title: Head-to-head comparison of nasal and nasopharyngeal sampling using SARS-CoV-2 rapid antigen testing in Lesotho

abstract:
ObjectivesTo assess the real-world diagnostic performance of nasal and nasopharyngeal swabs for SD Biosensor STANDARD Q COVID-19 Antigen Rapid Diagnostic Test (Ag-RDT).

MethodsIndividuals [≥]5 years with COVID-19 compatible symptoms or history of exposure to SARS-CoV-2 presenting at hospitals in Lesotho received two nasopharyngeal and one nasal swab. Ag-RDT from nasal and nasopharyngeal swabs were performed as point-of-care on site, the second nasopharyngeal swab used for polymerase chain reaction (PCR) as the reference standard.

ResultsOut of 2198 participants enrolled, 2131 had a valid PCR result (61% female, median age 41 years, 8% children), 84.5% were symptomatic. Overall PCR positivity rate was 5.8%. The sensitivity for nasopharyngeal, nasal, and combined nasal and nasopharyngeal Ag-RDT result was 70.2% (95%CI: 61.3-78.0), 67.3% (57.3-76.3) and 74.4% (65.5-82.0), respectively. The respective specificity was 97.9% (97.1-98.4), 97.9% (97.2-98.5) and 97.5% (96.7-98.2). For both sampling modalities, sensitivity was higher in participants with symptom duration [≤] 3days versus [≤] 7days. Agreement between nasal and nasopharyngeal Ag-RDT was 99.4%.

ConclusionsThe STANDARD Q Ag-RDT showed high specificity. Sensitivity was, however, below the WHO recommended minimum requirement of [≥] 80%. The high agreement between nasal and nasopharyngeal sampling suggests that for Ag-RDT nasal sampling is a good alternative to nasopharyngeal sampling.

Highlights- Prospective study on real-world diagnostic performance of nasal and nasopharyngeal SD Biosensor STANDARD Q COVID-19 Ag Test in 2131 participants in a rural African setting
- The sensitivity of the STANDARD Q COVID-19 Ag Test was below the World Health Organization requirement of [≥] 80% but met the specificity requirement of [≥]97%.
- Sensitivity was higher in the following subpopulations: persons with symptoms [≤]3 days, and Ct value < 25.
- In head-to-head comparison nasal and nasopharyngeal sampling had comparable sensitivity and specificity and an overall test agreement of 99.4%, indicating that the more convenient nasal sampling could be used for SARS-CoV-2 rapid antigen tests.
- 24 of the 2131 participants with COVID-19 symptoms had pulmonary tuberculosis with a positive Xpert Ultra test on sputum.

category: infectious diseases


title: COVID-19 severity prediction based on patient risk factors and number of vaccines received

abstract:
BackgroundVaccines are highly effective in preventing severe disease and death from COVID-19, and new medications that can reduce severity of disease have been approved. However, many countries are facing limited supply of vaccine doses and medications. A model estimating the probabilities for hospitalization and mortality according to individual risk factors and vaccine doses received could help prioritize vaccination and yet scarce medications to maximize lives saved and reduce the burden on hospitalization facilities.

MethodsElectronic health records from 101,039 individuals infected with SARS-CoV-2, since the beginning of the pandemic and until November 30, 2021 were extracted from a national healthcare organization in Israel. Logistic regression models were built to estimate the risk for subsequent hospitalization and death based on the number of BNT162b2 mRNA vaccine doses received and few major risk factors (age, sex, body mass index, hemoglobin A1C, kidney function, and presence of hypertension, pulmonary disease and malignancy).

ResultsThe models built predict the outcome of newly infected individuals with remarkable accuracy: area under the curve was 0.889 for predicting hospitalization, and 0.967 for predicting mortality. Even when a breakthrough infection occurs, having received three vaccination doses significantly reduces the risk of hospitalization by 66% (OR=0.339) and of death by 78% (OR=0.223).

ConclusionsThe models enable rapid identification of individuals at high risk for hospitalization and death when infected. These patients can be prioritized to receive booster vaccination and the yet scarce medications. A calculator based on these models is made publicly available on http://covidest.web.app


title: Magnitude and breadth of neutralizing antibody responses elicited by SARS-CoV-2 infection or vaccination

abstract:
Multiple SARS-CoV-2 variants that possess mutations associated with increased transmission and antibody escape have arisen over the course of the current pandemic. While the current vaccines have largely been effective against past variants, the number of mutations found on the Omicron (B.1.529) spike appear to diminish the efficacy of pre-existing immunity. Using pseudoparticles expressing the spike of several SARS-CoV-2 variants, we evaluated the magnitude and breadth of the neutralizing antibody response over time in naturally infected and in mRNA-vaccinated individuals. We observed that while boosting increases the magnitude of the antibody response to wildtype (D614), Beta, Delta and Omicron variants, the Omicron variant was the most resistant to neutralization. We further observed that vaccinated healthy adults had robust and broad antibody responses while responses were relatively reduced in vaccinated pregnant women, underscoring the importance of learning how to maximize mRNA vaccine responses in pregnant populations. Findings from this study show substantial heterogeneity in the magnitude and breadth of responses after infection and mRNA vaccination and may support the addition of more conserved viral antigens to existing SARS-CoV-2 vaccines.

One Sentence SummaryDiminished efficacy of pre-existing immunity to highly mutated SARS-CoV-2 variants.


title: Performance of COVIDSeq and Swift normalase amplicon SARS-CoV-2 panels for SARS-CoV-2 Genomes Sequencing: Practical Guide and Combining FASTQ Strategy

abstract: The whole genomic sequencing (WGS) of SARS-CoV-2 has been performed extensively and is playing a crucial role in fighting against COVID-19 pandemic. Obtaining sufficient WGS data from clinical samples is often challenging especially from the samples with low viral load. We evaluated two SARS-CoV-2 sequencing protocols for their efficiency/accuracy and limitations. Sequence coverage of >95% was obtained by Swift normalase amplicon SARS-CoV-2 panels (SNAP) protocol for all the samples with Ct [≤] 35 and by COVIDSeq protocol for 97% of samples with Ct [≤] 30. Sample RNA quantitation obtained using digital PCR provided more precise cutoff values. The quantitative digital PCR cutoff values for obtaining 95% coverage are 10.5 copies/L for SNAP protocol and 147 copies/L for COVIDSeq protocol. Combining FASTQ files obtained from 2 protocols improved the outcome of sequence analysis by compensating for missing amplicon regions. This process resulted in an increase of sequencing coverage and lineage call precision.


title: Urinary Biomarkers and Attainment of Cefepime Therapeutic Targets in Critically Ill Children

abstract:
INTRODUCTIONThe recommended therapeutic target for cefepime (FEP) is the time above MIC (fT>MIC). The frequency of target attainment and risk factors for sub-therapeutic concentrations in children have not been extensively studied.

METHODSWe performed a prospective observational pilot study in children in our PICU receiving standard dosing of FEP for suspected sepsis ([≥]2 SIRS criteria). Three FEP concentrations were measured per subject and a urine sample was collected prior to PK sampling for measurement of urinary biomarkers. We used log linear regression to calculate the fT>MIC for each subject across a range of MIC values (1-16 {micro}g/mL). We compared clinical factors/biomarkers between patients who did and did not achieve 100% fT>MIC for 8 {micro}g/mL (cut-point for Pseudomonas) and tested the correlation between covariates and FEP troughs.

RESULTS21 subjects were enrolled (median SIRS criteria: 3). PK sampling occurred after a median of 5 doses (range: 3-9). 43% of subjects achieved 100% fT>MIC for an MIC of 8 {micro}g/mL. Younger age (p=.005), higher estimated GFR (p=.03), and lower urinary NGAL (p=.006) and KIM-1 (.03) were associated with failure to attain 100% fT>8 {micro}g/mL. Age (r = 0.53), eGFR (r = - 0.58), urinary NGAL (r = 0.42) and KIM-1 (r = 0.50) were significantly correlated with FEP troughs.

CONCLUSIONSA significant proportion of critically ill children failed to attain target concentrations for treatment of Pseudomonas aeruginosa with FEP. Younger patients and those with good kidney function (high GFR, low urinary biomarkers) may be at highest risk for subtherapeutic FEP concentrations.

category: intensive care and critical care medicine


title: The individual and combined associations of depression and socioeconomic status with risk of major cardiovascular events: a prospective cohort study

abstract:
ObjectiveWe aimed to investigate the individual and combined associations of depression and low socioeconomic status (SES) with risk of major cardiovascular events (MCVE), defined as first-ever fatal or non-fatal stroke or myocardial infarction, in a large prospective cohort study.

MethodsWe used data from 466,238 UK Biobank participants, aged 40 - 69 years without cardiovascular disease, bipolar disorder or schizophrenia at baseline. We performed Cox proportional hazard models to estimate adjusted hazard ratios (HR) and 95% confidence intervals (CI) of the individual and combined associations of depression and each of educational attainment, area-based deprivation and income with risk of MCVE. We assessed effect modification and explored interaction on the additive and multiplicative scale.

ResultsDepression, low education, high area-based deprivation and low income were individually associated with increased risks of MCVE (adjusted HR, 95% CI: 1.28, 1.19 - 1.38; 1.20, 1.14 - 1.27; 1.17, 1.11 - 1.23; and 1.22, 1.16 - 1.29, respectively). Depression was associated with increased risks of MCVE among individuals with high and low SES. Individuals with depression and each of low education, high area-based deprivation and low income were at particularly high risk of MCVE (HR, 95% CI: 1.50, 1.38 - 1.63; 1.63, 1.46 - 1.82; 1.31, 1.23 - 1.40, respectively). There was interaction between depression and area-based deprivation on multiplicative and additive scales but no interaction with education or income.

ConclusionDepression was associated with increased risks of MCVE among individuals with high and low SES, with particularly high risks among those living in areas of high deprivation.

category: epidemiology


title: Long-term risk of cancer following pregnancies complicated by vaginal bleeding

abstract:
ObjectiveTo investigate an association of vaginal bleeding-affected deliveries with the long-term risk of cancer as compared with vaginal bleeding-unaffected deliveries and pregnancies ending in a termination or miscarriage.

DesignRegistry-based cohort study in Denmark, 1995-2017.

SettingDanish health and administrative registries.

ParticipantsDeliveries (N=37,085) affected by vaginal bleeding (VB) within 20 gestational weeks among 35,517 women, VB-unaffected deliveries (N=1,362,760) among 783,020 women, pregnancies ending in a termination (N=324,395) among 239,729 women or miscarriage (N=137,040) among 121,303 women.

Main outcome measuresIncidence rates (IR) per 10,000 person-years and cumulative incidence of cancer at the end of up to 24 years of follow-up, hazard ratios (HR) with 95% confidence intervals (CIs) adjusted for age, calendar year, reproductive history, history of chronic conditions, medication use, and socioeconomic factors using Cox proportional hazards regression.

ResultsWe observed 1,725 cancer events (IR=32.1, 95% CI: 30.6-33.6) following VB-affected deliveries, 52,620 events (IR=31.5, 95% CI: 31.2-31.7) following VB-unaffected deliveries, 12,925 events (IR=30.1, 95% CI: 29.6-30.6) following a termination and 6,080 events (IR=34.3, 95% CI: 33.4-35.1) following a miscarriage. We found no association between VB and any cancer in comparison with VB-unaffected deliveries (HR=0.98, 95% CI: 0.93-1.03), terminations (HR=1.00, 95% CI: 0.94-1.06) and miscarriages (HR=1.04, 95% CI: 0.94-1.14). Specifically, there was no increase in relative risk of breast (HR=0.94, 95% CI: 0.86-1.03), cervical (0.94, 0.77-1.14), ovarian and fallopian tube (1.16, 0.81-1.66), uterine cancer (0.78, 0.46-1.33) and other site-specific cancers across all comparisons and in sensitivity analyses.

ConclusionsHaving a VB-affected pregnancy ending in a delivery was not associated with an increased womens risk of cancer in comparison with having a VB-unaffected pregnancy ending in a delivery, termination or miscarriage.

WHAT IS ALREADY KNOWN ON THIS TOPICO_LIThe risk of breast, endometrial, and ovarian cancer is reduced in women with childbirths.
C_LIO_LIThe risk reduction for breast, endometrial, and ovarian cancer is also observed following pregnancies ending in a termination or miscarriage, suggesting a protective association with gestation irrespective of its outcome.
C_LI

WHAT THIS STUDY ADDSO_LIWhen compared with vaginal bleeding-unaffected deliveries, affected deliveries were not associated with the increased risk of any cancer and specifically of breast, cervical, ovarian and fallopian tube, and uterine cancer during the follow-up of up to 24 years.
C_LIO_LIIn comparison with pregnancies ending in a termination or miscarriage, pregnancies affected by vaginal bleeding were also not associated with subsequent risk of cancer.
C_LI


title: A phase I study of oral vitamin D3 supplementation in boys with X-linked adrenoleukodystrophy

abstract:
ObjectiveVitamin D status has been linked to risk of inflammatory brain lesions. We sought to assess the safety and pharmacokinetics of oral vitamin D dosing regimens in boys with X-linked adrenoleukodystrophy (ALD).

MethodsIn this open-label, multi-center, phase I study, we enrolled 21 ALD males without brain lesions, aged 1.5 to 25 years to oral vitamin D supplementation for 12 months. Our primary outcome was attainment of plasma 25-hydroxyvitamin D levels in target range (40-80ng/ml) at 6 and 12 months. Secondary outcomes included safety and glutathione levels in brain and blood. Participants were initially assigned to a fixed dosing regimen starting at 2,000 IU daily, regardless of weight. Following a mid-study safety assessment, we modified the dosing regimen so all subsequent participants were assigned to a weight-stratified dosing regimen starting as low as 1,000 IU daily.

ResultsBetween October 2016 and June 2019, we recruited 21 participants (n=12 fixed dose; n=9 weight-stratified) with a median age and weight of 6.7 years and 20 kilograms. Most participants achieved target plasma vitamin D levels at 6 and 12 months regardless of dosing regimen. In the fixed dose regimen, 6 of 12 participants had asymptomatic elevation in urine calcium:creatinine or plasma 25-hydroxyvitamin D; no laboratory deviations occurred with the weight-stratified regimen. Glutathione levels increased between baseline and 12 months in the brain but not in the blood.

ConclusionsOur weight-stratified vitamin D dosing regimen was well-tolerated and achieved target 25-hydroxyvitamin D levels in most participants. Brain glutathione levels increased over the 12-month trial period.

Clinicaltrials.gov identifierNCT02595489

Classification of EvidenceThis study provides Class II evidence that a weight-stratified dosing regimen of vitamin D supplementation is safe, well-tolerated, and effective at achieving moderately high vitamin D levels in boys with ALD.

Sources of fundingNIH/NINDS K23NS087151

category: neurology


title: Schizophrenia-associated somatic copy number variants from 12,834 cases reveal contribution to risk and recurrent, isoform-specific NRXN1 disruptions

abstract: While inherited and de novo copy number variants (CNV) have been implicated in the genetic architecture of schizophrenia (SCZ), the contribution of somatic CNVs (sCNVs), present in some but not all cells of the body, remains unknown. Here we explore the role of sCNVs in SCZ by analyzing blood-derived genotype arrays from 12,834 SCZ cases and 11,648 controls. sCNVs were more common in cases (0.91%) than in controls (0.51%, p = 2.68e-4). We observed recurrent somatic deletions of exons 1-5 of the NRXN1 gene in 5 SCZ cases. Allele-specific Hi-C maps revealed ectopic, allele-specific loops forming between a potential novel cryptic promoter and non-coding cis regulatory elements upon deletions in the 5 region of NRXN1. We also observed recurrent intragenic deletions of ABCB11, a gene associated with anti-psychotic response, in 5 treatment-resistant SCZ cases. Taken together our results indicate an important role of sCNVs to SCZ risk and treatment-responsiveness.

category: genetic and genomic medicine


abstract:
A protocol for a retrospective observational study to investigate the effect of frailty on outcomes of older adults admitted with major trauma. Patient data will be examined held within the Trauma and Audit Research Network (TARN) database, from 23 Major Trauma Centres in England, between April 2019 and March 2020. The two research questions are: 1) Is there any association between frailty and clinical outcomes in older people admitted with serious traumatic injuries? 2) Is there any association between a geriatrician review and clinical outcomes in an older people admitted with serious traumatic injuries? Patients 65 years old or over will be included. The primary outcome will be mortality as measured by time from hospital admission to death. Secondary outcomes will include day 30 mortality, post injury complications, and length of hospital stay. A mixed-effects multivariable Cox proportional hazards model will be used to analyse the data. A statistical analysis plan has been produced separately for each research question.

Signature PageThe undersigned confirm that the following protocol has been agreed and accepted and that the Chief Investigator agrees to conduct the study in compliance with the approved protocol and will adhere to the principles outlined in the Declaration of Helsinki, the Sponsors SOPs, and other regulatory requirement.

I agree to ensure that the confidential information contained in this document will not be used for any other purpose other than the evaluation or conduct of the investigation without the prior written consent of the Sponsor

I also confirm that I will make the findings of the study publically available through publication or other dissemination tools without any unnecessary delay and that an honest accurate and transparent account of the study will be given; and that any discrepancies from the study as planned in this protocol will be explained.

For and on behalf of the Study Sponsor

O_TBL View this table:
org.highwire.dtl.DTLVardef@1e4b038org.highwire.dtl.DTLVardef@ed6a06org.highwire.dtl.DTLVardef@cbd44borg.highwire.dtl.DTLVardef@1de8e7dorg.highwire.dtl.DTLVardef@5cbdcf_HPS_FORMAT_FIGEXP  M_TBL C_TBL Key Study Contacts

O_TBL View this table:
org.highwire.dtl.DTLVardef@b1937corg.highwire.dtl.DTLVardef@49cdf1org.highwire.dtl.DTLVardef@16fac3dorg.highwire.dtl.DTLVardef@94fe75org.highwire.dtl.DTLVardef@1cdd579_HPS_FORMAT_FIGEXP  M_TBL C_TBL Study Summary

O_TBL View this table:
org.highwire.dtl.DTLVardef@7a1db5org.highwire.dtl.DTLVardef@13496f2org.highwire.dtl.DTLVardef@1a1eb82org.highwire.dtl.DTLVardef@16cde16org.highwire.dtl.DTLVardef@6895db_HPS_FORMAT_FIGEXP  M_TBL C_TBL Plain Language SummaryThe majority of major injuries admitted to hospital are now in older people, with a fall from standing height being the most common reason for injury. Our study will look at older adults admitted to hospital with serious traumatic injuries across England and Wales. It will aim to work out firstly if there is an effect of frailty on peoples survival after injury. Frailty is the reserve a person has to cope with illness and is a measure of a person slowing down over time usually due to the collection of lots of health problems. Secondly, we will look at if being seen by an old age specialist (geriatrician) has an effect on a persons chances of surviving their injuries. The records we will look at are held collected routinely and held by a national database run by the Trauma and Audit Research Network (TARN) from the University of Manchester. They collect information from the 23 centres of major trauma excellence around the country and help researchers to work with them to access the anonymous data for specific research questions. We aim to use these results to help clinicians and health systems to improve how the fund and deliver care for older people.

Funding and Support in Kind

O_TBL View this table:
org.highwire.dtl.DTLVardef@4678c5org.highwire.dtl.DTLVardef@a2d3ceorg.highwire.dtl.DTLVardef@1ffae06org.highwire.dtl.DTLVardef@fa32e4org.highwire.dtl.DTLVardef@2357dc_HPS_FORMAT_FIGEXP  M_TBL C_TBL Role of Study Sponsor and FunderNorth Bristol Trust R&I - supporting the development of this work. No direct influence in any part of the work.

TARN - supporting development of the work. Will have input into the development, analysis and write-up of the work.

Study Steering Group

O_TBL View this table:
org.highwire.dtl.DTLVardef@5d5bc6org.highwire.dtl.DTLVardef@1342e9borg.highwire.dtl.DTLVardef@e00254org.highwire.dtl.DTLVardef@b910a3org.highwire.dtl.DTLVardef@1f37204_HPS_FORMAT_FIGEXP  M_TBL C_TBL Protocol Contributors

O_TBL View this table:
org.highwire.dtl.DTLVardef@1c2a63corg.highwire.dtl.DTLVardef@2fd1f2org.highwire.dtl.DTLVardef@18085bcorg.highwire.dtl.DTLVardef@cc2ebaorg.highwire.dtl.DTLVardef@10fc93c_HPS_FORMAT_FIGEXP  M_TBL C_TBL No patients were involved in the development of the protocol.

Study Flow Chart

O_TBL View this table:
org.highwire.dtl.DTLVardef@164962corg.highwire.dtl.DTLVardef@bf6304org.highwire.dtl.DTLVardef@fdc81aorg.highwire.dtl.DTLVardef@15c3b10org.highwire.dtl.DTLVardef@29a36b_HPS_FORMAT_FIGEXP  M_TBL C_TBL Study ProtocolA retrospective observational study to investigate the effect of frailty on outcomes of older adults admitted with major trauma.

category: geriatric medicine


title: Vaccination-infection interval determines cross-neutralization potency to SARS-CoV-2 Omicron after breakthrough infection by other variants

abstract:
BackgroundThe immune profile against SARS-CoV-2 has dramatically diversified due to a complex combination of exposure to vaccines and infection by various lineages/variants, likely generating a heterogeneity in protective immunity in a given population. To further complicate this, the Omicron variant, with numerous spike mutations, has emerged. These circumstances have created the need to assess the potential of immune evasion by the Omicron in individuals with various immune histories.

MethodsThe neutralization susceptibility of the variants including the Omicron and their ancestor was comparably assessed using a panel of plasma/serum derived from individuals with divergent immune histories. Blood samples were collected from either mRNA vaccinees or from those who suffered from breakthrough infections by the Alpha/Delta with multiple time intervals following vaccination.

FindingsThe Omicron was highly resistant to neutralization in fully vaccinated individuals without a history of breakthrough infections. In contrast, robust cross-neutralization against the Omicron were induced in vaccinees that experienced breakthrough infections. The time interval between vaccination and infection, rather than the variant types of infection, was significantly correlated with the magnitude and potency of Omicron-neutralizing antibodies.

ConclusionsImmune histories with breakthrough infections can overcome the resistance to infection by the Omicron, with the vaccination-infection interval being the key determinant of the magnitude and breadth of neutralization. The diverse exposure history in each individual warrants a tailored and cautious approach to understanding population immunity against the Omicron and future variants.

FundingThis study was supported by grants from the Japan Agency for Medical Research and Development (AMED).


title: Severity of COVID-19 reinfection and associated risk factors: findings of a cross-sectional study in Bangladesh

abstract:
BackgroundCOVID-19 reinfected patients suffer from diverse health consequences. Information on the severity of COVID-19 reinfection is scarce. The current study aimed to determine the proportion of COVID-19 reinfection and risk factors associated with its severity.

MethodsThis cross-sectional study targeted all COVID-19 patients reported in May 2021 at the Health Information Unit (HIU) of the Directorate General of Health Services (DGHS) of Bangladesh. We identified 473 (1.14%) reinfected patients out of 41408 diagnosed cases by reviewing their medical records. Considering the selection criteria and informed consent, we enrolled 404 reinfected patients. Data were collected through telephone interviews and reviewing medical records using a semi-structured questionnaire and a checklist.

ResultsThe majority of the reinfected patients were urban residents (98.0%). Around 13.0% of reinfected patients had <90% oxygen saturation, and 64.0% had an interval of 3-6 months between two attacks. The severity of reinfection included asymptomatic (12.9%), mild (8.9%), moderate (66.3%), and severe (11.9%) forms of infection. An interval of 3-6 months between two attacks had less chance of having mild (AOR=0.031, {rho}=0.000), moderate (AOR=0.132, {rho}=0.017), and severe (AOR=0.059, {rho}=0.002) infections. Patients who maintained physical distance had less chance of moderate-intensity reinfection (AOR=0.137, {rho}=0.013), while the vaccinated patients had a higher chance of moderate (AOR=16.127, {rho}=0.001) and severe (AOR=3.894, {rho}=0.047) intensity reinfection.

ConclusionTo avert COVID-19 reinfection and its severity, patients should be vigilant about preventive practices even after recovery. The study suggests vibrant interventions aligned with exposure, physical distancing, vaccination, and comorbidities for mitigating reinfection.


title: Rapid turnaround multiplex sequencing of SARS-CoV-2: comparing tiling amplicon protocol performance

abstract: Genome sequencing is pivotal to SARS-CoV-2 surveillance, elucidating the emergence and global dissemination of acquired genetic mutations. Amplicon sequencing has proven very effective for sequencing SARS-CoV-2, but prevalent mutations disrupting primer binding sites have necessitated the revision of sequencing protocols in order to maintain performance for emerging virus lineages. We compared the performance of Oxford Nanopore Technologies (ONT) Midnight and ARTIC tiling amplicon protocols using 196 Delta lineage SARS-CoV-2 clinical specimens, and 71 mostly Omicron lineage samples with S gene target failure (SGTF), reflecting circulating lineages in the United Kingdom during December 2021. 96-plexed nanopore sequencing was used. For Delta lineage samples, ARTIC v4 recovered the greatest proportion of [≥]90% complete genomes (81.1%; 159/193), followed by Midnight (71.5%; 138/193) and ARTIC v3 (34.1%; 14/41). Midnight protocol however yielded higher average genome recovery (mean 98.8%) than ARTIC v4 (98.1%) and ARTIC v3 (75.4%), resulting in less ambiguous final consensus assemblies overall. Explaining these observations were ARTIC v4s superior genome recovery in low viral titre/high cycle threshold (Ct) samples and inferior performance in high titre/low Ct samples, where Midnight excelled. We evaluated Omicron sequencing performance using a revised Midnight primer mix alongside prototype ARTIC v4.1 primers, head-to-head with the existing commercially available Midnight and ARTIC v4 protocols. The revised protocols both improved considerably the recovery of Omicron genomes and exhibited similar overall performance to one another. Revised Midnight protocol recovered [≥]90% complete genomes for 85.9% (61/71) of Omicron samples vs. 88.7% (63/71) for ARTIC v4.1. Approximate cost per sample for Midnight ({pound}12) is lower than ARTIC ({pound}16) while hands-on time is considerably lower for Midnight ([~]7 hours) than ARTIC protocols ([~]9.5 hours).


title: Shared brain and genetic architectures between mental health and physical activity

abstract: Physical activity is correlated with, and effectively treats various forms of psychopathology. However, whether biological correlates of physical activity and psychopathology are shared remains unclear. Here, we examined the extent to which the neural and genetic architecture of physical activity and mental health are shared. Using data from the UK Biobank (N=6,389), canonical correlation analysis was applied to estimate associations between the amplitude and connectivity strength of sub-networks of three major neurocognitive networks (default mode, DMN; salience, SN; central executive networks, CEN) with accelerometer-derived measures of physical activity and self-reported mental health. We estimated the genetic correlation between mental health and physical activity measures, as well as putative causal relationships by applying linkage disequilibrium score regression, genomic structural equational modeling, and latent causal variable analysis to genome-wide association summary statistics (GWAS N=91,105-500,199). Physical activity and mental health were associated with connectivity strength and amplitude of the DMN, SN, and CEN (rs[≥]0.12, ps<0.048). These neural correlates exhibited highly similar loading patterns across mental health and physical activity models even when accounting for their shared variance. This suggests a largely shared brain network architecture between mental health and physical activity. Mental health and physical activity were also genetically correlated (|rg|=0.085-0.121), but we found no evidence for causal relationships between them. Collectively, our findings provide empirical evidence that mental health and physical activity have shared brain and genetic architectures and suggest potential candidate sub-networks for future studies on brain mechanisms underlying beneficial effects of physical activity on mental health.

category: psychiatry and clinical psychology


title: The adverse impact of COVID-19 pandemic on cardiovascular disease prevention and management in England, Scotland and Wales: A population-scale descriptive analysis of trends in medication data

abstract:
ObjectivesTo estimate the impact of the COVID-19 pandemic on cardiovascular disease (CVD) and CVD management using routinely collected medication data as a proxy.

DesignDescriptive and interrupted time series analysis using anonymised individual-level population-scale data for 1.32 billion records of dispensed CVD medications across 15.8 million individuals in England, Scotland and Wales.

SettingCommunity dispensed CVD medications with 100% coverage from England, Scotland and Wales, plus primary care prescribed CVD medications from England (including 98% English general practices).

Participants15.8 million individuals aged 18+ years alive on 1st April 2018 dispensed at least one CVD medicine in a year from England, Scotland and Wales.

Main outcome measuresMonthly counts, percent annual change (1st April 2018 to 31st July 2021) and annual rates (1st March 2018 to 28th February 2021) of medicines dispensed by CVD/ CVD risk factor; prevalent and incident use.

ResultsYear-on-year change in dispensed CVD medicines by month were observed, with notable uplifts ahead of the first (11.8% higher in March 2020) but not subsequent national lockdowns. Using hypertension as one example of the indirect impact of the pandemic, we observed 491,203 fewer individuals initiated antihypertensive treatment across England, Scotland and Wales during the period March 2020 to end May 2021 than would have been expected compared to 2019. We estimated that this missed antihypertension treatment could result in 13,659 additional CVD events should individuals remain untreated, including 2,281 additional myocardial infarctions (MIs) and 3,474 additional strokes. Incident use of lipid-lowering medicines decreased by an average 14,793 per month in early 2021 compared with the equivalent months prior to the pandemic in 2019. In contrast, the use of incident medicines to treat type-2 diabetes (T2DM) increased by approximately 1,642 patients per month.

ConclusionsManagement of key CVD risk factors as proxied by incident use of CVD medicines has not returned to pre-pandemic levels in the UK. Novel methods to identify and treat individuals who have missed treatment are urgently required to avoid large numbers of additional future CVD events, further adding indirect cost of the COVID-19 pandemic.

category: cardiovascular medicine


title: Transplantation of IPSC-Derived Cardiomyocyte Patches for Ischemic Cardiomyopathy

abstract:
BackgroundDespite major therapeutic advances, heart failure remains a life-threatening disorder, with 26 million patients worldwide, causing more deaths than cancer as a non-communicable disease. Therefore, novel strategies for the treatment of heart failure continue to be an important clinical need. Based on preclinical studies, allogenic human-induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) patches have been proposed as a potential therapeutic candidate for heart failure. We report the implantation of allogeneic hiPSC-CM patches in a patient with ischemic cardiomyopathy (ClinicalTrials.gov, #jRCT2053190081).

MethodsThe patches were produced under clinical-grade conditions and displayed cardiogenic phenotypes and safety in vivo (severe immunodeficient mice) without any genetic mutations in cancer-related genes. The patches were then implanted via thoracotomy into the left ventricle epicardium of the patient under immunosuppressive agents.

ResultsPositron emission tomography and computed tomography confirmed the possible efficacy and did not detect tumorigenesis in either the heart or other organs; the clinical symptoms improved 6 months after surgery, without any major adverse events, suggesting that the patches were well-tolerated. Furthermore, changes in the wall motion in the transplanted site were recovered, suggesting a favorable prognosis and the potential tolerance to exercise.

ConclusionsThis study is the first report of a successful transplant of hiPSC-CMs for severe ischemic cardiomyopathy.


title: How To Enhance Empathy Nursing Students In Education: Literature Review

abstract:
IntroductionThe tendency of reducing student empathy requires efforts to improve it through education or training. The purpose of this review is to identify education, learning, or teaching that is used to increase student empathy.

MethodThe design used a Literature Systematic Review. Articles were conducted in three electronic databases guided by The PRISMA. Articles published in English and in 2019 to 2021.

ResultsThe result obtained 20 articles and will be reviewed. Eighteen articles show an effect or relationship between intervention and empathy. Training materials that can increase student empathy are the concept of empathy, communication, mindfulness, and transcultural nursing education. Education and training using patients/patient simulations to help improve student empathy, namely: expert patients, ECARE Program, polypharmacy effects; clinical Simulation of Inpatients, Lectures in class, Virtual Dementia Tour, living in poverty, and games for team interaction. Another method is through the KSS module, mannequin simulator experience, and peers.

ConclusionEducation and training on the concepts of empathy, communication, meditation, and cultural competence using Simulation and immersion methods with patients, being like patients, using mannequins, or interacting with vulnerable groups can increase student empathy. Faculty and lecturers can apply experiential learning methods with Simulation and immersion in learning or training courses.

category: nursing


title: Non-modifiable factors as moderators of the relationship between physical activity and brain volume: A cross-sectional UK Biobank study

abstract:
BackgroundGrey matter atrophy occurs as a function of ageing and is accelerated in dementia. Previous research suggests physical activity attenuates grey matter loss; however, there appears to be individual variability in this effect. Understanding factors that can affect the relationship between physical activity and brain volume may enable prediction of individual response, and aid in identifying those that gain the greatest neural benefits from physical activity. The current study examined the relationship between objectively-measured physical activity and brain volume; and whether this relationship is moderated by age, sex, or a priori candidate genetic factors.

MethodsData from 10,083 men and women (50 years and over) of the UK Biobank were used to examine: 1) the relationship between objectively-measured physical activity and brain volume; and 2) whether the relationship between objectively-measured physical activity and brain volume is moderated by age, sex, brain-derived neurotrophic factor (BDNF) Val66Met, or apolipoprotein (APOE) {varepsilon}4 allele carriage. All participants underwent a magnetic resonance imaging scan to quantify grey matter volumes, physical activity monitoring via accelerometry, and genotyping.

ResultsPhysical activity was associated with total grey matter volume (B = 0.14, p = 0.001, q = 0.005) and right hippocampal volume (B = 1.45, p = 0.008, q = 0.016). The physical activity*sex interaction predicted cortical grey matter (B = 0.22, p = 0.003, q = 0.004), total grey matter (B = 0.30, p < 0.001, q = 0.001), and right hippocampal volume (B = 3.60, p = 0.001, q = 0.002). Post-hoc analyses revealed males received benefit from higher physical activity levels, in terms of greater cortical grey matter volume (B = 0.13, p = 0.01), total grey matter volume (B=0.23, p < 0.001), and right hippocampal volume (B = 3.05, p = 0.008). No moderating effects of age, APOE {varepsilon}4 allele carriage, or BDNF Val66Met genotype were observed.

DiscussionOur results indicate that in males, but not females, an association exists between objectively-measured physical activity and grey matter volume. Future research should evaluate longitudinal brain volumetrics to better understand the nature of sex-effects on the relationship between physical activity and brain volume.


title: Comparison of outcomes from COVID infection in pediatric and adult patients before and after the emergence of Omicron

abstract:
BackgroundThe Omicron SARS-CoV-2 variant is rapidly spreading in the US since December 2021 and is more contagious than earlier variants. Currently, data on the severity of the disease caused by the Omicron variant compared with the Delta variant is limited. Here we compared 3-day risks of emergency department (ED) visit, hospitalization, intensive care unit (ICU) admission, and mechanical ventilation in patients who were first infected during a time period when the Omicron variant was emerging to those in patients who were first infected when the Delta variant was predominant.

MethodThis is a retrospective cohort study of electronic health record (EHR) data of 577,938 first-time SARS-CoV-2 infected patients from a multicenter, nationwide database in the US during 9/1/2021-12/24/2021, including 14,054 who had their first infection during the 12/15/2021-12/24/2021 period when the Omicron variant emerged ("Emergent Omicron cohort") and 563,884 who had their first infection during the 9/1/2021-12/15/2021 period when the Delta variant was predominant ("Delta cohort"). After propensity-score matching the cohorts, the 3-day risks of four outcomes (ED visit, hospitalization, ICU admission, and mechanical ventilation) were compared. Risk ratios, and 95% confidence intervals (CI) were calculated.

ResultsOf 14,054 patients in the Emergent Omicron cohort (average age, 36.4 {+/-} 24.3 years), 27.7% were pediatric patients (<18 years old), 55.4% female, 1.8% Asian, 17.1% Black, 4.8% Hispanic, and 57.3% White. The Emergent Omicron cohort differed significantly from the Delta cohort in demographics, comorbidities, and socio-economic determinants of health. After propensity-score matching for demographics, socio-economic determinants of health, comorbidities, medications and vaccination status, the 3-day risks in the Emergent Omicron cohort outcomes were consistently less than half those in the Delta cohort: ED visit: 4.55% vs. 15.22% (risk ratio or RR: 0.30, 95% CI: 0.28-0.33); hospitalization: 1.75% vs. 3.95% (RR: 0.44, 95% CI: 0.38-0.52]); ICU admission: 0.26% vs. 0.78% (RR: 0.33, 95% CI:0.23-0.48); mechanical ventilation: 0.07% vs. 0.43% (RR: 0.16, 95% CI: 0.08-0.32). In children under 5 years old, the overall risks of ED visits and hospitalization in the Emergent Omicron cohort were 3.89% and 0.96% respectively, significantly lower than 21.01% and 2.65% in the matched Delta cohort (RR for ED visit: 0.19, 95% CI: 0.14-0.25; RR for hospitalization: 0.36, 95% CI: 0.19-0.68). Similar trends were observed for other pediatric age groups (5-11, 12-17 years), adults (18-64 years) and older adults ([≥] 65 years).

ConclusionsFirst time SARS-CoV-2 infections occurring at a time when the Omicron variant was rapidly spreading were associated with significantly less severe outcomes than first-time infections when the Delta variant predominated.


title: Preserved recognition of Omicron Spike following COVID-19 mRNA vaccination in pregnancy

abstract:
BackgroundSARS-CoV-2 infection is associated with enhanced disease severity in pregnant women. Despite the potential of COVID-19 vaccines to reduce severe disease, vaccine uptake remained relatively low among pregnant women. Just as coordinated messaging from the CDC and leading obstetrics organizations began to increase vaccine confidence in this vulnerable group, the evolution of SARS-CoV-2 variants of concerns (VOC) including the Omicron VOC raised new concerns about vaccine efficacy, given their ability to escape vaccine-induced neutralizing antibodies. Early data point to a milder disease course following omicron VOC infection in vaccinated individuals. Thus, these data suggest that alternate vaccine induced immunity, beyond neutralization, may continue to attenuate omicron disease, such as antibody-Fc-mediated activity. However, whether vaccine induced antibodies raised in pregnancy continue to bind and leverage Fc-receptors remains unclear.

MethodsVOC including Omicron receptor binding domain (RBD) or full Spike specific antibody isotype binding titers and Fc{gamma}R binding were analyzed in pregnant women after the full dose regimen of either Pfizer/BioNtech BNT62b2 (n=10) or Moderna mRNA-1273 (n=10) vaccination using a multiplexing Luminex assay.

FindingsComparable, albeit reduced, isotype recognition was observed to the Omicron Spike and receptor binding domain (RBD) following both vaccines. Yet, despite the near complete loss of Fc-receptor binding to the Omicron RBD, Fc-receptor binding was largely preserved to the Omicron Spike.

InterpretationReduced binding titer to the Omicron RBD aligns with observed loss of neutralizing activity. Despite the loss of neutralization, preserved Omicron Spike recognition and Fc-receptor binding potentially continues to attenuate disease severity in pregnant women.

FundingNIH and the Bill and Melinda Gates Foundation

category: allergy and immunology


title: SARS-CoV-2 screening in patients in need of urgent inpatient treatment in the Emergency Department (ED) by digitally integrated point-of-care PCR: A clinical cohort study

abstract:
Patients in need of urgent inpatient treatment were recruited prospectively. A rapid point of care PCR test (POC-PCR; Liat(R)) for SARS-CoV2 was conducted in the ED and a second PCR-test from the same swab was ordered in the central laboratory (CL-PCR). POC-PCR analyzers were digitally integrated in the laboratory information system.

Overall, 160 ED patients were included. A valid POC-PCR-test result was available in 96.3% (n=154) of patients. N=16 patients tested positive for SARS-CoV-2 (10.0%). The POC PCR test results were available within 102 minutes (median, IQR: 56-211), which was significantly earlier compared to the CL PCR (811 minutes; IQR: 533-1289, p < 0.001). The diagnostic accuracy of the POC-PCR test was 100%. The implementation and digital LIS integration was successfully done. Staff satisfaction with the POC process was high.

The POC-PCR testing in the emergency department is feasible and shows a very high diagnostic performance.

Trial registration: DRKS00019207

category: emergency medicine


title: Baptism of fire: Modeling the effects of prescribed fire on tick-borne disease

abstract: Recently, tick-borne illnesses have been trending upward and are an increasing source of risk to peoples health in the United States. This is due to range expansion in tick habitats as a result of climate change. Thus, it is imperative to find a practical and cost-efficient way of managing tick populations. Prescribed burns are a common form of land management that can be cost efficient if properly managed and can be applied across large amounts of land. In this study, we present a compartmental model for ticks carrying Lyme disease and uniquely incorporate the effects of prescribed fire using an impulsive system to investigate the effects of prescribed fire intensity (high and low) and the duration between burns. Our study found that fire intensity has a larger impact in reducing tick population than the frequency between burns. Furthermore, burning at high intensity is preferable to burning at low intensity whenever possible, although high intensity burns may be unrealistic due to environmental factors. Annual burns resulted in the most significant reduction of infectious nymphs, which are the primary carriers of Lyme disease.


title: Performance on verbal fluency tasks depends on the given category/letter: Preliminary data from a multivariable analysis

abstract: Verbal fluency tasks are often used in neuropsychological research and may have predictive and diagnostic utility in psychiatry and neurology. However, researchers using verbal fluency have uncritically assumed that there are no category-or phoneme-specific effects on verbal fluency performance. We recruited 16 healthy young adult subjects and administered two semantic (animals, trees) and phonemic (K, M) fluency tasks. Because of the small sample size, results should be regarded as preliminary and exploratory. On the animal compared to the tree task, subjects produced significantly more legal words, had a significantly lower intrusion rate, significantly shorter first-response latencies and final silence periods, as well as significantly shorter between-cluster response latencies. These differences may be explained by differences in the category sizes, integrity of the categories borders, and efficiency of the functional connectivity between subcategories. On the K compared to the M task, subjects produced significantly more legal words and had significantly shorter between-cluster response times. Counterintuitively, a corpus analysis revealed there are more words starting with [<]m[>] compared to [<]k[>] in the experimental language. Our results potentially have important implications for research utilizing verbal fluency, including decreased reproducibility, questionable reliability of diagnostic and predictive tools based on verbal fluency, decreased knowledge accumulation, and increased number of publications with potentially misleading clinical interpretations.


title: Potential application of Rapid Antigen Diagnostic Tests for the detection of infectious individuals attending mass gatherings: a simulation study

abstract: Rapid Antigen Diagnostic Tests (RADTs) for the detection of SARS-CoV-2 offer advantages in that they are cheaper and faster than currently used PCR tests but have reduced sensitivity and specificity. One potential application of RADTs is to facilitate gatherings of individuals, through testing of attendees at the point of, or immediately prior to entry at a venue. Understanding the baseline risk in the tested population is of particular importance when evaluating the utility of applying diagnostic tests for screening purposes. We used incidence data to estimate the prevalence of infectious individuals in the community at a particular time point and simulated mass gatherings by sampling from a series of age cohorts. Nine different illustrative scenarios were simulated, small (n=100), medium (n=1000) and large (n=10,000) gatherings each with 3 possible age constructs: mostly younger, mostly older or a gathering with equal numbers from each age cohort. For each scenario, we estimated the prevalence of infectious attendees, then simulated the likely number of positive and negative test results, the proportion of cases detected and the corresponding positive and negative predictive values, and the cost per case identified. Our findings suggest that for each detected individual on a given day, there are likely to be 13.8 additional infectious individuals also present in the community. Prevalence of infectious individuals at events was highest with  mostly younger attendees (1.00%), followed by homogenous age gatherings (0.55%) and lowest with  mostly older events (0.26%). For small events (100 attendees) the expected number of infectious attendees was less than 1 across all age constructs of attendees. For large events (10,000 attendees) the expected number of infectious attendees ranged from 26 (95% confidence intervals 12 to 45) for mostly older events, to almost 100 (95% confidence intervals 46 to 174) infectious attendees for mostly younger attendees. Given rapid changes in SARS-CoV-2 incidence over time, we developed an RShiny app to allow users to run updated simulations for specific events.

category: public and global health


title: Executive dysfunction following SARS-CoV-2 infection: A cross-sectional examination in a population-representative sample

abstract:
BackgroundPrior studies have documented reliable associations between SARS-CoV-2 infection and adverse cognitive impact in older adults. The current study sought to determine whether SARS-CoV-2 infection and COVID-19 symptom severity are associated with cognitive dysfunction among young adults and middled-aged adults in the general population.

MethodThe Canadian COVID-19 Experiences Project (CCEP) survey involves 1,958 adults with equal representation of vaccinated and vaccine hesitant adults between the ages of 18 and 54 years. The sample comprised 1,958 adults with a mean age of 37 years (SD=10.4); 60.8% were female. The primary outcome was symptoms of cognitive dysfunction assessed via an abbreviated form of the Barkley Deficits in Executive Functioning Scale (BDEFS) and performance on a validated decision-making task.

ResultsYoung and middle-aged adults with a positive SARS-CoV-2 infection history reported a significantly higher number of symptoms of executive dysfunction (Madj=1.89, SE=0.08, CI: 1.74, 2.04; n=175) than their non-infected counterparts (Madj=1.63, SE=0.08, CI: 1.47,1.80; n=1,599; {beta}=0.26, p=.001). Among those infected, there was a dose-response relationship between COVID-19 symptom severity and level of executive dysfunction, with moderate ({beta}=0.23, CI: 0.003-0.46) and very/extremely severe ({beta}= 0.69, CI: 0.22-1.16) COVID-19 symptoms being associated with significantly greater dysfunction, compared to asymptomatic. These effects remained reliable and of similar magnitude after controlling for age, sex, vaccination status, income, and geographic region, and after removal of those who had been intubated during hospitalization. Similar effects were found for the decision-making task.

ConclusionsPositive SARS-CoV-2 infection history and COVID-19 symptom severity are associated with executive dysfunction among young and middle-aged adults with no history of medically induced coma. These findings are evident on self-reported and task-related indicators of cognitive function.


title: Delays during PBMC isolation have a moderate effect on yield, but severly compromise cell viability

abstract:
BackgroundPeripheral blood mononuclear cells (PMBCs) are a versatile material for clinical routine as well as for research projects. However, their isolation via density gradient centrifugation is still time-consuming. When samples are taken beyond usual laboratory handling times, it may sometimes be necessary to pause the isolation process. Our aim was to evaluate the impact of delays up to 48 hours after the density gradient centrifugation on PBMC yield, purity and viability.

MethodsPBMCs were isolated from samples of 20 donors, either with BD Vacutainer CPT tubes (CPT) or with the standard Ficoll method. Isolation was paused after initial density gradient centrifugation for 0, 24, or 48 hours. PBMC yield, purity and viability were compared.

ResultsThe yield did not change significantly over time when CPT were used (55%/52%/47%), but did after isolation with the standard method (62%/40%[p<0.0001]/53%[p<0.01]). Purity was only affected if CPT were used (95%/93%[p=n.s./92%[p<0.05] vs. 97% for all time points with standard method). Whereas viable PBMCs decreased steadily for CPT isolates (62%/51%[p<0.001]/36%[p<0.0001]), after standard Ficoll gradient isolation, cell apoptosis was more pronounced already after 24h delay, and viability did not further decrease after 48h (64%/44%[p<0.0001]/40%[p<0.0001]).

ConclusionsIn conclusion, our data suggests that post-centrifugation delays of up to 48h might have only a minor effect on cell yield and purity. However, at the same time, a relevant decrease in cell viability was observed, which could be partially compensated by the use of CPT if the isolation was resumed latest the day after blood withdrawal.

category: hematology


title: The efficacy of Andrographis paniculata (Burm.f.) Wall. ex Nees crude extract in hospitalised mild COVID-19 patients: a retrospective cohort study

abstract:
BackgroundAndrographis paniculata (AP) crude extract has been widely used in Thailand to treat mild COVID-19 infections since early 2020; however, supporting evidence is lacking.

PurposeTo evaluate the efficacy of AP compared with standard treatment among hospitalised mild COVID-19 patients.

Study designSingle-centre retrospective cohort study

MethodsWe collected data between March 2020 and August 2021 from COVID-19 patients admitted to one hospital in Thailand. Patients whose infection was confirmed by real-time polymerase chain reaction (RT-PCR) and had normal chest radiography were included, whereas those receiving favipiravir or who had unclear chest X-rays at admission were excluded. Participants were categorised as either AP or standard of care and followed for pneumonia confirmed by chest radiography. Multiple logistic regression was used to analyse the main results controlling for age, sex, history of diabetes, hypertension, statin use, and antihypertensive drug use.

ResultsA total of 605 out of 1,054 patients were included in the analysis. Of these, 59 patients (9.8%) developed pneumonia during the median follow-up of 7 days. The incidence rates of pneumonia were 13.93 (95% CI 10.09, 19.23) and 12.47 (95% CI 8.21, 18.94) per 1,000 person-days in the AP and standard of care groups, respectively. Compared to the standard of care group, the odds ratios of having pneumonia in the AP group were 1.24 (95% CI 0.71, 2.16; unadjusted model) and 1.42 (95% CI 0.79, 2.55; fully adjusted model). All sensitivity analyses produced consistent findings with the main results.

ConclusionWe do not have sufficient evidence to show the efficacy of AP in mild COVID-19 infections. Interestingly, we observed the potentially harmful signal of using AP. While waiting for insights from ongoing trials, APs use in this condition should be done with caution.

Key pointsO_ST_ABSWhat is already known about this subject?C_ST_ABS- Andrographis paniculata (AP) has been used to treat COVID-19 in Thailand since early 2020.
- Clinical evidence supporting the use of AP in COVID-19 infections is still lacking.

What does this study add?- We had insufficient evidence to show the efficacy of using AP in mild COVID-19 cases.
- AP might be potentially associated with an increased risk of pneumonia.

How might this impact clinical practice?- While waiting for ongoing trials, the use of APs in COVID-19 patients should be suspended.


title: Vaccines Elicit Highly Cross-Reactive Cellular Immunity to the SARS-CoV-2 Omicron Variant

abstract: The highly mutated SARS-CoV-2 Omicron (B.1.1.529) variant has been shown to evade a substantial fraction of neutralizing antibody responses elicited by current vaccines that encode the WA1/2020 Spike immunogen1, resulting in increased breakthrough infections and reduced vaccine efficacy. Cellular immune responses, particularly CD8+ T cell responses, are likely critical for protection against severe SARS-CoV-2 disease2-6. Here we show that cellular immunity induced by current SARS-CoV-2 vaccines is highly cross-reactive against the SARS-CoV-2 Omicron variant. Individuals who received Ad26.COV2.S or BNT162b2 vaccines demonstrated durable CD8+ and CD4+ T cell responses that showed extensive cross-reactivity against both the Delta and Omicron variants, including in central and effector memory cellular subpopulations. Median Omicron-specific CD8+ T cell responses were 82-84% of WA1/2020-specific CD8+ T cell responses. These data suggest that current vaccines may provide considerable protection against severe disease with the SARS-CoV-2 Omicron variant despite the substantial reduction of neutralizing antibody responses.


title: One year landscape of the inactivated virus vaccine triggered RBD-specific IgG, IgM and IgA responses against the Omicron variant

abstract: We reported the first map of vaccine stimulated RBD-specific antibody responses (IgG, IgM and IgA) against the Omicron variant. We generated the map using a protein microarray, by analyzing longitudinal sera collected spanning one year from individuals immunized with 3 doses of an inactivated virus vaccine. The IgG response to RBD-Omicron is: 1/3-1/5 that of RBD-wild type; [~]6x higher for the booster dose vs. the 2nd dose; and reaches the plateau in about two weeks after the booster dose, then drops [~]5x in another two weeks. Similar results were also obtained for IgM and IgA. Because of the high correlation between RBD-specific antibody response and the neutralization activity to authentic virus, we at least indirectly revealed the landscape of antibody protection against the Omicron variant throughout the vaccination stages. Our results strongly support the necessity of booster vaccination. However, post-booster vaccination may need to be considered.


title: Target attainment of extended-interval dosing of tobramycin in patients less than five years of age with cystic fibrosis: A pharmacokinetic analysis.

abstract:
BackgroundExtended interval dosing (EID) of tobramycin is recommended for treatment of pulmonary exacerbations in adults and older children with cystic fibrosis (CF), but data are limited in patients less than 5 years of age.

MethodsWe performed a retrospective population pharmacokinetic (PK) analysis of hospitalized children with CF <5 years of age prescribed intravenous tobramycin for a pulmonary exacerbation from March 2011 to September 2018 at our hospital. Children with normal renal function who had [≥]1 tobramycin concentration available were included. Nonlinear mixed effects population PK modeling was performed using NONMEM(R) using data from the first 48 hours of tobramycin treatment. Monte Carlo simulations were implemented to determine the fraction of simulated patients that met published therapeutic targets with regimens of 10-15 mg/kg/day once daily dosing.

ResultsFifty-eight patients received 111 tobramycin courses (range 1-9/patient). A 2-compartment model best described the data. Age, glomerular filtration rate, and vancomycin coadministration were significant covariates on tobramycin clearance. The typical values of clearance and central volume of distribution were 0.252 L/hr/kg^0.75 and 0.308 L/kg, respectively. No once daily regimens achieved all pre-specified targets simultaneously in >75% of simulated subjects. A dosage of 13 mg/kg/dose best met the predefined targets of Cmax >25 mg/L and AUC24 of 80-120 mg*h/L.

ConclusionsBased on our population PK analysis and simulations, once daily dosing of tobramycin would not achieve all therapeutic goals in young patients with CF. However, extended-interval dosing regimens may attain therapeutic targets in the majority of young patients.


title: Estimation the state of the Covid-19 epidemic curve in Mayotte

abstract: We study in this work some statistical methods to estimate the parameters resulting from the use of an age-structured contact mathematical epidemic model in order to analyze the evolution of the epidemic curve of Covid-19 in the French overseas department Mayotte from march 13, 2020 to february 26,2021. Using several statistic methods based on time dependent method, maximum likelihood, mixture method, we fit the probability distribution which underlines the serial interval distribution and we give an adapted version of the generation time distribution from Package R0. The best-fit model of the serial interval was given by a mixture of Weibull distribution. Furthermore this estimation allows to obtain the evolution of the time varying effective reproduction number and hence the temporal transmission rates. Finally based on others known estimates parameters we incorporate the estimated parameters in the model in order to give an approximation of the epidemic curve in Mayotte under the conditions of the model. We also discuss the limit of our study and the conclusion concerned a probable impact of non pharmacological interventions of the Covid-19 in Mayotte such us the re-infection cases and the introduction of the variants which probably affect the estimates.


title: Estimating the state of the Covid-19 epidemic curve in Mayotte during the period without vaccination


title: Natural history and epidemiology of cleft lip and palate: a registry-based study in Iran (2000-19)

abstract: The aim of this study was to provide the natural history and epidemiology of cleft lip and cleft palate in the northwest region of Iran between 2000 and 2019. Since 2000, infants born with birth defects have been registered in the Tabriz Registry of Congenital Anomalies (TRoCA). For this study, the information and data were collected using the TRoCA registry system. Prevalence of cleft lip and cleft palate was 1.48 (95% CI 1.34; 1.62) per 1000 live births over the past two decades in the region. The occurrence of cleft lip and cleft palate was more common in males than females. The fetal death ratio was 5 percent of live born children. The proportion of infants with cleft lip and cleft palate surviving to the second week was 54 percent. The results may have a role in planning and evaluating the strategies for primary prevention of cleft lip and cleft palate, particularly in high-risk populations.


title: Factors predicting serum clozapine levels in Middle Eastern patients

abstract:
BackgroundDespite its superiority over other drugs for psychosis, clozapine remains underused and is associated with many clinical challenges, including difficulties in predicting serum levels. We found no large or recent study that investigated the determinants of serum clozapine levels in Middle Eastern patients. We thus investigated the association between clozapine dose and serum levels and the clinical predictors of clozapine serum levels in Middle Eastern patients.

MethodsThis was a cross-sectional study including 94 patients of Middle Eastern ethnicity attending the Clozapine Clinic in King Saud University Medical City in Riyadh, Saudi Arabia.

ResultsThe average clozapine dose and serum level were 400 mg/daily and 705 ng/mL, respectively. Clozapine dose and serum levels were positively correlated (rs [94]=0.32, p=0.002). We generated a predictive model of serum clozapine levels which revealed that the daily dose, smoking status, use of fluvoxamine or lamotrigine, and body mass index (BMI) predicted 43.6% of the variance in serum levels (p<0.001). Using this model, we calculated that the maximum doses of clozapine to avoid levels above the optimal range (>650 ng/mL) were 300, 250, or 225 mg/day for non-smokers with a body mass index of 25, 30, or 35 kg/m2, respectively, and 475, 425, or 400 mg/day for smokers with a body mass index of 25, 30, or 35 kg/m2, respectively.

ConclusionsThis is a naturalistic study of the clozapine dose-level relationship and the clinical predictors of serum clozapine levels in Middle Eastern patients. These findings do not reduce the value of individualised therapeutic drug monitoring but may assist clinicians when prescribing clozapine to Middle Eastern patients. Further psychopharmacological studies are needed on this demographic population.


title: Factors predicting serum clozapine levels in Middle Eastern patients: an observational study


title: Cognitive predictors of vaccine hesitancy and COVID-19 mitigation behaviors in a population representative sample

abstract: With the continued threat of COVID-19, predictors of vaccination hesitancy and mitigation behaviors are critical to identify. Prior studies have found that cognitive factors are associated with some COVID-19 mitigation behaviors, but few studies employ representative samples and to our knowledge no prior studies have examined cognitive predictors of vaccine hesitancy. The purpose of the present study, conducted among a large national sample of Canadian adults, was to examine associations between cognitive variables (executive function, delay discounting, and temporal orientation) and COVID-19 mitigation behaviors (vaccination, mask wearing, social distancing, and hand hygiene). Findings revealed that individuals with few executive function deficits, limited delay discounting and who adopted a generally future-orientation mindset were more likely to be double-vaccinated and to report performing COVID-19 mitigation behaviors with high consistency. The most reliable findings were for delay discounting and future orientation, with executive function deficits predicting mask wearing and hand hygiene behaviors but not distancing and vaccination. These findings identify candidate mediators and moderators for health communication messages targeting COVID-19 mitigation behaviors and vaccine hesitancy.


title: The NILS study protocol - a retrospective validation study of a preoperative decision-making tool for non-invasive lymph node staging in women with primary breast cancer .

abstract:
BackgroundRoutine preoperative axillary ultrasonography has proven insufficient for detecting low-burden nodal metastatic deposits. For the majority of newly diagnosed breast cancer patients presenting with clinical T1-T2 N0 disease, the standard axillary staging by sentinel lymph node biopsy is not therapeutic. The pilot non-invasive lymph node staging (NILS) artificial neural network (ANN) model to predict nodal status was published in 2019. The aim of the current study is to assess the performance measures of the model for the prediction of healthy lymph nodes in clinically N0 breast cancer patients at two breast cancer centers in Sweden.

MethodsThis bicenter, observational, retrospective study has been designed to validate the NILS prediction model for nodal status using preoperatively collected clinicopathological and radiological data. A web-based implementation of the nodal status classifier has been developed and will be used in this study, resulting in an estimated probability of healthy lymph nodes for each study participant. Our primary endpoint is to report on the performance of the NILS prediction model to distinguish between healthy and metastatic lymph nodes (discrimination, N0 vs. N+) and compare the observed and predicted event rates of benign axillary nodal status (calibration).

DiscussionInternationally, there are numerous artificial intelligence projects involving non-invasive identification of N0 breast cancer. Here, we present a robust validation study based on external cohorts of our ANN model. Although validation is necessary to show generalizability, it is often overlooked. If the accuracy and discrimination reach a satisfactory level, our prediction tool can be implemented to assist medical professionals and breast cancer patients in shared decision-making on omitting sentinel node biopsy in patients predicted to be node-negative. In future, this may potentially save healthcare resources and reduce costs and adverse side effects. In addition, our study might prompt future studies of nodal metastases of malignancies in other organs, and thus might have implications beyond breast cancer.

Trial registrationThis study has been prospectively registered in the ISRCTN registry, identification number: 14341750

category: oncology


title: Up-regulated tumor intrinsic growth potential and decreased immune function orchestrate the evolution of lung adenocarcinoma

abstract:
IntroductionLung adenocarcinoma is the most common pathological subtype of lung cancer. Precursors of lung adenocarcinoma, namely adenocarcinoma in situ and minimally invasive adenocarcinoma, have a superb 5-year survival rate after surgical resection. A deeper understanding of the key genetic changes driving the progression of lung adenocarcinoma is needed.

MethodsIn this study, we performed whole-exome sequencing and RNA-sequencing on surgically resected 24 AIS, 74 MIA, 99 LUAD specimens and their adjacent paired normal tissues. Radiological, clinical, and pathological characteristics were recorded. Gene expression patterns were identified to find key pathways driving the progression of lung adenocarcinoma. Furthermore, genomic alterations and differential expression analyses were performed to compare tumors with different radiological manifestations. Finally, a progressive index was developed to quantitatively measure the level of imbalance between tumor intrinsic growth potential and immune microenvironment.

Results12 patterns of gene expression were identified. Pathways associated with tumor growth and metastasis were found to be up-regulated as tumors progressed, while pathways associated with immune function were found to be down-regulated. Deconvolution of RNA-seq data also showed a decrease of CD8+ T cells and an increase of Tregs as the tumors progressed. Furthermore, tumors with more solid components on CT scan had a higher mutation frequency of tumor suppressor genes, higher tumor mutation burden and higher frequency of somatic copy number alterations. Finally, tumor progressive index demonstrated an increasing trend with the progression of lung adenocarcinoma.

DiscussionOur results reveal the imbalance of tumor intrinsic factors and immune function orchestrate the progression of lung adenocarcinoma.


title: Large household reduces dementia mortality.

abstract:
BackgroundLarge households/families create more positive psychological well-being which may offer a life course protection against dementia development and deliver more comprehensive healthcare to dementia patients.

MethodsDementia specific mortality rates of the 183 member states of World Health Organization were calculated and matched with the respective country data on household size, Gross Domestic Product (GDP), urban and ageing. Scatter plots were produced to explore and visualize the correlations between household size and dementia mortality rates. Pearsons and nonparametric correlations were used to evaluate the strength and direction of the associations between household size and all other variables. Partial correlation of Pearsons moment-product approach was used to identify that household size protects against dementia regardless of the competing effects from ageing, GDP and urbanization. Multiple regression identified large household was a significant predictor of dementia mortality.

ResultsHousehold size was in a negative and moderately strong correlation (r = -0.6034, p < 0.001) with dementia mortality. This relationship was confirmed in both Pearson r (r= - 0.524, p<0.001) and nonparametric (rho{square}={square}-0.579, p{square}<{square}0.001) analyses. Regardless of the contribution of ageing, SES and urban lifestyle to dementia mortality, large household was an independent predictor of dementia mortality (r = -0.331, p <0.001) in partial correlation analysis. Stepwise multiple regression analysis selected large household as the variable having the greatest contribution to dementia mortality with R2 = 0.263 while ageing was placed second increasing R2 to 0.259. GDP and urbanization were removed as having no statistically significant influence on dementia mortality.

ConclusionsIndependent of ageing, urbanization and GDP, large household protects against dementia mortality. As part of dementia prevention, healthcare practitioners should encourage people to increase their positive interactions with persons from their neighbourhood or other fields where large household/family size is hard to achieve.


title: Integrin/TGF-Beta1 inhibitor GLPG-0187 blocks SARS-CoV-2 Delta and Omicron pseudovirus infection of airway epithelial cells which could attenuate disease severity

abstract: As COVID-19 continues to pose major risk for vulnerable populations including the elderly, immunocompromised, patients with cancer, and those with contraindications to vaccination, novel treatment strategies are urgently needed. SARS-CoV-2 infects target cells via RGD-binding integrins either independently or as a co-receptor with surface receptor angiotensin-converting enzyme 2 (ACE2). We used pan-integrin inhibitor GLPG-0187 to demonstrate blockade of SARS-CoV-2 pseudovirus infection of target cells. Omicron pseudovirus infected normal human small airway epithelial (HSAE) cells significantly less than D614G or Delta variant pseudovirus, and GLPG-0187 effectively blocked SARS-CoV-2 pseudovirus infection in a dose-dependent manner across multiple viral variants. GLPG-0187 inhibited Omicron and Delta pseudovirus infection of HSAE cells more significantly than other variants. Pre-treatment of HSAE cells with MEK inhibitor (MEKi) VS-6766 enhanced inhibition of pseudovirus infection by GLPG-0187. Because integrins activate TGF-{beta} signaling, we compared plasma levels of active and total TGF-{beta} in COVID-19+ patients. Plasma TGF-{beta}1 levels correlated with age, race, and number of medications upon presentation with COVID-19, but not with sex. Total plasma TGF-{beta}1 levels correlated with activated TGF-{beta}1 levels. In our preclinical studies, Omicron infects lower airway lung cells less efficiently than other COVID-19 variants. Moreover, inhibition of integrin signaling prevents SARS-CoV-2 Delta and Omicron pseudovirus infectivity, and may mitigate COVID-19 severity through decreased TGF-{beta}1 activation. This therapeutic strategy may be further explored through clinical testing in vulnerable and unvaccinated populations.


title: Regional pleural strain measurements during mechanical ventilation using ultrasound elastography: A randomised, crossover, proof of concept physiologic study

abstract:
BackgroundMechanical ventilation is a common therapy in operating rooms and intensive care units. When ill-adapted, it can lead to ventilator-induced lung injury (VILI), which is associated with poor outcomes. Excessive regional pulmonary strain is thought to be a major mechanism responsible for VILI. Scarce bedside methods exist to measure regional pulmonary strain. We propose a novel way to measure regional pleural strain using ultrasound elastography.

Research QuestionThe objective of this study was to assess the feasibility and reliability of pleural strain measurement by ultrasound elastography and to determine if elastography parameters would correlate with varying tidal volumes.

Study Design and MethodsA single-blind randomized crossover proof of concept study was conducted July to October 2017 at a tertiary care referral center. Ten patients requiring general anesthesia for elective surgery were recruited. After induction, patients were received tidal volumes of 6, 8, 10 and 12 mL.kg-1 in random order, while pleural ultrasound cineloops were acquired at 4 standardized locations. Ultrasound radiofrequency speckle tracking allowed computing various pleural translation, strain and shear components. These were screened to identify those with the best dose-response with tidal volumes using linear mixed effect models. Goodness-of-fit was assessed by the coefficient of determination. Intraobserver, interobserver and test-retest reliability were calculated using intraclass correlation coefficients.

ResultsAnalysis was possible in 90.7% of ultrasound cineloops. Lateral absolute shear, lateral absolute strain and Von Mises strain varied significantly with tidal volume and offered the best dose-responses and data modelling fits. Point estimates for intraobserver reliability measures were excellent for all 3 parameters (0.94, 0.94 and 0.93, respectively). Point estimates for interobserver (0.84, 0.83 and 0.77, respectively) and test-retest (0.85, 0.82 and 0.76, respectively) reliability measures were good.

InterpretationStrain imaging is feasible and reproducible, and may eventually guide mechanical ventilation strategies in larger cohorts of patients.

category: anesthesia


title: Estimating protection afforded by prior infection in preventing reinfection: Applying the test-negative study design

abstract:
BackgroundThe Coronavirus Disease 2019 (COVID-19) pandemic has highlighted an urgent need to use infection testing databases to rapidly estimate effectiveness of prior infection in preventing reinfection (PES) by novel variants of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

MethodsMathematical modeling was used to demonstrate the applicability of the test-negative, case-control study design to derive PES. Modeling was also used to investigate effects of bias in PES estimation. The test-negative design was applied to national-level testing data in Qatar to estimate PES for SARS-CoV-2 infection and to validate this design.

ResultsApart from the very early phase of an epidemic, the difference between the test-negative estimate for PES and the true value of PES was minimal and became negligible as the epidemic progressed. The test-negative design provided robust estimation of PES even when PES began to wane after prior infection. Assuming that only 25% of prior infections are documented, misclassification of prior infection status underestimated PES, but the underestimate was considerable only when >50% of the population was ever infected. Misclassification of latent infection, misclassification of current active infection, and scale-up of vaccination all resulted in negligible bias in estimated PES. PES against SARS-CoV-2 Alpha and Beta variants was estimated at 97.0% (95% CI: 93.6-98.6) and 85.5% (95% CI: 82.4-88.1), respectively. These estimates were validated using a cohort study design.

ConclusionsThe test-negative design offers a feasible, robust method to estimate protection from prior infection in preventing reinfection.


title: Statistical and agent-based modelling of the transmissibility of different SARS-CoV-2 variants in England and impact of different interventions

abstract: The English SARS-CoV-2 epidemic has been affected by the emergence of new viral variants such as B.1.177, Alpha and Delta, and changing restrictions. We used statistical models and calibration of an stochastic agent-based model Covasim to estimate B.1.177 to be 20% more transmissible than the wild type, Alpha to be 50-80% more transmissible than B.1.177 and Delta to be 65-90% more transmissible than Alpha. We used these estimates in Covasim (calibrated between September 01, 2020 and June 20, 2021), in June 2021, to explore whether planned relaxation of restrictions should proceed or be delayed. We found that due to the high transmissibility of Delta, resurgence in infections driven by the Delta variant would not be prevented, but would be strongly reduced by delaying the relaxation of restrictions by one month and with continued vaccination.


title: Rare schizophrenia risk variant burden is conserved in diverse human populations

abstract: Schizophrenia is a chronic mental illness that is amongst the most debilitating conditions encountered in medical practice. A recent landmark schizophrenia study of the protein-coding regions of the genome identified a causal role for ten genes and a concentration of rare variant signals in evolutionarily constrained genes1. This study -- and most other large-scale human genetic studies -- was mainly composed of individuals of European ancestry, and the generalizability of the findings in non-European populations is unclear. To address this gap in knowledge, we designed a custom sequencing panel based on current knowledge of the genetic architecture of schizophrenia and applied it to a new cohort of 22,135 individuals of diverse ancestries. Replicating earlier work, cases carried a significantly higher burden of rare protein-truncating variants among constrained genes (OR=1.48, p-value = 5.4 x 10-6). In meta-analyses with existing schizophrenia datasets totaling up to 35,828 cases and 107,877 controls, this excess burden was largely consistent across five continental populations. Two genes (SRRM2 and AKAP11) were newly implicated as schizophrenia risk genes, and one gene (PCLO) was identified as a shared risk gene for schizophrenia and autism. Overall, our results lend robust support to the rare allelic spectrum of the genetic architecture of schizophrenia being conserved across diverse human populations.


title: Mapping the antigenic diversification of SARS-CoV-2

abstract: Large-scale vaccination campaigns have prevented countless SARS-CoV-2 infections, hospitalizations and deaths. However, the emergence of variants that escape from immunity challenges the effectiveness of current vaccines. Given this continuing evolution, an important question is when and how to update SARS-CoV-2 vaccines to antigenically match circulating variants, similar to seasonal influenza viruses where antigenic drift necessitates periodic vaccine updates. Here, we studied SARS-CoV-2 antigenic drift by assessing neutralizing activity against variants-of-concern (VOCs) of a unique set of sera from patients infected with a range of VOCs. Infections with ancestral or Alpha strains induced the broadest immunity, while individuals infected with other VOCs had more strain-specific responses. Omicron was substantially resistant to neutralization by sera elicited by all other variants. Antigenic cartography revealed that all VOCs preceding Omicron belong to one antigenic cluster, while Omicron forms a new antigenic cluster associated with immune escape and likely requiring vaccine updates to ensure vaccine effectiveness.


title: The hyper-transmissible SARS-CoV-2 Omicron variant exhibits significant antigenic change, vaccine escape and a switch in cell entry mechanism

abstract: Vaccines based on the spike protein of SARS-CoV-2 are a cornerstone of the public health response to COVID-19. The emergence of hypermutated, increasingly transmissible variants of concern (VOCs) threaten this strategy. Omicron, the fifth VOC to be described, harbours 30 amino acid mutations in spike including 15 in the receptor-binding domain. Here, we demonstrate substantial evasion of neutralisation by Omicron in vitro using sera from vaccinated individuals. Importantly, these data are mirrored by a substantial reduction in real-world vaccine effectiveness that is partially restored by booster vaccination. We also demonstrate that Omicron does not induce cell syncytia and favours a TMPRSS2-independent endosomal entry pathway. Such marked changes in antigenicity and replicative biology may underlie the rapid global spread and altered pathogenicity of the Omicron variant.


title: Shielding individuals at high risk of COVID-19: a micro-simulation study

abstract:
BackgroundOne of the proposed interventions for mitigating COVID-19 epidemics, particularly in low-income and crisis-affected settings, is to physically isolate individuals known to be at high risk of severe disease and death due to age or co-morbidities. This intervention, known as  shielding, could be implemented in various ways. If shielded people are grouped together in residences and isolation is imperfect, any introduction of infections within the shielding group could cause substantial mortality and thus negate the interventions benefits. We explored the effectiveness of shielding under various modalities of implementation and considered mitigation measures to reduce its possible harms.

MethodsWe used an individual-based mathematical model to simulate the evolution of a COVID-19 epidemic in a population of which a fraction above a given age cut-off are relocated to shielding residences, in which they have variable levels of contacts with their original household, the outside world and fellow shielding residents. We set our simulation with the context of an internally displaced persons camp in Somaliland, for which we had recently collected data on household demographics and social mixing patterns. We compared an unmitigated epidemic with a shielding intervention accompanied by various measures to reduce the risk of virus introduction and spread within the shielding residences. We did sensitivity analyses to explore parameters such as residence size, reduction in contacts, basic reproduction number, and prior immunity in the population.

ResultsShielded residences are likely to be breached with infection during the outbreak. Nonetheless, shielding can be effective in preventing COVID-19 infections in the shielded population. The effectiveness of shielding is mostly affected by the size of the shielded residence, and by the degree by which contacts between shielded and unshielded individuals are reduced. Reductions in contacts between shielded individuals could further increase the effectiveness of shielding, but is only effective in larger shielded residences. Large shielded residences increase the risk of infection, unless very large reductions in contacts can be achieved. In epidemics with a lower reproduction number, the effectiveness of shielding could be negative effectiveness.

DiscussionShielding could be an effective method to protect the most at-risk individuals. It should be considered where other measures cannot easily be implemented, but with attention to the epidemiological situation. Shielding should only be implemented through small to medium-sized shielding residences, with appropriate mitigation measures such as reduced contact intensity between shielded individuals and self-isolation of cases to prevent subsequent spread.


title: Statistical Inference Using GLEaM Model with Spatial Heterogeneity and Correlation between Regions

abstract: A better understanding of the various patterns in the coronavirus disease 2019 (COVID-19) spread in different parts of the world is crucial to its prevention and control. Motivated by the celebrated GLEaM model (Balcan et al., 2010[1]), this paper proposes a stochastic dynamic model to depict the evolution of COVID-19. The model allows spatial and temporal heterogeneity of transmission parameters and involves transportation between regions. Based on the proposed model, this paper also designs a two-step procedure for parameter inference, which utilizes the correlation between regions through a prior distribution that imposes graph Laplacian regularization on transmission parameters. Experiments on simulated data and real-world data in China and Europe indicate that the proposed model achieves higher accuracy in predicting the newly confirmed cases than baseline models.


title: The common H202D variant in GDF-15 does not affect its bioactivity but can significantly interfere with measurement of its circulating levels

abstract: Genetic variants in proteins can interfere with measurement of their circulating concentrations. Given the growing biomedical importance of GDF-15, we wished to establish whether a common histidine to aspartate variant present in position 6 of the mature GDF-15 protein (H202D variant) interfered with its measurement by two commonly used immunoassays. We first examined the detectability of recombinant monomers, homodimers and heterodimers of GDF-15 by assays and/or reagents used in two widely used immunoassays (Roche Elecsys(R) GDF-15 and the R&D antibody combinations used in their Quantikine(R) and DuoSet(R) ELISAs). The Roche assay detected the H and D containing peptides similarly but the assays based on the R&D reagents consistently underreported concentrations of the D-containing variant peptide. Measurements of plasma concentrations of GDF-15 in genotyped human participants showed that the R&D reagents reported values in heterozygotes were [~]25% lower, and in homozygotes, 50% lower than the Roche assay. We finally studied the activation of the GDF-15 receptor, GFRAL-Ret, in a cell based assay and found that the activities of the HH and DD containing GDF-15 peptide were indistinguishable. These results have implications for the interpretation of genetic epidemiological studies which have used the R&D reagents to measure GDF-15, and for the emerging clinical use of GDF-15 as a diagnostic and prognostic biomarker. We provide correction equations, which may be of utility for the analysis of data generated with the R&D reagents where the genotype of the participants is known.


title: The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources

abstract:
PURPOSESeveral groups and resources provide information that pertains to the validity of gene-disease relationships used in genomic medicine and research; however, universal standards and terminologies to define the evidence base for the role of a gene in disease, and a single harmonized resource were lacking. To tackle this issue, the Gene Curation Coalition (GenCC) was formed.

METHODSThe GenCC drafted harmonized definitions for differing levels of gene-disease validity based on existing resources, and performed a modified Delphi survey with three rounds to narrow the list of terms. The GenCC also developed a unified database to display curated gene-disease validity assertions from its members.

RESULTSBased on 241 survey responses from the genetics community, a consensus term set was chosen for grading gene-disease validity and database submissions. As of December 2021, the database contains 15,241 gene-disease assertions on 4,569 unique genes from 12 submitters. When comparing submissions to the database from distinct sources, conflicts in assertions of gene-disease validity ranged from 5.3% to 13.4%.

CONCLUSIONTerminology standardization, sharing of gene-disease validity classifications, and resolution of curation conflicts will facilitate collaborations across international curation efforts and in turn, improve consistency in genetic testing and variant interpretation.


title: Antibody response to SARS-CoV-2 mRNA vaccine in lung cancer patients: Reactivity to vaccine antigen and variants of concern.

abstract:
PurposeWe investigated SARS-CoV-2 mRNA vaccine-induced binding and live-virus neutralizing antibody response in NSCLC patients to the SARS-CoV-2 wild type strain and the emerging Delta and Omicron variants.

Methods82 NSCLC patients and 53 healthy adult volunteers who received SARS-CoV-2 mRNA vaccines were included in the study. Blood was collected longitudinally, and SARS-CoV-2-specific binding and live-virus neutralization response to 614D (WT), B.1.617.2 (Delta), B.1.351 (Beta) and B.1.1.529 (Omicron) variants were evaluated by Meso Scale Discovery (MSD) assay and Focus Reduction Neutralization Assay (FRNT) respectively. We determined the longevity and persistence of vaccine-induced antibody response in NSCLC patients. The effect of vaccine-type, age, gender, race and cancer therapy on the antibody response was evaluated.

ResultsBinding antibody titer to the mRNA vaccines were lower in the NSCLC patients compared to the healthy volunteers (P=<0.0001). More importantly, NSCLC patients had reduced live-virus neutralizing activity compared to the healthy vaccinees (P=<0.0001). Spike and RBD-specific binding IgG titers peaked after a week following the second vaccine dose and declined after six months (P=<0.001). While patients >70 years had lower IgG titers (P=<0.01), patients receiving either PD-1 monotherapy, chemotherapy or a combination of both did not have a significant impact on the antibody response. Binding antibody titers to the Delta and Beta variants were lower compared to the WT strain (P=<0.0001). Importantly, we observed significantly lower FRNT50 titers to Delta (6-fold), and Omicron (79-fold) variants (P=<0.0001) in NSCLC patients.

ConclusionsBinding and live-virus neutralizing antibody titers to SARS-CoV-2 mRNA vaccines in NSCLC patients were lower than the healthy vaccinees, with significantly lower live-virus neutralization of B.1.617.2 (Delta), and more importantly, the B.1.1.529 (Omicron) variant compared to the wild-type strain. These data highlight the concern for cancer patients given the rapid spread of SARS-CoV-2 Omicron variant.


title: Nurses Perceptions regarding Current Skills in Minimizing Patient Aggression at a selected Psychiatric hospital in Lesotho

abstract:
BackgroundMeta-analysis of international literature indicate high frequencies of aggression in mental health setting. Several studies indicate that among professional health workers, nurses are more likely than other staff members to experience aggressive incidences from patients. Furthermore, based on cause, nurses apply range of interventions in managing aggression, however, despite their perceived value of their intervention in managing aggression, no single intervention is sufficient for handling aggressive patients to stay in control in wards. Despite high priority placed on patient aggression management, insufficient research studies have been conducted on nurses perceptions regarding current skills in minimizing patients aggression.

ObjectivesThe purpose of the study was to describe nurses perceptions regarding current assessment skills in minimizing patients aggression at selected Psychiatric hospital.

MethodologyNon-experimental, exploratory, descriptive research design was used to guide research process. All-inclusive sampling method was used with 119 nurses as respondents. Data was collected by means of a questionnaire, analyzed using SPSS version 25. Descriptive statistics procedure was used to present findings of the study.

ResultsMinority of respondents, (n=27) 22.7% agreed that their current assessment skills for minimizing patients aggression were good compared to majority of respondents, (n=92) 77.3%, who expressed a different opinion. This suggests that there is limited current assessment skills in identifying high risk aggressive patients in a selected Psychiatric hospital.

ConclusionThe findings of study indicate that there is limited current assessment skills in minimizing patients aggression at selected Psychiatric hospital. Therefore, there is need to provide comprehensive information on nurses current skills in minimizing patients aggression to obtain richer information.


title: Comparison of infectious SARS-CoV-2 from the nasopharynx of vaccinated and unvaccinated individuals

abstract: The frequency of SARS-CoV-2 breakthrough infections in fully vaccinated individuals increased with the emergence of the Delta variant, particularly with longer time from vaccine completion. However, whether breakthrough infections lead to onward transmission remains unclear. Here, we conducted a study involving 125 patients comprised of 72 vaccinated and 53 unvaccinated individuals, to assess the levels of infectious virus in vaccinated and unvaccinated individuals. Quantitative plaque assays showed no significant differences in the titers of virus between these cohorts. However, the proportion of nasopharyngeal samples with culturable virus was lower in the vaccinated patients relative to unvaccinated patients (21% vs. 40%). Finally, time-to-event analysis with Kaplan-Myer curves revealed that protection from culturable infectious virus waned significantly starting at 5 months after completing a 2-dose regimen of mRNA vaccines. These results have important implications in timing of booster dose to prevent onward transmission from breakthrough cases.


title: MEDIATION ANALYSIS TO INFORM POLICY ON CORONARY REVASCULARIZATION BY EXPECTED TIME TO TREATMENT: ANALYTICAL FRAMEWORK

abstract:
ObjectivesClinical guidelines favour coronary artery bypass grafting (CABG) over percutaneous coronary intervention (PCI) for patients with stable complex coronary disease. Yet the benefit of CABG as established in trials may not be generalizable to populations in which treatment method determines time to treatment, typically being longer for CABG. For cases in which the cardiac anatomy is suitable for either treatment, it is unclear whether it is appropriate to recommend CABG, which is likely to be delayed, if PCI can be performed sooner. This paper outlines an analytical framework for a policy analysis of the timing of coronary revascularization.

MethodsWe constructed a thought experiment to examine whether time to treatment will influence the advantage of CABG. We substantiated the use of mediation analysis to estimate the extent to which differences in outcomes between CABG and PCI would change if times to CABG were the same as times to PCI.

ResultsWe designed a study that uses data from a population-based patient registry to obtain effect measures of mediation analysis: the total effect, the natural indirect effect, and the natural direct effect. The partitioning of the total effect will allow us to estimate the proportional reduction in the risk of an outcome if the time to CABG was similar to that of PCI.

InterpretationTreatment recommendation, resource allocation and scheduling benchmarks will be guided by understanding the extent to which the time to treatment mediates the relation between revascularization method and outcome.

category: health systems and quality improvement