index was significantly worse at the time of follow-up (median difference 0.1 points on a scale of 0 to 1, IQR: -0.2 to 0.0). Females under the age of 50 years were five times less likely to report feeling recovered (adjusted OR 5.09, 95% CI 1.64 to 15.74), were more likely to have greater disability (adjusted OR 4.22, 95% CI 1.12 to 15.94), twice as likely to report worse fatigue (adjusted OR 2.06, 95% CI 0.81 to 3.31) and seven times more likely to become more breathless (adjusted OR 7.15, 95% CI 2.24 to 22.83) than men of the same age.

ConclusionsSurvivors of Covid-19 experienced long-term symptoms, new disability, increased breathlessness, and reduced quality of life. These findings were present even in young, previously healthy working age adults, and were most common in younger females. Policymakers should fund further research to identify effective treatments for long-Covid and ensure healthcare, social care and welfare support is available for individuals with long-Covid.

Section 1: What is already known on this topicO_LILong-term symptoms after hospitalisation for Covid-19 have been reported, but it is not clear what impact this has on quality of life.
C_LIO_LIIt is not known which patient groups are most likely to have long-term persistent symptoms following hospitalisation for Covid-19, or if this differs by disease severity.
C_LI

Section 2: What this study addsO_LIMore than half of patients reported not being fully recovered 7 months after onset of Covid-19 symptoms.
C_LIO_LIPreviously healthy participants and those under the age of 50 had higher odds of worse long-term outcomes compared to older participants and those with comorbidities.
C_LIO_LIYounger women and those with more severe acute disease in-hospital had the worst long-term outcomes.
C_LIO_LIPolicy makers need to ensure there is long-term support for people experiencing long-Covid and should plan for lasting long-term population morbidity. Funding for research to understand mechanisms underlying long-Covid and identify potential interventions for testing in randomised trials is urgently required.
C_LI


title: Detection of Mutations Associated with Variants of Concern Via High Throughput Sequencing of SARS-CoV-2 Isolated from NYC Wastewater

abstract:
Monitoring SARS-CoV-2 genetic diversity is strongly indicated because diversifying selection may lead to the emergence of novel variants resistant to naturally acquired or vaccine-induced immunity. To date, most data on SARS-CoV-2 genetic diversity has come from the sequencing of clinical samples, but such studies may suffer limitations due to costs and throughput. Wastewater-based epidemiology may provide an alternative and complementary approach for monitoring communities for novel variants. Given that SARS-CoV-2 can infect the cells of the human gut and is found in high concentrations in feces, wastewater may be a valuable source of SARS-CoV-2 RNA, which can be deep sequenced to provide information on the circulating variants in a community. Here we describe a safe, affordable protocol for the sequencing of SARS-CoV-2 RNA using high-throughput Illumina sequencing technology. Our targeted sequencing approach revealed the presence of mutations associated with several Variants of Concern at appreciable frequencies. Our work demonstrates that wastewater-based SARS-CoV-2 sequencing can inform surveillance efforts monitoring the community spread of SARS-CoV-2 Variants of Concern and detect the appearance of novel emerging variants more cheaply, safely, and efficiently than the sequencing of individual clinical samples.

IMPORTANCEThe SARS-CoV-2 pandemic has caused millions of deaths around the world as countries struggle to contain infections. The pandemic will not end until herd immunity is reached, that is, when most of the population has either recovered from SARS-CoV-2 infection or is vaccinated against SARS-CoV-2. However, the emergence of new SARS-CoV-2 variants of concern threatens to erase gains. Emerging new variants may re-infect persons who have recovered from COVID-19 or may evade vaccine-induced immunity. However, scaling up SARS-CoV-2 genetic sequencing to monitor Variants of Concern in communities around the world is challenging. Wastewater-based sequencing of SARS-CoV-2 RNA can be used to monitor the presence of emerging variants in large communities to enact control measures to minimize the spread of these variants. We describe here the identification of alleles associated with several variants of concern in wastewater obtained from NYC watersheds.


title: Age-related changes in the upper respiratory microbiome are associated with SARS-CoV-2 susceptibility and illness severity

abstract:
Children are less susceptible to SARS-CoV-2 and typically have milder illness courses than adults. We studied the nasopharyngeal microbiomes of 274 children, adolescents, and young adults with SARS-CoV-2 exposure using 16S rRNA gene sequencing. We find that higher abundances of Corynebacterium species are associated with SARS-CoV-2 infection and SARS-CoV-2-associated respiratory symptoms, while higher abundances of Dolosigranulum pigrum are present in SARS-CoV-2-infected individuals without respiratory symptoms. We also demonstrate that the abundances of these bacteria are strongly, and independently, associated with age, suggesting that the nasopharyngeal microbiome may be a potentially modifiable mechanism by which age influences SARS-CoV-2 susceptibility and severity.

SummaryEvaluation of nasopharyngeal microbiome profiles in children, adolescents, and young adults with a SARS-CoV-2-infected close contact identified specific bacterial species that vary in abundance with age and are associated with SARS-CoV-2 susceptibility and the presence of SARS-CoV-2-associated respiratory symptoms.


title: Emergence of the E484K Mutation in SARS-CoV-2 Lineage B.1.1.220 in Upstate New York

abstract: Ongoing surveillance detected a SARS-CoV-2 B.1.1.220 variant carrying the E484K substitution in four patients from a hospital network in upstate New York. Patients reported no travel history and shared no obvious epidemiological linkage. A search of online databases identified 12 additional B.1.1.220 with E484K, all of which were detected in New York since December 2020. Detailed genomic analyses suggests that the mutation has emerged independently in at least two different B.1.1.220 strains in this region.


title: Physical, cognitive and mental health impacts of COVID-19 following hospitalisation: a multi-centre prospective cohort study

abstract:
BackgroundThe impact of COVID-19 on physical and mental health, and employment following hospitalisation is poorly understood.

MethodsPHOSP-COVID is a multi-centre, UK, observational study of adults discharged from hospital with a clinical diagnosis of COVID-19 involving an assessment between two- and seven-months later including detailed symptom, physiological and biochemical testing. Multivariable logistic regression was performed for patient-perceived recovery with age, sex, ethnicity, body mass index (BMI), co-morbidities, and severity of acute illness as co-variates. Cluster analysis was performed using outcomes for breathlessness, fatigue, mental health, cognition and physical function.

FindingsWe report findings of 1077 patients discharged in 2020, from the assessment undertaken a median 5 [IQR4 to 6] months later: 36% female, mean age 58 [SD 13] years, 69% white ethnicity, 27% mechanical ventilation, and 50% had at least two co-morbidities. At follow-up only 29% felt fully recovered, 20% had a new disability, and 19% experienced a health-related change in occupation. Factors associated with failure to recover were female, middle-age, white ethnicity, two or more co-morbidities, and more severe acute illness. The magnitude of the persistent health burden was substantial and weakly related to acute severity. Four clusters were identified with different severities of mental and physical health impairment: 1) Very severe (17%), 2) Severe (21%), 3) Moderate with cognitive impairment (17%), 4) Mild (46%), with 3%, 7%, 36% and 43% feeling fully recovered, respectively. Persistent systemic inflammation determined by C-reactive protein was related to cluster severity, but not acute illness severity.

InterpretationWe identified factors related to recovery from a hospital admission with COVID-19 and four different phenotypes relating to the severity of physical, mental, and cognitive health five months later. The implications for clinical care include the potential to stratify care and the need for a pro-active approach with wide-access to COVID-19 holistic clinical services.

Funding: UKRI and NIHR


title: CBKH: The Cornell Biomedical Knowledge Hub

abstract: The rapidly increasing biomedical knowledge, derived from biological experiments or gained from clinical practice, has become the important treasure in the biomedical research. The emerging knowledge graphs (KGs) provide an efficient and effective way to organize and retrieval the huge and increasing volume of biomedical knowledge. A biomedical KG (BKG) typically stores and represents knowledge by constructing a semantic network describing entities and the relationships between them. Previous efforts have been conducted to construct and curate BKGs by comprehensively integrating various biomedical data resources. Though the resulting BKGs have made a significant progress in this filed in advancing biological and medical research, there remain a big gap to a perfect one that is comprehensive and fine-grained enough. To this end, in the present study, we collected and integrated data from diverse well-curated biomedical knowledge bases and BKGs to curate a more comprehensive one, named the integrative Biomedical Knowledge Hub (iBKH). To enhance the usage in accelerating biomedical research, we deployed iBKH using the famous graph database, Neo4j. This is a continuing effort and we are adding in more and more contents in iBKH to support the various complex needs in biomedical data analysis. Please contact us if you have better ideas and suggestions.

category: health informatics


title: iBKH: The integrative Biomedical Knowledge Hub


title: Where to learn to flatten the curve: a modelling study

abstract:
BackgroundIndividual behavioural decisions are responses to both a persons perceived social norms and could be driven by both their physical and social environment. In the context of the COVID-19 pandemic, these environments correspond to epidemiological risk from contacts and the social construction of risk by communication within networks of friends. Understanding when, and under which circumstances, each modality of influence can foster the widespread adoption of protective behaviours is critical for shaping useful, practical public health messaging that will best enhance the public response.

MethodsWe use a multiplex network approach to explore how information from both physical contact and social communication networks is driving a mitigating behavioural response to disease risk.

FindingsWe show that maintaining focus on awareness of risk in each individuals physical layer contacts promotes the greatest reduction in disease spread, but only when an individual is aware of the symptoms of a non-trivial proportion of their physical contacts (approximately 20% or more). Information from the communication layer was less useful when these connections matched less well with physical contacts and contributed little in combination with accurate information from the physical layer.

InterpretationWe conclude that maintaining social focus on local outbreak status will allow individuals to structure their perceived social norms appropriately and respond more rapidly when risk increases. Finding ways to relay accurate local information from trusted community leaders could improve mitigation even where more intrusive/costly strategies, such as contact-tracing, are not possible.


title: Introducing the 4Ps Model of Transitioning to Distance Learning: a convergent mixed methods study conducted during the COVID-19 pandemic.

abstract:
Significant concern has been raised regarding the effect of COVID-19 on medical education. The aim of this study was to shed light on the distance learning experiences of medical students and their instructors. A convergent mixed methods approach was utilized. Qualitative and quantitative data was collected using a survey.

The percentage of the total average of satisfaction among stakeholders was 76.4%. The qualitative analysis revealed several themes. This study introduced the 4Ps Model of Transitioning to Distance Learning. It would be useful to leverage the lessons-learned to tailor blended medical programs, with a reasonable melange of experiences. The study also contributes to the mixed methods research through showcasing a means of adapting it to evaluate critical situations reliably and rapidly.

category: medical education


title: Improving Pre-eclampsia Risk Prediction by Modeling Individualized Pregnancy Trajectories Derived from Routinely Collected Electronic Medical Record Data

abstract: Preeclampsia (PE) is a heterogeneous and complex disease associated with rising morbidity and mortality in pregnant women and newborns in the US. Early recognition of patients at risk is a pressing clinical need to significantly reduce the risk of adverse pregnancy outcomes. We assessed whether information routinely collected and stored on women in their electronic medical records (EMR) could enhance the prediction of PE risk beyond what is achieved in standard of care assessments today. We developed a digital phenotyping algorithm to assemble and curate 108,557 pregnancies from EMRs across the Mount Sinai Health System (MSHS), accurately reconstructing pregnancy journeys and normalizing these journeys across different hospital EMR systems. We then applied machine learning approaches to a training dataset from Mount Sinai Hospital (MSH) (N = 60,879) to construct predictive models of PE across three major pregnancy time periods (ante-, intra-, and postpartum). The resulting models predicted PE with high accuracy across the different pregnancy periods, with areas under the receiver operating characteristic curves (AUC) of 0.92, 0.83 and 0.89 at 37 gestational weeks, intrapartum and postpartum, respectively. We observed comparable performance in two independent patient cohorts with diverse patient populations (MSH validation dataset N = 38,421 and Mount Sinai West dataset N = 9,257). While our machine learning approach identified known risk factors of PE (such as blood pressure, weight and maternal age), it also identified novel PE risk factors, such as complete blood count related characteristics for the antepartum time period and ibuprofen usage for the postpartum time period. Our model not only has utility for earlier identification of patients at risk for PE, but given the prediction accuracy substantially exceeds what is achieved today in clinical practice, our model provides a path for promoting personalized precision therapeutic strategies for patients at risk.

category: obstetrics and gynecology


title: Determinants of anti-PD1 response and resistance in clear cell renal cell carcinoma

abstract: Antigen recognition and T-cell mediated cytotoxicity in clear-cell renal cell carcinoma (ccRCC) remains incompletely understood. To address this knowledge gap, we analysed 115 multiregion tumour samples collected from 15 treatment-naive patients pre- and post-nivolumab therapy, and at autopsy in three patients. We performed whole-exome sequencing, RNAseq, TCRseq, multiplex immunofluorescence and flow cytometry analyses and correlated with clinical response. We observed pre-treatment intratumoural TCR clonal expansions suggesting pre-existing immunity. Nivolumab maintained pre-treatment expanded, clustered TCR clones in responders, suggesting ongoing antigen-driven stimulation of T-cells. T-cells in responders were enriched for expanded TCF7+CD8+ T-cells and upregulated GZMK/B upon nivolumab-binding. By contrast, nivolumab promoted accumulation of new TCR clones in non-responders, replacing pre-treatment expanded clonotypes. In this dataset, mutational features did not correlate with response to nivolumab and human endogenous retrovirus expression correlated indirectly. Our data suggests that nivolumab potentiates clinical responses in ccRCC by binding pre-existing expanded CD8+ T-cells to enhance cytotoxicity.

category: oncology


title: Intra-tumoral epigenetic heterogeneity and aberrant molecular clocks in hepatocellular carcinoma

abstract: There is limited understanding of the epigenetic drivers of tumor evolution in hepatocellular carcinoma (HCC). We quantify epigenetic intra-tumoral heterogeneity (ITH) using regional enhanced reduced-representation bisulfite sequencing (eRRBS) DNA methylation data from 47 early stage, treatment-naive HCC biopsies across 9 patients. Integrating these data with matching RNAseq, targeted DNA sequencing, tumor-infiltrating lymphocyte (TIL) and hepatitis-B viral (HBV) expression, we computed regional differential methylation (DM) ITH signatures across 19,327 promoter regions, and 654,133 CpG islands, while overlapping with known methylation age marker genes (240/354). We found substantial ITH signatures in promoter and enhancer sites across 4/9 patients highlighting novel molecular pathways of tumor progression not otherwise detectable from RNA analysis alone. Additionally, we identify an epigenetic tumoral aging measure that reflects a complex tumor fitness phenotype as a potential proxy for tumor evolution. In order to compute clinical associations with epigenetic tumoral age, we use 450k array data from 377 HCC patients in the TCGA-LIHC single-biopsy cohort to calculate tumoral age and find evidence implying that epigenetically old tumors have lower fitness yet higher TIL burden. Our data reveal a novel, unique epigenetic ITH axis in HCC tumors that furthers our understanding of tumor evolution and may serve as a potential avenue for enhancing patient stratification and treatment.


title: The PKN1- TRAF1 signaling axis as a potential new target for chronic lymphocytic leukemia

abstract: TRAF1 is a pro-survival adaptor molecule in TNFR superfamily (TNFRSF) signaling. TRAF1 is overexpressed in many B cell cancers including refractory chronic lymphocytic leukemia (CLL). Little has been done to assess the role of TRAF1 in human cancer. Here we show that the protein kinase C related kinase Protein Kinase N1 (PKN1) is required to protect TRAF1 from cIAP-mediated degradation during constitutive CD40 signaling in lymphoma. We show that the active phospho-Thr774 form of PKN1 is constitutively expressed in CLL but minimally detected in unstimulated healthy donor B cells. Through a screen of 700 kinase inhibitors, we identified two inhibitors, OTSSP167 and XL-228, that inhibited PKN1 in the nanomolar range and induced dose-dependent loss of TRAF1 in RAJI cells. OTSSP167 and XL-228 treatment of primary patient CLL samples led to a reduction in TRAF1, pNF-{kappa}B p65, pS6, pERK, Mcl-1 and Bcl-2 proteins, and induction of activated caspase-3. OTSSP167 synergized with venetoclax in inducing CLL death, correlating with loss of TRAF1, Mcl-1 and Bcl-2. Although correlative, these findings suggest the PKN1-TRAF1 signaling axis as a potential new target for CLL. These findings also suggest OTSSP167 and venetoclax as a combination treatment for TRAF1 high CLL.


title: Low-Dose Naltrexone/Acetaminophen Combinations and Each Component in the Acute Treatment of Migraine: Findings of a Small, Randomized, Double-Blind, and Placebo-Controlled Clinical Trial

abstract:
We tested two low-dose naltrexone and acetaminophen combinations and each component in the acute treatment of migraine. The patients use a single-dose of the study medication for a moderate or severe pain intensity migraine attack. Patients were adults with migraine with or without aura experiencing 2 to 20 (average 6.4) monthly migraine days. The co-primary endpoints were pain-freedom and absence of prospectively-identified most bothersome migraine-associated symptom 2 hours after dosing. We randomized 92 patients; 72 completed the study (mean age, 43 years; 75% women). Pain-freedom at 2 hours was 10.2% higher than placebo with naltrexone 2.25 mg/acetaminophen 325 mg, 10.9% with naltrexone 3.25 mg/acetaminophen 325 mg, 17.3% with naltrexone 2.25 mg, and 31.3% with acetaminophen 325 mg. The treatment groups migraine burden at baseline was unbalanced due to randomized patients uneven study completion. The acetaminophen group had the lowest migraine burden, giving its results lower credibility.

Saliently, Low-dose naltrexone alone (n=19) had a 17.3% higher response rate for headache pain-freedom at 2 hours than placebo (n=17). The naltrexone and the placebo groups were the largest and had a balanced disease burden, implying higher credibility to the naltrexone group results. We found low-dose naltrexone and acetaminophen combination, low-dose naltrexone, and acetaminophen had higher response rates than placebo in treating headache pain. The most commonly reported adverse events were sedation, nausea, and dizziness. We postulate that naltrexones toll-like receptor (TLR4) antagonism properties prevent pro-inflammatory cytokines production in the trigeminal ganglion averting "overactive nerves" (laymans term) and migraine. Although this trial used low-dose naltrexone (defined as 1 - 5 mg/day), future phase 3 studies will test a range of naltrexone and acetaminophen combination doses.

category: pain medicine


title: The Acute Treatment of Migraine with Low-Dose Naltrexone/Acetaminophen Combinations and Each Component: Findings of a Small, Randomized, Double-Blind, and Placebo-Controlled Clinical Trial


title: The Acute Treatment of Migraine with Low-Dose Naltrexone and acetaminophen Combinations and Each Component: Findings of a Small, Randomized, Double-Blind, and Placebo-Controlled Clinical Trial


title: Genome-Wide Meta-Analysis of Late-Onset Alzheimer's Disease Using Rare Variant Imputation in 324,809 Subjects Identifies Novel Rare Variant Locus NCK2: The International Genomics of Alzheimer's Project (IGAP)

abstract: Risk for late-onset Alzheimers disease (LOAD) is driven by multiple loci primarily identified by genome-wide association studies, many of which are common variants with minor allele frequencies (MAF)> 0.01. To identify additional common and rare LOAD risk variants, we performed a GWAS on 25,170 LOAD subjects and 41,052 cognitively normal controls in 44 datasets from the International Genomics of Alzheimers Project (IGAP). Existing genotype data was imputed using the dense, high-resolution Haplotype Reference Consortium (HRC) r1.1 reference panel. Stage 1 associations of P<10-5 were meta-analyzed with the European Alzheimers Disease Biobank (EADB) (n=20,301 cases; 21,839 controls) (stage 2 combined IGAP and EADB). An expanded meta-analysis was performed using a GWAS of parental AD/dementia history in the UK Biobank (UKBB) (n=35,214 cases; 180,791 controls) (stage 3 combined IGAP, EADB, and UKBB). Common variant (MAF[≥]0.01) associations were identified for 29 loci in stage 2, including novel genome-wide significant associations at TSPAN14 (P=2.33x10-12), SHARPIN (P=1.56x10-9), and ATF5/SIGLEC11 (P=1.03x10-8), and newly significant associations without using AD proxy cases in MTSS1L/IL34 (P=1.80x10-8), APH1B (P=2.10x10-13), and CLNK (P=2.24x10-10). Rare variant (MAF<0.01) associations with genome-wide significance in stage 2 included multiple variants in APOE and TREM2, and a novel association of a rare variant (rs143080277; MAF=0.0054; P=2.69x10-9) in NCK2, further strengthened with the inclusion of UKBB data in stage 3 (P=7.17x10-13). Single-nucleus sequence data shows that NCK2 is highly expressed in amyloid-responsive microglial cells, suggesting a role in LOAD pathology.


title: Educational attainment as a modifier of the effect of polygenic scores for cardiovascular risk factors: cross-sectional and prospective analysis of UK Biobank

abstract:
BackgroundUnderstanding the interplay between educational attainment and genetic predictors of cardiovascular risk may improve our understanding of mechanisms relating educational attainment to cardiovascular disease.

MethodsIn up to 320 120 UK Biobank participants of White British ancestry (mean age = 57, female 54%), we created polygenic scores for nine cardiovascular risk factors or diseases: alcohol consumption, body mass index, low-density lipoprotein cholesterol, lifetime smoking behaviour, systolic blood pressure, atrial fibrillation, coronary heart disease, type 2 diabetes and stroke. We estimated whether educational attainment modified genetic susceptibility to these risk factors and diseases.

ResultsOn the additive scale, higher educational attainment reduced genetic susceptibility to higher BMI, smoking, atrial fibrillation and type 2 diabetes, but increased genetic susceptibility to higher LDL-C and higher systolic blood pressure.

On the multiplicative scale, there was evidence that higher educational attainment increased genetic susceptibility to atrial fibrillation and coronary heart disease, but no evidence of effect modification was found for all other considered traits.

ConclusionsEducational attainment modifies the genetic susceptibility to some cardiovascular risk factors and diseases. The direction of this effect was mixed across traits considered and differences in associations between the effect of the polygenic score across strata of educational attainment was uniformly small. Therefore, any effect modification by education of genetic susceptibility to cardiovascular risk factors or diseases is unlikely to contribute substantially to the mechanisms driving inequalities in cardiovascular risk.

Key MessagesO_LIThe role of educational attainment in modifying the effect of polygenic scores for a wide range of cardiovascular risk factors or diseases has not previously been studied
C_LIO_LIWe explore whether educational attainment modifies the effects of polygenic susceptibility to alcohol consumption, body mass index, low-density lipoprotein cholesterol, lifetime smoking behaviour, systolic blood pressure, atrial fibrillation, coronary heart disease, type 2 diabetes and stroke
C_LIO_LIEffect modification by education was observed for some cardiovascular polygenic scores, but not all.
C_LIO_LIEffects were not always in the hypothesised direction and were dependent on the scale of analysis.
C_LIO_LIModification of the effect of genetic susceptibility to cardiovascular risk factors or cardiovascular disease by educational attainment is unlikely to contribute substantially to the mechanisms driving inequalities in cardiovascular risk.
C_LI


title: FAT4 Identified as a Potential Modifier of Orofacial Cleft Laterality

abstract: Orofacial clefts (OFCs) are common (1 in 700 births) congenital malformations that include cleft lip (CL) and cleft lip and palate (CLP). These OFC subtypes are also heterogeneous themselves, with the cleft lip occurring on the left, right, or both sides of the upper lip. Unilateral CL and CLP have a 2:1 bias towards left-sided clefts, suggesting a nonrandom process. Here, we performed a study of left- and right-sided clefts within the CL and CLP subtypes to better understand the genetic factors controlling cleft laterality. We conducted genome-wide modifier analyses by comparing cases that had right unilateral CL (RCL; N=130), left unilateral CL (LCL; N=216), right unilateral CLP (RCLP; N=416), or left unilateral CLP (LCLP; N=638), and identified a candidate region on 4q28, 400 kb downstream from FAT4, that approached genome-wide significance for LCL vs. RCL (p = 8.4x10-8). Consistent with its potential involvement as a genetic modifier of cleft lip, we found that Fat4 exhibits a specific domain of expression in the mesenchyme of the medial nasal processes that form the median upper lip. Overall, these results suggest that the epidemiological similarities in left-to right-sided clefts in CL and CLP are not reflected in the genetic association results.