title: Homologous recombination deficiency (HRD) can predict the therapeutic outcomes of immuno-neoadjuvant therapy in NSCLC patients

abstract:
BackgroundNeoadjuvant immunotherapy is emerging as novel effective intervention in lung cancer but the study to prioritize effective surrogates indicating its therapeutic outcomes is limited. We investigated the genetic changes between patients with distinct response to neoadjuvant immunotherapy in non-small-cell lung cancer (NSCLC) for the derive of biomarkers with indicative capability in predicting outcomes.

MethodsIn this study, 3 adenocarcinoma and 11 squamous cell carcinoma NSCLC patients were treated by neoadjuvant immunotherapy with variated regimen followed by surgical resection. Pre-therapy FFPE or fresh tissues and blood samples were analyzed by whole-exome sequencing (WES). Genetic alternation comparisons were conducted between differently-responded patients. Multiple public cohorts were selected for validation.

ResultsDNA damage repair (DDR)-related InDel signatures and DDR-related gene mutations were enriched in better-responded patients, i.e. major pathological response (MPR) group. Besides, MPR patients exhibited provoked genome instability and unique homologous recombination deficiency (HRD) events. By further inspecting alternation status of homology-dependent recombination (HR) pathway genes, the clonal alternations were exclusively enriched in MPR group. Additionally, associations between HR gene alternations, percent of viable tumor cells and HRD event were identified, which orchestrated tumor mutational burden (TMB), mutational intratumor heterogeneity (ITH), somatic copy number alteration (SCNA) ITH and clonal neoantigen load in patients. Validations in public cohorts further supported the generality of our findings.

ConclusionsWe innovatively associated the HRD event with enhanced neoadjuvant immunotherapy response in lung cancer. The power of HRD event in patient therapeutic stratification persisted in multi-facet public cohorts. We propose the inspection of HR pathway gene status could serve as novel and additional indicators directing immune-neoadjuvant and immunotherapy treatment decisions for NSCLC patients.


title: Detection of COVID-19 dysosmia with paired crushable odorant ampules

abstract:
BackgroundSigns of anosmia can help detect COVID-19 infection when testing for viral positivity is not available. Inexpensive mass-produced disposable olfactory sensitivity tests suitable for worldwide use might serve not only as a screening tool for potential infection but also to identify cases at elevated risk of severe disease as anosmic COVID-19 patients have a better prognosis.

Methods and FindingsWe adopted paired crushable ampules with two concentrations of a standard test odorant (n-butanol) as standard of care in several clinics as community prevalence of COVID-19 infection waxed and waned. This was not a clinical trial; a chart review was undertaken to evaluate the operating characteristics and potential utility of the test device as RT-PCR testing became routine. The risk of anosmia was greater in COVID-19 patients. Olfactory sensitivity was concentration-dependent and decreased with aging. Hyposmia was detected across a wider age range than expected from the literature, and tests can be optimized to characterize different age groups.

Conclusionsn-Butanol at 0.32 and 3.2% in crushable ampules can be used to characterize olfactory function quickly and inexpensively and thus has potential benefits in pandemic screening, epidemiology, and clinical decision-making.

category: otolaryngology


title: Detection of COVID-19 and age-dependent dysosmia with paired crushable odorant ampules


title: Duration of mRNA vaccine protection against SARS-CoV-2 Omicron BA.1 and BA.2 subvariants in Qatar

abstract: The SARS-CoV-2 Omicron (B.1.1.529) variant has two subvariants, BA.1 and BA.2, that are genetically quite divergent. We conducted a matched, test-negative, case-control study to estimate duration of protection of mRNA COVID-19 vaccines, after the second dose and after a third/booster dose, against BA.1 and BA.2 infections in Qatars population. BNT162b2 effectiveness against symptomatic BA.1 infection was highest at 46.6% (95% CI: 33.4-57.2%) in the first three months after the second dose, but then declined to [~]10% or below thereafter. Effectiveness rapidly rebounded to 59.9% (95% CI: 51.2-67.0%) in the first month after the booster dose, but then started to decline again. BNT162b2 effectiveness against symptomatic BA.2 infection was highest at 51.7% (95% CI: 43.2-58.9%) in the first three months after the second dose, but then declined to [~]10% or below thereafter. Effectiveness rapidly rebounded to 43.7% (95% CI: 36.5-50.0%) in the first month after the booster dose, but then declined again. Effectiveness against COVID-19 hospitalization and death was in the range of 70-80% any time after the second dose, and was greater than 90% after the booster dose. Similar patterns of protection were observed for the mRNA-1273 vaccine. mRNA vaccines provide only moderate and short-lived protection against symptomatic Omicron infections, with no discernable differences in protection against either the BA.1 or BA.2 subvariants. Vaccine protection against COVID-19 hospitalization and death is strong and durable after the second dose, but is more robust after a booster dose.

category: epidemiology


title: Quantitative Trend Analysis of SARS-CoV-2 RNA in Municipal Wastewater Exemplified with Sewershed-Specific COVID-19 Clinical Case Counts

abstract: We present and demonstrate a quantitative statistical linear trend analysis (QTA) approach to analyze and interpret SARS-CoV-2 RNA wastewater surveillance results concurrently with clinical case data. This demonstration is based on the work completed under the Ontario (Canada) Wastewater Surveillance Initiative (WSI) by two laboratories in four large sewersheds within the Toronto Public Health (TPH) jurisdiction. The sewersheds were sampled over a 9-month period and data were uploaded to the Ontario Wastewater Surveillance Data and Visualization Hub (Ontario Dashboard) along with clinical case counts, both on a sewershed-specific basis. The data from the last 5-months, representing a range of high and low cases, was used for this demonstration. The QTA was conducted on a sewershed specific approach using the recommendations for public health interpretation and use of wastewater surveillance data by the United States Centers for Disease Control and Prevention (US CDC). The interpretation of the QTA results was based on the integration of both clinical and wastewater virus signals using an integration matrix in an interim draft guide by the Public Health Agency of Canada (PHAC). The key steps in the QTA consisted of (i) the calculation of Pepper Mild Mottle Virus (PMMoV), flow and flow-PMMoV-normalized virus loads; (ii) computation of the linear trends including interval estimation to identify the key inflection points using a segmented linear regression method and (iii) integrated interpretations based on consideration of both the cases and wastewater signals, as well as end user actionability. This approach is considered a complementary tool to commonly used qualitative analyses of SARS-CoV-2 RNA in wastewater and is intended to directly support public health decisions using a systematic quantitative approach.


title: Vaccination against SARS-CoV-2 in UK school-aged children and young people decreases infection rates and reduces COVID-19 symptoms

abstract:
BackgroundWe aimed to explore the effectiveness of one-dose BNT162b2 vaccination upon SARS-CoV-2 infection, its effect on COVID-19 presentation, and post-vaccination symptoms in children and young people (CYP) in the UK during periods of Delta and Omicron variant predominance.

MethodsIn this prospective longitudinal cohort study, we analysed data from 115,775 CYP aged 12-17 years, proxy-reported through the Covid Symptom Study (CSS) smartphone application. We calculated post-vaccination infection risk after one dose of BNT162b2, and described the illness profile of CYP with post-vaccination SARS- CoV-2 infection, compared to unvaccinated CYP, and post-vaccination side-effects.

FindingsBetween August 5, 2021 and February 14, 2022, 25,971 UK CYP aged 12-17 years received one dose of BNT162b2 vaccine. Vaccination reduced (proxy-reported) infection risk (-80{middle dot}4% and -53{middle dot}7% at 14-30 days with Delta and Omicron variants respectively, and -61{middle dot}5% and -63{middle dot}7% after 61-90 days). The probability of remaining infection-free diverged soon after vaccination, and was greater in CYP with prior SARS-CoV-2 infection. Vaccinated CYP who contracted SARS-CoV-2 during the Delta period had milder disease than unvaccinated CYP; during the Omicron period this was only evident in children aged 12-15 years. Overall disease profile was similar in both vaccinated and unvaccinated CYP. Post-vaccination local side-effects were common, systemic side-effects were uncommon, and both resolved quickly.

InterpretationOne dose of BNT162b2 vaccine reduced risk of SARS-CoV-2 infection for at least 90 days in CYP aged 12-17 years. Vaccine protection varied for SARS-CoV-2 variant type (lower for Omicron than Delta variant), and was enhanced by pre-vaccination SARS-CoV-2 infection. Severity of COVID-19 presentation after vaccination was generally milder, although unvaccinated CYP also had generally mild disease. Overall, vaccination was well-tolerated.

FundingUK Government Department of Health and Social Care, Chronic Disease Research Foundation, The Wellcome Trust, UK Engineering and Physical Sciences Research Council, UK Research and Innovation London Medical Imaging & Artificial Intelligence Centre for Value Based Healthcare, UK National Institute for Health Research, UK Medical Research Council, British Heart Foundation and Alzheimers Society, and ZOE Limited.

Research in context

Evidence before this studyWe searched PubMed database for peer-reviewed articles and medRxiv for preprint papers, published between January 1, 2021 and February 15, 2022 using keywords ("SARS-CoV-2" OR "COVID-19") AND (child* OR p?ediatric* OR teenager*) AND ("vaccin*" OR "immunization campaign") AND ("efficacy" OR "effectiveness" OR "symptoms") AND ("delta" or "omicron" OR "B.1.617.2" OR "B.1.1.529"). The PubMed search retrieved 36 studies, of which fewer than 30% specifically investigated individuals <18 years.

Eleven studies explored SARS-CoV-2 viral transmission: seroprevalence in children (n=4), including age-dependency of susceptibility to SARS-CoV-2 infection (n=1), SARS-CoV-2 transmission in schools (n=5), and the effect of school closure on viral transmission (n=1).

Eighteen documents reported clinical aspects, including manifestation of infection (n=13), symptomatology, disease duration, and severity in children. Other studies estimated emergency department visits, hospitalization, need for intensive care, and/or deaths in children (n=4), and explored prognostic factors (n=1).

Thirteen studies explored vaccination-related aspects, including vaccination of children within specific paediatric co-morbidity groups (e.g., children with Down syndrome, inflammatory bowel disease, and cancer survivors, n=4), mRNA vaccine efficacy in children and adolescents from the general population (n=7), and the relation between vaccination and severity of disease and hospitalization cases (n=2). Four clinical trials were conducted using mRNA vaccines in minors, also exploring side effects. Sixty percent of children were found to have side effects after BNT162b2 vaccination, and especially after the second dose; however, most symptoms were mild and transient apart from rare uncomplicated skin ulcers. Two studies focused on severe adverse effects and safety of SARS-CoV-2 vaccines in children, reporting on myocarditis episodes and two cases of Guillain-Barre syndrome. All other studies were beyond the scope of our research.

Added value of this studyWe assessed multiple components of the UK vaccination campaign in a cohort of children and young people (CYP) aged 12-17 years drawn from a large UK community-based citizen-science study, who received a first dose of BNT162b2 vaccine. We describe a variant-dependent protective effect of the first dose against both Delta and Omicron, with additional protective effect of pre-vaccination SARS- CoV-2 infection on post-vaccination re-infection. We compare the illness profile in CYP infected post-vaccination with that of unvaccinated CYP, demonstrating overall milder disease with fewer symptoms for vaccinated CYP. We describe local and systemic side-effects during the first week following first-dose vaccination, confirming that local symptoms are common, systemic symptoms uncommon, and both usually transient.

Implications of all the available evidenceOur data confirm that first dose BNT162b2 vaccination in CYP reduces risk of infection by SARS-CoV-2 variants, with generally local and brief side-effects. If infected after vaccination, COVID-19 is milder, if manifest at all. The study aims to contribute quantitative evidence to the risk-benefit evaluation of vaccination in CYP to inform discussion regarding rationale for their vaccination and the designing of national immunisation campaigns for this age group; and applies citizen-science approaches in the conduct of epidemiological surveillance and data collection in the UK community.

Importantly, this study was conducted during Delta and Omicron predominance in UK; specificity of vaccine efficacy to variants is also illustrated; and results may not be generalizable to future SARS-CoV-2 strains.


title: Did COVID-19 Vaccines Go to the Whitest Neighborhoods First? Racial Inequities in Six Million Phase 1 Doses Shipped to Pennsylvania

abstract:
Research on racial disparities in COVID-19 vaccination rates has focused primarily on vaccine hesitancy. However, vaccine hesitancy research is increasingly unable to account for racial disparities in vaccination rates in the U.S., which have shrunk rapidly over the past year. This and other evidence suggests that inequities in vaccine allocation and access may have contributed to vaccination rate disparities in the U.S. But to our knowledge, no previously published research has examined whether the geographic distribution of COVID-19 vaccines has led to greater access for White Americans than for Black Americans.

Here, we link neighborhood-level data on vaccine allocation to data on racial demographics to show that in the first 17 weeks of Pennsylvanias COVID-19 vaccine rollout (Phase 1), White people were 25% more likely than Black people to live in neighborhoods (census tracts) that received vaccine shipments. In the 17 weeks of Pennsylvanias de jure restrictions on vaccine eligibility, de facto geographic restrictions on vaccine access disproportionately disadvantaged Black people and favored White people. In revealing these vaccine inequities, our work builds on prior work to develop a theory-driven, evidence-based, reproducible framework for studying racial inequities in the distribution of COVID-19 vaccines.

category: public and global health


title: Effectiveness of Community-Based Rehabilitation (CBR) centres for improving physical fitness for community-dwelling older adults: a systematic review protocol

abstract:
IntroductionThe increasing ageing population has become a substantial challenge for both health care and social services in many Asian countries. There is a high incidence of chronic diseases and comorbidities in older populations, leading to impairments and functional disability. Functional disability may result in loss of independence, reduced quality of life and increased care needs. Community-based rehabilitation (CBR) aims to promote equality of opportunity and improve the social inclusion of individuals living with disability. CBR also provides rehabilitation to improve physical, mental, and social outcomes. However, there is limited evidence regarding the effectiveness of CBR for improving older adults physical fitness. The aim of this systematic review is to synthesise the evidence for the effectiveness of interventions delivered by CBR centres on physical fitness of community-dwelling older adults in Asian countries.

Methods and analysisA search on four English databases (CINAHL, Medline, Scopus and Proquest) and two Chinese databases (China National Knowledge Internet and Wanfang Database) will be conducted, from inception to 15 November 2021. Both English and Chinese publications will be included. Experimental and quasi-experimental studies using any type of control group will be included. The primary outcomes are physical fitness (capacity to perform activities and tasks). Secondary outcomes are performance of activities of daily living and health-related quality of life. The quality of all included studies will be assessed using the Joanna Briggs Institute (JBI) standardised critical appraisal tools. Two reviewers will independently complete study screening, selection, quality appraisal, and data extraction. Quantitative data where possible will be pooled in statistical meta-analysis. All statistical analyses will be performed using Review Manager (Rev Man) V.5.3 software.

Ethics and disseminationEthical approval is not required for this review. The findings of this review will be disseminated electronically through a peer-reviewed publication and conference presentations.

PROSPERO registration numberCRD42021292088

Strengths and limitationsO_LIFindings and evidence in this review will be summarised and graded using the Grading of Recommendations, Assessment, Development and Evaluation Pro (GRADEPro) approach.
C_LIO_LIA comprehensive literature search using both English and Chinese language databases will be conducted.
C_LIO_LIStudies included in the review may measure different outcomes which may limit pooling in meta-analysis.
C_LIO_LIDifferences in populations and interventions delivered in the included studies may result in high levels of heterogeneity, leading to less certainty about the recommendations from the review.
C_LI

category: rehabilitation medicine and physical therapy


title: Experience of Adults with Upper-limb Difference and their Views on Sensory Feedback for Prostheses: A Mixed Methods Study

abstract:
AO_SCPLOWBSTRACTC_SCPLOWO_ST_ABSBackgroundC_ST_ABSUpper-limb prostheses are regularly abandoned, in part due to the mismatch between user needs and prostheses performance. Sensory feedback is among several technological advances that have been proposed to reduce device abandonment rates. While it has already been introduced in some high-end commercial prostheses, limited data is available about user expectations in relation to sensory feedback. The aim of this study is thus to use a mixed methods approach to provide a detailed insight of users perceptions and expectations of sensory feedback technology, to ensure the addition of sensory feedback is as acceptable, engaging and ultimately as useful as possible for users and, in turn, reduce the reliance on compensatory movements that lead to overuse syndrome.

MethodsThe study involved an online survey (N=37) and video call interviews (N=15) where adults with upper-limb differences were asked about their experience with limb difference and prosthesis use (if applicable) and their expectations about sensory feedback to prostheses. The survey data were analysed quantitatively and descriptively to establish the range of sensory feedback needs and their variations across the different demographics. Reflective thematic analysis was performed on the interview data, and data triangulation was used to understand key behavioural issues to generate actionable guiding principles for the development of sensory feedback systems.

ResultsThe survey provided a list of practical examples and suggestions that did not vary with the different causes of limb difference or prosthesis use. The interviews showed that although sensory feedback is a desired feature, it must prove to have more benefits than drawbacks. The key benefit mentioned by participants was increasing trust, which requires a highly reliable system that provides input from several areas of the hand rather than just the fingertips. The feedback system should also complement existing implicit feedback sources without causing confusion or discomfort. Further, the effect sensory feedback has on the users psychological wellbeing was highlighted as an important consideration that varies between individuals and should therefore be discussed. The results obtained were used to develop guiding principles for the design and implementation of sensory feedback systems.

ConclusionsThis study provided the first mixed-methods research on the sensory feedback needs of adults with upper-limb differences, enabling a deeper understanding of their expectations and worries. Guiding principles were developed based on the results of a survey and interviews to inform the development and assessment of sensory feedback for upper-limb prostheses.


title: ACE2 gene expression and inflammatory conditions in periodontal microenvironment of COVID-19 patients with and without diabetes evaluated by qPCR

abstract:
ObjectiveChronic periodontitis has been proposed to be linked to coronavirus disease (COVID-19) on the basis of its inflammation mechanism. We aimed to evaluate this association by investigating the expression of Angiotensin Converting Enzyme-2 (ACE2) in periodontal compartments, which contain dysbiosis-associated pathogenic bacteria, and how it can be directly or indirectly involved in exacerbating inflammation in periodontal tissue.

Material and MethodsThis observational clinical study included 23 adult hospitalized patients admitted to Universitas Indonesia Hospital with PCR-confirmed COVID-19, while 6 non-COVID-19 participants come to periodontal clinic were included as control. Using real time-PCR (qPCR) and gingival crevicular fluids (GCF) samples from COVID-19 patients with and without diabetes and periodontitis, we assessed the mRNA expression of angiotensin-converting enzyme 2 (ACE2), IL-6, IL-8, complement C3, and LL-37 as well as the relative proportion of Porphyromonas gingivalis, Fusobacterium nucleatum, and Veillonella parvula to represent the dysbiosis condition in periodontal microenvironment. All analyses were performed to determine their relationship.

ResultsACE2 mRNA expression was detected in the GCF of periodontitis-COVID-19 patients with and without diabetes. However, only periodontitis-COVID-19 patients with diabetes showed a positive relationship between ACE2 expression and inflammatory conditions in the periodontal microenvironment. In addition, the interplay between pro-inflammatory cytokine (IL-6) and complement C3 could be used as a predictor of the severity of periodontal inflammation in COVID-19 patients with diabetes.

ConclusionThe study data show that the SARS-CoV-2 entry gene is expressed in the GCF of patients with COVID-19, and its expression correlates with inflammatory markers.

category: dentistry and oral medicine


title: Does a postpartum "Green Star" family planning decision aid for adolescent mothers reduce decisional conflict? : A quasi-experimental study

abstract:
AimTo our knowledge, there are still no studies in Tanzania regarding decision aids on long-acting reversible contraception. We evaluated the effects of our postpartum "Green Star" family planning decision aid on decisional conflict, knowledge, satisfaction, and uptake of long-acting reversible contraception among pregnant adolescents in Tanzania.

MethodsWe used a facility-based quasi-experimental design with control. The participants were purposively recruited and randomly assigned (intervention, n = 33; control, n = 33). The intervention received the routine family planning counseling and decision aid. The control received only the routine family planning counseling. The primary outcome was change in decisional conflict measured using the validated Decisional Conflict Scale (DCS). The secondary outcomes were knowledge, satisfaction, and contraception uptake. We hypothesized that pregnant adolescents who use the decision aid will have a lower DCS score.

ResultsWe recruited 66 pregnant adolescents; 62 completed the study. Participants in the intervention had a lower mean difference score in the DCS than participants in the control (intervention: -24.7 [SD 7.99] vs. control: -11.6 [SD 10.9], t = -5.53, p < 0.001). The mean difference score in knowledge was significantly higher in the intervention than in the control (intervention: 4.53 [SD 2.54] vs. control: 2.0 [SD 1.45], t = 4.88, p < 0.001). The mean score of satisfaction was significantly higher in the intervention than in the control (intervention: 100 [SD 0.0] vs. control: 55.8 [SD 30.7], t = 8.112, p < 0.001). Choice of contraception was significantly higher in the intervention [29 (45.3%)] than in the control [13 (20.3%)] (x2 = 17.73, p < 0.001).

ConclusionThe postpartum "Green Star" family planning decision aid was useful as it lowered decisional conflict, improved knowledge and satisfaction with decision making, and enhanced contraception uptake. The decision aid demonstrated positive applicability and affordability for pregnant adolescents in Tanzania.

category: sexual and reproductive health


title: Presence of Mediastinal Lymphadenopathy in Hospitalized Covid-19 Patients in a Tertiary Care Hospital in Pakistan - A cross-sectional study

abstract:
BackgroundThe aim of this study was to investigate the presence of mediastinal lymphadenopathy in hospitalized Covid-19 patients in a tertiary care hospital in the metropolitan city of Lahore, Pakistan from September 2020 till July 2021.

MethodsWe retrospectively collected data of Covid-19 patients hospitalized from September 2020 till July 2021. Only those patients who tested PCR positive through a nasopharyngeal swab, were enrolled in the study. Patients whose data were missing were excluded from this study. Our exclusion criteria included patients who tested negative on Covid-19 PCR, patients with comorbidities that may cause enlarged mediastinal lymphadenopathies such as haemophagocytic lymphohistiocytosis, neoplasia, tuberculosis, sarcoidosis or a systemic disease. The extent of lung involvement in Covid-19 patients was quantified by using a 25-point visual quantitative assessment called the Chest Computed Tomography Score. This score was then correlated with the presence of mediastinal lymphadenopathy.

FindingsOf the 210 hospitalized patients included in the study, 131 (62.4%) had mediastinal lymphadenopathy. The mean and median Severity Score of Covid-19 patients with mediastinal lymphadenopathy (mean: 17.1, SD:5.7; median: 17, IQR: 13-23) were higher as compared to those without mediastinal lymphadenopathy (mean: 12.3, SD:5.4; median: 12, IQR:9-16)

InterpretationOur study documents a high prevalence of mediastinal lymphadenopathy in hospitalized patients with Covid-19 with the severity score being higher in its presence representing a more severe course of disease.

category: infectious diseases


title: PTPRG activates m6A methyltransferase VIRMA to block mitochondrial autophagy mediated neuronal death in Alzheimer's disease

abstract: In Alzheimers disease (AD), neuronal death is one of the key pathology. However, the initiation of neuronal death in AD is far from clear, and new targets are urgently needed to develop effective therapeutic methods. This study analyzed sequencing data from single-cell RNAseq and spatialomics, and revealed the impact of global single-cell mapping and cell spatial distribution relationships in early stage of AD. We found that microglia subpopulation Mic_PTPRG can anchor neurons based on ligand-receptor interaction pairs and cause ectopic expression of PTPRG in neurons during AD progression. PTPRG in neurons can bind and upregulate VIRMA expression, which in turn increases the level of m6A methylation, enhances PRKN transcript degradation and represses translation. Repressed PRKN expression blocks the clearance of damaged mitochondria in neurons, which in turn reprograms neuronal energy and nutrient metabolic pathways and leads to neuronal death during AD progression. This study elucidates novel mechanisms, by which the PTPRG-dependent microglia-synaptic modification may play a role in AD, providing a new scientific basis for potential therapeutic targets for AD.

category: neurology


title: A shared genetic signature for common chronic pain conditions and its impact on biopsychosocial traits

abstract:
BackgroundThe multifactorial heterogenous nature of chronic pain with its multiple comorbidities presents a formidable challenge in disentangling the aetiology underlying patient symptoms.

MethodsHere, we performed genome-wide association studies (GWAS) of eight types of regional chronic pain using UK Biobank data (N=4,037-79,089 cases; N=239,125 controls), followed by bivariate linkage disequilibrium-score regression and latent causal variable analyses to determine (respectively) their genetic correlations and genetic causal proportion (GCP) parameters with 1,492 other complex traits.

FindingsWe report evidence of a shared genetic signature in common regional chronic pain types, with their genetic correlations and causal directions being broadly consistent across a wide array of biopsychosocial traits. Furthermore, we identified 5,942 significant genetic correlations, of which 570 trait pairs showed evidence of a likely causal association (|GCP| > 0{middle dot}6; 5% false discovery rate), including 488 traits contributing to chronic pain while 82 were affected by pain. A range of somatic pathologies (e.g., musculoskeletal, visceral), psychiatric factors (e.g., depression, trauma, anxiety, mania, bipolar disorder), socioeconomic factors (e.g., occupation) and other medical comorbidities (e.g., cardiovascular disease) contributed to an increased risk of regional chronic pain. Conversely, each chronic pain type contributed to various other traits such as increased medication use (e.g., analgesics) and risk of ischaemic heart disease and depression.

InterpretationFindings of this data-driven study, through comprehensive analysis of a vast range of biopsychosocial factors, are indicative of a common genetic signature underlying eight regional chronic pain types. We identify a broad range of traits with genetic causal effects upon chronic pain, which may inform development of novel diagnostic and therapeutic strategies, as well as provide convergent support for various existing approaches.

category: pain medicine


title: Integrative genomics analysis implicates decreased FGD6 expression underlying risk of intracranial aneurysm rupture

abstract:
BackgroundThe genetic determinants and mechanisms underlying intracranial aneurysm rupture (rIA) are largely unknown. Given the [~]50% mortality rate of rIA, approaches to identify patients at high-risk will inform screening, diagnostic, and preventative measures.

ObjectiveOur goal was to identify and characterize the genetic basis of rIA.

MethodsWe perform a genome-wide association study (GWAS) use functional genomics approaches to identify and characterize rIA-associated loci and genes. We perform a meta-analysis across 24 published GWAS of rIA. Single nucleotide polymorphisms (SNP), gene-burden analysis, and functional genomics identify and characterize genetic risk factors for rIA.

ResultsOur cohort contains 84,353 individuals (7,843 rIA cases and 76,510 controls). We identify 5 independent genetic loci reaching genome-wide significance (p<5.0x10-8) for rIA including rs12310399 (FGD6, OR=1.16), which to our knowledge, has not been implicated in prior GWAS of rIA. We then quantified gene-level mutation-burden across [~]20,000 genes, and only FGD6 (containing 21 rIA-associated SNPs) reached transcriptome-wide significance. Expression quantitative trait loci (eQTL) mapping indicates that rs12310399 causes decreased FGD6 gene expression in arterial tissue. Next, we utilized publicly available single-cell RNA sequencing of normal human cerebrovascular cells obtained during resection surgery and identify high expression of FGD6 in 1 of 3 arterial lineages but absent in perivascular cells. These data suggest how alterations in FGD6 may confer risk to rIA.

ConclusionWe identify and characterize a previously unknown risk loci for rIA containing FGD6. Elucidation of high-risk genetic loci may instruct population-genetic screening and clinical-genetic testing strategies to identify patients predisposed to rIA.

FundingNo funding sources were used for the material presented herein.

category: genetic and genomic medicine


title: Why does purpose in life predict mortality in older adults?

abstract:
BackgroundPrevious work documents a strong association between a higher sense of life purpose and lower all-cause mortality risk even when controlling for baseline health and proposes that life purpose intervention may provide a low-cost lever to improve health and longevity. Causation, however, is less clear--lower purpose may cause poorer health and decreased longevity, or poorer health may cause decreased longevity and lower purpose. We examine the extent that (1) more comprehensive health metrics and (2) horizon mitigate or strengthen the relation between purpose and mortality risk to better understand causation.

MethodsProspective cohort sample of 8 425 individuals aged 50 and older who were eligible to participate in the 2006 Health and Retirement Study Psychosocial and Lifestyle questionnaire. Individuals were followed for three subsequent four-year periods: 2006-2010, 2010-2014, and 2014-2018. A total of 1 597 individuals were excluded in the initial four-year period due to lack of follow up, sample weights, or covariates leaving an initial sample of 6 828 individuals. For the second and third four-year periods, an additional 168 and 349 respondents were lost to follow up, respectively. Cox models were estimated to examine the relation between life purpose and mortality for three horizons (years 1-4, 5-8, and 9-12) with more comprehensive measures of current health. Covariates included age, sex, education, race, marital status, smoking status, exercise, alcohol, BMI, and functional health score.

FindingsThe relation between life purpose and mortality was substantially attenuated or disappeared at longer horizons or when using more comprehensive measures of current health.

InterpretationMuch of the documented relation between life purpose and longevity arises from poor health causing higher mortality risk and lower purpose (i.e., reverse causation). As a result, life purpose intervention is likely to be less effective than the previous evidence suggests.

FundingNone.

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed and Google Scholar with no language or date restriction for the term "life purpose" and found four comprehensive reviews of the life purpose or psychological well-being (which included life purpose in the set of psychological well-being metrics) literatures in the last three years and a 2016 meta-analysis of the relation between life purpose and mortality. Although acknowledging it is possible that reverse causation plays a role in linking life purpose levels to subsequent morbidity and mortality, the prevalent view appears to be that even when controlling for current health levels, higher life purpose causes behavioral, biological, or stress buffering changes that, in turn, cause lower future morbidity and mortality.

Added value of this studyWe demonstrate that the relation between life purpose levels and mortality is substantially attenuated or eliminated when better controlling for current health or focusing on a longer horizon. Both results suggest that the relation between life purpose levels and future mortality risk primarily arises from life purpose proxying for current health levels. The evidence suggests poorer health causes lower life purpose rather than lower life purpose causing poorer health.

Implications of all the available evidenceAlthough life purpose intervention--either at the provider level or in public policy--may have benefits, it is unlikely to cause greater longevity.

category: health policy


title: Asexual stage synchronicity in symptomatic and asymptomatic falciparum malaria

abstract: Andrade et al have reported that P. falciparum parasitised erythrocytes circulate for longer in persistent asymptomatic infections than in symptomatic malaria. This radical suggestion, attributed to in-vivo adaptation by the parasite population to reduced cytoadherence, is based largely on in-vivo transcriptomic data from 24 Malian children: 12 with acute falciparum malaria and 12 with asymptomatic parasitaemia. We show that the reported analysis generated erroneous results because of data formatting issues. We also show that the algorithm used to estimate the average asexual parasite developmental stage (hours post-invasion) from in-vivo transcriptomic data breaks down when applied to asynchronous infections. We argue that comparisons between asymptomatic and symptomatic malaria of asexual parasite developmental stage distributions are confounded by differences in synchronicity and gametocytaemia, and also by selection bias (because schizogony often precipitates clinical presentation). There is no convincing evidence of an adaptive delayed cytoadherence phenotype in chronic P. falciparum infections.


title: Biomedical consequences of elevated cholesterol-containing lipoproteins and apolipoproteins

abstract:
AimsTo provide a comprehensive evaluation of the biomedical effects of circulating concentrations of cholesterol-containing lipoproteins and apolipoproteins.

Methods and ResultsNuclear magnetic resonance (NMR) spectroscopy was used to measure the cholesterol content of high density (HDL-C), very low-density (VLDL-C), intermediate-density (IDL-C), and low-density (LDL-C) lipoprotein fractions; apolipoproteins Apo-A1 and Apo-B; as well as total triglycerides (TG), remnant-cholesterol (Rem-chol) and total cholesterol (TC). The causal effects of these exposures were assessed against 33 cardiovascular as well as non-cardiovascular outcomes using two-sample univariable and multivariable Mendelian randomization. We observed that most cholesterol containing lipoproteins and apolipoproteins affected coronary heart disease (CHD), cIMT, carotid plaque, CRP and blood pressure. Through MVMR we showed that many of these exposures acted independently of the more commonly measured blood lipids: HDL-C, LDL-C and TG. We furthermore found that HF risk was increased by higher concentrations of TG, VLDL-C, Rem-Chol and Apo-B, often independently of LDL-C, HDL-C or TG. Finally, a smaller subset of these exposures could be robustly mapped to non-CVD traits such as Alzheimers disease (HDL-C, LDL-C, IDL-C, Apo-B), type 2 diabetes (VLDL-C, IDL-C, LDL-C), and inflammatory bowel disease (LDL-C, IDL-C).

ConclusionThe cholesterol content of a wide range of lipoprotein and apolipoproteins affected measures of atherosclerosis and CHD, implicating subfractions beyond LDL-C. Many of the observed effects acted independently of LDL-C, HDL-C, and TG, supporting the potential for additional, non-LDL-C, avenues to disease prevention.

category: cardiovascular medicine


title: Predicted serotype distribution in invasive pneumococcal disease (IPD) among children less than five years prior to the introduction of the Pneumococcal Conjugate Vaccine (PCV) in Nigeria

abstract:
BackgroundThe 10-valent pneumococcal conjugate vaccine (PCV10) was introduced in Nigeria without any baseline data on serotype distribution in invasive pneumococcal disease (IPD). To estimate the proportion of IPD attributable to different serotypes, in children aged <5 years, we used statistical models based on the serotype-specific nasopharyngeal carriage prevalence and invasive capacity (IC).

MethodsWe used the carriage data from one urban and one rural setting in Nigeria, collected within five months of PCV10 introduction (2016). For Model A, we used serotype-specific adult case-fatality ratios from Denmark as proxy for IC. In the second model, we used the ratio of IPD proportions to carriage prevalence (case-carrier ratios) from Kenya (Model B) and the ratio of IPD incidence to carriage acquisition (attack rates) from the UK (Model C) as measures of serotype IC.

ResultsThe models predict that serotypes with high carriage prevalence (6A, 6B, 19F and 23F) will dominate IPD. Additionally, Models B and C predictions emphasize serotypes 1, 4, 5, and 14, which were not prevalent in carriage but had high IC estimates. Non-PCV10 serotypes,6A and 19A, also dominated IPD predictions across models and settings. The predicted proportion of IPD attributed to PCV10 serotypes varied between 56% and 74% by model and setting.

ConclusionCarriage data can provide preliminary insights into IPD serotypes in settings that lack robust IPD data. The predicted PCV10-serotype coverage for IPD was moderately high. However, predictions for non-PCV10 serotypes indicate that higher-valency PCVs that cover serotypes 6A and 19A may have a larger impact on IPD reductions.


title: International travel as a risk factor for carriage of extended-spectrum β-lactamase-producing Escherichia coli in a large sample of European individuals - The AWARE Study

abstract: Antibiotic resistance (AR) is currently a major threat to global health, calling for a One Health approach to be properly understood, monitored, tackled, and managed. Potential risk factors for AR are often studied in specific high-risk populations, but are still poorly understood in the general population. Our aim was to explore, describe, and characterize potential risk factors for carriage of Extended-Spectrum Beta-Lactamase-resistant E. coli (ESBL-EC) in a large sample of European individuals aged between 16 and 67 years recruited from the general population in Southern Germany, the Netherlands, and Romania. Questionnaire and stool sample collection for this cross-sectional study took place from September 2018 to March 2020. Selective culture of participants stool samples was performed for detection of ESBL-EC. A total of 1,183 participants were included in the analyses: 333 from Germany, 689 from the Netherlands, and 161 from Romania. Travels to Northern Africa (aOR 4.03, 95% CI 1.67-9.68), Sub-Saharan Africa (aOR 4.60, 95% CI 1.60-13.26), and Asia (aOR 4.08, 95% CI 1.97-8.43) were identified as independent risk factors for carriage of ESBL-EC carriage. Therefore, travel to these regions should continue to be routinely inquired risk factors in clinical practice when considering antibiotic therapy.


title: "I wanna live and not think about the future" What place for advance care planning for people living with severe multiple sclerosis and their families? A qualitative study

abstract:
BackgroundLittle is known about how people with multiple sclerosis and their families comprehend advance care planning (ACP) and its relevance in their lives.

AimTo explore under what situations, with whom, how, and why do people with MS and their families engage in ACP

MethodsWe conducted a qualitative study comprising interviews with people living with MS and their families followed by an ethical discussion group with five health professionals representing specialties working with people affected by MS and their families. Twenty-seven people with MS and 17 family members were interviewed between June 2019 and March 2020. Interviews and the ethical discussion group were audio-recorded and transcribed verbatim. Data were analysed using the framework approach.

ResultsParticipants narratives focused on three major themes :(i) planning for an uncertain future; (ii) perceived obstacles to engaging in ACP that included uncertainty concerning MS disease progression, negative previous experiences of ACP discussions and prioritising symptom management over future planning; (iii) Preferences for engagement in ACP included a trusting relationship with a health professional and that information then be shared across services. Health professionals accounts from the ethical discussion group departed from viewing ACP as a formal document to that of an ongoing process of seeking preferences and values. They voiced similar concerns to people with MS about uncertainty and when to initiate discussions. Some shared concerns of a lack of confidence when having ACP discussions.

ConclusionThese findings support the need for a whole systems strategic approach where information about the potential benefits of ACP in all its forms can be shared with people with MS. Moreover, they highlight the need for health professionals to be skilled and trained in engaging in ACP discussions and where information is contemporaneously and seamlessly shared across services.

category: palliative medicine


title: I wanna live and not think about the future; What place for advance care planning for people living with severe multiple sclerosis and their families? A qualitative study


title: Understanding adherence to self-isolation in the first phase of COVID-19 response

abstract:
ObjectiveTo gain a better understanding of decisions around adherence to self-isolation advice during the first phase of the COVID-19 response in England.

DesignA mixed-methods cross sectional study.

Setting: EnglandParticipants COVID-19 cases and contacts who were contacted by Public Health England (PHE) during the first phase of the response in England (January-March 2020).

ResultsOf 250 respondents who were advised to self-isolate, 63% reported not leaving home at all during their isolation period, 20% reported leaving only for lower risk activities (dog walking or exercise) and 16% reported leaving for potentially higher risk, reasons (shopping, medical appointments, childcare, meeting family or friends). Factors associated with adherence to never going out included: the belief that following isolation advice would save lives, experiencing COVID-19 symptoms, being advised to stay in their room (rather than just "inside"), having help from outside and having regular contact by text message from PHE. Factors associated with non-adherence included being angry about the advice to isolate, being unable to get groceries delivered and concerns about losing touch with friends and family. Interviews highlighted that a sense of duty motivated people to adhere to isolation guidance and where people did leave their homes, these decisions were based on rational calculations of the risk of transmission - people would only leave their homes when they thought they were unlikely to come into contact with others.

ConclusionsMeasures of adherence should be nuanced to allow for the adaptations people make to their behaviour during isolation. Understanding adherence to isolation and associated reasoning during the early stages of the pandemic is an essential part of pandemic preparedness for future emerging infectious diseases.

Strengths and limitations of this studyO_LIOur participants were contacted directly by Public Health England during the first three months of the pandemic - the only cohort of cases and contacts who experienced self-isolation during this early phase of the pandemic.
C_LIO_LIResults may not be directly generalisable to wider populations or later phases of pandemic response.
C_LIO_LIWe classified reasons for leaving the home as higher or lower contact, as a proxy for potential risk of transmission, however further research published since we conducted our research as refined our understanding of transmission risk, highlighting the need for more in-depth research on adherence behaviour and transmission risk.
C_LIO_LIThe mixed methods approach combined quantitative measures of adherence with an exploration of how and why these decisions were being made in the same people.
C_LIO_LIOur study provides unique insights into self-isolation during the earliest stages of the pandemic, against a background of uncertainty and lack of information that will recur, inevitably, in the face of future pandemic and similar threats.
C_LI


title: Nocturnal Respiratory Rate Dynamics Enable Early Recognition of Impending Hospitalizations

abstract: The days and weeks preceding hospitalization are poorly understood because they transpire before patients are seen in conventional clinical care settings. Home health sensors offer opportunities to learn signatures of impending hospitalizations and facilitate early interventions, however the relevant biomarkers are unknown. Nocturnal respiratory rate (NRR) is an activity-independent biomarker that can be measured by adherence-independent sensors in the home bed. Here, we report automated longitudinal monitoring of NRR dynamics in a cohort of high-risk recently hospitalized patients using non-contact mechanical sensors under patients home beds. Since the distribution of nocturnal respiratory rates in populations is not well defined, we first quantified it in 2,000 overnight sleep studies from the NHLBI Sleep Heart Health Study. This revealed that interpatient variability was significantly greater than intrapatient variability (NRR variances of 11.7 brpm2 and 5.2 brpm2 respectively, n=1,844,110 epochs), which motivated the use of patient-specific references when monitoring longitudinally. We then performed adherence-independent longitudinal monitoring in the home beds of 34 high-risk patients and collected raw waveforms (sampled at 80 Hz) and derived quantitative NRR statistics and dynamics across 3,403 patient-nights (n= 4,326,167 epochs). We observed 23 hospitalizations for diverse causes (a 30-day hospitalization rate of 20%). Hospitalized patients had significantly greater NRR deviations from baseline compared to those who were not hospitalized (NRR variances of 3.78 brpm2 and 0.84 brpm2 respectively, n= 2,920 nights). These deviations were concentrated prior to the clinical event, suggesting that NRR can identify impending hospitalizations. We analyzed alarm threshold tradeoffs and demonstrated that nominal values would detect 11 of the 23 clinical events while only alarming 2 times in non-hospitalized patients. Taken together, our data demonstrate that NRR dynamics change days to weeks in advance of hospitalizations, with longer prodromes associating with volume overload and heart failure, and shorter prodromes associating with acute infections (pneumonia, septic shock, and covid-19), inflammation (diverticulitis), and GI bleeding. In summary, adherence-independent longitudinal NRR monitoring has potential to facilitate early recognition and management of pre-symptomatic disease.

category: respiratory medicine


title: HormoneBayes: a novel Bayesian framework for the analysis of pulsatile hormone dynamics.

abstract: The hypothalamus is the central regulator of reproductive hormone secretion. Pulsatile secretion of gonadotropin releasing hormone (GnRH) is fundamental to physiological stimulation of the pituitary gland to release luteinizing hormone (LH) and follicle stimulating hormone (FSH). Furthermore, GnRH pulsatility is altered in common reproductive disorders such as polycystic ovary syndrome (PCOS) and hypothalamic amenorrhea (HA). LH is measured routinely in clinical practice using an automated chemiluminescent immunoassay method and is the gold standard surrogate marker of GnRH. LH can be measured at frequent intervals (e.g., 10 minutely) to assess GnRH/LH pulsatility. However, this is rarely done in clinical practice because it is resource intensive, and there is no user-friendly and accessible method for computational analysis of the LH data available to clinicians. Here we present hormoneBayes, a novel open-access Bayesian framework that can be easily applied to reliably analyze serial LH measurements to assess LH pulsatility. The framework utilizes parsimonious models to simulate hypothalamic signals that drive LH dynamics, together with state-of-the-art (sequential) Monte-Carlo methods to infer key parameters and latent hypothalamic dynamics. We show that this method provides estimates for key pulse parameters including inter-pulse interval, secretion and clearance rates and identifies LH pulses in line with the current gold-standard deconvolution method. We show that these parameters can distinguish LH pulsatility in different clinical contexts including in reproductive health and disease in men and women (e.g., healthy men, healthy women before and after menopause, women with HA or PCOS). A further advantage of hormoneBayes is that our mathematical approach provides a quantified estimation of uncertainty. Our framework will complement methods enabling real-time in-vivo hormone monitoring and therefore has the potential to assist translation of personalized, data-driven, clinical care of patients presenting with conditions of reproductive hormone dysfunction.


title: Plasma p-tau181/Aβ1-42 ratio predicts Aβ-PET status and correlates with CSF-p-tau181/Aβ1-42 and future cognitive decline.

abstract:
BackgroundIn Alzheimers disease, plasma A{beta}1-42 and p-tau predict high amyloid status from A{beta}-PET, however the extent to which combination of both plasma assays predict remains unknown.

MethodsPrototype Simoa assays were used to measure plasma samples from cognitively normal (CN) and symptomatic adults in the Australian Imaging, Biomarkers and Lifestyle (AIBL) study.

ResultsThe p-tau181/A{beta}1-42 ratio showed the best prediction of A{beta}-PET across all participants (AUC=0.905, 95%CI:0.86-0.95) and in CN (AUC=0.873; 0.80-0.94), and symptomatic (AUC=0.908; 0.82-1.00) adults. Plasma p-tau181/A{beta}1-42 ratio correlated with CSF-p-tau181 (Elecsys(R), Spearmans {rho}=0.74, P<0.0001) and predicted abnormal CSF A{beta} (AUC=0.816, 0.74-0.89). The p-tau181/A{beta}1-42 ratio also predicted future rates of cognitive decline assessed by AIBL PACC or CDR-SOB (P<0.0001).

DiscussionPlasma p-tau181/A{beta}1-42 ratio predicted both A{beta}-PET status and cognitive decline, demonstrating potential as both a diagnostic aid and as a screening and prognostic assay for preclinical Alzheimers disease trials.


title: The French Early Breast Cancer Cohort (FRESH): a resource for breast cancer research and evaluations of oncology practices based on the French National Healthcare System Database (SNDS)

abstract:
BackgroundBreast cancer (BC) is the most frequent cancer and the leading cause of cancer-related death in women. The French National Cancer Institute has created a national cancer cohort to promote cancer research and improve our understanding of cancer using the National Health Data System (SNDS). This cohort amalgamates all cancer sites, with no detailed separate data for early BC.

ObjectivesWe describe the French Early Breast Cancer Cohort (FRESH).

MethodsAll French women aged 18 years or over, with early-stage BC newly diagnosed between January 1, 2011 and December 31, 2017, treated by surgery and registered in the general health insurance coverage plan were included in the cohort. Patients with suspected locoregional or distant metastases at diagnosis were excluded. BC treatments (surgery, chemotherapy, targeted therapy, radiotherapy, endocrine therapy), and diagnostic procedures (biopsy, cytology, imaging) were extracted from hospital discharge reports, outpatient care notes or pharmacy drug delivery data. BC subtype was inferred from the treatments received.

ResultsWe included 235,368 patients with early BC in the cohort (median age: 60 years). BC subtype distribution was as follows: luminal (80.2%), triple-negative (TNBC, 9.5%); HER2+ (10.3%), or unidentifiable (n=44,388, 18.9% of the cohort). Most patients underwent radiotherapy (n=200,685, 85.3%) and endocrine therapy (n=165,655, 70.4%), and 38.3% (n=90,252) received chemotherapy. Treatments and care pathways are described.

ConclusionThe FRESH Cohort is an unprecedented population-based resource facilitating future large-scale real-life studies aiming to improve care pathways and quality of care for BC patients.

category: oncology


title: Genome-by-Trauma Interaction Effects in Depression

abstract:
BackgroundSelf-reported trauma exposure has consistently been found to be a risk factor for Major Depressive Disorder (MDD) and several studies have reported interactions with genetic liability. To date, most studies have examined interaction effects with trauma exposure using genome-wide variants (single nucleotide polymorphisms SNPs) or polygenic scores, both typically capturing less than 3% of phenotypic risk variance. We sought to re-examine genome-by-trauma interaction effects using genetic measures utilising all available genotyped data and thus, maximising accounted variance.

MethodsMeasures of self-reported depression, neuroticism and trauma exposure for 148 129 participants with whole genome SNP data are available from the UK Biobank study. Here, we used a mixed-model statistical approach utilising genetic, trauma exposure and genome-by-trauma exposure interaction similarity matrices to explore sources of variation in depression and neuroticism.

FindingsOur approach estimated the heritability of MDD to be approximately 0{middle dot}160 [SE 0{middle dot}016]. Subtypes of self-reported trauma exposure (catastrophic, adult, childhood and full trauma) accounted for a significant proportion of the variance of each trait, ranging from 0{middle dot}056 [SE 0{middle dot}013] to 0{middle dot}176 [SE 0{middle dot}025]. The proportion of MDD risk variance accounted for by significant genome-by-trauma interaction ranged from 0{middle dot}074 [SE 0{middle dot}006] to 0{middle dot}201 [SE 0{middle dot}009]. Results from sex-specific analyses found genome-by-trauma interaction variance estimates approximately 5-fold greater for MDD in males than in females.

InterpretationThis is the first study to utilise an approach combining all genome-wide SNP data when exploring genome-by-trauma interaction effects in MDD and present evidence that interaction effects are influential in depression manifestation. This effect accounts for greater trait variance within males which points to potential differences in depression aetiology between the sexes. The methodology utilised in this study can be extrapolated to other environmental factors to identify modifiable risk environments and at-risk groups to target with interventions.

Research In ContextO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed up to January 30th 2022, with the following terms: ("gene environment interaction" OR "gene environment" OR "genome wide by environment" OR "GWEIS" OR "polygenic environment" OR ("gene" AND "environment")) AND ("polygenic risk score" OR "polygenic score" OR "genomic relationship matrix" OR "GRM") AND ("trauma" OR "environmental adversity" OR "stressful life events") AND ("depression" OR "major depressive disorder" OR "MDD" OR "depressive symptoms"). Date or language restrictions were not applied. We further reviewed the reference lists of identified articles. This search was supplemented by reviewing related articles identified by Google Scholar. We identified 12 relevant articles. Studies to date have not explored genome-by-environment interaction effects in depression using genomic similarity matrices, however, these effects have been explored using individual single nucleotide polymorphisms (SNPs) from genome-wide studies and polygenic scores (PGSs). Some findings suggest genome-by-environment interaction effects increase risk of depression. However, replication attempts have produced either inconsistent or null findings. Taken together, it is evident that findings have failed to provide consistent evidence of substantial interaction effects. These findings may be a result of limited statistical power in analyses due to genome-wide variants and PGSs failing to capture the polygenic nature of depression with sufficient precision.

Added value of this studyThis study is the first to explore genome-by-trauma interaction effects on MDD through the estimation of variance components using relationship matrices. Genomic relationship matrices (GRMs) utilise all available genotyped variants, thus, capturing a greater proportion of the trait variance and potentially providing greater power to detect genetic effects in comparison to PGSs. Additional relationship matrices capturing trauma exposure, and genome-by-trauma exposure similarity are computed and included into mixed linear models. We found evidence for substantial genome-by-trauma (including subtypes of trauma) exposure interaction effects on depression manifestation. Estimated genome-by-trauma interaction effects were larger in males than in females.

Implications of all the available evidenceOur findings are the first to show substantial genome-by-trauma effects on depression using whole genome methods. These findings highlight that the role of trauma exposure on depression manifestation may be non-additive and different between sexes. Exploring these effects in depth may yield important insight into various mechanisms, which may explain prevalence differences observed between males and females. Future work can build upon the framework we propose to explore genome-by-trauma interaction effects and the underlying molecular sites and mechanisms which are involved in depression manifestation.


title: Effectiveness of gamified team competition in the context of mHealth intervention for medical interns: a micro-randomized trial

abstract:
BackgroundTwin revolutions in wearable technologies and smartphone-delivered digital health interventions have significantly expanded the accessibility and uptake of personalized interventions in multiple domains of health sciences. Gamification, the application of gaming elements to increase enjoyment and engagement, has the potential to improve the effectiveness of digital health interventions. However, the effectiveness of competition gamification components remains poorly understood, challenging informed decisions on the potential adoption of these components in future studies and trial designs. We aimed to evaluate the effect of smartphone-based gamified team competition intervention on daily step count and sleep duration via a micro-randomized trial.

MethodsWe recruited first-year medical residents (interns) in the US, who downloaded the study app, provided consent, wore a wearable device, and completed a baseline survey. Teams were formed based on participating residents institutions and specialties, and subsequently randomized weekly to the competition or non-competition arms. In the competition arm, opponent teams and competition type (step count or sleep duration) were also randomly selected. Competition participants had access to the current competition scoreboard and competition history via the study app; they also received scheduled competition-related push notifications in a competition week. We estimated the main and moderated causal effects of competition on proximal daily step count and sleep duration. This trial is registered with ClinicalTrials.gov (NCT05106439).

FindingsBetween April and June 2020, we enrolled 2,286 medical interns from 263 institutions, of whom 1,936 were formed into 191 teams that met the criteria for participation in competitions between July 6 and September 27, 2020. 1,797 participants who had pre-internship baseline information were included in the analysis. Relative to the no competition arm, competition intervention significantly increased the mean daily step count by 111{middle dot}5 steps (SE 40{middle dot}4, p=0{middle dot}01), while competition did not significantly affect the mean daily sleep minutes (p=0{middle dot}69). Secondary moderator analyses indicated that, for each additional week-in-study, the causal effects of competition on daily step count and sleep minutes decreased by 9{middle dot}1 (11{middle dot}6) steps (p=0{middle dot}43) and 1{middle dot}9 (0{middle dot}6) minutes (p=0{middle dot}003), respectively. Intra-institutional competition negatively moderated the causal effect of competition upon daily step count by -114.9 (93{middle dot}7) steps (p=0{middle dot}22).

InterpretationGamified competition delivered via mobile app significantly increased daily physical activity which suggests that team competition can function as a mobile health intervention tool to increase short-term physical activity level.

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed for studies of mobile health intervention with gamified components: ("mobile health intervention", "mHealth intervention", "mobile health gamification"). We evaluated studies published before November 30, 2021. The search was not limited by language. Previous work affirmed that in mobile health interventions, gamification is effective for improving users physical activity and mental health. Most of previous work used feedback, reward, and progress bar as game mechanics, while none have rigorously examined the effectiveness of gamified team competition.

Added value of this studyThis study provides evidence that the gamified team competition has a positive effect on physical activity. The data that was intensively collected as part of this study can be used for further investigation.

Implications of all the available evidenceThe results of this study indicate that gamified team competition has the potential to improve the effectiveness of and engagement with mobile health interventions.

category: health informatics


title: Bayesian Hierarchical Model for Dose Finding Trial Incorporating Historical Data

abstract: The Multiple Comparison Procedure and Modelling (MCPMod) approach has been shown to be a powerful statistical tool that can significantly improve the design and analysis of dose finding studies under model uncertainty. Due to its frequentist nature, however, it is difficult to incorporate into MCPMod information from historical trials on the same drug. Recently, a Bayesian version of MCPMod has been introduced by Fleischer et al. (2022) to resolve this issue, which is particularly tailored to the situation where there is information about the placebo dose group from historical trials. In practice, information may also be available on active dose groups from early phase trials, e.g., a dose escalation trial and a preceding small Proof of Concept trial with only a placebo and a high dose. To address this issue, we introduce a Bayesian hierarchical framework capable of incorporating historical information about both placebo and active dose groups with the flexibility of modelling both prognostic and predictive between-trial heterogeneity. Our method is particularly useful in the situation where the effect sizes of two trials are different. Our goal is to reduce the necessary sample size in the dose finding trial while maintaining its target power.


title: Health shocks and changes in life purpose: Understanding the link between purpose and longevity

abstract:
BackgroundThe negative correlation between life purpose levels and subsequent morbidity and mortality is interpreted as evidence that a higher sense of life purpose causes healthier and longer lives. Causation, however, could run the other direction as a decline in health is, by definition, associated with greater morbidity and mortality risk and may also cause a decline in life purpose. We examine the relation between objective measures of changes in health and changes in purpose to better understand the causal mechanisms linking purpose to health and mortality.

MethodsProspective cohort sample of 12 745 individuals aged 50 and older who were eligible to participate in the 2006, 2010, or 2014 Health and Retirement Study Psychosocial and Lifestyle questionnaire. The final sample consists of 15 034 observations measured over three four-year periods from 5 147 individuals. Controlling for standard covariates, we examined the relation between changes in purpose and 14 contemporaneous and subsequent objectively measured changes in health--lung function, grip strength, walking speed, balance, and physician diagnoses of hypertension, diabetes, cancer, lung disease, heart condition, stroke, psychiatric problem, arthritis, dementia, and Alzheimers disease.

FindingsThere is strong evidence that negative health shocks cause a decline in life purpose as individuals who suffer a negative health shock experience a statistically meaningful contemporaneous decline in life purpose for 12 of the 14 changes in health metrics. In contrast, there is relatively weak evidence that a decline in purpose contributes to a deterioration of future health.

InterpretationMuch of the relation between life purpose levels and mortality risk arises from reverse causation--a decline in health causes both increased mortality risk and lower life purpose. There is little evidence that life purpose interventions would alter future morbidity or mortality.

FundingNone.

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed and Google Scholar with no language or date restriction for the term "life purpose" and found four comprehensive reviews of the life purpose or psychological well-being (which included life purpose in the set of psychological well-being metrics) literatures in the last three years and a 2016 meta-analysis of the relation between life purpose and mortality. Although acknowledging the possibility that reverse causation plays a role in linking life purpose levels to subsequent morbidity and mortality, the prevalent view appears to be that even when controlling for current health levels, higher life purpose causes behavioral, biological, or stress buffering changes that, in turn, cause lower future morbidity and mortality.

Added value of this studyBy focusing on changes in health, changes in life purpose, and a longer horizon, we find strong evidence that changes in health cause changes in life purpose, but, contrary to the conclusions of most previous work, there is little evidence changes in life purpose cause changes in behavior, biology, or stress-buffering that, in turn, cause changes in future health.

Implications of all the available evidenceAlthough life purpose intervention--either at the provider level or in public policy--may have benefits, there is little evidence to suggest it will cause greater longevity or lower future illness.


title: HIV-1 infection induces functional reprogramming of female plasmacytoid dendritic cells associated with enhanced TLR7 expression

abstract: Plasmacytoid dendritic cells (pDCs) express TLR7, a ssRNA-sensor encoded on the X chromosome, which escapes X chromosome inactivation (XCI) in females. pDCs are specialized in the production of type 1 interferons (IFN-I) through TLR7 activation which mediates both immune cell activation and also reactivation of latent HIV-1. The effect of HIV-1 infection in women under antiretroviral therapy (ART) on pDC functional responses remains poorly understood. Here, we show that pDCs from HIV/ART women exhibit exacerbated production of IFN- and TNF- as compared to uninfected controls (UC) upon TLR7-activation. Because TLR7 can escape XCI in female pDCs, we measured the contribution of TLR7 allelic expression using SNP haplotypic markers to rigorously tag the allele of origin of TLR7 gene at single cell resolution. Herein, we provide evidence that the functional reprogramming of pDCs in HIV/ART women is associated with enhanced transcriptional activity of the TLR7 locus from both X chromosomes, rather than differences in the frequency of TLR7 bi-allelic cells. These data reinforce the interest in targeting the HIV-1 reservoir using TLR7 agonists in women.

category: hiv aids


title: C allele of rs479200 of the host EGLN1 gene - a risk factor for severe COVID-19 (pilot study)

abstract:
BackgroundCoronavirus disease-2019 (COVID-19) symptoms can range from asymptomatic, moderate to severe manifestations that result in an overall global case fatality rate of 2-7 %. While each variant has had it challenges, and some variants are more severe than others, risk factors of severe COVID-19 are still under investigation. In this context, the host genetic predisposition is also a crucial factor to investigate. In the present study, we investigated host genotypes of the SNP rs479200 of the host EGLN1 gene, previously implicated in high altitude pulmonary edema (HAPE), some of whose symptoms such as hypoxia profoundly overlap with severe COVID-19.

MethodsAfter informed consent, 158 RT-PCR confirmed COVID-19 patients (March 2020 to June 2021) were enrolled in the study. Based on their clinical manifestations, disease severity was categorized by the clinical team. Blood samples were drawn and DNA was extracted from the clot to infer different genotypes of the SNP rs479200 of the host EGLN1 gene. PCR-RFLP analysis of the SNP rs479200 (C > T) was performed with an amplicon size of 367 bp. Various genotypes (TT, TC and CC) were assigned based on the presence/absence of a restriction site (T/GTACA) for restriction enzyme BsrGI. Allele frequencies, Hardy-Weinberg Equilibrium (HWE) and multinomial logistic regression were performed using statistical tool SPSS version 23 (IBM).

FindingsWe observed that the severe COVID-19 category was composed of comparatively younger patients with mean age (34.9{+/-}15.6), compared to asymptomatic and moderate categories whose mean age was 49.7{+/-}17.9 and 54.3{+/-}15.7, respectively. Preponderance of males and high heterozygosity (TC) was observed across the clinical categories. Notably, the frequency of C allele (0.664) was 2-fold higher than the T allele (0.336) in severe COVID-19 patients, whereas the allele frequencies were similar in asymptomatic and moderate category of COVID-19 patients. Multinomial logistic regression showed an association of genotypes with increasing clinical severity; odds ratio (adjusted OR-11.414 (2.564-50.812)) and (unadjusted OR-6.214 (1.84-20.99)) for the genotype CC in severe category of COVID-19. Interestingly, the TC genotype was also found to be positively associated with severe outcome (unadjusted OR-5.816 (1.489-22.709)), indicating association of C allele in imparting the risk of severe outcome.

InterpretationThe study provides strong evidence that the presence of C allele of SNP (rs479200) of the EGLN1 gene associates with severity in COVID-19 patients. Thus, the presence of C allele may be a risk factor for COVID-19 severity. This study opens new avenues towards risk assessment that include EGLN1 (rs479200) genotype testing and identifying patients with C allele who might be prioritized for critical care.


title: Broad Cross-reactive IgA and IgG Against Human Coronaviruses in Milk Induced by COVID-19 Vaccination and Infection

abstract:
It is currently unclear if SARS-CoV-2 infection or mRNA vaccination can also induce IgG and IgA against common human coronaviruses (HCoVs) in lactating parents. Here we prospectively analyzed human milk (HM) and blood samples from lactating parents to measure the temporal patterns of anti-SARS-CoV-2 specific and anti-HCoV cross-reactive IgA and IgG responses. Two cohorts were analyzed: a vaccination cohort (n=30) who received mRNA-based vaccines for COVID-19 (mRNA-1273 or BNT162b2), and an infection cohort (n=45) with COVID-19 disease. Longitudinal HM and fingerstick blood samples were collected pre- and post-vaccination or, for infected subjects, at 5 time-points 14 - 28 days after confirmed diagnosis. The anti-spike(S) and antinucleocapsid(N) IgA and IgG antibody levels against SARS-CoV-2 and HCoVs were measured by multiplex immunoassay (mPlex-CoV). We found that vaccination significantly increased the anti-S IgA and IgG levels in HM. In contrast, while IgG levels increased after a second vaccine dose, blood and HM IgA started to decrease. Moreover, HM and blood anti-S IgG levels were significantly correlated, but anti-S IgA levels were not. SARS2 acute infection elicited anti-S IgG and IgA that showed much higher correlations between HM and blood compared to vaccination. Vaccination and infection were able to significantly increase the broadly cross-reactive IgG recognizing HCoVs in HM and blood than the IgA antibodies in HM and blood. In addition, the broader cross-reactivity of IgG in HM versus blood indicates that COVID-19 vaccination and infection might provide passive immunity through HM for the breastfed infants not only against SARS-CoV-2 but also against common cold coronaviruses.

IMPORTANCEIt is unknown if COVID-19 mRNA vaccination and infection in lactating mothers results in cross-reactive antibodies against other common human coronaviruses. Our study demonstrates that mRNA vaccination and COVID-19 infection increase anti-spike SARS-CoV-2 IgA and IgG in both blood and milk. IgA and IgG antibody concentrations in milk were more tightly correlated with concentrations in blood after infection compared to mRNA vaccination. Notably, both infection and vaccination resulted in increased IgG against common seasonal {beta}-coronaviruses. This suggests that SARS-CoV-2 vaccination or infection in a lactating parent may result in passive immunity against SARS-CoV-2 and seasonal coronaviruses for the recipient infant.


title: Monocytes are the main source of STING-mediated IFN-alpha production

abstract:
BackgroundType I interferon (IFN-I) production by plasmacytoid dendritic cells (pDCs) occurs during viral infection, in response to Toll-like receptor 7 (TLR7) stimulation and is more vigorous in females than in males. Whether this sex bias persists in ageing people is currently unknown. In this study, we investigated the effect of sex and aging on IFN- production induced by PRR agonist ligands.

MethodsIn a large cohort of individuals from 19 to 97 years old, we measured the production of IFN- and inflammatory cytokines in whole-blood upon stimulation with either R-848, ODN M362 CpG-C, or cGAMP, which activate the TLR7/8, TLR9 or STING pathways, respectively. We further characterized the cellular sources of IFN-.

FindingsWe observed a female predominance in IFN- production by pDCs in response to TLR7 or TLR9 ligands. The higher TLR7-driven IFN- production in females was robustly maintained across ages, including the elderly. The sex-bias in TLR9-driven interferon production was lost after age 60, which correlated with the decline in circulating pDCs. By contrast, STING-driven IFN- production was similar in both sexes, preserved with aging, and correlated with circulating monocyte numbers. Indeed, monocytes were the primary cellular source of IFN- in response to cGAMP.

InterpretationWe show that the sex bias in the TLR7-induced IFN-I production is strongly maintained through ages, and identify monocytes as the main source of IFN-I production via STING pathway.

FundingThis work was supported by grants from Region Occitanie/Pyrenees-Mediterranee (#12052910, Inspire Program #1901175), University Paul Sabatier, and the European Regional Development Fund (MP0022856).

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSType I interferon (IFN-I) production by plasmacytoid dendritic cells (pDCs) occurs during infection with viruses, including SARS-CoV-2, in response to Toll-like receptor 7 (TLR7) stimulation. Early type I IFN production by pDCs in the respiratory tract through TLR7 activation is protective in severe COVID-19. The capacity of female pDCs to produce higher levels of interferon  (IFN-) in response to TLR7 ligands, compared to those of males, is one immune characteristic that robustly distinguishes the two sexes in middle-aged adults. It is currently unknown whether the superior ability of female pDCs to produce IFN-I upon TLR7 stimulation is maintained with age. In this study, we investigated the impact of sex and aging on the release of innate cytokines (IFN-, IFN-{gamma}, IL-1{beta}, IL-6, IL-8, TNF-, MCP1) in a whole-blood assay from 310 healthy volunteers (145 males and 165 females) from 19 to 97 years old, upon stimulation with either TLR7-, TLR9-ligands or with cGAMP, the natural product of cGAS which activates STING (Stimulator of IFN Gene) and has been reported to exhibit potent anti-tumor and adjuvant effects through induction of IFN-I by ill-defined cellular sources.

Added value of this studyWe observed that IFN- responses to TLR7 and TLR9 ligands were the only whole blood assay variables exhibiting sex differences among all 21 variables investigated (seven analytes analyzed after stimulation by three different ligands). Our results show that the accrued female response in the TLR7-induced IFN- production was robustly maintained over ages, including elderly subjects >80. In contrast, STING-induced IFN-I production was similar in both sexes and was maintained with aging possibly as a consequence of the age-related increase in circulating monocyte numbers. Indeed, we demonstrate for the first time that monocytes represent the main cellular source of IFN-I upon cGAMP stimulation of PBMCs.

Implications of all the available evidenceThis study demonstrates that the heightened TLR7 ligand-induced IFN- secretion by blood pDCs from females, compared to those from males, is maintained in elderly women, supporting the hypothesis that this pathway could contribute to enhanced protection against virus infections such as SARS-CoV-2 in females. This work also shows that cGAMP can promote IFN-I production by targeting monocytes, which numbers increase with aging, suggesting that STING ligands may be useful for vaccine design in the elderly in both sexes.

category: allergy and immunology


title: Association of left atrial structure and function with cognitive function among adults with metabolic syndrome

abstract:
BackgroundAtrial fibrillation has been associated with cognitive impairment. Whether subclinical abnormalities in atrial function and substrate predisposing to atrial fibrillation impact cognitive function has received limited attention.

MethodsWe tested associations of echocardiographic markers of atrial structure and function with cognitive functioning and decline among 510 participants with overweight/obesity and metabolic syndrome (mean age [standard deviation] of 64.4 [5.2] years in men and 66.5 [3.9] in women). Left atrial markers (volume index, emptying fraction, strain, function index, and stiffness index) were estimated based on transthoracic echocardiography. General cognitive functioning (Mini-mental examination), verbal ability (verbal fluency test), memory and attention (Digit Span Tests), and processing speed and executive function (Trail-Making Tests A and B) were assessed at baseline and at the two-year follow-up. Multiple linear regression was used to test associations of atrial markers (modeled in standard deviation units) with baseline and two-year changes in cognitive scores adjusting for demographic and health covariates.

ResultsLeft atrial structure and function was not associated with cognitive function at baseline. Larger left atrial volume index (standardized {beta} [95% confidence interval] = -0.13 [-0.22, -0.03]), lower peak longitudinal strain (-0.11 [-0.20, -0.01]), and higher stiffness index (-0.18 [-0.28, -0.08) were associated with 2-year worsening in Trail-Making Test A. Strain measurements were also associated with 2-year change in the Controlled Oral Word Association Test.

ConclusionOverall, adverse markers of left atrial structure and function were associated with 2-year detrimental executive function-related cognitive changes in a sample of participants at high risk for cardiovascular disease, highlighting left atrial substrate as a potential risk factor for cognitive decline and dementia.


title: Lower Risk of Paediatric Inflammatory Multisystem Syndrome (PIMS-TS) with the Delta variant of SARS-CoV-2

abstract:
Paediatric Inflammatory Multisystem Syndrome (PIMS-TS, also known as MIS-C) typically occurs 2-6 weeks after exposure to SARS-CoV-2. Early estimates suggested a risk of PIMS-TS of 1 in 3-4000 infected children. Whether this risk is sustained with new SARS-CoV-2 variants remains unknown.

We utilised prospective data from the NHS South Thames Paediatric Network (STPN), which manages all cases of PIMS-TS amongst 1.5 million children in South-East England, to assess trends over time. We compared PIMS-TS cases with two independent SARS-CoV-2 infection datasets. We used publicly available UK Health Security Agency case numbers weighted to child population distributions according to area population estimates from the Office for National Statistics (ONS). To avoid bias due to evolving testing behaviour, we also compared PIMS-TS cases to community infection rates, obtained from the ONS COVID-19 Infection Survey, which randomly selects individuals for fortnightly PCR tests. All three datasets were normalised to the peak of the Alpha wave, and plotted against time. PIMS-TS cases were plotted 40 days prior to hospitalisation, corresponding to the best fit of rising SARS-CoV-2 infection and PIMS-TS cases during the Alpha wave.

Compared with the Alpha wave, we found fewer cases of PIMS-TS relative to SARS-CoV-2 infections during both initial and subsequent Delta waves. This relative reduction continued into the Omicron wave.

Re-infection rates with the Alpha or Delta variants and vaccination rates were very low during the Delta wave. As a result, lower PIMS-TS rate relative to SARS-CoV-2 infections during the Delta wave is unlikely to be explained by population level immunity from prior infection or vaccination. It is most likely due to viral mutations in key antigenic epitopes responsible for triggering the hyperinflammatory response observed with PIMS-TS.

category: pediatrics


title: Lower Risk of Multisystem Inflammatory Syndrome in Children (MIS-C) with the Delta and Omicron variants of SARS-CoV-2


title: Unplanned ICU transfer from post-anesthesia care unit following cerebral surgery: A retrospective study

abstract:
BackgroundUnplanned transfer to intensive care unit (ICU) lead to reduced trust of patients and their families in medical staff and challenge medical staff to allocate scarce ICU resources. This study aimed to explore the incidence and risk factors of unplanned transfer to ICU during emergence from general anesthesia after cerebral surgery, and to provide guidelines for preventing unplanned transfer from post-anesthesia care unit (PACU) to ICU following cerebral surgery.

MethodsThis was a retrospective case-control study and included patients with unplanned transfer from PACU to ICU following cerebral surgery between January 2016 and December 2020. The control group comprised patients matched (2:1) for age ({+/-}5 years), sex, and operation date ({+/-}48 hours) as those in the case group. Stata14.0 was used for statistical analysis, and p <0.05 indicated statistical significance.

ResultsA total of 11,807 patients following cerebral surgery operations were cared in PACU during the study period. Of the 11,807 operations, 81 unscheduled ICU transfer occurred (0.686%). Finally, 76 patients were included in the case group, and 152 in the control group. The following factors were identified as independent risk factors for unplanned ICU admission after neurosurgery: low mean blood oxygen (OR=1.57, 95%CI: 1.20-2.04), low mean albumin (OR=1.14, 95%CI: 1.03-1.25), slow mean heart rate (OR=1.04, 95%CI: 1.00-1.08), blood transfusion (OR=2.78, 95%CI: 1.02-7.58), emergency surgery (OR=3.08, 95%CI: 1.07-8.87), lung disease (OR=2.64, 95%CI: 1.06-6.60), and high mean blood glucose (OR=1.71, 95%CI: 1.21-2.41).

ConclusionWe identified independent risk factors for unplanned transfer from PACU to ICU after cerebral surgery based on electronic medical records. Early identification of patients who may undergo unplanned ICU transfer after cerebral surgery is important to provide guidance for accurately implementing a patients level of care.

category: primary care research


title: Performing moderate to severe activity is safe and tolerable for healthy youth while wearing a cloth facemask

abstract:
ObjectiveTo investigate if wearing a cloth facemask could affect physiological and perceptual responses to exercise at distinct exercise intensities in healthy young individuals.

MethodsIn a crossover design, 9 participants (sex, female/male: 6/3; age: 13{+/-}1 years; BMI: 18.4{+/-}2.1 kg/m2; sexual maturity rating, I/II/III/IV: 0/3/4/2; VO2peak: 44.5{+/-}5.5 mL/kg/min) underwent a progressive square-wave test at four intensities: (1) at 80% of the ventilatory anaerobic threshold (VAT), (2) at VAT, and (3) at 40% between the VAT and V{square}O2peak wearing a triple-layered cloth facemask or not. These stages represented moderate, heavy, and very heavy domains and corresponded to 46{+/-}8%, 57{+/-}10% and 87{+/-}8% of V{square}O2peak. Participants then completed a final stage (severe) to exhaustion at a running speed equivalent to the maximum achieved during the cardio-respiratory exercise test (Peak). Physiological, metabolic, and perceptual measures were analysed.

ResultsMask did not affect spirometry (forced vital capacity [FVC], peak expiratory flow [PEF1], forced expiratory volume [FEV]; all p > 0.27; Figure 1), respiratory (inspiratory capacity [IC], end-expiratory volume to functional vital capacity ratio [EELV/FVC], EELV, respiratory frequency [Rf], tidal volume [VT], Rf/VT, end-tidal carbo dioxide pressure [PetCO2], ventilatory equivalent and carbon dioxide ratio [VE/VCO2]; all p > 0.196), hemodynamic (heart rate [HR], systolic and diastolic blood pressure [SBP; DBP]; all p > 0.41), rated perceived exertion (RPE; p = 0.04) or metabolic measures (lactate; p = 0.78 Figure 2) at rest or at any exercise intensity. In both conditions, the same number of children (4 out of 9) were unable to finish the Peak stage, whereas one child did not complete exercise at the heavy domain while wearing no mask.

O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/22272270v1_fig1.gif" ALT="Figure 1">
View larger version (31K):
org.highwire.dtl.DTLVardef@11c318borg.highwire.dtl.DTLVardef@1f8a25forg.highwire.dtl.DTLVardef@6c404corg.highwire.dtl.DTLVardef@f1794a_HPS_FORMAT_FIGEXP  M_FIG O_FLOATNOFigure 1.C_FLOATNO Spirometry data at rest with or without wearing a facemask. All data are expressed as mean and standard deviations. No significant differences between conditions were found.

C_FIG O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=100 SRC="FIGDIR/small/22272270v1_fig2.gif" ALT="Figure 2">
View larger version (19K):
org.highwire.dtl.DTLVardef@152222dorg.highwire.dtl.DTLVardef@141d0a0org.highwire.dtl.DTLVardef@1e7d5beorg.highwire.dtl.DTLVardef@181b51a_HPS_FORMAT_FIGEXP  M_FIG O_FLOATNOFigure 2.C_FLOATNO Ratings of perceived exertion (Panel A) and blood lactate concentration (Panel B) during a progressive square-wave test with or without wearing a facemask. Data expressed as means and standard deviations and individual data.

C_FIG ConclusionsThis study shows that performing moderate to severe activity is safe and tolerable for healthy youth while wearing a cloth facemask. ClinicalTrials.gov: NCT04887714

category: sports medicine


title: Modifiable lifestyle activities affect cognition in cognitively healthy middle-aged individuals at risk for late-life Alzheimer's Disease.

abstract: It is now acknowledged that Alzheimers Disease (AD) processes are present decades before the onset of clinical symptoms, but it remains unknown whether lifestyle factors can protect against these early AD processes in mid-life. We asked whether modifiable lifestyle activities impact cognition in middle-aged individuals who are cognitively healthy, but at risk for late life AD. Participants (40-59 years) completed cognitive and clinical assessments at baseline (N = 210) and two years follow-up (N = 188). Mid-life activities were measured with the Lifetime of Experiences Questionnaire. We assessed the impact of lifestyle activities, known risk factors for sporadic late-onset AD (Apolipoprotein E {square}4 allele status, family history of dementia, and the Cardiovascular Risk Factors Aging and Dementia score), and their interactions on cognition. More frequent engagement in physically, socially and intellectually stimulating activities was associated with better cognition (verbal, spatial and relational memory), at baseline and follow-up. Critically, more frequent engagement in these activities was associated with stronger cognition (verbal and visuospatial functions, and conjunctive short-term memory binding) in individuals with family history of dementia. Impaired visuospatial function is one of the earliest cognitive deficits in AD and has previously associated with increased AD risk in this cohort. Additionally, conjunctive memory functions have been found impaired in the pre-symptomatic stages of AD. These findings suggest that modifiable lifestyle activities offset cognitive decrements due to AD risk in mid-life and support the targeting of modifiable lifestyle activities for the prevention of Alzheimers Disease.

category: public and global health


title: Acidity of expiratory aerosols controls the infectivity of airborne influenza virus and SARS-CoV-2

abstract:
Enveloped viruses are prone to inactivation when exposed to strong acidity levels characteristic of atmospheric aerosol. Yet, the acidity of expiratory aerosol particles and its effect on airborne virus persistence has not been examined. Here, we combine pH-dependent inactivation rates of influenza A virus and SARS-CoV-2 with microphysical properties of respiratory fluids under indoor conditions using a biophysical aerosol model. We find that particles exhaled into indoor air become mildly acidic (pH {approx} 4), rapidly inactivating influenza A virus within minutes, whereas SARS-CoV-2 requires days. If indoor air is enriched with non-hazardous levels of nitric acid, aerosol pH drops by up to 2 units, decreasing 99%-inactivation times for both viruses in small aerosol particles to below 30 seconds.Conversely, unintentional removal of volatile acids from indoor air by filtration may elevate pH and prolong airborne virus persistence. The overlooked role of aerosol pH has profound implications for virus transmission and mitigation strategies.

One Sentence SummaryRespiratory viruses are sensitive to aerosol pH, an unidentified factor in the mitigation of airborne virus transmission


title: Obesity, hypertension and tobacco use associated with left ventricular remodelling and hypertrophy in South African Women: Birth to Twenty Plus Cohort

abstract:
BackgroundLeft ventricular hypertrophy (LVH) is a known marker of increased risk in developing future life-threating CVD, though it is unclear how health risk factors, such as obesity, blood pressure and tobacco use, associate with left ventricular (LV) remodelling and LVH across generations of urban African populations.

MethodsBlack female adults (n=123; age: 29-68 years) and their children (n=64; age: 4-10; 55% female) were recruited from the Birth to Twenty Plus Cohort in Soweto, South Africa. Tobacco and alcohol use, physical activity, presence of diabetes mellitus, heart disease and medication were self-reported. Height, weight, and blood pressure were measured in triplicate. Echocardiography was used to assess LV mass at end-diastole, perpendicular to the long axis of the LV and indexed to body surface area to determine LVH.

ResultsHypertension and obesity prevalence were 35.8% and 59.3% for adults and 45.3% and 6.3% for children. Self-reported tobacco use in adults was 22.8%. LVH prevalence was 35.8% (n=44) in adults (75% eccentric; 25% concentric), and 6.3% (n=4) in children (all eccentric). Prevalence of concentric remodelling was 15.4% (n=19) in adults and observed in one child. In adults, obesity (OR: 2.54 (1.07-6.02; p=0.02) and hypertension (3.39 (1.08-10.62; p=0.04) significantly increased the odds of LVH, specifically eccentric LVH, while concentric LVH was associated with self-reported tobacco use (OR: 4.58 (1.18-17.73; p=0.03; n=11). Although no logistic regression was run within children, of the four children LVH, three had elevated blood pressure and the child with normal blood pressure was overweight.

ConclusionsThe association between obesity, hypertension, tobacco use and LVH in adults, and the 6% prevalence of LVH in children, calls for stronger public health efforts to control risk factors and monitor children at who are risk.


title: Independent effect and joint effect of polygenic liabilities for schizophrenia and bipolar disorder on cognitive aging and education attainment

abstract: To elucidate the specific and shared genetic background of schizophrenia (SCZ) and bipolar disorder (BPD) to better understand their nosology, this study explored the independent and joint effects of polygenic liabilities for SCZ and BPD on cognitive aging and educational attainment among a collection of 80318 unrelated community participants from the Taiwan Biobank. Using the Psychiatric Genomics Consortium meta-analysis as a discovery sample, we calculated the polygenic risk score (PRS) for SCZ (PRSSCZ) and BPD (PRSBPD), shared PRS between SCZ and BPD (PRSSCZ+BPD), and SCZ-specific, differentiated from BPD, PRS (PRSSCZvsBPD). Based on the sign concordance of the susceptibility variants with SCZ and BPD, PRSSCZ was split into PRSSCZ_concordant and PRSSCZ_discordant and PRSBPD was split into PRSBPD_concordant and PRSBPD_discordant. Linear regression models were used to estimate the association with cognitive aging as measured by the Mini-Mental State Examination (MMSE) in individuals aged [≥] 60 years. Ordinal logistic regression models were used to estimate the association with educational attainment. PRSSCZ was negatively associated with MMSE (beta=-0.063, p<0.001), while PRSBPD was positively associated with MMSE (beta=0.04, p=0.01). A larger difference between PRSSCZ and PRSBPD was associated with lower MMSE scores (beta=-0.052, p<0.001). Both PRSSCZ_concordant and PRSSCZ_discordant were negatively associated with MMSE scores, without a synergistic effect. There was a complex interaction between PRSBPD_concordant and PRSBPD_discordant on the MMSE scores. PRSSCZ+BPD (beta=-0.09, p=0.01) and PRSSCZvsBPD (beta=-0.13, p<0.001) predicted a decrease in MMSE scores during the follow-up. PRSSCZ, PRSBPD, and PRSSCZ+BPD were positively associated with educational attainment, whereas PRSSCZvs BPD was negatively associated with educational attainment. This study provides evidence for the contrasting effect of polygenic liabilities for SCZ and BPD on cognitive aging and partially supports the hypothesis that the heterogeneity of SCZ and the positive association of polygenic liability for SCZ with education might be attributed to the shared part with BPD.

category: epidemiology