title: An outbreak inside an outbreak: rising incidence of carbapenem-resistant isolates during the COVID-19 pandemic. Report from a tertiary care center in Argentina.

abstract:
IntroductionCOVID-19 outbreaks have left us to deal with an aftermath on many fronts. In particular, disproportionate use of antibiotics, high ICU burden and longer in-hospital stays during the pandemic have been proposed to aggravate the emergency posed by carbapenem-resistant isolates (CRI), specially through carbapenemase production. However, there have been few reports worldwide regarding changes in CRI incidence and little latinamerican literature.

ObjectiveWe set out to determine whether the incidence of CRI rose in a tertiary care center in Santa Fe, Argentina during the time period with active cases of COVID-19.

MethodsAnalytic epidemiologic study retrospectively designed. Two time periods were defined: P1 (without active cases of COVID-19) from September, 2019 to August, 2020 and P2 (starting at the onset of the first wave of COVID-19 in this institution) from September, 2020 to June 2021. All clinically-relevant microbiological samples -those meant for diagnostic purposes-taken during the study period from patients in the Internal Medicine and Surgical wards as well as the Intensive Care Units were included. Incidence was calculated by dividing the number of CRI during each time frame by the count of patient-day during that same period, multiplied by a hundred.

Results9,135 hospitalizations, 50,145 patient-days of analysis. A total of 7285 clinical samples were taken, with an overall positivity for CRI of 12.1% (n=883). Overall CRI incidence during P2 was 2.5 times higher than in P1 (2.52 vs 0.955/100 patient-days, p <0.001). ICU CRI incidence raised from 6.78 to 8.69/100 patient-days in P2 (p=0.006).

ConclusionWe found alarming rates of CRI in our center, 2.5 times higher than previous to the first COVID-19 wave, similar to other reports worldwide. To our knowledge, this is one of the few Latin-American reports on the effect of the COVID-19 pandemic on CRI incidence.


title: Age and product dependent vaccine effectiveness against SARS-CoV-2 infection and hospitalisation among adults in Norway: a national cohort study, January to September 2021.

abstract:
BackgroundSARS-CoV-2 vaccines show high effectiveness against infection and (severe) disease. However, few studies estimate population level vaccine effectiveness against multiple COVID-19 outcomes, by age and including homologous and heterologous vaccine regimens.

MethodsUsing Cox proportional hazard models on data from 4 293 544 individuals (99% of Norwegian adults), we estimated overall, age-, and product-specific vaccine effectiveness against SARS-CoV-2 infection, hospitalisation, ICU admission and death in Norway, using data from national registries. Vaccine status was included as time-dependent variable and we adjusted for sex, pre-existing medical conditions, country of birth, county of residence, and crowded living conditions.

FindingsAdjusted vaccine effectiveness among fully vaccinated is 72{middle dot}1% (71{middle dot}2-73{middle dot}0) against SARS-CoV-2 infection, 92{middle dot}9% (91{middle dot}2-94{middle dot}2) against hospitalisation, 95{middle dot}5% (92{middle dot}6-97{middle dot}2) against ICU admission, and 88{middle dot}0% (82{middle dot}5-91{middle dot}8) against death. Among partially vaccinated, the effectiveness is 24{middle dot}3% (22{middle dot}3-26{middle dot}2) against infection and 82{middle dot}7% (77{middle dot}7-86{middle dot}6) against hospitalisation. Vaccine effectiveness against infection is 84{middle dot}7% (83{middle dot}1-86{middle dot}1) for heterologous mRNA vaccine regimens, 78{middle dot}3% (76{middle dot}8-79{middle dot}7) for Spikevax (Moderna; mRNA-1273), 69{middle dot}7% (68{middle dot}6-70{middle dot}8) for Comirnaty (Pfizer/BioNTech; BNT162b2), and 60{middle dot}7% (57{middle dot}5-63{middle dot}6) for Vaxzevria (AstraZeneca; ChAdOx nCoV-19; AZD1222) with a mRNA dose among fully vaccinated.

InterpretationWe demonstrate good protection against SARS-CoV-2 infection and severe disease in fully vaccinated, including heterologous vaccine regimens, which could facilitate rapid immunization. Partially vaccinated were less likely to get severe disease than unvaccinated, though protection against infection was not as high, which could be essential in making vaccine prioritisation policies especially when availability is limited.

FundingNorwegian Institute of Public Health, Helse Bergen Health Trust

category: infectious diseases


title: Myocarditis After mRNA-1273 Vaccination: A Population-Based Analysis of 151 Million Vaccine Recipients Worldwide

abstract:
BackgroundGrowing evidence indicates a causal relationship between SARS-CoV-2 infection and myocarditis. Post-authorization safety data have also identified myocarditis as a rare safety event following mRNA COVID-19 vaccination, most notably among younger adult males and after dose 2. To further evaluate the potential risk after vaccination, we queried the Moderna global safety database to assess the occurrence of myocarditis/myopericarditis among mRNA-1273 vaccine recipients worldwide since first international Emergency Use Authorization issuance.

MethodsReports of myocarditis/myopericarditis entered into the Moderna global safety database from December 18, 2020 to September 30, 2021 were reviewed and classified based on the Brighton Collaboration case definition. The cumulative observed occurrence of myocarditis/myopericarditis was assessed by calculating the reported rate after any known dose of mRNA-1273 according to age and sex. This reporting rate was compared to a population-based incidence rate (US military) to calculate observed-to-expected rate ratios (RR).

ResultsThrough September 30, 2021, a total of 1,439 cases of myocarditis/myopericarditis among approximately 151.1 million mRNA-1273 vaccine recipients were reported to the Moderna global safety database. The overall reporting rate among all vaccine recipients was 0.95 cases per 100,000 vaccine recipients, which was lower than the expected rate from the reference population (2.12 cases per 100,000 vaccine recipients; RR [95% CI]: 0.45 [0.42-0.48]). When stratified by sex and age, observed rates were highest for males aged [≤]39 years, particularly those aged 18-24 years (7.40 cases per 100,000 vaccine recipients), which was higher than expected (RR [95% CI]: 3.49 [2.88-4.22]). For males and females aged <18 years, the rate ratio for myocarditis was 1.05 (95% CI, 0.52-2.13) and 0.21 (95% CI, 0.04-0.94), respectively. When considering only cases occurring within 7 days after vaccination, the observed rate was highest for males aged 18-24 years after dose 2 (4.9 cases per 100,000 doses administered).

ConclusionMyocarditis/myopericarditis accounted for 0.4% of adverse events reported to the Moderna global safety database after mRNA-1273 vaccination; rates were higher than expected in males aged 18-24 years, with most occurring by 7 days after dose 2, but were not higher than expected for the overall population of vaccine recipients and were lower than that observed in individuals infected with SARS-CoV-2.


title: Quantification and progress over time of specific antibodies against SARS-CoV-2 in breast milk of lactating women vaccinated with BNT162b2 Pfizer-BioNTech COVID-19 vaccine (LacCOVID)

abstract:
ImportanceTo our knowledge, this is the first study to analyze long-term passage (6 months after immunization) of specific antibodies induced by BNT162b2 COVID-19 vaccine through breast milk.

ObjectivesMain objective: to determine SARS-CoV-2 vaccine induced antibody levels in the breast milk of lactating women 4 weeks after mRNA BNT162b2 Pfizer-BioNTech COVID-19 complete vaccination.

Secondary objectives: to analyze SARS-CoV-2 antibody levels (breast milk and serum) at different time-points after vaccination, examine the correlation of SARS-CoV-2 antibody levels between serum and breast milk, describe adverse events related to vaccination (AErV) in both mothers and infants and determine the rate of COVID-19 infections.

DesignProspective cohort study between February and September 2021.

SettingParc Sanitari Sant Joan de Deu, an urban hospital in Spain.

ParticipantsDuring our health worker vaccination campaign at our hospital between January and March 2, we recruited 33 lactating women vaccinated with BNT162b2 Pfizer-BioNTech COVID-19.

ResultsA total of 33 volunteers were included in the study. The median (IQR) age of mothers was 38 (36-39) years and 15 (10-22) months for the infants.

Primary end-point: at 4 w after second dose median (IQR) IgG-S1 levels for serum-milk pairs were 12,478 (6,870-20,801) to 50.4 (24.3-104) arbitrary units (AU) per mL.

Secondary end-pointsSARS-CoV-2 antibody levels at different time-points were (serum-milk): 519 (234-937) to 1 (0-2.9) AU/mL at 2w after first dose, 18,644 (9,923-29,264) to 78 (33.7-128) AU/mL at 2w, 4,094 (2,413-8,480) to 19.9 (10.8-51.9) AU/mL at 12w, and 1,350 (831-2,298) to 8.9 (7.8-31.5) at 24w after second dose.

We found a positive correlation of SARS-CoV-2 antibody levels between serum and breast milk (Pearson correlation coefficient 0.68).

No serious AErV were observed.

We found two (6%) COVID-19 vaccine breakthrough infections.

ConclusionsPfizer-BioNTech COVID-19 vaccination is safe during breastfeeding and it transmits antibodies into breast milk with a positive correlation with serum levels, and both decrease over time in a 6-month follow-up. Infants of breastfeeding vaccinated women could be protected for at least six months after vaccination and serum determination of SARS-CoV-2 IgG-S1 could indicate the breastmilk levels of antibodies during this period.


title: Physical activity and health: Findings from Finnish monozygotic twin pairs discordant for physical activity

abstract: Genetic and early environmental differences including early health habits associate with future health. To provide insight on the causal nature of these associations, monozygotic (MZ) twin pairs discordant for health habits provide an interesting natural experiment. Twin pairs discordant for leisure-time physical activity (LTPA) in early adult life are thus a powerful study design to investigate the associations between long-term LTPA and indicators of health and wellbeing. We have used this study design by identifying 17 LTPA discordant twin pairs from two Finnish twin cohorts and summarize key findings of these studies in this paper. The carefully characterized rare long-term LTPA discordant MZ twin pairs have participated in multi-dimensional clinical examinations. The occurrence of type 2 diabetes and death has been evaluated on the basis of prospective questionnaire data and register follow-up among a larger number of twin pairs. Key findings highlight that, compared to less active twins in such MZ twin pairs, the twins with higher long-term LTPA have higher physical fitness, reduced body fat, reduced visceral fat, reduced liver fat, increased lumen diameters of conduit arteries to the lower limbs, increased bone mineral density in loaded bone areas, increased high-density lipoprotein cholesterol levels and reduced occurrence of type 2 diabetes. However, we have not been able to document differences in the life expectancy between the less and more active twin siblings of the LTPA discordant MZ twin pairs. The findings are in agreement with intervention studies but not with all observational studies in which genetic factors are not controlled for.

category: sports medicine


title: Development of a core measurement set for research in degenerative cervical myelopathy: a study protocol (AO Spine RECODE-DCM CMS)

abstract:
IntroductionProgress in degenerative cervical myelopathy (DCM) is hindered by inconsistent measurement and reporting of outcomes. This can, for example, impede the aggregation of data and comparison of outcomes between studies. This limitation can be reversed by developing a core measurement set (CMS) for use in DCM research. Previously, the AO Spine Research Objectives and Common Data Elements for DCM (AO Spine RECODE-DCM) defined  what should be measured in DCM: specifically, the core data elements and core outcome set of the disease. The next step of this initiative is to determine  how to measure these features. The current protocol outlines the steps necessary for the development of a CMS for DCM research and audit.

Methods and analysisThe CMS will be developed in accordance with the guidance developed by the Core Outcome Measures in Effectiveness Trials (COMET) and the Consensus-based Standards for the selection of health Measurement Instruments (COSMIN). The process will involve five phases: (1) agreement on the measurement constructs and approaches to their evaluation; (2) the formation of a long list of potential measurement instruments, by identifying existing instruments and assessing their psychometric properties; (3) the aggregation of evidence concerning  when measurements should be taken; (4) consensus about which instruments to include in the CMS; and (5) implementation.

Ethics and disseminationEthical approval was obtained from the University of Cambridge. Dissemination strategies to promote awareness and adoption of the CMS include peer-reviewed scientific publications; conference presentations; podcasts; the identification of AO Spine RECODE-DCM ambassadors; and engagement with relevant journals, funders, and the DCM community.

Impact of this workThe proposed project will enable standardised and comprehensive measurement in DCM clinical trials. The CMS will be established using a robust, global, and multi-stakeholder consensus process, with broad representation of healthcare professionals and individuals living with the disease. It will focus on measurement instruments currently in use. This ensures that the CMS will be immediately usable and suited for widespread adoption. The development of better outcome instruments in DCM remains a top 10 research priority and this work will hence facilitate knowledge generation for this important disease.

category: neurology


title: Intraoperative localization and preservation of reading in ventral occipitotemporal cortex

abstract:
Resective surgery in language-dominant ventral occipitotemporal cortex (vOTC) carries the risk of causing impairment to reading. As it is not on the lateral surface, it is not easily accessible for intraoperative mapping and extensive stimulation mapping can be time consuming. Here we assess the feasibility of using task-based electrocorticography (ECoG) recordings intraoperatively to help guide stimulation mapping of reading in vOTC.

In 11 patients undergoing extraoperative, intracranial seizure mapping we recorded induced broadband gamma activation (70 - 150 Hz) during a visual category localizer. Word-responsive cortex localized in this manner showed a high sensitivity (72%) to stimulation-induced reading deficits, and the confluence of ECoG and stimulation positive sites appears to demarcate the visual word form area.

In two additional patients, with pathologies necessitating resections in language-dominant vOTC, task-based functional mapping was performed intraoperatively using subdural ECoG, alongside direct cortical stimulation. Cortical areas critical for reading were mapped and successfully preserved, while enabling pathological tissue to be completely removed. Data collection is possible in <3 minutes and initial intraoperative data analysis takes <3 minutes, allowing for rapid assessment of broad areas of cortex.

Eloquent cortex in ventral visual cortex can be rapidly mapped intraoperatively using ECoG. This method acts to guide high-probability targets for stimulation, with limited patient participation, and can be used to avoid iatrogenic dyslexia following surgery.


title: Highly-specific early detection of colorectal cancer by novel non-invasive serum methylation biomarkers

abstract:
BackgroundEarly detection through screening programs has proven to be the most effective strategy to reduce the incidence and mortality of colorectal cancer. The most widely implemented non-invasive screening test is the fecal immunochemical test, which presents an inadequate sensitivity for the detection of precancerous advanced adenomas. This fact, together with the modest participation rates in screening programs, highlights the need for a blood test that could improve both the adherence to screening and the selection to colonoscopy.

MethodsIn this study, we conducted a serum-based discovery and validation of circulating cell-free DNA (cfDNA) methylation biomarkers for colorectal cancer screening in a multicentre cohort of 433 serum samples including healthy controls, benign pathologies, advanced adenomas, and colorectal cancer. First, we performed an epigenome-wide methylation analysis with the MethylationEPIC array in 280 cfDNA samples using a pooling approach, followed by a robust prioritization of candidate biomarkers for the joint detection of advanced adenomas and colorectal cancer (advanced neoplasia). Then, candidate biomarkers were validated by pyrosequencing in independent individual 153 cfDNA samples.

ResultsWe report GALNT9, UPF3A, WARS, and LDB2 as new non-invasive methylation biomarkers for the early detection of colorectal advanced neoplasia. A model composed of GALNT9, UPF3A, WARS, and LDB2 reported a sensitivity of 62.1% and a specificity of 97.4% for the detection of advanced neoplasia. On the other hand, the combination of GALNT9 and UPF3A by logistic regression discriminated advanced neoplasia with 78.8% sensitivity and 100% specificity, outperforming the commonly used fecal immunochemical test and the methylated SEPT9 blood test.

ConclusionsSerum methylation levels of GALNT9, UPF3A, WARS, and LDB2 represent highly specific and sensitive novel blood-based biomarkers for the detection of colorectal cancer and premalignant advanced adenomas of both distal and proximal locations. The reported results show the feasibility of DNA sample pooling strategies for biomarker discovery. Overall, this study highlights the utility of cfDNA methylation for the early detection of colorectal neoplasia, with the potential to be implemented as a non-invasive test for colorectal cancer screening.

category: oncology


title: Serum methylation of GALNT9, UPF3A, WARS, and LDB2 as non-invasive biomarkers for the early detection of colorectal cancer and premalignant adenomas


title: Reducing false-positive SARS-CoV-2 diagnoses using long-range RT-qPCR

abstract:
During the Coronavirus Disease 2019 (COVID-19) pandemic, residual SARS-CoV-2 genome and subgenomic RNA fragments were observed in recovered COVID-19 patients. The presence of such RNAs in the absence of live virus leads to incorrectly positive RT-qPCR results, potentially delaying medical procedures and quarantine release. We here propose a simple modification to turn commercial COVID-19 RT-qPCR protocols into long-range RT-qPCR assays that can differentiate between infectious and non-infectious influenza and coronavirus RNA levels. We find that the long-range RT-qPCR method has a sensitivity that is indistinguishable from a commercial Taq-Path COVID-19 RT-qPCR assay when tested on clinical samples taken withing 5 days of the onset of symptoms. In clinical samples taken at least 15 days after the onset of symptoms when patients had recovered from COVID-19, the modified RT-qPCR protocol leads to significantly fewer positive diagnoses. These findings suggest that the long-range RT-qPCR method may improve test-to-release protocols and expand the tools available for clinical COVID-19 diagnosis.

ImportanceVarious molecular tests can detect viral RNA in clinical samples. However, these molecular tests cannot differentiate between RNA from infectious viruses or residual viral genome fragments that are not infectious. In several percent of COVID-19 patients, such residual viral RNAs can be detected long after recovery and the disappearance of infectious SARS-CoV-2. These "persistently-positive" RT-qPCR results are different from false-positive RT-qPCR results, which can be generated due to in vitro cross-reactivity or contaminations. However, the detection of RNA fragments leads to incorrect conclusions about the status of a COVID-19 patient and an incorrect diagnosis. We here modified the commercial Taq-Path COVID-19 RT-qPCR kit to make this test less sensitive to residual viral RNA genome fragments, reducing the likelihood that incorrect RT-qPCR results affect the treatment or quarantine status of recovered COVID-19 patients.


title: Reducing persistently positive SARS-CoV-2 diagnoses using long-range RT-qPCR


title: Differentiating between infectious and non-infectious influenza A virus and coronavirus RNA levels using long-range RT-qPCR


title: Genetic variation within the human papillomavirus type 16 genome is associated with oropharyngeal cancer prognosis

abstract:
PurposeA significant barrier to adoption of de-escalated treatment protocols for human papillomavirus-driven oropharyngeal cancer (HPV-OPC) is that few predictors of poor prognosis exist. We conducted the first large whole-genome sequencing (WGS) study to characterize the genetic variation of the HPV16 genome and to evaluate its association with HPV-OPC patient survival.

Patients and Methods460 OPCs from 2 large US medical centers (1980-2017) underwent HPV16 WGS. Site-specific variable positions (SNPs) across the HPV16 genome were identified. Cox proportional hazards models estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for overall survival by HPV16 SNPs. Harrell C-index and time-dependent positive predictive value (PPV) curves and areas under the PPV curves were used to evaluate the predictive accuracy of HPV16 SNPs for overall survival.

Results384 OPCs (83.48%) passed quality control filters with sufficient depth and coverage of HPV16 genome sequencing to be analyzed. 284 HPV16 SNPs with a minor allele frequency >1% were identified. Eight HPV16 SNPs were significantly associated with worse survival after false discovery rate (FDR) correction (individual prevalence:1.0%-5.5%; combined prevalence: 15.10%); E1 gene position 1053 (HR for overall survival [HRos]:3.75,95%CI:1.77-7.95;Pfdr=0.0099); L2 gene positions 4410 (HRos:5.32,95%CI:1.91-14.81;Pfdr=0.0120), 4539 (HRos:6.54,95%CI:2.03-21.08;Pfdr=0.0117); 5050 (HRos:6.53,95%CI:2.34-18.24;Pfdr=0.0030) and 5254 (HRos:7.76,95%CI:2.41-24.98;Pfdr=0.0030); and L1 gene positions 5962 (HRos:4.40,95%CI:1.88-10.31;Pfdr=0.0110) and 6025 (HRos:5.71,95%CI:2.43-13.41;Pfdr=0.0008) and position 7173 within the upstream regulatory region (HRos:9.90,95%CI:3.05-32.12;Pfdr=0.0007). Median survival time for patients with [≥]1 high-risk HPV16 SNPs was 3.96 years compared to 18.67 years for patients without a high-risk SNP; log-rank test P<0.001. HPV16 SNPs significantly improved the predictive accuracy for overall survival above traditional factors (age, smoking, stage, treatment): increase in C-index was 0.069 (95% CI: 0.019-0.119, P <0.001); increase in area under the PPV curve for predicting 5-year survival was 0.068 (95%CI: 0.015-0.111, P =0.008).

ConclusionsHPV16 genetic variation is associated with HPV-OPC prognosis and can improve prognostic accuracy.

category: epidemiology


title: Protection offered by mRNA-1273 versus BNT162b2 vaccines against SARS-CoV-2 infection and severe COVID-19 in Qatar

abstract:
BACKGROUNDGrowing evidence suggests that COVID-19 vaccines differ in effectiveness against breakthrough infection or severe COVID-19, but vaccines have yet to be investigated in controlled studies that head-to-head compare immunity of one to another. This study compared protection offered by the mRNA-1273 (Moderna) vaccine with that of the BNT162b2 (Pfizer-BioNTech) vaccine in Qatar.

METHODSIn a population of 1,531,736 vaccinated persons, two matched retrospective cohort studies were designed and used to investigate differences in mRNA-1273 and BNT162b2 vaccine protection, after the first and second doses, from December 21, 2020 to October 20, 2021.

RESULTSAfter dose 1, cumulative incidence of breakthrough infection was 0.79% (95% CI: 0.75-0.83%) for mRNA-1273-vaccinated individuals and 0.86% (95% CI: 0.82-0.90%) for BNT162b2-vaccinated individuals, 21 days post-injection. Adjusted hazard ratio (AHR) for breakthrough infection was 0.89 (95% CI: 0.83-0.95; p=0.001). AHR was constant in the first two weeks at 1, but it declined to 0.67 (95% CI: 0.57-0.77; p<0.001) in the third week after dose 1. AHR for any severe, critical, or fatal COVID-19 was 0.71 (95% CI: 0.53-0.95; p=0.020). After dose 2, cumulative incidence was 0.59% (95% CI: 0.55-0.64%) for mRNA-1273-vaccinated individuals and 0.84% (95% CI: 0.79-0.89%) for BNT162b2-vaccinated individuals, 180 days post-injection. AHR for breakthrough infection was 0.69 (95% CI: 0.63-0.75; p<0.001) and was largely constant over time after dose 2. AHR for any severe, critical, or fatal COVID-19 was 0.37 (95% CI: 0.10-1.41; p=0.147).

CONCLUSIONSmRNA-1273 vaccination is associated with lower SARS-CoV-2 breakthrough infection and COVID-19 hospitalization and death than BNT162b2 vaccination, but the number of hospitalizations and deaths was exceedingly small for both vaccines. Both vaccines demonstrated strikingly similar patterns of build-up of protection after the first dose and waning of protection after the second dose.


title: Comprehensive analysis of GBA using a novel algorithm for Illumina whole-genome sequence data or targeted Nanopore sequencing

abstract: GBA variants cause the autosomal recessive Gaucher disease, and carriers are at increased risk of Parkinsons disease (PD) and Lewy body dementia (LBD). The presence of a highly homologous nearby pseudogene (GBAP1) predisposes to a range of structural variants arising from either gene conversion or reciprocal recombination, the latter resulting in copy number gains or losses, complicating genetic testing and analysis. To date, short-read sequencing has not been able to fully resolve these or other variants in the key homology region, and targeted long-read sequencing has not previously resolved reciprocal recombinants. We present and validate two independent methods to resolve recombinant alleles and other variants in GBA: Gauchian, a novel bioinformatics tool for short-read, whole-genome sequencing data analysis, and Oxford Nanopore long-read sequencing after enrichment with appropriate PCR. The methods were concordant for 42 samples including 30 with a range of recombinants and GBAP1-related mutations, and Gauchian outperforms the GATK Best Practices pipeline. Applying Gauchian to Illumina sequencing of over 10,000 individuals from publicly available cohorts shows that copy number variants (CNVs) spanning GBAP1 are relatively common in Africans. CNV frequencies in PD and LBD are similar to controls, but gains may coexist with other mutations in patients, and a modifying effect cannot be excluded. Gauchian detects a higher frequency of GBA variants in LBD than PD, especially severe ones. These findings highlight the importance of accurate GBA mutation detection in these patients, which is possible by either Gauchian analysis of short-read whole genome sequencing, or targeted long-read sequencing.

category: genetic and genomic medicine


title: What can data mining tell us about patient safety? Using linear discriminant analysis to identify characteristics associated with positive safety rating in London NHS organisations.

abstract:
ObjectiveTo identify key characteristics associated with a CQC positive and negative safety rating across London NHS organisations.

DesignAdvanced data analytics and linear discriminant analysis.

Data sourcesLinked CQC data with patient safety variables sources from 10 publicly available datasets.

MethodsIterative cycles of data extraction, insight generation, and analysis refinement were done and involved regular meetings between the NHS London Patient Safety Leadership Forum and analytic team to optimise academic robustness alongside with translational impact. Ten datasets were selected based on data availability, usability, and relevance and included data from April 2018 to December 2019. Data pre-processing was conducted in R. Missing values were imputed using the median value while empty variables were removed. London NHS organisations were categorised based on their safety rating into two groups: those rated as  inadequate or  requires improvement (RI) and those rated as  Good or  outstanding (Good). Variable filtering reduced the number of variables from 1104 to 207. The top ten variables with the largest effect sizes associated with Good and RI organisations were selected for inspection. A Linear Discriminant Analysis (LDA) was trained using the 207 variables. Effect sizes and confidence intervals for each variable were calculated. Dunns and Kruskal-Wallis tests were used to identify significant differences between RI and Good organisations.

ResultsTen variables for Good and RI NHS organisations were identified. Key variables for Good organisations included: Organisation response to address own concerns (answered by nurse/midwife) (Good organisation = 0.691, RI organisation = 0.618, P<.001); fair career progression (answered by medical/dental staff) (Good organisation = 0.905, RI organisation = 0.843, P<.001); existence of annual work appraisal (answered by medical/dental staff)) (Good organisation = 0.922, RI organisation = 0.873, P<.001); organisations response to patients concerns (Good organisation = 0.791, RI organisation = 0.717, P<.001); harassment, bullying or abuse from staff (answered by AHPHSSP) (Good organisation = 0.527, RI organisation = 0.454, P<.001); adequate materials supplies and equipment (answered by  Other staff) (Good organisation = 0.663, RI organisation = 0.544, P<.001); organisation response to address own concerns (answered by medical/dental staff) (Good organisation = 0.634, RI organisation = 0.537, P<.001); staff engagement (answered by medical/dental staff) (Good organisation = 0.468, RI organisation = 0.376, P<.001); provision of clear feedback (answered by "other" staff) (Good organisation = 0.719, RI organisation = 0.650, P<.001); and collection of patient feedback (answered by wider healthcare team) (Good organisation = 0.888, RI organisation = 0.804, P<.001).

ConclusionsOur study shows that healthcare providers that received positive safety inspections from regulators have significantly different characteristics in terms of staff perceptions of safety than those providers rated as inadequate or requiring improvement. Particularly, organisations rated as good or outstanding are associated with higher levels of organisational safety, staff engagement and capacities to collect and listen to patient experience feedback. This work exemplifies how a partnership between applied healthcare and academic research organisations can be used to address practical considerations in patient safety, resulting in a translational piece of work.

category: health systems and quality improvement


title: Malaria molecular surveillance in the Peruvian Amazon with novel highly multiplexed Plasmodium falciparum Ampliseq assay

abstract:
Molecular surveillance for malaria has great potential to support national malaria control programs (NMCPs). To bridge the gap between research and implementation, several applications (use cases) have been identified to align research, technology development, and public health efforts. For implementation at NMCPs, there is an urgent need for feasible and cost-effective tools.

We designed a new highly-multiplexed deep sequencing assay (Pf AmpliSeq), compatible with benchtop sequencers, allowing for high accuracy sequencing at higher coverage and lower cost than WGS, targeting genomic regions of interest. The novelty of the assay is in its high number of targets multiplexed in one easy workflow, combining population genetic markers with 13 near full-length resistance genes, applicable for many different use cases. We provide a first proof-of-principle for hrp2 and hrp3 deletion detection using amplicon sequencing. Initial sequence data processing can be performed automatically, and subsequent variant analysis requires minimal bioinformatic skills using any tabulated data analysis program.

The assay was validated with a retrospective sample collection (n = 254) from the Peruvian Amazon between 2003 and 2018. By combining phenotypic markers and a within-country 28-SNP-barcode, we were able to distinguish different lineages with multiple resistant (dhfr/dhps/crt/mdr1) haplotypes and hrp2 and hrp3 deletions, increasing in recent years. We found no evidence suggesting the emergence of ART-resistance in Peru. These findings indicate a parasite population under drug pressure, but susceptible to current antimalarials, and demonstrates the added value of a highly multiplexed molecular tool to inform malaria strategies and surveillance systems.

ImportanceWhile the power of next generation sequencing technologies to inform and guide malaria control programs has become broadly recognized, integration of genomic data for operational incorporation into malaria surveillance remains a challenge in most malaria endemic countries.

The main obstacles include limited infrastructure and accessibility to high-throughput sequencing facilities and the need for local capacity to run in-country analysis of genomes at a large enough scale to be informative for surveillance. In addition, there is a lack of standardized laboratory protocols and automated analysis pipelines to generate reproducible and timely results useful for relevant stakeholders.

With our standardized laboratory and bioinformatic workflow, malaria genetic surveillance data can be readily generated by surveillance researchers and malaria control programs in endemic countries, increasing ownership and ensuring timely results for informed decision and policy-making.


title: Malaria molecular surveillance in the Peruvian Amazon with a novel highly multiplexed Plasmodium falciparum Ampliseq assay


title: Addressing medical and social needs to reduce unnecessary health care utilization and costs: a qualitative study

abstract:
BackgroundThere are few if any well-known approaches to reducing avoidable health care utilization and costs in patients with social needs. This studys objective was to explore the goals, and approaches to organizing and delivering care, of interventions attempting to reduce avoidable resource use by addressing patients medical and social needs.

MethodsSemi-structured interviews were conducted with study investigators about early interventions in the peer-reviewed literature. A template analysis approach was used to review interview transcripts for common themes and create a final code list. Coder dyads separately coded each interview and resolved any discrepancies.

ResultsInterviews were conducted with 15 investigators of interventions that delivered a variety of health services and addressed several individual social needs. Participants frequently described their overall goal as meeting patients diverse needs to prevent unnecessary acute care utilization. Reported approaches to addressing medical needs included assistance with receipt of primary care and care coordination across settings. Social needs were described as tightly linked with medical needs; addressing social support and housing were perceived as distinct from addressing other social needs. Participants described their overall approach to meeting patients needs in terms of establishing connections, partnership, respect, and being adaptable to patients priorities.

ConclusionsFindings shed new light on how to simultaneously address medical and social needs. Opportunities for future research include evaluating different approaches to addressing medical needs (primary care versus care coordination), separately evaluating the impacts of housing or social support, and hiring and training procedures to promote trauma-informed, patient-centered care.


title: Derivation and validation of a type 2 diabetes treatment selection algorithm for SGLT2-inhibitor and DPP4-inhibitor therapies based on glucose-lowering efficacy: cohort study using trial and routine clinical data

abstract:
ObjectiveTo establish whether clinical patient characteristics routinely measured in primary care can identify people with differing short-term benefits and risks for SGLT2-inhibitor and DPP4-inhibitor therapies, and to derive and validate a treatment selection algorithm to identify the likely optimal therapy for individual patients.

DesignProspective cohort study.

SettingRoutine clinical data from United Kingdom general practice (Clinical Practice Research Datalink [CPRD]), and individual-level clinical trial data from 14 multi-country trials of SGLT2-inhibitor and DPP4-inhibitor therapies.

Participants26,877 new users of SGLT2-inhibitor and DPP4-inhibitor therapy in CPRD over 2013-2019, and 10,414 participants randomised to SGLT2-inhibitor or DPP4-inhibitor therapy in 14 clinical trials, including 3 head-to-head trials of the two therapies (n=2,499).

Main outcome measuresThe primary outcome was achieved HbA1c 6 months after initiating therapy. Clinical features associated with differential HbA1c outcomes with SGLT2-inhibitor and DPP4-inhibitor therapies were identified in routine clinical data, with associations then tested in trial data. A multivariable treatment selection algorithm to predict differential HbA1c outcomes was developed in a CPRD derivation cohort (n=14,069), with validation in a CPRD validation cohort (n=9,376) and the head-to-head trials. In CPRD, we further explored the relationship between model predictions and secondary outcomes of weight loss and treatment discontinuation.

ResultsThe final treatment selection algorithm included HbA1c, eGFR, ALT, age, and BMI, which were identified as predictors of differential HbA1c outcomes with SGLT2-inhibitor and DPP4-inhibitor therapies using both routine and trial data. In validation cohorts, patient strata predicted to have a [≥]5 mmol/mol HbA1c reduction with SGLT2-inhibitor therapy compared with DPP4-inhibitor therapy (38.8% of CPRD validation sample) had an observed greater reduction of 8.8 mmol/mol [95%CI 7.8-9.8] in the CPRD validation sample, a 5.8 mmol/mol (95%CI 3.9-7.7) greater reduction in the Cantata D/D2 trials, and a 6.6 mmol/mol [95%CI 2.2-11.0]) greater reduction in the BI1245.20 trial. In CPRD, there was a greater weight reduction with SGLT2-inhibitor therapy regardless of predicted glycaemic benefit. Strata predicted to have greater reduction in HbA1c on SGLT2-inhibitor therapy had a similar risk of discontinuation as on DPP4-inhibitor therapy. In contrast, strata predicted to have greater reduction in HbA1c with DPP4-inhibitor therapy were half as likely to discontinue DPP4-inhibitor therapy than SGLT2-inhibitor therapy.

ConclusionsRoutinely measured clinical features are robustly associated with differential glycaemic responses to SGLT2-inhibitor and DPP4-inhibitor therapies. Combining features into a treatment selection algorithm can inform clinical decisions concerning optimal type 2 diabetes treatment choices.

Key messagesO_ST_ABSWhat is already known on this subjectC_ST_ABSO_LIDespite there being multiple glucose-lowering treatment options available for people with type 2 diabetes, current guidelines do not provide clear advice on selecting the optimal treatment for most patients.
C_LIO_LIIt is unknown whether routinely measured clinical features modify the risks and benefits of two common treatment options, DPP4-inhibitor or SGLT2-inhibitor therapy, and which could be used to target these treatments to those patients most likely to benefit.
C_LI

What this study addsO_LIUsing data from 10,414 participants in 14 randomised trials, and 26,877 patients in UK primary care, we show several routinely available clinical features, notably glycated haemoglobin (HbA1c) and kidney function, are robustly associated with differential HbA1c responses to initiating SGLT2-inhibitor and DPP4-inhibitor therapies.
C_LIO_LICombining clinical features into a multivariable treatment selection model identifies validated patient strata with 1) a >5 mmol/mol HbA1c benefit for SGLT2-i therapy compared with DPP4-inhibitor therapy ; 2) a 50% reduced risk of early treatment discontinuation with DPP4-inhibitor therapy compared with SGLT2-inhibitor therapy.
C_LIO_LIOur findings demonstrate a precision medicine approach based on routine clinical features can inform clinical decisions concerning optimal type 2 diabetes treatment choices.
C_LI

category: endocrinology


title: Implementation of Unassisted and Community-Based HIV Self-Testing (HIVST) during the COVID-19 pandemic among Men-who-have-sex-with-Men (MSM) and Transgender Women (TGW): A Demonstration Study in Metro Manila, Philippines

abstract:
ObjectiveThe study aimed to demonstrate the feasibility of an unassisted and community-based HIV self-testing (HIVST) distribution model and to evaluate its acceptability among men-having-sex-with-men (MSM) and transgender women (TGW).

MethodsOur observational study focused on implementing the HIVST service in Metro Manila, Philippines. Convenience sampling was done with the following inclusion criteria: MSM or TGW, at least 18 years old, and had no previous HIV diagnosis. Individuals taking HIV Pre-exposure Prophylaxis (PrEP), on Antiretroviral Therapy (ART), or female sex at birth were excluded. The implementation of the study was online using a virtual assistant and delivery system via courier due to COVID-19-related lockdowns. Feasibility was measured by the number of HIVST kits successfully delivered and utilized and the HIV point prevalence rate. Moreover, acceptability was evaluated by a 10-item system usability scale (SUS). HIV prevalence was estimated with linkage to care prioritized for reactive participants.

ResultsOut of 1,690 kits distributed, only 953 (56.4%) participants reported their results. Overall HIV point prevalence was 9.8%, with 56 (60.2%) reactive participants linked to further testing. Furthermore, 27.4% of respondents self-reported, and 13.4% of the reactive participants were first-time testers. The HIVST service had an overall mean {+/-} standard deviation SUS score of 81.0 {+/-} 13.0, rendering the HIVST kits very acceptable.

ConclusionsHIVST is acceptable and feasible to MSM and TGW. Online platforms are an innovative and effective way to deliver HIVST service during a pandemic. However, messaging to entice people to use the kit must be differentiated based on their age, gender identity and expression, and previous HIVST experience to offer the service efficiently to the target populations.

category: public and global health


title: Polygenic risk scores based on European GWAS correlate to disease prevalence differences around the world

abstract:
BackgroundComplex disorders are caused by a combination of genetic, environmental and lifestyle factors, and their prevalence can vary greatly across different populations. Genome wide association studies (GWAS) can help identify common variants that underlie disease risk. However, despite their increasing number, the vast majority of studies focuses on European populations, leading to questions regarding the transferability of findings to non-Europeans. Here, we investigated whether polygenic risk scores (PRS) based on European GWAS correlate to disease prevalence within Europe and around the world.

ResultsGWAS summary statistics of 20 different disorders were used to estimate PRS in nine European and 24 worldwide reference populations. We estimated the correlation between average genetic risk for each of the 20 disorders and their prevalence in Europe and around the world. A clear variation in genetic risk was observed based on ancestry and we identified populations that have a higher genetic liability for developing certain disorders both within European and global regions. We also found significant correlations between worldwide disease prevalence and PRS for 13 of the studied disorders with obesity genetic risk having the highest correlation to disease prevalence. For these 13 disorders we also found that the loci used in PRS are significantly more conserved across the different populations compared to randomly selected SNPs as revealed by Fst and linkage disequilibrium structure.

ConclusionOur results show that PRS of world populations calculated based on European GWAS data can significantly capture differences in disease risk and identify populations with the highest genetic liability to develop various conditions. Our findings point to the potential transferability of European-based GWAS results to non-European populations and provide further support for the validity of GWAS.


title: Impact of Exercise-induced Dehydration on Perceived Exertion During Endurance Exercise: A Systematic Review with Meta-analysis

abstract: Understanding the impact of stressors on the rating of perceived exertion (RPE) is relevant from a performance and exercise adherence/participation standpoint. Athletes and recreationally active individuals dehydrate during exercise. No attempt has been made to systematically determine the impact of exercise-induced dehydration (EID) on RPE. The present meta-analysis aimed to determine the effect of EID on RPE during endurance exercise and examine the moderating effect of potential confounders using a meta-analytical approach. Data analyses were performed on raw RPE values using random-effects models weighted mean effect summaries and meta-regressions with robust standard errors, and with a practical meaningful effect set at 1 point difference between euhydration (EUH) and EID. Only controlled crossover studies measuring RPE with a Borg scale in healthy adults performing [≥] 30 min of continuous endurance exercise while dehydrating or drinking to maintain EUH were included. Sixteen studies were included, representing 147 individuals. Mean body mass loss with EUH was 0.5 {+/-} 0.4%, compared to 2.3 {+/-} 0.5% with EID (range 1.7 to 3.1%). Within an EID of 0.5 to 3% body mass, a maximum difference in RPE of 0.81 points (95% CI: 0.36-1.27) was observed between conditions. A meta-regression revealed that RPE increases by 0.21 points for each 1% increase in EID (95% CI: 0.12-0.31). Humidity, ambient temperature and aerobic capacity did not alter the relationship between EID and RPE. Therefore, the effect of EID on RPE is unlikely to be practically meaningful until a body mass loss of at least 3%.


title: A Pilot Randomized Controlled Trial of de novo Belatacept-Based Immunosuppression in Lung Transplantation

abstract: The development of donor-specific antibodies (DSA) after lung transplantation is common and results in adverse outcomes. In kidney transplantation, Belatacept has been associated with a lower incidence of DSA, but experience with Belatacept in lung transplantation is limited. We conducted a 2-center pilot randomized controlled trial of de novo immunosuppression with Belatacept after lung transplantation to assess the feasibility of conducting a pivotal trial. Twenty-seven participants were randomized to Control (Tacrolimus, Mycophenolate Mofetil, and prednisone, n = 14) or Belatacept-based immunosuppression (Tacrolimus, Belatacept, and prednisone until day 89 followed by Belatacept, Mycophenolate Mofetil, and prednisone, n = 13). All participants were treated with rabbit anti-thymocyte globulin for induction immunosuppression. We permanently stopped randomization and treatment with Belatacept after 3 participants in the Belatacept arm died compared to none in the Control arm. Subsequently, 2 additional participants in the Belatacept arm died for a total of 5 deaths compared to none in the Control arm (log rank p = 0.016). We did not detect a significant difference in DSA development, acute cellular rejection, or infection between the 2 groups. We conclude that this investigational regimen using Belatacept after lung transplantation is associated with significantly increased mortality.

category: transplantation


title: A Remote Digital Memory Composite to Detect Cognitive Impairment in Memory Clinic Samples in Unsupervised Settings using Mobile Devices

abstract:
INTRODUCTIONMobile app-based unsupervised monitoring of cognition holds the promise to facilitate case-finding in clinical care and the individual detection of cognitive impairment in clinical and research settings. In the context of Alzheimers disease, this is particularly relevant for patients who seek medical advice due to memory complaints.

OBJECTIVEWe developed a Remote Digital Memory Composite score from an unsupervised remote and mobile cognitive assessment battery focused on episodic memory and long-term recall and assessed its construct validity using a neuropsychological composite score for early cognitive impairment in Alzheimers disease, the Preclinical Alzheimers Cognitive Composite (PACC5). We also assessed the test-retest reliability of the Remote Digital Memory Composite score across two independent test sessions. Finally, we assessed the diagnostic accuracy of the remote and unsupervised cognitive assessment battery when predicting PACC5-based cognitive impairment in a memory clinic sample and healthy controls.

SETTINGThis was an add-on study of the DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE) which was also performed in a separate memory clinic-based sample.

PARTICIPANTSA total of 102 study participants were included as healthy controls (HC; n=25), cognitively unimpaired first-degree relatives of AD patients (REL; n=7), individuals with subjective cognitive decline (SCD; n= 48) or patients with mild cognitive impairment (MCI; n=22).

MEASUREMENTSWe analyzed results from the objects-in-rooms recall (ORR) test, the mnemonic discrimination for objects and scenes (MDT-OS) test and the complex scene recognition (CSR) test implemented on the neotiv digital platform to derive a Remote Digital Memory Composite. Participants used the neotiv mobile app to complete one unsupervised test session every two weeks on their own mobile device in an environment of their choice. We assessed the relationships of the Remote Digital Memory Composite acquired through the mobile app and in-clinic measures of the PACC5 conducted by trained neuropsychologists in the memory clinics participating in the DELCODE study.

RESULTS102 participants provided technically complete data for at least one single session of each of the three test paradigms, of which 87 participants provided data from at least two test sessions of each task. The derived Remote Digital Memory Composite score was highly correlated with the PACC5 score across all participants (r=.75, p<0.001), and also in those without complaints (HC and REL, r=.51, p=0.003) and those with complaints separately (SCD and MCI, r=.76, p<0.001). Good test-retest reliability for the Remote Digital Memory Composite score was observed in those with at least two assessments of the three tests. (r=.74; p<.0001). Diagnostic accuracy for discriminating PACC5-based memory impairment from no impairment was high (AUC = 0.9) with a sensitivity of 0.83 and a specificity of 0.74.

CONCLUSIONOur results indicate that unsupervised mobile cognitive assessments in a memory clinic setting using the implementation in the neotiv digital platform has high construct validity and results in a good discrimination between cognitively impaired and unimpaired individuals based on the PACC5 score. Thus, it is feasible to complement neuropsychological assessment of episodic memory with unsupervised, remote assessments on mobile devices. This contributes to recent efforts for implementing remotely performed episodic memory assessment for case-finding and monitoring in large research trials and clinical care.


title: The role of KPNA2 mutations in breast cancer prognosis: A survey of publicly available databases

abstract:
Breast cancer, comprising of several sub-phenotypes, is a leading cause of female cancer-related mortality in the UK and accounts for 15% of all cancer cases. Chemoresistant sub phenotypes of breast cancer remain a particular challenge. However, the rapidly-growing availability of clinical datasets, presents the scope to underpin a data driven precision medicine-based approach exploring new targets for diagnostic and therapeutic interventions. We report a survey of several publicly available databases probing the expression and prognostic role of Karyopherin-2 alpha (KPNA2) in breast cancer prognosis. Aberrant KPNA2 overexpression is directly correlated with aggressive tumour phenotypes and poor patient survival outcomes. We examined the existing information available on a range of commonly occurring mutations of KPNA2 and their correlation with patient survival.

Our analysis of clinical gene expression datasets show that KPNA2 is frequently amplified in breast cancer, with differences in expression levels observed as a function of patient age and clinicopathologic parameters. We also found that aberrant KPNA2 overexpression is directly correlated with poor patient prognosis, warranting further investigation of KPNA2 as an actionable target for patient stratification or the design of novel chemotherapy agents.

In the era of big data, the wealth of datasets available in the public domain can be used to underpin proof of concept studies evaluating the biomolecular pathways implicated in chemotherapy resistance in breast cancer.


title: Functional changes of visual cortex in pre- and post- operative intermittent exotropia patients: study protocol for a non-randomized case-control clinical trial

abstract:
IntroductionIntermittent exotropia (IXT) is the most common type of divergent squint. IXT is primarily a cortical neurologic dysfunction disorder, occurring as a result of insufficient maintaining of sensory and motor fusion. Recent reports have demonstrated the relationship between IXT and visual cortical impairment. We plan to assess blood oxygen level-dependent (BOLD)- functional magnetic resonance imaging (fMRI) in IXT patients during the pre-and post-operation follow-ups to evaluate the functional changes of the visual cortex.

Methods and analysisA total of 90 Chinese subjects will be recruited, and the age is between 18 and 60 years old. The subjects include the Surgical treatment (ST) group (45 IXT subjects who will perform surgery) and the Healthy control (HC) group (45 age - and sex - and education matched healthy volunteers). The assessments include the following aspects: general ophthalmic, optometry, binocular vision test, Newcastle Control Score (NCS), and fMRI. Each subject completes the rest-state BOLD-fMRI, and the sequences include echo planar imaging (EPI) pulse and 3-dimensional brain volume (3D-BRAVO) to acquire high-resolution images. The follow-up schedule is 6 and 12months after the surgery. The primary outcome will be determined by cortex changes in BOLD-fMRI in ST group before and after the surgery. We also compare the HC group with the pre-operation subjects in the ST group. The secondary outcomes are changes of strabismus examinations, binocular visual function examinations, and NCS.

Ethics and disseminationEthical approval has been obtained from the Medical Ethics Committee of the Beijing Tongren Hospital. We plan to publish the results of this study in a peer-reviewed journal article.

Trial registration numberChiCTR2100048852

Strengths and limitations of this studyO_LIThe present study is advanced which aims to explore the functional changes in the visual cortex in IXT patients before and after surgery through rest-state 3.0T BOLD-fMRI. We also explore the relationships between changes of cortex and ocular examination.
C_LIO_LIThe follow-up comparison between the visual cortex and ophthalmic changes will enrich our understanding of the impairment and plasticity of visual function in IXT patients.
C_LIO_LILoss to follow-up of participants is possible after the surgery in this study.
C_LIO_LIThe present study focuses on IXT patients with surgical indications. We did not carry on the study on the different subtypes or the different severity of IXT.
C_LI

category: ophthalmology


title: USE OF FLUNARIZINE AS A PREVENTIVE FOR VESTIBULAR MIGRAINE CRISES IN COMPARISON WITH OTHER DRUGS: SYSTEMATIC LITERATURE REVIEW

abstract:
INTRODUCTIONVestibular migraine is the main cause of episodic vertigo and the second most common cause of dizziness in adults. Treatment for vestibular migraine encompasses the prevention of crises and the control of acute symptoms.

Flunarizine works by preventing the contraction of labyrinthine vessels and altering blood flow, thus preventing symptoms. Due to the high prevalence of the disease, its negative impacts on individual health and increased expenditure on public health, preventive pharmacological and non-pharmacological treatment must be implemented early.

PURPOSETo evaluate the efficacy of Flunarizine as a preventive for migraine and vestibular crises compared to other preventive drugs.

MATERIAL AND METHODSScientific articles were searched in the databases using the terms (vestibular migraine OR migrainous vertigo) AND (flunarizine) AND (prophylaxis). Subsequently, a systematic literature review and meta-analysis was performed, including 3 randomized clinical trials comparing flunarizine and other preventive drugs in terms of efficacy and safety for preventing migraine vertigo attacks. The studies were analyzed using a ROB table, analysis using the GRADE method and meta-analysis.

RESULTSQualitatively, the analysis showed that flunariniza was positive for decreasing the frequency of vertigo in cases of vestibular migraine, with a moderate degree of evidence, a relative risk of 0.34 and a confidence interval of 0.15 to 0.76.

CONCLUSIONSThere are few studies available in the scientific literature on the use of flunarizine in vestibular migraine, many of which are heterogeneous among themselves, mainly in the way of evaluating and monitoring patients, carried out mainly through subjective methods.

The meta-analysis showed a positive result for flunarizine as a preventive drug for the studied population. Furthermore, in all the studies analyzed, no serious side effects resulting from the use of the medication were reported, which makes it safe for patients to use.

Flunarizine is a good drug for the prevention of vestibular migraine, especially in reducing the number of attacks, with a good level of evidence.

category: otolaryngology


title: Considerations for Developing and Implementing an Online Community-Based Exercise Intervention for Adults Living with HIV: a qualitative study

abstract:
ObjectivesTo describe the need for and utility of online community-based exercise (CBE) interventions with adults living with HIV and identify factors to consider in developing and implementing an online CBE intervention with adults living with HIV.

DesignQualitative descriptive study using web-based semi-structured interviews.

ParticipantsWe recruited adults representing at least one of five stakeholder groups with experience in CBE and/or HIV: 1) adults living with HIV, 2) rehabilitation professionals, 3) fitness personnel, 4) educators with eLearning experience, and 5) representatives from HIV community-based organizations (CBOs).

Data CollectionWe asked participants to describe their experiences with online CBE, need and utility for online CBE, and factors in developing and implementing online CBE interventions. We analyzed data using group-based content analytical techniques.

ResultsAmong the 11 participants, most had experience working with adults living with HIV (73%) or with tele-health/rehabilitation/coaching in HIV or other chronic conditions (91%). Participants identified the need and utility for online CBE interventions to increase accessibility and continuity of care with adults living with HIV. Six factors to consider in developing and implementing online CBE included: 1)person-specific considerations (episodic nature of HIV, stigma, HIV disclosure), 2)accessibility of program (physical space to exercise, reliable internet, access to devices, digital literacy), 3)program delivery and technology (live versus pre-recorded online classes, multiple online platforms for delivery, physical activity tracking, troubleshooting technology), 4)attributes of program personnel (working with CBOs, relatable instructors, diverse staff), 5)program content and design (tailored exercise classes, educational sessions) and 6)building community (shared experiences, peer support, social opportunities).

ConclusionsThere is a need and utility for online CBE in the context of HIV. Considerations for development and implementation span individual, structural and technical, and community dimensions. Results can inform the future development and implementation of online CBE with adults living with HIV and other chronic episodic conditions.

STRENGTHS & LIMITATIONS OF THIS STUDYO_LITo our knowledge, this is the first qualitative study exploring the perspectives of key stakeholders in developing and implementing an online community-based exercise (CBE) program for adults living with HIV.
C_LIO_LIInsights gained from this study can help to inform future online community-based exercise programming for adults living with HIV and other chronic and episodic conditions.
C_LIO_LIWe used the Model for ASsessment of Telemedicine applications (MAST) framework as a conceptual foundation to design the interview guide, which enabled us to comprehensively explore diverse aspects of telemedicine services in relation to information, communication and technology.
C_LIO_LIAll interviews were conducted online with participants who had access to technological devices and reliable internet, therefore, results may not be transferable to individuals or contexts without access to technology.
C_LIO_LIMost participants were living in Canada, hence, it is unclear how results may be transferable to other geographical contexts.
C_LI

category: hiv aids


title: Viral load and infectivity of SARS-CoV-2 in paired respiratory and oral specimens from symptomatic, asymptomatic or post-symptomatic individuals

abstract:
In the present study, we assessed the diagnostic sensitivity and determined the viral load and infectivity of SARS-CoV-2 in paired respiratory (nasopharyngeal and anterior nares) and oral samples (saliva and sublingual swab). Samples were collected from 77 individuals of which 75 were diagnosed with COVID-19 and classified as symptomatic (n=29), asymptomatic (n=31), or post-symptomatic (n=15). Specimens were collected at one time point from each individual, between day 1 to 23 after the initial COVID-19 diagnosis, and included self-collected saliva (S), or sublingual (SL) swab, and bilateral anterior nares (AN) swab, followed by healthcare provider collected nasopharyngeal (NP) swab. Sixty-three specimen sets were tested using five assay/platforms. The diagnostic sensitivity of each assay/platform and specimen type was determined. Of the 63 specimen sets, SARS-CoV-2 was detected in 62 NP specimens, 52 AN specimens, 59 saliva specimens, and 31 SL specimens by at least one platform. Infectious SARS-CoV-2 was isolated from 21 NP, 13 AN, 12 saliva, and one SL specimen out of 50 specimen sets. SARS-CoV-2 isolation was most successful up to 5 days after initial COVID-19 diagnosis using NP specimens from symptomatic patients (16 of 24 positives, 66.67%), followed by specimens from asymptomatic patients (5 of 17 positives, 29.41%), while it was not very successful with specimens from post-symptomatic patients. Benefits of self-collected saliva and AN specimens balance the loss of sensitivity relative to NP specimens. Therefore, saliva and AN specimens are acceptable alternatives for symptomatic SARS-CoV-2 diagnostic testing or surveillance with increased sampling frequency of asymptomatic individuals.

ImportanceThe dynamics of infection with SARS-CoV-2 has a significant impact on virus infectivity and in the diagnostic sensitivity of molecular and classic virus detection tests. In the present study we determined the diagnostic sensitivity of paired respiratory (nasopharyngeal and anterior nares swabs) and oral secretions (saliva and sublingual swab) and assessed infectious virus shedding patterns by symptomatic, asymptomatic or post-symptomatic individuals. Understanding the diagnostic performance of these specimens and the patterns of infectious virus shedding in these bodily secretions provides critical information to control COVID-19, and may help to refine guidelines on isolation and quarantine of positive individuals and their close contacts identified through epidemiological investigations.


title: Cost-effectiveness analysis of BNT162b2 COVID-19 booster vaccination in the United States

abstract:
BackgroundOver 86% of older adults aged [≥]65 years are fully vaccinated against SARS-COV-2 in the United States (US). Waning protection of the existing vaccines promotes the new vaccination strategies, such as providing a booster shot for those fully vaccinated.

MethodsWe developed a decision-analytic Markov model of COVID-19 to evaluate the cost-effectiveness of a booster strategy of Pfizer-BioNTech BNT162b2 (administered 6 months after 2nd dose) in those aged [≥]65 years, from a healthcare system perspective.

FindingsCompared with 2-doses of BNT162b2 without a booster, the booster strategy in a 100,000 cohort of older adults would incur an additional cost of $3.4 million, but save $6.7 million in direct medical costs in 180 days. This corresponds to a benefit-cost ratio of 1.95 and a net monetary benefit of $3.4 million. Probabilistic sensitivity analysis indicates that with a COVID-19 incidence of 9.1/100,000 person-day, a booster strategy has a high chance (67%) of being cost-effective. The cost-effectiveness of the booster strategy is highly sensitive to the population incidence of COVID-19, with a cost-effectiveness threshold of 8.1/100,000 person-day. This threshold will increase with a decrease in vaccine and booster efficacies. Doubling the vaccination cost or halving the medical cost for COVID-19 treatment alone would not alter the conclusion of cost-effectiveness, but certain combinations of the two might render the booster strategy not cost-effective.

InterpretationOffering BNT162b2 boosters to older adults aged [≥]65 years in the US is likely to be cost-effective. Less efficacious vaccines and boosters may still be cost-effective in settings of high SARS-COV-2 transmission.

FundingNational Natural Science Foundation of China. Berlina and Bill Gates Foundation


title: Novel protein markers of androgen activity in humans: proteomic study of plasma from young chemically castrated men

abstract:
BackgroundReliable biomarkers ofv androgen activity in humans are lacking. The aim of this study was, therefore, to identify new protein markers of biological androgen activity and test their predictive value in relation to low vs. normal testosterone values and some androgen deficiency linked pathologies.

MethodsBlood samples from 30 healthy GnRH-antagonist treated males were collected at three time points: a) before GnRH antagonist administration; b) 3 weeks later, just before testosterone undecanoate injection, and c) after additional 2 weeks. Subsequently they were analysed by mass spectrometry to identify potential protein biomarkers of testosterone activity. Levels of proteins most significantly associated with testosterone fluctuations were further tested in a cohort of 75 hypo- and eugonadal males suffering from infertility. Associations between levels of those markers and cardio-metabolic parameters, bone mineral density as well as androgen receptor CAG repeat lengths, were explored.

ResultsUsing ROC analysis, 4-hydroxyphenylpyruvate dioxygenase (4HPPD), insulin-like growth factor-binding protein 6 (IGFBP6) and fructose-bisphosphate aldolase (ALDOB), as well as a Multi Marker Algorithm, based on levels of 4HPPD and IGFBP6, were shown to be best predictors of low (< 8 nmol/L) vs. normal (> 12 nmol/L) testosterone. They were also more strongly associated with metabolic syndrome and diabetes than testosterone levels. Levels of ALDOB and 4HPPD levels also showed association with AR CAG-repeat lengths.

ConclusionsWe identified potential new protein biomarkers of testosterone action. Further investigations to eluciadate their clinical potential are warranted.


title: Revisiting the estimation of Covid-19 prevalence: Implications for rapid testing

abstract: Surveillance studies for Covid-19 prevalence estimation are subject to sampling bias due to oversampling of symptomatic individuals and error-prone tests, particularly rapid antigen tests which are known to have high false negative rates for asymptomatic individuals. This results in naive estimators which can be very far from the truth.In this work, we present a method that removes these two sources of error directly. Moreover, our procedure can be easily extended to the stratified error situation in which a test has very different error rate profiles for symptomatic and asymptomatic individuals as is the case for rapid antigen testing. The result is an easily understandable four-step algorithm that produces much more reliable prevalence estimates as demonstrated on data from the Israeli Ministry of Health. Thus it may re-open the debate about whether we are under-valuing rapid testing as a surveillance tool and may have policy implications in Third-World countries or disadvantaged communities where access to PCR testing may be less accessible.


title: The efficacy of sampling strategies for estimating scabies prevalence

abstract:
BackgroundEstimating scabies prevalence in communities is crucial for identifying the communities with high scabies prevalence and guiding interventions. There is no standardisation of sampling strategies to estimate scabies prevalence in communities, and a wide range of sampling sizes and methods have been used. The World Health Organization recommends household sampling or, as an alternative, school sampling to estimate community-level prevalence. Due to varying prevalence across populations, there is a need to understand how sampling strategies for estimating scabies prevalence interact with scabies epidemiology to affect accuracy of prevalence estimates.

MethodsWe used a simulation-based approach to compare the efficacy of different sampling methods and sizes. First, we generate synthetic populations with Australian Indigenous communities characteristics and then, assign a scabies status to individuals to achieve a specified prevalence using different assumptions about scabies epidemiology. Second, we calculate an observed prevalence for different sampling methods and sizes.

ResultsThe distribution of prevalence in population groups can vary substantially when the underlying scabies assignment method changes. Across all of the scabies assignment methods combined, the simple random sampling method produces the narrowest 95% confidence interval for all sampling percentages. The household sampling method introduces higher variance compared to simple random sampling when the assignment of scabies includes a household-specific component. The school sampling method overestimates community prevalence when the assignment of scabies includes an age-specific component.

DiscussionOur results indicate that there are interactions between transmission assumptions and surveillance strategies, emphasizing the need for understanding scabies transmission dynamics. We suggest using the simple random sampling method for estimating scabies prevalence. Our approach can be adapted to various populations and diseases.

Author summaryScabies is a parasitic infestation that is commonly observed in underprivileged populations. A wide range of sampling sizes and methods have been used to estimate scabies prevalence. With differing key drivers of transmission and varying prevalence across populations, it can be challenging to determine an effective sampling strategy. In this study, we propose a simulation approach to compare the efficacy of different sampling methods and sizes. First, we generate synthetic populations and then assign a scabies status to individuals to achieve a specified prevalence using different assumptions about scabies epidemiology. Second, we calculate an observed prevalence for different sampling methods and sizes. Our results indicate that there are interactions between transmission assumptions and surveillance strategies. We suggest using the simple random sampling method for estimating prevalence as it produces the narrowest 95% confidence interval for all sampling sizes. We propose guidelines for determining a sample size to achieve a desired level of precision in 95 out 100 samples, given estimates of the population size and a priori estimates of true prevalence. Our approach can be adapted to various populations, informing an appropriate sampling strategy for estimating scabies prevalence with confidence.


title: Identifying patient-level risk factors associated with non-β-lactam resistance outcomes in invasive methicillin-resistant Staphylococcus aureus infections in the United States using chain graphs

abstract: Methicillin-resistant Staphylococcus aureus (MRSA) is one of the most common causes of hospital- and community-acquired infections. MRSA is resistant to many antibiotics, including {beta}-lactam antibiotics, fluoroquinolones, lincosamides, macrolides, aminoglycosides, tetracyclines, and chloramphenicol. Graphical models such as chain graphs can be used to quantify and visualize the interactions among multiple resistant outcomes and their explanatory variables. In this study, we analyzed MRSA surveillance data collected by the Centers for Disease Control and Prevention (CDC) as part of the Emerging Infections Program (EIP) using chain graphs with the objective of identifying risk factors for individual phenotypic resistance outcomes (reported as minimum inhibitory concentration, MIC) while considering the correlations among themselves. Some phenotypic resistances have low connectivity to other outcomes or predictors (e.g. tetracycline, vancomycin, doxycycline, and rifampin). Levofloxacin was the only resistant associated with healthcare use. Blood culture was the most common predictor of MIC. Patients with positive blood culture had significantly increased MIC to chloramphenicol, erythromycin, gentamicin, lincomycin, and mupirocin, and decreased daptomycin and rifampin MICs. Chain graphs show the unique and common risk factors associated with resistance outcomes.


title: Neurodevelopmental outcomes of infants secondary to in utero exposure to maternal SARS-CoV-2 infection: A national prospective study in Kuwait

abstract:
BackgroundAn increasing proportion of women are being infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during pregnancy. Intrauterine viral infections induce an increase in the levels of proinflammatory cytokines, which inhibit the proliferation of neuronal precursor cells and stimulate oligodendrocyte cell death, leading to abnormal neurodevelopment. Whether a maternal cytokine storm can affect neonatal brain development is unclear. The objective of the present study is to assess neurodevelopmental outcomes in neonates born to mothers with SARS-CoV-2 infections during pregnancy.

MethodsIn this prospective cohort study, the neurodevelopment status of infants (N=298) born to women with SARS-CoV-2 infections during pregnancy was assessed at 10-12 months post discharge using the Ages and Stages Questionnaire, 3rd edition (ASQ-3). The ASQ-3 scores were classified into developmental delays (cutoff score: [≤]2 standard deviations (SDs) below the population mean) and no delay (score >2 SDs above the population mean).

ResultsApproximately 10% of infants born to mothers with SARS-CoV-2 infections during pregnancy showed developmental delays. Two of 298 infants tested positive for SARS-CoV-2, and both had normal ASQ-3 scores. The majority of the pregnant women had SARS-CoV-2 infection during their third trimester. The risk of developmental delays among infants was higher in those whose mothers had SARS-CoV-2 infections during the first (P=0.039) and second trimesters (P=0.001) than in those whose mothers had SARS-CoV-2 infections during the third trimester. Infants born at <31 weeks gestation were more prone to developmental delays than those born at >31 weeks gestation (10% versus 0.8%; P=0.002).

ConclusionThe findings of the study highlight the need for long term neurodevelopmental assessment of infants born to mothers with SARS-CoV-2 infection.

category: pediatrics


title: Age Based Trends for Unplanned Pediatric Rehospitalizations in the United States

abstract:
BACKGROUND AND OBJECTIVESHospital readmission rate helps to highlight the effectiveness of post-discharge care. There remains a paucity of plausible age based categorization especially for ages below one year for hospital readmission rates.

METHODSData from 2017 Healthcare cost and utilization project National readmissions database was analyzed for ages 0-18 years. Logistic regression analysis was performed to identify predictors for unplanned early readmissions.

RESULTSWe identified 5,529,389 inpatient pediatric encounters which were further divided into age group cohorts. The overall rate of readmissions was identified at 3.2%. Beyond infancy, the readmission rate was found to be 6.7%. Across all age groups, the major predictors of unplanned readmission were cancers, diseases affecting transplant recipients and sickle cell patients. It was determined that reflux, milk protein allergy, hepatitis and inflammatory bowel diseases were significant comorbidities leading to readmission. Anxiety, depression and suicidal ideation depicted higher readmission rates in those older than 13 years. Across ages 1-4 yrs, dehydration, asthma and bronchitis were negative predictors of unplanned readmission.

CONCLUSIONSThirty-day unplanned readmissions remain a problem leading to billions of tax-payer-dollars lost per annum. Effective strategies for mandatory outpatient follow-up may help the financial aspect of care while also enhancing the quality of care.


title: After the Haiti 2021 Earthquake: Triage and treatment data for a cohort of patients transported for higher level of care

abstract:
IntroOn August 14, a magnitude 7.2 earthquake occurred in the South of Haiti, killing over 2,200 people and leaving at least 12,000 injured. On August 17th, a joint task force coordinated the triage, treatment, and transport for patients arriving at the Port-au-Prince airport from the South.

MethodsFrom August 17th-27th, approximately 243 patients were encountered at the Port-au-Prince airport. For the first three days of operations, written notes, reports, and various chat logs from WhatsApp were used to compile this data.

Results243 patents were encountered at the airport Triage and Treatment from August 17 to August 27. Orthopedic injuries were the most common presenting injury with 20% of patients having a pelvis fracture (the most prevalent injury). Of the 174 with known transfer destinations, 118 (68%) were transported to one of three tertiary care hospitals, with 99 going via ground ambulance to the two in Port au Prince, and 19 going via HAA helicopter to Mirebalais. Once treatment operations were initiated, 106 patients received some form of treatment at the airport while awaiting transport.

DiscussionInteragency coordination was the key to rapid scale up. To address the most prevalent patient issues, a treatment bundle was conceptualized a few days into operations that consisted of IV fluids, analgesia, IV antibiotics, wound debridement and cleaning, and tetanus prophylaxis.


title: Fatigue in Incident Peritoneal Dialysis and Mortality: A Real-World Side-by-Side Study in Brazil and the United States

abstract:
BackgroundWe tested if fatigue in incident Peritoneal Dialysis associated with an increased risk for mortality, independently from main confounders.

MethodsWe conducted a side-by-side study from two of incident PD patients in Brazil and the United States. We used the same code to independently analyze data in both countries during 2004 to 2011. We included data from adults who completed KDQOL-SF vitality subscale within 90 days after starting PD. Vitality score was categorized in four groups: >50 (high vitality), [≥]40 to [≤]50 (moderate vitality), >35 to <40 (moderate fatigue), [≤]35 (high fatigue; reference group). In each countrys cohort, we built four distinct models to estimate the associations between vitality (exposure) and all-cause mortality (outcome): (i) Cox regression model; (ii) competitive risk model accounting for technique failure events; (iii) multilevel survival model of clinic-level clusters; (iv) multivariate regression model with smoothing splines treating vitality as a continuous measure. Analyses were adjusted for age, comorbidities, PD modality, hemoglobin, and albumin. A mixed-effects meta-analysis was used to pool hazard ratios (HRs) from both cohorts to model mortality risk for each 10-unit increase in vitality.

ResultsWe used data from 4,285 PD patients (Brazil n=1,388 and United States n=2,897). Model estimates showed lower vitality levels within 90 days of starting PD were associated with a higher risk of mortality, which was consistent in Brazil and the United States cohorts. In the multivariate survival model, each 10-unit increase in vitality score was associated with lower risk of all-cause mortality in both cohorts (Brazil HR=0.79 [95%CI 0.70 to 0.90] and United States HR=0.90 [95%CI 0.88 to 0.93], pooled HR=0.86 [95%CI 0.75 to 0.98]). Results for all models provided consistent effect estimates.

ConclusionsAmong patients in Brazil and the United States, lower vitality score in the initial months of PD was independently associated with all-cause mortality.

category: nephrology


title: Systematic Review of Cerebral Phenotypes Associated with Monogenic Cerebral Small Vessel Disease

abstract:
BackgroundCerebral small vessel disease (cSVD) is an important cause of stroke and vascular dementia. Most cases are multifactorial, but an emerging minority have a monogenic cause. While NOTCH3 is the best-known gene, several others have been reported. We aimed to summarise the cerebral phenotypes associated with these more recent cSVD genes.

MethodsWe performed a systematic review (PROSPERO: CRD42020196720), searching Medline/Embase (conception to July 2020) for any language publications describing COL4A1/2, TREX1, HTRA1, ADA2, or CTSA pathogenic variant carriers. We extracted data about individuals characteristics, clinical and vascular radiological cerebral phenotypes. We summarised phenotype frequencies per gene, comparing patterns across genes.

ResultsWe screened 6,485 publications including 402, and extracted data on 390 COL4A1, 123 TREX1, 44 HTRA1 homozygous, 41 COL4A2, 346 ADA2, 82 HTRA1 heterozygous, and 14 CTSA individuals. Mean age ranged from 15 (ADA2) to 59 years (HTRA1 heterozygotes). Clinical phenotype frequencies varied widely: stroke 9% (TREX1) to 52% (HTRA1 heterozygotes), cognitive features 0% (ADA2) to 64% (HTRA1 homozygotes), psychiatric features 0% (COL4A2; ADA2) to 57% (CTSA). Among individuals with neuroimaging, vascular radiological phenotypes appeared common, ranging from 62% (ADA2) to 100% (HTRA1 homozygotes; CTSA). White matter lesions were the most common pathology, except in ADA2 and COL4A2 cases, where ischaemic and haemorrhagic lesions dominated, respectively.

ConclusionsThere appear to be differences in cerebral manifestations across cSVD genes. Vascular radiological changes were more common than clinical neurological phenotypes, and present in the majority of individuals with reported neuroimaging. However, these results may be affected by age and biases inherent to case reports. In the future, better characterisation of associated phenotypes, as well as insights from population-based studies, should improve our understanding of monogenic cSVD to inform genetic testing, guide clinical management, and help unravel underlying disease mechanisms.


title: Post-stroke executive function impairments in relation to white matter damage due to stroke lesions versus leukoaraiosis

abstract:
ImportanceExecutive function impairments are highly prevalent post-stroke and are a feature of vascular dementia. Computed tomography (CT) neuroimaging is routinely acquired in clinical settings. Therefore, determining the prognostic utility of CT-derived markers for post-stroke cognitive outcomes is of key clinical and academic interest.

ObjectiveTo determine whether post-stroke executive function is associated with stroke-related white matter damage and/or white matter hypoattenuations of presumed vascular origin (WMHs) on routine CT brain scans.

DesignRetrospective cross-sectional analysis of data collected within the Oxford Cognitive Screening (OCS) programme (2016-2020).

SettingPatients were recruited at Oxford University Hospitals acute stroke unit. Follow-up cognitive assessment was conducted six-months post-stroke at patients homes.

ParticipantsOCS programme recruited a consecutive patient sample with a confirmed diagnosis of stroke, who were minimum 18 years old, able to remain alert for 20 minutes, and able to provide informed consent. This study included all patients who completed six-month follow-up assessment with the Oxford Cognitive Screen-Plus (OCS-Plus) and had a usable acute CT scan with a visible stroke lesion.

Main Outcome and MeasuresAssociation between post-stroke executive function and both stroke-specific white matter damage and WMHs on routine CT. Executive function was evaluated using the OCS-Plus Rule Finding task. Stroke lesions were manually delineated on CT, and stroke-related white matter damage was quantified then dichotomised using the HCP-842 atlas. WMHs were visually rated using the Age-Related White Matter Changes scale and dichotomised as present or absent.

ResultsAmong 87 stroke patients (mean/SD age = 73.60/11.75; 41 female; 61 ischaemic stroke), multivariable linear regression analyses demonstrated that poorer executive function six-months post-stroke was associated with both stroke damage to the medial lemniscus (B= - 8.86, p< .001, 95% CI [-13.29 -4.43]) and the presence of WMHs (B= -5.42, p= .005, 95% CI [-9.12 -1.72]), after adjusting for covariates including age and education.

Conclusions and RelevancePoorer post-stroke executive functioning was associated with both localised patterns of stroke-specific white matter damage and white matter degeneration. Our results confirm the necessary role of white matter integrity for executive functioning post-stroke and highlight the prognostic utility of CT-derived neuroimaging markers for long-term post-stroke cognitive outcomes.


title: Post-stroke executive function in relation to white matter damage on clinically acquired CT brain imaging


title: Maternal immune response and placental antibody transfer after COVID-19 vaccination across trimester and platforms

abstract: The availability of three COVID-19 vaccines in the United States provides an unprecedented opportunity to examine how vaccine platforms and timing of vaccination in pregnancy impact maternal and neonatal immunity. Here, we characterized the antibody profile after Ad26.COV2.S, mRNA-1273 or BNT162b2 vaccination in 158 pregnant individuals, and evaluated transplacental antibody transfer by profiling maternal and umbilical cord blood in 175 maternal-neonatal dyads. These analyses revealed lower vaccine-induced functions and Fc-receptor binding after Ad26.COV2.S compared to mRNA vaccination, and subtle advantages in titer and function with mRNA-1273 versus BN162b2. mRNA vaccinees had higher titers and functions against SARS-CoV-2 variants of concern. First and third trimester vaccination resulted in enhanced maternal immune responses relative to second trimester. Higher cord:maternal transfer ratios following first and second trimester vaccination reflect placental compensation for waning maternal titers. These results support vaccination early in pregnancy to maximize maternal protection throughout gestation, without compromising neonatal antibody protection.

category: obstetrics and gynecology


title: Environmental and behavioral exposure pathways associated with diarrhea and enteric pathogen detection in twenty-six week old urban Kenyan infants: a cross-sectional study

abstract:
The prevalence of enteric pathogen detection in children in low-income countries climbs rapidly between birth and 6 months of age. Few studies have tested whether improved household environmental and behavioral hygiene conditions protects infants from exposure to enteric pathogens spread via unhygienic human and animal sanitation conditions, especially during this early window of infancy. This cross-sectional study utilized enrollment survey data among households with 6 month old infants in Kisumu, Kenya participating in the Safe Start cluster-randomized controlled trial to estimate associations between household water access and treatment, animal vectors, sanitation access, hand washing practices, supplemental feeding, and flooring, with the outcomes of caregiver-reported 7-day diarrhea prevalence and sum count of different enteric viruses, bacteria, and parasites pathogens in infant stool. Then, we tested whether household environmental hygiene and behavioral practices moderated associations between infant exposure outcomes and latrine access and domestic animal co-habitation. We found that reported handwashing after handling animals and before eating were strongly associated with lower risk of caregiver-reported diarrhea, while owning and co-habitating with animals (versus no animals), living in a household with vinyl covered dirt floors (versus finished floors), and feeding infants cow milk (versus no milk) were strongly associated with pathogen detection in infants. Caregiver handwashing after child or self-defecation moderated the relationship between shared sanitation (vs private) sanitation access and infant exposure to pathogens such that handwashing had the greatest benefit for preventing pathogen exposure of infants in households with private latrines. In the absence of handwashing, access to private sanitation posed no benefits over shared latrines for protecting infants from exposure. Our evidence highlights eliminating animal co-habitation, improving flooring, improving post-defecation and food-related handwashing, and improving safety of cow milk sources and/or safe household storage of milk as interventions to prevent enteric pathogen exposure of infants less than 6 months age.

Key QuestionsO_ST_ABSWhat is already known?C_ST_ABSThe population prevalence of enteric infections and diarrhea climbs rapidly in the first year of life. Risk factors for pediatric infections include unhygienic human and animal sanitary conditions that introduce feces into the environment, as well as intermediate environmental and behavioral exposure pathways. Research examining the mitigating role of improved environmental and behavioral conditions in preventing infant exposure to human and animal sanitary conditions is limited.

What are the new findings?Contact with domestic animals and feeding infants cow milk are leading risk factors for exposure to enteric pathogens by 6 months age in Kisumu, while handwashing after animal handling and before eating are protective factors against self-reported diarrhea. The benefits of access to a private improved latrine (versus shared) for protecting infants from pathogen exposure were conditional upon caregivers washing hands after defecation or child-defecation.

What do the new findings imply?Interventions that keep animals out of infant living spaces and that improve food-related and post-defecation handwashing may be the most effective strategies for controlling the population prevalence of enteric infections in infants between birth and 6 months age in Kisumu and similar settings.

category: occupational and environmental health


title: A cohort study on the duration of Plasmodium falciparum infections during the dry season in The Gambia

abstract:
BackgroundIn areas where Plasmodium falciparum malaria is highly seasonal, a dry season reservoir of blood-stage infection is essential for initiating transmission during the following wet season, bridging transmission seasons several months apart. Understanding infections during the dry season could thus inform approaches for malaria control.

MethodsIn The Gambia, a cohort of 42 individuals with qPCR positive P. falciparum infections at the end of the transmission season (December) were followed monthly until the end of the dry season (May) to evaluate the duration of detectable infections. The influence of human host (age, sex, haemoglobin concentration and genotype, and P. falciparum-specific antibodies), and parasitological (parasite density, gametocyte density and genotypic multiplicity of infection) factors was investigated.

ResultsA large proportion of individuals infected at the end of the wet season had detectable infections until the end of the dry season (40.0%; 16/40), with the majority of these infections also harbouring gametocytes (81.3%; 13/16). 22 infections were classified as persistent (detectable for at least 3 months), 17 were classified as short-lived (undetectable within 2 months), and 3 were treated (due to symptoms). At the start of the dry season, the majority of persistent infections (82%; 18/22) had parasite densities >10 p/{micro}L compared to only 5.9% (1/17) of short-lived infections. Persistent infections (59%; 13/22) were also more likely to be multi-clonal than short-lived infections (5.9%; 1/17), they were most common in 5 to 15 year old children (63%; 12/19), and were associated with individuals having higher levels of P. falciparum-specific antibodies (p = 0.058).

ConclusionsAsymptomatic persistent dry season infections in The Gambia were multiclonal with higher parasite densities at the beginning of the dry season, mostly occurring in school age children and adults with higher P. falciparum-specific antibodies. Screening and treating asymptomatic, malaria-infected individuals during the dry season may reduce the human reservoir of malaria responsible initiating transmission in the wet-season.

category: infectious diseases


title: Aortic stenosis post-COVID-19: A mathematical model on waiting lists and mortality

abstract:
ObjectivesTo provide estimates for how different treatment pathways for the management of severe aortic stenosis (AS) may affect NHS England waiting list duration and associated mortality.

DesignWe constructed a mathematical model of the excess waiting list and found the closed-form analytic solution to that model. From published data, we calculated estimates for how the following strategies may affect the time to clear the backlog of patients waiting for treatment and the associated waiting list mortality.

Interventions1) increasing the capacity for the treatment of severe AS, 2) converting proportions of cases from surgery to transcatheter aortic valve implantation, and 3) a combination of these two.

ResultsIn a capacitated system, clearing the backlog by returning to pre-COVID-19 capacity is not possible. A conversion rate of 50% would clear the backlog within 666 (95% CI, 533-848) days with 1419 (95% CI, 597-2189) deaths whilst waiting during this time. A 20% capacity increase would require 535 (95% CI, 434-666) days, with an associated mortality of 1172 (95% CI, 466-1859). A combination of converting 40% cases and increasing capacity by 20% would clear the backlog within a year (343 (95% CI, 281-410) days) with 784 (95% CI, 292-1324) deaths whilst awaiting treatment.

ConclusionA strategy change to the management of severe AS is required to reduce the NHS backlog and waiting list deaths during the post-COVID-19  recovery period. However, plausible adaptations will still incur a substantial wait and many hundreds dying without treatment.

category: cardiovascular medicine


title: Covid-19 Pandemic and its Effect on Residents' Mental Well-Being

abstract: Concerns about COVID-19s long-term consequences on the mental health of frontline health professionals are mounting as the entire world strives anew to contain it. The primary objective of this research is to describe the impact of working during the COVID-19 pandemic on junior doctors mental health and to investigate the effect of the COVID-19 pandemic on junior doctors training and professional performance. A cross-sectional online survey using the Google Forms platform was conducted from May 1st to May 30th, 2021, in 311 healthcare workers who were currently enrolled in a residency program at the Kuwait Institutional of Medical Specialization (KIMS). Socio-demographic details of each health worker were collected and the scores related to depression, anxiety, and stress were measured using the previously validated depression anxiety stress scale-21 (DASS-21). Higher stress scores were seen in those who were devoid of the option to work with COVID-19 patients (adjusted {beta} 5.1 (95%CI:1.2-9);p=0.01), who reported that working during the pandemic affected their study schedule (adjusted {beta} 4.8 (95%CI:1.6-8.1);p= 0.004), and who lost off service training time (adjusted {beta} 2.7 (95%CI:0.13-5.2); p=0.034). Further, the anxiety scores were significantly higher in females. The impact of the ongoing pandemic on residents mental health is grave, necessitating psychological treatment and support. The study discovered various factors linked to depression, anxiety, and stress. As a result, these aspects must be regarded to protect the residents mental health.

category: psychiatry and clinical psychology