title: A mixed method study on supportive supervision of Community Health Workers from Central India

abstract:
IntroductionSupportive supervision of the Community health workers (CHWs) are critical for their efficient functioning in various health programs. CHWs in India are supervised by facilitators known as ASHA Sahyogini. Our study aimed at investigating the linkage between knowledge and skills of CHW facilitators and their CHWs. To understand the problems encountered by the CHW facilitators while assisting their CHWs. Also, to determine the perceptions of CHWs on nature of supportive supervision of their facilitators.

MethodsA mixed method explanatory study using purposive sampling was conducted in a rural block of Madhya Pradesh (Central India). The CHWs were categorised into relatively high performing (RHP) and relatively low performing (RLP) groups based on their performance-based incentives received during (2017-2018). Quantitative component comprised of self-administered questionnaire and skill assessment while the qualitative component comprised of three focussed group discussion with RHP, RLP CHWs and their facilitators.

ResultsThe mean (SD) supportive supervision score given by CHW facilitators were found to be significantly associated with CHWs performance. Problems faced by CHW facilitators while assisting their CHWs resulted from inadequate education of CHWs, insufficient incentives, transport problems and repetitive surveys. While some CHWs perceived to have received good assistance from their facilitators, there were a few who were not dependant on their facilitators and executed duties by self.

ConclusionCHWs performance cannot be ascribed completely to the CHW facilitators performance. The challenges perceived by CHW facilitators were unmodifiable and requires them to strongly motivate and support their CHWs in order to improve their functionality.

category: primary care research


title: DRAGON-Data: A platform and protocol for integrating genomic and phenotypic data across large psychiatric cohorts

abstract:
IntroductionCurrent psychiatric diagnoses, although heritable, have not been clearly mapped onto distinct underlying pathogenic processes. The same symptoms often occur in multiple disorders, and a substantial proportion of both genetic and environmental risk factors are shared across disorders. However, the relationship between shared symptomatology and shared genetic liability is still poorly understood. Well-characterised, cross-disorder samples are needed to investigate this matter, but currently few exist, and severe mental disorders are poorly represented in existing biobanking efforts. Purposely curated and aggregated data from individual research groups can fulfil this unmet need, resulting in rich resources for psychiatric research.

Methods and analysesAs part of the Cardiff MRC Mental Health Data Pathfinder, we have curated and harmonised phenotypic and genetic information from 15 studies within the MRC Centre for Neuropsychiatric Genetics and Genomics to create a new data repository, DRAGON-DATA. To date, DRAGON-DATA includes over 45,000 individuals: adults or children with psychiatric diagnoses, affected probands with family members and individuals who carry a known neurodevelopmental copy number variant (ND-CNV). We have processed the available phenotype information to derive core variables that can be reliably analysed across groups. In addition, all datasets with genotype information have undergone rigorous quality control, imputation, CNV calling and polygenic score generation.

Ethics and DisseminationDRAGON-DATA combines genetic and non-genetic information and is available as a resource for research across traditional psychiatric diagnostic categories. Its structure and governance follow standard UK ethical requirements (at the level of participating studies and the project as a whole) and conforms to principles reflected in the EU data protection scheme (GDPR). Algorithms and pipelines used for data harmonisation are currently publicly available for the scientific community, and an appropriate data sharing protocol will be developed as part of ongoing projects (DATAMIND) in partnership with HDR UK.

category: psychiatry and clinical psychology


title: The rapid identification and diagnosis of meniscus injuries by Magnetic Resonance Imaging using a deep learning model

abstract:
ObjectiveThe meniscus tear is a common problem in sports trauma. The imaging diagnosis mainly depends on the MRI. To improve the diagnostic accuracy and efficiency, a deep learning model was employed in this study and the identification efficiency has been evaluated.

MethodsThe standard knee MRI images of 924 individual patients were used to complete the training, validation, and testing process. The Mask R-CNN was considered as the deep learning network structure, and the ResNet50 was considered as the backbone network. The deep learning model was trained and validated with a dataset containing 504 and 220 patients, respectively. The accuracy testing was performed on a dataset of 200 patients and reviewed by an experienced radiologist and a sports medicine physician.

ResultsAfter training and validation, the deep learning model effectively recognized the healthy and injured meniscus. The overall average precision of the bounding box and pixel mask was more than 88% when the IoU threshold value was 0.75. The detailed average precision of three types of menisci (healthy, torn, and degenerated) was ranged from 68% to 80%. The overall sensitivity of the bounding box and pixel mask was more than 74% at the IoU threshold from 0.50 to 0.95. The diagnosis accuracy for the healthy, torn, and degenerated meniscus was 87.50%, 86.96%, and 84.78%, respectively.

ConclusionThe Mask R-CNN recognized effectively and predicted the meniscus injury, especially for the tears that occurred at different parts of the meniscus. The recognition accuracy was admirable. The diagnostic accuracy can be further improved with the increase of the training sample size. Therefore, this tool has great potential in the application for the diagnosis of meniscus injury.

The translational potential of this articleDeep learning model has unique effect in reducing doctors workload and improving diagnosis accuracy. It can identify and classify injured and healthy meniscus more accurately after training and learning datasets. The torn and degenerated meniscus can also be distinguished by this model. This technology could serve as an effective tool for clinical MRI-assisted diagnostics in meniscus injury.

category: radiology and imaging


title: RNAseq of amniotic fluid cell-free RNA: insights into the pathophysiology of congenital cytomegalovirus infection

abstract:
BackgroundCongenital cytomegalovirus (cCMV) is the most common perinatal infection and a significant cause of sensorineural hearing loss, cerebral palsy and neurodevelopmental disability. There is a paucity of human gene expression studies examining the pathophysiology of CMV infection.

ObjectivesThe aim of this study was to perform a whole transcriptomic assessment of amniotic fluid from pregnancies with live fetuses to identify differentially-expressed genes and enriched Gene Ontology categories associated with cCMV infection.

Study designAmniotic fluid supernatant was prospectively collected from pregnant women undergoing amniocentesis for suspected cCMV due to first trimester maternal primary infection or ultrasound features suggestive of fetal infection. Women who had received therapy to prevent fetal infection were excluded. cCMV was diagnosed via viral PCR of amniotic fluid; CMV-infected fetuses were paired with noninfected controls, matched for gestational age and fetal sex. Paired-end RNA sequencing was performed on amniotic fluid cell-free RNA with the Novaseq6000 at a depth of 30 million reads/sample. Following quality control and filtering, reads were mapped to the human genome and counts summarised across genes. Differentially expressed genes were identified using two approaches: voomWithQualityWeights in conjunction with limma and RUVSeq with edgeR. Genes with a false discovery rate (FDR) < 0.05 were considered statistically significant. Differential exon usage was analysed using DEXSeq. Functional analysis was performed using Gene Set Enrichment Analysis and Ingenuity Pathway Analysis. Manual curation of differentially regulated genes was also performed.

ResultsAmniotic fluid samples were collected from 50 women; 16 (32%) had cCMV confirmed by PCR. After excluding 3 samples without matched controls, 13 CMV-infected samples collected at 18-23 weeks and 13 CMV-negative gestation matched controls were submitted for RNA sequencing and analysis (total n=26). Ten of the 13 pregnancies with CMV-infected fetuses had amniocentesis due to serological evidence of maternal primary infection with normal fetal ultrasound, and three had amniocentesis due to ultrasound abnormality suggestive of CMV infection. Four CMV-infected pregnancies ended in termination (n=3) or fetal death (n=1), and 9 resulted in live births. Pregnancy outcomes were available on 11 of the 13 CMV-negative controls; all resulted in live births of clinically-well infants.

Differential gene expression analysis revealed 309 up-regulated and 32 down-regulated genes in the CMV-infected group compared with the CMV-negative group. Gene set enrichment analysis showed significant enrichment of multiple Gene Ontology categories involving the innate immune response to viral infection and interferon signalling. Of the 32 significantly down-regulated genes, 8 were known to be involved in neurodevelopment and preferentially expressed by the brain. Six specific cellular restriction factors involved in host defence to CMV infection were upregulated in the CMV-infected group. Ingenuity Pathway Analysis predicted activation of pathways involved in  progressive neurological disease, and  inflammatory neurological disease.

ConclusionsIn this next generation sequencing study, we reveal new insights into the pathophysiology of cCMV infection. These data on the upregulation of the intraamniotic innate immune response to CMV infection and the dysregulation of neurodevelopmental genes may inform future approaches to developing prognostic markers and assessing fetal responses to in utero therapy.

category: obstetrics and gynecology


title: Corneal cisterns as drainage aqueducts

abstract:
ImportanceAnterior chamber paracentesis (ACP) is a known method of rapid reduction of IOP. The mechanism of how corneal fluid clears after ACP is not well described.

ObjectiveTo determine the mechanism of instantaneous corneal clearing of edema after ACP.

Design, setting, and participantsThis case series includes consecutive patients with high IOP and associated corneal edema, who presented to the Glaucoma Services of our tertiary care center. Pre- and post-intervention (ACP) ASOCTs were analyzed.

Main outcome measuresResolution of corneal edema (clinical picture) and imaging of peripheral cornea and iridocorneal angle area.

ResultsTen consecutive patients who underwent an ACP were included in this study. The mean IOP pre-intervention was 48.4 {+/-} 8.2 mmHg. ASOCT showed ill-defined conventional pathways of aqueous outflow, which were blocked by peripheral anterior synechiae in 4 eyes. Immediately post ACP, the IOP was 16.3 {+/-} 5.6 mmHg (p < 0.001) and corneal edema resolved immediately. We found on ASOCT, that the intrastromal hypolucency of the peripheral cornea, (corneal cistern) which was limited in extent and U shaped, showed a posterior extension into the corneo-limbal junction to form well-defined anastomoses with the conventional aqueous drainage channels demonstrating a direct conduit for intracorneal fluid to egress. In 2/10 eyes, Schlemms canal opened intracamerally as well, suggesting direct reflux of intra-corneal fluid into the anterior chamber.

Conclusion and RelevanceAfter an ACP, in eyes with corneal edema to relieve IOP, we observed that the intracorneal cisterns undergo peripheral extension to drain corneal fluid through the conventional distal outflow channels.

category: ophthalmology


title: Association of Age-Related Macular Degeneration With Mortality: A Propensity Score-Matched Analysis

abstract:
PurposeTo investigate the association between age-related macular degeneration (AMD) and 10-year all-cause and cause-specific mortality using a large-scale population-based sample.

MethodsData from the 2005-2008 cycles of the National Health and Nutrition Examination Survey were used to assess the risk of mortality in relation to AMD in a propensity score-matched cohort. AMD status was assessed by retinal images with the standardized grading scheme. Mortality data until 31st December 2015 were derived from mortality archives. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for survival.

ResultsA total of 4691 participants were included. After a median follow-up of 8.42 (IQR: 7.58-9.67) years, 698 participants died. Participants with any AMD had an increased risk of all-cause mortality (HR, 2.02; 95% CI, 1.37-2.98). Similar results were observed for early (HR, 1.93; 95% CI, 1.31-2.85) and late AMD (HR, 4.29; 95% CI, 2.10-8.79). For cause-specific mortality, any (HR, 2.17; 95% CI, 1.39-3.39), early (HR, 2.18; 95% CI, 1.36-3.51), and late AMD (HR, 3.95; 95% CI, 1.65-9.46) were associated with significantly higher mortality due to causes other than cardiovascular disease (CVD) or cancer. Late AMD independently predicted a higher risk of CVD mortality (HR, 2.48; 95% CI, 1.32-4.65).

ConclusionsThe current study showed that any, early, and late AMD were associated with increased risks of all-cause mortality and mortality due to causes other than CVD or cancer. In addition, we found that late AMD was associated with increased risks of CVD mortality.

SynopsisLate macular degeneration independently predicted higher cardiovascular disease mortality. Any, early and late age-related macular degeneration were associated with higher all-cause mortality and mortality due to causes other than cardiovascular disease or cancer.


title: Protocol for a Systematic Review to validate or not, the philosophic explanation under the mechanism of action of the Tension Band Wiring to estabilizase an Olecranon fracture.

abstract:
Olecranon fractures in young people are commonly treated surgically. When a transverse pattern is presented the most used method to fix the fracture is the Tension Band Wiring. The AO Foundation proposed a theory for the mechanism of action of this device. It could transform the tensile forces on the posterior side into compression forces on the joint side during flexion of the elbow. Our objective is to systematically review the available literature in order to confirm or not this hypothesis.

We will include biomedical research studies evaluating Tension Band Wiring function. We are planning to search on Medline, Embase and other sources including grey literature. The studies will be selected and the data extracted. Results will include a descriptive analysis and a meta-analysis to compare the observed compression force before and after the flexion of the elbow.

Our findings will be discussed having in mind the potentially clinical implications of results.

category: orthopedics


title: Persistent delirium in older hospital patients: an updated systematic review and meta-analysis

abstract:
IntroductionPersistent delirium is recognised as a substantial problem, but there are few insights into which patient groups might be particularly affected. Delirium is associated with future dementia progression. Yet whether this occurs subclinically over months and years, or persistent delirium merges into worsened dementia is not understood.

MethodsWe adopted an identical approach to a previous systematic review, only including studies using a recognised diagnostic framework for ascertaining delirium at follow-up (persistent delirium). We applied risk of bias assessments based on Standards of Reporting of Neurological Disorders criteria. Estimates were pooled across studies using random-effects meta-analysis, and we estimated associations with age and follow-up duration using meta-regression.

ResultsWe identified 13 new cohorts, which we added to 8 from the previous systematic review (21 relevant studies reporting persistent delirium over 37 time points). Studies were mainly at low risk of bias. Pooled delirium prevalence estimates at discharge were 40% (95% CI 24% to 54%, 10 studies). Meta-regression showed variation in prevalence of persistent delirium over time (0.6% per week, 95% CI -1.2 to -0.1, p=0.02). Older study sample age was associated with higher prevalence of persistent delirium (8.8% per SD age, 95% CI 1.1% to 17%). The rate of improvement was the same regardless of age, but the overall burden was higher with older age such that 44% (95% CI 11% to 76%) of 95-year-olds would be expected to have persistent delirium at 12 months.

ConclusionsThis systematic review emphasises the key importance of delirium as a persistent and extensive problem, particularly in the oldest-old. Addressing persistent delirium will require a whole-system, integrated approach in order to detect, follow-up and implement opportunities for recovery across all healthcare settings.

category: geriatric medicine


title: The economic burden of low back pain in KwaZulu-Natal, South Africa: a prevalence-based cost-of-illness analysis from the healthcare provider's perspective.

abstract:
BackgroundGlobally, low back pain (LBP) is associated with high economic costs due to healthcare expenditure and production loss. There is lack of evidence regarding this in low-and-middle-income-countries (LMICs), including South Africa. Thus, the study aimed to determine the economic burden of LBP from the providers perspective.

MethodsWe used a retrospective prevalence-based cost-of-illness methodology to estimate the direct medical cost of LBP. Direct medical costs constituted costs associated with healthcare utilisation in inpatient care, outpatient care, investigations, consultations, and cost of auxiliary devices. We used diagnostic-specific data obtained from hospital clinical reports. All identifiable direct medical costs were estimated using a top-down approach for costs associated with healthcare and a bottom-up approach for costs associated with inpatient and outpatient care.

ResultsThe prevalence of CLBP was 24.3% (95% CI: 23.5 - 25.1). The total annual average direct medical costs associated with LBP was US$5.4 million. Acute LBP and CLBP contributed 17% (US$0.92 million) and 83% (US$4.48 million) of the total annual average direct medical cost, respectively. The per patient total annual average direct medical cost for acute LBP and CLBP were US$99.43 and US$1,516.67, respectively. The total average cost of medication per patient for acute and CLBP were US$82.53 and US$320.31, respectively. Overall, the outpatient care costs contributed the largest share (38.9%, US$2.10 million) of the total average direct medical cost, 54.9% (US$1.15 million) of which was attributed to NSAIDs and only 10% (US$0.21 million) of the total outpatient cost was due to rehabilitation. The total average cost of diagnostic investigations was estimated at US$831,595.40, which formed 15.4% of the average total cost.

ConclusionThe economic burden of LBP is high in South Africa. Majority of costs were attributed to CLBP. Action should be taken to develop culturally validated cost-effective prevention measures to mitigate the burden of LBP.

category: health economics


title: Social disparities in unplanned 30-day readmission rates after hospital discharge in patients with chronic health conditions: A retrospective cohort study using patient level hospital administrative data linked to the population census in Switzerland

abstract: Unplanned readmissions shortly after discharge from hospital are common in chronic diseases. The risk of readmission has been shown to be related both to hospital care, e.g., medical complications, and to patients resources and abilities to manage the chronic disease at home and to make appropriate use of outpatient medical care. Despite a growing body of evidence on social determinants of health and health behaviour, little is known about the impact of social and contextual factors on readmission rates. The objective of this study was to analyse possible effects of educational, financial and social resources of patients with different chronic health conditions on unplanned 30 day-readmission risks. The study made use of nationwide inpatient hospital data that was linked with Swiss census data. The sample included n=62,109 patients aged 25 and older, hospitalized between 2012 and 2016 for one of 12 selected chronic conditions. Multivariate logistic regressions analysis was performed. Our results point to a significant association between social factors and readmission rates for patients with chronic conditions. Patients with upper secondary education (OR=1.26, 95% CI: 1.11, 1.44) and compulsory education (OR=1.51, 95% CI: 1.31, 1.74) had higher readmission rates than those with tertiary education when taking into account demographic, social and health status factors. Having private or semi-private hospital insurance was associated with a lower risk for 30-day readmission compared to patients with mandatory insurance (OR=0.81, 95% CI: 0.73, 0.90). We did not find a general effect of social resources, measured by living with others in a household, on readmission rates. The risk of readmission for patients with chronic conditions was also strongly predicted by type of chronic condition and by factors related to health status, such as previous hospitalizations before the index hospitalization (+77%), number of comorbidities (+15% higher probability per additional comorbidity) as well as particularly long hospitalizations (+64%). Stratified analysis by type of chronic condition revealed differential effects of social factors on readmissions risks. Compulsory education was most strongly associated with higher odds for readmission among patients with lung cancer (+142%), congestive heart failure (+63%) and back problems (+53%). We assume that low socioeconomic status among patients with chronic conditions increases the risk of unplanned 30-day readmission after hospitalisation due to factors related to their social situation (e.g., low health literacy, lower financial possibilities), which may negatively affect cooperation with care providers and adherence to recommended therapies as well as hamper active participation in the medical process and the development of a shared understanding of the disease and its cure. Higher levels of comorbidity in socially disadvantaged patients can also make appropriate self-management and use of outpatient care more difficult. Our findings suggest a need for increased preventive measures for disadvantaged populations groups to promote early detection of diseases and to remove financial or knowledge-based barriers to medical care. Socially disadvantaged patients should also be strengthened more in their individual and social resources for coping with illness.

category: health systems and quality improvement


title: Safety Profile of Sinopharm COVID-19 Vaccine and Breakthrough Infections in Pakistan

abstract:
BackgroundTo determine the safety profile of Sinopharm COVID-19 vaccine and identify breakthrough infections.

MethodThe study design was analytical cross sectional. An online questionnaire was filled by 1033 respondentsbetween 16th and 22nd April 2021. Adults who had received both doses of Sinopharm COVID-19 vaccine more than a week ago or only a single dose with serious side effect were included in the study. The frequency and severity of vaccination related side effects were assessed and breakthrough infection identified.

ResultsThe mean age of participants was 36.7 {+/-} 12.91(18 - 92) years. Ninety one percent of participants (n=946) were health care professionals. One fifth (n=225/1033, 21.8%) had suffered from COVID-19 infection prior to vaccination, confirmed using the nasal RT-PCR test. None of the participants reported serious (grade III) or life threatening (grade IV) adverse reactions after either of the two doses. The most common side effects after the first dose were pain at injection site (20.3%), fatigue (20.3%), headache (13.9%), myalgia (12.5%) and fever (9.3%) whereas after the second dose were fatigue (16.8%), pain at injection site (15.8%), myalgia (14%) and fever (6.7%). The side effects were more common in participants who had previous history of COVID-19 infection. Of 225 previously infected participants, 97(43.1%) (p value=0.020) and 90 (40%) (p value=0.001) participants had side effects after 1st and 2nd dose respectively. 16 participants (1.55%) developed PCR positive COVID-19 infection two weeks after the second dose while 3(0.29%) participants had a re-infection. There was one case of probable severe COVID-19 infection, 2 weeks after the second dose and recovered completely with treatment.

ConclusionOur study shows that Sinopharm COVID-19 vaccine is generally safe with no serious side effects. The side effects were however, more common in inviduals who already had COVID-19 infection. The COVID-19 breakthrough infection and reinfection could occur after the vaccination.

category: infectious diseases


title: SARS-CoV-2 surveillance (09/2020 - 03/2021) in elementary schools and daycare facilities in Bavaria

abstract: Here we report our results of a multi-center, open cohort study ("COVID-Kids-Bavaria") investigating the distribution of SARS-CoV-2 among children and staff in 99 daycare facilities and 48 elementary schools in Bavaria, Germany. Overall, 2568 children (1337 school children, 1231 preschool children) and 1288 adults (466 teachers, 822 daycare staff) consented to participate in the study and were randomly tested in three consecutive phases (September/October 2020, November/December 2020, March 2021). In total, 7062 throat swabs were analyzed for SARS-CoV-2 by RT-PCR. In phase I, only one daycare worker tested positive. In phase II, SARS-CoV-2 was detected in three daycare workers, two preschool children, and seven school children. In phase III, no sample tested positive. This corresponds to a positive test rate of 0.05% in phase I, 0.4% in phase II and 0% in phase III. After phase III, antibody testing was offered to 713 study participants in elementary schools. A seroprevalence rate of 7.7% (students) and 4.5% (teachers) was determined. We conclude that during the initial waves of the SARS-CoV-2 pandemic, the risk of a positive SARS-CoV-2 result correlated positively with the local 7-day incidence. Thus, an increased risk of SARS-CoV-2 transmission in the setting of daycare and elementary schooling was unlikely.


title: Seroprevalence of anti-SARS coronavirus 2 antibodies in Thai adults during the first three epidemic waves

abstract: This study sought to determine the anti-SARS-CoV-2 antibody status of 4111 Thai people from May 2020 to April 2021, a period which spanned the first two and part of the third epidemic wave of the COVID-19 in Thailand. Participants comprised 142 COVID-19 patients, 2113 individuals at risk due to their occupations [health personnel, airport officers, public transport drivers, and workers in entertainment venues (pubs, bars and massage parlors)], 1856 individuals at risk due to sharing workplaces or living communities with COVID-19 patients, and 553 Thai citizens returning after extended periods in countries with a high disease prevalence. All sera were tested in a microneutralization assay and a chemiluminescence immunoassay (CLIA) for IgG against the N protein. Furthermore, we performed an immunofluorescence assay to resolve discordant results between the two assays. Antibody responses developed in 88% (15 of 17) of COVID-19 patients at 8 days and in 94-100% between 15 and 60 days after disease onset. Neutralizing antibodies persisted for at least 8 months, longer than the IgG did, against the N protein. None of the health providers, airport officers, and public transport drivers were seropositive, while the antibodies were present in 0.44% of entertainment workers. This study showed the seropositivity of 1.9, 1.5, and 7.5% during the 3 epidemic waves, respectively, in Bangkok residents who were at risk due to sharing workplaces or communities with COVID-19 patients. Also, antibody prevalence was 1.3% in Chiang Mai people during the first epidemic wave, and varied between 6.5 and 47.0% in Thais returning from high-risk countries. This serosurveillance study found a low infection rate of SARS-CoV-2 in Thailand before the emergence of the Delta variant in late May 2021. The findings support the Ministry of Public Healths data, which are based on numbers of patients and contact tracing.


title: Effectiveness of COVID-19 Vaccines in preventing Infectiousness, Hospitalization and Mortality: A Historical Cohort Study Using Iranian Registration Data During Vaccination program

abstract:
BackgroundThere are some concerns about the effectiveness of the inactivated and vector-based vaccines against SARS-CoV-2 in the real-world settings with the emergence of new mutations, especially variants of concern. Data derived from administrative repositories during mass-vaccination campaigns or programs are of interest to study vaccine effectiveness (VE).

MethodsUsing 4-repository administrative data linkage, we conducted a historical cohort study on a target population of 3,628,857 inhabitants aged at least 18 years residing in Southern Iran.

ResultsWe estimated 71.9% [95% CI: 70.7-73.1%], 81.5% [95% CI: 79.5-83.4%], 67.5% [95% CI: 59.5-75.6%], and 86.4% [95% CI: 84.1-88.8%] hospitalization reduction for those who received the full vaccination schedule of BIBP-CorV, ChAdOx1-S/nCoV-19, rAd26-rAd5, and BIV1-CovIran vaccines, respectively. A high reduction in mortality - at least 85% - was observed in all age subgroups of fully immunized population.

ConclusionThe pragmatic implementation of a vaccination plan including all available vaccine options in the Iranian population was associated with a significant reduction in documented COVID-19 infection, hospitalization, and death associated with COVID-19.

Key pointsThe mass vaccination program with implementing a group of vaccines, that even for some of them (rAd26-rAd5, and BIV1-CovIran vaccines) have been only regionally authorized for emergency use, has been associated with a dramatic reduction in documented COVID-19 infection, as well as in hospitalization and deaths related to the COVID-19 diagnosis.


title: Human influenza virus infection elicits distinct patterns of monocyte and dendritic cell mobilization in blood and the nasopharynx

abstract: During respiratory viral infections, the precise roles of monocytes and dendritic cells (DCs) in the nasopharynx in limiting infection and influencing disease severity are incompletely described. We studied circulating and nasopharyngeal monocytes and DCs in healthy individuals and in patients with mild respiratory infections (primarily influenza A virus, IAV). As compared to healthy controls (HCs), patients with acute IAV infection displayed reduced DC but increased intermediate monocytes frequencies in blood, and an accumulation of most monocyte and DC subsets in the nasopharynx. IAV patients had more mature monocytes and DCs in the nasopharynx, and higher levels of TNF, IL-6 and IFN in plasma and the nasopharynx. In blood, monocytes, the most frequent cellular source of TNF during IAV infection, remained responsive to additional stimulation with TLR7/8L. Immune responses in older patients skewed towards increased monocytes rather than DCs suggesting a contributory role for monocytes in disease severity. In patients with other respiratory virus infections, we observed changes in monocyte and DC frequencies in the nasopharynx distinct from IAV patients, while differences in blood were more similar across patient groups. Together, our findings demonstrate tissue-specific and pathogen-specific patterns of monocyte and DC function during human respiratory viral infections and highlight the importance of comparative investigations in blood and the nasopharynx.

category: allergy and immunology


title: CSF sphingomyelin metabolites in Alzheimer's disease, neurodegeneration, and neuroinflammation

abstract:
INTRODUCTIONSphingomyelin (SM) levels have been associated with Alzheimers disease (AD), but the association direction has been inconsistent and research on cerebrospinal fluid (CSF) SMs has been limited by sample size, breadth of SMs examined, and diversity of biomarkers available.

METHODSLeveraging two longitudinal AD cohorts with metabolome-wide CSF metabolomics data (n=502), we analyzed the relationship between the levels of 12 CSF SMs, and AD diagnosis and biomarkers of pathology, neurodegeneration, and neuroinflammation using logistic, linear, and linear mixed effects models.

RESULTSNo SMs were significantly associated with AD diagnosis, mild cognitive impairment, or amyloid biomarkers. Phosphorylated tau, neurofilament light, -synuclein, neurogranin, soluble triggering receptor expressed on myeloid cells 2, and chitinase-3-like-protein 1 were each significantly, positively associated with at least 5 of the SMs.

DISCUSSIONThe associations between SMs and biomarkers of neurodegeneration and neuroinflammation, but not biomarkers of amyloid or diagnosis of AD, point to SMs as potential biomarkers for neurodegeneration and neuroinflammation that may not be AD-specific.

category: epidemiology


title: Determinants of Late Initiation for Antenatal Care Follow up Among Pregnant Mothers Attending Public Health Centers at Jimma Town, South West Ethiopia, 2021: Unmatched Case Control Study.

abstract:
BackgroundWorld Health Organization recommends that, a woman without complications should have at least four antenatal care visits, the first of which should take place during the first trimester (not > 16 weeks). But, high proportion of pregnant women in most of developing countries attended first ANC at a late time. In Ethiopia, magnitude of late ANC follow up initiation is 64% and in study area 68.7% however determinants of the problem were not identified particularly in the study area.

ObjectiveTo identify determinants of late antenatal care initiation among pregnant women attending antenatal care in public health centers of Jimma town, south west Ethiopia 2021.

MethodsFacility based unmatched case control study was conducted from May 1-30. The cases (n=177) were mothers who attended their first antenatal care visit at >= 16 weeks of gestational age and the controls (n=177) were mothers who attended their first antenatal care visit at <16 weeks of gestational age during the data collection period. Data was collected through face to face interview using pre tested structured questionnaire. Descriptive and summary statistics was done. Bivariable and multivariable logistic regression analysis was done using SPSS version 21.0 to identify candidate variables at P-value <0.25 and determinants of late ANC initiation at P-value <0.05 respectively.

ResultsThe current study identified that, being age > 25 years (AOR= 2.623, 95% CI 1.059 - 6.496), poor knowledge about ANC (AOR= 3.856, 95% CI 1.266-11.750), lack of history of abortion (AOR= 3.326, 95% CI 1.082-10.224), place of previous delivery (AOR=3.926, 95%CI 1.023-15.063), recognizing pregnancy through missed period(AOR= 3.631, 95% CI 1.520-8.674), pregnancy related pain(AOR= 3.499, 95% CI 1.423 - 8.603) and lack of family support (AOR=2.647, 95% CI 1.092-6.415) were determinants of late ANC initiation.

ConclusionBeing age > 25 years, poor knowledge about ANC, lack of history of abortion, place of previous delivery, recognizing pregnancy through missed period, pregnancy related pain, and lack of family support during ANC booking were determinants of late ANC initiation.Health facilities and respective health care providers should provide health education at facility level regularly with due attention to late ANC initiation.


title: Transmission dynamics and vaccination strategies for Crimean-Congo haemorrhagic fever virus in Afghanistan: a modelling study

abstract:
BackgroundCrimean-Congo haemorrhagic fever virus (CCHFV) is a highly pathogenic virus for which a safe and effective vaccine is not yet available, despite being considered a priority emerging pathogen. Understanding transmission patterns and the use of potential effective vaccines are central elements of the future plan against this infection.

MethodsWe developed a series of models of transmission amongst livestock, and spillover infection into humans. We use real-world human and animal data from a CCHFV endemic area in Afghanistan (Herat) to calibrate our models. We assess the value of environmental drivers as proxy indicators of vector activity, and select the best model using deviance information criteria. Finally we assess the impact of vaccination by simulating campaigns targeted to humans or livestock, and to high-risk subpopulations (i.e, farmers).

FindingsSaturation deficit is the indicator that better explains tick activity trends in Herat. Recent increments in reported CCHFV cases in this area are more likely explained by increased surveillance capacity instead of changes in the background transmission dynamics. Modelling suggests that clinical cases only represent 31% (95% CrI 28%-33%) of total infections in this area. Vaccination campaigns targeting humans would result in a much larger impact than livestock vaccination (266 vs 31 clinical cases averted respectively) and a more efficient option when assessed in courses per case averted (35 vs 431 respectively). Targeted vaccination to farmers is impactful and more efficient, resulting in 19 courses per case averted (95% CrI 7-62) compared to targeting the general population (35 95% CrI 16-107)

InterpretationCCHFV is endemic in Herat, and transmission cycles are well predicted by environmental drivers like saturation deficit. Vaccinating humans is likely to be more efficient and impactful than animals, and importantly targeted interventions to high risk groups like farmers can offer a more efficient approach to vaccine roll-out.

FundingW.J.E., JFV and MHAC were funded by the Department of Health and Social Care using UK Aid funding managed by the National Institute for Health Research (Vaccine Efficacy Evaluation for Priority Emerging Diseases: PR-OD-1017-20002). The views expressed in this publication are those of the authors and not necessarily those of the Department of Health and Social Care.


title: Analysis of clinical trial registry entry histories using the novel R package cthist

abstract:
Historical clinical trial registry data can only be retrieved by manually accessing individual clinical trials through registry websites. This limits the feasibility, accuracy and reproducibility of certain kinds of research on clinical trial activity and presents challenges to the transparency of the enterprise of human research. This paper presents cthist, a novel, free and open source R package that enables mass downloading of clinical trial registry entry histories and returns structured data for analysis.

Documentation of the implementation of the package cthist is provided, as well as 3 brief case studies with example code.


title: The Global case-fatality rate of COVID-19 has been declining disproportionately between top vaccinated countries and the rest of the world

abstract:
Globally 58.83% human population received at least one dose of the COVID-19 vaccines as of 5 January 2021. COVID-19 vaccination rollout is progressing at varied rates globally and data on the impact of mass vaccination on infection and case-fatality rates require definition. We compared the global reported cumulative case-fatality rate (rCFR) between top-20 countries with COVID-19 vaccination rates (>125 doses/100 people) and the rest of the world, before and after commencement of vaccination programmes.

We considered the 28th day of receiving the first vaccine in the world as a cut-off to compare the pre-vaccine period (Jan 1, 2020 - Jan 5, 2021) and the post-vaccine period (Jan 6, 2021-Jan 5, 2022). We used a Generalized linear mixed model (GLMM) with a beta distribution to investigate the association between the CFR and potential predictors of each country and reported the relative risk (RR) of each variable.

The mean rCFR of COVID-19 in the top-20 countries with vaccination rates was 1.83 (95% CI: 1.24-2.43) on 5 Jan 2021 and 1.18 (95% CI: 0.73-1.62) on 5 Jan 2022. The CFR for the rest of the world on 5 Jan 2021 was 2.32 (95% CI: 1.86-2.79) and 2.20 (95% CI: 1.86-2.55) on 5 January 2022. In Sub-Saharan Africa, the CFR remained roughly unchanged at 1.97 (95% CI: 1.59-2.35) on 5 Jan 2021 and 1.98 (95% CI:1.58-2.37) on 5 Jan 2022. The GLMM showed vaccination (/100 population) (RR:0.37) and Stringency Index (RR:0.88) were strong protective factors for the countrys COVID-19 CFR indicating that both vaccination and lockdown measures help in the reduction of COVID-19 CFR.

The rCFR of COVID-19 continues to decline, although at a disproportionate rate between top vaccinated countries and the rest of the world. Vaccine equity and faster roll-out across the world is critically important in reducing COVID-19 transmission and CFR.

Key Questions

What is already knownO_LIVaccination can reduce the case-fatality rate of COVID-19. Globally, the COVID-19 vaccination rollout is progressing at varied rates.
C_LI

What are the new findingsO_LIIn the top-20 countries with vaccination, >200 doses of vaccines are given per 100 people on 5th Jan 2022, In the rest of the word, the figure is 105, and in Sub-Saharan Africa (SSA) only 15.72
C_LIO_LIAfter the introduction of COVID-19 vaccination the reported case-fatality rate (rCFR) of COVID-19 has reduced by 35% in the top-20 countries with vaccination, 8% in the rest of the world roughly unchanged in SSA.
C_LIO_LIThe doses of COVID-19 vaccines (/100 people) and rCFR has a negative correlation on 5 Jan 2022 (r=-0.296, p<0.001).
C_LIO_LIThe COVID-19 vaccination and Stringency Index are strong protective factors for the countrys COVID-19 rCFR indicating that both vaccination and lockdown measures help in reduction of COVID-19 rCFR.
C_LI

What do the new findings implyO_LIThe disproportionate case-fatality rate of COVID-19 between top vaccinated countries and the rest of the world demand fast and equitable vaccine rollout globally to reduce COVID-19 transmission and CFR
C_LI


title: The Impact of Frequent SARS-CoV-2 Testing on Weekly Case Rates Among Long-Term Care Facilities in Florida

abstract: SARS-CoV-2 testing frequency may be as important as test performance for disease control. We analyzed 1,292,165 SARS-CoV-2 test results among 361 long-term care facilities across Florida after implementing twice monthly testing (June 2020-April 2021). Our findings demonstrate that an increase in testing frequency reduced weekly case rates.


title: The impact of recurrent rapid test strategies on the effectiveness of at-home antiviral treatments for SARS-CoV-2

abstract: As has been consistently demonstrated, rapid tests administered at regular intervals can offer significant benefits to both individuals and their communities at large by helping identify whether an individual is infected and potentially infectious. An additional advantage to the individual is that positive tests may be provided sufficiently early enough during their infection that treatment with antiviral treatments can effectively inhibit development of severe disease, particularly when PCR uptake is limited and delays to receipt of results are substantial. Here, we provide a quantitative illustration of the extent to which rapid tests administered at various intervals can deliver benefits accrued from the novel Pfizer treatment (Paxlovid). We find that strategies for which tests are administered more routinely, i.e. every other day or once every three days, are associated with greater reductions in the risk of hospitalization and correspondingly, higher proportions of the infected population benefiting from treatment. We further observed that reduced positive-test-to-treatment delays and increased treatment coverage have a critical influence on average treatment benefits, signaling the importance of treatment access.


title: Elevated COVID-19 Case Rates of Government Employees, District of Columbia, 2020-22

abstract:
The rate ratios of COVID-19 cases among 5 District of Columbia departments personnel with reference to D.C. residents were found greater than one from March 2020 to early January 2022, suggesting higher case rates for emergency responders and frontline personnel than for general population. Vaccination is highly recommended.

Article summary lineGovernment employees from five D.C. departments, especially fire fighters and police officers, experienced higher COVID-19 case rates than D.C. residents.


title: Hypnosis and music interventions for pain, anxiety, sleep, and well-being in palliative care: a systematic review and meta-analysis

abstract:
BackgroundMaintaining quality of life is a primary goal of palliative care (PC). Complementary interventions can help meet the needs of patients at the end of life.

ObjectivesThis meta-analysis aims to 1) evaluate the feasibility, acceptability, and fidelity of music and hypnosis interventions designed for patients in PC; 2) evaluate the impact of these interventions on pain, anxiety, sleep, and well-being.

MethodsRelevant studies were sourced from major databases. We selected both randomised controlled trials (RCT) and studies relying on pre-post design with details of the intervention(s).

ResultsFour RCT and seven non-randomised pre-post studies met the inclusion criteria. Overall, the feasibility and acceptability of the interventions reached an adequate level of satisfaction. However, only three studies reported using a written protocol. The meta-analysis of RCT indicated a significant decrease in pain with an effect size of -0.42, p = .003. The small number of RCT studies did not allow us to quantify the effects for other variables. Analyses of data from pre-post designs indicated a favourable outcome for pain, anxiety, sleep, and well-being.

ConclusionDespite the limited number of studies included in our meta-analysis, hypnosis and music intervention in the context of PC shows promising results in terms of feasibility and acceptability, as well as improvements on pain, anxiety, sleep and well-being. The available studies are insufficient to compare the efficacy across interventions and assess the potential benefits of their combinations. These results underscore the importance of further research on well-described complementary interventions relying on hypnosis and music.

Key Messages Box O_TEXTBOXWhat was already known?O_LIThere is a need for validated complementary palliative care interventions.
C_LIO_LIMusic and hypnosis intervention have shown significant effects for pain, anxiety, sleep, and well-being management in many populations.
C_LI

What are the new findings?O_LIHypnosis and music interventions show medium effect size for pain reduction in palliative care.
C_LIO_LIThe preliminary analysis of pre-post data shown promising results for pain, anxiety, sleep, and well-being in palliative care.
C_LI

What is their significance?O_LIThe good feasibility and acceptability of these interventions justify their use in clinical settings.
C_LIO_LIMore RCT studies with manualised interventions are needed to standardise the procedures, determine effect size and allow for a systematic comparison across interventions.
C_LI

C_TEXTBOX

category: palliative medicine


title: PBPK-led guidance for the treatment of cystic fibrosis patients taking elexacaftor-tezacaftor-ivacaftor with the newly approved fixed dose combination nirmatrelvir-ritonavir (PAXLOVID) for the treatment of COVID-19

abstract:
BackgroundCystic fibrosis transmembrane conductance regulator (CFTR) modulating therapies including elexacaftor, tezacaftor, and ivacaftor (ETI) are primarily eliminated through cytochrome P450 (CYP) 3A-mediated metabolism. This creates a therapeutic challenge to the treatment of COVID-19 with nirmatrelvir-ritonavir in people with cystic fibrosis (pwCF) due to the potential for significant drug-drug interactions (DDI). However, pwCF are more at risk of serious illness following COVID-19 infection and hence it is important to manage the DDI risk and provide treatment options.

MethodsCYP3A-mediated DDI of ETI was evaluated using a physiologically based pharmacokinetic (PBPK) modeling approach. Modeling was performed incorporating physiological information and drug dependent parameters of ETI to predict the effect of ritonavir (the CYP3A4 inhibiting component of the combination) on pharmacokinetics of ETI. The ETI models were verified using independent clinical pharmacokinetic and DDI data of ETI with a range of CYP3A modulators.

ResultsWhen ritonavir was administered on day 1 through 5, the predicted AUC ratio of ivacaftor (the most sensitive CYP3A substrate) on day 6 was 9.31, indicating that its metabolism was strongly inhibited. Based on the predicted DDI, the dose of ETI should be reduced when co-administered with nirmatrelvir-ritonavir to elexacaftor 200mg-tezacaftor 100mg-ivacaftor 150mg on days 1 and 5, with resumption of full dose ETI on day 9, considering the residual inhibitory effect of ritonavir as a mechanism-based inhibitor.

ConclusionsCoadministration of nirmatrelvir-ritonavir requires a significant reduction in the ETI dosing frequency with delayed resumption of full dose due to the mechanism-based inhibition with ritonavir.

category: pharmacology and therapeutics


title: PBPK-led guidance for cystic fibrosis patients taking elexacaftor-tezacaftor-ivacaftor with nirmatrelvir-ritonavir for the treatment of COVID-19


title: A systematic review of the factors associated with suicide attempts among sexual-minority adolescents

abstract:
IntroductionSuicide attempt is a worldwide major public health problem, that accounts for 1.4% of all deaths worldwide Recent literature reported higher risk of suicide attempt among adolescents associated with sexual minority status but few systematic reviews focused on the risk and protective factors. For that reason, it seems necessary to examine risk and protective factors of attempted suicide in sexual minority adolescents.

MethodsWe conducted a systematic review of published studies on factors associated with suicide attempts in LGBT adolescents. 4 databases up to December 2020 were searched to find relevant studies.

ResultsIn addition to the factors usually found in general population (gender, ethnic minorities, childhood trauma, psychiatric symptoms, addictive behaviors), some factors have been independently associated with suicide attempt in LGBT population: early coming out, not acceptable by families, not satisfied with LGBT friendship, too few number of friends, physical abuse, sexual abuse and bullying. The protective factors of suicide attempt reported in LGBT population were feeling safety at school, teacher support, anti-bullying policy, and other adults support.

ConclusionEffective preventive measures for suicide attempt among LGBT youth need to be developed and implemented. The impact of interventions targeting teacher responses to LGBT stigma, discussion of LGBT issues in class and reactions of family and friends to the coming out of LGBT youth should be further investigated.


title: Aerosol measurement identifies SARS-CoV 2 PCR positive adults compared with healthy controls

abstract:
BackgroundSARS-CoV-2 is spread primarily through droplets and aerosols. Exhaled aerosols are generated in the lung periphery by  reopening of collapsed airways. Aerosol measuring may detect highly contagious individuals ("super spreaders or super-emitters") and discriminate between SARS-CoV-2 infected and non-infected individuals. This is the first study comparing exhaled aerosols in SARS-CoV-2 infected individuals and healthy controls.

DesignA prospective observational cohort study in 288 adults, comprising 64 patients testing positive by SARS CoV-2 PCR before enrollment, and 224 healthy adults testing negative (matched control sample) at the University Hospital Frankfurt, Germany, from February to June 2021. Study objective was to evaluate the concentration of exhaled aerosols during physiologic breathing in SARS-CoV-2 PCR-positive and -negative subjects. Secondary outcome measures included correlation of aerosol concentration to SARS-CoV-2 PCR results, change in aerosol concentration due to confounders, and correlation between clinical symptoms and aerosol.

ResultsThere was a highly significant difference in respiratory aerosol concentrations between SARS-CoV-2 PCR-positive (median 1490.5/L) and -negative subjects (median 252.0/L; p<0.0001). There were no significant differences due to age, sex, smoking status, or body mass index. ROC analysis showed an AUC of 0.8918.

ConclusionsMeasurements of respiratory aerosols were significantly elevated in SARS-CoV-2 positive individuals and may become a helpful tool in detecting highly infectious individuals via a noninvasive breath test.

Clinical Trial NumberClinicalTrials.gov Identifier: NCT04739020.

Summary of the main pointIn this prospective, comparative cohort study, higher numbers of exhaled respiratory aerosols correlate with a positive PCR test for SARS-CoV-2. Measurement of exhaled aerosols may become a helpful tool in detecting contagious individuals via a readily available breath test.

category: respiratory medicine


title: Virtual Epileptic Patient (VEP): Data-driven probabilistic personalized brain modeling in drug-resistant epilepsy

abstract: One-third of 50 million epilepsy patients worldwide suffer from drug resistant epilepsy and are candidates for surgery. Precise estimates of the epileptogenic zone networks (EZNs) are crucial for planning intervention strategies. Here, we present the Virtual Epileptic Patient (VEP), a multimodal probabilistic modeling framework for personalized end-to-end analysis of brain imaging data of drug resistant epilepsy patients. The VEP uses data-driven, personalized virtual brain models derived from patient-specific anatomical (such as T1-MRI, DW-MRI, and CT scan) and functional data (such as stereo-EEG). It employs Markov Chain Monte Carlo (MCMC) and optimization methods from Bayesian inference to estimate a patients EZN while considering robustness, convergence, sensor sensitivity, and identifiability diagnostics. We describe both high-resolution neural field simulations and a low-resolution neural mass model inversion. The VEP workflow was evaluated retrospectively with 53 epilepsy patients and is now being used in an ongoing clinical trial (EPINOV).

category: neurology


title: Graph Theoretical Measures of Fast Ripples Support the Epileptic Network Hypothesis.

abstract:
The epileptic network hypothesis and epileptogenic zone (EZ) hypothesis are two theories of ictogenesis. The network hypothesis posits that coordinated activity among interconnected nodes produces seizures. The EZ hypothesis posits that distinct regions are necessary and sufficient for seizure generation. High-frequency oscillations (HFOs), and particularly fast ripples (FR), are thought to be biomarkers of the EZ. We sought to test these theories by comparing HFO rates and networks in surgical responders and non-responders, with no appreciable change in seizure frequency or severity, within a retrospective cohort of 48 patients implanted with stereo-EEG electrodes. We recorded inter-ictal activity during non-rapid eye movement sleep and semi- automatically detected and quantified HFOs. Each electrode contact was localized in normalized coordinates. We found that the accuracy of seizure-onset zone (SOZ) electrode contact classification using HFO rates (ripples 80-250 Hz, and FR 250-600 Hz) was not significantly different in surgical responders and non-responders, suggesting that in non-responders the EZ partially encompassed the SOZ(s) (p>0.05). We also found that in the responders, FR on oscillations exhibited a higher spectral content in the SOZ compared to the non-SOZ (p<1e-5). In contrast, in the non-responders the FR had a lower spectral content in the SOZ (p<1e-5). We constructed two different networks of FR with a spectral content > 350 Hz. The first was a rate- distance network that multiplied the Euclidian distance between FR generating contacts by the average rate of FR in the two contacts. The radius of the rate-distance network, which excluded SOZ nodes, discriminated non-responders, including patients not offered resection or responsive neurostimulation (RNS) due to diffuse multi-focal onsets, with an accuracy of 0.77 [95% confidence interval (CI) 0.56-0.98]. The second FR network was constructed using the mutual information (MI) between the timing of the events to measure functional connectivity. For most non-responders, this network had a longer characteristic path length, lower mean local efficiency in the non-SOZ, and a higher nodal strength among non-SOZ nodes relative to SOZ nodes. The graphical theoretical measures from the rate-distance and MI networks of 22 non-RNS treated patients was used to train a support vector machine, which when tested on 13 distinct patients classified non-responders with an accuracy of 0.92 [95% CI 0.75-1]. These results support the epileptic network hypothesis, refute the EZ hypothesis, and suggest that surgical non-responders, and patients not selected for resection or RNS, exhibit a decentralized FR network consisting of widely distributed, hyperexcitable FR generating nodes.

Abbreviated SummaryWeiss et al., report that fast ripples form a correlational network. In poor epilepsy surgery candidates, and patients that dont respond to surgery, the networks are widespread, highly active, and decentralized. This can be used to plan effective surgeries and supports the theory that seizures require a coordinated epileptic network.

Graphical abstract

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title: Single-nuclei paired multiomic analysis of young, aged, and Parkinson's disease human midbrain reveals age-associated glial changes and their contribution to Parkinson's disease

abstract: Age is the primary risk factor for Parkinsons disease (PD), but how aging changes the expression and regulatory landscape of the brain remains unclear. Here, we present a single-nuclei multiomic study profiling shared gene expression and chromatin accessibility of young, aged and PD post-mortem midbrain samples. Combined multiomic analysis of midbrain nuclei along a pseudopathogenesis trajectory reveals all glial cell types are affected by age, but microglia and oligodendrocytes are further altered in PD. We present evidence for a novel age-associated oligodendrocyte subtype that appears during normal aging, characterized by elevated protein folding and chaperone-mediated autophagy pathways. Differential gene and protein-protein interaction analyses show that these functions are significantly compromised in PD. Peak-gene association from our paired data identifies differential cis-elements linked to regulation of differentially expressed genes between PD patients and neurologically healthy controls. Our study suggests a previously undescribed role for oligodendrocytes in aging and PD pathogenesis.


title: The relationship between work disability and subsequent suicide or self-harm: A systematic scoping review.

abstract:
BackgroundWork disability occurs when an injury, illness or other health condition limits the ability of a worker to participate in paid employment. Several lines of evidence suggest that people with work disability are also at increased risk of suicide and intentional self-harm, however the evidence on this relationship has not previously been the subject of systematic review.

ObjectiveThis systematic scoping review aims to assess and summarise the research literature regarding the relationship between work disability and subsequent suicide or intentional self-harm.

MethodsPeer-reviewed quantitative and qualitative studies published in English from 1st January 2000 were included if they reported suicide or self-harm outcomes in people aged 15 years or older with work disability. Narrative synthesis summarised findings according to the system of work disability income support.

ResultsLiterature search yielded 859 records of which 47 eligible studies were included, including nine set in workers compensation, 20 in sickness absence, 13 in disability pension systems, and five from mixed cohorts. Of 44 quantitative studies, 41 reported a positive relationship between work disability and suicidal behaviour. The relationship is observed consistently across nations, work disability income support systems and in people with a range of health conditions. Several factors elevate risk of suicidal behaviour, including presence of mental health conditions and longer work disability duration. There were few quality studies in some nations and no suicide prevention interventions.

ConclusionThe risk of suicide and intentional self-harm is elevated in people experiencing work disability. While further observational research is required to fill evidence gaps, this review suggests the need for governments, employers and those involved in the delivery of care and support to people with work disability to focus on identification and monitoring of those at greatest risk of suicidal behaviour, as well as suicide prevention.

category: occupational and environmental health


title: Applying a genetic risk score for prostate cancer to men with lower urinary tract symptoms in primary care to predict prostate cancer diagnosis: a cohort study in the UK Biobank

abstract:
ObjectivesTo assess how accurately a genetic risk score (GRS) can identify incident prostate cancer in men seeing their general practitioner with lower urinary tract symptoms.

DesignCohort study.

SettingUK Biobank data linked to primary care records.

ParticipantsMen registered with the UK Biobank, eligible for the primary care data linkage, with a record showing that they consulted their general practitioner with lower urinary tract symptoms (LUTS) that could indicate possible undiagnosed prostate cancer.

Main outcome measuresA diagnosis of prostate cancer within two years of the patients first consultation with their general practitioner for LUTS.

ResultsA GRS is associated with prostate cancer in men with symptoms (OR=2.54 [2.16 to 2.99] p=5e-29). An integrated risk model including age and GRS applied to symptomatic men predicted prostate cancer with an AUC of 0.768 (0.739 to 0.796). Men aged 40 years and under in the bottom four GRS quintiles, aged 50 years and under in the bottom two GRS quintiles, and aged 50 to 60 years in the bottom GRS quintile had a two-year prostate cancer incidence below 1%, despite the presence of symptoms. The negative predictive value of the combined model exceeded 99%.

ConclusionsThis study is the first to apply a genetic risk score in a clinical setting to improve the triage of men with symptoms of prostate cancer. It demonstrates the added benefit of incorporating an estimate of genetic risk of prostate cancer into the clinical assessment of symptomatic men in primary care. Assessment of prostate cancer risk in men with LUTS is currently based on presenting clinical features alone. Men with the lowest genetic risk of developing prostate cancer could safely avoid invasive investigation, with adequate safety netting, whilst those identified with the greatest risk could be fast-tracked for further investigation.

category: oncology


title: The quality of vital signs measurements in electronic medical records varies by hospital, specialty, and patient demographics

abstract:
ObjectiveTo assess the frequency of digit preference in recording of vital signs in electronic healthcare records (EHRs) and associated patient and hospital factors.

Study Design and SettingWe used EHR data from Oxford University Hospitals, UK, between 01-January-2016 and 30-June-2019 and multivariable logistic regression to investigate associations between temperature readings of 36.0{degrees}C or systolic and diastolic blood pressure (SBP/DBP) readings both ending in zero and patient age, sex, ethnicity, deprivation, comorbidities, calendar time, hour of day, days into admission, hospital, day of week and speciality.

ResultsIn 4,305,914 records from 143,352 patients, there was an excess of temperature readings of 36.0{degrees}C (15.1%, 649,976/4,305,914), compared to an expected 4.9% from the underlying distribution. 2.2% (95,215) BP readings had a SBP and DBP both ending in zero vs. 1% expected by chance. Digit preference was more common in older and male patients, as length of stay increased, following a previous normal set of vital signs and typically more common in medical vs. surgical specialities. Differences were seen between hospitals, however, digit preference reduced over calendar time.

ConclusionVital signs may not always be accurately documented. Allowances and adjustments may be needed in observational analyses using these factors as outcomes or exposures.

Whats New?O_ST_ABSKey findingsC_ST_ABS{blacksquare} Digit preference in the recording of vital signs in electronic healthcare records is common, affecting approximately 10% of temperature measurements and 1% of blood pressure recordings in a large UK teaching hospital group
{blacksquare}These findings were obtained in hospitals using a semi-automated data capture system that required manual re-entry of vital signs into a tablet computer prior to automated upload to electronic patient records
{blacksquare}Digit preference was associated with patient characteristics and was more common in older and male patients, as length of stay increased and following previously normal vital signs
{blacksquare}Digit preference varied between hospitals, but decreased over time
{blacksquare}Digit preference was generally more common in medical compared to surgical specialties

What this adds to what is known{blacksquare} Most previous studies of data quality in electronic patient records have focused on the accuracy of coding
{blacksquare}This study focuses on the accuracy of numeric values in patient records, and also adds new data on patient and hospital factors associated with the accuracy of values in electronic patient records

Implications{blacksquare} Clinicians and researchers need to be aware that vital signs may not always be accurately documented
{blacksquare}Appropriate allowances and adjustments for digit preference should be considered in observational analyses using these factors as outcomes or exposures.
{blacksquare}Further work is required to understand the mechanisms behind values preference on a systems, patient and clinician level

category: health informatics


title: Clinically relevant combined effect of polygenic background, rare pathogenic germline variants, and family history on colorectal cancer incidence

abstract:
Background and aimsSummarised in polygenic risk scores (PRS), the effect of common, low penetrant genetic variants associated with colorectal cancer (CRC), can be used for risk stratification.

MethodsTo assess the combined impact of the PRS and other main factors on CRC risk, 163,516 individuals from the UK Biobank were stratified as follows: 1. carriers status for germline pathogenic variants (PV) in CRC susceptibility genes (APC, MLH1, MSH2, MSH6, PMS2), 2. low (<20%), intermediate (20-80%), or high PRS (>80%), and 3. family history (FH) of CRC. Multivariable logistic regression and Cox proportional hazards models were applied to compare odds ratios (OR) and to compute the lifetime incidence, respectively.

ResultsDepending on the PRS, the CRC lifetime incidence for non-carriers ranges between 6% and 22%, compared to 40% and 74% for carriers. A suspicious FH is associated with a further increase of the cumulative incidence reaching 26% for non-carriers and 98% for carriers. In non-carriers without FH, but high PRS, the CRC risk is doubled, whereas a low PRS even in the context of a FH results in a decreased risk. The full model including PRS, carrier status, and FH improved the area under the curve (AUC) in risk prediction (0.704).

ConclusionThe findings demonstrate that CRC risks are strongly influenced by the PRS for both a sporadic and monogenic background. FH, PV, and common variants complementary contribute to CRC risk. The implementation of PRS in routine care will likely improve personalized risk stratification, which will in turn guide tailored preventive surveillance strategies in high, intermediate, and low risk groups.


title: Effect of removing race correction factor in glomerular filtration rate estimation on predicting acute kidney injury after percutaneous coronary intervention

abstract:
BackgroundRace is a social and not a biological construct. Major societies have recommended removing a race correction factor when estimating glomerular filtration rate (eGFR). eGFR is a strong predictor for acute kidney injury (AKI) after percutaneous coronary intervention (PCI). We assessed the effect of removal of the race correction factor in eGFR calculation on the predictive ability of contemporary models for AKI after PCI.

MethodsWe used data from the American College of Cardiologys National Cardiovascular Data Registry (NCDR) CathPCI registry to assess the effect of removing a race correction in eGFR calculation on two previously published AKI models developed using NCDR data - a logistic regression-based model and a gradient boosting machine learning (ML) model. We first assessed the calibration and discrimination of these models with and without race correction and subsequently included race as an independent predictor in a model without race-corrected eGFR. We assessed model performance overall, and stratified by Black and non-Black subgroups. The models were trained on the same cohort used to develop the NCDR models and validated with a contemporaneous validation data set.

ResultsWe included 947,091 PCI procedures in 915,223 patients (mean age 64.8 years; 7.9% were Black and 32.8% women) with an AKI rate of 7.4%. In the NCDR model, inclusion of race correction in eGFR significantly underestimated AKI risk among Black patients (predicted 7.6% vs observed 10.2%) while slightly overestimating risk among non-Black patients (predicted 7.4% vs observed 7.1%). Removing the race correction partially corrected the underestimation among Black patients (predicted 8.2%). Including race as an independent predictor and introducing interaction terms further reduced the underestimation (predicted 10.1%). The receiver-operating-characteristic curve (AUC) was similar among these models, but was consistently lower in Black patients. Compared with the logistic model, the ML model had better calibration in Black patients (with race correction predicted 8.6% and without 8.7%) but still underestimated AKI risk. With race included as a predictor, the ML model achieved similarly good calibration in Black patients (predicted 10.1%). The AUCs of ML models were better than the logistic models but did not differ based on the inclusion of the race correction.

ConclusionRemoving the race correction in eGFR calculation has a positive effect of reducing the underestimation of the risk of AKI following PCI for Black patients. However, despite the reduction in underestimation, Black patients remain at elevated risk for AKI compared to non-Black patients. There is a need to better capture the determinants of this higher AKI risk through richer data and advanced modeling techniques.


title: Quantifying the direct and indirect protection provided by insecticide treated bed nets against malaria

abstract:
Long lasting insecticide treated mosquito nets (LLINs) provide both direct and indirect protection against bites from mosquitoes potentially transmitting malaria. Direct personal protection is provided to net users given both the nets physical barrier and its insecticidal action. Indirect mass protection for the community is afforded through reduced infectious bites per person annually (entomological inoculation rate, EIR). Quantifying these protective effects can help strategize options for net interventions, particularly as insecticide-resistant mosquitoes spread.

These types of protection are inherently linked, rendering it impossible to empirically quantify the contribution of each to the overall  community effect, instead we investigate this with a modelling framework and compare model predictions to trends with Demographic Health Survey (DHS) data.

Our modelling exercise predicts that in a situation with an EIR of 100, the reduction in EIR from an untreated net used by 80% of the population is 52% [95% CI: 12% - 84%] for users and 21% [95% CI: 0% - 57%] for non-users. Due to the impact of the insecticide, the reduction in EIR for LLINs is 89% [95% CI: 67% - 98%] for users and 74% [95% CI: 48% - 92%] for non-users, but this protection reduces as insecticide resistance in mosquitoes increases. Modelled trends in the difference in protection between users and non-users across endemicity and net usage levels are consistent with DHS data (2000-2018).

This study supports the concept of a community effect from LLINs, highlights the value of blocking and killing mosquitoes for community protection. Achieving high LLIN usage is always preferential, but there remains protection to non-users as the number of people using nets increases.


title: Extreme γ' fibrinogen levels in COVID-19 patients

abstract:
BackgroundCOVID-19 progression can be accompanied by a "cytokine storm" that leads to secondary sequelae such as thrombosis and acute respiratory distress syndrome. Several inflammatory cytokines have been associated with COVID-19 progression, but have far too much daily intra-individual variability to be useful in tracking the course of the disease. In contrast, we have shown that the inflammatory biomarker {gamma} fibrinogen ({gamma} Fbg) has a 6-fold lower coefficient of variability compared to other inflammatory markers such as hs-CRP. Objectives: The aims of the study were to measure {gamma} Fbg in serial blood samples from COVID-19 patients at a tertiary care medical center in order to investigate its association with clinical measures of disease progression.

MethodsCOVID-19 patients at a tertiary care medical center were retrospectively enrolled between 3/16/2020 and 8/1/2020. {gamma} Fbg was measured using a commercial ELISA. Results: Our results showed that nine out of the seventeen patients with COVID-19 had extremely high levels of {gamma} Fbg. {gamma} Fbg levels were significantly associated with the need for ECMO and with mortality.

ConclusionsWe found that COVID-19 patients can develop extraordinarily high levels of {gamma} Fbg. The previous highest {gamma} Fbg level that we are aware of was 80.3 mg/dL found in a study of 10,601 participants in the ARIC study. These results have several important clinical implications. {gamma} Fbg contains a high affinity binding site for thrombin that binds to anion-binding exosite II on thrombin and protects it from inactivation by heparin. High levels of {gamma} Fbg therefore provide a reservoir of heparin-resistant clot-bound thrombin when the {gamma} Fbg is clotted. These findings have potential implications regarding prophylactic anticoagulation of COVID-19 patients and suggest that heparin prophylaxis may be less effective than using other anticoagulants, particularly direct thrombin inhibitors.


title: Molecular diagnosis of SARS-CoV-2: a validation of saliva samples

abstract: Nasopharyngeal swabs are the most used in sample collecting for covid-19 tests in SARS-CoV-2 molecular diagnosis. However, this sampling method presents some disadvantages, since, in addition to being dependent on imported materials, it is invasive, causes discomfort in patients, and, presents the risk of contamination for the medical collection team. This study aimed at validating saliva samples to obtain viral RNA to be used in the molecular diagnostic test for SARS-CoV-2 using the RT-qPCR technique. Results presented 93,44% concordance in in comparison to nasopharyngeal swabs sampling. Therefore, saliva samples used in SARS-CoV-2 RT-qPCR detection tests presented consistent results.


title: Human Parainfluenza 2 & 4: clinical and genetic epidemiology in the UK, 2013-2017, reveals distinct disease features and co-circulating genomic subtypes

abstract: Human Parainfluenza viruses (HPIV) are constituted by four members of the genetically distinct genera of Respirovirus (type 1 and 3) and Orthorubulavirus (type 2 and 4), causing significant upper and lower respiratory tract infections in both children and adults worldwide. However, despite frequent molecular diagnosis, they are frequently considered collectively or with HPIV4 overlooked entirely. We therefore investigated clinical and viral epidemiological distinctions of the relatively less prevalent Orthorubulaviruses HPIV2 & 4 at a regional UK hospital across four winter epidemic seasons. HPIV2 & 4 infection was observed across all age groups, but predominantly in children under 9 and adults over 40, with almost twice as many HPIV4 as HPIV2 cases. Fever, abnormal haematology, elevated C-reactive protein and hospital admission were more frequently seen in HPIV2 than HPIV4 infection. Each of the four seasonal peaks of either HPIV2, HPIV4 or both, closely matched that of RSV, occurring in November and December and preceding that of Influenza A. A subset of viruses were partially sequenced, indicating co-circulation of multiple subtypes of both HPIV2 & 4, but with little variation between each epidemic season or from limited global reference sequences.


title: "I feel like my body is broken": Exploring the experiences of people living with long COVID

abstract:
BackgroundLong COVID, an illness affecting a subset of individuals after COVID-19, is distressing and poorly understood. Exploring the experiences of people with long COVID could help inform current conceptualizations of the illness, guide supportive care strategies, and validate patients perspectives on the condition. Thus, the objective of this study was to better understand and explore individuals experiences with long COVID and commonly reported symptoms, using qualitative data collected from open-ended survey responses.

MethodsData were collected from adults living with long COVID following a confirmed or suspected SARS-CoV-2 infection who participated in a larger observational, online survey. Within the larger survey, participants had the option of answering seven open-ended items. Data from the open-ended items were analyzed following guidelines for reflective thematic analysis.

ResultsFrom the 213 who were included in the online survey, 169 participants who primarily self-identified as women (88.2%), aged 40-49 (33.1%), and who had been experiencing long COVID symptoms for [≥] 6 months (58.6%) responded to the open-ended questions. Four overlapping and interconnected themes were identified: (1) My long COVID symptoms are numerous, hard to describe, and debilitating, (2) All aspects of my day-to-day functioning have been impacted, (3) I can no longer be physically active, and (4) I keep asking for help, but no one is listening, and very little is working.

ConclusionFindings highlight the complex nature of long COVID and show the ways in which individuals affected by the illness are negatively impacted. Participants recounted struggling and altering their daily activities while managing relapsing-remitting symptoms, an uncertain prognosis, lost pre-COVID identities, and a healthcare system (that does not always offer guidance nor take them seriously). More support and recognition for the condition are needed to help this cohort navigate the process of adapting to long COVID.


title: Capturing intrahost recombination of SARS-CoV-2 during superinfection with Alpha and Epsilon variants in New York City

abstract: Recombination is an evolutionary process by which many pathogens generate diversity and acquire novel functions. Although a common occurrence during coronavirus replication, recombination can only be detected when two genetically distinct viruses contemporaneously infect the same host. Here, we identify an instance of SARS-CoV-2 superinfection, whereby an individual was simultaneously infected with two distinct viral variants: Alpha (B.1.1.7) and Epsilon (B.1.429). This superinfection was first noted when an Alpha genome sequence failed to exhibit the classic S gene target failure behavior used to track this variant. Full genome sequencing from four independent extracts revealed that Alpha variant alleles comprised between 70-80% of the genomes, whereas the Epsilon variant alleles comprised between 20-30% of the sample. Further investigation revealed the presence of numerous recombinant haplotypes spanning the genome, specifically in the spike, nucleocapsid, and ORF 8 coding regions. These findings support the potential for recombination to reshape SARS-CoV-2 genetic diversity.


title: Antigenic determinants of SARS-CoV-2-specific CD4+ T cell lines reveals M protein-driven dysregulation of interferon signaling

abstract: We generated CD4+ T cell lines (TCLs) reactive to either SARSCoV-2 spike (S) or membrane (M) proteins from unexposed naive T cells from six healthy donor volunteers to understand in fine detail whether the S and M structural proteins have intrinsic differences in driving antigen-specific CD4+ T cell responses. Having shown that each of the TCLs were antigen-specific and antigen-reactive, single cell mRNA analyses demonstrated that SARS-CoV-2 S and M proteins drive strikingly distinct molecular signatures. Whereas the S-specific responses are virtually indistinguishable from those responses induced by other viral antigens (e.g. CMV), the M protein-specific CD4+ TCLs have a transcriptomic signature that indicate a marked suppression of interferon signaling, characterized by a downregulation of the genes encoding ISG15, IFITM1, IFI6, MX1, STAT1, OAS1, IFI35, IFIT3 and IRF7 (a molecular signature which is not dissimilar to that found in severe COVID-19). Our study suggests a potential link between the antigen specificity of the SARS-CoV-2-reactive CD4+ T cells and the development of specific sets of adaptive immune responses. Moreover, the balance between T cells of significantly different specificities may be the key to understand how CD4+ T cell dysregulation can determine the clinical outcomes of COVID-19.


title: BNT162b2 vaccine boosts neutralizing antibodies to ancestral SARS-CoV-2 & Omicron variant in adults who previously received two doses of inactivated vaccine

abstract:
BackgroundLimited data exist on antibody responses to mixed vaccination strategies involving inactivated COVID-19 vaccines, particularly in the context of emerging variants.

MethodsWe conducted an open label trial of a third vaccine dose of an mRNA vaccine (BNT162b2, Fosun Pharma/BioNTech) in adults aged [≥]30 years who had previously received two doses of inactivated COVID-19 vaccine. We collected blood samples before administering the third dose and 28 days later, and tested for antibodies to the ancestral virus using a binding assay (ELISA), a surrogate virus neutralization test (sVNT) and a live virus plaque reduction neutralization test (PRNT). We also tested for antibodies against the Omicron variant using live-virus PRNT.

ResultsIn 315 participants, a third dose of BNT162b2 substantially increased antibody titers on each assay. Mean ELISA levels increased from an optical density (OD) of 0.3 to 2.2 (p<0. 001), and mean sVNT levels increased from an inhibition of 17% to 96% (p<0.001). In a random subset of 20 participants, the geometric mean PRNT50 titers rose very substantially by at least 24 fold from Day 0 to Day 28 against the ancestral virus (p<0.001) and rose by at least 11 fold against the Omicron variant (p<0.001). In daily monitoring, post-vaccination reactions subsided within 7 days for over 99% of participants.

ConclusionsA third dose of COVID-19 vaccination with an mRNA vaccine substantially improved antibody levels against the ancestral virus and the Omicron variant with well-tolerated safety profile, in adults who had received two doses of inactivated vaccine 6 months earlier.

SummaryIn this open label trial of Chinese adults aged [≥]30 years who received two doses of inactivated COVID-19 vaccine 6 months earlier, third-dose mRNA vaccine substantially improved antibody levels against the ancestral virus and Omicron variant with well-tolerated safety profile.


title: Immunogenicity of a third dose of BNT162b2 to ancestral SARS-CoV-2 & Omicron variant in adults who received two doses of inactivated vaccine


title: A booster dose of mRNA-based COVID-19 vaccines fosters the development of an immune response in immunosuppressed fragile patients.

abstract:
SARS-CoV-2 vaccination has proven effective in inducing an immune response in healthy individuals and is progressively allowing to overcome the pandemic. Recent evidence has shown that response to vaccination in some vulnerable patients may be diminished, and it has been proposed a booster dose. We tested the kinetic of development of serum antibodies to the SARS-CoV-2 Spike protein, their neutralizing capacity, the CD4 and CD8 IFN-{gamma} T cell response in 328 subjects, including 131 immunocompromised individuals (cancer, rheumatologic, and hemodialysis patients), 160 healthcare workers (HCW) and 37 subjects older than 75 yo, after vaccination with two or three doses of mRNA vaccines. We stratified the patients according to the type of treatment. We found that immunocompromised patients, depending on the type of treatment, poorly respond to SARS-CoV-2 mRNA vaccines. However, an additional booster dose of vaccine induced a good immune response in almost all of the patients except those receiving anti-CD20 antibody. Similarly to HCW, previously infected and vaccinated immunocompromised individuals demonstrate a stronger SARS-CoV-2 specific immune response than those who are vaccinated without prior infection.

Summary blurbImmunocompromised patients poorly respond to two doses of SARS-CoV-2 mRNA vaccines. However, an additional booster dose elicits a strong humoral and cellular immune response in these subjects.


title: mRNA COVID-19 vaccine booster fosters B and T cell responses in immunocompromised patients


title: Causal associations between body fat accumulation and COVID-19 severity: A Mendelian randomization study

abstract:
PurposeThe causal effects of body fat mass and body fat-free mass on coronavirus disease 2019 (COVID-19) severity remain unclear. Here, we used Mendelian randomization (MR) to evaluate the causal relationships between body fat-related traits and COVID-19 severity.

Material and MethodsWe identified single nucleotide polymorphisms associated with body mass index (BMI) and direct measures of body fat (i.e., body fat percentage, body fat mass, and body fat-free mass) in 461,460, 454,633, 454,137, and 454,850 individuals of European ancestry from the UK Biobank, respectively. We then performed two-sample MR to ascertain their effects on severe COVID-19 (cases: 4,792; controls: 1,054,664) from the COVID-19 Host Genetics Initiative.

ResultsWe found that an increase in BMI, body fat percentage, and body fat mass by one standard deviation were each associated with severe COVID-19 (odds ratio (OR)BMI = 1.49, 95%CI: 1.19-1.87, P = 5.57x10-4; ORbody fat percentage = 1.94, 95%CI: 1.41-2.67, P = 5.07x10-5; and ORbody fat mass = 1.61, 95%CI: 1.28-2.04, P = 5.51x10-5). Further, we evaluated independent causal effects of body fat mass and body fat-free mass using multivariable MR and revealed that only body fat mass was independently associated with severe COVID-19 (ORbody fat mass = 2.91, 95%CI: 1.71-4.96, P = 8.85x10-5 and ORbody fat-free mass = 1.02, 95%CI: 0.61-1.67, P = 0.945).

ConclusionsThis study demonstrates the causal effects of body fat accumulation on COVID-19 severity and indicates that the biological pathways influencing the relationship between COVID-19 and obesity are likely mediated through body fat mass.

category: endocrinology


title: Temporal trends in legionellosis national notification data and the effect of COVID-19, Switzerland, 2000- 2020

abstract: The notification rate of legionellosis in Switzerland and other European countries has markedly increased over the last 20 years. Here, we investigated the Swiss notification data on legionellosis from 2000-2020 in regards of overall time trend, content and data quality. We further explored the impact of the COVID-19 pandemic on the reported case numbers using an interrupted time series approach. Between 2000 and 2020, 5,980 cases were included in our analysis. The annual crude notification rate for legionellosis cases increased from 1.1/100,000 population (CI: 0.9 - 1.4) in 2000 to 5.6/100,000 population (CI: 5.1 - 6.1) in 2020. In recent years, the summer peaks have been more pronounced and some shifted earlier in the year. The highest notification rate was recorded in 2018 with 6.7/100,000 population (CI: 6.2 - 7.3). The hospitalisation rate for notified cases remained high across all study years (89.9%), while the case fatality rate slightly decreased (from 7.7% to 3.6%). COVID-19 containment measures, such as travel restrictions and/or related behavioural changes, are associated with a temporary decline in cases of 35%. Overall, the quality of the notification data was good. Clinical data were more susceptible to interferences than data from laboratory reporting, which could be observed most clearly in the decline of clinical reports by 4.3 percentage points in 2020. As the case classification for Legionnaires disease includes pneumonia symptoms, this decline could lead to an underestimation of Legionnaires disease cases, yet the continuous reporting though the diagnostic laboratories suggested a robust surveillance system for legionellosis in Switzerland.


title: Reevaluation of Seroprevalence using a Semi-quantitative Anti-spike IgG in Health Care workers at an Academic Medical Center in Boston, Massachusetts

abstract:
BackgroundAccurate measurement of antibodies is a necessary tool for assessing exposure to SARS-CoV-2 and facilitating understanding of the role of antibodies in immunity. Most assays are qualitative in nature and employ a threshold to determine presence of antibodies. Semi-quantitative assays are now available. Here we evaluate the semi-quantitative SARS-CoV-2 IgG II (anti-spike (S)) assay. We aim to reassess the seroprevalence using anti-S assay and subsequently compare it to the previously measured IgG (anti-nucleoprotein (N)) in health care workers at an academic medical center in Boston.

Methods1743 serum samples from HCWs at Boston Medical Center were analyzed for SARS-CoV-2 anti-S IgG and IgM using the Abbott SARS-CoV-2 IgG II and{square}Abbott AdviseDx{square}SARS-CoV-2 IgM assay, respectively. Precision, linearity, positive and negative concordance with prior RT-PCR test were evaluated for anti-S IgG. Seroprevalence and its association with demographics variables was also assessed.

ResultsLinearity and precision results were clinically acceptable. The positive and negative concordance for anti-S IgG with RT-PCR was 88.2% (95% CI: 79.4% - 94.2%) and 97.43% (95% CI: 95.2% - 98.8%), respectively. Overall, 126 (7.2%) of 1,743 participants were positive by anti-S IgG. Among the 1302 participants with no prior RT-PCR, 40 (3.1%) were positive for anti-S IgG antibody. The original agreement in this population with the qualitative, anti-N IgG assay was 70.6%. Upon optimizing the threshold from 1.4 to 0.49 S/CO of the anti-N IgG assay, the positive agreement of the assay increases to 84.7%.

ConclusionThe anti-S IgG assay demonstrated reproducible and reliable measurements. This study highlights the presence of asymptomatic transmission among individuals with no prior history of positive RT-PCR. It also highlights the need for optimizing thresholds of the qualitative SARS-CoV-2 IgG assay for better agreement between assays by the same vendor.


title: A high-throughput approach measures cell type-specific telomere lengths in fixed archival tissues from patient cohorts for research on prognosis

abstract: Telomeres, the repetitive DNA elements at chromosome ends, are pivotal for maintenance of genome integrity. Previous studies from our group and others have highlighted the translational potential of tissue-based telomere length measurements to address the clinical challenge of improving diagnosis, individualized risk stratification, and accurate prognostication of different diseases. Here, we describe a high-throughput method that quantitates cell type-specific telomere lengths at a single cell level in archival tissues from patient cohorts for research on prognosis. This approach is based on telomere-specific fluorescence in situ hybridization (FISH) combined with multiplex immunostaining for cell type-specific antibodies, followed by semi-automated slide scanning and multi-channel acquisition of fluorescent images using the TissueFAXS Plus microscopy workstation and TissueQuest software (TissueGnostics). Here, we demonstrate that this method is sufficiently robust and reproducible to detect biologically significant differences in telomere lengths in archived tissues either on whole slides or sampled across tissue microarrays, which is essential when assessing prognosis in large patient cohorts.

category: pathology


title: Associations between maternal iron supplementation in pregnancy and offspring growth and cardiometabolic risk outcomes in infancy and childhood

abstract: It was previously observed that maternal iron supplementation in pregnancy was associated with increased offspring size and adiposity at birth, possibly mediated through increased risk of gestational diabetes. In this study we explored associations of maternal iron supplementation in pregnancy with postnatal offspring growth in infancy and indices of cardiometabolic disease risk factors such as glucose tolerance, insulin sensitivity and blood pressure in mid-childhood (at [~]9.5 years of age) in the Cambridge Baby Growth Study. In infancy adiposity-promoting associations with maternal iron supplementation in pregnancy were evident at 3 months of age (e.g. mean difference in skinfold thickness: {beta}=+0.15 mm, p=0.02, in n=341 whose mothers supplemented versus 222 that did not; waist circumference: {beta}=+0.7 cm, p=0.04, in n=159 and 78, respectively) but differences lessened after this time (e.g. 3-12 month change in mean difference in skinfold thickness: {beta}=-0.2 mm, p=0.03, in n=272 and 178, respectively). At [~]9.5 years of age associations with maternal iron supplementation in pregnancy were not evident for markers of growth, glucose tolerance, insulin sensitivity or secretion. However, children whose mothers supplemented with iron in pregnancy had lower mean arterial blood pressures ({beta}=-1.0 mmHg, p=0.03, in n=119 and 78, respectively). These results suggest that most of the associations of maternal iron supplementation in pregnancy on growth and adiposity evident at birth disappear during infancy, but there may be some evidence of long-term nutritional programming evident later in childhood.

category: pediatrics


title: Infection and transmission risks in schools and contribution to the COVID-19 pandemic in Germany - a retrospective observational study using nation-wide and regional health and education agency notification data

abstract:
IntroductionCurrently, information on infection and transmission risks of students and teachers in schools, the effect of infection control measures for schools as well as the contribution of schools to the overall population transmission of SARS-CoV-2 in Germany are limited to regional data sets restricted to short phases of the pandemic.

MethodsWe used German federal state (NUTS-2) and county (NUTS-3) data from national and regional public health and education agencies to assess infection risk and secondary attack rates (SARs) from March 2020 to October 2021 in Germany. We used multiple regression analysis and infection dynamic modelling, accounting for urbanity, socioeconomic factors, local population infection dynamics and age-specific underdetection to investigate the effects of infection control measures.

ResultsWe included (1) nation-wide NUTS-2 level data from calendar weeks (W) 46-50/2020 and W08-40/2021 with 304676 infections in students and 32992 in teachers; (2) NUTS-3 level data from W09-25/2021 with 85788 student and 9427 teacher infections and (3) detailed data from 5 regions covering W09/2020 to W27/2021 with 12814 infections, 43238 contacts and 4165 secondary cases for students (for teachers 14801, 5893 and 472 respectively).

In counties with mandatory surgical mask wearing during class in all schools infection risk of students and teachers was reduced by 56/100.000 persons per 14 days and by 30% and 24% relative to the population respectively. Overall contribution to population infections of contacts in school settings was 2-13%. It was lowest during school closures and vacation and highest during normal presence class intervals. Infection risk for students increased with age and was similar to or lower than the population risk during second and third waves in Germany and higher in summer 2021. Infection risk of teachers was higher than the population during the second wave and similar or lower thereafter with stricter measures in place. SARs for students and staff were below 5% in schools throughout the study period. SARs in households more than doubled from 14% W21-39/2020 to 29-33% in W08-23/2021. Most contacts were reported for schools, yet most secondary cases originated in households. In schools, staff predominantly infected staff and students predominantly infected students.

ConclusionOpen schools under hygiene measures and testing strategies contribute up to 13% of nation-wide infections in Germany and as little as 2% during vacations/school closures. Tighter infection control measures stabilised school SARs whilst household SARs more than doubled as more transmissible variants became prevalent in Germany. Mandatory mask wearing during class in all school types effectively reduces secondary transmission in schools, as do reduced attendance class models.

category: public and global health