title: Waning, Boosting and a Path to Endemicity for SARS-CoV-2.

abstract: In many countries, an extensive vaccination programme has substantially reduced the public-health impact of SARS-CoV-2, limiting the number of hospital admissions and deaths compared to an unmitigated epidemic. Ensuring a low-risk transition from the current situation to one in which SARS-CoV-2 is endemic requires maintenance of high levels of population immunity. The observed waning of vaccine efficacy over time suggests that booster doses may be required to maintain population immunity especially in the most vulnerable groups. Here, using data and models for England, we consider the dynamics of COVID-19 over a two-year time-frame, and the role that booster vaccinations can play in mitigating the worst effects. We find that boosters are necessary to suppress the imminent wave of infections that would be generated by waning vaccine efficacy. Projecting further into the future, the optimal deployment of boosters is highly sensitive to their long-term action. If protection from boosters wanes slowly (akin to protection following infection) then a single booster dose to the over 50s may be all that is needed over the next two-years. However, if protection wanes more rapidly (akin to protection following second dose vaccination) then annual or even biannual boosters are required to limit subsequent epidemic peaks an reduce the pressure on public health services.


title: Modeling COVID-19 epidemic trends and health system needs leading to projections for developing countries: a case study of Thailand

abstract: Thailand was the first country outside China to report a COVID-19 case but had a mild impact from the outbreak especially at the beginning of the pandemic. This study systematically investigates the evolution of the COVID-19 epidemic in Thailand from January 2020 to March 2021 to uncover the COVID-19 situation in the country. By modeling all health districts throughout the country, the study found that COVID-19 contributed to an increase in excess deaths and that COVID-19 deaths might be underreported. There was a lag time in ramping up testing although testing is key to control the disease. The estimated total number of beds required by COVID-19 seems low, but it may not ensure the capacity to take care of critical cases that required ICU beds, specific medical equipment, and trained medical staff.

category: epidemiology


title: Likelihood of being Physically Inactive from a Nationally Representative sample of Autistic Children

abstract: Despite the many health risks of physical inactivity, studies have demonstrated individual, family, and environmental determinants of inactivity for autistic children. However, these studies never examined these correlates at the same time. Therefore, the purpose of this study was to explore these ecological domains concurrently when examining physical inactivity correlates for autistic children. This study used data from the 2016-2020 National Survey of Childrens Health. The authors predicted physical inactivity while controlling for child, parental/household, and neighborhood correlates with autism status as the comparison group. When controlling for covariates, children with co-occurring autism and intellectual and developmental disability (IDD) (adjusted odds ratio (aOR)= 1.91, 95% confidence interval (CI): 1.36-2.68) or ASD only (aOR = 1.91, CI: 1.48-2.48) were significantly more likely to be inactive when compared to children without autism or IDD. However, autism medicine and autism severity were not predictors for obese autistic children. These findings indicate that it is important to take a holistic, ecological approach when exploring the correlates of inactivity for autistic children.

category: public and global health


title: COVID-19: a study about the impact of coronavirus on physicians of La Plata, Argentina

abstract:
BackgroundIn Argentina, the burden of COVID-19 on health systems and physicians was substantial with difficulties on daily triage decisions which have to be made in the context of grave shortages of basic equipment and consumables.

Purposethis study was performed to understand what physicians were experiencing during the COVID-19 pandemic in La Plata (capital city of Buenos Aires province, Argentina).

MethodsA cross-sectional study was performed; a questionnaire was sent by e-mail to physicians who work in this city during November 2020. The questionnaire was made based on Medscape US and International Physicians COVID-19 Experience Report: Risk, Burnout, Loneliness.

Statistical analysistest for normality was performed employing the Kolmogorov-Smirnov test while Chi-square test of independence to examine the relationship between sex and workplace with nominal variables. For categorical variables, Kendalls tau correlation was performed to test for independence. ANOVA was developed to examine differences between physicians age. Statistical significance was set to p < 0.05 in all cases. All statistical analysis was done employing SPSS Statistics, Version 24 (IBM, USA).

Results203 physicians answered the questionnaire; the majority of physicians (96%) considered stressful their experience during pandemic and reported distress episodes being for more than 60% the most stressful of their practices, 30% presented depression and were medically treated, while 32.7% felt loneliness with 4 physicians with suicidal thoughts.

ConclusionThe results highlight the need to protect the psychological well-being of the healthcare community, and to invest resources to significantly promote the mental health of professionals.


title: Hyperconnectivity and altered dynamic interactions of a nucleus accumbens network in post-stroke depression

abstract:
ObjectivesPost-stroke depression (PSD) is a common complication after stroke. To date, no consistent locus of injury is associated with this complication. Here, we probed network dynamics in four functional circuits tightly linked to major depressive disorder and investigated structural alterations within these networks in PSD.

MethodsForty-four participants with recent stroke and 16 healthy volunteers were imaged with 3T structural, diffusion and resting-state functional MRI and completed the Geriatric Depression Scale (GDS). Associations between GDS and functional connectivity were investigated within networks seeded from nucleus accumbens (NAc), amygdala and dorsolateral prefrontal cortex. In addition, the default mode network (DMN) was identified by connectivity with medial prefrontal cortex (mPFC) and posterior cingulate cortex (PCC). Circuits that exhibited altered activity associated with GDS were further investigated by extracting within-network volumetric and microstructural measures from structural images.

ResultsFunctional connectivity within the NAc-seeded network and DMN correlated positively with depressive symptoms. Normal anticorrelations between these two networks were absent in patients with PSD. PCC grey matter volume as well as microstructural measures in mPFC and the medial forebrain bundle, a major projection pathway interconnecting the NAc-seeded network and links to mPFC, were associated with GDS scores.

ConclusionsDepression after stroke is marked by reduced mutual inhibition between functional circuits involving NAc and DMN as well as volumetric and microstructural changes within these networks. Aberrant network dynamics present in patients with PSD are therefore likely to be influenced by secondary, pervasive alterations in grey and white matter, remote from the site of injury.

category: radiology and imaging


title: Interleukin-33 stimulates stress in the endoplasmic reticulum of the human myometrium via an influx of calcium during initiation of labor

abstract:
BackgroundInflammation is currently recognized as one of the major causes of premature delivery. As a member of the IL-1{beta} family, interleukin-33 (IL-33) has been shown to be involved in a variety of pregnancy-related diseases. This study aims to investigate the potential function of IL-33 in uterine smooth muscle cells during labor.

MethodsSamples of myometrium from term pregnant ([≥]37 weeks gestation) women were frozen or cells were isolated and cultured. Immunohistochemistry and western blotting were used to identify the distribution of IL-33. Cultured cells were incubated with LPS to mimic inflammation as well as 48C to block endoplasmic reticulum (ER) stress and BAPTA-AM, a calcium chelator.

ResultsSimilar with onset of labor, LPS could reduce the expression of nuclear IL-33 in a time-limited manner and induced ER stress. Meanwhile, Knockdown of IL-33 increased LPS-induced calcium concentration, ER stress and phosphorylation of NF-{kappa}B and p38. In addition, siRNA IL-33 further simulates LPS enhanced COX-2 expression via NF-{kappa}B and p38 pathways. IL-33 expression was decreased in the nucleus with the onset of labor. LPS induced ER stress and increased expression of the labor-associated gene, COX-2, as well as IL-6 and IL-8 in cultured myometrial cells. IL-33 also increased COX-2 expression. However, after IL-33 was knockdown, the stimulating effect of LPS on calcium was enhanced. 48C also inhibited the expression of COX-2 markedly. The expression of calcium channels on the membrane and intracellular free calcium ion were both increased accompanied by phosphorylated NF-{kappa}B and p38.

ConclusionsThese data suggest that IL-33 may be involved in initiation of labor by leading to stress of the ER via an influx of calcium ions in human uterine smooth muscle cells.

FundingThis study was supported by grants from the National Natural Science Foundation of China (Nos. 81300507).

category: obstetrics and gynecology


title: Phenotypic distinctions of BLM- and RMI1-associated Bloom syndrome

abstract: Bloom syndrome (BS) is an autosomal recessive disease with characteristic clinical features of primary microcephaly, growth deficiency, skin lesions, cancer predisposition, and immunodeficiency. Here, we report the clinical and molecular findings of eight patients from six families diagnosed with BS. We identified causative mutations in all families, three different homozygous mutations in BLM and one causative homozygous mutation in RMI1. The homozygous c.581_582delTT (p.Phe194*) and c.3164G>C (p.Cys1055Ser) mutations in BLM have already been reported in BS patients, while the c.572_573delGA (p.Arg191Lysfs*4) is novel. Interestingly, whole-exome sequencing revealed a homozygous loss-of-function mutation in RMI1 in two BS patients of a consanguineous Turkish family. All BS patients had primary microcephaly, intrauterine growth delay, and short stature, presenting the phenotypic hallmarks of BS. However, a narrow face, skin lesions, and upper airway infections were observed only in some of the patients. Overall, patients with homozygous BLM mutations had a more severe BS phenotype compared to patients carrying the homozygous RMI1 mutation, especially in terms of immunodeficiency and associated recurrent infections. Low-level immunoglobulins were observed in all BLM-mutated patients, emphasizing the immunodeficiency profile of the disease, which should be considered as an important phenotypic characteristic of BS, especially in the current Covid-19 pandemic era.

category: genetic and genomic medicine


title: Simultaneous identification of viruses and SARS-CoV-2 variants with programmable DNA nanobait

abstract: Respiratory infections are the major cause of death from infectious disease worldwide. The clinical presentation of many respiratory viruses is indistinguishable; therefore, diagnostic approaches that can identify multiple pathogens are essential for patient management. We aimed to address this challenge with self-assembled DNA nanobait that can simultaneously identify multiple short RNA targets. The nanobait approach relies on specific target selection via toehold-mediated strand displacement and rapid read-out via nanopore sensing. Here, we show this platform can concurrently identify several common respiratory viruses, detecting a panel of short targets of viral nucleic acids from SARS-CoV-2, respiratory syncytial virus (RSV), rhinovirus, influenza, and parainfluenza. Our nanobait could be reprogrammed to discriminate viral variants, and we identified several key SARS-CoV-2 variants with single-nucleotide resolution. We increased assay specificity with bespoke nanobait that could identify numerous short RNA targets in the same viral sample in a complex background of the human transcriptome. Notably, we found that the sequence position in the viral RNA secondary structure is critical for nanobait design. Lastly, we show that nanobait could discriminate between samples extracted from oropharyngeal swabs from negative and positive SARS-CoV-2 patients using programmable target cleavage without pre-amplification. Our system allows for multiplexed identification of native RNA molecules, providing a new scalable approach for diagnostics of multiple respiratory viruses in a single assay.

category: infectious diseases


title: A Flexible Data-Driven Framework for COVID-19 Case Forecasting Deployed in a Developing-world Public Health Setting

abstract:
Forecasting infection case counts and estimating accurate epidemiological parameters are critical components of managing the response to a pandemic. This paper describes a modular, extensible framework for a COVID-19 forecasting system, primarily deployed during the first Covid wave in Mumbai and Jharkhand, India. We employ a variant of the SEIR compartmental model motivated by the nature of the available data and operational constraints. We estimate best fit parameters using Sequential Model-Based Optimization (SMBO), and describe the use of a novel, fast and approximate Bayesian model averaging method (ABMA) for parameter uncertainty estimation that compares well with a more rigorous Markov Chain Monte Carlo (MCMC) approach in practice. We address on-the-ground deployment challenges such as spikes in the reported input data using a novel weighted smoothing method. We describe extensive empirical analyses to evaluate the accuracy of our method on ground truth as well as against other state-of-the-art approaches. Finally, we outline deployment lessons and describe how inferred model parameters were used by government partners to interpret the state of the epidemic and how model forecasts were used to estimate staffing and planning needs essential for addressing COVID-19 hospital burden.

CCS CONCEPTSO_LIApplied computing [->] Health care information systems; Forecasting;
C_LIO_LIComputing methodologies [->] Modeling methodologies.
C_LI


title: How and why do Quality Circles work for General Practitioners - a realist approach

abstract:
ObjectivesTo understand how and why general practitioners in quality circles (QC) reflect on and improve routine practice over time. To provide practical guidance for participants and facilitators to implement and for policy makers to organise this complex social intervention.

DesignA theory-driven mixed method

SettingPrimary health care

MethodWe collected data in four stages to develop and refine the programme theory of QCs: 1) co-inquiry with Swiss and European stakeholders to develop a preliminary programme theory; 2) realist review with systematic searches in MEDLINE, Embase, PsycINFO, and CINHAL (1980-2020) to extend the preliminary programme theory; 3) programme refinement through interviews with participants, facilitators, tutors and managers of quality circles; 4) consolidation through interviews and iterative searches for theories enabling us to strengthen the programme theory.

Sources of dataThe co-inquiry comprised 3 interviews and 3 focus groups with 50 European experts. From the literature search we included 108 papers to develop the literature-based programme theory. In stage 3, we used data from 40 participants gathered in 6 interviews and 2 focus groups to refine the programme theory. In stage 4, five interviewees from different health care systems consolidated our programme theory.

ResultRequirements for successful QCs are governmental trust in GPs abilities to deliver quality improvement, training, access to educational material and performance data, protected time, and financial resources. Group dynamics strongly influence success; facilitators should ensure participants exchange knowledge and generate new concepts in a safe environment. Peer interaction promotes professional development and psychological well-being. With repetition, participants gain confidence to put their new concepts into practice.

ConclusionQCs can improve practice, promote professional development, and psychological well-being given adequate professional and administrative support.

Strengths and limitations of this studyO_LITo our knowledge, this is the first published research that explains how and why general practitioners participating in quality circles may improve standard practice and their psychological well-being over time.
C_LIO_LIThe findings can be used to inform practice and policy decisions.
C_LIO_LIThe resulting theory relies on the detail and depth of the reports in the literature and the veracity and adequacy of the information participants revealed in interviews and focus groups.
C_LIO_LITo mitigate the risk of selection bias if researchers choose underlying theories and synthesise them ad hoc, we used stakeholders mental model and programme documentation as our framework for analysis.
C_LI

category: primary care research


title: Diabetes Technology Experiences of Young People Living with Type 1 Diabetes Mellitus and their Parents: Hybrid Theoretical Foundation Guided Analysis

abstract:
Abstract (unstructured)An important strategy to understand young peoples needs regarding technologies for Type 1 Diabetes Mellitus (T1DM) management is to examine their day-to-day experiences with these technologies. This study aimed to describe T1DM youth and their caregivers experiences and preferences regarding insulin pumps, sensor technologies, and related communication technologies based on a hybrid theoretical foundation, as well as to describe derived ideal device characteristics. Sixteen face-to-face interviews were conducted with young people and their parents. Data analysis included data-driven thematic analysis followed by theory-driven analysis (Unified Theory of Acceptance and Use of Technology; value sensitive design). Initial themes derived from the interviews included aspects of self-management, device use, technological characteristics, and feelings associated with device types. Interview findings were congruent with factors from the two theories. Discussions around ideal devices focused on reliability, flexibility, and automated closed loop systems that enabled an independent life for young people and alleviated parental anxiety. Reality deviated from expectations, with inaccuracy problems and technical failures reported. Technologies for diabetes self-management require continual advancement to meet the needs of young people with T1DM and their caregivers. Understanding experiences and challenges with devices enabled us to identify theory-supported device characteristics useful for the designing of improved technologies.

Extended abstract (structured)O_ST_ABSBackgroundC_ST_ABSAn important strategy to understand young peoples needs and preferences regarding technologies for Type 1 Diabetes Mellitus (T1DM) management is to examine their day-to-day experiences with these technologies.

ObjectiveThis study aimed to describe T1DM youth and their caregivers experiences and preferences regarding insulin pumps, sensor technologies, and related communication technologies based on a hybrid theoretical foundation, as well as to describe derived ideal device characteristics.

Materials and MethodsSixteen face-to-face interviews were conducted with young people with T1DM and their parents about their diabetes technology use. A combination of data-driven thematic analysis in a first stage, and theory-driven analysis in a second stage was used to incorporate in-depth study analysis and existing theoretical literature. Relevant literature included technology adoption (Unified Theory of Acceptance and Use of Technology/UTAUT) and value sensitive design (VSD) models. Based on this approach ideal device characteristics for young people with T1DM were summarized.

ResultsInitial themes derived from the interviews included aspects of diabetes self-management, device use, and specific device-related technological characteristics and feelings associated with the specific device types (continuous glucose monitoring, insulin pump, flash glucose monitoring). The interview data delivered information congruent with all UTAUT and VSD factors except for one (privacy). Discussions around ideal diabetes devices focused on reliability, flexibility, and automated closed loop systems that enabled an independent and normal life for adolescents, and alleviated parental anxiety. However, in line with the previous systematic review, the interview analysis showed that reality deviated from these expectations, with inaccuracy problems reported for continuous glucose monitoring devices, and technical failures occurring in both continuous glucose monitoring devices and insulin pumps.

ConclusionsUTAUT and VSD approaches were found useful as a combined foundation for structuring our study findings. Technologies for diabetes self-management require continual advancement to meet the needs and expectations of young people with T1DM and their caregivers. Understanding their experiences, as well as challenges with the devices, enabled us to identify theory-supported ideal device characteristics that can be useful in the designing and developing of improved technologies.

category: endocrinology


title: Minimal in-school SARS-CoV-2 transmission with strict mitigation protocols at two independent schools in Nashville, TN

abstract:
BACKGROUNDThe COVID-19 pandemic has greatly impacted school operations. To better understand the role of schools in COVID-19 transmission, we evaluated infections at two independent schools in Nashville, TN during the 2020-2021 school year.

METHODSThe cumulative incidence of COVID-19 within each school, age group, and exposure setting were estimated and compared to local incidence. Primary attack rates were estimated among students quarantined for in-school close contact.

RESULTSAmong 1401 students who attended school during the study period, 98 cases of COVID-19 were reported, corresponding to cumulative incidence of 7.0% (95% confidence interval (CI): 5.7-8.5). Most cases were linked to household (58%) or community (31%) transmission, with few linked to in-school transmission (11%). Overall, 619 students were quarantined, corresponding to >5000 person-days of missed school, among whom only 5 tested positive for SARS-CoV-2 during quarantine (primary attack rate: 0.8%, 95% CI: 0.3, 1.9). Weekly case rates at school were not correlated with community transmission.

CONCLUSIONThese results suggest that transmission of COVID-19 in schools is minimal when strict mitigation measures are used, even during periods of extensive community transmission. Strict quarantine of contacts may lead to unnecessary missed school days with minimal benefit to in-school transmission.


title: ChAdOx1 n-COV-19 Vaccine Side Effects Among Health Care Workers in Trinidad and Tobago

abstract:
BackgroundThe pharmaceutical firms have been lauded for the swift development, trial, approval, and rollout of various Covid-19 vaccines. However, a key issue in the vaccination campaign relates to vaccine hesitancy due to concerns on Covid-19 vaccines safety.

MethodA retrospective longitudinal study was carried out via a telephone validated questionnaire. The questionnaire domains included demographic data, medical and COVID-19 related anamneses, and local and systemic side effects 48 hours after receiving the first dose of the vaccine and 48 hours after receiving the second dose of the vaccine.

ResultsThe questionnaire was administered to a sample of 687 healthcare workers (Male = 275; Female = 412). The results indicated that the incidence of reported fever, body pain, chills, nausea, myalgia, headache, malaise, fatigue and other systemic symptoms declined significantly 48 hours after administration of the second dose compared to the first dose. The Chi-square test and multiple logistics regression results were consistent in demonstrating that younger vaccine recipients were more likely to report fever, body pain, chills, nausea, myalgia, headache, fatigue and other symptoms compared to older vaccine recipients. The multiple logistics regression indicate that female vaccine recipients had greater odds of reporting headache, fatigue, discomfort and less likely to report no symptoms compared to male vaccine recipients, 48 hours after receiving both doses.

ConclusionsThe findings indicate that on average, vaccine recipients reported fewer number of local and systemic side effects within 48 hours after receiving the second dose compared to 48 hours after receiving the first dose. The findings have implications on public health policy efforts to lower vaccine hesitancy.


title: Variance-quantitative trait loci enable systematic discovery of gene-environment interactions for cardiometabolic serum biomarkers

abstract: Gene-environment interactions (GEIs) represent the modification of genetic effects by environmental exposures and are critical for understanding disease and informing personalized medicine. GEIs often induce differential phenotypic variance across genotypes; these variance-quantitative trait loci (vQTLs) can be prioritized in a two-stage GEI detection strategy to greatly reduce the computational and statistical burden and enable testing of a broader range of exposures. We performed genome-wide vQTL analysis for 20 serum cardiometabolic biomarkers by multi-ancestry meta-analysis of 350,016 unrelated participants in the UK Biobank, identifying 182 independent locus-biomarker pairs (p < 4.5x10-9). Most vQTLs were concentrated in a small subset (4%) of loci with genome-wide significant main effects, and 44% replicated (p < 0.05) in the Womens Genome Health Study (N = 23,294). Next, we tested each vQTL for interaction across 2,380 exposures, identifying 846 significant GEIs (p < 2.4x10-7). Specific examples demonstrated interaction of triglyceride-associated variants with distinct body mass-versus body fat-related exposures as well as genotype-specific associations between alcohol consumption and liver stress at the ADH1B gene. Our catalog of vQTLs and GEIs is publicly available in an online portal.


title: Phase 2 dose-ranging study of the virologic efficacy and safety of the combination COVID-19 antibodies casirivimab and imdevimab in the outpatient setting

abstract:
BackgroundThe monoclonal antibody combination casirivimab and imdevimab (REGEN-COV(R)) reduced viral load, hospitalisation, or death when administered 1:1 as an intravenous (IV) dose [≥]1200 mg in a phase 3 COVID-19 outpatient study. Availability of subcutaneous (SC) and/or lower IV doses should increase accessibility and/or drug supplies for patients.

MethodsThis is a double-blind, placebo-controlled study of SARS-CoV-2-infected outpatients who were asymptomatic, or symptomatic but without risk factors for severe COVID-19. Patients were randomised to single IV dose (517 patients) of REGEN-COV 300, 600, 1200 or 2400 mg or placebo; or a single SC dose (286 patients) of REGEN-COV 600 or 1200 mg or placebo. The primary endpoint was time-weighted average daily change from baseline (TWACB) in viral load from day 1 (baseline) through day 7 in patients seronegative to SARS-CoV-2 at baseline.

FindingsAll REGEN-COV treatments showed significant (p<0{middle dot}001 versus pooled placebo) virologic reduction through day 7. Least-squares mean differences in TWACB viral load for the treatments versus placebo ranged from -0{middle dot}56 to -0{middle dot}71 log10 copies/mL. Each REGEN-COV treatment showed significant (p<0{middle dot}001 versus pooled placebo) and similar virologic reduction through day 7. There were no safety concerns, dose-related safety findings, grade [≥]2 infusion related/hypersensitivity reactions, grade [≥]3 injection-site reactions, nor fatalities. Two serious adverse events not related to COVID-19 or the study drug were reported.

InterpretationIn asymptomatic and low-risk symptomatic SARS-CoV-2-infected outpatients seronegative for antibodies against SARS-CoV-2 at baseline, REGEN-COV significantly and comparably reduced viral load at all IV and SC doses.

FundingRegeneron Pharmaceuticals, Inc. and Hoffman-La Roche

RESEARCH IN CONTEXTO_ST_ABSEvidence before this studyC_ST_ABSEarly phase 1/2 data in coronavirus disease 2019 (COVID-19) outpatients (NCT04425629) found that the REGEN-COV(R) antibody combination, casirivimab and imdevimab, administered 1:1 as a single intravenous (IV) dose of 2400 mg or 8000 mg significantly reduced viral load over the first week compared to placebo. Enhanced viral clearance was more pronounced in patients who were seronegative for antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), or who had high viral load at baseline. The phase 3 portion of this outpatient treatment study subsequently evaluated 1200 mg IV and 2400 mg IV doses, demonstrating consistent virologic efficacy, further demonstrating that REGEN-COV treatment reduced risk of COVID-19-related hospitalisation or all-cause death, and shortened time to symptom resolution. Virologic clearance was similar among those treated with any of the three doses (8000 mg, 2400 mg, or 1200 mg); therefore, maximal virologic efficacy may have been achieved at the 1200 mg dose in this treatment setting. These results warranted investigation of lower dose regimens.

Added value of this studyThe present dose-ranging study evaluated whether a lower dose regimen could demonstrate virologic efficacy similar to that observed with 1200 mg IV and 2400 mg IV doses in outpatient treatment study. Exploration of a wider dose range will provide further characterisation of the clinical effects of REGEN-COV. Moreover, identifying a lower efficacious dose could bolster the ability to provide an adequate therapeutic supply of REGEN-COV in the setting of a global pandemic. A 1200 mg subcutaneous (SC) dose of REGEN-COV also prevented COVID-19 in household contacts of SARS-CoV-2-infected individuals (NCT04452318). The availability of a SC regimen could improve access for patients who have confirmed SARS-CoV-2 infection but for who IV infusion is not feasible.

Implications of all the available evidenceDespite the growing number of therapeutics with authorisation or approval for the treatment and/or prevention of COVID-19, there remains a significant global need for effective COVID-19 therapies. Additional therapeutics and dosing regimens will be required to meet demand and to meet the needs of specific patient populations. Lower IV doses of REGEN-COV, and the option of SC administration, should increase accessibility for patients. This increased availability needs to be weighed against several unanswered questions, including 1) whether the correlation between decreased viral load in the nasopharynx and improvement in clinical outcome holds at lower doses of REGEN-COV, and 2) whether the reduced drug exposure margins are sufficient to prevent viral escape and emergence of variants of concern.


title: Cellular and Humoral Immunity to Ebola Zaire Glycoprotein and Viral Vector Proteins Following Immunization with Recombinant Vesicular Stomatitis Virus-Based Ebola Vaccine (rVSV{triangleup}G-EBOV-GP)

abstract: While effective at preventing Zaire ebolavirus (EBOV) disease, cellular immunity to EBOV and vector-directed immunity elicited by the recombinant vesicular stomatitis virus expressing Ebola glycoprotein (rVSV{Delta}G-EBOV-GP) vaccine remains poorly understood. Sera and peripheral blood mononuclear cells were collected from 32 participants enrolled in a prospective multicenter study [ClinicalTrials.gov NCT02788227] before vaccination and up to six months post-vaccination. IgM and IgG antibodies, IgG-producing memory B cells, and T cell reactivity to EBOV glycoprotein, vesicular stomatitis virus-Indiana strain (VSV-I) matrix protein, and VSV-I nucleoprotein were measured using ELISA, ELISpot, and intracellular cytokine staining, respectively. Eleven participants previously received a different investigational Ebola vaccine. All participants met positivity criteria for IgG antibodies to, and circulating IgG-producing memory B cells to, EBOV glycoprotein following rVSV{Delta}G-EBOV-GP vaccination. Transient IgM and IgG antibody responses to VSV-I matrix protein (n=1/32 and n=0/32, respectively) and nucleoprotein (n=2/32 and n=1/32, respectively) were infrequently detected, as were IgG-producing memory B cells recognizing VSV-I matrix protein (n=3/31) and nucleoprotein (n=2/31). CD4+ and CD8+ T cell responses to EBOV glycoprotein were present in 15/32 and 19/32 participants at baseline and in 32/32 and 23/32 participants one month post-vaccination, respectively. CD4+ and CD8+ T cell responses to VSV-I matrix protein (n=17/32 and n=16/32, respectively) and VSV-I nucleoprotein (n=23/32 for both CD4+ and CD8+ responses) were common post-vaccination. T cell responses were predominantly mono-cytokine, except CD8+ responses to EBOV glycoprotein among heterologous Ebola vaccine-experienced participants and CD8+ responses to VSV-I nucleoprotein. Overall, rVSV{Delta}G-EBOV-GP elicits robust humoral and memory B cell responses to EBOV glycoprotein in both Ebola vaccine-naive and heterologous Ebola vaccine-experienced individuals and can generate vector-directed T cell immunity. Further research is needed to understand the significance of pre-existing vector-directed immunity on responses to booster doses of rVSV{Delta}G-EBOV-GP and other rVSV-vectored vaccines.


title: Unexposed populations and potential COVID-19 burden in European countries

abstract: We estimate the potential remaining COVID-19 burden in 19 European countries by estimating the proportion of each countrys population that has acquired immunity to severe disease through infection or vaccination. Our results suggest that many European countries could still face a substantial burden of hospitalisations and deaths, particularly those with lower vaccination coverage, less historical transmission, and/or older populations. Continued non-pharmaceutical interventions and efforts to achieve high vaccination coverage are required in these countries to limit severe COVID-19 outcomes.


title: Unexposed populations and potential COVID-19 burden in European countries as of 21st November 2021


title: Characterization of the humoral immune response to BNT162b2 in elderly residents of long-term care facilities five to seven months after vaccination

abstract:
The elderly residing in long-term care facilities (LTCFs) are a group at high risk for COVID-19. Hence, monitoring of the vaccine-based immunity has a pivotal role in identifying strategies to provide optimal protection in this population. We examined the immune response to the mRNA vaccine BNT162b2 against COVID-19 five to seven months after completing a two-dose regimen.

We determined significantly lower anti-SARS-CoV-2 antibody titers in 298 SARS-CoV-2 naive residents who were at least 75 years of age (mean 51.60 BAU/ml) (median age 87 years, range 75 to 101 years) when compared to health care workers (HCWs) aged 18 to 70 years (mean 156.99 BAU/ml, p < 0.001). Of the SARS-CoV-2 naive residents, 29 had detectable neutralizing antibodies against the Delta variant (9.5%), and 14 of those (48.3%) only had a borderline titer of 1:10. Of 114 HCWs, 36 (31.6%) had detectable neutralizing antibodies. In a group of 14 elderly residents who had had a PCR-confirmed breakthrough infection, the mean antibody titer was significantly higher than in the other two groups (3199.65 BAU/mL) (p < 0.001), and 12 (85.7%) had detectable neutralizing antibodies against the Delta variant.

Our data demonstrate that 90.5% of elderly residents of LTCFs had no detectable neutralization-competent antibodies against the dominant Delta variant five to seven months after vaccination, and that neutralizing antibody titers were restored following a break-through infection. Our results suggest that both residents and health care workers in LTCFs would benefit from a booster vaccine six months after completing the two-dose schedule or earlier.


title: COVID-19 vaccinations: perceptions and behaviours in people with primary ciliary dyskinesia

abstract: Primary ciliary dyskinesia (PCD) is a rare genetic disease that causes recurrent respiratory infections. People with PCD may be at high risk of severe COVID-19 and vaccination against SARS-CoV-2 is therefore important. We studied vaccination willingness, speed of vaccination uptake, side effects, and changes in social contact behavior after vaccination in people with PCD. We used data from COVID-PCD, an international participatory cohort study. A questionnaire was e-mailed to participants in May 2021 that asked about COVID-19 vaccinations. 423 participants from 31 countries replied (median age: 30 years; 261 (62%) female). Vaccination uptake and willingness was high with 273 of 287 adults (96%) being vaccinated or willing to be in June 2021; only 4% were hesitant. The most common reasons for hesitancy were fear of side effects (reported by 88%). Mild side effects were common but no participant reported severe side effects. Half of participants changed their social contact behaviour after vaccination by seeing friends and family more often. The high vaccination willingness in the study population might reflect the extraordinary effort taken by PCD support groups to inform people about COVID-19 vaccination. Clear and specific public information and involvement of representatives is important for high vaccine uptake.


title: Genomic landscape of SARS-CoV-2 pandemic in Brazil suggests an external P.1 variant origin

abstract: Brazil was the epicenter of worldwide pandemics at the peak of its second wave. The genomic/proteomic perspective of the COVID-19 pandemic in Brazil can bring new light to understand the global pandemics behavior. In this study, we track SARS-CoV-2 molecular information in Brazil using real-time bioinformatics and data science strategies to provide a comparative and evolutive panorama of the lineages in the country. SWeeP vectors represented the Brazilian and worldwide genomic/proteomic data from GISAID between 02/2020 - 08/2021. Clusters were analyzed and compared with PANGO lineages. Hierarchical clustering provided phylogenetic and evolutionary analysis of the lineages, and we tracked the P.1 (Gamma) variant origin. The genomic diversity based on Chaos estimation allowed us to compare richness and coverage among Brazilian states and other representative countries. We found that epidemics in Brazil occurred in two distinct moments, with different genetic profiles. The P.1 lineages emerged in the second wave, which was more aggressive. We could not trace the origin of P.1 from the variants present in Brazil in 2020. Instead, we found evidence pointing to its external source and a possible recombinant event that may relate P.1 to the B.1.1.28 variant subset. We discussed the potential application of the pipeline for emerging variants detection and the stability of the PANGO terminology over time. The diversity analysis showed that the low coverage and unbalanced sequencing among states in Brazil could have allowed the silenty entry and dissemination of P.1 and other dangerous variants. This comparative and evolutionary analysis may help to understand the development and the consequences of the entry of variants of concern (VOC).


title: Viral kinetic modeling and clinical trial simulation predicts disruption of respiratory disease trials by non-pharmaceutical COVID-19 interventions

abstract: Clinical research in infectious respiratory diseases has been profoundly affected by non-pharmaceutical interventions (NPIs) against COVID-19. On top of trial delays or even discontinuation which have been observed in all disease areas, NPIs altered transmission pattern of many seasonal respiratory viruses which followed regular patterns for decades before the pandemic. Clinical trial design based on pre-pandemic historical data therefore needs to be put in question. In this article, we show how knowledge-based mathematical modeling can be used to address this issue. We set up an epidemiological model of respiratory tract infection (RTI) sensitive to a time dependent between-host transmission rate and coupled this model to a mechanistic description of viral RTI episodes in an individual patient. By reducing the transmission rate when the lockdown was introduced in the United Kingdom in March 2020, we were able to reproduce the perturbed 2020 RTI disease burden data. Using this setup, we simulated several NPIs scenarios of various strength (none, mild, medium, strong) and conducted placebo-controlled in silico clinical trials in pediatric patients with recurrent RTIs (RRTI) quantifying annual RTI rate distributions. In interventional arms, virtual patients aged 1-5 years received the bacterial lysate OM-85 (approved in several countries for the prevention of pediatric RRTIs) through a pro-type I immunomodulation mechanism of action described by a physiologically based pharmacokinetics and pharmacodynamics approach (PBPK/PD). Our predictions showed that sample size estimates based on the ratio of RTI rates (or the post-hoc power of fixed sample size trials) are not majorly impacted under NPIs which are less severe (none, mild and medium NPIs) than a strict lockdown (strong NPI). However, NPIs show a stronger impact on metrics more relevant for assessing the clinical relevance of the effect such as absolute benefit. This dichotomy shows the risk that successful trials (even with their primary endpoints being met) still get challenged in risk benefit assessment during the review of market authorization. Furthermore, we found that a mild NPI scenario already affected the time to recruit significantly when sticking to eligibility criteria complying with historical data. In summary, our model predictions can help rationalize and forecast post-COVID-19 trial feasibility. They advocate for gauging absolute and relative benefit metrics as well as clinical relevance for assessing efficacy hypotheses in trial design and they question eligibility criteria misaligned with the actual disease burden.


title: PBPK modelling of dexamethasone in patients with COVID-19 and liver disease

abstract: The aim of the study was to apply Physiologically-Based Pharmacokinetic (PBPK) modelling to predict the effect of liver disease (LD) on the pharmacokinetics (PK) of dexamethasone (DEX) in the treatment of COVID-19. A whole-body PBPK model was created to simulate 100 adult individuals aged 18-60 years. Physiological changes (e.g., plasma protein concentration, liver size, CP450 expression, hepatic blood flow) and portal vein shunt were incorporated into the LD model. The changes were implemented by using the Child-Pugh (CP) classification system. DEX was qualified using clinical data in healthy adults for both oral (PO) and intravenous (IV) administrations and similarly propranolol (PRO) and midazolam (MDZ) were qualified with PO and IV clinical data in healthy and LD adults. The qualified model was subsequently used to simulate a 6 mg PO and 20 mg IV dose of DEX in patients with varying degrees of LD, with and without shunting. The PBPK model was successfully qualified across DEX, MDZ and PRO. In contrast to healthy adults, the simulated systemic clearance of DEX decreased (35% - 60%) and the plasma concentrations increased (170% - 400%) in patients with LD. Moreover, at higher doses of DEX, the AUC ratio between healthy/LD individuals remained comparable to lower doses. The exposure of DEX in different stages of LD was predicted through PBPK modelling, providing a rational framework to predict PK in complex clinical scenarios related to COVID-19. Model simulations suggest dose adjustments of DEX in LD patients are not necessary considering the low dose administered in the COVID-19 protocol.

category: pharmacology and therapeutics


title: Plasma Soluble Tumor Necrosis Factor Receptor Concentrations and Clinical Events after Hospitalization: Findings from ASSESS-AKI and ARID studies

abstract:
BackgroundThe role of plasma soluble tumor necrosis factor receptor (sTNFR)1 and sTNFR2 in the prognosis of clinical events after hospitalization with or without acute kidney injury (AKI) is unknown.

MethodsWe measured sTNFR1 and sTNFR2 obtained 3 months post-discharge using samples from Assessment, Serial Evaluation, and Subsequent Sequelae of Acute Kidney Injury (ASSESS-AKI) and AKI Risk in Derby (ARID) that enrolled patients with and without AKI. The associations between biomarkers with longitudinal kidney disease incidence and progression, heart failure and death were evaluated. Analyses were adjusted for demographics and key covariates at the 3-month visit.

ResultsAmong 1474 participants with plasma biomarker measurements, 19% developed kidney disease progression, 14% had later heart failure, and 21% died over a median follow-up of 4.4 years. For the kidney outcome, the adjusted HRs per doubling in concentration were 2.9 (2.2-3.9) for sTNFR1 and 1.9 (1.5-2.5) for sTNFR2. AKI during the index hospitalization did not modify the association between biomarkers and kidney events. For heart failure, the adjusted HRs per doubling in concentration were 1.9 (1.4-2.5) for sTNFR1 and 1.5 (1.2-2.0) for sTNFR2. For mortality, the adjusted HRs were 3.3 (2.5-4.3) for sTNFR1 and 2.5 (2.0-3.1) for sTNFR2. The findings in ARID were qualitatively similar for the magnitude of association between biomarkers and outcomes.

ConclusionPlasma sTNFR1 and sTNFR2 measured 3 months after discharge were independently associated with clinical events, regardless of AKI status during the index admission. sTNFR1 and sTNFR2 may assist with the risk stratification of patients during follow-up.

Significance StatementSoluble tumor necrosis factor receptor 1 (sTNFR1) and sTNFR2 associate with kidney outcomes in patients with chronic kidney disease with and without diabetes mellitus. However, their role in the post-hospitalization stage is unknown. High sTNFR1 and sTNFR2 obtained 3 months after discharge associate with kidney events, heart failure hospitalizations, and death among patients who did and did not have acute kidney injury (AKI). Furthermore, sTNFRs provide discriminative value at the time of predicting kidney events. These findings were demonstrated in two large independent prospective cohorts. sTNFR1 and sTNFR2 may detect patients at risk of future adverse events even when patients do not meet the clinical criteria for AKI or exhibit biochemical abnormalities.

category: nephrology


title: Denoised VEGFR2 expression relates to sunitinib efficacy in advanced Clear Cell Renal Cell Carcinoma

abstract:
Short summaryPersonalized biomarkers can facilitate decision making upon multiple therapeutic options in ccRCC. VEGFR2 expression denoised with 37 normal and tumor gene-expressions relates to sunitinib effect whereas raw VEGFR2 expression doesnt relate to sunitinib effect.

BackgroundSeveral studies suggested that molecular analysis of patients with advanced clear cell renal cell carcinoma (ccRCC) could indicate whether a patient is susceptible of benefiting from sunitinib in first-line systemic treatment compared to immunotherapies. However, data remain conflicting and no predictive biomarker is validated so far to decipher if sunitinib could still represent a good therapeutic option in first line setting and beyond.

MethodsPREDMED(R) denoised the tumor RNA expression of 37 genes including KDR (encoding VEGFR2) estimated by RT-qPCR, by normalizing it on the expression of normal kidney tissue and cell types. We investigated the performance of PREDMED(R) VEGFR2-scoring to predict the clinical effect of sunitinib for patients affected by ccRCC.

ResultsAmong the 34 ccRCC patients samples retrospectively retrieved from the UroCCR project (NCT03293563), high VEGFR2 scores were associated with objective clinical responses under sunitinib treatment and low scores with stable disease or progression with a sensitivity of 86%, a specificity of 67% and an AUC of 72.5% (95%CI[50.1-94.9]; p=0.04). VEGFR2 scores were significantly and positively related to progression-free survival (HR = 0.465; 95%CI[0.221-0.978]; p=0.0311) and overall survival (HR = 0.400; 95%CI[0.192-0.834]; p=0.0134) under sunitinib treatment. In our cohort, raw VEGFR2 expression (before PREDMED(R) processing) was not related to the above mentioned outcomes.

ConclusionWe describe a gene-expression based algorithm that is accurately related to the effect of sunitinib for patients with ccRCC. We further plan a validation of PREDMED(R) for combinatorial strategies involving antiangiogenics and immune-checkpoint blockers.

category: oncology


title: Nanopore 16S rRNA sequencing reveals alterations in nasopharyngeal microbiome and enrichment of Mycobacterium and Mycoplasma in patients with COVID 19

abstract: The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) is a major global health concern. This virus infects the upper respiratory tract and causes pneumonia-like symptoms. So far, few studies have shown that respiratory infections alter nasopharyngeal (NP) microbiome diversity and enrich opportunistic pathogens. In this study, we have sequenced the 16S rRNA variable regions, V1 through V9, extracted from NP samples of control and COVID-19 (symptomatic and asymptomatic) participants using the Oxford Nanopore technology. Comprehensive bioinformatics analysis investigating the alpha/beta diversities, non-metric multidimensional scaling, correlation studies, canonical correspondence analysis, linear discriminate analysis, and dysbiosis index analysis revealed control and COVID-19-specific NP microbiomes. We observed significant dysbiosis in COVID-19 NP microbiome with abundance of opportunistic pathogens such as Cutibacterium, Corynebacterium, Oerskovia, and Cellulomonas in asymptomatic patients, and of Streptomyces and Mycobacteriaceae family in symptomatic patients. Furthermore, we observed sharp rise in enrichment of opportunistic pathogens in symptomatic patients, with abundance of Mycobacteria and Mycoplasma, which strongly correlated with the occurrences of chest pain and fever. Our findings contribute novel insights regarding emergence of opportunistic pathogens in COVID-19 patients and their relationship with symptoms, suggesting their potential role in coinfections.


title: Pathogens detected using a syndromic molecular diagnostic platform in patients hospitalized with severe respiratory illness in South Africa in 2017

abstract:
BackgroundPneumonia continues to be a leading cause of death globally; however, in >50% of cases, an etiological agent is not identified. We describe the use of a multi-pathogen platform, TaqMan array card (TAC) real-time PCR, for the detection of pathogens in patients hospitalized with severe respiratory illness (SRI).

MethodsWe conducted prospective hospital-based surveillance for SRI among patients at two sentinel sites in South Africa between January and December 2017. Patients were included in this study if a blood specimen and at least one respiratory specimen (naso- and oro-pharyngeal (NP/OP) swabs and/or sputum) were available for testing. We tested respiratory specimens for 21 respiratory pathogens and blood samples for nine bacteria using TAC. Pathogen detection was compared by age group and HIV status using the chi-squared test.

ResultsDuring 2017, 956 patients were enrolled in SRI surveillance, and of these, 637 (67%) patients were included in this study (637 blood, 487 NP/OP and 411 sputum specimens tested). At least one pathogen was detected in 83% (527/637) of patients. Common pathogens detected included H. influenzae (225/637; 35%), S. pneumoniae (224/637; 35%), rhinovirus (144/637; 23%), S. aureus (129/637; 20%), K. pneumoniae (85/637; 13%), M. tuberculosis (75/637; 12%), and respiratory syncytial virus (57/637; 9%). Multiple pathogens ([≥]2) were co-detected in 57% (364/637) of patients.

ConclusionWhile use of a multi-pathogen platform was useful in the detection of a pathogen in the majority of the patients, pathogen co-detections were common and would need clinical assessment for usefulness in individual-level treatment and management decisions.


title: Vaccine effectiveness against COVID-19 related hospital admission in the Netherlands: a test-negative case-control study

abstract:
IntroductionReal-world vaccine effectiveness (VE) estimates are essential to identify potential groups at higher risk of break-through infections and to guide policy. We assessed the VE of COVID-19 vaccination against COVID-19 hospitalization, while adjusting and stratifying for patient characteristics.

MethodsWe performed a test-negative case-control study in six Dutch hospitals. The study population consisted of adults eligible for COVID-19 vaccination hospitalized between May 1 and June 28 2021 with respiratory symptoms. Cases were defined as patients who tested positive for SARS-CoV-2 by PCR during the first 48 hours of admission or within 14 days prior to hospital admission. Controls were patients tested negative at admission and did not have a positive test during the 2 weeks prior to hospitalization. VE was calculated using multivariable logistic regression, adjusting for calendar week, sex, age, comorbidity and nursing home residency. Subgroup analysis was performed for age, sex and different comorbidities. Secondary endpoints were ICU-admission and mortality.

Results379 cases and 255 controls were included of whom 157 (18%) were vaccinated prior to admission. Five cases (1%) and 40 controls (16%) were fully vaccinated (VE: 93%; 95% CI: 81 - 98), and 40 cases (11%) and 70 controls (27%) were partially vaccinated (VE: 70%; 95% CI: 50-82). A strongly protective effect of vaccination was found in all comorbidity subgroups. No ICU-admission or mortality were reported among fully vaccinated cases. Of unvaccinated cases, mortality was 10% and 19% was admitted at the ICU

ConclusionCOVID-19 vaccination provides a strong protective effect against COVID-19 related hospital admission, in patients with and without comorbidity.


title: Comparing the performance of risk stratification scores in Brugada syndrome: a multi-centre study

abstract:
IntroductionThe management of Brugada Syndrome (BrS) patients at intermediate risk of arrhythmic events remains controversial. The present study evaluated the predictive performance of different risk scores in an Asian BrS population and its intermediate risk subgroup.

MethodsThis is a retrospective territory-wide cohort study of consecutive patients diagnosed with BrS from January 1st, 1997 to June 20th, 2020 in Hong Kong. The primary outcome is sustained ventricular tachyarrhythmias. A novel predictive score was developed. Machine learning-based nearest neighbor and Gaussian Naive Bayes models were also developed. The area under the receiver operator characteristic (ROC) curve (AUC) was compared between the different scores.

ResultsThe cohort consists of 548 consecutive BrS patients (7% female, age at diagnosis: 50{+/-}16 years old, follow-up duration: 84{+/-}55 months). For risk stratification in the whole BrS cohort, the score developed by Sieira et al. showed the best performance with an AUC of 0.805, followed by the Shanghai score (0.698), and the scores by Okamura et al. (0.667), Delise et al. (0.661), Letsas et al. (0.656) and Honarbakhsh et al. (0.592). A novel risk score was developed based on variables and weighting from the best performing score (the Sieira score), with the inclusion of additional variables significant on univariable Cox regression (arrhythmias other than ventricular tachyarrhythmias, early repolarization pattern in the peripheral leads, aVR sign, S-wave in lead I and QTc [≥]436 ms). This score has the highest AUC of 0.855 (95% CI: 0.808-0.901). The Gaussian Naive Bayes model demonstrated the best performance (AUC: 0.97) compared to logistic regression and nearest neighbor models.

ConclusionThe inclusion of investigation results and more complex models are needed to improve the predictive performance of risk scores in the intermediate risk BrS population.

category: cardiovascular medicine


title: Projecting vaccine demand and impact for emerging zoonotic pathogens

abstract: Despite large outbreaks in humans seeming improbable for a number of zoonotic pathogens, several pose a concern due to their epidemiological characteristics and evolutionary potential. To enable effective responses to these pathogens in the event that they undergo future emergence, the Coalition for Epidemic Preparedness Innovations is advancing the development of vaccines for several pathogens prioritized by the World Health Organization. A major challenge in this pursuit is anticipating demand for a vaccine stockpile to support outbreak response. We developed a modeling framework for outbreak response for emerging zoonoses under three reactive vaccination strategies. Annual vaccine regimen requirements for a population-wide strategy ranged from >670,000 (95% prediction interval: 0-3,630,000) regimens for Lassa virus to 1,190,000 (95% PrI: 0-8,480,000) regimens for Rift Valley fever virus, while the regimens required for ring vaccination or targeting healthcare workers (HCWs) were several orders of magnitude lower (between 1/25 and 1/700) than those required by a population-wide strategy. For each pathogen and vaccination strategy, reactive vaccination typically prevented fewer than 10% of cases, because of their presently low R0 values. Targeting HCWs had a higher per-regimen impact than population-wide vaccination. Our framework provides a flexible methodology for estimating vaccine stockpile needs and the geographic distribution of demand under a range of outbreak response scenarios.


title: Polygenic risk prediction and SNCA haplotype analysis in a Latino Parkinson's disease cohort

abstract:
BackgroundLarge-scale Parkinsons disease (PD) genome-wide association studies (GWAS) and meta-analyses have, until recently, only been conducted on subjects with European-ancestry. Consequently, polygenic risk scores (PRS) constructed using PD GWAS data are likely to be less predictive when applied to non-European cohorts.

MethodsUsing GWAS data from Nalls et al. 2019, we constructed a PD PRS for a Latino PD cohort (LARGE-PD) and tested it for association with PD status. We validated the PRS performance through testing the PD PRS in an independent cohort of Latino PD patients and by repeating the PRS analysis in LARGE-PD with the addition of 440 external Peruvian controls. To explore the global distribution of PD PRS, we utilized 1000 Genomes Project (1KGP) and Peruvian Genome Project (PGP) data to estimate PD risk allele frequencies. We also tested SNCA haplotypes for association with PD risk using logistic regression in LARGE-PD and a European-ancestry PD cohort from the International Parkinson Disease Genomics Consortium (IPDGC).

ResultsThe GWAS-significant PD PRS had an area under the receiver-operator curve (AUC) of 0.668 (95% CI: 0.640-0.695) and explained 2.2% of the phenotypic variance on the liability scale in LARGE-PD. The inclusion of external Peruvian data as controls mitigated this result, dropping the AUC 0.632 (95% CI: 0.607-0.657). In 1KGP Latinos, we found the PD PRS to exhibit a bias by ancestry. At the SNCA locus, haplotypes differ by ancestry. Ancestry-specific SNCA haplotypes were associated with PD status in both LARGE-PD and the IPDGC cohort (p-value < 0.05). Apart from rs356182, these haplotypes share as little as 14% of their variants.

ConclusionThe PD PRS has potential for PD risk prediction in Latinos, but variability caused by admixture patterns and bias in the PD PRS calculated using only European-ancestry data limits its utility. The inclusion of diverse subjects can help elucidate PD risk loci and improve risk prediction in non-European cohorts. In the case of the SNCA locus, by leveraging a Latino cohort, we provide orthogonal evidence for rs356182 causality.


title: Globally elevated excitation-inhibition ratio in children with autism spectrum disorder and below-average intelligence

abstract:
BACKGROUNDAn altered balance of neuronal excitation and inhibition (E-I balance) might be implicated in the co-occurrence of autism and intellectual disability, but this hypothesis has never been tested. E-I balance changes can be estimated from the spectral slope of the aperiodic 1/f neural activity. Herein, we used magnetoencephalography (MEG) to test whether the 1/f slope would differentiate ASD children with and without intellectual disability.

METHODSMEG was recorded at rest with eyes open/closed in 49 boys with ASD aged 6-15 years with a broad range of IQs, and in 49 age-matched typically developing (TD) boys. The cortical source activity was estimated using the LCMV beamformer approach. We then extracted the 1/f slope by fitting a linear function in to the log-log-scale power spectra in the high-frequency range.

RESULTSThe grand averaged 1/f slope was steeper in the eyes closed than in the eyes open condition, but had high rank-order stability between them. In line with the previous research, the slope flattened with age. Children with ASD and below-average (<85) IQ had flatter slopes than either TD or ASD children with average IQ. These group differences could not be explained by differences in signal-to-noise ratio or periodic (alpha and beta) activity.

CONCLUSIONSThe atypically flattened spectral slope of aperiodic activity in children with ASD and below-average IQ suggests a shift of the global E-I balance toward hyper-excitation. The spectral slope can provide an accessible non-invasive biomarker of the E-I ratio for translational research and making objective judgments about treatment effectiveness.

category: psychiatry and clinical psychology


title: Feasibility and acceptability of Narrative Exposure Therapy to treat individuals with PTSD who are homeless or vulnerably housed: A pilot randomized controlled trial.

abstract:
BackgroundAnnually, there are least 235,000 individuals experiencing homelessness in Canada. These individuals are more likely to have complex health issues, including mental health issues such as post-traumatic stress disorder (PTSD). Diagnosed PTSD rates in the homeless are more than double that of the general population, ranging between 21% and 53%. In the homeless population, complex PTSD (cPTSD) appears to be more common than PTSD. One treatment option for cPTSD is Narrative Exposure Therapy (NET), a brief trauma focused psychotherapy which attempts to place the trauma within a narrative of the persons life. Previous studies suggest NET may be an effective option for those who are homeless. In this study, our primary aim was to assess the feasibility and acceptability of delivering community-based NET to individuals with PTSD who were homeless or vulnerably housed.

MethodsThis pilot randomized controlled trial (RCT) enrolled participants who were 18 years of age or older, currently homeless or vulnerably housed, and with active symptoms of PTSD. Participants were randomized to either NET alone or NET plus the addition of a genealogical assessment. Demographic and clinical data were collected at the baseline visit. Symptoms of PTSD, drug use and housing status were re-assessed at follow-up visits. Rates of referral, consent and retention were also examined as part of feasibility.

ResultsTwenty-two potential participants were referred to the study. Six were not able to be contacted, one was excluded prior to contact, and the remaining 15 consented to participate. Of these, one was a screen failure and 14 were randomized equally to the treatment arms. One randomized participant was withdrawn for safety. The main point of attrition was prior to starting therapy (3/13). Once therapy was initiated, retention was high with 80% of participants completing all six sessions of therapy. Seven participants completed all follow-up sessions.

ConclusionDelivering NET in a community-based setting and completing genealogical assessments was both feasible and acceptable to those who are homeless or vulnerably housed. Once therapy had been initiated, participants were likely to stay engaged. A large RCT should be conducted to evaluate effectiveness and feasibility on an increased scale.

Trial Registrationclinicaltrials.gov, identifier NCT03781297. Registered: December 19, 2018, https://clinicaltrials.gov/ct2/show/NCT03781297.

Key messages regarding feasibilityO_LIWhat uncertainties existed regarding the feasibility?
Narrative Exposure Therapy (NET) is an individual trauma focused psychotherapy recommended in guidelines for the treatment of post-traumatic stress disorder (PTSD). However, in people who are homeless or vulnerably housed, there have been no randomised controlled trials of trauma focused therapies for PTSD. We wanted to find out if it was feasible to recruit and retain people who were homeless with PTSD in a randomized controlled trial of a trauma informed therapy. We wanted to test the acceptability and feasibility of offering NET alone compared to NET plus a genealogical assessment. We also wanted to see if it was acceptable and practical to incorporate a genealogical assessment as part of NET.
C_LIO_LIWhat are the key feasibility findings?
The key feasibility finding is that it is feasible to recruit and retain people who are homeless into a randomized controlled trial of a trauma informed therapy. However, recruitment could be improved by a better process for engaging potential participants between referral and enrollment as about a third of the referred population were lost at this stage. Not having trained therapists available also delayed recruitment.
C_LIO_LIWhat are the implications of the feasibility findings for the design of the main study?
We will explicitly develop materials for use at the referral step by potential referrers. This will include an online training video which will address issues of trust and how to address them when discussing the potential study. We will also develop a process for training and recruiting therapists. Since this study was completed, we have done two further training workshops to create a pool of potential therapists in Ottawa. We will also engage with another site in Ontario to widen the population base of potential participants.
C_LI


title: Understanding the association between mental health knowledge and mental health service utilization among Black adults

abstract: Mental health knowledge limitations may contribute to the treatment gap among Black adults. We conducted an online cross-sectional study of Black adults in the United States (n = 262, aged 18-65 years) from diverse ethnic backgrounds (African-Americans, African immigrants, Afro-Caribbean immigrants). Gamma regression using generalized linear models was used to estimate the associations between mental health knowledge and willingness to seek help from mental health professionals. After adjusting for age, education and ethnicity, participants with higher specific knowledge about mental health (such as recognition of schizophrenia as a mental illness) were 26% more likely to report willingness to seek help from a mental health professional for personal and emotional problems (RR = 1.26, CI: 1.12 - 1.41, p < 0.001). Knowledge building interventions (such as psychoeducation) that seek to increase specific knowledge (rather than general knowledge) may correlate more strongly with utilization of mental health services among Black adults.


title: Perspectives on mental illness stigma among African immigrant pregnant and post-partum women in an urban setting: a brief report

abstract:
PurposeThis study assessed the perspectives of pregnant and post-partum African immigrant women on mental illness.

MethodsWe conducted a focus group session (N=14) among pregnant and postpartum African immigrant women in June 2020. We used an inductive driven thematic analysis to identify themes related to mental health stigma.

ResultsFive core themes emerged: conceptualization of mental health, community stigmatizing attitudes, biopsychosocial stressors, management of mental health and methods to reduce stigma.

ConclusionUnderstanding the perspectives of pregnant African immigrant women at the intersection of their race, ethnicity, gender and migration is necessary to improve engagement with mental health services.


title: Cerebellar and Prefrontal Structures Associated with Executive Functioning in Pediatric Patients with Congenital Heart Defects

abstract:
ObjectiveChildren, adolescents, and young adults with congenital heart defects (CHD) often display cognitive and behavioral manifestations of executive dysfunction. We consider the prefrontal and cerebellar brain structures as mechanisms for executive dysfunction among those with CHD.

Method55 participants with CHD (M age = 13.93) and 95 healthy controls (M age = 13.13) completed magnetic resonance imaging (MRI) of the brain, from which we extracted volumetric data on prefrontal and cerebellar regions. Participants also completed neuropsychological tests of executive functioning; their parents completed behavioral ratings of their executive functions.

ResultsCompared to healthy controls, those with CHD had smaller cerebellums and lateral, medial, and orbital prefrontal regions, they performed more poorly on tests of working memory, inhibitory control, and mental flexibility, and their parents rated them as having poorer executive functions across several indices. Across both groups, there were significant correlations for cerebellar and/or prefrontal volumes with cognitive assessments of working memory, mental flexibility, and inhibitory control and with behavioral ratings of working memory, task initiation, and emotional control. Greater prefrontal volumes were associated with better working memory, among those with larger cerebellums (with group differences based on the measure and the prefrontal region). Greater prefrontal volumes were related to better emotional regulation only among participants with CHD with smaller cerebellar volumes, and with poorer inhibition and emotional regulation only among healthy controls with larger cerebellar volumes.

ConclusionThe cerebellum modulates the relationships between prefrontal regions and executive functioning differently for pediatric patients with CHD versus health controls.


title: Exploiting convergent evolution to derive a pan-cancer cisplatin sensitivity gene expression signature

abstract:
Precision medicine offers remarkable potential for the treatment of cancer, but is largely focused on tumors that harbor actionable mutations. Gene expression signatures can expand the scope of precision medicine by predicting response to traditional (cytotoxic) chemotherapy agents without relying on changes in mutational status. We present a novel signature extraction method, inspired by the principle of convergent evolution, which states that tumors with disparate genetic backgrounds may evolve similar phenotypes independently. This evolutionary-informed method can be utilized to produce signatures predictive of response to over 200 chemotherapeutic drugs found in the Genomics of Drug Sensitivity in Cancer Database. Here, we demonstrate its use by extracting the Cisplatin Response Signature, CisSig, for use in predicting a common trait (sensitivity to cisplatin) across disparate tumor subtypes (epithelial-origin tumors). CisSig is predictive of cisplatin response within the cell lines and clinical trends in independent datasets of tumor samples. Finally, we demonstrate preliminary validation of CisSig for use in muscle-invasive cancer, predicting overall survival in patients who undergo cisplatin-containing chemotherapy. This novel methodology can be used to produce robust signatures for the prediction of traditional chemotherapeutic response, dramatically increasing the reach of personalized medicine in cancer.

Translational RelevanceMost precision medicine research focuses on using targeted drugs on patients with known driver mutations, yet the majority of patients dont have actionable mutations. Using a novel signature extraction method, we produce the Cisplatin Response Signature (CisSig) to predict how well patients with epithelial-origin tumors will respond to cisplatin, a common cytotoxic chemotherapy. We show that expression of CisSig is correlated to clinical trends of cisplatin use in treatment guidelines using independent tumor databases. Then, we look at preliminary validation of CisSig for use in patients with muscle-invasive bladder cancer. Using two independent cohorts of pre-treatment tumor samples, we show that a CisSig-trained model is predictive of overall survival in patients who did receive cisplatin, but this signal is lost in patients who did not receive cisplatin-indicating that the model is predictive of therapeutic response, not simply prognosis.


title: Economic analyses of interventions for student mental health and wellbeing: protocol for a systematic review

abstract:
BackgroundStudents in higher education exhibit higher rates of mental health problems than the general population and often lack access to effective treatments and services. The COVID-19 pandemic has exacerbated already high levels of need. Policymakers must have the relevant evidence to inform resource allocation and investment decisions about student mental health services.

AimWe aim to identify and summarise economic analyses of interventions to prevent and treat mental health problems in university students in terms of the studies findings and the methods used.

MethodWe will review all published economic analyses relating to interventions designed to prevent or treat student mental health problems. We will search the following databases: PubMed, MEDLINE, Embase, Web of Science, EconLit, PsycINFO and the National Health Service Economic Evaluation Databases (NHS EED). The review will be conducted following PRISMA guidelines. Key data items relating to the methods and results of the included studies will be extracted, and the resulting database will be made publicly available.

RegistrationThis review is registered on PROSPERO (ID CRD42021250228)

FundingThis research is funded by UK Research and Innovation (grant number ES/S00324X/1).

category: health economics


title: Evaluating Digital Device Technology in Alzheimer's Disease via Artificial Intelligence

abstract: The use of digital technologies may help to diagnose Alzheimers Disease (AD) at the pre-symptomatic stage. However, before implementation into clinical practice, digital measures (DMs) need to be evaluated for their diagnostic benefit compared to established questionnaire-based assessments, such as the Mini-Mental State Examination (MMSE) for cognition and Functional Activity Questionnaire (FAQ) for daily functioning. Moreover, the quantitative and qualitative relationship of DMs to these well understood scores needs to be clarified to aid interpretation. In this work we analyzed data from 148 subjects, 58 cognitively normal and 90 at different stages of the disease, which had performed a smartphone based virtual reality game to assess cognitive function. In addition, we used clinical data from Alzheimers Disease Neuroimaging Initiative (ADNI). We employed an Artificial Intelligence (AI) based approach to elucidate the relationship of DMs to questionnaire-based cognition and functional activity scores. In addition, we used Machine Learning (ML) and statistical methods to assess the diagnostic benefit of DMs compared to questionnaire-based scores. We found non-trivial relationships between DMs, MMSE, and FAQ which can be visualized as a complex network. DMs, in particular those reflecting scores of individual tasks in the virtual reality game, showed a better ability to discriminate between different stages of the disease than questionnaire-based methods. Our results indicate that DMs have the potential to act as a crucial measure in the early diagnosis and staging of AD.

category: health informatics


title: Purchasing high-cost medical equipment in hospitals: A systematic review

abstract:
ObjectivesTo systematically review academic literature for empirical studies on any processes, procedures, methods or approaches to purchasing high-cost medical equipment within hospitals in high-income countries.

DesignSystematic review

MethodsOn 13 August 2020, we searched the following from inception: Cost-Effectiveness Analysis Registry, EconLit and ProQuest Dissertations & Theses A&I via ProQuest, Embase, MEDLINE, and MEDLINE in Process via Ovid SP, Google and Google Scholar, Health Management and Policy Database via Ovid SP, IEEE Xplore Digital Library, International HTA Database, NHS EED via CRD Web, Science Citation Index-Expanded, Conference Proceedings Citation Index-Science, and Emerging Sources Citation Index via Web of Science, Scopus, and Zetoc conference search. Studies were included if they described the approach to purchasing (also known as procurement or acquisition) of high-cost medical devices and/or equipment conducting within hospitals in high-income countries between 2000-2020. Studies were screened, data extracted, and summarised.

ResultsOf 9437 records, 24 were included, based in 12 different countries and covering equipment types ranging from surgical robots to MRI scanners and orthopaedic implants. Study types included descriptions of processes taking place within or across hospitals (n=14), out of which three reported cost savings; empirical studies in which hospital records or participant data were analysed (n=8), and evaluations or pilots of proposed purchasing processes (n=2). Studies mainly highlight the importance of multidisciplinary involvement (especially clinical engineers and clinicians) in purchasing decision-making to balance technical, financial, safety and clinical aspects of device selection, and the potential of increasing evidence-based decisions using approaches ranging from hospital-based health technology assessments, ergonomics, to conducting user  trials of the device in use before purchase.

ConclusionsWe highlight the lack of rigorous empirical work on this topic, calling for more intervention based and empirical work to advance the evidence base in this domain to advance knowledge, policy and practice.

Strengths and limitations of this study- First systematic review of empirical work conducted in hospitals on purchasing of high-cost medical devices
- Broad search covering a range of disciplines and study types
- Limited to high-cost equipment which is challenging to differentiate across studies and has no standardised  value globally

category: health systems and quality improvement


title: Ultrafast RNA extraction-free SARS-CoV-2 detection by direct RT-PCR using a rapid thermal cycling approach

abstract: The surging COVID19 pandemic has underlined the need for quick, sensitive, and high-throughput SARS-CoV-2 detection assays. Although many different methods to detect SARS-CoV-2 particles in clinical material have been developed, none of these assays are successful in combining all three of the above characteristics into a single, easy-to-use method that is suitable for large-scale use. Here we report the development of a direct RT-PCR SARS-CoV-2 detection method that can reliably detect minute quantities of SARS-CoV-2 gRNA in nasopharyngeal swab samples as well as the presence of human genomic DNA. An extraction-less validation protocol was carried out to determine performance characteristics of the assay in both synthetic SARS-CoV-2 RNA as well as clinical specimens. Feasibility of the assay and analytical sensitivity was first determined by testing a dilution series of synthetic SARS-CoV-2 RNA in two different solvents (water and AMIES VTM), revealing a high degree of linearity and robustness in fluorescence readouts. Following analytical performance using synthetic RNA, the limit of detection was determined at equal to or less than 1 SARS-CoV-2 copy/ul of sample in a commercially available sample panel that contains surrogate clinical samples with varying SARS-CoV-2 viral load. Lastly, we benchmarked our method against a reference qPCR method by testing 87 nasopharyngeal swab samples. The direct endpoint ultra-fast RT-PCR method exhibited a positive percent agreement score of 98.5% and a negative percent agreement score of 100% as compared to the reference method, while RT-PCR cycling was completed in 27 minutes/sample as opposed to 60 minutes/sample in the reference qPCR method. In summary, we describe a rapid direct RT-PCR method to detect SARS-CoV-2 material in clinical specimens which can be completed in significantly less time as compared to conventional RT-PCR methods, making it an attractive option for large-scale SARS-CoV-2 screening applications.


title: Divergent lineages of pathogenic Leptospira species are widespread and persisting in the environment in Puerto Rico, USA

abstract:
BackgroundLeptospirosis, caused by Leptospira bacteria, is a common zoonosis worldwide more prevalent in the tropics. Reservoir species and risk factors have been identified but surveys for environmental sources of leptospirosis are rare. Furthermore, understanding of environmental Leptospira containing pathogenic genes and possibly capable of causing disease is incomplete and could result in some pathogenic strains evading detection, thereby convoluting diagnosis, prevention, and epidemiology.

Methodology/Principal FindingsWe collected environmental samples from 22 sites in Puerto Rico during three sampling periods over 14-months (Dec 2018-Feb 2020); 10 water and 10 soil samples were collected at each site. Samples were screened for pathogenic Leptospira DNA using the lipL32 PCR assay and positive samples were sequenced to assess genetic diversity. One urban site in San Juan was sampled three times over 14 months to assess persistence in soil; live leptospires were obtained during the last sampling period. Isolates were whole genome sequenced and LipL32 expression was assessed in vitro.

We detected pathogenic Leptospira DNA at 15/22 sites; both soil and water were positive at 5/15 sites. We recovered lipL32 sequences from 83/86 positive samples (15/15 positive sites) and secY sequences from 32/86 (10/15 sites); multiple genotypes were identified at 12 sites. These sequences revealed significant diversity across samples, including four novel lipL32 phylogenetic clades. Most samples from the serially sampled site were lipL32 positive at each time point. We sequenced the genomes of six saprophytic and two pathogenic Leptospira isolates; the latter represent a novel pathogenic Leptospira species likely belonging to a new serogroup.

Conclusions/SignificanceDiverse and novel pathogenic Leptospira are widespread in the environment in Puerto Rico. The disease potential of the novel lineages is unknown but several persisted for >1 year in soil, which could contaminate water. This work increases understanding of environmental Leptospira and should improve leptospirosis surveillance and diagnostics.

Author SummaryLeptospirosis is a common zoonotic disease worldwide, but more prevalent in the tropics. Cases are more common following severe weather events, possibly due to flooding, which may more readily distribute soil and/or water contaminated with Leptospira spp., the disease agents. Human cases increased following the 2017 hurricanes that ravaged Puerto Rico (Maria and Irma), prompting environmental sampling of soil and water to assess the presence, abundance, and persistence of pathogenic leptospires in these environments. The goal was to better understand these potential reservoirs of human and animal disease. Divergent and novel groups of pathogenic Leptospira were abundant and widespread in soil and water in Puerto Rico and sometimes persisted in these environments for >1 year. However, most groups we identified have not previously been described from humans and/or other animals, so the disease potential of these novel organisms is unknown. The results of this study reveal a tremendous amount of previously uncharacterized Leptospira diversity in soil and water in Puerto Rico, which could contribute to cryptic disease. The description and characterization of these novel types improves our understanding of the genus Leptospira, and will aid in the developent of improved diagnostics and preventative tools to advance public health outcomes.


title: Evaluation of methods for whole genome sequencing of Enterococcus faecium in a diagnostic laboratory

abstract:
Enterococcus faecium is an important nosocomial pathogen associated with hospital transmission and outbreaks. Based on growing evidence that bacterial whole genome sequencing enhances hospital outbreak investigation of other bacterial species, our aim was to develop and evaluate methods for low volume clinical sequencing of E. faecium. Using a test panel of 22 E. faecium isolates associated previously with hospital transmission, we developed laboratory protocols for DNA extraction and library preparation, which in combination with the Illumina MiniSeq can generate sequence data within 24 hours. The final laboratory protocol took 3.5 hours and showed 98% reproducibility in producing sufficient DNA for sequencing. Repeatability and reproducibility assays based on the laboratory protocol and sequencing demonstrated 100% accuracy in assigning species, sequence type (ST) and (when present) detecting vanA or vanB, with all isolates passing the quality control metrics. Minor variation was detected in base calling of the same isolate genome when tested repeatedly due to variations in mapping and base calling, but application of a SNP cut-off ([≤]15 SNPs) to assign isolates to outbreak clusters showed 100% reproducibility. An evaluation of contamination showed that controls and test E. faecium sequence files contained <0.34% and <2.12% of fragments matching another species, respectively. Deliberate contamination experiments confirmed that this was insufficient to impact on data interpretation. Further work is required to develop informatic tools prior to implementation into clinical practice.

ImportanceEnterococcus faecium is a leading cause of hospital infections, particularly in the immunocompromised, and has been shown to be associated with hospital transmissions. Whole-genome sequencing is a highly discriminatory technique that has been shown to be capable of identifying transmissions that may otherwise go undetected by conventional infection control methods. This could be a powerful adjunct to infection control, since previous studies have shown that there are numerous hospital outbreaks of E. faecium, which can extend over multiple wards and years. In this study, we developed and evaluated laboratory methods for low volume clinical sequencing of E. faecium, to allow uptake in smaller local diagnostic laboratories. We demonstrated that sequencing could be performed within 24-48 hours of the sample flagging positive. This would allow a more rapid turnaround time, compared to sending isolates to the reference laboratory, providing an opportunity for infection control to act earlier to prevent further transmission.


title: Mono- and bi-allelic effects of coding variants on disease in 176,899 Finns

abstract: Identifying Mendelian diseases with recessive inheritance is challenging as the majority of cases are caused by compound heterozygous genotypes which require sequencing data in families to definitively identify. Bottleneck events, such as in the Finnish population, enrich specific homozygous variants to higher frequencies and thus facilitate identification of disease associations through easily recognized homozygous genotypes. Here, we study homozygous and heterozygous effects of 82,516 coding variants on 2,444 disease endpoints using nationwide electronic health record (EHR) data of 176,899 Finns. We find known and novel associations to homozygous genotypes across a broad spectrum of phenotypes such as retinal dystrophy, adult-onset cataract and female infertility (13/20 of which would have been missed by the traditional additive GWAS model). With these results, and supporting simulations, we demonstrate the added benefit of homozygous scans in GWAS. We further use these results to explore inheritance patterns of known Mendelian variants. We find many Mendelian variants whose inheritance cannot be adequately described with the traditional definition of dominant or recessive. In particular, we find disease risk in heterozygous carriers of variants known to cause disease with recessive inheritance, as well as for variants labeled benign in ClinVar. Our results demonstrate how biobank efforts, particularly in founder populations, can broaden our understanding of the impact of genetic variants.


title: Plasma biomarkers associated with survival and thrombosis in hospitalized COVID-19 patients

abstract: Severe coronavirus disease-19 (COVID-19) has been associated with fibrin-mediated hypercoagulability and thromboembolic complications. To evaluate potential biomarkers of coagulopathy and disease severity in COVID-19, we measured plasma levels of eight biomarkers potentially associated with coagulation, fibrinolysis, and platelet function in 43 controls and 63 COVID-19 patients, including 47 patients admitted to the intensive care unit (ICU) and 16 non-ICU patients. COVID-19 patients showed significantly elevated levels of fibrinogen, tissue plasminogen activator (t-PA), and its inhibitor plasminogen activation inhibitor 1 (PAI-1), as well as ST2 (the receptor for interleukin 33) and von Willebrand factor (vWF) compared to the control group. We found that higher levels of t-PA, ST2, and vWF at the time of admission were associated with lower survival rates, and that thrombotic events were more frequent in patients with initial higher levels of vWF. These results support a predictive role of specific biomarkers such as t-PA and vWF in the pathophysiology of COVID-19. The data provide support for the case that hypercoagulability in COVID-19 is fibrin-mediated, but also highlights the important role that vWF may play in the genesis of thromboses in the pathophysiology of COVID-19. Interventions designed to enhance fibrinolysis and reduce platelet aggregation might prove to be useful adjuncts in the treatment of coagulopathy in a subset of COVID-19 patients.

category: hematology


title: Rapid, Reliable and Robust approach for extraction-free RT-PCR based detection of SARS-CoV-2 in clinical setting to expedite large scale screening

abstract: Rapid, reliable and robust method for the detection of SARS-CoV-2 is an indispensable need for diagnostics. The development of diagnostic method will aid to address further waves of the pandemic potentially with rapid surveillance of disease; and to allay the fears. To meet this challenge, we have developed a rapid RT-qPCR method for the detection of 3 target genes or confirmatory genes in less than 30 minutes. The assay showed 100% sensitivity and 100% specificity when tested on 120 samples. We compared a conventional extraction based method with extraction-free method, and then further reduced the run time of extraction free method. Additionally, we have validated our rapid RT-qPCR method for the assessment of pooled sample. We hereby propose a most reliable approach for the mass screening of samples with ease of operation at low cost. Finally we designed a single tube analysis method which provides qualitative as well as quantitative results in minimum time.


title: SARS-CoV-2 RNA is enriched by orders of magnitude in solid relative to liquid wastewater at publicly owned treatment works

abstract: Wastewater-based epidemiology has gained attention throughout the world for detection of SARS-CoV-2 RNA in wastewater to supplement clinical testing. Methods have been developed using both the liquid and the solid fraction of wastewater, with some studies reporting higher concentrations in solids. To investigate this relationship further, we collaborated with six other laboratories to conduct a study across five publicly owned treatment works (POTWs) where both primary solids and raw wastewater influent samples were collected and quantified for SARS-CoV-2 RNA. Solids and influent samples were processed by participating laboratories using their respective methods and retrospectively paired based on date of collection. SARS-CoV-2 RNA concentrations by mass (gene copies per gram) were higher in solids than in influent by approximately three orders of magnitude. Concentrations in matched solids and influent were positively and significantly correlated at all five POTWs. RNA concentrations in both solids and influent were correlated to COVID-19 incidence rates in the sewershed and thus representative of disease burden; the solids methods appeared to produce a comparable relationship between SARS-CoV-2 RNA concentration measurements and incidence rates across all POTWs. Solids and influent methods showed comparable sensitivity, N gene detection frequency, and calculated empirical incidence rate lower limits. Analysis of solids has the advantage of using less sample volume to achieve similar sensitivity to influent methods.


title: SARS-CoV-2 reinfection trends in South Africa: analysis of routine surveillance data

abstract:
IntroductionGlobally, there have been more than 404 million cases of SARS-CoV-2, with 5.8 million confirmed deaths, as of February 2022. South Africa has experienced four waves of SARS-CoV-2 transmission, with the second, third, and fourth waves being driven by the Beta, Delta, and Omicron variants, respectively. A key question with the emergence of new variants is the extent to which they are able to reinfect those who have had a prior natural infection.

RationaleWe developed two approaches to monitor routine epidemiological surveillance data to examine whether SARS-CoV-2 reinfection risk has changed through time in South Africa, in the context of the emergence of the Beta (B.1.351), Delta (B.1.617.2), and Omicron (B.1.1.529) variants. We analyze line list data on positive tests for SARS-CoV-2 with specimen receipt dates between 04 March 2020 and 31 January 2022, collected through South Africas National Notifiable Medical Conditions Surveillance System. Individuals having sequential positive tests at least 90 days apart were considered to have suspected reinfections. Our routine monitoring of reinfection risk included comparison of reinfection rates to the expectation under a null model (approach 1) and estimation of the time-varying hazards of infection and reinfection throughout the epidemic (approach 2) based on model-based reconstruction of the susceptible populations eligible for primary and second infections.

Results105,323 suspected reinfections were identified among 2,942,248 individuals with laboratory-confirmed SARS-CoV-2 who had a positive test result at least 90 days prior to 31 January 2022. The number of reinfections observed through the end of the third wave in September 2021 was consistent with the null model of no change in reinfection risk (approach 1). Although increases in the hazard of primary infection were observed following the introduction of both the Beta and Delta variants, no corresponding increase was observed in the reinfection hazard (approach 2). Contrary to expectation, the estimated hazard ratio for reinfection versus primary infection was lower during waves driven by the Beta and Delta variants than for the first wave (relative hazard ratio for wave 2 versus wave 1: 0.71 (CI95: 0.60-0.85); for wave 3 versus wave 1: 0.54 (CI95: 0.45-0.64)). In contrast, the recent spread of the Omicron variant has been associated with an increase in reinfection hazard coefficient. The estimated hazard ratio for reinfection versus primary infection versus wave 1 was 1.75 (CI95: 1.48-2.10) for the period of Omicron emergence (01 November 2021 to 30 November 2021) and 1.70 (CI95: 1.44-2.04) for wave 4 versus wave 1. Individuals with identified reinfections since 01 November 2021 had experienced primary infections in all three prior waves, and an increase in third infections has been detected since mid-November 2021. Many individuals experiencing third infections had second infections during the third (Delta) wave that ended in September 2021, strongly suggesting that these infections resulted from immune evasion rather than waning immunity.

ConclusionPopulation-level evidence suggests that the Omicron variant is associated with substantial ability to evade immunity from prior infection. In contrast, there is no population-wide epidemiological evidence of immune escape associated with the Beta or Delta variants. This finding has important implications for public health planning, particularly in countries like South Africa with high rates of immunity from prior infection. Further development of methods to track reinfection risk during pathogen emergence, including refinements to assess the impact of waning immunity, account for vaccine-derived protection, and monitor the risk of multiple reinfections will be an important tool for future pandemic preparedness.

category: epidemiology


title: Increased risk of SARS-CoV-2 reinfection associated with emergence of the Omicron variant in South Africa


title: Increased risk of SARS-CoV-2 reinfection associated with emergence of Omicron in South Africa


title: A Mathematical Model for Stability Analysis of Covid like Epidemic/Endemic/Pandemic

abstract: The transmission and spread of infectious disease like Covid-19 occurs through horizontal and vertical mode. The causative pathogens for such kind of disease may be bacterium, protozoa, virus or toxin. The infectious diseases like AIDS, SARS, MARS, Polio Plague, Bubonic Plague and Covid-19 have destroyed the social and economic structure of world population. The world scientific community adopts different mechanisms to model and analyse the population dynamics of infectious disease outbreaks. Mathematical Modelling is the most effective tool to take the informed decision about the containment, control and eradication of the pandemic. The main focus of Government and public health authorities is to design the strategy in destabilising the spread and impact of the infections. A series of models-SIR, SEIR, SEIRD, SEAIHCRD, SAUQAR has been under study to combat the Covid-19 since its inception. An effort has been made to design the model based on reproduction number, endemic equilibrium and disease-free equilibrium to curtail the impact of Covid-19 through stability analysis methods-Hurwitz stability criteria, Lyapunov Method and Linear Stability Analysis.