title: Understanding the cultural environment of the outpatient care setting for patients with dementia receiving cancer treatment: a qualitative study

abstract:
IntroductionPeople with dementia have poorer cancer outcomes than those without, and experience inequalities in access to, and quality of, care. Outpatient environments, where radiotherapy, chemotherapy and immunotherapy cancer treatments typically take place, have largely been excluded from research. This study was conducted to understand provision of treatment and support and experiences of care for people with dementia undergoing cancer treatment in the outpatient setting.

Materials and methodsUsing observation, interviews and document analysis, data were collected to scrutinise the cultural environment of ambulatory care, comprising the physical fabric of the care setting; interactions, behaviours and perceptions of those in the care setting; and the organizational, clinical and interactional processes involved in care delivery. The study was conducted in the outpatient oncology departments of two large teaching hospitals in England between January 2019-July 2021.

ResultsData were gathered from a wide range of sources, including 15 hours of observation, and interviews with patients (n=2), caregivers (n=7) and staff (n=20). Evidence from this study suggests the cultural environment of the outpatient care setting reflects and supports the standardised processing of people for cancer treatment. Dementia introduces a wider set of care requirements not catered for by this standardised treatment model and associated processes. Data showed the needs of patients with dementia could be addressed most effectively when individualised, as opposed to standardised care, was offered.

ConclusionThere is work to be done in outpatient cancer services to ensure responsiveness to individual patient need. This could be achieved by having an established way (or ways) of eliciting needs, preferences and expectations, a belief that a persons needs and expectations are legitimate, and that effort should be made to address them, with the ability to accommodate these needs and expectations.

Patient or public contributionpatients and caregivers were involved in the study design and development of study materials including the interview topic guide. They also assisted with discussion and clarification of study findings.

category: oncology


title: The impact of fatty acids biosynthesis on the risk of cardiovascular diseases in Europeans and East Asians: A Mendelian randomization study

abstract: Despite early interest, the evidence linking fatty acids to cardiovascular diseases remains controversial. We used Mendelian randomization to explore the involvement of polyunsaturated (PUFA) and monounsaturated (MUFA) fatty acids biosynthesis in the aetiology of several cardiovascular disease endpoints in up to 1,153,768 European and 212,453 East Asian ancestry individuals. As instruments, we selected single nucleotide polymorphisms (SNP) mapping to genes with well-known roles in PUFA (i.e. FADS1/2 and ELOVL2) and MUFA (i.e. SCD) biosynthesis. Our findings suggest that higher PUFA biosynthesis rate (proxied by rs174576 near FADS1/2) is related to higher odds of multiple cardiovascular diseases, particularly ischemic stroke, peripheral artery disease and venous thromboembolism, whereas higher MUFA biosynthesis rate (proxied by rs603424 near SCD) is related to lower odds of coronary artery disease among Europeans. Results were unclear for East Asians as most effect estimates were imprecise. By triangulating multiple approaches (i.e. uni-/multi-variable Mendelian randomization, a phenome-wide scan, genetic colocalization and within-sibling analyses), our results are compatible with higher low- density lipoprotein (LDL)-cholesterol (and possibly glucose) being a downstream effect of higher PUFA biosynthesis rate. Our findings indicate that genetically-determined PUFA and MUFA biosynthesis are involved in the aetiology of cardiovascular diseases and suggest LDL-cholesterol as a potential mediating trait between PUFA biosynthesis and cardiovascular diseases risk.

category: epidemiology


title: Antibody Responses In Non-Severe SARS-CoV-2 Infections Are Driven By CD4+ T cells and Age.

abstract: SARS-CoV-2 infection causes a spectrum of clinical outcomes and diverse memory responses. Population studies indicate that viral neutralizing antibody responses are protective, but do not always develop post-infection. Other antiviral antibody effector functions, T-cell responses, or immunity to seasonal coronaviruses (OC43, 229E) have been implicated but not defined in all ages. Here, we identify that children and adult subjects generate polyfunctional antibodies to the spike protein after asymptomatic infection or mild disease, with some subjects developing cellular responses without seroconversion. Diversity in immunity was explained by two clusters distinguished by CD4+ T-cell cytokines, age, and antibodies to seasonal coronaviruses. Post-vaccination neutralizing responses were predicted by specific post-infection immune measures, including IL-2, spike-IgA, OC43-IgG1, 229E-IgM. We confirm a key role for CD4+ T cell cytokines in functionality of anti-spike antibodies, and show that antibody diversity is impacted by age, Th/Th2 cytokine biases, and antibody isotypes to SARS-CoV-2 and seasonal coronaviruses.

category: allergy and immunology


title: Strengthening vaccination delivery system resilience in the context of protracted humanitarian crisis: a realist-informed systematic review

abstract:
BackgroundChildhood vaccination is among the most effective public health interventions available for the prevention of communicable disease, but coverage in many humanitarian settings is sub-optimal. This systematic review critically evaluated peer-review and grey literature evidence on the effectiveness of system-level interventions for improving vaccination coverage in protracted crises, focusing on how they work, and for whom, to better inform preparedness and response for future crises.

MethodsRealist-informed systematic review of peer-reviewed and grey literature. Keyword-structured searches were performed in MEDLINE, EMBASE and Global Health, CINAHL, the Cochrane Collaboration and WHOLIS, and grey literature searches performed through the websites of UNICEF, the Global Polio Eradication Initiative (GPEI) and Technical Network for Strengthening Immunization Services. Results were independently double-screened for inclusion on title and abstract, and full text. Data were extracted using a pre-developed template, capturing information on the operating contexts in which interventions were implemented, intervention mechanisms, and vaccination-related outcomes. Study quality was assessed using the MMAT tool. Findings were narratively synthesised.

Results50 studies were included, most describing interventions applied in conflict or near-post conflict settings in sub-Saharan Africa, and complex humanitarian emergencies. Vaccination campaigns were the most commonly addressed adaptive mechanism (n=17). Almost all campaigns operated using multi-modal approaches combining service delivery through multiple pathways (fixed and roving), health worker recruitment and training and community engagement to address both vaccination supply and demand. Creation of collaterals through service integration showed generally positive evidence of impact on routine vaccination uptake by bringing services closer to target populations and leveraging trust that had already been built with communities. Robust community engagement emerged as a key unifying mechanism for outcome improvement across almost all of the intervention classes, in building awareness and trust among crisis-affected populations. Some potentially transformative mechanisms for strengthening resilience in vaccination delivery were identified, but evidence for these remains limited.

ConclusionA number of interventions to support adaptations to routine immunisation delivery in the face of protracted crisis are identifiable, as are key unifying mechanisms (multi-level community engagement) apparently irrespective of context, but evidence remains piecemeal. Adapting these approaches for local system resilience-building remains a key challenge.

category: public and global health


title: Epidemiological impact and cost-effectiveness analysis of COVID-19 vaccination in Kenya

abstract:
BackgroundFew studies have assessed the benefits of COVID-19 vaccines in settings where most of the population had been exposed to SARS-CoV-2 infection.

MethodsWe conducted a cost-effectiveness analysis of COVID-19 vaccine in Kenya from a societal perspective over a 1.5-year time frame. An age-structured transmission model assumed at least 80% of the population to have prior natural immunity when an immune escape variant was introduced. We examine the effect of slow (18 months) or rapid (6 months) vaccine roll-out with vaccine coverage of 30%, 50% or 70% of the adult (> 18 years) population prioritizing roll-out in over 50-year olds (80% uptake in all scenarios). Cost data were obtained from primary analyses. We assumed vaccine procurement at $7 per dose and vaccine delivery costs of $3.90-$6.11 per dose. The cost-effectiveness threshold was USD 919.

FindingsSlow roll-out at 30% coverage largely targets over 50-year-olds and resulted in 54% fewer deaths (8,132(7,914 to 8,373)) than no vaccination and was cost-saving (ICER=US$-1,343 (-1,345 to - 1,341) per DALY averted). Increasing coverage to 50% and 70%, further reduced deaths by 12% (810 (757 to 872) and 5% (282 (251 to 317) but was not cost-effective, using Kenyas cost-effectiveness threshold ($ 919.11). Rapid roll-out with 30% coverage averted 63% more deaths and was more cost-saving (ICER=$-1,607 (-1,609 to -1,604) per DALY averted) compared to slow roll-out at the same coverage level, but 50% and 70% coverage scenarios were not cost-effective.

InterpretationWith prior exposure partially protecting much of the Kenyan population, vaccination of young adults may no longer be cost-effective.

KEY QUESTIONSO_ST_ABSWhat is already known?C_ST_ABSO_LIThe COVID-19 pandemic has led to a substantial number of cases and deaths in low-and middle-income countries.
C_LIO_LICOVID-19 vaccines are considered the main strategy of curtailing the pandemic. However, many African nations are still at the early phase of vaccination.
C_LIO_LIEvidence on the cost-effectiveness of COVID-19 vaccines are useful in estimating value for money and illustrate opportunity costs. However, there is a need to balance these economic outcomes against the potential impact of vaccination.
C_LI

What are the new findings?O_LIIn Kenya, a targeted vaccination strategy that prioritizes those of an older age and is deployed at a rapid rollout speed achieves greater marginal health impacts and is better value for money.
C_LIO_LIGiven the existing high-level population protection to COVID-19 due to prior exposure, vaccination of younger adults is less cost-effective in Kenya.
C_LI

What do the new findings imply?O_LIRapid deployment of vaccines during a pandemic averts more cases, hospitalisations, and deaths and is more cost-effective.
C_LIO_LIAgainst a context of constrained fiscal space for health, it is likely more prudent for Kenya to target those at severe risk of disease and possibly other vulnerable populations rather than to the whole population.
C_LI

category: health economics


title: A within-host model of SARS-CoV-2 infection

abstract: Within-host models have been used to successfully describe the dynamics of multiple viral infections, however, the dynamics of SARS-CoV-2 virus infection remain poorly understood. A greater understanding of how the virus interacts with the host can contribute to more realistic epidemiological models and help evaluate the effect of antiviral therapies and vaccines. Here, we present a within-host model to describe SARS-CoV-2 viral dynamics in the upper respiratory tract of individuals enrolled in the UK COVID-19 Human Challenge Study. Using this model, we investigate the viral dynamics and provide timescales of infection that independently verify key epidemiological parameters important in the management of an epidemic. In particular, we estimate that an infected individual is first capable of transmitting the virus after approximately 2.1 days, remains infectious for a further 8.3 days, but can continue to test positive using a PCR test for up to 27 days.

category: infectious diseases


title: Can process mapping and a multi-site Delphi of perioperative professionals inform our understanding of system-wide factors that may impact operative risk?

abstract:
ObjectivesTo examine whether the use of process mapping and a multidisciplinary Delphi can identify potential contributors to perioperative risk. We hypothesised that this approach may identify factors not represented in common perioperative risk tools and give insights of use to future research in this area.

DesignMultidisciplinary modified Delphi study

SettingTwo centres (one tertiary, one secondary) in the United Kingdom during 2020 amidst coronavirus pressures.

Participants91 stakeholders from 23 professional groups involved in the perioperative care of older patients. Key stakeholder groups were identified through the use of process mapping of local perioperative care pathways.

ResultsResponse rate ranged from 51% in round one to 19% in round three. After round one, free text suggestions from the panel were combined with variables identified from perioperative risk scores. This yielded a total of 410 variables that were voted on in subsequent rounds. Including new suggestions from round two, 468/519 (90%) of the statements presented to the panel reached a consensus decision by the end of round three. Identified risk factors included patient level factors (such as ethnicity and socio-economic status); and organisational or process factors related to the individual hospital (such as policies, staffing, and organisational culture). 66/160 (41%) of the new suggestions did not feature in systematic reviews of perioperative risk scores or key process indicators. No factor categorised as  organisational is currently present in any perioperative risk score.

ConclusionsThrough process mapping and a modified Delphi we gained insights into additional factors that may contribute to perioperative risk. Many were absent from currently used risk stratification scores. These results enable an appreciation of the contextual limitations of currently used risk tools and could support future research into the generation of more holistic datasets for the development of perioperative risk assessment tools.

Strengths and Weaknesses- Novel use of process mapping to identify key perioperative stakeholders
- Multidisciplinary Delphi panel to gain breadth of perspective
- Performed across two sites
- Comprehensive results may be of use to other researchers designing perioperative research databases
- Results may be limited by low response rate in final round (although majority of consensus decisions made in round two)

category: anesthesia


title: Predicting past and future SARS-CoV-2-related sick leave using discrete time Markov modelling

abstract:
BackgroundPrediction of SARS-CoV-2-induced sick leave among healthcare workers (HCWs) is essential for being able to plan the healthcare response to the epidemic.

MethodsDuring first wave of the SARS-Cov-2 epidemic (April 23rd to June 24th, 2020), the HCWs in the greater Stockholm region in Sweden were invited to a study of past or present SARS-CoV-2 infection. We develop a discrete time Markov model using a cohort of 9449 healthcare workers (HCWs) who had complete data on SARS-CoV-2 RNA and antibodies as well as sick leave data for the calendar year 2020. The one-week and standardized longer term transition probabilities of sick leave and the ratios of the standardized probabilities for the baseline covariate distribution were compared with the referent period (an independent period when there were no SARS-CoV-2 infections) in relation to PCR results, serology results and gender.

ResultsThe one-week probabilities of transitioning from healthy to partial sick leave or full sick leave during the outbreak as compared to after the outbreak were highest for healthy HCWs testing positive for large amounts of virus (3.69, (95% confidence interval, CI: 2.44-5.59) and 6.67 (95% CI: 1.58-28.13), respectively). The proportion of all sick leaves attributed to COVID-19 during outbreak was at most 55% (95% CI: 50%-59%).

ConclusionsA robust Markov model enabled use of simple SARS-CoV-2 testing data for quantifying past and future COVID-related sick leave among HCWs, which can serve as a basis for planning of healthcare during outbreaks.


title: SARS-CoV-2 testing of aircraft wastewater shows that mandatory tests and vaccination pass before boarding did not prevent massive importation of Omicron variant in Europe

abstract:
BackgroundMost new SARS-CoV-2 epidemics in France occurred following importation from abroad of emerging viral variants. Currently, the control of such risk of new variant importation is based on the negativity of a screening test (PCR or antigenic) and on an up-to-date vaccine status, such as International Air Transport Association travel pass.

MethodsWastewater of 2 planes arriving in Marseille (France) from Addis-Ababa (Ethiopia) on December 2021 were i) tested by RT-PCR for SARS-CoV2 detection, and variants screening; these tests were carried out between landing and custom clearance, ii)sequenced by MiSeq Illumina.

Antigenic tests and sequencing by NovaSeq were carried out on respiratory samples collected from the 56 passengers of the second flight.

ResultsSARS-CoV-2 RNA suspected of being from the Omicron BA.1 variant was detected on the aircrafts wastewater.,

SARS-CoV2 RNA was detected for 11 (20%) passengers and the Omicron BA.1 variant was identified.

ConclusionOur work shows the efficiency of aircraft wastewater testing to detect SARS-CoV-2 cases among travelers and identify the viral genotype. It also highlights the low performance for incoming flights from outside Europe to France of the current filter strategy that combines requirement for a vaccine pass and a negative testing before boarding.


title: How time-scale differences in asymptomatic and symptomatic transmission shape SARS-CoV-2 outbreak dynamics

abstract: Asymptomatic and symptomatic SARS-CoV-2 infections can have different characteristic time scales of transmission. These time-scale differences can shape outbreak dynamics as well as bias population-level estimates of epidemic strength, speed, and controllability. For example, prior work focusing on the initial exponential growth phase of an outbreak found that larger time scales for asymptomatic vs. symptomatic transmission can lead to under-estimates of the basic reproduction number as inferred from epidemic case data. Building upon this work, we use a series of nonlinear epidemic models to explore how differences in asymptomatic and symptomatic transmission time scales can lead to changes in the realized proportion of asymptomatic transmission throughout an epidemic. First, we find that when asymptomatic transmission time scales are longer than symptomatic transmission time scales, then the effective proportion of asymptomatic transmission increases as total incidence decreases. Moreover, these time-scale-driven impacts on epidemic dynamics are enhanced when infection status is correlated between infector and infectee pairs (e.g., due to dose-dependent impacts on symptoms). Next we apply these findings to understand the impact of time-scale differences on populations with age-dependent assortative mixing and in which the probability of having a symptomatic infection increases with age. We show that if asymptomatic generation intervals are longer than corresponding symptomatic generation intervals, then correlations between age and symptoms lead to a decrease in the age of infection during periods of epidemic decline (whether due to susceptible depletion or intervention). Altogether, these results demonstrate the need to explore the role of time-scale differences in transmission dynamics alongside behavioural changes to explain outbreak features both at early stages (e.g., in estimating the basic reproduction number) and throughout an epidemic (e.g., in connecting shifts in the age of infection to periods of changing incidence).


title: Waning of PCV13 vaccine-induced antibody levels within the first year of life, using a 3+0 schedule: an observational population-level serosurveillance study among children under 5 years old in Blantyre, Malawi

abstract:
BackgroundPneumococcal conjugate vaccines (PCVs) induce serotype-specific IgG antibody, effectively reducing vaccine-serotype (VT) carriage and invasive pneumococcal disease (IPD). IgG production wanes approximately 1 month after vaccination in absence of serotype-specific exposure. With uncertainty around correlate of protection (CoP) estimates and with persistent VT carriage and VT-IPD following PCV13 introduction, we undertook population-level immunogenicity profiling among children <5 years in Blantyre, Malawi.

MethodsFor 638 children, capsule-specific IgG to PCV13 VTs, two non-VTs, and IgG to three pneumococcal proteins were measured using an enzyme-linked immunosorbent assay and a direct-binding electrochemiluminescence-based multiplex assay. A linear spline regression model estimated population-level, serotype-specific immunogenicity profiles. A linear regression model was used to validate putative CoPs.

FindingsImmunogenicity profiles revealed a consistent pattern among VTs except serotype 3: a vaccine-induced IgG peak followed by waning to a nadir and subsequent increase in titre. For serotype 3 there was no apparent vaccine-induced increase. Heterogeneity in parameters included age range at post-vaccination-nadir (11{middle dot}2 [19F, 23F] to 27{middle dot}3 [7F] months). Titres dropped below IPD CoPs among 9 VTs and below carriage CoPs for 10 VTs. Study data estimated a range of carriage CoPs (0{middle dot}50g/mL to 2{middle dot}5g/mL). Increasing antibody among older children and seroincident events were consistent with ongoing VT exposure.

InterpretationA 3+0 PCV13 schedule with high uptake has not led to sustained population-level antibody immunity beyond the first year of life. Indeed, post-vaccine antibody concentrations dropped below putative CoPs for several VTs, potentially contributing to persistent VT carriage and residual VT-IPD in Malawi and other similar settings.

FundingBill & Melinda Gates Foundation, Wellcome UK, and National Institute for Health & Care Research.


title: Prevalence and associated factors of khat chewing among pregnant women: A Systematic Review and Meta-analysis

abstract:
BackgroundKhat (Catha edulis) is a stimulant plant, broadly cultivated and consumed in the Horn of Africa and the Arabian Peninsula. It contains Cathinone, which is an amphetamines-like chemical and causes various adverse outcomes for pregnant women and babies when it is consumed during pregnancy. Decisive estimates of the prevalence of khat chewing and related risk factors which may increase this practice have not been determined.

AimTo determine the pooled prevalence and associated factors of khat chewing among pregnant women in the Horn Africa and the Arabian Peninsula countries with a view to informing targeted interventions for the region.

MethodThe study protocol was prepared and registered on PROSPERO, ID CRD42021190837. A database search including Gray literature and Google scholar was explored to identify 667 studies. Finally, 14 studies were considered relevant for meta-analysis, after removing 259 duplicates, 388 unrelated topics and 6 studies with full text examination. The Newcastle-Ottawa Scale quality assessment tool was used to assess the quality of the studies. The pooled prevalence was determined by using the random-effect model and the p- values of [≤] 0.05 were considered stastically significant to examine associations. Statistical heterogeneity amongst the studies was assessed by Cochrane chi-square and the I2 statistical test.

Main FindingsFrom the meta-analysis of 14 studies with 15,343 study participants, the pooled prevalence of khat chewing among pregnant women was 21.42%, 95% CI (14.49 - 29.29); (I 2=99.05% (p<0.0001). The results of the meta-analysis demonstrated that pregnant women who had a khat chewing partner [OR 6.50 (95% CI 5.01, 8.43)]; low educational status [OR 2.53 (95% CI 2.24 - 2.85)], lived in rural area [OR 1.69 (95% CI 1.52 - 1.88)] or had a low level of income [OR 1.70 (95% CI 1.55 - 1.87)] were significantly more likely to chew khat during pregnancy.

ConclusionThe prevalence of khat chewing amongst pregnant women in the Horn of Africa and the Arabian Peninsula has never been measured before and was found to be high. Partners khat chewing status, maternal low educational and economic status were the main factors associated with the problem. Designing intervention strategies to specifically target these risk factors and reduce the burden of the problem for women and their babies is urgently needed.


title: Association between household composition and severe COVID-19 outcomes in older people by ethnicity: an observational cohort study using the OpenSAFELY platform

abstract:
Ethnic differences in the risk of severe COVID-19 may be linked to household composition. We quantified the association between household composition and risk of severe COVID-19 by ethnicity for older individuals. With the approval of NHS England, we analysed ethnic differences in the association between household composition and severe COVID-19 in people aged 67 or over in England. We defined households by number of generations living together, and used multivariable Cox regression stratified by location and wave of the pandemic and accounted for age, sex, comorbidities, smoking, obesity, housing density and deprivation. We included 2 692 223 people over 67 years in wave 1 (01/02/2020-31/08/2020) and 2 731 427 in wave 2 (01/09/2020-31/01/2021). Multigenerational living was associated with increased risk of severe COVID-19 for White and South Asian older people in both waves (e.g. wave 2, 67+ living with 3 other generations vs 67+ year olds only: White HR 1{middle dot}61 95% CI 1{middle dot}38-1{middle dot}87, South Asian HR 1{middle dot}76 95% CI 1{middle dot}48-2{middle dot}10), with a trend for increased risks of severe COVID-19 with increasing generations in wave 2. Multigenerational living was associated with severe COVID-19 in older adults. Older South Asian people are over-represented within multigenerational households in England, especially in the most deprived settings. The number of generations in a household, number of occupants, ethnicity and deprivation status are important considerations in the continued roll-out of COVID-19 vaccination and targeting of interventions for future pandemics.

FundingThis research was funded in part, by the Wellcome Trust. For the purpose of open access, the author has applied a CC-BY public copyright licence to any Author Accepted Manuscript version arising from this submission.


title: Subcortical brain volumes in young infants exposed to antenatal maternal depression: Findings from a South African birth cohort

abstract:
BackgroundSeveral studies have reported enlarged amygdala and smaller hippocampus volumes in children and adolescents exposed to maternal depression. It is unclear whether similar volumetric differences are detectable in the infants first weeks of life, following exposure in utero. We investigated subcortical volumes in 2-to-6 week old infants exposed to antenatal maternal depression (AMD) from a South African birth cohort.

MethodsAMD was measured with the Beck Depression Inventory 2nd edition (BDI-II) at 28-32 weeks gestation. T2-weighted structural images were acquired during natural sleep on a 3T Siemens Allegra scanner. Subcortical regions were segmented based on the University of North Carolina neonatal brain atlas. Volumetric estimates were compared between AMD-exposed (BDI-II20) and unexposed (BDI-II<14) infants, adjusted for age, sex and total intracranial volume using analysis of covariance.

ResultsLarger volumes were observed in AMD-exposed (N=49) compared to unexposed infants (N=75) for the right amygdala (1.98% difference, p=0.039) and bilateral caudate nucleus (left: 5.78% difference, p=0.001; right: 6.06% difference, p<0.001). A significant AMD-by-sex interaction was found for the hippocampus (left: F(1,118)=4.80, p=0.030; right: F(1,118)=5.16, p=0.025), reflecting greater volume in AMD-exposed females (left: 5.09% difference, p=0.001, right: 3.53% difference, p=0.010), but not males.

ConclusionsVolumetric differences in subcortical regions can be detected in AMD-exposed infants soon after birth, suggesting structural changes may occur in utero. Female infants might exhibit volumetric changes that are not observed in male infants. The potential mechanisms underlying these early volumetric differences, and their significance for long-term child mental health, require further investigation.

category: pediatrics


title: How do primary care providers perceive their role at ensuring opioid safety? A qualitative exploration from those on the front lines

abstract:
IntroductionPrescribing naloxone is recommended by the Centers for Disease Control and Prevention to reduce the risk of death from an opioid overdose. Naloxone is rarely prescribed, even when indicated; improving our understanding of how primary care providers (PCP) perceive their role in naloxone prescribing is essential to increase opioid medication safety. The objectives of this study were to: (1) describe how PCPs perceive their role in prescribing naloxone for patients who are at high risk of an overdose and (2) describe PCP-reported barriers and facilitators of naloxone prescribing.

MethodsCurrently practicing providers completed semi-structured interviews, based on Theory of Planned Behavior, to understand their attitudes toward naloxone, their perceived role in naloxone prescribing, and facilitators/barriers to prescribing naloxone.

ResultsEleven interviews were conducted with physicians (n=2), physician assistants (n=8), and a nurse practitioner (n=1). Providers held generally positive attitudes toward naloxone as a  rescue medication. Negative attitudes toward naloxone include the perception of facilitating risky opioid use. Providers suggested that whomever prescribes the opioid pain medication should be primarily responsible for prescribing naloxone. Providers noted that stigma may prevent them from discussing naloxone during clinic visits. Increasing visit time and receiving support/education from organizational and professional society leadership were identified as important facilitators of naloxone prescribing.

ConclusionsWhile providers were aware of what naloxone was used for, there was reticence in discussing this medication with patients. Providers reported that whomever prescribes a pain medication should be primarily responsible for ensuring medication safety. If primary care organizations would like to improve opioid medication safety, ensuring that providers feel supported and receive needed education are essential.

category: primary care research


title: Disruption of long-term psychological distress trajectories during the COVID-19 pandemic: evidence from three British birth cohorts

abstract:
ImportanceMental health disorders were among the leading global contributors to years lived with disability prior to the COVID-19 pandemic onset, and growing evidence suggests that population mental health outcomes have worsened since the pandemic started. The extent that these changes have altered common age-related trends in psychological distress, where distress typically rises until mid-life and then falls in both sexes, is unknown.

ObjectiveTo analyse whether long-term pre-pandemic psychological distress trajectories have altered during the pandemic, and whether these changes have been different across generations and by sex.

DesignCross-cohort study with prospective data collection over a 40-year period (earliest time point: 1981; latest time point: February/March 2021).

SettingPopulation-based (adult general population), Great Britain.

ParticipantsMembers of three nationally representative birth cohorts which comprised all people born in Great Britain in a single week of 1946, 1958, or 1970, and who participated in at least one of the data collection waves conducted after the start of the pandemic (40.6%, 42.8%, 39.4%, respectively).

Exposure(s)Time, COVID-19 pandemic.

Main Outcome(s) and Measure(s)Psychological distress factor scores, as measured by validated self-reported questionnaires.

Results16,389 participants (2,175 from the 1946 birth cohort, 52.8% women; 7,446 from the 1958 birth cohort, 52.4% women; and 6,768 from the 1970 birth cohort, 56.2% women) participated in the study. By September/October 2020, psychological distress levels had reached or exceeded the levels of the peak in the pre-pandemic life-course trajectories, with larger increases in younger cohorts: Standardised Mean Differences (SMD) and 95% confidence intervals (CIs) of -0.02 [-0.07, 0.04], 0.05 [0.02, 0.07], and 0.09 [0.07, 0.12] for the 1946, 1958, and 1970 birth cohorts, respectively. Increases in distress were larger among women than men, widening the pre-existing inequalities observed in the pre-pandemic peak and in the most recent pre-pandemic assessment.

Conclusions and RelevancePre-existing long-term psychological distress trajectories of adults born between 1946 and 1970 were disrupted during the COVID-19 pandemic, particularly among women, who reached the highest levels ever recorded in up to 40 years of follow-up data. This may impact future trends of morbidity, disability, and mortality due to common mental health problems.

category: psychiatry and clinical psychology


title: The impact of sexual violence in mid-adolescence on girls' mental health: evidence from a longitudinal population-based study

abstract:
BackgroundA large gender gap appears in internalising mental health during adolescence. There is little high-quality longitudinal population-based research investigating the role of sexual violence experiences, which are disproportionately experienced by females. This study estimates the impact of sexual violence experiences in adolescent girls on mental ill-health.

MethodsLongitudinal data from girls in the UK Millennium Cohort Study are used. The impact of sexual violence experiences on psychological distress, self-harm and attempted suicide at age 17 is examined using both multivariable confounder adjusted and propensity matching approaches.

FindingsThe analytic samples for multivariable and matched analyses were, respectively, 5,134 and 4,355 participants. In the final adjusted model, sexual violence was associated with greater mean psychological distress (mean difference 2.23 [1.67 - 2.79])), and higher risk of high distress (RR 1.74 [1.44 - 2.09]), self-harming (RR 2.04 [1.70 - 2.45]), and attempting suicide (RR 2.26 [1.64 - 3.11]) at age 17 years. Similar results were found for the matched analyses for all mental health outcomes: psychological distress (mean difference 1.97 [1.58 - 2.36]; RR 1.60 [1.41 - 1.81]), self-harm (RR 1.64 [1.48 - 1.82]), and attempted suicide (RR 1.81 [1.47 - 2.22]). Estimates of population attributable fractions suggested that, in a scenario with no sexual violence, we could expect 25-37% fewer incident mental health problems at this age.

InterpretationOur findings highlight the substantial role of sexual violence experiences in the poorer mental health outcomes experienced by adolescent girls and the substantial changes needed at societal and policy levels to prevent sexual violence and its impacts.

FundingMedical Research Council.


title: Adults' self-reported barriers and enablers to riding a bike for transport: a systematic review

abstract: Riding a bike for transport purposes is an effective way to improve population and environmental health. Despite this, participation levels in many countries are low. Identifying the barriers and enablers to riding a bike for transport is essential to developing interventions that encourage bike riding. In this mixed-methods systematic review, we aimed to identify the perceived barriers and enablers to adults riding a bike for transport in Organisation for Economic Development (OECD) countries. A systematic database search was conducted to identify relevant peer-reviewed and grey literature. Fifty-five papers/reports met eligibility criteria. There were 34 barriers and 21 enablers identified. The leading barriers related to riding on the road alongside motor vehicles. Other factors identified included the provision and quality of cycling infrastructure, personal factors such as physical fitness, attitudinal factors such as community perceptions of cyclists, and environmental factors. While this review highlights the complexity of factors that influence the uptake of riding a bike for transport, many of the leading factors could be overcome through the provision of high-quality protected infrastructure for bike riders. Other interventions to address other known barriers and enablers are needed to increase the uptake of bike riding.


title: Prosocial motivation for vaccination

abstract: Vaccination has both private and public benefits. We ask whether social preferences--concerns for the well-being of other people--influence ones decision regarding vaccination. We measure these social preferences for 549 online subjects: We give each subject $4 to play a public-good game and make contributions to public welfare. To the extent that one gets vaccinated out of concern for the health of others, contribution in this game is analogous to an individuals decision to obtain vaccination. We collect COVID-19 vaccination history separately to avoid experimenter-demand effects. We find a strong result: Contribution in the public-good game is associated with greater demand to voluntarily receive a first dose, and thus also to vaccinate earlier. Compared to a subject who contributes nothing, one who contributes the maximum ($4) is 48% more likely to obtain a first dose voluntarily in the four-month period that we study (April through August 2021). People who are more pro-social are indeed more likely to take a voluntary COVID-19 vaccination.


title: ClearSpeechTogether: a rater blinded, single, controlled feasibility study of speech intervention for speakers with progressive ataxia

abstract:
BackgroundProgressive ataxias frequently lead to speech disorders and consequently impact on communication participation and psychosocial wellbeing. Whilst recent studies demonstrate the potential for improvements in these areas, these treatments generally require intensive input which can reduce acceptability of the approach.

A new model of care - ClearSpeechTogether - is proposed which maximises treatment intensity whilst minimising demands on clinician. This study aimed to establish feasibility and accessibility of this approach and at the same time determine the potential benefits and adverse effects on people with progressive ataxias.

MethodThe study targeted people with progressive ataxia and mild-moderate speech and gross motor impairment. ClearSpeechTogether consisted of four individual sessions over two weeks followed by 20 patient-led group sessions over four weeks. All sessions were provided online. Quantitative and qualitative data were collected for evaluation.

ResultsNine participants completed treatment. Feasibility and acceptability were high and no adverse effects were reported. Statistical tests found significantly reduced vocal strain, improved intelligibility for reading, and increased participation and confidence. Participant interviews highlighted the value of group support, from psychosocial perspectives and in supporting speech strategy internalisation and generalisation.

DiscussionClearSpeechTogether presented an effective intervention in a small group of people with progressive ataxia. It matched or exceeded the outcomes previously reported for intensive, individual therapy while minimising clinician time demands. Furthermore, its unique peer led group intervention design appeared effective in addressing intractable psychosocial issues. ClearSpeechTogether is potentially cost-effective, providing intensive delivery with few clinician sessions, thus maximising the input available from health care providers.

category: rehabilitation medicine and physical therapy


title: Comparison of immunogenicity and safety of inactivated, adenovirus-vectored and heterologous adenovirus-vectored/mRNA vaccines in patients with systemic lupus erythematosus and rheumatoid arthritis: a prospective cohort study

abstract:
BackgroundImpaired immune response to COVID-19 vaccines have been observed in autoimmune rheumatic disease patients. Determining the most effective and safe vaccine regimen is critically needed in such a population. We aim to compare the immunogenicity and safety of three COVID-19 vaccine regimens in patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA).

MethodsSLE and RA patients aged 18-65 years who received inactivated (CoronaVac or COVILO), adenovirus-vectored (AZD1222), or heterogeneous (AZD1222/BNT162b2) vaccines were enrolled. Humoral and cellular immune responses were assessed at day 28 after the second vaccination. This was performed using the serum binding antibody level against receptor-binding domain of the SARS-CoV-2 spike protein (anti-RBD Ig) and IFNy-ELISpot assay (ELISpot) respectively. Reactogenicity was reviewed on day 7 following each vaccination. Disease activity was assessed before and on day 28 after the second vaccination.

ResultsThe cohort consisted of 94 patients (64 SLE and 30 RA). Inactivated, AZD1222, and AZD1222/BNT162b2 vaccines were administered to 23, 43, and 28 patients, respectively. Anti-RBD titers were lowest in the inactivated vaccine group (2.84 AU/mL; 95% CI 0.96-8.44), followed by AZD1222 (233.7 AU/mL; 95% CI 99.0 - 505.5) and AZD1222/BNT162b2 (688.6 AU/mL; 95% CI 271 - 1745), p 0<0.0001. After adjusting for relevant factors, the inactivated vaccine was associated with the lowest humoral response, while adenovirus-vectored/mRNA vaccine was the highest. The proportion of positive ELISpot test was also lowest in the inactivated vaccine group (27%), followed by the adenovirus-vectored vaccine (67%), and adenovirus-vectored/mRNA vaccine (73%)(p = 0.03). All types of vaccine were well-tolerated. There was no flare of autoimmune disease post-vaccination.

ConclusionAdenovirus-vectored and adenovirus-vectored/mRNA vaccines elicited a stronger humoral and cellular immune response than inactivated vaccines, suggesting that they may be more suitable in SLE and RA patients receiving immunosuppressive therapy.

category: rheumatology


title: Ambulatory detection of isolated REM sleep behavior disorder combining actigraphy and clinical questionnaire

abstract:
ImportanceIsolated rapid-eye-movement sleep behavior disorder (iRBD) is in most cases a prodrome of neurodegenerative synucleinopathies, affecting 1-2 % of middle-aged and older adults, however accurate ambulatory diagnostic methods are lacking. Questionnaires lack specificity in non-clinic populations. Wrist actigraphy can detect characteristic features in individuals with RBD, however high frequency actigraphy has rarely been used.

ObjectiveTo develop a machine learning classifier using high frequency (1-second resolution) actigraphy and a short patient survey for detecting iRBD with high accuracy and precision.

DesignAnalysis of [≥]7 nights home actigraphy data and 9-item questionnaire (RBD Innsbruck inventory and 3 prodromal synucleinopathy symptoms) in a dataset including patients with iRBD, sleep clinic patients with other sleep disorders, and community controls.

SettingSingle-center study at the Stanford Sleep Center.

ParticipantsOf 108 participants, 83 completed the study, including 41 definitive iRBD cases, and 42 age- and sex-matched controls, including 21 sleep clinic patients with RBD mimics (other parasomnias, sleep apnea, periodic limb movements) or other sleep disorders, and 21 community controls.

ExposureNo intervention

Main OutcomesSensitivity, specificity, accuracy, and precision of classifiers based on actigraphy, on questionnaire data, and both.

ResultsThe actigraphy classifier achieved 95.1% (95 % CI: 88.1 - 98.7) sensitivity and 92.9% (95 % CI: 84.9 - 97.3) precision using all nights recorded, and 88.5 % sensitivity and 90.1 % precision over one night, with performance plateauing after 7 to 10 nights. The questionnaire classifier achieved 91.6 % accuracy and 92.5 % precision, exceeding performance of questionnaire alone. Concordant predictions between actigraphy and questionnaire reached specificity and precision of 100 % (95 % CI: 95.7 - 100.0) with 87.8 % sensitivity (95 % CI: 79.0 - 94.1).

Conclusions and RelevanceActigraphy detected iRBD with high accuracy in a mixed clinical and community cohort. Combined with a short clinical questionnaire, performance reached 100% precision and 87.8% sensitivity. This fully remote procedure can be used to diagnose iRBD in specialty outpatient settings. This cost-effective method has potential for large scale screening of iRBD in the general population.

Key pointsO_ST_ABSQuestionC_ST_ABSCan ambulatory actigraphy and a short prodromal synucleinopathy questionnaire increase the accuracy of RBD screening?

FindingIn a dataset of 41 iRBD cases and 42 clinic and community controls, the combination of actigraphy and a 9-item questionnaire reached specificity of 100 % (95% CI: 95.7 - 100.0) and sensitivity of 87.8 % (95% CI: 79.0 - 94.1).

MeaningCombination of ambulatory actigraphy and questionnaire can be used in both general and specialty outpatient settings for detecting individuals at high risk of having iRBD. This cost-effective, multimodal strategy has potential for large scale screening in the general population.

category: neurology


title: Psychometric properties of the Copenhagen Burnout Inventory (CBI) in Italian physicians

abstract:
BackgroundAssessing burnout in physicians is relevant as it can adversely affect both their mental and physical health by also decreasing the quality of care, especially since the onset of the COVID-19 pandemic. This study aimed at standardizing the Copenhagen Burnout Inventory (CBI), a psychometrically sound, worldwide-spread tool, in Italian physicians.

MethodsNine-hundred and fifteen Italian physicians were web-administered the CBI, Patient Health Questionnaire-8 (PHQ-8), Generalized Anxiety Disorder-7 (GAD-7) and General Self-Efficacy Scale (GSE). The present CBI is a self-report questionnaire including 18 Likert items (range=19-90) assessing Personal, Work-related and Client-related Burnout. Client-related adaptation was performed. Construct validity, factorial structure (Confirmatory Factor Analysis) and internal consistency were tested. Diagnostic accuracy was assessed simultaneously against the PHQ-8, GAD-7 and GSE.

ResultsAll CBI measures yielded optimal internal consistency (Cronbachs =.90-.96). The CBI met its original three-factor model (CFI=.94; TLI=.93; RMSEA=.09; SRMR=.04), was positively related with the PHQ-8 (r=.76) and GAD-7 (r.=73), whereas negatively with the GSE (r=-.39), and yielded optimal diagnostics (AUC=.93; sensitivity=.91 and specificity=.85 at the optimal cut-off of 69/90).

DiscussionThe CBI is a valid, reliable and normed tool to assess burnout levels in physicians, whose use is encouraged in both clinical practice and research as being short-lived, easy to use and openly accessible.

category: occupational and environmental health


title: Strategies to investigate and mitigate collider bias in genetic and Mendelian randomization studies of disease progression

abstract: Genetic studies of disease progression can be used to identify factors that may influence survival or prognosis, which may differ from factors which influence on disease susceptibility. Studies of disease progression feed directly into therapeutics for disease, whereas studies of incidence inform prevention strategies. However, studies of disease progression are known to be affected by collider (also known as "index event") bias since the disease progression phenotype can only be observed for individuals who have the disease. This applies equally to observational and genetic studies, including genome-wide association studies and Mendelian randomization analyses. In this paper, our aim is to review several statistical methods that can be used to detect and adjust for index event bias in studies of disease progression, and how they apply to genetic and Mendelian Randomization studies using both individual and summary-level data. Methods to detect the presence of index event bias include the use of negative controls, a comparison of associations between risk factors for incidence in individuals with and without the disease, and an inspection of Miami plots. Methods to adjust for the bias include inverse probability weighting (with individual-level data), or Slope-hunter and Dudbridges index event bias adjustment (when only summary-level data are available). We also outline two approaches for sensitivity analysis. We then illustrate how three methods to minimise bias can be used in practice with two applied examples. Our first example investigates the effects of blood lipid traits on mortality from coronary heart disease, whilst our second example investigates genetic associations with breast cancer mortality.

category: genetic and genomic medicine


title: Unhealthy Lifestyle Mediates the Adverse Influence of Childhood Traumas on Acceleration of Aging: Analysis of 110,596 UK Biobank Participants

abstract:
BackgroundAccelerated aging makes adults more vulnerable to chronic diseases and death. This study evaluates the association of childhood traumas with a phenotypic aging measure that captures mortality and morbidity risk, and the role of unhealthy lifestyle in mediating these associations.

MethodsWe assembled data from 110,596 members of the UK Biobank aged 40-69 years who participated in the baseline survey (2006-2010) and online mental health questionnaire (2016). A phenotypic aging measure--Phenotypic Age Acceleration (PhenoAgeAccel) was calculated, with the higher value indicating the acceleration of aging. Body mass index, smoking status, alcohol consumption, physical activity, and diet were combined to construct an unhealthy lifestyle score (range: 0-5). Childhood traumas including physical neglect, emotional neglect, sexual abuse, physical abuse, and emotional abuse were assessed. General linear regression and formal mediation analysis were performed.

ResultsEach individual childhood trauma and cumulative childhood traumas were significantly associated with PhenoAgeAccel. For instance, compared with participants who did not experience childhood traumas, those who experienced four ({beta}=0.292, standard error [SE]: 0.091) or five childhood traumas had higher PhenoAgeAccel ({beta}=0.669, SE: 0.169) in fully adjusted models. The formal mediation analysis revealed that unhealthy lifestyle partially mediated the associations of childhood traumas with PhenoAgeAccel (26.1%-42.6%).

ConclusionsIn a large sample from UKB, childhood traumas were positively associated with acceleration of aging; and more importantly, unhealthy lifestyle partially mediated these associations. These findings reveal a novel pathway from childhood traumas to late-life health through lifestyle and underscore the potential of more psychological strategies beyond lifestyle interventions to promote healthy aging.

category: geriatric medicine


title: Examining the association between genetic risk for depression, wellbeing and schizophrenia, and proximity to greenspace

abstract:
It is unclear whether associations between between greenspace and mental health reflects those with better mental health seeking out greener environments.

To examine this we 1) test associations between depression, wellbeing and schizophrenia polygenic scores (PGS) with two greenspace measures in UK Biobank (N=238,306 and 293,922), 2) estimate multilevel-models (MLM), clustering individuals by local geography and, 3) conduct one-sample Mendelian randomisation (MR) to estimate causal effects.

Depression and schizophrenia PGS were associated with lower greenspace, whilst wellbeing PGS was associated with higher greenspace. Locally-clustered MLM demonstrated attenuation for the individual wellbeing PGS association and a reversal of effect for the schizophrenia PGS association. MR revealed evidence of a causal effect of increased depression liability on decreased greenspace.

Therefore, greater liability to depression may cause selection into less green neighbourhoods. Our results also highlight how individual-level PGS associations can be biased by contextual, between-area differences in outcome.


title: Risks and challenges in COVID-19 infection prevention and control in a hospital setting: perspectives of healthcare workers in Thailand

abstract: In hospital settings, awareness of, and responsiveness to, COVID-19 are crucial to reducing the risk of transmission among healthcare workers (HCWs) and protecting them from infection. Healthcare professionals can offer insights into the practicalities of infection prevention and control measures and on how the protective equipment and training could best be delivered during the pandemic. This study aimed to inform the development of future recommendations to optimise compliance with appropriate use of these measures, and to improve the guidance to reduce their risk of the disease. Drawing on in-depth interviews with HCWs in a hospital in Thailand, several factors influence the use of multiple prevention measures: concerns about infection, availability of the equipment supply, barriers to work performance, and physical limitations in the hospital setting. Setting a ventilated outdoor space for screening and testing, and interaction through mobile technology, were perceived to reduce the transmission risk for staff and patients. Adequate training, clear guidelines, streamlined communications, and management support are crucial to encourage appropriate use of, and adherence to, implementation of infection prevention and control (IPC) measures among HCW. Further study should explore the perceptions and experience of health professionals in local health facilities and community-based workers during the pandemic, particularly in resource-limited settings.


title: Effectiveness of the neutralizing antibody sotrovimab among high-risk patients with mild to moderate SARS-CoV-2 in Qatar

abstract: Effectiveness of sotrovimab against severe, critical, or fatal COVID-19 was investigated in Qatar using a case-control study design at a time when BA.2 Omicron subvariant dominated incidence. Adjusted odds ratio of progression to severe, critical, or fatal COVID-19, comparing those sotrovimab-treated to those untreated, was 2.67-fold higher (95% CI: 0.60-11.91).


title: A protein signature associated with active tuberculosis identified by plasma profiling and network-based analysis

abstract:
ObjectivesTuberculosis (TB) is a bacterial infectious disease caused by Mycobacterium tuberculosis. Annually, an estimated 10 million people are diagnosed with active TB, and approximately 1.4 million dies of the disease. If left untreated, each person with active TB will infect 10 to 15 new individuals every year. Therefore, interrupting disease transmission by accurate early detection and diagnosis, paired with appropriate treatment is of major importance. In this study, we aimed to identify biomarkers associated with the development of active TB that can then be further developed for clinical testing.

MethodsWe assessed the relative plasma concentration of 92 proteins associated with inflammation in individuals with active TB (n=19), latent TB (n=13), or healthy controls (n=10). We then constructed weighted protein co-expression networks to reveal correlations between protein expression profiles in all samples. After clustering the networks into four modules, we assessed their association with active TB.

ResultsOne module consisting of 16 proteins was highly associated with active TB. We used multiple independent transcriptomic datasets from studies investigating respiratory infections and non-TB diseases. We then identified and removed genes encoding proteins within the module that were low expressed in active TB or associated with non-TB diseases, resulting in a 12-protein plasma signature associated with active TB.

ConclusionWe identified a plasma protein signature that is highly enriched in patients with active TB but not in individuals with latent TB or healthy controls and that also had minimal cross-reactivity with common viral or bacterial lower respiratory tract infections.


title: Usage and awareness of antiviral medications for COVID-19

abstract: We surveyed people that recently tested positive for SARS-CoV-2 to assess the frequency and correlates of early treatment seeking behavior. Among high risk respondents, 66.0% were aware of treatment for COVID-19 and 36.3% had sought treatment, however only 1.7% reported use of an antiviral for SARS-CoV-2 infection. More public outreach is needed to raise awareness of the benefits of treatment for COVID-19.


title: Radiologist observations of chest X-rays (CXR) predict sputum smear microscopy status in TB Portals, a real-world database of tuberculosis (TB) cases

abstract: The Tuberculosis (TB) Portals is an international program of 14 countries connecting clinical, genomic, and radiologist specialists to develop an openly available repository of deidentified TB cases with multi-modal data such as case clinical characteristics, pathogen genomics, and radiomics. This real-world data resource contains over 4000 TB cases, principally drug resistant cases, with over 4000 chest X-rays (CXR) images. The scope of curated data offers a case-focused perspective into the drivers of disease incorporating the chronological context of the presented CXR data. Here, we analyze a cohort consisting of new TB cases to understand the relationship between baseline sputum microscopy status and nearby Chest X rays images. The Timika score, a lung biomarker of disease severity, was derived for each CXR using available radiologist observations. The Timika score along with the radiologist observations were compared for predictive performance of baseline sputum microscopy status. Baseline sputum microscopy status is a useful marker of pre-treatment disease severity and infectiousness. The modeling results support that both the radiologist observations as well as Timika score are predictive of smear status and that Timika score performs similarly to the top 5 radiologist features by feature selection. Moreover, inferential statistical analysis identifies the factors having the greatest association with sputum smear positivity such as presence of radiologist observations in both lungs, presence of cavity, presence of nodule, and Timika score itself. The results are consistent with prior reports showing Timika Score utility for predicting baseline sputum smear and disease status. We report testing of Timika Score on the largest, openly available real-world dataset of TB cases that can serve as a reference to explore extant and new TB disease severity scores bridging radiological, microbiological, and clinical data. To illustrate, we visualize Timika score from images in our database with other cases characteristics demonstrating that this score captures lung biomarker status consistent with known clinical risk factors.


title: A statistical genomics framework to trace bacterial genomic predictors of clinical outcomes in Staphylococcus aureus bacteraemia

abstract: Outcomes for patients with severe bacterial infections are determined by the interplay between host, pathogen, and treatments. Most notably, patient age and antibiotic resistance contributes significantly to poor outcomes. While human genomics studies have provided insights into the host genetic factors impacting outcomes of Staphylococcus aureus infections, comparatively little is known about S. aureus genotypes and disease severity. Building on the idea that bacterial pathoadaptation is a key driver of clinical outcomes, we develop a new genome-wide association study (GWAS) framework to identify adaptive bacterial mutations associated with clinical treatment failure and mortality in three large and independent S. aureus bacteraemia cohorts, comprising 1358 episodes. We discovered S. aureus loci with previously undescribed convergent mutations linked to both poorer infection outcomes and reduced susceptibility to vancomycin. Our research highlights the potential of vancomycin-selected mutations and vancomycin MIC as key explanatory variables to predict SAB severity. The contribution of bacterial variation was much lower for clinical outcomes (heritability < 5%), however, GWAS allowed us to identify additional, MIC-independent candidate pathogenesis loci. Using supervised machine-learning, we were able to quantify the predictive potential of these adaptive S. aureus signatures, along with host determinants of bacteraemia outcomes. The statistical genomics framework we have developed is a powerful means to capture adaptive mutations and find bacterial factors that influence and predict severe infections. Our findings underscore the importance of systematically collected, rich clinical and microbiological data to understand bacterial mechanisms promoting treatment failure.


title: COVID-19 patients share common, corticosteroid-independent features of impaired host immunity to pathogenic molds

abstract: Patients suffering from coronavirus disease-2019 (COVID-19) are at high risk for deadly secondary fungal infections such as COVID-19-associated pulmonary aspergillosis (CAPA) and COVID-19-associated mucormycosis (CAM). Despite this clinical observation, direct experimental evidence for severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2)-driven alterations of antifungal immunity is scarce. Using an ex-vivo whole blood (WB) stimulation assay, we challenged blood from twelve COVID-19 patients with Aspergillus fumigatus and Rhizopus arrhizus antigens and studied the expression of activation, maturation, and exhaustion markers, as well as cytokine secretion. Compared to healthy controls, T-helper cells from COVID-19 patients displayed increased expression levels of the exhaustion marker PD-1 and weakened A. fumigatus- and R. arrhizus-induced activation. While baseline secretion of proinflammatory cytokines was massively elevated, WB from COVID-19 patients elicited diminished release of T-cellular (e.g., IFN-{gamma}, IL-2) and innate immune cell-derived (e.g., CXCL9, CXCL10) cytokines in response to A. fumigatus and R. arrhizus antigens. Additionally, samples from COVID-19 patients showed deficient granulocyte activation by mold antigens and reduced fungal killing capacity of neutrophils. These features of weakened anti-mold immune responses were largely decoupled from COVID-19 severity, the time elapsed since diagnosis of COVID-19, and recent corticosteroid uptake, suggesting that impaired anti-mold defense is a common denominator of the underlying SARS-CoV-2 infection. Taken together, these results expand our understanding of the immune predisposition to post-viral mold infections and could inform future studies of immunotherapeutic strategies to prevent and treat fungal superinfections in COVID-19 patients.


title: Epidemiological investigation of the COVID-19 outbreak in Vellore district in South India using Geographic Information Surveillance (GIS)

abstract: Objectives: Geographical Information Surveillance (GIS) is an advanced digital technology tool that maps location-based data and helps in epidemiological modeling. We applied GIS to analyze patterns of spread and hotspots of COVID-19 cases in Vellore district in South India. Methods: Laboratory-confirmed COVID-19 cases from the Vellore district and neighboring taluks from March 2020 to June 2021 were geo-coded and spatial maps were generated. Time trends exploring urban-rural burden with an age-sex distribution of cases and other variables were correlated with outcomes. Results: A total of 45,401 cases of COVID-19 were detected with 20730 cases during the first wave and 24671 cases during the second wave. The overall incidence rates of COVID-19 were 462.8 and 588.6 per 100,000 populations during the first and second waves respectively. The pattern of spread revealed epicenters in densely populated urban areas with radial spread sparing rural areas in the first wave. The case fatality rate was 1.89% and 1.6% during the first and second waves that increased with advancing age. Conclusions: Modern surveillance systems like GIS can accurately predict the trends and pattern of spread during future pandemics. A real-time mapping can help design risk mitigation strategies thereby preventing the spread to rural areas.


title: Regional replacement of SARS-CoV-2 variant BA.1 with BA.2 as observed through wastewater surveillance

abstract:
An understanding of circulating SARS-CoV-2 variants can inform pandemic response, vaccine development, disease epidemiology, and use of monoclonal antibody treatments. We developed custom assays targeting characteristic mutations in SARS-CoV-2 variants Omicron BA.1 and BA.2 and confirmed their sensitivity and specificity in silico and in vitro. We then applied these assays to daily wastewater solids samples from eight publicly owned treatment works in the greater Bay Area of California, USA, over four months to obtain a spatially and temporally intensive data set. We documented regional replacement of BA.1 with BA.2 in agreement with, and ahead of, clinical sequencing data. This study highlights the utility of wastewater surveillance for real time tracking of SARS-CoV-2 variant circulation.

SynopsisWastewater surveillance was used to document regional emergence of SARS-CoV-2 variant Omicron BA.2 ahead of clinical surveillance.

Graphical Abstract

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title: Snotwatch COVID-Toes: An ecological study of chilblains and COVID-19 diagnoses in Victoria, Australia

abstract:
BackgroundThe COVID-19 pandemic has caused widespread illness with varying clinical manifestations. One less-commonly-reported presentation of COVID-19 infection is chilblain-like lesions.

AimsWe conducted an ecological analysis of chilblain presentations in comparison with confirmed and suspected COVID-19 infections in a primary care setting to establish that a relationship exists between the two.

Study DesignOur study collated data from three Primary Health Networks across Victoria, Australia, from 2017-2021, to understand patterns of chilblain presentations prior to and throughout the pandemic. Using a zero-inflated negative binomial regression analysis, we estimated the relationship between local minimum temperature, COVID-19 infections and the frequency of chilblain presentations.

ResultsWe found a 5.72 risk ratio of chilblain incidence in relation to COVID-19 infections and a 3.23 risk ratio associated with suspected COVID-19 infections. COVID-19 infections were also more strongly associated with chilblain presentations in 0-16-year-olds throughout the pandemic in Victoria.

ConclusionOur study statistically demonstrates that chilblains are significantly associated with COVID-19 infections in a primary care setting. This has major implications for clinicians aiming to diagnose COVID-19 infections or determine the cause of a presentation of chilblains. Additionally, we demonstrate the utility of large-scale primary care data and its potential application to monitoring the spread of COVID-19 infections across the state, supporting current epidemiological efforts for COVID-19 tracking.


title: Monitoring One Heart to Help Two: Heart Rate Variability and Resting Heart Rate using Wearable Technology in Active Women Across the Perinatal Period

abstract:
BACKGROUNDCharacterizing normal heart rate variability (HRV) and resting heart rate (RHR) in healthy women over the course of a pregnancy allows for further investigation into disease states, as pregnancy is the ideal time period for these explorations due to known decreases in cardiovascular health. To our knowledge, this is the first study to continuously monitor HRV and RHR using wearable technology in healthy pregnant women.

METHODSA total of eighteen healthy women participated in a prospective cohort study of HRV and RHR while wearing a WHOOP(R) strap prior to conception, throughout pregnancy, and into postpartum. The study lasted from March 2019 to July 2021; data were analyzed using linear mixed models with splines for non-linear trends.

RESULTSEighteen women were followed for an average of 405.8 days (SD=153). Minutes of logged daily activity decreased from 28 minutes pre-pregnancy to 14 minutes by third trimester. A steady decrease in daily HRV and increase in daily RHR were generally seen during pregnancy (HRV Est. = -0.10, P<0.0001; RHR Est. = 0.05, P<0.0001). The effect was moderated by activity minutes for both HRV and RHR. However, at 49 days prior to birth there was a reversal of these indices with a steady increase in daily HRV (Est.=0.38, P< 0.0001) and decrease in daily RHR (Est. = -0.23, P< 0.0001), regardless of activity level, that continued into the postpartum period.

CONCLUSIONSIn healthy women, there were significant changes to HRV and RHR throughout pregnancy, including a rapid improvement in cardiovascular health prior to birth that was not otherwise known. Physical activity minutes of any type moderated the known negative consequences of pregnancy on cardiovascular health. By establishing normal changes using daily data, future research can now evaluate disease states as well as physical activity interventions during pregnancy and their impact on cardiovascular fitness.

category: obstetrics and gynecology


title: Computational analysis of peripheral blood smears detects disease-associated cytomorphologies

abstract: Many hematological diseases are characterized by altered abundance and morphology of blood cells and their progenitors. Myelodysplastic syndromes (MDS), for example, are a type of blood cancer manifesting via a range of cytopenias and dysplastic changes of blood and bone marrow cells. While experts analyze cytomorphology to diagnose MDS, similar alterations can be observed in other conditions such as haematinic deficiency anemias, and definitive diagnosis requires complementary information such as blood counts, karyotype and molecular testing. However, recent works demonstrated that computational analysis of bone marrow slides predicts not only MDS or AML but also the presence of specific mutations. Here, we present and make available Haemorasis, a computational method that detects and characterizes white and red blood cells (WBC and RBC, respectively) in peripheral blood slides, and apply it to over 300 individuals with different conditions (SF3B1-mutant and SF3B1-wildtype MDS, megaloblastic anemia and iron deficiency anemia), where Haemorasis detects over half a million WBC and millions of RBC. We then show how these large sets of cell images can be used in diagnosis and prognosis, whilst identifying novel associations between computational morphotypes and disease. We find that hypolobulated neutrophils and large RBC are characteristic of SF3B1-mutant MDS, and, while prevalent in both iron deficiency and megaloblastic anemia, hyperlobulated neutrophils are larger in the latter. Finally, we externally validate these methods, showing they generalize to other centers and scanners.

category: hematology


title: Japanese Encephalitis emergence in Australia: the potential population at risk

abstract: In Australia, Japanese Encephalitis virus circulated in tropical north Queensland between 1995 and 2005. In 2022, a dramatic range expansion across the southern states resulted in 24 confirmed human cases and three deaths. We discuss the outbreak drivers and estimate the potential size of the human population at risk.


title: Estimation of the Ascertainment Bias in Covid Case Detection During the Omicron Wave

abstract: Covid cases in the general population have been historically underreported due to a variety of reasons including limited access to PCR testing at the start of the pandemic, lack of nation-wide surveillance testing, and discouraged testing unless symptomatic. Concerns about underreporting have increased during the Omicron surge due to the expanded use of at-home rapid tests which are not required to be officially reported. For the state of Illinois, we have found that reported cases constituted only 50%-70% of the actual cases during the pre-Omicron waves (August 2020-December 2021). During the first Omicron (BA1) wave, this fraction dropped to 20-25% (i.e., only 1 in 4 to 1 in 5 cases are reported). During the ongoing second Omicron (BA2) surge, this fraction has further decreased to 10-15% (i.e., only 1 in 7 to 1 in 10 cases are reported). These estimates have important implications on understanding the extent of the Omicron surge at the state and national levels.

category: epidemiology


title: Asian Lung Cancer Absolute Risk Models for lung cancer mortality based on China Kadoorie Biobank

abstract:
BackgroundLung cancer is the leading cause of cancer mortality globally. Early detection through screening can markedly improve prognosis and prediction models can identify high-risk individuals for screening. However, most models have been developed in North American cohorts of smokers and much less is known about risk factors for never-smokers, which represent a growing proportion of lung cancers, particularly for Asian populations.

MethodsBased on the China Kadoorie Biobank, a population-based prospective cohort study of 512,714 adults age 30-79 recruited between 2004-2008 with up to 12 years of follow-up, we built an Asian Lung Cancer Absolute Risk Model (ALARM) for lung cancer mortality using flexible parametric survival models, separately for ever- and never-smokers. Model performance was evaluated in a 25% held-out test set using the time-dependent area under the receiver operating characteristic curve (AUC) and by comparing the model-predicted and observed risks for agreement (i.e. calibration).

ResultsPredictors assessed in the never-smoker lung cancer mortality model were age, sex, household income, lung function, history of emphysema/bronchitis, family history of cancer, personal cancer history, BMI, passive smoking, and indoor air pollution. The ever-smoker model additionally assessed smoking status (former vs. current), duration, intensity, and years since cessation. The 5-year AUC based on the hold-out test set for the never and ever-smoker models were 0.77 (95% CI: 0.73-0.81) and 0.81 (95% CI: 0.79-0.84), respectively. The maximum 5-year risk for never and ever smokers were 2.7% and 14.0%, respectively.

ConclusionsThis study is among the first to develop and test risk models specifically for Asian population, separately for never (ALARM-NS) and ever-smokers (ALARM-ES). Our models identify Asian never- and ever-smokers at high-risk of death due to lung cancer with a high degree of accuracy, and may identify those with risks exceeding common eligibility thresholds who would likely benefit from lung cancer screening.


title: Estimating the distribution of COVID-19-susceptible, -recovered, and -vaccinated individuals in Germany up to April 2022

abstract: After having affected the population for two years, the COVID-19 pandemic has reached a phase where a considerable number of people in Germany have been either infected with a SARS-CoV-2 variant, vaccinated, or both. Yet the full extent to which the population has been in contact with either virus or vaccine remains elusive, particularly on a regional level, because (a) infection counts suffer from under-reporting, and (b) the overlap between the vaccinated and recovered subpopulations is unknown. Since previous infection, vaccination, or especially a combination of both reduce the risk of severe disease, a high share of individuals with SARS-CoV-2 immunity lowers the probability of severe outbreaks that could potentially overburden the public health system once again, given that emerging variants do not escape this reduction in susceptibility. Here, we estimate the share of immunologically naive individuals by age group for each of the 16 German federal states by integrating an infectious disease model based on weekly incidences of SARS-CoV-2 infections in the national surveillance system and vaccine uptake, as well as assumptions regarding under-ascertainment. We estimate a median share of 7.0% of individuals in the German population have neither been in contact with vaccine nor any variant as of March 31, 2022 (quartile range [3.6%- 9.8%]). For the adult population at higher risk of severe disease, this figure is reduced to 3.5% [1.3%-5.5%] for ages 18-59 and 4.3% [2.7%-5.8%] for ages 60 and above. However, estimates vary between German states mostly due to heterogeneous vaccine uptake. Excluding Omicron infections from the analysis, 16.1% [14.0%-17.8%] of the population in Germany, across all ages, are estimated to be immunologically naive, highlighting the large impact the Omicron wave had until the beginning of spring in 2022.


title: Human health effects of recycling and reusing plastic packaging in the food system: a systematic review and meta-analysis of life cycle assessments.

abstract:
Circular strategies, including recycling and reuse of food packaging, are critical responses to the plastic pollution crisis and could provide co-benefits and trade-offs for human health. Our meta-analysis of life cycle assessment (LCA) data quantifies possible health effects using Disability-Adjusted Life Years (DALYs) mediated by climate change, ozone, air pollution, toxicity, and water scarcity. We found strong evidence for reduced health risks with both a higher percentage of recycled content and a greater end-of-life recycling rate, resulting in around a day of healthy life saved per tonne of plastic packaging recycled. On average, reusable packaging reduced the health impacts associated with single use plastics after 30 uses, which is unlikely reflected in current consumer behaviour. Data from low- and middle-income countries, and greater use of health indicators in LCA, are urgently needed. LCA is a unique tool that could be optimised for interdisciplinary public health research on circular economies.

TeaserLife cycle assessment meta-analysis shows recycling and reusing plastic food packaging could provide human health co-benefits, and some risks.


title: Immune and pathophysiologic profiling of antenatal COVID-19 in the GIFT cohort: A Singaporean case-control study.

abstract:
BackgroundCOVID-19 has been a major public health threat for the past two years, with disproportionate effects on the elderly, immunocompromised, and pregnant women. While much has been done in delineating immune dysfunctions and pathogenesis in the former two groups, less is known about the diseases progression in expectant women and children born to them. To address this knowledge gap, we profiled the immune responses in maternal and child sera as well as breast milk in terms of antibody and cytokine expression and performed histopathological studies on placentae obtained from mothers convalescent from antenatal COVID-19.

Methods and findingsA total of 17 mother-child dyads (8 cases of antenatal COVID-19 and 9 healthy unrelated controls; 34 individuals in total) were recruited to the Gestational Immunity For Transfer (GIFT) study. Maternal and infant sera, and breast milk samples were collected over the first year of life. All samples were analyzed for IgG and IgA against whole SARS-CoV-2 spike protein, the spike receptor-binding domain (RBD), and previously reported immunodominant epitopes, with conventional ELISA approaches. Cytokine levels were quantified in maternal sera using multiplex microbead-based Luminex arrays. The placentae were examined microscopically. We found high levels of virus-specific IgG in convalescent mothers and similarly elevated titers in newborn children. Virus-specific IgG in infant circulation waned within 3-6 months of life. Virus-specific IgA levels were variable among convalescent individuals sera and breast milk. Convalescent mothers also showed a blood cytokine signature indicative of a persistent pro-inflammatory state. Four placentae presented signs of acute inflammation marked by neutrophil infiltration even though >50 days had elapsed between virus clearance and delivery. Administration of a single dose of BNT162b2 mRNA vaccine to mothers convalescent from antenatal COVID-19 increased virus-specific IgG and IgA titers in breast milk.

ConclusionsAntenatal SARS-CoV-2 infection led to high plasma titres of virus-specific antibodies in infants postnatally. However, this was not reflected in milk; milk-borne antibody levels varied widely. Additionally, placentae from COVID-19 positive mothers exhibited signs of acute inflammation with neutrophilic involvement, particularly in the subchorionic region. Virus neutralisation by plasma was not uniformly achieved, and the presence of antibodies targeting known immunodominant epitopes did not assure neutralisation. Antibody transfer ratios and the decay of transplacentally transferred virus-specific antibodies in neonatal circulation resembled that for other pathogens. Convalescent mothers showed signs of chronic inflammation marked by persistently elevated IL17RA levels in their blood. A single dose of the Pfizer BNT162b2 mRNA vaccine provided significant boosts to milk-borne virus-specific antibodies, highlighting the importance of receiving the vaccine even after natural infection with the added benefit of enhanced passive immunity. The study is registered at clinicaltrials.gov under the identifier NCT04802278.


title: Comparison of tests done and Tuberculosis cases detected by Xpert MTB/RIF and Xpert MTB/RIF-Ultra in Uganda

abstract:
BackgroundUganda introduced Xpert(R) MTB/RIF assay into its TB diagnostic algorithm in January 2012. In July 2018, this assay was replaced with Xpert(R) MTB/RIF Ultra assay. We set out to compare the tests done and tuberculosis cases detected by Xpert(R) MTB/RIF and Xpert(R) MTB/RIF Ultra assay in Uganda.

MethodsThis was a before and after study, with the tests done and TB cases detected between Jan-June 2019 when using Xpert(R) MTB/RIF Ultra assay compared to those done between Jan-June 2018 while using Xpert(R) MTB/RIF assay. This data was analyzed using Stata version 13, it was summarized into measures of central tendency and the comparison between Xpert(R) MTB/RIF Ultra and Xpert(R) MTB/RIF was explored using a two-sided T-test which was considered significant if p <0.05.

ResultsOne hundred and twelve (112) GeneXpert sites out of a possible 239 were included in the study. 128,476 (M: 1147.11, SD: 842.88) tests were performed with Xpert(R) MTB/RIF Ultra assay, with 9693 drug-susceptible TB (DS-TB) cases detected (M: 86.54, SD: 62.12) and 144 (M: 1.28, SD: 3.42) Rifampicin Resistant TB cases (RR-TB). Whilst 107, 890 (M: 963.30, SD: 842.88) tests were performed with Xpert(R) MTB/RIF assay between, 8807 (M: 78.63, SD: 53.29) DS-TB cases were detected, and 147 (M: 1.31, SD: 2.39) RR-TB cases. The Number Need to Test (NNT) to get one TB case was 12 for Xpert(R) MTB/RIF and 13 for Xpert (R)MTB/RIF Ultra. On comparing the two assays in terms of test performance (p=0.75) and case detection both susceptible TB (p=0.31) and RR-TB (p=0.95) were not found statistically significant.

ConclusionsThis study found no significant difference in test performance and overall detection of DS-TB and RR-TB when using Xpert(R) MTB/RIF Ultra and Xpert(R) MTB/RIF assays. The health systems approach should be used to elucidate all the probable potential of Xpert(R) MTB/RIF Ultra.


title: Do Some Super-Spreaders Spread Better? Effects of individual heterogeneity in epidemiological traits

abstract: Many high-profile outbreaks are driven by super-spreading, including HIV, MERS, Ebola, and the SARS-Cov-2 pandemic. That super-spreading is a common feature of epidemics is immutable, however, the relative importance of 2super-spreaders to the outcome of an epidemic, and the individual-level traits that lead to super-spreading, is less clear. For example, an individual may contribute disproportionately to transmission by way of an extremely high contact rate or by way of low recovery, but how these two super-spreaders differ in their effect on epidemiological dynamics is unclear. Furthermore, epidemiological traits may often covary with one another in ways that promote or inhibit super-spreading. What patterns of covariation, and between what traits, are most likely to lead to large epidemics driven by super-spreading? Using stochastic individual-based simulations of an SIR epidemiological model, we explore how variation and covariation between transmission-related traits (contact rate and infectiousness) and duration-related traits (virulence and recovery) of infected individuals affects super-spreading and peak epidemic size. We show that covariation matters when contact rate and infectiousness covary: peak epidemic size is largest when they covary positively and smallest when they covary negatively. We did not see that more super-spreading always leads to larger epidemics, rather, we show that the relationship between super-spreading and peak epidemic size is dependent on which traits are covarying. This suggests that there may not necessarily be any general relationship between the frequency of super-spreading and the size of an epidemic.


title: Genetic variations in EIF2AK3 are associated with neurocognitive impairment in people living with HIV

abstract: Coding and noncoding single-nucleotide variants (SNVs) of EIF2AK3, which encodes an integrated stress response (ISR) kinase, may play a role in neurodegenerative disorders. We used a candidate gene approach to determine the correlation of EIF2AK3 SNVs with neurocognitive (NC) impairment (NCI), which can persist with viral suppression from antiretroviral therapy (ART) in people with HIV (PWH). This retrospective study of prospectively collected data included participants of the CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) cohort, after excluding participants with severe neuropsychiatric comorbidities. Genome-wide data previously obtained in the CHARTER cohort participants (n=1,047) were analyzed to interrogate the association of three noncoding EIF2AK3 SNVs with the continuous global deficit score (GDS) and global NCI (GDS[≥]0.5). Targeted sequencing (TS) was performed in 992 participants with available genomic DNA to determine the association of three coding EIF2AK3 SNVs with GDS and NCI. Analyses included univariable and multivariable methods such as analysis of variance and regression. Multivariable models covaried demographic, disease-associated, and treatment characteristics. The cohort characteristics were as follows: median age, 43.1 years; females, 22.8%; European ancestry, 41%; median CD4+ T cell counts, 175/{micro}L (nadir) and 428/{micro}L (current). At first assessment, 70.5% used ART and 68.3% of these had plasma HIV RNA [≤] 200 copies/mL. A minority of participants had at least one risk allele for rs6739095 (T,41.7%), rs1913671 (C,41.4%), and rs11684404 (C,39.4%). All three noncoding EIF2AK3 SNVs were associated with significantly worse GDS and more NCI (all p<0.05). By TS, fewer participants had at least one risk allele for rs1805165 (G,30.9%), rs867529 (G,30.9%), and rs13045 (A,41.2%). Homozygosity for all three coding SNVs was associated with significantly worse GDS and more NCI (all p<0.001). By multivariable analysis, the rs13045 A risk allele, current ART use, and Beck Depression Inventory-II (BDI) > 13 were independently associated with GDS and NCI (p<0.001). The other two coding SNVs did not significantly correlate with GDS or NCI after including rs13045 in the model. The coding EIF2AK3 SNVs were specifically associated with worse performance in executive functioning, motor functioning, learning, and verbal fluency. Coding and non-coding SNVs of EIF2AK3 were associated with global NC and domain-specific performance. The effects were small-to-medium in size but were present in multivariable analyses. Specific SNVs in EIF2AK3 may be an important component of genetic vulnerability to NC complications in PWH. Identification of host factors that predict NCI could allow for earlier interventions, including those directly modulating the ISR, to improve NC outcomes.

category: hiv aids


title: Transcriptome and DNA methylome analysis of peripheral blood samples reveals incomplete restoration and transposable element activation after 3-month recovery of COVID-19

abstract: Comprehensive analyses showed that SARS-CoV-2 infection caused COVID-19 and induced strong immune responses and sometimes severe illnesses. However, cellular features of recovered patients and long-term health consequences remain largely unexplored. In this study, we collected peripheral blood samples from recovered COVID-19 patients (average age of 35.7 years old) from Hubei province, China, 3 months after discharge; and carried out RNA-seq and whole-genome bisulfite sequencing (WGBS) to identify hallmarks of recovered COVID-19 patients. Our analyses showed significant changes both in expression and DNA methylation of genes and transposable elements (TEs) in recovered COVID-19 patients. We identified 639 misregulated genes and 18516 differentially methylated regions (DMRs) in total. Genes with aberrant expression and DMRs were found to be associated with immune responses and other related biological processes, implicating prolonged overreaction of the immune system in response to SARS-CoV-2 infection. Notably, a significant amount of TEs were aberrantly activated and TE activation was positively correlated with COVID-19 severity. Moreover, differentially methylated TEs may regulate adjacent gene expression as regulatory elements. Those identified transcriptomic and epigenomic signatures define and drive the features of recovered COVID-19 patients, helping determine the risks of long COVID-19, and providing guidance for clinical intervention.


title: Survival rate of positive peritoneal cytology in endometrial cancer; a systematic review and meta-analysis

abstract:
BackgroundThe impact of positive peritoneal cytology on survival rate of endometrial cancer patients in different stages and histopathology is still controversial. We performed a systematic review and meta-analysis to investigate the influence of positive peritoneal cytology (PPC) on survival rate of patients with endometrial carcinoma.

MethodsA systematic literature search of PubMed, Embase, Scopus, and Cochrane databases was conducted up to November 24, 2020. The quality of included studies was evaluated by Quality in prognosis study (QUIPS) tool.

ResultsInitially, 3014 articles were found, of which 65 met the inclusion criteria for qualitative analysis and 27 studies on 75897 patients with endometrial cancer were included in the meta-analysis. PPC was associated with a lower overall survival in endometrial cancer (HR= 2.102; 95% CI:1.629-2.711; P< 0.001). The findings also identified PPC as an independent prognostic factor for both disease-free survival (HR= 3.052; 95% CI: 2.348-2967; P< 0.001) and cancer specific survival (HR= 3.461; 95% CI: 2.280-5.254; P< 0.001). In addition, we meta-analyzed the studies in 21 subgroups based on staging and histopathology of the endometrial cancer which all identified PPC as a non-prognostic factor for cancer of endometrium.

ConclusionPPC is an independent prognostic factor for endometrial cancer survival rate in all staging and histopathologic subgroups.


title: Seasonal patterns of SARS-CoV-2 transmission in secondary schools: a modelling study

abstract:
BackgroundThe Omicron variant has caused a new wave of SARS-CoV-2 infections worldwide. We explore crucial epidemiological parameters driving seasonal patterns of SARS-CoV-2 transmission in secondary schools and assess various infection control interventions over a 2.5-year time frame.

MethodsWe developed an agent-based model parameterised with data from secondary schools in the Netherlands. We modelled the circulation of Omicron assuming a stable introduction rate of infections and accounted for uncertainty in epidemiological parameters describing virus transmissibility, susceptibility to reinfection, vaccine immune escape, and waning of sterilising immunity. We quantified the SARS-CoV-2 health burden defined as number of symptomatic student days. We further evaluated the cost-benefit (number of prevented infected students per absent student) for reactive quarantine interventions, regular screening using antigen tests, and annual booster vaccinations.

FindingsDurability of sterilising immunity is a key parameter that governs temporal SARS-CoV-2 transmission patterns in secondary schools. Our model predicts pronounced within-school seasonal patterns with dominant autumn outbreaks and smaller winter outbreaks and a maximum prevalence of 2.9% (95% CI: 0.7%-6.6%) symptomatic students during infection peaks. Regular screening and annual booster vaccination may reduce the health burden up to 15% (95% CI: 1.5%-27.8%) and have a higher cost-benefit ratio than reactive quarantine interventions (reduction: 4.3%; 95% CI: -10.1% to 17.6%).

InterpretationImmunity waning will determine the intensity and pattern of SARS-CoV-2 transmission in secondary schools in the medium-term future. If mitigation strategies are needed, screening and annual booster vaccination have the highest cost-benefit by reducing viral transmission with little educational disruption.


title: Whole-Genome Sequencing Of Omicron Identified Multiple Outbreaks And Introduction Events In India During November 2021 and January 2022

abstract:
The variant of Concern(VOC), Omicron is the predominant variant circulating throughout the world of the SARS COV2 pandemic during the third wave including India. The World Health Organisation has designated this highly mutated variant as a VOC due to its high transmissibility and risk of reinfection. Whole-genome sequencing and analysis were performed for SARS-CoV2 PCR positive samples between Dec21 to Jan22. From the 133 omicron variants detected, genomic analysis was carried out by contextualizing them with 1586 complete genomes of Omicron from India obtained from GISAID.

The Omicron variant prevalence in India has increased in a log phase within 3 months in most of the metropolitan cities. The sublineage BA.1 was first observed in the country, while the BA.2 sublineage was introduced to Delhi in the mid of December 2021. The two outbreaks observed were of BA.2 variant and were observed to spread to multiple cities in a short time. The rapid spread and specific mutations in the outbreak samples of Omicron indicate that the variant is highly transmissible when compared to previous variants. The study shows the importance of genomic sequence to identify the emergence of clusters and take actions to prevent further spreading events.


title: Digging deeper into GWAS signal using GRIN implicates additional genes contributing to suicidal behavior

abstract: Genome-wide association studies (GWAS) identify genetic variants underlying complex traits but are limited by stringent genome-wide significance thresholds. Here we dramatically relax GWAS stringency by orders of magnitude and apply GRIN (Gene set Refinement through Interacting Networks), which increases confidence in the expanded gene set by retaining genes strongly connected by biological networks from diverse lines of evidence. From multiple GWAS summary statistics of suicide attempt, a complex psychiatric phenotype, GRIN identified additional genes that replicated across independent cohorts and retained genes that were more biologically interrelated despite a relaxed significance threshold. We present a conceptual model of how these retained genes interact through neurobiological pathways to influence suicidal behavior and identify existing drugs associated with these pathways that would not have been identified under traditional GWAS thresholds. We demonstrate that GRIN is a useful community resource for improving the signal to noise ratio of GWAS results.