title: Heterologous immunisation with vector vaccine as prime followed by mRNA vaccine as boost leads to humoral immune response against SARS-CoV-2, which is comparable to that according to a homologous mRNA vaccination scheme

abstract:
BackgroundThe humoral immune response after primary immunisation with a SARS-CoV-2 vector vaccine (AstraZeneca AZD1222, ChAdOx1 nCoV-19, Vaxzevria) followed by an mRNA vaccine boost (Pfizer/BioNTech, BNT162b2; Moderna, m-1273) was examined and compared with the antibody response after homologous vaccination schemes (AZD1222/AZD1222 or BNT162b2/BNT162b2).

MethodsSera from 59 vaccinees were tested for anti-SARS-CoV-2 immunoglobulin G (IgG) and virus-neutralising antibodies (VNA) with four IgG assays, a surrogate neutralisation test (sVNT), and a Vero cell-based neutralisation test (cVNT) using the B.1.1.7 variant of concern (VOC; alpha) as antigen. Investigation was done before and after heterologous (n=31 and 42) or homologous booster vaccination (AZD1222/AZD1222, n=8/9; BNT162b2/BNT162b2, n=8/8). After the second immunisation, 26 age and gender matched sera (AZD1222/mRNA, n=9; AZD1222/AZD1222, n=9; BNT162b2/BNT162b2, n=8) were also tested for VNA against VOC B.1.617.2 (delta) in the cVNT. The strength of IgG binding to separate SARS-CoV-2 antigens was measured by avidity.

ResultsAfter the first vaccination, prevalence of IgG directed against (trimeric) SARS-CoV-2 spike (S)-protein and its receptor-binding domain (RBD) varied from 55-95 % (AZD1222) to 100% (BNT162b2), depending on the vaccine used and the SARS-CoV-2 antigen used. The booster vaccination resulted in 100 percent seroconversion and appearance of highly avid IgG as well as VNA against VOC B.1.1.7. The results of the anti-SARS-CoV-2 IgG tests showed an excellent correlation to the VNA titres against this VOC. The agreement of cVNT and sVNT results was good. However, the sVNT seems to overestimate non and weak B.1.1.7-neutralising titres. The mean anti-SARS-CoV-2 IgG and B.1.1.7-neutralising titres were significantly higher after heterologous vaccination compared to the homologous AZD1222 scheme. If VOC B.1.617.2 was used as antigen, significantly lower mean VNAs were measured in the cVNT, and three (33.3%) vector vaccine recipients had a VNA titre <1:10.

ConclusionsThe heterologous SARS-CoV-2 vaccination leads to a strong antibody response with anti-SARS-CoV-2 IgG and VNA titres at a level comparable to that of a homologous BNT162b2 vaccination scheme. Irrespectively of the chosen immunisation regime, highly avid IgG antibodies can be detected just two weeks after the second vaccine dose indicating the development of a robust humoral immunity. The observed reduction in the VNA titre against VOC B.1.617.2 is remarkable and may be attributed to a partial immune escape of the delta variant.


title: The anti-SARS-CoV-2 immunoglobulin G levels and neutralising capacities against alpha and delta virus variants of concern achieved after initial immunisation with vector vaccine followed by mRNA vaccine boost are comparable to those after double immunisation with mRNA vaccines

category: infectious diseases


title: Utilization of health care services before and after media attention about fatal side effects of the AstraZeneca vaccine

abstract:
BackgroundSurvey studies have found that vaccinated persons tend to report more side effects after being given information about side effects rather than benefits. However, the impact of high media attention about vaccine-related side effects on the utilization of health care is unknown. We aimed to assess whether utilization of health care services for newly vaccinated health care workers changed after media attention about fatal side effects of the AstraZeneca vaccine on March 11th, 2021, and whether changes differed by age, sex, or occupation.

MethodsWe utilized individual-level data on health care use, vaccination, employment, and demographics available in the Norwegian emergency preparedness register Beredt C19. In all 99,899 health care workers in Norway who were vaccinated with AstraZeneca between February 11th and March 11th, we used an event-study design with a matched comparison group to compare the change in primary and inpatient specialist care use from 14 days before to 14 days after the information shock on March 11th, 2021.

ResultsPrimary health care use increased with 8.2 daily consultations per 1,000 health care workers (95% CI 7.51 to 8.89) the week following March 11th for those vaccinated with AstraZeneca (n = 99,899), compared with no increase for the unvaccinated comparison group (n = 186,885). Utilization of inpatient care also increased with 0.8 daily hospitalizations per 1,000 health care workers (95% CI 0.37 to 1.23) in week two after March 11th. The sharpest increase in daily primary health care use in the first week after March 11th was found for women aged 18-44 (10.6 consultations per 1,000, 95% CI 9.52 to 11.68) and for cleaners working in the health care sector (9.8 consultations per 1,000, 95% CI 3.41 to 16.19).

ConclusionsHealth care use was higher after the media reports of a few cases of fatal or severe side effects of the AstraZeneca vaccine. Our results suggest that the reports did not only lead vaccinated individuals to contact primary health care more, but also that physicians referred and treated more cases to specialist care after the new information.

category: health economics


title: Mode of Presentation and Outcomes of COVID-19 Cases in a Tertiary Hospital in Nigeria

abstract: Coronavirus disease 2019 (COVID-19) has spread across the globe with its consequent human and economic challenges. To achieve effective control of the pandemic, efforts need to be holistic and global. Understanding patients demographics and clinical characteristics will assist in the control of the infection. However, there is a paucity of studies on the clinical presentation of COVID-19 patients from Nigeria and indeed Africa. Thus, this retrospective case series evaluated the medical records of COVID-19 patients admitted in a tertiary hospital in Nigeria. Patients demographics, and other clinical variables were assessed and presented. Data of 14 patients with complete records were included in the study. Most of the patients (78.6%) were males and the mean age of the study participants is 63.5 years (SD; 11.5). The commonest presenting symptoms were fever (93%), cough (71.4%), and dyspnoea (57.1%). At presentation, 13 patients had coexisting diseases while 8 (57.0%) patients had moderate disease and the remaining 6 (43.0%) had severe cases. After management, 1 patient died, two were referred and 11 recovered and were discharged alive. Thus, this study has identified advanced age, male gender, and comorbidity as increased risk factors for hospitalisation. The patient survival outcome in this study was also good.


title: Transmission of SARS-CoV-2 into and within immigrant households. Nation-wide registry-study from Norway

abstract:
BackgroundMinority ethnic groups and immigrants have been hit disproportionally hard by COVID-19 in many developed countries, including Norway. Most transmissions of SARS-CoV-2 occur in households.

MethodsUsing individual-level registry data of all Norwegian residents we compared infections across all multi-person households. A household with at least one member born abroad was defined as an immigrant household. For the subset of households where at least one person tested positive for SARS-CoV-2 from August 1st 2020 to May 1st 2021, we calculated secondary attack rates (SARs) as the percent of other household members testing positive within 14 days after the first household member tested positive. Logistic regression model was used to adjust for sex, age, household composition and geography.

ResultsAmong all multi-person households in Norway (n=1 421 642), immigrant households (n=341 604) comprised more members on average (3.2) than households with only Norwegian-born members (2.8). The share of immigrant households where at least one member had been tested, was 56% (vs 49% in the households with only Norwegian-born members), and the share where at least one member was infected was 3.7% (vs 1.4% in households with only Norwegian-born members). Secondary attack rates were higher in immigrant (32%) than Norwegian-born households (20%). Results differed considerably by country of birth, with secondary attack rates particularly high in households from Syria, Iraq, Turkey, and Pakistan, also after adjustment for sex, age, household composition and geography.

ConclusionSARS-CoV-2 is more frequently introduced into multi-person immigrant households than into households with only Norwegian-born members, and transmission within the household occurs more frequently in immigrant households. The results are likely related to living conditions, family composition or differences in social interaction, emphasizing the need to prevent introduction of SARS-CoV-2 into these vulnerable households.


title: Indications that Stockholm has reached herd immunity, given limited restrictions, against several variants of SARS-CoV-2

abstract: "When COVID-19 cases go up, public compliance with restrictions is poor, when cases go down, public compliance is good." In this article, we question this explanation and show that relatively low levels of sero-prevalence helps to keep cases down. In other words, the herd-immunity threshold appears to be much lower than previously thought. We construct a mathematical model taking pre-immunity, antibody waning and more infectious variants of concern into consideration, thereby providing a theoretical framework in which the cases in Stockholm county can be fully predicted without relying on neither oscillations in restrictions (and public compliance thereof) nor vaccination roll-out. We also show that it is very difficult to match the data from Stockholm without including pre-immunity, or, which turns out to be equivalent, great variations in susceptibility.


title: Pre-immunity: the Schrodinger's cat of immunology

abstract: Early 2020, catastrophic consequences of COVID-19 was predicted in the do-nothing scenario, based on mathematical models for epidemiology. As data began to emerge, several scientists noted that growth did not seem exponential, as the models predicted, leading to speculations of pre-existing immunity or immunological dark matter to explain this pattern. On the other hand, reports of choir-rehearsals infecting most members seemed to refute this, and the topic remained inconclusive. We provide a mathematical theory in which both observations are true; on a population level, pre-immunity exists, on an individual level, it doesnt. This theory demonstrates that established formulas relating e.g. R0 and the herd-immunity threshold are wrong. We derive new mathematical formulas, which applies to any virus whose transmission dynamics is associated with large individual variability in susceptibility to the infection. Contrary to great variability in infectivity, which we show has no bearing on the mathematical modeling, variability in susceptibility actually manifests itself as pre-immunity on a macroscopic scale, thus making pre-immunity a necessity for accurate mathematical modeling.

category: epidemiology


title: Genotoxicity evaluation of levonorgestrel-releasing intrauterine system (LNG-IUS) in exfoliated cervical cells using the micronucleus (MN) test

abstract:
PurposeThis study aimed to determine whether any relationships exist between the levonorgestrel-releasing intrauterine system (LNG-IUS) and micronuclei or other nuclear anomalies, including condensed chromatin, karyorrhexis, and karyolysis, on the cervical epithelium in young women.

MethodsA prospective observational study was conducted. The study population comprised healthy women aged [≤]40 years who were referred for birth control. Cervical smears that were obtained from 18 women before and three months after LNG-IUS insertion were tested for micronuclei and other nuclear anomaliesusing the micronucleus test.

ResultsThe results revealed no statistically significant difference (P>0.05) in the frequency of micronucleated exfoliated cervical mucosa cells after LNG-IUS exposure. However, LNG-IUS was able to increase other nuclear alterations closely related to cytotoxicity.

ConclusionsData indicated that exposure to LNG-IUS may not be a factor in inducing chromosomal damage, but it can promote cytotoxicity.

category: genetic and genomic medicine


title: Bias, precision and timeliness of historical (background) rate comparison methods for vaccine safety monitoring: an empirical multi-database analysis

abstract:
Using real-world data and past vaccination data, we conducted a large-scale experiment to quantify bias, precision and timeliness of different study designs to estimate historical background (expected) compared to post-vaccination (observed) rates of safety events for several vaccines. We used negative (not causally related) and positive control outcomes. The latter were synthetically generated true safety signals with incident rate ratios ranging from 1.5 to 4.

Observed vs. expected analysis using within-database historical background rates is a sensitive but unspecific method for the identification of potential vaccine safety signals. Despite good discrimination, most analyses showed a tendency to overestimate risks, with 20%-100% type 1 error, but low (0% to 20%) type 2 error in the large databases included in our study. Efforts to improve the comparability of background and post-vaccine rates, including age-sex adjustment and anchoring background rates around a visit, reduced type 1 error and improved precision but residual systematic error persisted. Additionally, empirical calibration dramatically reduced type 1 to nominal but came at the cost of increasing type 2 error.

Our study found that within-database background rate comparison is a sensitive but unspecific method to identify vaccine safety signals. The method is positively biased, with low (<=20%) type 2 error, and 20% to 100% of negative control outcomes were incorrectly identified as safety signals due to type 1 error. Age-sex adjustment and anchoring background rate estimates around a healthcare visit are useful strategies to reduce false positives, with little impact on type 2 error.

Sufficient sensitivity was reached for the identification of safety signals by month 1-2 for vaccines with quick uptake (e.g., seasonal influenza), but much later (up to month 9) for vaccines with slower uptake (e.g., varicella-zoster or papillomavirus). Finally, we reported that empirical calibration using negative control outcomes reduces type 1 error to nominal at the cost of increasing type 2 error.


title: Optimising health and economic impacts of COVID-19 vaccine prioritisation strategies in the WHO European Region

abstract:
BackgroundCountries in the World Health Organization (WHO) European Region differ in terms of the COVID-19 vaccine roll-out speed. We evaluated the health and economic impact of different age-based vaccine prioritisation strategies across this demographically and socio-economically diverse region.

MethodsWe fitted country-specific age-stratified compartmental transmission models to reported COVID-19 mortality in the WHO European Region to inform the immunity level before vaccine roll-out. Building upon broad recommendations from the WHO Strategic Advisory Group of Experts on Immunisation (SAGE), we examined four strategies that prioritise: all adults (V+), younger (20-59 year-olds) followed by older adults (60+) (V20), older followed by younger adults (V60), and the oldest adults (75+) (V75) followed by incremental expansion to successively younger five-year age groups. We explored four roll-out scenarios based on projections or recent observations (R1-4) - the slowest scenario (R1) covers 30% of the total population by December 2022 and the fastest (R4) 80% by December 2021. Five decision-making metrics were summarised over 2021-22: mortality, morbidity, and losses in comorbidity-adjusted life expectancy (cLE), comorbidity- and quality-adjusted life years (cQALY), and the value of human capital (HC). Six sets of infection-blocking and disease-reducing vaccine efficacies were considered.

FindingsThe optimal age-based vaccine prioritisation strategies were sensitive to country characteristics, decision-making metrics and roll-out speeds. Overall, V60 consistently performed better than or comparably to V75. There were greater benefits in prioritising older adults when roll-out is slow and when VE is low. Under faster roll-out, V+ was the most desirable option.

InterpretationA prioritisation strategy involving more age-based stages (V75) does not necessarily lead to better health and economic outcomes than targeting broad age groups (V60). Countries expecting a slow vaccine roll-out may particularly benefit from prioritising older adults.

FundingWorld Health Organization, Bill and Melinda Gates Foundation, the Medical Research Council (United Kingdom), the National Institute of Health Research (United Kingdom), the European Commission, the Foreign, Commonwealth and Development Office (United Kingdom), Wellcome Trust

Research in ContextO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed and medRxiv for articles published in English from inception to 9 Jun 2021, with the search terms: ("COVID-19" OR "SARS-CoV-2") AND ("priorit*) AND ("model*") AND ("vaccin*") and identified 66 studies on vaccine prioritization strategies. Of the 25 studies that compared two or more age-based prioritisation strategies, 12 found that targeting younger adults minimised infections while targeting older adults minimised mortality; an additional handful of studies found similar outcomes between different age-based prioritisation strategies where large outbreaks had already occurred. However, only two studies have explored age-based vaccine prioritisation using models calibrated to observed outbreaks in more than one country, and no study has explored the effectiveness of vaccine prioritisation strategies across settings with different population structures, contact patterns, and outbreak history.

Added-value of this studyWe evaluated various age-based vaccine prioritisation strategies for 38 countries in the WHO European Region using various health and economic outcomes for decision-making, by parameterising models using observed outbreak history, known epidemiologic and vaccine characteristics, and a range of realistic vaccine roll-out scenarios. We showed that while targeting older adults was generally advantageous, broadly targeting everyone above 60 years might perform better than or comparably to a more detailed strategy that targeted the oldest age group above 75 years followed by those in the next younger five-year age band. Rapid vaccine roll-out has only been observed in a small number of countries. If vaccine coverage can reach 80% by the end of 2021, prioritising older adults may not be optimal in terms of health and economic impact. Lower vaccine efficacy was associated with greater relative benefits only under relatively slow roll-out scenarios considered.

Implication of all the available evidenceCOVID-19 vaccine prioritization strategies that require more precise targeting of individuals of a specific and narrow age range may not necessarily lead to better outcomes compared to strategies that prioritise populations across broader age ranges. In the WHO European Region, prioritising all adults equally or younger adults first will only optimise health and economic impact when roll-out is rapid, which may raise between-country equity issues given the global demand for COVID-19 vaccines.


title: Case-control study of neuropsychiatric symptoms following COVID-19 hospitalization in 2 academic health systems

abstract:
Neuropsychiatric symptoms may persist following acute COVID-19 illness, but the extent to which these symptoms are specific to COVID-19 has not been established. We utilized electronic health records across 6 hospitals in Massachusetts to characterize cohorts of individuals discharged following admission for COVID-19 between March 2020 and May 2021, and compared them to individuals hospitalized for other indications during this period. Natural language processing was applied to narrative clinical notes to identify neuropsychiatric symptom domains up to 150 days following hospitalization. Among 6,619 individuals hospitalized for COVID-19 drawn from a total of 42,961 hospital discharges, the most commonly documented symptom domains between 31 and 90 days after initial positive test were fatigue (13.4%), mood and anxiety symptoms (11.2%), and impaired cognition (8.0%). In models adjusted for sociodemographic features and hospital course, none of these were significantly more common among COVID-19 patients; indeed, mood and anxiety symptoms were less frequent (adjusted OR 0.72 95% CI 0.64-0.92). Between 91 and 150 days after positivity, most commonly-detected symptoms were fatigue (10.9%), mood and anxiety symptoms (8.2%), and sleep disruption (6.8%), with impaired cognition in 5.8%. Frequency was again similar among non-COVID-19 post-hospital patients, with mood and anxiety symptoms less common (aOR 0.63, 95% CI 0.52-0.75). Neuropsychiatric symptoms were common up to 150 days after initial hospitalization, but occurred at generally similar rates among individuals hospitalized for other indications during the same period. Post-acute sequelae of COVID-19 thus may benefit from standard if less-specific treatments developed for rehabilitation after hospitalization.

FundingR01MH120227, R01MH116270 (Perlis)

category: psychiatry and clinical psychology


title: Understanding COVID-19 vaccine hesitancy in Pakistan: The paradigm of Confidence, Convenience and Complacency; A Cross-sectional study.

abstract:
Background and objectivesVaccine hesitancy is a big obstacle for vaccination programs, as is anticipated for the COVID-19 vaccination program, resulting in low uptake of vaccines thereby hindering the process of reaching herd immunity. Bearing this in mind the current study was aimed to explore the determinants of vaccine hesitancy amongst the Pakistani population.

MethodologyA cross-sectional study was carried out from November 2020 to March 2021. The conceptual framework of the study was based on the 3Cs (Confidence, Convenience, Complacency) model. The google-forms-based questionnaire was disseminated amongst the general population. Data collected were entered into SPSS version 26 and analyzed.

ResultsOf the 421 participants, 68.4% were women. Non-healthcare workers were 55.8% of respondents. Of vaccine-hesitant individuals, 26.13% reported they were very unlikely to get vaccinated. The vaccine was not safe as it came out too fast was agreed upon by 12.6% of individuals, 50.6% were worried about experiencing side-effects, 18% believed the vaccine will not offer protection and 5.9% believed the vaccine would cause death. Low Practice of SOP in non-Healthcare workers was the strongest contributor to vaccine hesitancy (OR: 5.338, p=0.040, 95% CI: 1.082-26.330) followed by High complacency (p=0.026) and Moderate Complacency (OR: 0.212, p=0.007, 95% CI: 0.069-0.654) towards COVID-19 vaccination. In Healthcare workers the strongest contributor to vaccine hesitancy was having a Moderate Confidence (OR: 0.323, p=0.042, 95% CI: 0.109-0.958) in the vaccine followed by Moderate Convenience (OR: 0.304, p=0.049, 95% CI: 0.093-0.993) for vaccination

ConclusionCampaigning and communication strategies to reaffirm confidence in the COVID-19 vaccine and educating the general population about the vaccine could lead to increased perception of vaccine safety and effectiveness thereby restoring confidence in vaccine and decreasing vaccine hesitancy. Likewise, working to increase vaccine convenience and decreasing complacency towards the COVID-19 vaccine would translate into high vaccine uptake.

category: public and global health


title: Awareness, treatment, and control of diabetes in Bangladesh: evidence from the Bangladesh Demographic and Health Survey 2017/18

abstract:
BackgroundThe prevalence of diabetes is increasing in Bangladesh; however, the management of diabetes assessed by diabetes awareness, treatment, and control, remains poor. We aimed to estimate the age-standardised prevalence of awareness, treatment, and control of diabetes and its associated factors.

MethodsIn this cross-sectional study, data from 1,174 Bangladeshi adults aged 18 years and older available from the most recent nationally representative Bangladesh Demographic and Health Survey (BDHS) 2017-18 were analysed. Awareness, treatment, and control of diabetes were our outcomes of interest. Age-stadarised prevalence of awareness, treatment, and control were estimated using the direct standardisation. Multilevel mixed-effects Poisson regression models were used to identify factors associated with awareness, treatment, and control of diabetes.

ResultsAmong those with diabetes (n=1,174), only 30.9% (95% CI, 28.2-33.6) were aware that they had the condition, and 28.2% (95% CI, 25.6-30.7) were on treatment. Among those treated for diabetes, only 26.5% (95% CI, 19.5-33.5) had controlled diabetes. Prevalences for awareness, treatment and control were even lower in men than women. Factors positively associated with awareness and treatment were increasing age and hypertension while factors negatively associated with awareness and treatment were being men and having lower education. Factors associated with poor control were secondary education and residing in Rajshahi and Rangpur divisions.

ConclusionThis study provides evidence of poor management of diabetes in Bangladesh, especially in men. Less than one-third of the people with diabetes were aware of their condition. Just over one-fourth of the people with diabetes were on treatment, and those were treated one-fourth had controlled diabetes. Interventions targeting younger people, in particular men and those with lower education, are urgently needed. The government needs to strengthen diabetes management programs within primary health care and address structural factors including the costs of diabetes care to improve awareness, treatment, and control of diabetes in Bangladesh.


title: Comparison of immunogenicity between BNT162b2 and ChAdOx1 SARS-CoV-2 vaccines in a large haemodialysis population

abstract:
BackgroundLimited data exists on the immunogenicity of vector-based SARS-CoV-2 vaccines in patients with kidney disease. Given their use in over 180 countries, such data is of upmost importance to inform policy on optimal vaccination strategies. This study compares the immunogenicity of BNT162b2 with ChAdOx1 in patients receiving haemodialysis.

Methods1021 patients were screened for spike protein antibodies (anti-S) following 2 doses of either BNT162b2 (n=523) or ChAdOx1 (n=498). 191 patients underwent assessment with T-cell ELISpot assays. 65 health care workers were used as a control group.

ResultsAnti-S was detected in 936 (91.2%) of patients post-vaccination. There was no difference in seroconversion rates between infection-naive patients who received BNT162b2, 248/281 (88.3%), compared with ChAdOx1, 227/272 (83.5%), p=0.11. Anti-S concentrations were higher following BNT162b, 462(152-1171) BAU/ml, compared with ChAdOx-1 79(20-213) BAU/ml, p<0.0001. Immunosuppression was associated with failure to seroconvert (p<0.0001); whilst being active on the transplant wait list was a predictor for seroconversion (p=0.02).

Only 73 (38.2%) of patients had detectable T-cell responses post-vaccination, with no proportional difference between infection-naive patients who received BNT162b2, 2/19 (10.5%), versus ChAdOx1, 15/75 (20.0%), p=0.34. There were no quantitative differences in T-cell responses in infection-naive patients, with a median 2(0-16) SFU/106 PBMCs and 10(4-28) SFU/106 PBMCs in those receiving BNT162b2 and ChAdOx1 respectively, p=0.35. These responses were significantly weaker compared with healthy controls.

ConclusionsEnhanced immunogenicity was seen with BNT162b2 compared with ChAdOx1, driven by superior humoral responses, with attenuated T-cell responses to both vaccines. Comparative data on clinical efficacy is now required.

Significance StatementLimited data exist on the immunogenicity of vector-based SARS-CoV-2 vaccines in patients with kidney disease. Given their use in over 180 countries worldwide, such data are of upmost importance to inform policy on optimal vaccination strategies. This study compares the immunogenicity of BNT162b2 (n=523) against the adenovirus vector vaccine, ChAdOx1 (n=498), in 1021 haemodialysis patients. In infection-naive patients, overall seroconversion rates were comparable, however, spike protein antibody concentrations were significantly higher following BNT162b2. No difference in T-cell responses was seen, however, all naive patients had weaker responses compared with healthy controls. Equivalent attenuated cellular responses to both vaccines, with greater humoral responses to BNT162b2, suggests BNT162b2 has superior immunogenicity in this patient population, with data on clinical efficacy required.

category: nephrology


title: Rare variants in IFFO1, DTNB and NLRC3 associate with Alzheimer's disease CSF profile of neuronal injury and inflammation

abstract: Alzheimers disease (AD) biomarkers represent several neurodegenerative processes, such as synaptic dysfunction, neuronal inflammation and injury, as well as amyloid pathology. We performed an exome-wide rare variant analysis of six AD biomarkers ({beta}-amyloid, total/phosphorylated tau, Nfl, YKL-40, and Neurogranin) to discover genes associated with these markers. Genetic and biomarker information was available for 480 participants from two studies: EMIF-AD and ADNI. We applied a principal component (PC) analysis to derive biomarkers combinations, which represent statistically independent biological processes. We then tested whether rare variants in 9,576 protein-coding genes associate with these PCs using a Meta-SKAT test. We also tested whether the PCs are intermediary to gene effects on AD symptoms with a SMUT test. One PC loaded on Nfl and YKL-40, indicators of neuronal injury and inflammation. Three genes were associated with this PC: IFFO1, DTNB and NLRC3. Mediation tests suggest, that these genes also affect dementia symptoms via inflammation/injury. We also observed an association between a PC loading on Neurogranin, a marker for synaptic functioning, with GABBR2 and CASZ1, but no mediation effects. The results suggest that rare variants in IFFO1, DTNB and NLRC3 heighten susceptibility to neuronal injury and inflammation, potentially by altering cytoskeleton structure and immune activity disinhibition, resulting in an elevated dementia risk. GABBR2 and CASZ1 were associated with synaptic functioning, but mediation analyses suggest that the effect of these two genes on synaptic functioning is not consequential for AD development.

category: neurology


title: DeepOS: pan-cancer prognosis estimation from RNA-sequencing data

abstract: RNA-sequencing (RNA-seq) analysis offers a tumor-centered approach of growing interest for personalizing cancer care. However, existing methods - including deep learning models - struggle to reach satisfying performances on survival prediction based upon pan-cancer RNA-seq data. Here, we present DeepOS, a novel deep learning model that predicts overall survival (OS) from pan-cancer RNA-seq with a concordance-index of 0.715 and a survival AUC of 0.752 across 33 TCGA tumor types whilst tested on an unseen test cohort. DeepOS notably uses (i) prior biological knowledge to condense inputs dimensionality, (ii) transfer learning to enlarge its training capacity through pre-training on organ prediction, and (iii) mean squared error adapted to survival loss function; all of which contributed to improve the model performances. Interpretation showed that DeepOS learned biologically-relevant prognosis biomarkers. Altogether, DeepOS achieved unprecedented and consistent performances on pan-cancer prognosis estimation from individual RNA-seq data.

category: oncology


title: Exploring the relationship between schizophrenia and cardiovascular disease: A genetic correlation and multivariable Mendelian randomization study

abstract:
ImportanceIndividuals with schizophrenia have a reduced life-expectancy compared to the general population, largely due to an increased risk of cardiovascular disease (CVD). Clinical and epidemiological studies have been unable to fully unravel the nature of this relationship.

ObjectiveInvestigate genetic correlations and potential bi-directional effects between liability to schizophrenia and CVD.

Design, setting, and participantsWe obtained summary-data of genome-wide-association studies of schizophrenia (N=130,644), heart failure (N=977,323), coronary artery disease (N=332,477), systolic and diastolic blood pressure (N=757,601), heart rate variability (N=46,952), QT interval (N=103,331), early repolarization and dilated cardiomyopathy ECG patterns (N=63,700). We computed genetic correlations with linkage disequilibrium score regression and conducted bi-directional Mendelian randomization (MR). With multivariable MR, we investigated whether associations were mediated by smoking, body mass index, physical activity, lipid levels, or type 2 diabetes. To ensure robustness, we applied a range of sensitivity methods.

Main outcomes and measuresSchizophrenia, heart failure, coronary artery disease, systolic blood pressure, diastolic blood pressure, heart rate variability, QT interval, early repolarization, dilated cardiomyopathy.

ResultsGenetic correlations between liability to schizophrenia and CVD were close to zero (-0.02 to 0.04). With MR, we found robust evidence that liability to schizophrenia increases heart failure risk. This effect remained consistent with multivariable MR. There was also evidence that liability to schizophrenia increases early repolarization risk, largely mediated by BMI and lipid levels. Finally, there was evidence that liability to schizophrenia increases heart rate variability, a direction of effect contrasting previous studies. In the other direction, there was weak evidence that higher systolic, but not diastolic, blood pressure increases schizophrenia risk.

Conclusions and relevanceOur findings indicate that liability to schizophrenia increases the risk of heart failure, and that this is not mediated by key health behaviours. This is consistent with the notion that schizophrenia is characterised by a systemic dysregulation of the body (including inflammation and oxidative stress) with detrimental effects on the heart. To decrease cardiovascular mortality among schizophrenia patients, priority should lie with optimal treatment and interventions in early stages of psychoses. We also identified early repolarization, currently understudied, as a potential CVD marker among patients with schizophrenia.


title: Set-based rare variant association tests for biobank scale sequencing data sets

abstract: UK Biobank has released the large-scale whole-exome sequencing (WES) data, but the best practices remain unclear for rare variant tests, and an existing approach, SAIGE-GENE, can have inflated type I error rates with high computation costs. Here, we propose SAIGE-GENE+ with greatly improved type I error control and computational efficiency compared to SAIGE-GENE. In the analysis of UKBB WES data of 30 quantitative and 141 binary traits, SAIGE-GENE+ identified 551 gene-phenotype associations. In addition, we showed that incorporating multiple MAF cutoffs and functional annotations can help identify novel gene-phenotype associations.


title: Impacts of COVID-19 public measures on country-level trade flows: Global panel regression analysis

abstract: As of 10 July 2021, there have been over 186 million cases of COVID-19 and more than four million died as a result of this disease. The COVID-19 outbreak has also contributed to tremendous global decline in trade flows. The rapid spread of COVID-19 and the measures implemented by governments to contain the pandemic have had serious consequences for the worlds economies. While the pandemic has affected the international movement of people, goods and services, there is still limited systematic research regarding the possible associations between the COVID-19 measures on countries international trade flows. To fill this gap, we conducted regression analysis based on country level time series data from the United Nations and World Bank datasets. The results of the random effects panel regression models show that, the country import and export values are positively affected by health-related policies, while there is a negative association between stringency measures and import and export values. More specifically, school closing, stay-at-home requirements, and testing policy measures were found to have significant negative effects on countries trade values. In contrast, facial covering policies were found to have significant positive effects on countries import, export and total trade values.


title: Does trust in government improve Covid-19's crisis management?

abstract:
Countries have adopted several measures to control the spread of Covid-19. However, substantial differences remain in terms of performance in controlling the virus, potentially due to heterogeneity in citizen engagement with government measures. Drawing on this observation, this paper seeks to analyze the effect of pre-crisis ties, particularly trust in government, on crisis management, proxied by the number of Covid-19 cases and deaths per million population. We examine this question based on a sample of 41 countries for which data are available. Results reveal that a high level of trust in government predicts better crisis management in terms of relatively low levels of cases and deaths. These results, which successfully pass a series of robustness tests, may vary according to level of contamination and increase with time.

JEL ClassificationE71, H12, I12, I18, I38, Z18


title: Comparing organ donation decisions for next-of-kin versus the self: Results of a national survey

abstract:
ObjectivesIntensive care audits point to family refusal as a major barrier to organ donation. In this study, we sought to understand refusal by accounting for the decision-makers mindset. This focused on: (1) how decisions compare when made on behalf of a relative (versus the self); and (2) confidence in decisions made for family members.

DesignCross-sectional survey in Singapore.

SettingParticipants were recruited from community settings via door-to-door sampling and community eateries.

Participants973 adults who qualified as organ donors in Singapore.

ResultsAlthough 68.1% of participants were willing to donate their own organs, only 51.8% were willing to donate a relatives. Using machine learning, we found that consistency was predicted by: (i) religion, and (ii) fears about organ donation. Conversely, participants who were willing to donate their own organs but not their relatives were less driven by these factors, and may instead have resorted to heuristics in decision-making. Finally, we observed how individuals were overconfident in their decision-making abilities: although 78% had never discussed organ donation with their relatives, the large majority expressed high confidence that they would respect their relatives wishes upon death.

ConclusionsThese findings underscore the distinct psychological processes involved when donation decisions are made for family members. Amidst a global shortage of organ donors, addressing the decision-makers mindset (e.g., overconfidence, the use of heuristics) may be key to actualizing potential donors identified in intensive care units.

Strengths and Limitations of this StudyO_LIWe used a multi-disciplinary approach combining psychology theory and machine learning analyses to understand family refusal in a novel manner.
C_LIO_LIWe directly compared organ donation decisions made from the self versus for next-of-kin, and also documented overconfidence in the decision-making process.
C_LIO_LIThe study was conducted in an urban setting and may not apply to rural contexts.
C_LI

category: health policy


title: Vaccine serologic responses among transplant patients associate with COVID-19 infection and T peripheral helper cells

abstract:
BackgroundTherapeutically immunosuppressed transplant recipients exhibit attenuated responses to COVID-19 vaccines. To better understand the immune alterations that determined poor vaccine response, we correlated quantities of circulating T and B cell subsets at baseline with longitudinal serologic responses to SARS-CoV-2 mRNA vaccination in heart and lung transplant recipients.

MethodsSamples at baseline and at approximately 8 and 30 days after each vaccine dose for 22 heart and lung transplant recipients with no history of COVID-19, four heart and lung transplant recipients with prior COVID-19 infection, and 12 healthy controls undergoing vaccination were analyzed. Anti-spike protein receptor binding domain (RBD) IgG and pseudovirus neutralization activity were measured. Proportions of B and T cell subsets at baseline were comprehensively quantitated.

ResultsAt 8-30 days post vaccination, healthy controls displayed robust anti-RBD IgG responses, whereas heart and lung transplant recipients showed minimally increased responses. A parallel absence of activity was observed in pseudovirus neutralization. In contrast, three of four (75%) transplant recipients with prior COVID-19 infection displayed robust responses at levels comparable to controls. Baseline levels of activated PD-1+ HLA-DR+ CXCR5- CD4+ T cells (also known as T peripheral helper [TPH] cells) and CD4+ T cells strongly predicted the ability to mount a response.

ConclusionsImmunosuppressed patients have defective vaccine responses but can be induced to generate neutralizing antibodies after SARS-CoV-2 infection. Strong correlations of vaccine responsiveness with baseline TPH and CD4+ T cell numbers highlights a role for T helper activity in B cell differentiation into antibody secreting cells during vaccine response.


title: Machine Learning Model for Predicting Number of COVID19 Cases in Countries with Low Number of Tests

abstract: The COVID-19 pandemic has presented a series of new challenges to governments and health care systems. Testing is one important method for monitoring and therefore controlling the spread of COVID-19. Yet with a serious discrepancy in the resources available between rich and poor countries not every country is able to employ widespread testing. Here we developed machine learning models for predicting the number of COVID-19 cases in a country based on multilinear regression and neural networks models. The models are trained on data from US states and tested against the reported infections in the European countries. The model is based on four features: Number of tests Population Percentage Urban Population and Gini index. The population and number of tests have the strongest correlation with the number of infections. The model was then tested on data from European countries for which the correlation coefficient between the actual and predicted cases R2 was found to be 0.88 in the multi linear regression and 0.91 for the neural network model. The model predicts that the actual number of infections in countries where the number of tests is less than 10% of their populations is at least 26 times greater than the reported numbers.


title: A systematic review and meta-analysis of inpatient mortality associated with nosocomial and community COVID-19 exposes the vulnerability of immunosuppressed adults

abstract:
BackgroundLittle is known about the mortality of hospital-acquired (nosocomial) COVID-19 infection globally. We investigated the risk of mortality and critical care admission in hospitalised adults with nosocomial COVID-19, relative to adults requiring hospitalisation due to community-acquired infection.

MethodsWe systematically reviewed the peer-reviewed and pre-print literature from 1/1/2020 to 9/2/2021 without language restriction for studies reporting outcomes of nosocomial and community-acquired COVID-19. We performed a random effects meta-analysis (MA) to estimate the 1) relative risk of death and 2) critical care admission, stratifying studies by patient cohort characteristics and nosocomial case definition.

Results21 studies were included in the primary MA, describing 8,246 admissions across 8 countries during the first wave, comprising 1517 probable or definite nosocomial COVID-19, and 6729 community-acquired cases. Across all studies, the risk of mortality was 1.31 times greater in patients with nosocomial infection, compared to community-acquired (95% CI: 1.01 to 1.70). Rates of critical care admission were similar between groups (Relative Risk, RR=0.74, 95% CI: 0.50 to 1.08). Immunosuppressed patients diagnosed with nosocomial COVID-19 were twice as likely to die in hospital as those admitted with community-acquired infection (RR=2.14, 95% CI: 1.76 to 2.61).

ConclusionsAdults who acquire SARS-CoV-2 whilst already hospitalised are at greater risk of mortality compared to patients admitted following community-acquired infection; this finding is largely driven by a substantially increased risk of death in individuals with malignancy or who had undergone transplantation. These findings inform public health and infection control policy, and argue for individualised clinical interventions to combat the threat of nosocomial COVID-19, particularly for immunosuppressed groups.

Systematic review registration: PROSPERO CRD42021249023


title: SARS-CoV-2 seroprevalence in asymptomatic or mild symptomatic people and symptomatic patients with negative PCR results: The hidden perspective in epidemiological reports

abstract:
BackgroundSARS-CoV-2 has led to the current pandemic of respiratory disease. The reports of confirmed COVID-19 cases based on molecular tests do not completely cover the total number of infected people. These reports do not include the asymptomatic or mildly symptomatic patients and also the patients with false-negative RT-PCR results, while the infection is contagious in all of these conditions.

ObjectiveIn this study, we tried to improve our conception of the hidden perspective of SARS-CoV-2 in epidemiological reports.

MethodsFrom May 30 to June 17, 2020, blood samples were collected from two groups of people: asymptomatic or mild symptomatic volunteer participants and severe symptomatic hospitalized patients with negative PCR results. Detection of SARS-CoV-2 antibody was done with ELISA kit targeting N or S proteins.

ResultsTotally 716 samples from volunteer participants and 81 samples from symptomatic hospitalized patients with negative PCR were evaluated. The test performance-adjusted seroprevalence (95% CI) of SARS-CoV-2 anti-N IgG was 17.3% (8.8%, 25.8%) for volunteers and 25.5% (12.8%, 39.7%) for anti-N and S IgM in hospitalized group. There was an association between high-risk occupations, high-risk behaviors, or symptomatic diseases with positive SARA-Cov-2 N antibody results. Among anti-N positive infected individuals, 49.2% (21.4%, 78.8%) were anti-S positive.

ConclusionThe results showed that SARS-COV-2 infection occurs in asymptomatic or mildly symptomatic individuals, but in more than half of them, the produced antibody is not protective. Findings of hospitalized patients also showed that the combination of IgM assay with real-time PCR improves the detection of the disease by more than 25% in negative molecular cases.


title: A Rapid Saliva Test for Monitoring Immune Protection against SARS-CoV-2 and its Variants

abstract: Given the ongoing transmission and emergence of SARS-Cov-2 variants globally, it is critical to have a timely assessment on individuals immune responses as well as population immunity. Important questions such as the durability of COVID-19 immunity or the efficacy of vaccines require large datasets to generate meaningful insights. However, due to the complexity and relatively high-cost of many immunity assays and the needs for blood-drawing specialists, these assays were mostly limited to small-scale clinical studies. Our work demonstrated the potential of a non-invasive, inexpensive and data-driven solution for large-scale immunity surveillance and for predictive modeling of vaccine efficacy. Combining a proprietary saliva processing method and an ultra-sensitive digital detection technology, we were able to rapidly gather information regarding personalized immune response following infection or vaccination, monitor temporal evolution, and optimize predictive models for variant protection.


title: Appropriate relaxation of non-pharmaceutical interventions minimizes the risk of a resurgence in SARS-CoV-2 infections in spite of the Delta variant

abstract:
We analyze the relaxation of non-pharmaceutical interventions (NPIs) under an increasing number of vaccinations in Germany. For the spread of SARS-CoV-2 we employ a SIR-type model that accounts for age-dependence and includes realistic contact patterns between age groups. The implementation of NPIs occurs on changed contact patterns, improved isolation, or reduced infectiousness when, e.g., wearing masks. We account for spatial heterogeneity and commuting activities in between regions in Germany, and the testing of commuters is considered as a further NPI. We include the ongoing vaccination process and analyze the effect of the B.1.617.2 (Delta) variant, which is considered to be 40% - 60% more infectious then the currently dominant B.1.1.7 (Alpha) variant. We explore different opening scenarios under the ongoing vaccination process by assuming that local restrictions are either lifted in early July or August with or without continued wearing of masks and testing. Our results indicate that we can counteract the resurgence of SARS-CoV-2 despite the Delta variant with appropriate timing for the relaxation of NPIs. In all cases, however, school children are hit the hardest.

Author summaryOne of the greatest challenges within the Covid-19 pandemic is to identify the timing and amount of non-pharmaceutical interventions (face masks, travel bans, school closures, etc). In the year 2021 more and more people are getting vaccinated. When can we finally lift all restrictions and stop wearing masks? In order to provide more insights to this question, we use a mathematical model which is capable of simulating the effects of non-pharmaceutical interventions in Germany while accounting for age-dependent factors as well as commuting activities between regions. We include the vaccination process and analyze the much more infectious Delta coronavirus variant. We simulate scenarios that consider the timing of the return to pre-pandemic contacts as well as when to suspend wearing masks and testing. Our results show that a later opening by 1 August in combination with masks and testing reduces the chance of a further infection wave considerably. From the retrospective view of the revision, we see that the rise in infections at the end of summer could have been well predicted by our scenarios that considered lifting of NPIs in July as it happened in many places. In all of our scenarios, the infection manifests in the younger age groups.


title: Time-to-event assessment for the discovery of the proper prognostic value of clinical biomarkers optimized for COVID-19

abstract: In the early days of the pandemic, clinical biomarkers for COVID -19 have been investigated to predict patient mortality. A decision tree has been proposed previously comprising three variables, i.e., lactic dehydrogenase (LDH), high-sensitivity C-reactive protein (CRP), and lymphocyte percentage, with more than 90% accuracy in a public cohort. In this work, we highlighted the importance of the cohort made publicly available and complemented the findings by incorporating further evaluation. Results confirmed poor short-term prognosis to abnormal levels of some laboratorial indicators, such as LDH, CRP, lymphocytes, interleukin-6, and procalcitonin. In addition, our findings provide insights into COVID-19 research, such as key levels of fibrin degradation products, which are directly associated with the Dimerized plasmin fragment D and could indicate active coagulation and thrombosis. Still, we highlight here the prognostic value of interleukin-6, a cytokine that induces inflammatory response and may serve as a predictive biomarker.


title: The antibody landscapes against Group 1 and 2 influenza virus hemagglutinin following AS03 and MF59 adjuvanted H5N1 vaccination

abstract: Current seasonal and pre-pandemic influenza vaccines induce short-lived predominantly strain-specific and limited heterosubtypic responses. To better understand how vaccine adjuvants AS03 and MF59 may provide improved antibody responses to vaccination, we interrogated serum from subjects who received 2 doses of inactivated monovalent influenza A/Indonesia/05/2005 vaccine with or without AS03 or MF59 using hemagglutinin (HA) microarrays. The arrays were designed to reflect both full length and globular head HA proteins derived from 17 influenza A subtypes (H1 to H16 and H18) and influenza B strains. We observed significantly increased strain-specific and broad homo- and hetero-subtypic antibody responses with both AS03 and MF59 adjuvanted vaccination with AS03 achieving a higher titer and breadth of IgG responses relative to MF59. Adjuvanted vaccine was also associated with the elicitation of stalk directed antibody. Finally, we established good correlation of the array antibody responses to H5 antigens with standard hemagglutination inhibition and microneutralization titers.


title: Highly versatile antibody binding assay for the detection of SARS-CoV-2 infection

abstract:
Monitoring the burden and spread of infection with the new coronavirus SARS-CoV-2, whether within small communities or in large geographical settings, is of paramount importance for public health purposes. Serology, which detects the host antibody response to the infection, is the most appropriate tool for this task, since virus-derived markers are most reliably detected during the acute phase of infection. Here we show that our ELISA protocol, which is based on antibody binding to the Receptor Binding Domain (RBD) of the S1 subunit of the viral Spike protein expressed as a novel fusion protein, detects antibody responses to SARS-CoV-2 infection and COVID-19 vaccination.

We also show that our ELISA is accurate and versatile. It compares favorably with commercial assays widely used in clinical practice to determine exposure to SARS-CoV-2. Moreover, our protocol accommodates use of various blood- and non-blood-derived biospecimens, such as breast milk, as well as dried blood obtained with microsampling cartridges that are appropriate for remote collection. As a result, our RBD-based ELISA protocols are well suited for seroepidemiology and other large-scale studies requiring parsimonious sample collection outside of healthcare settings.


title: Spatiotemporal droplet dispersion measurements demonstrate face masks reduce risks from singing: results from the COvid aNd FacEmaSkS Study (CONFESS)

abstract:
BackgroundCOVID-19 has restricted singing in communal worship. We sought to understand variations in droplet transmission and the impact of wearing face masks.

MethodsUsing rapid laser planar imaging, we measured droplets while participants exhaled, said  hello or  snake, sang a note or  Happy Birthday, with and without surgical face masks. We measured mean velocity magnitude (MVM), time averaged droplet number (TADN) and maximum droplet number (MDN). Multilevel regression models were used.

ResultsIn 20 participants, sound intensity was 71 Decibels (dB) for speaking and 85 dB for singing (p<0.001). MVM was similar for all tasks with no clear hierarchy between vocal tasks or people and >85% reduction wearing face masks. Droplet transmission varied widely, particularly for singing. Masks decreased TADN by 99% (p<0.001) and MDN by 98% (p<0.001) for singing and 86-97% for other tasks. Masks reduced variance by up to 48%. When wearing a mask, neither singing task transmitted more droplets than exhaling.

ConclusionsWide variation exists for droplet production. This significantly reduced when wearing face masks. Singing during religious worship wearing a face mask appears as safe as exhaling or talking. This has implications for UK public health guidance during the COVID-19 pandemic.


title: Evidence of SARS-Cov-2-specific memory B cells six months after vaccination with BNT162b2 mRNA vaccine

abstract:
SARS-CoV-2 mRNA vaccines have demonstrated high efficacy and immunogenicity, but limited information is currently available on memory B cells generation and long-term persistence. Here, we investigated Spike-specific memory B cells and humoral responses in 145 subjects, up to six months after the BNT162b2 vaccine (Comirnaty) administration. Spike-specific antibody titers peaked 7 days after the second dose and significant titers and neutralizing activity were still observed after six months, despite a progressive decline over time. Concomitant to antibody reduction, Spike-specific memory B cells, mostly IgG class-switched, increased in blood of vaccinees and persisted six months after vaccination. Following in vitro restimulation, circulating memory B cells reactivated and produced Spike-specific antibodies. A high frequency of Spike-specific IgG+ plasmablasts, identified by computational analysis 7 days after boost, positively correlated with the generation of IgG+ memory B cells at six months.

These data demonstrate that mRNA BNT162b2 vaccine elicits strong B cell immunity with Spike-specific memory B cells that still persist six months after vaccination, playing a crucial role for rapid response to SARS-CoV-2 virus encounter.

One Sentence SummarymRNA BNT162b2 vaccine elicits persistent spike-specific memory B cells crucial for rapid response to SARS-CoV-2 virus encounter


title: The QuantuMDx Q-POC SARS-CoV-2 RT-PCR assay for rapid detection of COVID-19 at point-of-care: preliminary evaluation of a novel technology

abstract:
BackgroundAccurate, affordable, and rapid point-of-care (PoC) diagnostics are critical to the global control and management of the COVID-19 pandemic. The current standard for accurate diagnosis of SARS-CoV-2 is laboratory-based reverse transcription polymerase chain reaction (RT-PCR). Here, we report a preliminary prospective performance evaluation of the QuantuMDx Q-POC SARS CoV-2 RT-PCR assay.

MethodsBetween November 2020 and March 2021, we obtained 49 longitudinal nose and throat swabs from 29 individuals hospitalised with RT-PCR confirmed COVID-19 at St Georges NHS Foundation Trust, London (UK). In addition, we obtained 101 mid nasal swabs from healthy volunteers in June 2021. We then used these samples to evaluate the Q-POC SARS-CoV-2 RT-PCR assay. The primary analysis was to compare the sensitivity and specificity of the Q-POC test against a reference laboratory-based RT-PCR assay.

ResultsThe overall sensitivity of the Q-POC test compared with the reference test was 96.88% (83.78%-99.92% CI) for a cycle threshold (Ct) cut-off value for the reference test of 35 and 80.00% (64.35% to 90.95% CI) without altering the reference tests Ct cut-off value of 40.

ConclusionsThe Q-POC test is a sensitive, specific and rapid point-of-care test for SARS-CoV-2 at a reference Ct cut-off value of 35. The Q-POC test provides an accurate and affordable option for RT-PCR at point-of-care without the need for sample pre-processing and laboratory handling. The Q-POC test would enable rapid diagnosis and clinical triage in acute care and other settings.


title: Performance evaluation of a multinational data platform for critical care in Asia

abstract:
ObjectiveWe aimed to evaluate the quality of a multinational intensive care unit (ICU) network of registries of critically ill patients established in seven Asian low and middle income countries (LMICs).

MethodsThe Critical Care Asia federated registry platform enables ICUs to collect clinical, outcome and process data for aggregate and unit-level analysis. The evaluation used the standardised criteria of the Directory of Clinical Databases (DoCDat) and a framework for data quality assurance in medical registries. Six reviewers assessed structure, coverage, reliability and validity of the ICU registry data. Case mix and process measures on patient episodes from June to December 2020 were analysed.

ResultsData on 20,507 consecutive patient episodes from 97 ICUs in Afghanistan, Bangladesh, India, Malaysia, Nepal, Pakistan and Vietnam were included. The quality level achieved according to the ten prespecified DoCDat criteria was high (average score 3.4 out of 4) as was the structural and organizational performance -- comparable to ICU registries in high-income countries. Identified strengths were types of variables included, reliability of coding, data completeness and validation. Potential improvements include extension of national coverage.

ConclusionThe Critical Care Asia platform evaluates well using standardised frameworks for data quality and equally to registries in resource-rich settings.

FundingThis work was undertaken as part of the existing Wellcome Innovations Flagship award, Collaboration for Research, Improvement and Training in Critical CARE in ASIA (ref. 215522/Z/19/Z). The funder had no role in the decision to publish or in the preparation of this manuscript.

category: intensive care and critical care medicine


title: Plasma P-selectin is an early marker of thromboembolism in COVID-19

abstract: Coagulopathy and thromboembolism are known complications of SARS-CoV-2 infection. The mechanisms of COVID-19-associated hematologic complications involve endothelial cell and platelet dysfunction and have been intensively studied. We leveraged a prospectively collected acute COVID-19 biorepository to study the association of plasma levels of a comprehensive list of coagulation proteins with the occurrence of venous thromboembolic events (VTE). We included in our analysis 305 subjects with confirmed SARS-CoV-2 infection who presented to an urban Emergency Department with acute respiratory distress during the first COVID-19 surge in 2020; 13 (4.2%) were subsequently diagnosed with venous thromboembolism during hospitalization. Serial samples were obtained and assays were performed on two highly-multiplexed proteomic platforms. Nine coagulation proteins were differentially expressed in patients with thromboembolic events. P-selectin, a cell adhesion molecule on the surface of activated endothelial cells, displayed the strongest association with the diagnosis of VTE, independent of disease severity (p=0.0025). This supports the importance of endothelial activation in the mechanistic pathway of venous thromboembolism in COVID-19. P-selectin together with D-dimer upon hospital presentation provided better discriminative ability for VTE diagnosis than D-dimer alone.

category: cardiovascular medicine


title: ONLINE QUERIES AS A CRITERION FOR EVALUATION OF THE EPIDEMIOLOGICAL STATUS AND EFFECTIVENESS OF COVID-19 EPIDEMIC CONTROL MEASURES

abstract:
Monitoring online queries can provide early and accurate information about the spread of COVID-19 in the population and about the effectiveness of COVID-19 epidemic control measures.

The purpose of the studyAssessment of significance of online queries regarding smell impairment to evaluate the epidemiological status and effectiveness of COVID-19 epidemic control measures.

Materials and methodsWeekly online queries from Yandex Russian users regarding smell impairment were analysed in regions and large cities of Russia from 16/3/2020 to 21/2/2021. A total of 81 regions of Russia and several large cities, such as Moscow, St. Petersburg, and Nizhny Novgorod, were included in the study.

ResultsA strong positive direct correlation (r>0.7) was found between the number of smell-related queries in Yandex new cases of COVID-19 in 59 out of 85 Russian regions and large cities (70%). During the "first" peak of COVID-19 incidence in Russia (April-May 2020), the increase in the number of smell-related queries outpaced the increase in the number of new cases by 1-2 weeks in 23 out of 59 regions of Russia. During the "second" peak of COVID-19 incidence in Russia (October-December 2020), the increase in the number of smell-related queries outpaced the increase in the number of new cases by 1-2 weeks in 36 regions of Russia, including Moscow. We also estimated the increase in the query/new case ratio during the "second" peak of incidence for 45 regions. It was found that the query/new case ratio increased by more than 100% in 24 regions. The regions where the increase in queries was more than 160% compared to new infection cases during the "second" peak of incidence demonstrated significantly higher search activity related to levofloxacin than the regions where the increase in queries was lower than 160% compared to the increase in new infection cases.

ConclusionThe sudden interest in smell impairment and growing frequency of online queries among the population can be used as an indicator of the spread of coronavirus infection among the population as well as for evaluation of the effectiveness of COVID-19 epidemic control measures.


title: Mapping First to Second wave transition of covid19 Indian data via Sigmoid function and prediction of Third wave

abstract: Understanding first and second wave of covid19 Indian data along with its few selective states, we have realized a transition between two Sigmoid pattern with twice larger growth parameter and maximum values of cumulative data. As a result of those transition, time duration of second wave shrink to half of that first wave with four times larger peak values. It is really interesting that the facts can be easily understood by simple algebraic expressions of Sigmoid function. After understanding the crossing zone between first and second wave curves, a third wave Sigmoid pattern is guessed.


title: Using population based Kalman estimator to model COVID-19 epidemics in France: estimating the burden of SARS-CoV-2 and the effects of NPI.

abstract: In response to the ongoing COVID-19 pandemic caused by SARS-CoV-2, governments are taking a wide range of non-pharmaceutical interventions (NPI). These measures include interventions as stringent as strict lockdown but also school closure, bar and restaurant closure, curfews and barrier gestures i.e. social distancing. Disentangling the effectiveness of each NPI is crucial to inform response to future outbreaks. To this end, we first develop a multi-level estimation of the French COVID-19 epidemic over a period of one year. We rely on a global extended Susceptible-Infectious-Recovered (SIR) mechanistic model of the infection including a dynamical (over time) transmission rate containing a Wiener process accounting for modeling error. Random effects are integrated following an innovative population approach based on a Kalman-type filter where the log-likelihood functional couples data across French regions. We then fit the estimated time-varying transmission rate using a regression model depending on NPI, while accounting for vaccination coverage, apparition of variants of concern (VoC) and seasonal weather conditions. We show that all NPI considered have an independent significant effect on the transmission rate. We additionally demonstrate a strong effect from weather conditions which decrease transmission during the summer period, and also estimate increased transmissibility of VoCs.


title: Using Population Based Kalman Estimator to Model COVID-19 Epidemics in France: Estimating the Effects of Non-pharmaceutical Interventions on the Dynamics of Epidemics.


title: STUDY OF BLOOD GROUP ANALYSIS AND ITS CORRELATION WITH LYMPHOPENIA IN COVID 19 INFECTED CASES OUR EXPERIENCE IN TERITARY CARE HOSPITAL.

abstract:
AIMS AND OBJECTIVESTo study the distribution and frequencies of ABO and Rhesus (Rh) blood groups among confirmed cases of Covid-19 infection. We also studied the relation between ABO blood group system and lymphopenia and studied the gender association in COVID-19 patients.

METHODESA hospital based retrospective study was conducted at Government Medical College Suryapet from 01 Aug 2020 to 30 Sep 2020. A total of 200 Covid cases were included in the study who came to the hospital with the complaints of Fever, Sore throat, Body Pains, Cough, Breathlessness, Diarrhoea etc. Patients confirmed Covid infection was tested for blood grouping and RH typing by using forward blood grouping with the help of commercially available standard monoclonal antisera. CBP was processed in sysmax 5 part Haematology analyser. Blood group frequency was tested also assed the gender association, Covid patients presents with lymphopenia the relation between the ABO blood group and lymphocyte count was determined.

RESULTSMales were more compared to the females .Middle aged group male patients were more commonly involved. Most predominant blood group was group B 79(39.5%), group O 78(39%),group A 37(18.5%), group AB 6(3%),most of them were 190 (95%)Rh positive, only 10 Rh negative (5%).To assess the Lymphopenia in our study we divided the absolute lymphocyte count into 5 groups. Group 1 cases are more 58 (29%), Group 2 91(45.5%), Group 3 30 (15%), Group 4 16(8%), Group 5 5(2.5%).

CONCLUSIONMale patients with blood group B were more compared to other blood groups however more number of studies are necessary to confirm these findings in a larger sample and among individuals of different ethnicities.

category: pathology


title: The risk of drug resistance during long-acting antimicrobial therapy

abstract: The emergence of drug resistance during antimicrobial therapy is a major global health problem, especially for chronic infections like HIV, hepatitis B and C, and TB. Sub-optimal adherence to long-term treatment is an important contributor to resistance risk. New long-acting drugs are being developed for weekly, monthly, or less frequent dosing to improve adherence, but may lead to long-term exposure to intermediate drug levels. In this study we analyze the effect of dosing frequency on the risk of resistance evolving in the presence of time-varying drug levels. We find that long-acting therapies can increase, decrease, or have little effect on resistance, depending on the source (pre-existing or de novo) and degree (full or partial) of resistance, and whether the drug is absorbed - as well as cleared - more slowly. For long-acting therapies with slow drug clearance but rapid absorption, and for partially-resistant strains, longer dosing intervals tend to reduce resistance risks even if they dont improve adherence, and adherence improvements amplify these effects. In other scenarios, long-acting therapies are more susceptible to resistance and must substantially improve adherence to overcome this deficit. If subpopulations of microbes persist and can reactivate during suboptimal treatment, longer-acting therapies may substantially increase the risk of resistance. Our results show that drug kinetics affect selection for resistance in a complicated manner, and that pathogen-specific models are needed to evaluate the benefit of new long-acting therapies.

category: pharmacology and therapeutics


title: Emerging models and trends in mental health crisis care in England: a national investigation of crisis care systems

abstract:
BackgroundInpatient psychiatric care is unpopular and expensive, and development and evaluation of alternatives is a long-standing policy and research priority around the world. In England, the three main models documented over the past fifty years (teams offering crisis assessment and treatment at home; acute day services; and residential crisis services in the community) have recently been augmented by several new service models. These are intended to enhance choice and flexibility within catchment area acute care systems, but remain largely undocumented in the research literature. We therefore aimed to describe the types and distribution of crisis care models across England through a national survey.

MethodsWe carried out comprehensive mapping of crisis resolution teams (CRTs) using previous surveys, websites and multiple official data sources. Managers of CRTs were invited to participate as key informants who were familiar with the provision and organisation of crisis care services within their catchment area. The survey could be completed online or via telephone interview with a researcher, and elicited details about types of crisis care delivered in the local catchment area.

ResultsWe mapped a total of 200 adult CRTs and completed the survey with 184 (92%). Of the 200 mapped adult CRTs, there was a local (i.e., within the adult CRT catchment area) children and young persons CRT for 84 (42%), and an older adults CRT for 73 (37%). While all but one health region in England provided CRTs for working age adults, there was high variability regarding provision of all other community crisis service models and system configurations. Crisis cafes, street triage teams and separate crisis assessment services have all proliferated since a similar survey in 2016, while provision of acute day units has reduced.

ConclusionsThe composition of catchment area crisis systems varies greatly across England and popularity of models seems unrelated to strength of evidence. A group of emerging crisis care models with varying functions within service systems are increasingly prevalent: they have potential to offer greater choice and flexibility in managing crises, but an evidence base regarding impact on service user experiences and outcomes is yet to be established.


title: Suicidal Ideation in Dementia: Associations with Neuropsychiatric Symptoms and Subtype Diagnosis

abstract:
ObjectivesTo investigate factors associated with suicidal ideation around the time of dementia diagnosis. We hypothesised that relatively preserved cognition, co-occurring physical and psychiatric disorders, functional impairments and dementia diagnosis subtype would be associated with higher risk of suicidal ideation.

DesignCross-sectional study using routinely collected electronic mental healthcare records.

SettingNational Health Service secondary mental healthcare services in South London, United Kingdom, which serve a population of over 1.36 million residents.

ParticipantsPatients who received a diagnosis of dementia (Alzheimers, vascular, mixed Alzheimers/vascular or dementia with Lewy bodies) between 1/1/2007-30/6/2016. 11,787 people with dementia were identified during the observation period.

MeasurementsA natural language processing algorithm was used to identify recorded clinician statements about suicidal ideation around the time of dementia diagnosis.

Sociodemographic and clinical characteristics were also measured around the time of diagnosis. We compared people diagnosed with non-Alzheimers dementia to those with Alzheimers and used statistical models to adjust for putative confounders.

Results4.8% of patients identified with dementia had recorded suicidal ideation. Recorded suicidal ideation was almost twice as common in dementia with Lewy bodies compared to other dementia diagnoses studied. After adjusting for sociodemographic and clinical factors, dementia with Lewy bodies, physical illnesses or disability and neuropsychiatric symptoms were significantly associated with suicidal ideation. Mini-Mental State Examination score at diagnosis was not associated with suicidal ideation.

ConclusionsAlthough completed suicide is rare, suicidal ideation is present in sufficient proportions of people with dementia to justify treatment of potentially modifiable risk factors within dementia care pathways.


title: COVID-19 vaccine hesitancy in the UK: A longitudinal household cross-sectional study

abstract:
STRUCTURED ABSTRACTO_ST_ABSBackgroundC_ST_ABSThe global morbidity and mortality burden of COVID-19 has been substantial, often widening pre-existing inequalities. The approved COVID-19 vaccines have shown great promise in reducing disease transmission and severity of outcomes. However, the success of the COVID-19 vaccine rollout is dependent on public acceptance and willingness to be vaccinated. In this study, we aim to examine how the attitude towards public sector officials and the government impact vaccine willingness with a secondary aim to understand the impact of ethnicity on this relationship.

MethodsThis cross-sectional study used data from a UK population based longitudinal household survey (Understanding Society COVID-19 study, Understanding Society: the UK Household Longitudinal Study) between April 2020-January 2021. Data from 22421 participants in Waves 6 and 7 of the study were included after excluding missing data. Demographic details in addition to previous survey responses relating to public sector/governmental trust were included in as covariates in the main analyses. A logit model was produced to describe the association between public sector/governmental mistrust and the willingness for vaccination with interaction terms included to account for ethnicity/socio-economic status.

FindingsIn support of existing literature, we identified those from BAME groups were more likely to be unwilling to take the COVID-19 vaccine. We found that positive opinions towards public sector officials (OR 2.680: 95% CI 1.888 - 3.805) and the UK government (OR 3.400; 95% CI 2.454 - 4.712) led to substantive increase in vaccine willingness. Most notably we identified this effect to be vary across ethnicity and socio-economic status with those from South Asian background (OR 4.513; 95% CI 1.012 - 20.123) the most unwilling to be vaccinated when their trust in public sector officials were affected.

InterpretationThese findings suggests that trust in public sector officials may play a key factor in the low vaccination rates particularly seen in at risk groups. Given the additional morbidity/mortality risk posed by COVID-19 to those from lower socio-economic or ethnic minority backgrounds, there needs to be urgent public health action to review how to tailor health promotion advice given to these groups and examine methods to improve trust in public sector officials and the Government.

FundingNo funding

RESEARCH IN CONTEXTO_ST_ABSEvidence before this studyC_ST_ABSA systematic literature search on Pubmed and MedRxiv from database inception to 2nd July 2021 was conducted. The broad terms included were "COVID" OR "SARS-CoV-2*" AND "hesitancy" OR "willingness." There were no age or language restrictions. We identified numerous observational studies examining prevalence of willingness and hesitancy towards taking the vaccine in a variety of global settings. However, there were fewer studies which examined the reasons behind decisions relating to vaccine hesitancy and in particular in communities relevant to those most at risk in the United Kingdom.

Added value of this studyTo our knowledge, this is the first attempt to exploring the role of trust in the public sector officials and in the Government with UK COVID-19 vaccination willingness. We found that negative pre-existing opinions around public sector/Government significantly reduced vaccine willingness with an increased effect size noted in those from lower socio-economic and BAME backgrounds.

Implications of all the available evidenceOur findings support pre-existing prevalence data suggesting a reduced willingness for vaccination in lower socio-economic/BAME communities. However, our findings build on existing literature by suggesting that trust in public sector officials may play a key factor in the low vaccination rates. Given the additional morbidity/mortality risk posed by COVID-19 to those from lower socio-economic or ethnic minority backgrounds there needs to be urgent public health action to review how to tailor health promotion advice given to these groups and examine methods to improve trust in public sector officials and the Government.


title: Bioactive Metabolomic Profiles of Scleroderma-PAH are different than idiopathic PAH and associated with worse clinical outcomes

abstract:
The molecular signature in patients with systemic sclerosis (SSc)-associated pulmonary arterial hypertension (SSc-PAH) relative to idiopathic pulmonary arterial hypertension (IPAH) remain unclear. We hypothesize that patients with SSc-PAH exhibit unfavorable bioactive metabolite derangements compared to IPAH that contribute to their poor prognosis and limited response to therapy. We sought to determine whether circulating bioactive metabolites are differentially altered in SSc-PAH versus IPAH.

Plasma biosamples from 415 patients with SSc-PAH (cases) and 1115 patients with IPAH (controls) were included in the study. Over 700 bioactive metabolites were assayed in plasma samples from independent discovery and validation cohorts using liquid chromatography - mass spectrometry (LC-MS) based approaches. Regression analyses were used to identify metabolites which exhibited differential levels between SSc-PAH and IPAH and associated with disease severity.

From among hundreds of circulating bioactive molecules, twelve metabolites were found to distinguish between SSc-PAH and IPAH, as well as associate with PAH disease severity. SSc-PAH patients had increased levels of fatty acid metabolites including lignoceric acid and nervonic acid, as well as kynurenine, polyamines, eicosanoids/oxylipins and sex hormone metabolites relative to IPAH. In conclusion, SSc-PAH patients are characterized by an unfavorable bioactive metabolic profile that may explain the poor and limited response to therapy. These data provide important metabolic insights into the pathogenesis of SSc-PAH.

Take Home MessageAmong patients with PAH, those with SSc-PAH suffer disproportionately worse outcomes and disease course. This study represents the most comprehensive analysis of bioactive metabolites profiling comparing two subgroups of PAH. The findings shed light on key differences between SSc-PAH and IPAH that provide important metabolic insight into the disease pathogenesis.

category: respiratory medicine


title: Comparison of humoral and cellular responses in kidney transplant recipients receiving BNT162b2 and ChAdOx1 SARS-CoV-2 vaccines

abstract:
BackgroundAttenuated immune responses to mRNA SARS-CoV-2 vaccines have been reported in solid organ transplant recipients. Most studies have assessed serological responses alone, and there is limited immunological data on vector-based vaccines in this population. This study compares the immunogenicity of BNT162b2 with ChAdOx1 in a cohort of kidney transplant patients, assessing both serological and cellular responses.

Methods920 patients were screened for spike protein antibodies (anti-S) following 2 doses of either BNT162b2 (n=490) or ChAdOx1 (n=430). 106 patients underwent assessment with T-cell ELISpot assays. 65 health care workers were used as a control group.

ResultsAnti-S was detected in 569 (61.8%) patients. Seroconversion rates in infection-naive patients who received BNT162b2 were higher compared with ChAdOx1, at 269/410 (65.6%) and 156/358 (43.6%) respectively, p<0.0001. Anti-S concentrations were higher following BNT162b, 58(7.1-722) BAU/ml, compared with ChAdOx1, 7.1(7.1-39) BAU/ml, p<0.0001. Calcineurin inhibitor monotherapy, vaccination occurring >1st year post-transplant and receiving BNT162b2 was associated with seroconversion.

Only 28/106 (26.4%) of patients had detectable T-cell responses. There was no difference in detection between infection-naive patients who received BNT162b2, 7/40 (17.5%), versus ChAdOx1, 2/39 (5.1%), p=0.15. There was also no difference in patients with prior infection who received BNT162b2, 8/11 (72.7%), compared with ChAdOx1, 11/16 (68.8%), p=0.83.

ConclusionsEnhanced humoral responses were seen with BNT162b2 compared with ChAdOx1 in kidney transplant patients. T-cell responses to both vaccines were markedly attenuated. Clinical efficacy data is still required but immunogenicity data suggests weakened responses to both vaccines in transplant patients, with ChAdOx1 less immunogenic compared with BNT162b2.

category: transplantation


title: Investigation research on the demand of pre-job training for nursing students in higher vocational colleges

abstract:
ObjectivesTo investigate the pre-job training demand of nursing students in higher vocational colleges, lay a foundation for the development of scientific and standardized pre-job training program and help nursing students smoothly transition to clinical practice state from student status.

MethodsA self-designed questionnaire was used to investigate 822 nursing students of grade 2018 in our school from four aspects: the necessity of pre-job training, the demand content of pre-job training, the demand of skill enhancement program, and the stress source of pre-internship.

ResultsDemand rate of the pre-job training of nursing students in the college was 99.5%, and main demand of the training content were nursing skill training (96.8%), nursing safety and occupational protection (95.1%), nursing theory training (92.9%); the main demand of nursing skills enhancement program were closed intravenous infusion (90.3%), (intradermal, subcutaneous, intramuscular) injection (87.8%), cardiopulmonary resuscitation (81.8%), and indwelling catheterization (77.5%); the main stress sources of pre-internship was lack of confidence in theory and skills, accounts for 61.1% in total 760 students.

ConclusionThe pre-job training courses in higher vocational colleges should be close to the clinical needs of students, it is necessary to carry out pre-job training courses according to main demand of the training content, the main demand of nursing skills enhancement program and the main stress sources of pre-internship in the college; this article may provide reference for our school and other vocational colleges to develop pre-job training program.

category: medical education


title: Alterations to the gut microbiome after sport-related concussion and subconcussive impacts in a collegiate football players cohort.

abstract: Concussions, both single and repetitive, during contact sports cause brain and body alterations in athletes. The role of the brain-gut connection and changes in the microbiota have not been well established after a head injury or concussion-related health consequences. We recruited 33 Division I Collegiate football players and collected blood, stool, and saliva samples throughout the athletic season. Analysis of the gut microbiome reveals a decrease in abundance for two bacterial species, Eubacterium rectale, and Anaerostipes hadrus, after a diagnosed concussion. No significant differences were found regarding the salivary microbiome. Serum biomarker analysis shows an increase in GFAP blood levels in athletes during athletic activity. Additionally, S100{beta} and SAA blood levels were positively correlated with the abundance of Eubacterium rectale species among athletes exposed to subconcussive impacts. These novel findings provide evidence that detecting changes in the gut microbiome may pave the way for improved concussion diagnosis following head injury.


title: Student nurses' views on shift patterns: what do they prefer and why? Results from a Tweetchat

abstract:
AimTo understand student nurses views around shift patterns.

DesignQualitative study

MethodWe held a Tweetchat in May 2019, where we asked questions around the frequency of 12-hour shifts working on placement; schedule flexibility while on placement; which shift patterns they preferred and why. Data from the Tweetchat were analysed to identify emerging themes and inductively develop a coding frame.

ResultsSeventy-three nursing students participated in the Tweetchat. The majority (68%) of respondents reported that they work 12-hour shifts on placements. We identified three main overarching themes: "Achieving a personal equilibrium"; "Meeting the needs of the care environment", "Factors affecting negotiation capacity". Data highlighted a conflict for most students, where they preferred 12-hour shifts because of more time off for study, paid work, and leisure, while acknowledging 12-hour shifts had a negative effect on fatigue, exhaustion, and their ability to achieve self-care (i.e. poor diet, no exercise).

category: nursing


title: A reinforcement learning model to inform optimal decision paths for HIV elimination

abstract:
The  Ending the HIV Epidemic (EHE) national plan aims to reduce annual HIV incidence in the United States from 38,000 in 2015 to 9,300 by 2025 and 3,300 by 2030. Diagnosis and treatment are two most effective interventions, and thus, identifying corresponding optimal combinations of testing and retention-in-care rates would help inform implementation of relevant programs. Considering the dynamic and stochastic complexity of the disease and the time dynamics of decision-making, solving for optimal combinations using commonly used methods of parametric optimization or exhaustive evaluation of pre-selected options are infeasible. Reinforcement learning (RL), an artificial intelligence method, is ideal; however, training RL algorithms and ensuring convergence to optimality are computationally challenging for large-scale stochastic problems. We evaluate its feasibility in the context of the EHE goal.

We trained an RL algorithm to identify a  sequence of combinations of HIV-testing and retention-in-care rates at 5-year intervals over 2015-2070, which optimally leads towards HIV elimination. We defined optimality as a sequence that maximizes quality-adjusted-life-years lived and minimizes HIV-testing and care-and-treatment costs. We show that solving for testing and retention-in-care rates through appropriate reformulation using proxy decision-metrics overcomes the computational challenges of RL. We used a stochastic agent-based simulation to train the RL algorithm. As there is variability in support-programs needed to address barriers to care-access, we evaluated the sensitivity of optimal decisions to three cost-functions.

The model suggests to scale-up retention-in-care programs to achieve and maintain high annual retention-rates while initiating with a high testing-frequency but relaxing it over a 10-year period as incidence decreases. Results were mainly robust to the uncertainty in costs. However, testing and retention-in-care alone did not achieve the 2030 EHE targets, suggesting the need for additional interventions. The results from the model demonstrated convergence. RL is suitable for evaluating phased public health decisions for infectious disease control.


title: SARS-CoV-2 variants of concern exhibit reduced sensitivity to live-virus neutralization in sera from CoronaVac vaccinees and naturally infected COVID-19 patients

abstract: Recent surges in SARS-CoV-2 variants of concern (VOCs) call for the need to evaluate levels of vaccine-and infection-induced SARS-CoV-2 neutralizing antibodies (NAbs). CoronaVac (Sinovac Biotech, Beijing, China) is currently being used for mass vaccination in Thailand as well as other low-income countries. Three VOCs currently circulating within Thailand include the B.1.1.7 (Alpha), B.1.351 (Beta), and B.1.617.2 (Delta) strains. We assessed NAb potency against the prototypic strain containing the original spike sequence (WT) compared to that against the 3 VOCs using sera derived from a cohort of healthcare workers who received a full 2-dose regimen of CoronaVac. Sera from two other cohorts consisting of COVID-19 patients who had been hospitalized in 2020 and 2021 were evaluated for comparison. We found that, despite equally robust production of S1-RBD-binding IgG and 100% seropositivity, sera from both CoronaVac vaccinees and naturally infected individuals had significantly reduced neutralizing capacity against all 3 VOCs compared to WT. Strikingly, NAb titers against Alpha and Beta were comparable, but Delta appears to be significantly more refractory to NAbs in all groups. Our results may help inform on CoronaVac NAb-inducing capacity, which is a proxy for vaccine efficacy, in the context of the WT strain and 3 VOCs. Our results also have critical implications for public health decision-makers who may need to maintain efficient mitigation strategies amid a potentially high risk for infection with VOCs even in those who have been previously infected.

category: infectious diseases


title: Use of 1-MNA to Improve Exercise Tolerance and Fatigue in Patients After COVID-19

abstract:
BackgroundCoronavirus disease 2019 (COVID-19) is a serious respiratory disease that results from infection with a newly discovered coronavirus (SARS-COV-2). Unfortunately, COVID-19 is not only a short-term infection but that patients (pts) recovering from SARS-CoV2 infection complain of persisting symptoms including: fatigue, diffuse myalgia and weakness, which may lead to chronic fatigue syndrome. There is currently no evidence that nutritional supplements and/or physical exercise can assist in the recovery of pts with chronic fatigue syndrome. 1-Methylnicotinamide (1-MNA) is an endogenic substance that is produced in the liver when nicotinic acid is metabolized. 1-MNA demonstrates anti-inflammatory and anti-thrombotic properties. Therefore, we investigated whether 1-MNA supplements could improve exercise tolerance and decrease fatigue among patients recovering from SARS-CoV-2.

MethodsThe study population was composed of pts after COVID-19, expressing subjective feelings of limited tolerance to exercise. The selected pts were randomized into two groups: GrM0 - without supplementation; GrM1 - with 1-MNA supplementation. At the beginning of the study (Phase 0), in both groups, a 6-minute walk test (6MWT) was carried out and fatigue assessment with Fatigue Severity Scale (FSS) was performed. After 1 month (Phase 1), a follow up FSS and 6MWT once more were performed in both groups.

ResultsA significant improvement in the mean distance covered in the 6MWT was noted among the pts in GrM1, compared to those in GrM0. We also noted that in GrM1 the 6MWT distance was significantly higher after 1 month of supplementation with 1-MNA, compared to the beginning of the study (515.18 m in Phase 0 vs 557.8m in Phase 1; p = 0.000034). In GrM1, significantly more pts improved their distance in the 6MWT (23 out of 25 pts, equal to 92%), by a mean of 47 meters, compared to GrM0 (15 of 25 pts, equal to 60%) (p = 0.0061). After one month, significantly more patients in the group without 1-MNA had severe fatigue (FSS [≥] 4) compared to the group with supplementation (GrM1 = 5 pts (20%) vs GrM0 = 14pts (56%); p = 0.008).

Conclusions1-MNA supplementation significantly improved physical performance in a 6-minute walk test and reduced the percentage of patients with severe fatigue after COVID-19. The comprehensive action of 1-MNA, including anti-inflammatory and anticoagulant effects, as well as activation of the SIRT1 enzyme, may be beneficial for the recovery of patients with persistent symptoms of fatigue and low tolerance to exercise after COVID-19.


title: An update on statistical modeling for quality risk assessment of clinical trials

abstract:
BackgroundAs investigator site audits have largely been conducted remotely during the COVID-19 pandemic, remote quality monitoring has gained some momentum. To further facilitate the conduct of remote Quality Assurance (QA) activities for clinical trials, we developed new quality indicators, building on a previously published statistical modeling methodology.

MethodsWe modeled the risk of having an audit or inspection finding using historical audits and inspections data from 2011 - 2019. We used logistic regression to model finding risk for 4 clinical impact factor (CIF) categories: Safety Reporting, Data Integrity, Consent and Protecting Endpoints.

ResultsWe could identify 15 interpretable factors influencing audit finding risk of 4 out of 5 CIF categories. They can be used to realistically predict differences in risk between 25 and 43% for different sites which suffice to rank sites by audit and inspection finding risk.

ConclusionContinuous surveillance of the identified risk factors and resulting risk estimates could be used to complement remote QA strategies for clinical trials and help to manage audit targets and audit focus also in post-pandemic times.

category: health systems and quality improvement


title: Statistical modeling for quality risk assessment of clinical trials: follow-up at the era of remote auditing


title: Factors associated with transmission in COVID-19 outbreaks in long-term care facilities

abstract:
BackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has had a disproportionate impact on residents in long-term care facilities (LTCFs). Through our experience and data from managing COVID-19 exposures and outbreaks in LTCFs in the Fraser Health region in British Columbia, Canada, we identified risk factors associated with outbreak severity to inform current outbreak management strategies and future pandemic preparedness planning efforts.

MethodsWe used a retrospective cohort study design to evaluate the association between non-modifiable factors (facility building, organization level, and resident population characteristics), modifiable factors (assessments for infection prevention and control (IPC) and public health measures), and severity of COVID-19 outbreaks (attack rate) in LTCFs. We modelled the COVID-19 attack rates in LTCF outbreaks using negative binomial regression models.

ResultsFrom March 1, 2020 to January 10, 2021, a total of 145 exposures to at least one confirmed case of COVID-19 in 82 LTCFs occurred. For every item not met in the assessment tool, a 22% increase in the attack rate was observed (rate ratio 1.2 [95% CI 1.1 - 1.4]) after adjusting for other risk factors such as age of the facility, index case type (resident vs. staff) and proportion of single bed rooms.

ConclusionOur findings highlight the importance of assessing IPC and public health measures for outbreak management. They also demonstrate the important modifiable and non-modifiable risk factors associated with COVID-19 outbreaks in our jurisdiction. We hope these findings will inform ongoing outbreak management and future pandemic planning efforts.