title: Analyzing the Impact of a Real-life Outbreak Simulator on Pandemic Mitigation: an Epidemiological Modeling Study

abstract:
Operation Outbreak (OO), an app-based, educational outbreak simulator, seeks to engage, educate, and empower citizens to prevent and better respond to infectious disease outbreaks. We examine the utility of OO for further understanding and mitigating the spread of communicable diseases. The OO smartphone app uses Bluetooth to spread a virtual pathogen among nearby participants devices to simulate an outbreak, providing an experiential learning opportunity. Deployed at many college campuses and other settings, the app collects these anonymized spatio-temporal data, including the time and duration of the contacts among participants of the simulation. Here, we report the distribution, timing, duration, and connectedness of student social contacts at two university deployments and uncover cryptic transmission pathways through individuals second-degree contacts. We then construct epidemiological models based on the contact networks generated by OO to predict the transmission pathways of hypothetical pathogens with varying reproductive numbers. Finally, we show that the granularity of OO data enables institutions to improve outbreak mitigation by proactively and strategically testing and/or vaccinating individuals based on individual social interaction levels.

BIGGER PICTUREOutbreak simulation technology can greatly enhance individual and community pandemic preparedness while also helping us understand and mitigate outbreak spread. Building on an existing platform called Operation Outbreak (OO)--an app-based program that spreads a virtual pathogen via Bluetooth among participants smartphones--we demonstrate the power of this approach. We investigate the first- and second-degree contacts of OO participants, analyzing the differential risk associated with various local contact network structures. We use OO data to construct an epidemiological model, with which communities may predict the spread of infectious agents and assess the effectiveness of mitigation measures. Based on our findings, we advocate for the wider adoption of outbreak simulation technology to study the implications of social mixing patterns on outbreaks within close-knit communities, to aid pandemic preparedness and response.


title: Contact investigation of tuberculosis in Brunei Darussalam: Evaluation and risk factor analysis

abstract:
IntroductionWe evaluated the yield of tuberculosis (TB) contact investigation in Brunei Darussalam, and identified the associated factors for latent TB infection (LTBI) diagnosis, as well as for initiating and completing LTBI treatment.

MethodsData was extracted and digitalised for all close contacts of pulmonary TB cases at the National TB Coordinating Centre from January 2009 to December 2018. Generalising estimating equations (GEE) logistic regression models were used to determine the associated factors. Manual matching against electronic health records system was done to identify contacts who had progressed to active TB disease.

ResultsAmong 10,537 contacts, 9.9% (n= 1047) were diagnosed as LTBI, out of which 43.0% (n= 450) initiated LTBI treatment. Among those who initiated, 74.0% (n= 333) completed LTBI treatment. Contact factors associated with LTBI diagnosis include being male (Adjusted Odds Ratio (aOR)= 1.18 [95%CI: 1.03,1.34), local (aOR= 0.70 [95% CI: 0.56,0.88]), and a household contact. Local LTBI cases had higher odds of initiating LTBI treatment (aOR= 1.86 [95% CI: 1.26,2.73]). Also, LTBI cases detected from local (aOR= 2.32 [95% CI: 1.08,4.97]) and smear positive PTB index cases had higher odds of completing LTBI treatment. Among 1047 LTBI cases, 5 (0.5%) progressed to active PTB within 1-8 years post-LTBI diagnosis.

DiscussionLTBI burden is disproportionately high towards foreign nationals, with higher odds of LTBI diagnosis but lower odds of treatment initiation. Establishing digital databases and building TB laboratory capacity for molecular typing would be useful to determine the contribution of LTBI or reactivation towards TB incidence in Brunei.

Key messagesO_LIBrunei is an intermediate TB burden country with stagnating TB incidence since 2004, despite having an established national TB programme.
C_LIO_LIWe undertook this study to evaluate the contact investigation process and also tounderstand the contribution of LTBI towards TB incidence in the country.
C_LIO_LIThe associated factors of LTBI diagnosis include being, male, foreign and a household contact. Local cases had higher odds of initiating LTBI treatment when compared to foreign nationals.
C_LIO_LIStrengthening LTBI screening and treatment among foreign nationals could be an important step towards reducing TB incidence in Brunei.
C_LI

category: epidemiology


title: SARS-CoV-2 Testing Strategies for Outbreak Mitigation in Vaccinated Populations

abstract: Although COVID-19 vaccines are globally available, waning immunity and emerging vaccine-evasive variants of concern have hindered the international response as COVID-19 cases continue to rise. Mitigating COVID-19 requires testing to identify and isolate infectious individuals. We developed a stochastic compartmentalized model to simulate SARS-CoV-2 spread in the United States and India using Reverse Transcriptase Polymerase Chain Reaction (RT-PCR) assays, rapid antigen tests, and vaccinations. We detail the optimal testing frequency and coverage in the US and India to mitigate an emerging outbreak even in a vaccinated population: overall, maximizing frequency is more important, but high coverage remains necessary when there is sustained transmission. We show that a resource-limited vaccination strategy still requires high-frequency testing and is 16.50% more effective in India than the United States. Tailoring testing strategies to transmission settings can help effectively reduce cases more than if a uniform approach is employed without regard to differences in location.


title: Resting State fMRI for Motor Cortex Mapping in Children with Epilepsy

abstract:
Task-based fMRI is commonly used to localize motor functions prior to epilepsy surgery. Not all children are able to follow task instructions in the scanner, limiting fMRI motor mapping. We present a data-driven method to automatically delineate the motor cortex using task-free, resting state fMRI (rsfMRI) data of children with epilepsy and controls.

We preprocessed anatomical and rsfMRI images (64 patients, 12 controls) using fMRIPrep. We used FSL MELODIC tool for whole brain ICA estimation in multiple orders, to generate several sets of independent components. We defined a motor component selection process based on Discriminability Index-based Component Identification (DICI) score, resulting from comparing binarized component to the Human Motor Area Template (HMAT) in subjects native brain space. Components with the largest DICI score and their peak in the template were combined to form the whole-brain ICA Motor Map (wIMM). We validated wIMM by comparing individual results with finger tapping motor task activation, and evaluated its reproducibility in controls with two runs of rsfMRI.

The hit rate between wIMM and motor task activation ranged 60 to 77% across all participants. Sensitivity of wIMM for capturing the task activation was 87.5% among 32 patients and 100% in 11 controls with available task results. The mean Dice similarity in results from repeated runs was 0.70 in controls.

Our results shows the sensitivity and reproducibility of an automated motor mapping based on ICA analysis of rsfMRI in children with epilepsy. The ICA maps may provide different, but useful, information than task fMRI. Future studies will expand our method to mapping other brain functions, and may lead to a surgical planning tool for patients who cannot perform task fMRI and help predict their postsurgical function.

category: neurology


title: Not all roads lead to the immune system: The Genetic Basis of Multiple Sclerosis Severity Implicates Central Nervous System and Mitochondrial Involvement

abstract: Multiple sclerosis (MS) is a leading cause of neurological disability in adults. Heterogeneity in MS clinical presentation has posed a major challenge for identifying genetic variants associated with disease outcomes. To overcome this challenge, we used prospectively ascertained clinical outcomes data from the largest international MS Registry, MSBase. We assembled a cohort of deeply phenotyped individuals with relapse-onset MS. We used unbiased genome-wide association study and machine learning approaches to assess the genetic contribution to longitudinally defined MS severity phenotypes in 1,813 individuals. Our results did not identify any variants of moderate to large effect sizes that met genome-wide significance thresholds. However, we demonstrate that clinical outcomes in relapse-onset MS are associated with multiple genetic loci of small effect sizes. Using a machine learning approach incorporating over 62,000 variants and demographic variables available at MS disease onset, we could predict severity with an area under the receiver operator curve (AUROC) of 0.87 (95% CI 0.83 - 0.91). This approach, if externally validated, could quickly prove useful for clinical stratification at MS onset. Further, we find evidence to support central nervous system and mitochondrial involvement in determining MS severity.


title: A PRACTICAL MODEL FOR EARLY IDENTIFICATION OF PROSPECTIVE HIGH NEED HIGH COST PATIENTS

abstract:
BackgroundHigh Need-High Cost (HNHC) patients are those who experience poor health outcomes and high health care costs. Early identification may improve outcomes and lower costs.

AimDevelopment of a model using retrospective data to identify patients at risk for becoming HNHC patients, in order to efficaciously plan interventions.

MethodsData from a large Israeli Health Maintenance Organization (HMO) that includes 488,615 clients above the age of 21 were examined. Multivariate linear regression models were developed using 2012-2016 health expenditure as a dependent variable.

ResultsThe number of yearly purchases of medications for chronic disorders, yearly outpatient visits, yearly emergency department and hospital admissions and the last measured HgA1c level were highly predictive of increased expenditure over a five-year period. Each of these indicators has a different coefficient of influence.

ConclusionsWe developed a predictive model, based on easily obtained data from electronic medical records that enabled us to identify a population at risk for becoming HNHC in the next five years, a time window allows for intervention. Further research is needed to evaluate whether this is an early enough stage to implement pro-active intervention in the primary care setting.

Trial registrationretrospectively registered.

HIGHLIGHTSIn this study, we developed a numerical point system calculator, to indicate a risk score for health deterioration within 5 years of patients, by using numerical indicators existing in standard EMR data.

The indicators introduced into this calculated risk can guide healthcare providers to the needed areas of intervention. The display of indicators also promotes optimization of care management and continuity of care.

This risk score is expected to focus the attention of primary care teams on the population that will benefit most from it, as well as to evaluate the effectiveness of specific interventions.

category: health systems and quality improvement


title: Modinterv COVID-19: An online platform to monitor the evolution of epidemic curves

abstract:
BackgroundThe COVID-19 pandemic is one of the worst public health crises the world has ever faced. A major hindrance in making apt decisions by health control systems is the fact that protocols tested in other epidemics are no guarantee of success to control the COVID-19 epidemic, given its singular nature and complexity. The occurrence of two or more waves of infections all over the world poses an even greater challenge. An effective way to assist health authorities in adopting public policies to face the COVID-19 pandemic depends on smart analytics and visualization.

PurposeWe present the software Modinterv as a tool to monitor, in an automated and user-friendly manner, the evolution and trend of COVID-19 epidemic curves, both for cases and deaths.

MethodsThe Modinterv software uses parametric generalized growth models, together with machine learning algorithms, to fit epidemic curves with one or two waves of infections of cases and deaths for countries around the world as well as for states and cities in Brazil and the USA. The richness of the implemented models lies in the possibility of detecting the distinct acceleration regimes of the disease in places where there are one or two waves of infections.

ResultsWe show how growth models can be combined with machine learning algorithms in an automated software that can identify the current stage of the COVID-19 epidemic curve in the selected place. We describe the backend structure of software as well as its practical use. The software helps the user not only to understand the current stage of the epidemic in the chosen location but also to make short term predictions as to how the curves may evolve.

category: infectious diseases


title: N-glycans mannosylation controls T-cell development by reprogramming thymocyte commitment, fate and repertoire

abstract:
T-cell development is a major physiological process occurring in complex organisms, that ensures the formation of T-cell receptors diverse repertoire, to recognize antigens throughout the life of the organism. The thymus offers a microenvironment for efficient development, where progenitor populations go through maturation steps, which, when not regulated, are associated with disease onset, including autoimmune disorders and cancer. Glycosylation is a major post-translational modification that occurs in virtually all cells, including T lymphocytes, regulating receptor- turnover, affinity and signaling. However, there is a missing knowledge on how glycans regulate lymphocyte development and their impact in T-cell functions. We discovered stage-specific glycosylation profiles in human and murine thymocyte populations. Thereafter, we generated two glycoengineered mouse models displaying N-glycosylation pathway deficiencies, at early DN stages, lacking the Mgat1 or Mgat2 genes. We demonstrated remarkable defects in key T-cell developmental stages, such as {beta}- and DP-selection, natural regulatory T-cell generation,{gamma}{delta} T development/differentiation and thymic egression, in Mgat1-deficient thymocytes, indicating a pathogenic role of mannose N-glycans in development. We also demonstrated that a single N- glycan antenna (modelled in Mgat2-deficient thymocytes) is sufficient to rescue key developmental processes. In conclusion, we demonstrated that mannosylated thymocytes render a dysregulation in T-cell development, associated with disease.

Graphical abstract

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category: allergy and immunology


title: The Public Health Impact of a US Menthol Cigarette Ban on the Non-Hispanic Black Population: A Simulation Study

abstract:
IntroductionAs the US Food and Drug Administration (FDA) evaluates implementing a ban on menthol cigarettes and cigars, it is critical to estimate the potential public health effects of such a ban. With high rates of menthol cigarette use by the non-Hispanic Black (NHB) population and important smoking-related health disparity implications, the impact of the ban on this population merits strong consideration.

MethodsWe apply the previously developed Menthol Smoking and Vaping Model. A Status Quo Scenario is developed using population, smoking and vaping data specific to the NHB population. Estimates from a recent expert elicitation on behavioral impacts of a menthol cigarette ban on the NHB population are used to develop a Menthol Ban Scenario implemented in 2021. The public health impacts of the menthol ban are estimated as the difference between smoking and vaping attributable deaths (SVADs) and life years lost (LYLs) in the Status Quo and the Menthol Ban Scenarios from 2021-2060.

ResultsUnder the Menthol Ban Scenario, overall smoking is projected to decline by 35.1% in 2026, and by 24.0% in 2060 relative to the Status Quo Scenario. With these reductions, SVADs are estimated to fall by about 18.5% and LYLs by 22.1%, translating to 255,000 premature deaths averted, and 3.9 million life-years gained over a 40-year period.

ConclusionsA menthol cigarette ban will substantially reduce the smoking-associated health impact on the NHB population thereby reducing health disparities.

category: public and global health


title: Interscapular fat is associated with impaired glucose tolerance and insulin resistance independent of visceral fat mass

abstract:
Dysregulated body fat distribution is a major determinant of various diseases. Adipose tissue in different localizations of the body appear to have protective or detrimental properties. Particularly increased visceral fat mass and ectopic lipids in the liver are linked to metabolic disorders such as insulin resistance and type 2 diabetes. Furthermore, interscapular fat is considered to be a non-classical, but metabolically active, fat compartment.

In this study, we measured interscapular fat mass and investigated its relationship with glucose tolerance, insulin sensitivity and insulin secretion in 822 subjects with a wide range of body mass index (BMI) and different glucose tolerance status. Magnetic resonance imaging was used to quantify body fat depots and an oral glucose tolerance test (OGTT) was performed to determine glucose metabolism.

Elevated interscapular fat mass was positively associated with age, BMI, total body, visceral and subcutaneous adipose tissue mass. High interscapular fat mass associated with elevated fasting glucose levels, glucose levels at 2 hours during the OGTT, glycated hemoglobin, as well as with insulin resistance, independently of sex, age, total body and visceral fat mass.

In conclusion, interscapular fat might be a highly specific fat compartment with potential impact on glucose metabolism and the pathogenesis of diabetes mellitus. Since this depot is assessible by ultrasound, it could represent a feasible target to quantify metabolic risk in the future.

category: endocrinology


title: Food insecurity disparities and mental health impacts among cancer survivors during the COVID-19 pandemic

abstract:
Food insecurity can negatively impact adherence and receipt of high-quality cancer care. The purpose of the study was to (1) compare the prevalence of COVID-19 associated food insecurity by cancer history and (2) examine determinants associated with COVID-19 related food insecurity among cancer survivors.

We used nationally-representative data from the COVID-19 Household Impact Survey (n = 10,760), collected at three time points: April 20-26, May 4-10, and May 30th -June 8th of 2020. Our primary exposure was cancer survivor status, based on participants self-report of a cancer diagnosis (n=854, 7.1%). Primary outcomes of food insecurity were categorized on how often participants reported the following: "We worried our food would run out before we got money to buy more" or "The food that we bought just didnt last, and we didnt have money to get more"; Respondents were categorized as food insecure if they chose often true or sometimes true. Multivariable Poisson regression was used to identify demographic determinants of food insecurity among cancer survivors.

Thirty-two percent of cancer survivors were food insecure. Cancer survivors aged 30-44 years and those aged [≥]60 were more likely to report being food insecure compared to respondents without a history of cancer in the same age categories (30-44 years, 59.9% versus 41.2% p = 0.01, [≥]60 years 27.2% versus 20.2%, p = 0.01). Cancer survivors without a high school diploma were more likely to report food insecurity compared to adults with no history of cancer (87.0% versus 64.1%, p = 0.001). In multivariable models, uninsured cancer survivors (adjusted Prevalence Ratio (aPR) aPR: 2.39, 95% CI: 1.46-3.92) and those on Medicaid (aPR: 2.10, 95% CI: 1.40-3.17) were also more likely to report being food insecure.

Food insecurity during the COVID-19 pandemic is vast but disparities persist. Among cancer survivors, differences in food insecurity were observed by age and SES.


title: COVID-19 vaccines uptake: Public knowledge, awareness, perception among adult Africans

abstract:
IntroductionThe willingness of Africas population to take the COVID-19 vaccines is critical to the efficiency of national immunisation programmes. This study surveys the views of adult African inhabitants toward vaccination and the possibility of participating or not participating in governments efforts to get citizens vaccinated.

MethodA cross-sectional online survey of adult Africans was undertaken from December 2020 to March 2021. Responses were anonymised. The Pearson Chi-square test was performed to determine whether or not there were any variations in knowledge, awareness, perception and acceptance of the COVID-19 vaccines among the participants. Binomial logistic regression was used to evaluate the factors associated with willingness to accept COVID-19 vaccines and participate in immunisation programmes.

ResultsThe results indicate that COVID-19 vaccines are more likely to be used by adult Africans over the age of 18 who are largely technologically savvy (55 percent) if the vaccine is made broadly available. A total of 33 percent of those who responded said they were unlikely to receive the vaccine, with another 15 percent stating they were undecided. Aside from that, we found that vaccine hesitancy was closely associated with socio-demographic characteristics such as age, gender, education and source of information. We also found that there were widespread conspiracies and myths about the COVID-19 vaccines.

ConclusionMore than two-thirds of African adults who participated in the survey indicated they would not receive the COVID-19 vaccine, with majority of them expressing skepticisms about the vaccines efficacy. It is possible that many of the people who would not be vaccinated would have an impact on the implementation of a COVID-19 immunisation programme that is meant for all of society. Majority of the respondents were unwilling to pay for the COVID-19 vaccines when made available. An awareness campaign should be focused on promoting the benefits of vaccination at the individual and population levels, as well as on taking preemptive actions to debunk misconceptions about the vaccines before they become further widespread.


title: SARS-CoV-2 mRNA vaccination fails to elicit humoral and cellular immune responses in multiple sclerosis patients receiving fingolimod

abstract: SARS-CoV-2 mRNA vaccination of healthy individuals is highly immunogenic and protective against severe COVID-19. However, there are limited data on how disease-modifying therapies (DMTs) alter SARS-CoV-2 mRNA vaccine immunogenicity in patients with autoimmune diseases. Here we investigated the induction and stability of vaccine-specific antibodies, B cells, and T cells in multiple sclerosis (MS) patients on different DMTs in a prospective cohort study up to 6 months after homologous prime-boost mRNA vaccination. We analysed 103 MS patients of which 86 received anti-CD20-based B cell depletion (aCD20-BCD), fingolimod, interferon-{beta}, dimethyl fumarate, glatiramer acetate, teriflunomide or natalizumab, and compared them to 17 untreated MS patients. In contrast to all other DMTs and untreated patients, treatment with aCD20-BCD or fingolimod significantly reduced anti-S1 IgG, serum neutralizing activity, and RBD- and S2-specific B cells. MS patients receiving fingolimod additionally lacked S1- and S2-reactive CD4+ T cell responses. The duration of fingolimod treatment, rather than peripheral blood B and T cell counts prior to vaccination, determined whether patients successfully developed humoral immune responses. Fingolimod blocks the ability of immune cells to recirculate and migrate within secondary lymphoid organs demonstrating that functional immune responses require not only immune cells themselves but also access of these cells to the site of inoculation and their unimpeded movement. The absence of humoral and T cell responses in fingolimod-treated MS patients suggests that these patients are at risk for severe SARS-CoV-2 infections despite vaccination, which is highly relevant for clinical decision-making and adapted protective measures, particularly in light of additional recently approved S1P receptor antagonists for MS treatment.


title: Flexibility of brain dynamics predicts clinical impairment in Amyotrophic Lateral Sclerosis

abstract:
Amyotrophic lateral sclerosis (ALS) is a multisystem disorder. This view is widely supported by clinical, molecular and neuroimaging evidence. As a consequence, predicting clinical features requires a comprehensive description of large-scale brain activity. Flexible dynamics is key to support complex adaptive responses. In health, brain activity reconfigures over time, involving different brain areas. Brain pathologies can induce more stereotyped dynamics, which, in turn, are linked to clinical impairment. Hence, based on recent evidence that brain functional networks become more connected as ALS progresses, we hypothesized that loss of flexible dynamics in ALS would predict their clinical condition.

To test this hypothesis, we quantified flexibility utilizing the "functional repertoire" (i.e. the number of unique patterns) expressed during the magnetoencephalography (MEG) recording, based on source-reconstructed signals. Specifically, 42 ALS patients and 42 healthy controls underwent MEG and MRI recordings. The activity of the brain areas was reconstructed in the classical frequency bands, and the functional repertoire was estimated to quantify spatio-temporal fluctuations of brain activity. In order to verify if the functional repertoire predicted disease severity, we built a multilinear model and validated it using a k-fold cross validation scheme.

The comparison between the two groups revealed that ALS patients showed more stereotyped brain dynamics (P < 0.05), with reduced size of the functional repertoire. The relationship between the size of the functional repertoire and the clinical scores in the ALS group was investigated using Spearmans coefficient, showing significant correlations in both the delta and the theta frequency bands. In order to prove the robustness of our results, the k-fold cross validation model was used. We found that the functional repertoire significantly predicted both clinical staging (P < 0.001 and P < 0.01, in delta and theta bands, respectively) and impairment (P < 0.001, in both delta and theta bands).

In conclusion, our work shows that: 1) ALS pathology reduces the flexibility of brain dynamics; 2) sub-cortical regions play a key role in determining brain dynamics; 3) reduced brain flexibility predicts the stage of the disease as well as the severity of the symptoms. Based on these findings, our approach provides a non-invasive tool to quantify alterations in brain dynamics in ALS (and, possibly, other neurodegenerative diseases), thus opening new diagnostic opportunities as well as a framework to test disease-modifying interventions.


title: White matter brain age as a biomarker of cerebrovascular burden in the ageing brain

abstract: As the brain ages, it almost invariably accumulates vascular pathology, which differentially affects the white matter. The microstructure of the white matter may therefore reveal a brain age reflecting cerebrovascular disease burden and a relationship to vascular risk factors. In this study, a white matter specific brain age was developed from diffusion weighted imaging (DWI) using a three-dimensional convolutional neural network (3D-CNN) deep learning model in both cross-sectional data from UK biobank participants (n = 37327) and a longitudinal subset (n = 1409) with an average of 2.25 years follow up. We achieved a mean absolute error (MAE) of white matter brain age prediction of 2.84 years and a Pearsons r of 0.902 with chronological age in the test participants. The average white matter brain age gap (WMBAG) of the baseline 1409 participants with repeated scans were 0.36 {+/-} 0.11 years younger than that of other participants in the baseline test sample with single time-point MRI scan (n = 9759). Individual vascular risk factors and the cumulative vascular risk score were significantly correlated with greater WMBAG Obesity was observed to be correlated with WMBAG only in the male participants. Participants with one, two, and three or more vascular risk factors, compared to those without any, showed an elevated WMBAG of 0.54, 1.23, and 1.94 years, respectively. Baseline WMBAG was also associated significantly with processing speed, executive and global cognition after Bonferroni correction. The significant associations of diabetes and hypertension with poor processing speed and executive function were found to be mediated through the WMBAG. However, the vascular risk factors did not associate with the two-year change in WMBAG in the longitudinal dataset. Our analysis suggests that tissue-specific brain age can be successfully targeted for the examination of the most relevant risk factors and cognition, although longer-term longitudinal data are needed to demonstrate its dynamic characteristics. The results suggest an intriguing possibility that a white matter brain age gap can serve as a potential neuroimaging biomarker for an individuals cerebrovascular ageing process.


title: Impact of moderate alcohol consumption on brain iron and cognition: observational and genetic analyses

abstract:
Brain iron deposition has been linked to several neurodegenerative conditions and reported in alcohol dependence. Whether iron accumulation occurs in moderate drinkers is unknown. Our objectives were to investigate causal relationships between alcohol consumption and brain iron levels and to examine whether higher brain iron represents a potential pathway to alcohol-related cognitive deficits.

Multi-organ susceptibility-weighted magnetic resonance imaging was used to ascertain iron content of brain (quantitative susceptibility mapping (QSM) and T2*) and liver tissues (T2*), a marker of systemic iron. Observational associations between brain iron markers and self-reported alcohol consumption (n=22,254 UK Biobank participants) were compared with associations with genetically-predicted alcohol intake from two-sample Mendelian randomization (MR). Potential pathways to alcohol-related iron brain accumulation through elevated systemic iron stores (liver) were explored in causal mediation analysis. Cognition was assessed at the time of scan and in online follow-up.

Alcohol consumption was associated with markers of higher iron in putamen ({beta}=0.09 standard deviation (S.D.) [95% confidence interval 0.07 to 0.10]), caudate ({beta}=0.06 [0.04 to 0.07]) and substantia nigra ({beta}=0.04 [0.02 to 0.05]), and lower iron in the thalami ({beta}= -0.05 [-0.06 to -0.03]). Quintile-based analyses found these effects in those consuming >7 units (56g) alcohol weekly. MR analyses provided some evidence these relationships are causal. A 1 S.D. higher genetically-predicted number of alcoholic drinks weekly associated with 0.25 [0.01 to 0.49] S.D. higher putamen susceptibility and 0.28 [0.05 to 0.50] S.D. higher hippocampus susceptibility. Genetically-predicted alcohol use disorder was causally related to higher putamen susceptibility (0.18 [0.001 to 0.35] S.D.), serum iron (0.12 [0.05 to 0.19] S.D.) and transferrin saturation (0.11[0.03 to 0.19] S.D.). Elevated liver iron was observed at just >11 units (88g) alcohol weekly (0.03 mg/g [0.01-0.05] higher c.f. <7 units (56g) weekly). Systemic iron levels partially mediated associations of alcohol intake with brain iron accumulation (proportion mediated: 32% [22 to 49]). Markers of higher basal ganglia iron were associated with accelerated age-related decline in executive function and fluid intelligence, and slower reaction times.

This study represents the largest investigation of moderate alcohol consumption and iron homeostasis to date. Even low levels of alcohol consumption were associated with iron accumulation in the brain, suggesting a potential mechanism for alcohol-related cognitive decline.

category: nutrition


title: Incidence and associated factors of elderly mortality following hip fracture in Brazil: a systematic review and meta-analysis

abstract:
IntroductionHip fractures are an important health problem worldwide, and several factors are associated with the mortality. This study aimed to investigate the factors associated with hip fractures in the elderly, based on studies on the population residing in Brazil, and the relationship of fractures with mortality.

MethodProspective and retrospective primary observational studies including hospitalized men and/or women aged 60 or older presenting hip fracture due to bone fragility were selected on the Databases. Independent researchers conducted the study selection process and data extraction. A meta-analysis was performed to determine the hospital mortality rate at 90 days, six months, and one year. The Newcastle-Ottawa scale (NOS) was used to assess the quality of the included studies, and the meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).

ResultTwenty-five studies totalizing 3,949 patients were included in the systematic review. The population was mainly composed of women (2,680/67.86%). Most patients were in the age group of 70 to 80 years old. Meta-analysis findings: 1) hospital mortality (19 studies, n = 3,175), 10.22% (95% CI 7.27-14.17%; I2 88%); 2) 90-day mortality (3 studies, n = 543), 9.74% (95% CI 3.44-24.62%; I2 90%); 3) six-month mortality (3 studies, n = 205), 24.78% (95% CI 17.07-34.51%; I2 51%); 4) one-year mortality (13 studies, n = 2,790), 21.88% (95% CI 17.5-26.99%; I2 88%). The factors most related to mortality in the studies were: 1) demographic: Older age, male sex; 2) Attributed to clinical conditions: high scoring in preoperative risk scores, comorbidities, neurological/cognitive disorders, functional status; and 3) hospital factors: preoperative period and infections.

ConclusionThis review identified variables, including functional status and cognitive changes, related to hip fracture mortality. Knowing these predictors allows for early intervention and planning to adapt health systems to the growing demands of the elderly population.

category: orthopedics


title: Single cell sequencing analysis uncovers genetics-influenced CD16+monocytes and memory CD8+T cells involved in severe COVID-19

abstract:
BackgroundUnderstanding the host genetic architecture and viral immunity contributes to the development of effective vaccines and therapeutics for controlling the COVID-19 pandemic. Alterations of immune responses in peripheral blood mononuclear cells play a crucial role in the detrimental progression of COVID-19. However, the effects of host genetic factors on immune responses for severe COVID-19 remain largely unknown.

MethodsWe constructed a powerful computational framework to characterize the host genetics-influenced immune cell subpopulations for severe COVID-19 by integrating GWAS summary statistics (N = 969,689 samples) with four independent scRNA-seq datasets (N = 606,534 cells).

ResultsWe found that 34 risk genes were significantly associated with severe COVID-19, and the number of highly-expressed genetics-risk genes increased with the severity of COVID-19. Three cell-subtypes that are CD16+monocytes, megakaryocytes, and memory CD8+T cells were significantly enriched by COVID-19-related genetic association signals. Notably, three causal risk genes of CCR1, CXCR6, and ABO were specifically expressed in these three cell types, respectively. CCR1+CD16+monocytes and ABO+ megakaryocytes with significant up-regulated genes including S100A12, S100A8, S100A9, and IFITM1 confer higher risk to the cytokine storms among severe patients. CXCR6+ memory CD8+ T cells exhibit a notable polyfunctionality of multiple immunologic features, including elevation of proliferation, migration, and chemotaxis. Moreover, we observed a prominent increase in cell-cell interactions of both CCR1+ CD16+monocytes and CXCR6+ memory CD8+T cells in severe patients compared to normal controls among both PBMCs and lung tissues, and elevated interactions with epithelial cells could contribute to enhance the resident to lung airway for against COVID-19 infection.

ConclusionsWe uncover a major genetics-modulated immunological shift between mild and severe infection, including an increase in up-regulated genetic-risk genes, excessive secreted inflammatory cytokines, and functional immune cell subsets contributing high risk to severity, which provides novel insights in parsing the host genetics-influenced immune cells for severe COVID-19.

category: genetic and genomic medicine


title: The use of social media platforms by migrant and ethnic minority populations during the COVID-19 pandemic: a systematic review

abstract:
ObjectiveTo determine the extent and nature of social media use in migrant and ethnic minority communities for COVID-19 information, and implications for preventative health measures including vaccination intent and uptake.

DesignA systematic review of published and grey literature following the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines

Eligibility Criteria for study selectionGlobal research reporting the use of social media by migrants and/or ethnic minority groups in relation to COVID-19.

Data extractionWe extracted data on key outcomes, study design, country, population under study, and sample size.

Results1849 unique records were screened, and 21 data sources included in our analysis involving migrant and ethnic minority populations in the UK, US, China, Jordan, Qatar, and Turkey. We found evidence of consistent use of a range of social media platforms for COVID-19 information in some migrant and ethnic minority populations (including WeChat, Facebook, WhatsApp, Instagram, Twitter, YouTube), which may stem from difficulty in accessing COVID-19 information in their native languages or from trusted sources. There were positive and negative associations with social media use reported, with some evidence suggesting circulating misinformation and social media use may be associated with lower participation in preventative health measures, including vaccine intent and uptake, findings of which are likely relevant to multiple population groups.

ConclusionsSocial media platforms are an important source of information about COVID-19 for some migrant and ethnic minority populations. Urgent actions and further research are now needed to better understand the use of social media platforms for accessing health information by different population groups - particularly groups who are marginalised from health systems - effective approaches to tackling circulating misinformation, and to seize on opportunities to make better use of social media platforms to support public health communication and improve vaccine uptake.

RegistrationThis study has been registered with PROSPERO (CRD42021259190).

category: health policy


title: Characteristics and preparedness for COVID-19 outbreaks of Australian residential aged care facilities: A cross-sectional survey

abstract:
ObjectiveTo provide an overview of Australian residential aged care facilities (RACFs) COVID-19 outbreak preparedness and responses, 12 months after the pandemic began in early 2020.

MethodsA cross-sectional survey of RACF managers was conducted as part of an overview of COVID-19 experience during 2020. Survey questions were based on findings of previous outbreak reviews.

ResultsComparison with available data from the Australian Institute for Health and Welfare suggested that survey respondents (n=331) were a representative sample. Almost all RACFs had outbreak management plans, including provision for a surge workforce. However, anticipated staff replacements fell short of those often required during outbreaks. Staff of most (83%) RACFs had completed online infection control training, and a smaller proportion (73%) face-to-face training, by the time of the survey. Exploratory analyses to identify RACF characteristics associated with increased outbreak risk found a strong association with location in Victoria (adjusted risk ratio [aRR] 12.8) where most community transmission occurred during 2020. The only other association was an increased risk in facilities where all staff had not completed face-to-face infection control training (aRR 2.1). Respondents ranked leadership and management; planning and preparation; and infection control as the top three of seven critical lines of defence against COVID-19.

ConclusionSurvey results suggest that, in early 2021, most Australian RACFs were better prepared for the ongoing risk of COVID-19 than in 2020. Continued implementation of the Aged Care Royal Commissions recommendations is needed to ensure the aged care sector is prepared for future infectious disease emergencies.


title: Early genomic, epidemiological, and clinical description of the SARS-CoV-2 Omicron variant in Mexico City

abstract:
BackgroundOmicron is the most mutated SARS-CoV-2 variant that has emerged, resulting in viral phenotype alterations, which can affect transmissibility, disease severity, and immune evasiveness. Genomic surveillance of a highly transmissible variant is important in cities with millions of inhabitants and an economic center such as Mexico City. In this work, we describe the early effects of the Omicron variant in Mexico City, exploring its genomic profile and clinical description.

MethodologyWe sequenced SARS-CoV-2-positive samples in November and December 2021 and we using the public database GISAID. Haplotype and phylogenetic analyses were performed to genomically characterize Omicron. We used the Mexican federal database toexplore the association with clinical information such as symptoms and vaccination status.

FindingsThe first case of Omicron was detected on November 16, 2022, and until December 31, 2021, we observed an increase from 88% in sequenced samples. Nineteen nonsynonymous mutations were found in the Omicron RBD, and we further explored the R346K substitution, which was prevalent in 42% of the samples and associated with immune escape by monoclonal antibodies. In the phylogenetic analysis, we found that there were several independent exchanges between Mexico and the world, and there was an event followed by local transmission that gave rise to most of the Omicron diversity in Mexico City. The haplotype analysis allowed us to observe that there was no association between haplotype and vaccination status. Of the patients with clinical data, 66% were vaccinated, none of the reported comorbidities were associated with Omicron, the presence of odynophagia and absence of dysgeusia were significant predictor symptoms for Omicron, and the Ct value on RT-qPCR was lower in Omicron.

ConclusionsGenomic surveillance in highly populated and fast-moving urban regions such as Mexico City is key to detecting the emergence and spread of SARS-CoV-2 variants in a timely manner, even weeks before the onset of an infection wave, to detect patterns that can inform public health decisions. It is also necessary to continue sequencing to detect the spread of any mutation that may affect the therapeutic efficacy or guide it.


title: Comparable Neutralization of the SARS-CoV-2 Omicron BA.1 and BA.2 Variants

abstract:
The SARS-CoV-2 Omicron variant (B.1.1.529) has three major lineages BA.1, BA.2, and BA.31. BA.1 rapidly became dominant and has demonstrated substantial escape from neutralizing antibodies (NAbs) induced by vaccination2-4. BA.2 has recently increased in frequency in multiple regions of the world, suggesting that BA.2 has a selective advantage over BA.1. BA.1 and BA.2 share multiple common mutations, but both also have unique mutations1 (Fig. 1A). The ability of BA.2 to evade NAbs induced by vaccination or infection has not yet been reported. We evaluated WA1/2020, Omicron BA.1, and BA.2 NAbs in 24 individuals who were vaccinated and boosted with the mRNA BNT162b2 vaccine5 and in 8 individuals who were infected with SARS-CoV-2 (Table S1).

O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=61 SRC="FIGDIR/small/22270533v1_fig1.gif" ALT="Figure 1">
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View larger version (26K):
org.highwire.dtl.DTLVardef@1b39fc8org.highwire.dtl.DTLVardef@1bf16ceorg.highwire.dtl.DTLVardef@7248ecorg.highwire.dtl.DTLVardef@111a215_HPS_FORMAT_FIGEXP  M_FIG O_FLOATNOFigure 1.C_FLOATNO Neutralizing antibody responses to Omicron BA.1 and BA.2. A. Cartoon showing BA.1 and BA.2 mutations in the SARS-CoV-2 Spike. NTD, N-terminal domain; RBD, receptor binding domain; RBM, receptor binding motif; SD1, subdomain 1; SD2, subdomain 2; FP, fusion peptide; HR1, heptad repeat 1; HR2, heptad repeat 2. B. Neutralizing antibody (NAb) titers by a luciferase-based pseudovirus neutralization assay in individuals two weeks following initial BNT162b2 vaccination (Prime), prior to boost (Pre-Boost), and two weeks following the third boost with BNT162b2 (Boost). C. NAb titers in 8 individuals following infection with SARS-CoV-2 Omicron BA.1, of whom 7 were vaccinated. The individual with negative NAb titers was unvaccinated and was sampled 4 days following diagnosis and hospitalization with severe COVID-19 pneumonia. Responses were measured against the SARS-CoV-2 WA1/2020, Omicron BA.1, and BA.2 variants. Medians (red bars) are depicted and shown numerically with fold differences.

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org.highwire.dtl.DTLVardef@a84ecborg.highwire.dtl.DTLVardef@1cd2d42org.highwire.dtl.DTLVardef@1567410org.highwire.dtl.DTLVardef@ddcf54org.highwire.dtl.DTLVardef@56b617_HPS_FORMAT_FIGEXP  M_TBL O_FLOATNOTable S1.C_FLOATNO O_TABLECAPTIONStudy population.

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title: Comparison of two T cell assays to evaluate T cell responses to SARS-CoV-2 following vaccination in naive and convalescent healthcare workers

abstract:
BackgroundT cell responses to SARS-CoV-2 following infection and vaccination are less characterised than antibody responses, due to a more complex experimental pathway.

MethodsWe measured T cell responses in 108 healthcare workers (HCWs) in an observational cohort study, using the commercialised Oxford Immunotec T-SPOT Discovery SARS-CoV-2 assay (OI T-SPOT) and the PITCH ELISpot protocol established for academic research settings.

ResultsBoth assays detected T cell responses to SARS-CoV-2 spike, membrane and nucleocapsid proteins. Responses were significantly lower when reported by OI T-SPOT than by PITCH ELISpot. Four weeks after two doses of either Pfizer/BioNTech BNT162b or ChAdOx1 nCoV-19 AZD1222 vaccine, the responder rate was 63% for OI T-SPOT Panels1+2 (peptides representing SARS-CoV-2 spike protein excluding regions present in seasonal coronaviruses), 69% for OI T-SPOT Panel 14 (peptides representing the entire SARS-CoV-2 spike), and 94% for the PITCH ELISpot assay. The two OI T-SPOT panels correlated strongly with each other showing that either readout quantifies spike-specific T cell responses, although the correlation between the OI T-SPOT panels and the PITCH ELISpot was moderate.

ConclusionThe standardisation, relative scalability and longer interval between blood acquisition and processing are advantages of the commercial OI T-SPOT assay. However, the OI T-SPOT assay measures T cell responses at a significantly lower magnitude compared to the PITCH ELISpot assay, detecting T cell responses in a lower proportion of vaccinees. This has implications for the reporting of low-level T cell responses that may be observed in patient populations and for the assessment of T cell durability after vaccination.


title: Molecular epidemiology of AY.28 and AY.104 delta sub-lineages in Sri Lanka

abstract:
BackgroundThe worst SARS-CoV-2 outbreak in Sri Lanka was due to the two Sri Lankan delta sub-lineages AY.28 and AY.104. We proceeded to further characterize the mutations and clinical disease severity of these two sub-lineages.

Methods705 delta SARS-CoV-2 genomes sequenced by our laboratory from mid-May to November 2021 using Illumina and Oxford Nanopore were included in the analysis. The clinical disease severity of 440/705 individuals were further analyzed to determine if infection with either AY.28 or AY.104 was associated with more severe disease. Sub-genomic RNA (sg-RNA) expression was analyzed using periscope.

ResultsAY.28 was the dominant variant throughout the outbreak, accounting for 67.7% of infections during the peak of the outbreak. AY.28 had three lineage defining mutations in the spike protein: A222V (92.80%), A701S (88.06%), and A1078S (92.04%) and seven in the ORF1a: R24C, K634N, P1640L, A2994V, A3209V, V3718A, and T3750I. AY.104 was characterized by the high prevalence of T95I (90.81%) and T572L (65.01%) mutations in the spike protein and by the absence of P1640L (94.28%) in ORF1a with the presence of A1918V (98.58%) mutation. The mean sgRNA expression levels of ORF6 in AY.28 were significantly higher compared to AY.104 (p < 0.0001) and B.1.617.2 (p < 0.01). Also, ORF3a showed significantly higher sgRNA expression in AY.28 compared to AY.104 (p < 0.0001). There was no difference in the clinical disease severity or duration of hospitalization in individuals infected with these sub lineages.

ConclusionsTherefore, AY.28 appears to have a fitness advantage over the parental delta variant (B.1.617.2) and AY.104 possibly due to the A222V mutation. AY.28 also had a higher expression of sg-RNA compared to other sub-lineages. The clinical implications of these should be further investigated.


title: Limitations of molecular and antigen test performance for SARS-CoV-2 in symptomatic and asymptomatic COVID-19 contacts

abstract:
ObjectivesCOVID-19 has brought unprecedented attention to the crucial role of diagnostics in pandemic control. We compared SARS-CoV-2 test performance by sample type and modality in close contacts of SARS-CoV-2 cases.

MethodsClose contacts of SARS-CoV-2 positive individuals were enrolled after informed consent. Clinician-collected nasopharyngeal (NP) swabs in viral transport media (VTM) were tested with a nucleic acid test (NAT). NP VTM and self-collected passive drool were tested using the PerkinElmer real-time reverse transcription PCR (RT-PCR) assay. For the first 4 months of study, mid-turbinate swabs were tested using the BD Veritor rapid antigen test. NAT positive NP samples were tested for infectivity using a VeroE6TMPRSS2 cell culture model.

ResultsBetween November 17, 2020, and October 1, 2021, 235 close contacts of SARS-CoV-2 cases were recruited, including 95 with symptoms (82% symptomatic for <5 days) and 140 asymptomatic individuals. NP swab reference tests were positive for 53 (22.6%) participants; 24/50 (48%) were culture positive. PerkinElmer testing of NP and saliva samples identified an additional 28 (11.9%) SARS-CoV-2 cases who tested negative by clinical NAT. Antigen tests performed for 99 close contacts showed 83% positive percent agreement (PPA) with reference NAT among early symptomatic persons, but 18% PPA in others; antigen tests in 8 of 11 (72.7%) culture-positive participants were positive.

ConclusionsContacts of SARS-CoV-2 cases may be falsely negative early after contact, which more sensitive platforms may identify. Repeat or serial SARS-CoV-2 testing with both antigen and molecular assays may be warranted for individuals with high pretest probability for infection.


title: Cumulative seroprevalence among healthcare workers after the first wave of the COVID-19 pandemic in El Salvador, Central America.

abstract:
BackgroundThe impact of novel coronavirus disease 2019 (COVID-19) on healthcare workers (HCWs) has been under-evaluated in Central America. We performed a seroepidemiological survey at a tertiary healthcare facility in El Salvador, where a large number of confirmed and far more suspected cases of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infected HCWs had been documented during the first wave of the pandemic.

MethodsDuring January-February 2021, a total 973 HCWs were tested for SARS-CoV-2 antibodies. Participants completed a questionnaire asking of their demographic data. Occupational risk was assessed by statistically comparing the seropositivity rates among different occupational categories.

ResultsOverall seroprevalence in HCWs reached 52.6% (512 of 973). Of the seropositive individuals, 61.7% (316 of 512) had experienced a documented COVID-19 diagnosis, while the remaining 38.3% (196 of 512) were unrecognized seroconversions. Differences in seropositivity rates existed between occupational categories; nurses demonstrated the highest at 63.8% (222 of 348, risk ratio 1.44, p < 0.0001), followed by auxiliary HCWs assigned to patient-related work (55.9%, 52 of 93), and medical doctors (46.7%, 50 of 107). Several non-patient-related professions showed above-average seroprevalence, suggesting substantial SARS-CoV-2 contacts outside the workplace: 60.0% (6 of 10) and 68.0% (17 of 25) for nutritionists and pharmacists, respectively.

ConclusionsSARS-CoV-2 seroprevalence exceeded 50% among HCWs in El Salvador, with disparity among occupational categories with different workplace exposure risks. Importance of not only nosocomial infection prevention but also screening for transmissions having occurred outside the workplace were highlighted to efficiently control nosocomial spreads during a pandemic wave.

Key pointsHealthcare workers in El Salvador were tested for SARS-CoV-2 antibodies. Seroprevalence reached 52.6%, with disparity among occupation; nurses ranked highest at 63.8% seropositivity. Alongside nosocomial transmissions, high seroprevalence associated with non-patient-related work suggested substantial SARS-CoV-2 contacts outside the workplace.


title: Clinical Severity and mRNA Vaccine Effectiveness for Omicron, Delta, and Alpha SARS-CoV-2 Variants in the United States: A Prospective Observational Study

abstract:
ObjectivesTo characterize the clinical severity of COVID-19 caused by Omicron, Delta, and Alpha SARS-CoV-2 variants among hospitalized adults and to compare the effectiveness of mRNA COVID-19 vaccines to prevent hospitalizations caused by each variant.

DesignA case-control study of 11,690 hospitalized adults.

SettingTwenty-one hospitals across the United States.

ParticipantsThis study included 5728 cases hospitalized with COVID-19 and 5962 controls hospitalized without COVID-19. Cases were classified into SARS-CoV-2 variant groups based on viral whole genome sequencing, and if sequencing did not reveal a lineage, by the predominant circulating variant at the time of hospital admission: Alpha (March 11 to July 3, 2021), Delta (July 4 to December 25, 2021), and Omicron (December 26, 2021 to January 14, 2022).

Main Outcome MeasuresVaccine effectiveness was calculated using a test-negative design for COVID-19 mRNA vaccines to prevent COVID-19 hospitalizations by each variant (Alpha, Delta, Omicron). Among hospitalized patients with COVID-19, disease severity on the WHO Clinical Progression Ordinal Scale was compared among variants using proportional odds regression.

ResultsVaccine effectiveness of the mRNA vaccines to prevent COVID-19-associated hospitalizations included: 85% (95% CI: 82 to 88%) for 2 vaccine doses against Alpha; 85% (95% CI: 83 to 87%) for 2 doses against Delta; 94% (95% CI: 92 to 95%) for 3 doses against Delta; 65% (95% CI: 51 to 75%) for 2 doses against Omicron; and 86% (95% CI: 77 to 91%) for 3 doses against Omicron. Among hospitalized unvaccinated COVID-19 patients, severity on the WHO Clinical Progression Scale was higher for Delta than Alpha (adjusted proportional odds ratio [aPOR] 1.28, 95% CI: 1.11 to 1.46), and lower for Omicron than Delta (aPOR 0.61, 95% CI: 0.49 to 0.77). Compared to unvaccinated cases, severity was lower for vaccinated cases for each variant, including Alpha (aPOR 0.33, 95% CI: 0.23 to 0.49), Delta (aPOR 0.44, 95% CI: 0.37 to 0.51), and Omicron (aPOR 0.61, 95% CI: 0.44 to 0.85).

ConclusionsmRNA vaccines were highly effective in preventing COVID-19-associated hospitalizations from Alpha, Delta, and Omicron variants, but three vaccine doses were required to achieve protection against Omicron similar to the protection that two doses provided against Delta and Alpha. Among adults hospitalized with COVID-19, Omicron caused less severe disease than Delta, but still resulted in substantial morbidity and mortality. Vaccinated patients hospitalized with COVID-19 had significantly lower disease severity than unvaccinated patients for all the variants.


title: Molecular markers for early stratification of disease severity and progression in COVID-19

abstract: COVID-19 infections have imposed immense pressure on the healthcare system of most countries. While the initial studies have identified better therapeutic and diagnostic approaches, the disease severity is still assessed by close monitoring of symptoms by healthcare professionals due to the lack of biomarkers for disease stratification. In this study, we have probed the immune and molecular profiles of COVID-19 patients at 48-hour intervals after hospitalization to identify early markers, if any, of disease progression and severity. Our study reveals that the molecular profiles of patients likely to enter the host-immune response mediated moderate or severe disease progression are distinct even in the early phase of infection when severe symptoms are not yet apparent. Our data from 37 patients suggest that at hospitalization, IL6 (>300pg/ml) and IL8 levels (>200pg/ml) identify cytokine-dependent disease progression. Monitoring their levels will facilitate timely intervention using available immunomodulators or precision medicines in those likely to progress due to cytokine storm and help improve outcomes. Additionally, it will also help identify cytokine-independent progressive patients, not likely to benefit from immuno-modulators or precision drugs.


title: Factors Associated with Active Trachoma among Children in Ebinat District, South Gondar Zone, North West Ethiopia: a community-based cross-sectional study

abstract:
BackgroundDespite the availability of effective prevention strategies and treatments, trachoma is still the major cause of infectious blindness worldwide. The majority of blindness from trachoma is currently reported from sub-Saharan Africa, with the greatest burden in Ethiopia. This study aimed to determine the prevalence and factors associated with active trachoma among children aged 1-9 years in Ebinat District.

MethodsA community-based cross-sectional study design was conducted in Ebinat District, South Gondar Zone, North West Ethiopia from March 1-30 2018. A multi-stage random cluster sampling technique was employed and all children 1-9 years old from the selected households were clinically examined for trachoma by ophthalmic nurses using the World Health Organization (WHO) simplified clinical grading scheme. A total of 565 children were included. Data were analyzed using SPSS. Multivariable logistic regression was used to identify factors associated with active trachoma among children.

ResultThe overall prevalence of active trachoma was 36.1% (95% CI: 32.0% - 40.0%). Of all active trachoma cases, 26.5% and 9.6% were trachomatous follicular and trachomatous follicular-intense respectively. Discharge on the eye (AOR=8.23; 95% CI: 4.27-15.87), presence of liquid waste around the main house (AOR=2.31; 95% CI: 1.47-3.61), presence of human feces around the main house (AOR=2.64; 95% CI: 1.61-4.35), unclean faces (AOR= 5.71; 95% CI: 2.18 - 14.96), not washing face and hands frequently (AOR= 2.28; 95% CI: 1.33-3.90), not using soap while washing face and hands (AOR=1.95; 95% CI: 1.21-3.34), and having more flies on childrens face (AOR=1.74; 95% CI: 1.12-2.73) were significantly associated with active trachoma.

Conclusion and recommendationActive trachoma is a major public health problem among children in the Ebinat District. Surgery for trichiasis, antibiotics for active disease, facial hygiene, and environmental improvement (SAFE) strategy at school and community are recommended to lower the burden of trachoma in the Ebinat District, Northwest Ethiopia.


title: Improving estimates of social contact patterns for the airborne transmission of respiratory pathogens

abstract:
BackgroundData on social contact patterns are widely used to parameterise age-mixing matrices in mathematical models of infectious diseases designed to help understand transmission patterns or estimate intervention impacts. Despite this, little attention is given to how social contact data are collected and analysed, or how the types of contact most relevant for transmission may vary between different infections. In particular, the majority of studies focus on close contacts only - people spoken to face-to-face. This may be appropriate for infections spread primarily by droplet transmission, but it neglects the larger numbers of  shared air casual contacts who may be at risk from airborne transmission of pathogens such as Mycobacterium tuberculosis, measles, and SARS-CoV-2.

MethodsWe conducted social contact surveys in communities in two provinces of South Africa in 2019 (KwaZulu-Natal and Western Cape). In line with most studies, we collected data on people spoken to (close contacts). We also collected data on places visited and people present, allowing casual contact patterns to be estimated. Using these data, we estimated age mixing patterns relevant for i) droplet and ii) non-saturating airborne transmission. We also estimated a third category of pattern relevant for the transmission of iii) Mycobacterium tuberculosis (Mtb), an airborne infection where saturation of household contacts plays an important role in transmission dynamics.

ResultsEstimated contact patterns by age did not vary greatly between the three transmission routes/infections, in either setting. In both communities, relative to other adult age groups, overall contact intensities were lower in 50+ year olds when considering contact relevant for non-saturating airborne transmission or the transmission of Mycobacterium tuberculosis than when considering contact relevant for droplet transmission.

ConclusionsOur findings provide some reassurance that the widespread use of close contact data to parameterise age-mixing matrices for transmission models of airborne infections may not be resulting in major inaccuracies. The contribution of older age groups to transmission may be over-estimated, however. There is a need for future social contact surveys to collect data on casual contacts, to investigate whether our findings can be generalised to a wider range of settings, and to improve model predictions for infections with substantial airborne transmission.


title: Research Letter: Genetically determined blood pressure traits are associated with increased risk of aortic dissection: a Mendelian randomization study

abstract:
ObjectiveTo identify blood pressure traits influencing aortic dissection susceptibility using Mendelian randomization (MR).

MethodsSummary statistics of AD genome-wide association studies (GWAS) was obtained from FinnGen R5 release, which included 470 individuals with AD and 206541 controls. Firstly, inverse variance weighted (IVW) was used to calculate the overall OR for blood pressure traits. Further, directional pleiotropy and heterogeneity were tested as well as MR pleiotropy residual sum and outlier (MR-PRESSO) method.

ResultsPositive associations were observed between DBP (OR=1.13, 95%CI 1.09-1.18, P-adjusted < 0.001), hypertension (OR=9.71, 95%CI 2.45-38.25, P-adjusted = 0.006) and AD. Further, there was potential causal relationship between MAP and AD (OR=1.15, 95%CI 1.02-1.30, P-unadjusted = 0.020). No significant association between SBP or PP and AD in the European populations were observed. No directional pleiotropy was observed. Heterogeneity was only detected in the genetic instruments for SBP (Cochrans Q statistics = 491.7, P = 0.010). The MR-PRESSO suggested one outlier SNP for SBP and one for PP which did not affect the result above.

ConclusionIn this study, we identified a forward causation between hypertension, SBP and AD. In addition, there were nominal significant causations between MAP and AD. No significant causal relationships were detected between other investigated blood pressure traits (SBP, PP) and AD.

category: cardiovascular medicine


title: AI-aided dynamic prediction of bleeding and ischemic risk after coronary stenting and subsequent DAPT

abstract:
BackgroundContemporary risk scores for ischemic or bleeding event prediction after drug-eluting stent (DES) implantation are limited to the determination of a single time duration for dual antiplatelet therapy (DAPT) and lack flexibility in providing dynamic risk stratification.

ObjectivesThis study sought to develop artificial intelligence (AI) models to dynamically predict the ischemic and bleeding risks at different time intervals for patients with DES implantation for personalized decision support for antiplatelet therapy.

MethodsWe identified 81,594 adult patients who received DES implantation in the United States from the Cerner HealthFacts(R) dataset. The total prediction window covered 12-30 months after DES implantation. We designed eight prediction scenarios with four prediction intervals (3, 6, 12, and 18 months). Five AI models were developed for the ischemic and bleeding risk stratification. Model performance was assessed using the area under the receiver operating characteristic curve (AUROC).

ResultsOur proposed AI model outperformed the clinical guideline-recommended tool-the DAPT score- for 12m-30m prediction (with AUROC 0.82 vs. 0.79 for ischemia, 0.77 vs 0.72 for bleeding). In the scenarios that are not covered by the DAPT score, our models demonstrated robust performance (AUROC ranges were 0.79-0.80 for ischemia and 0.75-0.76 for bleeding).

ConclusionsAs the first effort dedicated to dynamically forecasting adverse endpoints after DES implantation given DAPT continuation or discontinuation, our AI-empowered approach demonstrates superior capabilities for risk stratification, holding value as a novel clinical tool that can refine the prognostic judgments of clinicians and achieve optimal DAPT management.

Condensed abstractWe proposed an innovative AI-based dynamic prediction system that forecasts the ischemic and bleeding events after coronary stenting in varying time intervals given DAPT continuation or discontinuation. Our AI model not only demonstrated superiority compared with the clinical guideline-recommended tool-the DAPT score in the 12-30 months prediction, but also achieved robust performance in other scenarios that were not covered by the DAPT score. Our AI-driven approach holds value as a novel clinical tool that can refine the prognostic judgments of clinicians, enable better informed clinical decisions, and facilitate optimal DAPT management in the context of precision cardiovascular medicine.


title: Efficacy and safety of GLP-1 receptor agonists versus SGLT-2 inhibitors in overweight/obese patients with or without diabetes mellitus: a systematic review and network meta-analysis

abstract:
ObjectiveTo compare the efficacy and safety between and within glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose co-transporter 2 inhibitors (SGLT-2is) in overweight or obese adults with or without diabetes mellitus.

MethodsPubMed, ISI Web of Science, Embase and Cochrane Central Register of Controlled Trials (CENTRAL) database were comprehensively searched to identify randomised controlled trials (RCTs) of effects of GLP-1RAs and SGLT-2is in overweight or obese participants from inception to Jan 16, 2022. The efficacy outcomes were the changes of body weight, glycemic control and blood pressure. The safety outcomes were the serious adverse events and discontinuation due to adverse events. The mean differences (MDs), odds ratios (ORs), 95% credible intervals (95% CI), the surface under the cumulative ranking (SUCRA) were evaluated for each outcome by network meta-analysis.

ResultsSixty one RCTs were included in our analysis. Both GLP-1RAs and SGLT-2is conferred greater extents in body weight reduction, achieving at least 5% weight loss, HbA1c and fasting plasma glucose decrease compared with placebo. GLP-1RAs was superior to SGLT-2is in HbA1c reduction (MD: -0.39%, 95% CI: -0.70 to -0.08). GLP-1RAs had high risk of adverse events, while SGLT-2is were relatively safe. Based on intraclass comparison, semaglutide 2.4mg was the most efficacious agent in losing body weight (MD: -11.51kg, 95% CI: -12.83 to -10.21, SUCRA: 0.99), decreasing HbA1c (MD: -1.49%, 95% CI: -2.07 to -0.92, SUCRA: 0.93), fasting plasma glucose (MD: -2.15mmol/L, 95% CI: -2.83 to -1.59, SUCRA: 0.92), reducing systolic blood pressure (MD: -4.89mmHg, 95% CI: -6.04 to -3.71, SUCRA: 0.96), diastolic blood pressure (MD: -1.59mmHg, 95% CI: -2.37 to -0.86) while it was associated with high risk of adverse events.

ConclusionsSemaglutide 2.4mg showed greatest effects on losing body weight, controlling glycemic level and reducing blood pressure while it was associated with high risk of adverse events.

ARTICLE SUMMARYO_ST_ABSStrengths and limitations of this studyC_ST_ABS{blacktriangleright} Different types of GLP-1RAs and SGLT-2is in overweight/obese patients with or without diabetes mellitus were compared and analyzed in the study.
{blacktriangleright}In the absence of direct  head-to-head comparisons of GLP-1RAs and SGLT-2is in overweight or obese adults with or without diabetes mellitus, network meta-analysis was performed to compare the efficacy and safety of the drugs.
{blacktriangleright}The efficacy and safety between different dose of liraglutide and semaglutide was compared and analyzed in the study.
{blacktriangleright}Limitation of this study was that the numbers of RCTs included were few in some comparisons.


title: Protection of COVID-19 vaccination and previous infection against Omicron BA.1 and Delta SARS-CoV-2 infections, the Netherlands, 22 November 2021- 19 January 2022

abstract:
Given the emergence of the SARS-CoV-2 Omicron BA.1 variant and the roll-out of booster COVID-19 vaccination, evidence is needed on protection conferred by primary vaccination, booster vaccination and previous SARS-CoV-2 infection against Omicron BA.1 compared with Delta infection.

We employed a test-negative design and used multinomial logistic regression on data from community PCR testing in the Netherlands, from 22 November 2021 to 19 January 2022. S-gene target failure (SGTF) was used as proxy for Omicron BA.1 infection versus Delta.

A total of 528,488 tests were included, of which 38,975 SGTF and 41,245 non-SGTF infections. Protection from primary vaccination was 33% (95% confidence interval (CI): 31-35) and from previous infection 25% (95% CI: 21-29) against Omicron BA.1 infection. Protection against Delta infection was higher with 76% (95% CI: 75-76) for primary vaccination and 78% (95% CI: 76-80) for previous infection. Higher protection was observed in individuals with both primary vaccination and earlier infection compared with either one. Waning of vaccine- or infection-induced protection over time was observed against both variants. Booster vaccination considerably increased vaccine effectiveness against Omicron BA.1 to 76% (95% CI: 72-79) and 68% (95% CI: 67-69) with and without previous infection, respectively.

Primary vaccination with current COVID-19 vaccines and pre-Omicron SARS-CoV-2 infections offer low protection against Omicron BA.1 infection. Booster vaccination considerably increases protection against Omicron BA.1, although protection remains lower than against Delta.


title: The influence of biological, epidemiological, and treatment factors on the establishment and spread of drug-resistant Plasmodium falciparum

abstract:
The effectiveness of artemisinin-based combination therapies (ACTs) to treat Plasmodium falciparum malaria is threatened by resistance. The complex interplay between sources of selective pressure - treatment properties, biological factors, transmission intensity, and access to treatment - obscures understanding how, when, and why resistance establishes and spreads across different locations. We developed a disease modelling approach with emulator-based global sensitivity analysis to systematically quantify which of these factors drive establishment and spread of drug resistance. Drug resistance was more likely to evolve in low transmission settings due to the lower levels of (i) immunity and (ii) within-host competition between genotypes. Spread of parasites resistant to artemisinin partner drugs depended on the period of low drug concentration (known as the selection window). Spread of partial artemisinin resistance was slowed with prolonged parasite exposure to artemisinin derivatives and accelerated when the parasite was also resistant to the partner drug. Thus, to slow the spread of partial artemisinin resistance, molecular surveillance should be supported to detect resistance to partner drugs and to change ACTs accordingly. Furthermore, implementing more sustainable artemisinin-based therapies will require extending parasite exposure to artemisinin derivatives, and mitigating the selection windows of partner drugs, which could be achieved by including an additional long-acting drug.

Impact StatementDetailed models of malaria and treatment dynamics were combined with emulator-based global sensitivity analysis to elucidate how the interplay of drug properties, infection biology, and epidemiological dynamics drives evolution of resistance to artemisinin-based combination therapies. The results identify mitigation strategies.


title: COVID-19 outbreaks in Australia during a period of high epidemic control, 2020

abstract:
To describe characteristics of COVID-19 outbreaks in Australia to guide policy development for mitigation of future outbreaks, we conducted a retrospective analysis of COVID-19 outbreaks affecting two or more people reported to COVID-Net--an Australian national surveillance network--from 28 January until 27 December 2020. The COVID-Net surveillance network covered all Australian states and territories, with an estimated population of 25,649,985 persons as at 31 June 2020. We reported the epidemiology of COVID-19 outbreaks in Australia, including the setting in which they occurred, size, and duration.

853 outbreaks of COVID-19 were reported; associated with 13,957 confirmed cases, of whom 2,047 were hospitalised, and 800 died. The pattern of outbreaks followed a similar trend to the epidemic in Australia, defined by two distinct peaks in mid-March and July. Victoria reported the greatest number of outbreaks across all settings aligned with the second wave of infections. Outbreaks most commonly occurred in the workplace/industry setting (22%, 190/853), followed by education (14%, 122/853), residential aged care (13%, 114/853) and hospitals (10%, 83/853). The majority (40%, 340/853) of outbreaks had 6 to 24 cases, and the median outbreak duration increased in proportion with the number of associated cases.

This report summarising COVID-19 outbreaks in Australia identifies settings of highest risk. Surveillance of outbreaks informs our understanding of transmission dynamics in Australia relative to national and jurisdictional interventions. For settings that are high risk for COVID-19, it is important to prioritise planning, surveillance, and implementation of control measures.


title: Cross-Sectional Study of University students attitudes to on campus delivery of COVID-19 vaccines and future-proofing MenACWY and MMR vaccination rates by adopting COVID-19 vaccine roll-out strategies

abstract:
BackgroundUniversity students are a critical group for vaccination programmes against COVID-19, meningococcal disease (MenACWY), and measles, mumps and rubella (MMR). We aimed to evaluate risk factors for vaccine hesitancy (refusal or intention to refuse a vaccine) and views of university students about on-campus vaccine delivery.

MethodsCross-sectional anonymous online questionnaire study of undergraduate students at a British university in June 2021. Chi-squared, Fishers exact, univariate and multivariate tests were applied to detect associations.

ResultsComplete data were obtained from 827 participants (7.6% response-rate). Two-thirds (64%; 527/827) reported having been vaccinated against COVID-19 and a further 23% (194/827) agreed to be vaccinated. Other responses were either unclear (66) or indicated an intention to refuse vaccination (40). Hesitancy for COVID-19 vaccines was 5% (40/761). COVID-19 vaccine hesitancy was associated with black ethnicity (aOR, 7.01, 95% CI, 1.8-27.3) and concerns about vaccine side-effects (aOR, 1.72; 95% CI, 1.23-2.39). Lower levels of vaccine hesitancy were detected amongst students living in private accommodation (aOR, 0.13; 95% CI, 0.04-0.38) compared to those living at home. Uncertainty about their personal vaccine status was frequently observed for MMR (11%) and MenACWY (26%) vaccines. Campus-associated COVID-19 vaccine campaigns were definitely (45%) or somewhat (16%) favoured by UK-based students and more so among UK-based international students (62% and 12%, respectively).

ConclusionsVaccine hesitancy among students of black ethnicity and those living at home requires further exploration because attitudes in these groups may affect COVID-19 vaccine uptake. High levels of uncertainty among students about their MMR and MenACWY vaccine status are also a concern for the effectiveness of these vaccine programmes. This issue could be tackled by extending the capabilities of digital platforms for accessing vaccine information, such as the NHSapp in the UK. Sector-wide implementation of on-campus vaccine delivery may also improve vaccine uptake, especially for international students.


title: Estimating the risk reduction of isolation on COVID-19 non-household transmission and severe/critical illness in non-immune individuals: September to November 2021

abstract: In the fall 2021, immunity mandates/passports for COVID-19 started to be discussed and implemented globally. In addition to increasing vaccination levels, these interventions isolate non-immune individuals from various settings to reduce non-household transmission and severe/critical illness. This is based on the hypothesis that the non-immune are at high absolute risk of these outcomes. However, these absolute risks were not quantified in the literature such that the absolute risk reductions of isolation on these outcomes remain unknown. This study estimated these absolute risks from September to November 2021 prior to the emergence of Omicron (B.1.1.529) using known data on the risk of infection, transmission in non-household settings, and age-stratified severe/critical illness in non-immune individuals for the Delta (B.1.617.2) variant, focusing on the European Union, United Kingdom, United States, Canada, Australia, and Israel. This allowed us to quantify the absolute risk reductions of isolation on (1) non-household transmission from the non-immune and (2) severe/critical illness amongst the non-immune in these regions during this period. We observed that on any given day the absolute risk reductions of isolation were typically small for transmission in most types of non-household settings and severe/critical illness in most age-groups, especially those aged <40. During a wave or sustained higher infection risks, the risk reductions were modest only for transmission in intimate social gatherings and severe/critical illness in adults aged [≥]50-60. The limitations of this study and the implications for the expected benefits of isolating non-immune individuals on reducing these outcomes are discussed.


title: First genotype-phenotype study in TBX4 syndrome: gain-of-function mutations causative for lung disease

abstract:
RationaleDespite the increasing frequency of TBX4-associated pulmonary arterial hypertension (PAH), genotype-phenotype associations are lacking and may provide important insights.

MethodsWe assembled a multi-center cohort of 137 patients harboring monoallelic TBX4 variants and assessed the pathogenicity of missense variation (n = 42) using a novel luciferase reporter assay containing T-BOX binding motifs. We sought genotype-phenotype correlations and undertook a comparative analysis with PAH patients with BMPR2 causal variants (n = 162) or no identified variants in PAH associated genes (n = 741) genotyped via the NIHR BioResource - Rare Diseases (NBR).

ResultsFunctional assessment of TBX4 missense variants revealed gain-(n=8) or loss-of-function effects (n=23) with a similar wide phenotypic spectrum, ranging from early-onset developmental lung disease to adult-onset PAH. Variants located in the T-BOX and nuclear localization domains associated with earlier presentation (p = 0.002) and increased incidence of interstitial lung disease (p = 0.001). Event-free survival (death or transplantation) was marginally lower in the T-BOX group (p = 0.049) with adjustment for age and sex. Carriers of TBX4 variants were diagnosed at a younger age (p < 0.001) and had worse baseline lung function (FEV1, FVC) (p < 0.001) compared to the BMPR2 and no identified causal variant groups.

ConclusionsWe demonstrated that TBX4 syndrome is not strictly the result of haploinsufficiency but can also be caused by gain-of-function. The pleiotropic effects of TBX4 in lung disease may be in part explained by the differential effect of pathogenic mutations located in critical protein domains.

category: respiratory medicine


title: BASH-GN: A new machine learning derived questionnaire for screening obstructive sleep apnea

abstract:
PurposeThis study aims to develop a machine learning based questionnaire (BASH-GN) to classify obstructive sleep apnea (OSA) risk by considering risk factor subtypes.

MethodsA total of 4,527 participants that met study inclusion criteria were selected from Sleep Heart Health Study Visit 1 (SHHS 1) database. Another 1,120 records from Wisconsin Sleep Cohort (WSC) served as an independent test data set. Participants with an apnea hypopnea index (AHI) [≥] 15/h were considered as high OSA risk. Potential risk factors were ranked using mutual information between each factor and the AHI, and only the top 50% were selected. We classified the subjects into 2 different groups, low- and high phenotype groups, according to their risk scores. We then developed the BASH-GN, a machine learning based questionnaire that consists of two logistic regression classifiers for the 2 different subtypes of OSA risk prediction.

ResultsWe evaluated the BASH-GN on the SHHS 1 test set (n = 1237) and WSC set (n = 1120) and compared its performance with four commonly used OSA screening questionnaires, the Four-Variable, Epworth Sleepiness Scale, Berlin, and STOP-BANG. The model outperformed these questionnaires on both test sets regarding the area under the receiver operating characteristic (AUROC) and the area under the precision-recall curve (AUPRC). The model achieved AUROC (SHHS 1: 0.78, WSC: 0.76) and AUPRC (SHHS 1: 0.72, WSC: 0.74), respectively. The questionnaire is available at: https://c2ship.org/bash-gn

ConclusionConsidering OSA subtypes when evaluating OSA risk can improve the accuracy of OSA screening.


title: Is Netrin-1 Associated with the Development of Fibrosis in Systemic Sclerosis?

abstract:
Objectives and AimsNetrin-1 is a laminin class protein that guides the axonal during the first embryonic development, has pushing and pulling properties and axonal chemoattractant activity. Netrin-1 has been shown to increase the development of fibrosis in mouse lung and human SSc lung cell culture. In this study, we aimed to investigate the relationship between Netrin-1 and Systemic sclerosis (SSc) and to emphasize the role of Netrin-1 in the pathophysiology of SSc, by increasing the known VEGF and M2 macrophage expression, which supports the fibrotic process.

MethodsThe study included 56 SSc patients with a mean age of 48.08{+/-}13.59 years and 58 healthy volunteers with a mean age of 48.01{+/-}11.59 years. SSc organ involvements were scanned retrospectively from patient files and patients were grouped according to SSc complications. Calculation of Netrin-1 levels was performed using a quantitative sandwich enzyme immunoassay method with an ELISA kit (Elabscience, Texas, USA; catalog number: E-EL-H2328; lot number: GZWTKZ5SWK). Modified Rodnan scoring (MRS) was used for skin thickness scoring in SSc patients.

ResultsThe mean of Netrin-1 was found to be significantly higher in SSc (309.51{+/-}211.86) than in controls (125.36{+/-}83.8) (p<0.001). In ROC analysis, a cut-off value of 354.24 for Netrin in SSc was found to provide a diagnostic sensitive confidence interval with 32.8% sensitivity and 98.3% specificity (AUC[95% CI]: 0.746-0.895, p<0.001). No significant correlation was found between netrin-1 level, organ involvement in SSc, and MRS (p>0.05).

ConclusionIn this study, we found that there is a significant relationship between Netrin-1 levels and SSc disease. Our study is the first clinical study in which Netrin-1 elevation was demonstrated in SSc patients.

KEY MESSAGESO_ST_ABSWhat is already known about this subject?C_ST_ABSNetrin-1 has proangiogenic, antiapoptotic,c, and anti-inflammatory properties and is closely related to the development of fibrosis.

What does this study add?SSc hasta populasyonunda Netrin-1 plazma duzeylerini de[g]erlendiren bir calsma bulunmamaktadr. Bu calsmada SScde Netrin-1 ortalamasn sa[g]lkl kontrollere gore anlaml derecede yuksek oldu[g]unu bulunmustur (p<0,001).

How might this impact clinical practice or future developments?Considering the known roles of VEGF and M2 macrophages in the development of SSc and their close relationship with Netrin-1, further studies in this area seem to create a fertile field in understanding the complex pathophysiology of SSc and offering new therapeutic options.

category: rheumatology


title: Trends in pregnancy-associated cervical cancer in Japan between 2012 and 2017: A multicenter survey

abstract: Large-scale data on maternal and neonatal outcomes of pregnancy-associated cervical cancer in Japan are scarce, and treatment strategies have not been established. We conducted this multicenter retrospective observational study at 523 secondary/tertiary care hospitals in Japan to investigate the clinical features and trends in pregnancy-related cervical cancer treatments. We collected data for 290 patients with pregnancy-associated cervical cancer (during pregnancy, n=203; postpartum, n=87) diagnosed between January 1, 2012, and December 31, 2017. Of the 40 patients diagnosed at [≥]22 gestational weeks, 34 (85.0%) were carefully followed until delivery without intervention. Of the 163 patients diagnosed at <22 gestational weeks, 111 and 52 patients continued and terminated their pregnancies, respectively. Although the termination rate increased with cervical cancer stage, 90 patients with stage IB1 disease had a variety of treatment options, including termination of pregnancy. When we divided the 59 stage IB1 patients who continued their pregnancy into four groups based on the primary treatment (strict follow-up, conization, trachelectomy, and neoadjuvant chemotherapy), there were no significant differences in progression-free or overall survival. The percentile of birth weight at delivery was smaller in the neoadjuvant chemotherapy group than in the strict follow-up group (P =.02). The full-term delivery rate was relatively higher in the trachelectomy group (35%) than in the other groups. In conclusion, treatment decisions, including pregnancy termination for pregnancy-associated cervical cancer, should be made after estimating the stage, with careful consideration of both maternal and fetal benefits. These findings will help in developing treatment guidelines for pregnancy-associated cervical cancer.

category: obstetrics and gynecology


title: Strategies to support early- and mid-career cardiovascular researchers to thrive

abstract:
BackgroundRecent evidence indicates that high numbers of cardiovascular (CV) researchers have considered leaving the research and academic sector due to lack of job security and low funding success. Thus, there is an urgent need to develop solutions to support the retention of early- and mid-career researchers (EMCRs). Here, we aimed to explore the current challenges faced by CV EMCRs, identify solutions to support their career progression and retention, and define a pathway forward to provide a thriving CV EMCR culture in Australia.

MethodsAustralian CV EMCRs (<15 years post-PhD; n=34) participated in 90-minute online focus groups (n=7) to examine current CV research culture, equity in career progression and solutions (including a timeframe and level of priority) to overcome challenges to career success. Participants were purposefully grouped based on socio-demographic information, including years post-PhD, gender, ethnicity, sexual orientation and caring responsibilities.

ResultsParticipants identified that current metrics only rewarded a narrow set of successes and did not support a collaborative culture. The current appraisal of career disruption in grant applications was identified as inadequate to address underrepresented researchers, such as women and those from culturally-diverse backgrounds. EMCRs proposed 92 solutions aimed at interpersonal, organisational or external levels, with capacity building and equitable opportunities as key focus areas.

ConclusionPragmatic, cost-effective and implementable opportunities were identified to support the career progression of CV EMCRs to create a more sustainable, equitable and supportive workforce. This information can be used to strategically engage key stakeholders to enable CV EMCRs to thrive.


title: Increased household transmission and immune escape of the SARS-CoV-2 Omicron variant compared to the Delta variant: evidence from Norwegian contact tracing and vaccination data

abstract: Understanding the rapid epidemic growth of the novel SARS-CoV-2 Omicron variant is critical for public health management. We compared the secondary attack rate (SAR) of the Omicron and Delta variants in households using Norwegian contact tracing data from December 2021 to January 2022. Omicron SAR was higher (51%) than Delta (36%), with a relative risk (RR) of 1.41 (95% CI 1.27-1.56). We observed increased susceptibility to Omicron infection in household contacts compared to Delta independent of vaccination status; however, considering booster vaccinated contacts, the mean SAR was lower for both variants. We found increased Omicron transmissibility in all vaccination groups of primary cases, except partially vaccinated, compared to Delta. In particular, Omicron SAR for boosted primary cases was high, 46% vs 11 % for Delta (RR 4.34; 95% CI 1.52-25.16). In conclusion, booster doses decrease the infection risk of Delta and Omicron but have limited effect in preventing Omicron transmission.


title: Sexual Orientation Experiences of Discrimination: Internal structure and consistency in a diverse Colombian population

abstract: The study aimed to determine the dimensionality, internal consistency, and nomological validity of the Sexual Orientation Experiences of Discrimination (SOEOD-9) among lesbian, gay, bisexual, and queer people in Santa Marta, Colombia. The study included 303 individuals between 18 and 70 years old. Participants completed the SOEOD-9. Dimensionality was explored using confirmatory (CFA) factor analysis; internal consistency with Cronbachs alpha and McDonalds omega; and nomological validity with Students test. The SOEOD-9 presented two factors that explained 51.6% of the variance and high internal consistency. Nevertheless, the CFA showed poor indicators of goodness-of-fit for the two-dimensional solution. A five-item version (SOEOD-5) improved overall performance (dimensionality, internal consistency, and nomological validity). In conclusion, the SOEOD-9 shows a two-factor internal structure with poor goodness-of-fit indicators and acceptable internal consistency and nomological validity. The SOEOD-5 presents better global indicators of dimensionality, internal consistency, and nomological validity.


title: Sexual Orientation Experiences of Discrimination: Dimensionality, internal consistency, and nomological validity in a diverse Colombian population


title: Changes in the number of public health nurses employed in local governments in Japan during the Covid-19 pandemic: A cross-sectional study

abstract:
ObjectivesThis study aims to clarify the recruitment of public health nurses in local governments in Japan during the Covid-19 pandemic.

Study designA cross-sectional study.

MethodsA cross-sectional study of 150 local governments that have public health centers in Japan was conducted. The survey period was November to December 2021. The survey items were the number of full-time and part-time public health nurses (PHNs), the number of PHNs who resigned or retired from the job, and the number of PHN recruitment examinations for each year from 2017 to 2021. For all variables, the mean, standard deviation, maximum, and minimum values for each type of municipality and year were calculated, and a one-way analysis of variance was performed.

ResultsThe recovery rate was 54.0% (81/150). Although a statistically significant difference was not recorded in the change in employment status of PHNs from 2019 to 2020, during the year that COVID-19 infection began in Japan, the number of full-time PHNs increased by only 2.6 at the maximum, while the number of part-time PHNs was 5.2{+/-}8.3 to 10.8{+/-}9.6 (p = 0.61) for prefectures, from 13.6{+/-}13.1 to 21.5{+/-}34.8 (p = 0.23) for city, and from 16.8{+/-}26.8 to 52.3{+/-}132.5 (p = 0.70) for ward.

ConclusionsThis study reveals that support for the increased workload due to COVID-19 is heavily dependent on part-time PHNs. Drastic change to the ideal way of the original countermeasure to Covid-19 in Japan or the supply of stronger human support to the public health center might be desired.

category: nursing


title: Environmental monitoring and health assessment in an industrial town in central India: A cross-sectional study protocol

abstract:
BackgroundTextile industry has been widely implicated in environmental pollution. The health effects of residing near manufacturing industries are not well documented in India, especially in central India. Hence, a cross-sectional environmental monitoring and health assessment study was initiated as per directions of the local authorities.

MethodsComprehensive exposure data about the concentrations of relevant pollutants in the ambient air and ground water samples in the study area will be collected over 1 year. Using stratified random sampling, 3003 apparently healthy adults will be selected from the study area. Sociodemographic and anthropometric information, relevant medical and family history, and investigations including spirometry, electrocardiogram, neurobehavioral tests, and laboratory investigations (complete blood count, lipid profile and random blood glucose) will be conducted. Finally Iodine azide test and heavy metal level detection in urine and blood samples respectively will be conducted in a subset of selected participants to assess individual pollution exposure. Ethics approval has been obtained from the Institutional Ethics Committee of the National Institute for Research in Environmental Health (No: NIREH/IEC-7-II/1027, dated 07/01/2021).

DiscussionThis manuscript describes the protocol for a multi-disciplinary study that aims to conduct environmental monitoring and health assessment in residential areas near viscose rayon and associated chemical manufacturing industries. Although India is the second largest manufacturer of rayon, next only to China, and viscose rayon manufacturing has been documented to be a source of multiple toxic pollutants, there is a lack of comprehensive information about the health effects of residing near such manufacturing units in India. Therefore implementing this study protocol will aid in filling in this knowledge gap.

category: occupational and environmental health


title: A Bibliometric Analysis of Ophthalmology Resident Research Productivity in the United States

abstract:
PurposeTo quantify scholarly activity of ophthalmology residents during residency and assess what factors may be associated with greater research productivity of these residents.

MethodsOphthalmology residents who graduated in 2021 were identified from their respective program websites. Bibliometric data published by these residents between the beginning of their PGY-2 year (July 1st, 2018) until three months after graduation (September 30th, 2021) were captured through searches via PubMed, Scopus, and Google Scholar. The association of the following factors with greater research productivity numbers was analyzed: residency tier, medical school rank, sex, doctorate degree, type of medical degree, and international medical graduate status. Residency programs were sorted into five tiers by Doximity "reputation" and medical schools were stratified into US News Top 40 and non-Top 40 schools.

ResultsWe found 418 ophthalmology residents from 98 residency programs. These residents published a mean ({+/-}SD) number of 2.68{+/-}3.81 peer-reviewed publications, 2.39{+/-}3.40 ophthalmology-related publications, and 1.18{+/-}1.96 first-author publications each. The mean ({+/-}SD) h-index for this cohort was 0.79{+/-}1.17. Upon multivariate analysis, we discovered significant correlations between both residency tier and medical school rank and all bibliometric variables assessed. Pairwise comparisons revealed that residents from higher tier programs had greater research productivity numbers than those from lower tier programs.

ConclusionsWe obtained bibliometric standards for ophthalmology residents on a national scale. Residents who graduated from higher-ranked residency programs and medical schools possessed higher h-indices and published more peer-reviewed publications, ophthalmology-related articles, and first author publications.

category: ophthalmology