title: Global Epidemiology and Genetic Environment of mcr genes: A One Health Systematic Review of Current and Emerging Trends

abstract:
BackgroundMobile colistin resistance (mcr) genes modify Lipid A molecules of the lipopolysaccharide, changing the overall charge of the outer membrane.

MethodsA systematic review of all studies published between January 2015 to July 2021 was performed. Included articles described mcr genes in the context of their genetic environment, fitness cost, crystal structure, their enzymatic activity and the risk factors associated with the acquisition of mcr. Studies describing the epidemiology of mcr genes and novel therapeutics were included.

Results and DiscussionTen mcr genes have been described to date within eleven Enterobacteriaceae species, with Escherichia coli, Klebsiella pneumoniae, and Salmonella species being the most predominant. They are present worldwide in 72 countries, with human specimens currently having the highest incidence. This is due to the wide dissemination of mcr in livestock animals, meat, manure, the environment, and wastewater samples, increasing the risk of transmission via foodborne, zoonotic, and vector-borne routes to humans. The stability and spread of mcr genes were mediated by mobile genetic elements such as the IncHI2 conjugative plasmid, which is associated with multiple mcr-variants and other antibiotic resistance genes. The cost of acquiring mcr is reduced by compensatory adaptation mechanisms. MCR proteins are well conserved via structurally. Hence, MCR-1 inhibitors and therapeutics should be applicable to all MCR proteins.

ConclusionMcr genes have spread from animals into the clinical setting, threatening public health. Combination therapies are a promising option for managing and treating colistin-resistant Enterobacteriaceae isolates whilst reducing the toxic effects of colistin.

Importance/HighlightsO_LIMcr genes are associated with mobile genetic elements that are facilitating its global dissemination.
C_LIO_LIUsing colistin as a growth promoter increases the risk of acquiring mcr-positive Enterobacteriaceae in food-producing animals.
C_LIO_LIThere is a higher incidence of mcr genes in humans than animals.
C_LIO_LIMCR proteins are phosphoethanolamine (PEtN) transferases that mediate the transfer of PEtN from its primary phosphatidylethanolamine to lipid A.
C_LIO_LIMultiple compounds can synergistically restore colistins activity, reducing its dosage and toxicity.
C_LIO_LICRISPR-Cas9, endolysins-engineered enzymes, and antimicrobial peptides are promising therapies for colistin resistance
C_LI

Tweet: "Within bacteria, mobile colistin resistance genes have spread widely, with a high incidence in human samples. Its critical to comprehend the genetic tools facilitating this spread and their mechanisms of action. These are detailed in this paper, as are new therapeutic strategies for managing these resistance genes."


title: Assessing the heterogeneity in the transmission of infectious diseases from time series of epidemiological data

abstract: Structural features and the heterogeneity of disease transmissions play an essential role in the dynamics of epidemic spread. But these aspects can not completely be assessed from aggregate data or macroscopic indicators such as the effective reproduction number. We propose an index of effective aggregate dispersion (EffDI) that indicates the significance of infection clusters and superspreading events in the progression of outbreaks by carefully measuring the level of stochasticity in time series of reported case numbers. This allows to detect the transition from predominantly clustered spreading to a diffusive regime with diminishing significance of singular clusters, which can be decisive for the future progression of outbreaks and relevant in the planning of containment measures. We evaluate EffDI for SARS-CoV-2 case data in different countries and compare the results with a quantifier for the socio-demographic heterogeneity in disease transmissions in a case study to substantiate that EffDI qualifies as a measure for the heterogeneity in transmission dynamics.

category: epidemiology


title: Government restriction efficiency on curbing COVID-19 pandemic transmission in Western Europe

abstract: In this article we assess the effectiveness of the restrictions, implemented at government level, to curb the first wave of the COVID-19 outbreak (January-May 2020) in seven European countries. The analysis put in evidence a strong correlation (correlation coefficient greater than 0.85) between one of the statistical parameters of the distribution representing the temporal evolution of the weekly number of patients admitted into the Intensive Cure Unit (ICU), i.e., the skewness, and the Stringency Index, an aggregate synthetic variable that reflects the level of implemented restrictions by a specific country on a scale between 0 (no restrictions) and 100 (full lockdown). Then, to assess if the skewness is consistent in effectively reflecting the applied restrictions, we computed the skewness for non-Covid flu outbreaks during four years from 2014-2015 to 2018-2019 and Covid-19 outbreak, where no restrictions were applied in Italy. The results highlight a significant difference between the values of the skewness for the normal flu with respect to the COVID-19 outbreak. This large difference put in evidence that the implemented restrictions modify the skewness of the ICU hospitalized patient number distribution. The skewness then can be used as a valid indicator to assess if the restriction had any effect on pandemic transmission and can be used as a support for decision makers.


title: Incidence of Enteric Fever in Juba, South Sudan

abstract: We apply a new serosurveillance tool to estimate typhoidal Salmonella burden from dried blood spots in Juba, South Sudan, finding a seroincidence rate of 35 per 100 person-years and cumulative incidence of 78% over four years.


title: Seroincidence of Enteric Fever in Juba, South Sudan


title: A compartmental Mathematical model of COVID-19 intervention scenarios for Mumbai

abstract: A new mathematical method with an outstanding potential to predict the incidence of COVID-19 diseases has been proposed. The model proposed is an improvement to the SEIR model. In order to improve the basic understanding of disease spread and outcomes, four compartments included presymptomatic, asymptomatic, quarantine hospitalized and hospitalized. We have studied COVID-19 cases in the city of Mumbai. We first gather clinical details and fit it on death cases using the Lavenberg-Marquardt model to approximate the various parameters. The model uses logistic regression to calculate the basic reproduction number over time and the case fatality rate based on the age-category scenario of the city of Mumbai. Two types of case fatality rate are calculated by the model: one is CFR daily, and the other is total CFR. The total case fatality rate is 4.2, which is almost the same as the actual scenario. The proposed model predicts the approximate time when the disease is at its worst and the approximate time when death cases barely arise and determines how many hospital beds in the peak days of infection would be expected. The proposed model outperforms the classic ARX, SARIMAX and the ARIMA model. And It also outperforms the deep learning models LSTM and Seq2Seq model. To validate results, RMSE, MAPE and R squared matrices are used and are represented using Taylor diagrams graphically.


title: Risk Factors and Pivotal Periods: Marital Status over 28 Years for Parents of Individuals with Autism

abstract: Longitudinal, prospective analyses of marital status in parents of individuals with autism are needed. We describe the timing of divorce, and the factors that contribute to divorce in a longitudinal sample of families of individuals with autism. Participants included parents of 219 children, initially referred for autism and other developmental delays, followed to age 30 years. Approximately 36% of individuals with autism in our sample experienced a parental divorce by age 30. Higher rates of divorce were associated with maternal education, race and age at childs birth, as well as autism symptom severity and diagnosis. Divorces were most common in early years (under age 5) and also in the teenage years and beyond (over age 15). After age 15, higher risk was associated with higher cognitive ability and daily living skills, and being a multiplex family. Results suggest that divorce risk in families of children with autism remains high through childhood into early adulthood. Understanding factors related to changes in marital status may help us better support families across time.

category: psychiatry and clinical psychology


title: Cross-cultural adaptation and validation of the COVID Stress Scales in Greek

abstract:
BackgroundDuring the COVID-19 pandemic, several instruments were developed to measure the psychological impact of COVID-19, such as fear, anxiety, post-traumatic stress, phobia, etc.

ObjectiveTo adapt cross-cultural and validate the "COVID Stress Scales" in Greek.

MethodsWe conducted a cross-sectional study with 200 participants between November 2021 to February 2022. All participants were adults, and a convenience sample was obtained. We applied the forward-backward translation method to create a Greek version of the "COVID Stress Scales". We assessed reliability of the questionnaire with test-retest method in a 10-day window, and we assessed validity of the questionnaire with exploratory factor analysis.

ResultsOur five-factor model explained 72% of the variance and totally confirmed the factors of the initial "COVID Stress Scales". In particular, we found the following five factors: (a) COVID-19 danger and contamination (eleven items), (b) COVID-19 socioeconomic consequences (six items), (c) COVID-19 xenophobia (six items), (d) COVID-19 traumatic stress (six items), and (e) COVID-19 compulsive checking (six items). Cronbachs coefficients alpha for the five factors that emerged from the exploratory factor analysis were greater than 0.89 indicating excellent internal reliability.

ConclusionsWe found that the "COVID Stress Scales" is a reliable and valid tool to measure stress due to the COVID-19 in the Greek population.

category: public and global health


title: Coexisting autoantibodies against transcription factor Sp4 are associated with decreased cancer risk in dermatomyositis patients with anti-TIF1gamma autoantibodies

abstract:
ObjectivesIn dermatomyositis (DM), different autoantibodies are associated with unique clinical phenotypes. For example, anti-TIF1{gamma} autoantibodies are associated with a substantially increased risk of cancer. The purpose of this study was to discover novel DM autoantibodies.

MethodsPhage ImmunoPrecipitation Sequencing using sera from 67 DM patients suggested that transcription factor Sp4 is a novel autoantigen; this was confirmed by showing that patient sera immunoprecipitated full-length Sp4 protein. Sera from 371 Johns Hopkins myositis patients (255 with DM, 28 with antisynthetase syndrome [ASyS], 40 with immune-mediated necrotizing myopathy [IMNM], 29 with inclusion body myositis [IBM], and 19 with polymyositis [PM]), 75 rheumatologic disease controls (25 with Sjogrens syndrome, 25 with systemic lupus erythematosus, and 25 with rheumatoid arthritis), and 200 healthy comparators were screened for anti-SP4 autoantibodies by an enzyme-linked immune absorption assay. Serum from 23 Spanish TIF1{gamma}-positive DM patients was also screened for anti-Sp4 autoantibodies

ResultsAnti-Sp4 autoantibodies were present in 11.4% of DM and 8% of rheumatoid arthritis patients but not in any other clinical group. Among DM patients, 90% of anti-Sp4 autoantibodies were detected in patients with anti-TIF1{gamma} autoantibodies. Among anti-TIF1{gamma}-positive DM patients from Johns Hopkins and Spain, those with coexisting anti-Sp4 autoantibodies had a decreased risk of cancer (0% vs. 31%; p=0.001, Chi-squared test).

ConclusionsAnti-Sp4 autoantibodies are enriched in anti-TIF1{gamma}-positive DM patients without cancer, suggesting that the development of an anti-Sp4 immune response may correlate with a relatively low risk of cancer in these patients.

KEY MESSAGESO_ST_ABSWhat is already known about this subject?C_ST_ABSO_LIDermatomyositis patients with anti-TIF1{gamma} autoantibodies have an increased risk of cancer.
C_LI

What does this study add?O_LIAnti-Sp4 autoantibodies are enriched in dermatomyositis patients with anti-TIF1{gamma} autoantibodies.
C_LIO_LIAnti-Sp4 autoantibodies are only found in dermatomyositis patients without cancer.
C_LIO_LIMuscle strength is greater in dermatomyositis patients with anti-Sp4 autoantibodies.
C_LIO_LIAnti-Sp4 autoantibodies are not present in patients with antisynthetase syndrome, immune-mediated necrotizing myopathy, or inclusion body myositis.
C_LIO_LIAutoantibodies against Sp4 are absent in those with systemic lupus erythematosus or Sjogrens syndrome and present in 8% of those with rheumatoid arthritis.
C_LI

How might this impact on clinical practice?Testing for anti-Sp4 autoantibodies may define a population of anti-TIF1{gamma}-positive dermatomyositis patients without a substantially increased risk of cancer.

category: rheumatology


title: Genetic Polymorphisms Associated with Adverse Pregnancy Outcomes in Nulliparas

abstract:
BackgroundAdverse pregnancy outcomes (APOs) affect a large proportion of pregnancies and represent an important cause of morbidity and mortality worldwide. Yet, the pathophysiology of APOs is poorly understood, limiting our ability to prevent and treat these conditions.

ObjectiveTo search for genetic risk markers for four APOs, we performed genome-wide association studies (GWAS) for preterm birth, preeclampsia, gestational diabetes, and pregnancy loss.

Study DesignA total of 9,757 nulliparas from the nuMoM2b study were genotyped. We clustered participants by their genetic ancestry and focused our analyses on the three sub-cohorts with the largest sample sizes: European (EUR, n=6,082), African (AFR, n=1,425), and American (AMR, n=846). Association tests were carried out separately for each sub-cohort and brought together via meta-analysis. Four APOs were tested by GWAS: preeclampsia (n=7,909), gestational length (n=4,781), gestational diabetes (n=7,617), and pregnancy loss (n=7,809). Using the results of the genome-wide associations for each APO, SNP-based heritability of these traits was inferred using LDscore. Putative regulatory effects were inferred by transcriptome-wide association analysis.

ResultsTwo variants were significantly associated with pregnancy loss (rs62021480: OR = 3.29, P = 7.83x10-11, and rs142795512: OR = 4.72, P = 9.64x10-9), implicating genes TRMU and RGMA in this APO. An intronic variant was significantly associated with gestational length (rs73842644: beta = -0.667, P = 4.9x10-8). Three loci were significantly associated with gestational diabetes (rs72956265: OR = 3.09, P = 2.98x10-8, rs10890563: OR = 1.88, P = 3.53x10-8, rs117689036: OR = 3.15, P = 1.46x10-8), located on or near ZBTB20, GUCY1A2, and MDGA2, respectively. Several loci previously correlated with preterm birth (in genes WNT4, EBF1, PER3, IL10, and ADCY5), gestational diabetes (in TCF7L2), and preeclampsia (in MTHFR) were found to be associated with these outcomes in our cohort as well.

ConclusionOur study identified genetic associations with gestational diabetes, pregnancy loss, and gestational length. We also confirm correlations of several previously identified variants with these APOs.

Disclosure StatementThe authors declare no conflict of interest

Source of financial supportPrecision Health Initiative of Indiana University, National Institutes of Health award R01HD101246 to DMH and PR. Cooperative agreement funding from the National Heart, Lung, and Blood Institute and the Eunice Kennedy Shriver National Institute of Child Health and Human Development: grant U10-HL119991 to RTI International; grant U10-HL119989 to Case Western Reserve University; grants U10-HL120034 and R01LM013327 to Columbia University; grant U10-HL119990 to Indiana University; grant U10-HL120006 to the University of Pittsburgh; grant U10-HL119992 to Northwestern University; grant U10-HL120019 to the University of California, Irvine; grant U10-HL119993 to University of Pennsylvania; and grant U10-HL120018 to the University of Utah. National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health to Clinical and Translational Science Institutes at Indiana University (grant UL1TR001108) and University of California, Irvine (grant UL1TR000153).

category: obstetrics and gynecology


title: Myocarditis and Pericarditis following COVID-19 Vaccination: Evidence Syntheses on Incidence, Risk Factors, Natural History, and Hypothesized Mechanisms

abstract:
ObjectivesMyocarditis and pericarditis are adverse events of special interest after vaccination for COVID-19. Evidence syntheses were conducted on incidence rates, risk factors for myocarditis and pericarditis after COVID-19 mRNA vaccination, clinical presentation and short- and longer-term outcomes of cases, and proposed mechanisms and their supporting evidence.

DesignSystematic reviews and evidence reviews.

Data sourcesMedline, Embase and the Cochrane Library were searched from October 2020 to January 10, 2022; reference lists and grey literature (to January 13, 2021).

Review methodsLarge (>10,000) or population-based/multisite observational studies and surveillance data (incidence and risk factors) reporting on confirmed myocarditis or pericarditis after COVID-19 vaccination; case series (n[≥]5, presentation, short-term clinical course and longer-term outcomes); opinions/letters/reviews/primary studies focused on describing or supporting hypothesized mechanisms. A single reviewer completed screening and another verified 50% of exclusions, using a machine-learning program to prioritize records. A second reviewer verified all exclusions at full text, extracted data, and (for incidence and risk factors) risk of bias assessments using modified Joanna Briggs Institute tools. Team consensus determined certainty of evidence ratings for incidence and risk factors using GRADE.

Results46 studies were included (14 on incidence, 7 on risk factors, 11 on characteristics and short-term course, 3 on longer term outcomes, and 21 on mechanisms). Incidence of myocarditis after mRNA vaccines is highest in male adolescents and young adults (12-17y: range 50-139 cases per million [low certainty] and 18-29y: range 28-147 per million [moderate certainty]). For 5-11 year-old males and females and females 18-29 years of age, incidence of myocarditis after vaccination with Pfizer may be fewer than 20 cases per million (low certainty). There was very low certainty evidence for incidence after a third dose of an mRNA vaccine. For 18-29 year-old males and females, incidence of myocarditis is probably higher after vaccination with Moderna compared to Pfizer (moderate certainty). Among 12-17, 18-29 and 18-39 year-olds, incidence of myocarditis/pericarditis after dose 2 of an mRNA vaccine may be lower when administered [≥]31 days compared to [≤]30 days after dose 1 (low certainty). Data specific to males aged 18-29 indicated that the dosing interval may need to increase to [≥]56 days to substantially drop incidence. For clinical course and short-term outcomes only one small series (n=8) was found for 5-11 year olds. In cases of adolescents and adults, the majority (>90%) of myocarditis cases involved 20-30 year-old males with symptom onset 2 to 4 days after second dose (71-100%). Most cases were hospitalized ([≥]84%) for a short duration (2-4 d). For pericarditis, data is limited but more variation has been reported in patient age, sex, onset timing and rate of hospitalization. Case series with longer-term (3 mo; n=38) follow-up suggest persistent ECG abnormalities, as well as ongoing symptoms and/or a need for medications or restriction from activities in >50% of patients. 16 hypothesized mechanisms are described, with little direct supporting or refuting evidence.

ConclusionsAdolescent and young adult males are at the highest risk of myocarditis after mRNA vaccination. Pfizer over Moderna and waiting more than 30 days between doses may be preferred for this population. Incidence of myocarditis in children aged 5-11 may be very rare but certainty was low. Data on clinical risk factors was very limited. Clinical course of mRNA related myocarditis appears to be benign although longer term follow-up data is limited. Prospective studies with appropriate testing (e.g., biopsy, tissue morphology) will enhance understanding of mechanism(s).

Funding and Registration noThis project was funded in part by the Canadian Institutes of Health Research (CIHR) through the COVID-19 Evidence Network to support Decision-making (COVID-END) at McMaster University. Not registered.

Summary boxWhat is already known about this topic?

Case reports and surveillance signals of myocarditis (inflammation of the heart muscle) and pericarditis (inflammation of the two-layered sac surrounding the heart) after COVID-19 vaccination appeared as early as April 2021.

These have prompted ongoing surveillance and research of these complications to investigate their incidence, possible attribution to the vaccines, and clinical course.

What this study adds

This review critically appraises and synthesizes the available evidence to-date on the incidence of and risk factors for myocarditis and pericarditis after COVID-19 vaccination in multiple countries. It summarizes the presentation and clinical course of over 8000 reported cases and describes some initial reports of longer term outcomes. Further, many possible mechanisms are outlined and discussed.

Though low, the incidence of myocarditis is probably the highest in young males aged 12-29 years and is probably higher with Moderna than Pfizer mRNA vaccines. Longer dosing intervals may be beneficial. Most cases are mild and self-limiting, though data in 5-11 year-olds is very limited. Continued active surveillance with longer term follow-up is warranted.

category: infectious diseases


title: Risk of Suicide Ideation in Comorbid Substance Use Disorder and Major Depression.

abstract:
BackgroundSuicidal behaviour is commonly associated with major depression (MD) and substance use disorders (SUDs). However, there is a paucity of research on risk for suicide ideation among individuals with comorbid SUDs and MD in the general population.

ObjectivesThis study investigated the associated risk of suicide ideation in comorbid SUDs - cannabis use disorder (CUD), alcohol use disorder (AUD), drug use disorder (DUD) with depression in a nationally representative sample.

MethodsMultilevel logistic regression models were used to analyze the 2012 Canadian Community Health Survey (CCHS-MHC) data. This is a cross-sectional survey of nationally representative samples of Canadians (n = 25,113) aged 15 years and older residing in the ten Canadian provinces between January and December 2012. Diagnoses of MD episode, AUD, DUD, CUD, and suicide risk were based on the WHO-CIDI-3.0 derived from DSM-IV diagnostic criteria.

ResultsComorbidity was found to be the strongest predictor of suicide ideation. Compared to those with no diagnosis, individuals with a comorbid diagnosis of AUD with MDE, CUD with MDE, or DUD with MDE were 9 to 16 times more likely to have suicide ideation. A diagnosis of MDE was a significant predictor of suicide ideation with about a 7-fold increased risk.

ConclusionSuicide is a preventable public health issue. Our study found a significantly increased risk of suicide ideation among persons who have comorbid SUD with MD. Effective integration of mental health and addictions services could mitigate the risk of suicide and contribute to better outcomes.

category: addiction medicine


title: Unquantifiably low aldosterone concentrations are prevalent in hospitalised COVID-19 patients but may not be revealed by chemiluminescent immunoassay

abstract:
ObjectivePrevious studies have reported conflicting findings regarding aldosterone levels in patients hospitalised with COVID-19. We therefore used the gold-standard technique of liquid chromatography tandem mass-spectrometry (LCMSMS) to address this uncertainty.

DesignAll patients admitted to Cambridge University Hospitals with COVID-19 between March 10, 2020 and May 13, 2021, and in whom a stored blood sample was available for analysis, were eligible for inclusion.

MethodsAldosterone was measured by LCMSMS and by immunoassay; cortisol and renin were determined by immunoassay.

ResultsUsing LCMSMS, aldosterone was below the limit of detection (<70 pmol/L) in 74 (58.7%) patients. Importantly, this finding was discordant with results obtained using a commonly employed clinical immunoassay (Liaison Diasorin(R)), which over-estimated aldosterone compared to the LCMSMS assay (intercept 14.1 [95% CI -34.4 to 54.1] + slope 3.16 [95% CI 2.09 to 4.15] pmol/L). The magnitude of this discrepancy did not clearly correlate with markers of kidney or liver function. Solvent extraction prior to immunoassay improved the agreement between methods (intercept -14.9 [95% CI -31.9 to -4.3] and slope 1.0 [95% CI 0.89 to 1.02] pmol/L) suggesting the presence of a water-soluble metabolite causing interference in the direct immunoassay. We also replicated a previous finding that blood cortisol concentrations were often increased, with increased mortality in the group with serum cortisol levels >744 nmol/L (p=0.005).

ConclusionWhen measured by LCMSMS, aldosterone was found to be profoundly low in a significant proportion of patients with COVID-19 at the time of hospital admission. This has likely not been detected previously due to high levels of interference with immunoassays in patients with COVID-19, and this merits further prospective investigation.

category: endocrinology


title: Descriptive epidemiology of cardiorespiratory fitness in UK adults: The Fenland Study.

abstract:
BackgroundCardiorespiratory fitness is rarely measured in population studies. Most studies of fitness do not examine differences by population subgroups or seasonal trends.

MethodsWe used a validated submaximal exercise test to measure fitness in 5976 women and 5316 men, residing in England. We expressed fitness as maximal oxygen consumption per kilogram total body mass (VO2maxtbm) and fat free mass (VO2maxffm). Descriptive statistics were computed across anthropometric and sociodemographic characteristics, as well as across the year. Progressive multivariable analyses were performed to examine mediation by physical activity energy expenditure (PAEE) and BMI.

ResultsMean{+/-}SD VO2maxtbm was lower in women (35.4{+/-}7.6 ml{middle dot}min-1{middle dot}kg-1) than men (42.1{+/-}7.4 ml{middle dot}min-1{middle dot}kg-1) but VO2maxffm was similar (women: 59.7{+/-}11.8 ml{middle dot}min-1{middle dot}kg-1; men: 62.5{+/-}10.4 ml{middle dot}min-1{middle dot}kg-1). Fitness was inversely associated with age but not after adjustment for PAEE. People in more physically demanding jobs were fitter compared to those in sedentary jobs but this association was attenuated in women and reversed in men following adjustment for total PAEE. PAEE and BMI and were positively associated with fitness at all levels of adjustment when fitness was expressed relative to fat-free mass. Fitness during summer was 4% higher than the winter among women, but did not differ by season among men.

ConclusionsFitness was inversely associated with age but less steeply than anticipated, suggesting older generations are comparatively fitter than younger generations. PAEE and BMI were stronger determinants of the variance in fitness than any other characteristic including age. This emphasizes the importance of modifiable physical activity behaviours in public health interventions.

KEY MESSAGESO_LIFitness was inversely associated with age but less steeply than anticipated, suggesting older generations are comparatively fitter than younger generations
C_LIO_LIRelationships between cardiorespiratory fitness and sociodemographic characteristics were primarily mediated by physical activity.
C_LIO_LIA one standard deviation difference in physical activity had the same impact on cardiorespiratory fitness as being 25 years younger
C_LI


title: Fine-scale variation in the effect of national border on COVID-19 spread: A case study of the Saxon-Czech border region

abstract: The global extent and temporally asynchronous pattern of COVID-19 spread have repeatedly highlighted the role of international borders in the fight against the pandemic. Additionally, the deluge of high resolution, spatially referenced epidemiological data generated by the pandemic provides new opportunities to study disease transmission at heretofore inaccessible scales. Existing studies of cross-border infection fluxes, for both COVID-19 and other diseases, have largely focused on characterizing overall border effects. Here, we couple fine-scale incidence data with localized regression models to quantify spatial variation in the inhibitory effect of an international border. We take as a case study the border region between the German state of Saxony and the neighboring regions in northwestern Czechia, where municipality-level COVID-19 incidence data are available on both sides of the border. Consistent with past studies, we find an overall inhibitory effect of the border, but with a clear asymmetry, where the inhibitory effect is stronger from Saxony to Czechia than vice versa. Furthermore, we identify marked spatial variation along the border in the degree to which disease spread was inhibited. In particular, the area around Lobau in Saxony appears to have been a hotspot for cross-border disease transmission. The ability to identify infection flux hotspots along international borders may help to tailor monitoring programs and response measures to more effectively limit disease spread.


title: Delirium due to hip fracture is associated with activated immune-inflammatory pathways and a reduction in negative immunoregulatory mechanisms.

abstract: The objectives of this study were to delineate whether delirium is associated with activation of the immune-inflammatory response system (IRS) as indicated by activation of M1, Thelper (Th)1, and Th17 profiles, and/or by reduced activities of the compensatory immunoregulatory system (CIRS), including Th2 and Tregulatory profiles. We recruited 65 elderly patients with a low energy impact hip fracture who underwent hip fracture operation. The CAM-ICU and the Delirium Rating Scale, Revised-98-Thai version (DRS-R-98) were assessed pre-operatively and 1, 2 and 3 days after surgery. Blood samples (day 1 and 2) post-surgery were assayed for cytokines/chemokines using a MultiPlex assay and the neutrophil/lymphocyte ratio. We found that delirium and/or the DRS-R-98 score were associated with IRS activation as indicated by activated M1, Th1, Th17 and T cell growth profiles and by attenuated CIRS functions. The most important IRS biomarkers were CXCL8, interleukin (IL)-6, and tumor necrosis factor-, and the most important CIRS biomarkers were IL-4 and soluble IL-1 receptor antagonist. We found that 42.5% of the variance in the actual changes in the DRS-R-98 score (averaged from day 1 to day 3) was explained by T cell growth factors, baseline DRS-R-98 scores and age. The pain scores during delirium were significantly and positively associated with CXCL8 and CCL3 and negatively with IL-4 and sIL-1RA. An increase in the NLR reflects overall IRS, M1, Th1, Th17, and Th2 activation. In conclusion, post-hip surgery delirium is associated with activated IRS pathways and appears especially in patients with lowered CIRS functions.


title: Multi-ancestry meta-analysis identifies 2 novel loci associated with ischemic stroke and reveals heterogeneity of effects between sexes and ancestries

abstract: Cerebrovascular accident (stroke) is the second leading cause of death and disability worldwide. Stroke prevalence varies by sex and ancestry, which could be due to genetic heterogeneity between subgroups. We performed a genome-wide meta-analysis of 16 biobanks across multiple ancestries to study the genetic contributions underlying ischemic stroke (60,176 cases, 1,310,725 controls) as part of the Global Biobank Meta-analysis Initiative (GBMI). Two novel loci associated ischemic stroke with plausible candidate genes, FGF5 and CENPQ/MUT, were identified after replication in four additional datasets. One locus showed significant ancestry heterogeneity (PDE3A) and two loci showed significant sex-heterogeneity (SH3PXD2A and ALDH2). The ALDH2 locus had a male-specific association for stroke in GBMI (P-value males = 1.67e-24, P-value females = 0.126). To test whether we would see a difference in the predictive power of sex-specific polygenic risk scores (PRSs), we compared the C-indexes for sex-specific and sex-combined PRSs in HUNT dataset. A sex-combined PRS was more successful at predicting stroke cases than a sex-specific PRS, most likely due to more stable effect estimates from the sex-combined summary-statistics. These approaches can be applied to further unravel the genetic underpinnings of stroke and other complex diseases.

category: genetic and genomic medicine


title: Characteristics and healthcare use of patients attending virtual walk-in clinics: a cross-sectional analysis

abstract:
ImportanceVirtual walk-in clinics have proliferated since the onset of COVID-19. Yet, little is known about those who participate in this care model, and how virtual walk-in clinics contribute to care continuity and patient healthcare utilization.

ObjectivesTo describe the characteristics and healthcare use of patients using virtual walk-in clinics compared to the general population, and a subset that received any virtual family physician visit.

DesignThis was a retrospective, population-based, cross-sectional study.

SettingOntario, Canadas most populous province.

ParticipantsPatients who had received at least one family physician visit at one of 13 virtual walk-in clinics from April 1st to December 31st, 2020. They were compared to Ontario residents who had any virtual family physician visit in the same time period.

Main Outcome(s) and Measure(s)Patient characteristics and 30-day post-visit healthcare utilization.

ResultsVirtual walk-in patients (N=132,168) had fewer comorbidities and lower previous healthcare utilization than Ontarians with any virtual visit. Less than 0.1% of virtual walk-in visits were with a patients own family physician. Compared to Ontarians having any virtual family physician visit, virtual walk-in patients were significantly less likely to have a subsequent in-person visit with the same physician (0.2% vs. 11.0%, SMD = 0.48), more likely to have a subsequent virtual visit (30.3% vs. 21.9%, SMD = 0.19), and twice as likely to have an emergency department visit within 30 days (8.3% vs. 4.1%, SMD = 0.18), an effect that persisted after adjustment and across rurality groups: large urban (aOR 2.26; 95% CI 2.08-2.45), small urban (aOR 2.08; 95% CI 1.99-2.18), and rural (aOR 1.87; 95% CI 1.69-2.07).

Conclusions and RelevanceCompared to Ontarians attending any family physician virtual visit, virtual walk-in patients were less likely to have a subsequent in-person physician visit, but were more likely to visit the emergency department. Low continuity and the lack of physical examination may be contributing to increased emergency department utilization for virtual walk-in clinic patients.

category: health policy


title: Rapid review of government issued documents relevant to mitigation of COVID-19 in the US food manufacturing and processing industry

abstract: We surveyed publicly available records published by the United States (US) government between the start of the Coronavirus Disease 2019 (COVID-19) pandemic and September 30th, 2021, to identify documents containing resources or guidelines about COVID-19 mitigation relevant to the US food manufacturing and processing industry (hereafter referred to as "the food processing industry"). Among 36 documents identified and reviewed (including 35 from government agencies and one from a relevant professional association), we extracted 19 categories of mitigation strategies covering the themes of employee biosafety, surveillance, vaccination, social distancing, and worker education. We concluded that the priority of COVID-19 mitigation in the food processing industry was to protect the health and safety of industry workers while maintaining food supply chain resilience to minimize disturbance in the food market and avoid food crisis. A collated list of the identified documents and their comprehensive review will (i) aid researchers and public health workers in interpreting the potential impacts of the recommended mitigations on the epidemiology of the disease among workers in the food processing industry and (ii) help the food processing industry sort out the most essential strategies to take in face of a pandemic.


title: A causal inference approach for estimating effects of non-pharmaceutical interventions during Covid-19 pandemic

abstract: In response to the outbreak of the coronavirus disease 2019 (Covid-19), governments worldwide have introduced multiple restriction policies, known as non-pharmaceutical interventions (NPIs). However, the relative impact of control measures and the long-term causal contribution of each NPI are still a topic of debate. We present a method to rigorously study the effectiveness of interventions on the rate of the time-varying reproduction number Rt and on human mobility, considered here as a proxy measure of policy adherence and social distancing. We frame our model using a causal inference approach to quantify the impact of five governmental interventions introduced until June 2020 to control the outbreak in 113 countries: confinement, school closure, mask wearing, cultural closure, and work restrictions. Our results indicate that mobility changes are more accurately predicted when compared to reproduction number. All NPIs, except for mask wearing, significantly affected human mobility trends. From these, schools and cultural closure mandates showed the largest effect on social distancing. We also found that closing schools, issuing face mask usage, and work-from-home mandates also caused a persistent reduction on Rt after their initiation, which was not observed with the other social distancing measures. Our results are robust and consistent across different model specifications and can shed more light on the impact of individual NPIs.


title: Assessment of Potential Risk Factors for COVID-19 among Health Care Workers in a Health Care Setting in Delhi, India -A Cohort Study

abstract:
IntroductionHealth care workers (HCW) are among the most vulnerable for contracting the COVID-19 infection. Understanding the extent of human-to-human transmission of the COVID-19 infection among HCW is critical in management of this infection and for policy making. We did this study to observe seropositivity and estimate new infection by seroconversion among HCW and predict the risk factors for infection.

MethodsA cohort study was conducted at a tertiary dedicated COVID-19 hospital in New Delhi during first and second wave of the COVID-19 pandemic. All HCW working in the hospital during the study period who come in contact with the patients, were our study population. The data was collected by a detailed face to face interview along with serological assessment for anti-COVID-19 antibodies at baseline and endline, and assessment of daily symptoms. Prediction of potential risk factors for seroprevalence and seroconversion was done by logistic regression keeping the significance at p<0.05.

ResultsA total of 192 HCW were recruited in this study, out of which, 119 (61.97%) at baseline and 108 (77.7%) at endline were seropositive for COVID-19. About two-third (63.5%) had close contact, 5.2% had exposure during aerosol procedures, 30.2% had exposure with a patients body fluid while majority (85.4%) had exposure to contact surface around the patient. Almost all were wearing PPE and following IPC measures during their recent contact with a COVID-19 patient. Seroconversion was observed among 36.7% of HCWs while 64.0% had a serial rise in titer of antibodies during the follow-up period. Association of seropositivity was observed negatively with doctors [OR:0.353, CI:0.176-0.710], COVID-19 symptoms [OR:0.210, CI:0.054-0.820], comorbidities [OR:0.139, CI: 0.029 - 0.674], and recent Infection Prevention Control (IPC) training [OR:0.250, CI:0.072 - 0.864], while positively associated with partially [OR:3.303, CI: 1.256-8.685], as well as fully vaccination for COVID-19 [OR:2.428, CI:1.118-5.271]. Seroconversion was positively associated with doctor as profession [OR: 13.04, CI: 3.39 - 50.25] and with partially [OR: 4.35, CI: 1.070 - 17.647], as well as fully vaccinated for COVID-19 [OR: 6.08, CI: 1.729 - 21.40]. No significant association was observed between adherence to any of the IPC measures and PPE (personal protective equipment) adopted by the HCW during the recent contact with COVID-19 patients and seroconversion.

ConclusionA high seropositivity and seroconversion could be either due to exposure to COVID-19 patients or concurrent immunization against COVID-19 disease. In this study the strongest association of seropositivity and seroconversion was observed with recent vaccination. IPC measures were practiced by almost all the HCW in these settings, and thus were not found to be affecting seroconversion. Further study using anti N antibodies serology, which are positive following vaccination may help us to find out the reason for the seropositivity and seroconversion in HCW.


title: COVID-19 in Tunisia (North Africa): IgG and IgG subclass antibody responses to SARS-CoV-2 according to disease severity

abstract: Coronavirus disease 2019 (COVID-19) expresses a wide spectrum of disease severity. We investigated the profile of IgG and IgG subclass antibody responses to SARS- CoV-2 in Tunisian patients with COVID-19 according to disease severity (86 patients with severe disease and 63 with mild to moderate disease). Two in house developed ELISA with excellent performance were used to test for antibodies to the nucleocapsid (N) protein and the receptor-binding domain of the spike antigen (S-RBD) of SARS-CoV-2. IgG, IgG1 and IgG3 antibodies were significantly higher in patients with severe disease compared to non-severe disease. Antibodies to S-RBD or the N protein were dominated by IgG1 and IgG3 or IgG1/IgG3 and IgG2 subclasses respectively. In patients with severe disease, IgG antibodies   appearance to S-RBD was delayed compared to the N protein. IgG subclass imbalance may reflect the pathophysiology of COVID-19 and may herald disease aggravation. This study brings information on the immune responses to SARS-CoV-2 in North African patients and completes the picture drawn on COVID-19 in different African populations and worldwide.

category: allergy and immunology


title: A causal framework for assessing the transportability of clinical prediction models

abstract:
BACKGROUNDMachine learning promises to support the diagnosis of dementia and Alzheimers Disease, but may not perform well in new settings. We present a framework to assess the transportability of models predicting cognitive impairment in external settings with different demographics.

METHODSWe mapped and quantified relationships between variables associated with cognitive impairment using causal graphs, structural equation models, and data from the ADNI study. These estimates generated datasets for training and validating prediction models. We measured transportability to external settings with interventions on age, APOE {varepsilon}4, and sex, using calibration metric differences.

RESULTSModels predicting with causes of the outcome were 1.3-12.8 times more transportable than those predicting with consequences. Logistic and lasso models had better calibration in internal validation settings than random forest and boosted models.

DISCUSSIONApplying a framework considering causal relationships is crucial to assess transportability. Future research could investigate more interventions and methods to quantify causal relationships in risk prediction.

Research in contextO_LISystematic Review: Machine learning models supporting the diagnosis of cognitive impairment may not perform well in external validation settings. Theoretical research established that models can be more transportable to external settings when predictors are causes of the outcome. Causal frameworks and practical examples to assess transportability are needed.
C_LIO_LIInterpretation: We developed and applied a causal framework to assess the transportability of models predicting cognitive impairment to settings with different demographics using a causal graph and interventions on semi-synthetic data. Our results add a practical example showing that models are more transportable when predicting with causes of the outcome rather than with its consequences. This supports using causal frameworks in prediction models to improve transportability.
C_LIO_LIFuture directions: Our framework can be extended to include more complex semi-synthetic data generation methods to quantify causal relationships. Further applications to risk prediction models could assess transportability under different interventions that simulate complex differences between populations.
C_LI


title: Cerebrospinal fluid and brain α-synuclein seed amplification in autopsy-confirmed Lewy body disease relates to the distribution of pathology

abstract:
ObjectiveTo determine the sensitivity and specificity of -synuclein seed amplification assay (Syn-SAA) in antemortem and postmortem CSF and brain homogenate samples of autopsy-confirmed patients with a spectrum of Lewy-related pathology (LRP).

MethodsAntemortem CSF samples were examined from 119 subjects with standardized neuropathological examinations from OHSU and UCSD (56 additional postmortem CSF samples available). The assay was also applied to frontal cortex and amygdala tissue to determine if the results could be explained by a regional variation in the propensity for seed aggregation. Sensitivity, specificity, and assay kinetics were compared across pathology groups and clinical data was compared across Syn-SAA positive and negative groups.

ResultsFifty-three LRP-individuals and 66 LRP+ individuals (neocortical (n=38), limbic (n=7), and amygdala-predominant (n=21)) were included. There was a sensitivity of 97.8% and specificity of 98.1% of the Syn-SAA to identify patients with limbic/neocortical pathology from antemortem CSF. Sensitivity to detect amygdala-predominant pathology was only 14.3%. Postmortem CSF and brain tissue Syn-SAA analyses showed a similar detection pattern, with higher positivity in samples from limbic/neocortical cases. Kinetic parameters of aggregation were significantly slower in amygdala-predominant cases compared to limbic and neocortical cases.

InterpretationIn this multicenter study of autopsy-confirmed subjects with a spectrum of Lewy-related pathology, we confirm that the Syn-SAA using CSF and brain tissue reliably identifies -synuclein seeds in patients with diffuse pathology and related cognitive symptoms. Pathological -synuclein in the amygdala appears less likely to form detectable seeds, which may result from differences in abundance, conformation, or strains of -synuclein.

Summary for Social Media If PublishedO_LITwitter handles of the authors: none
C_LIO_LIAlpha-synuclein seed amplification assays have shown high sensitivity and specificity in clinically defined DLB and PD cohorts
C_LIO_LIIt is less well known how well these assays detect synuclein seeds across a pathologically defined spectrum of Lewy body disease. Here we examine the ability of the Syn-SAA to detect alpha-synuclein seeds in a multicenter cohort of autopsy-validated cases with a spectrum of Lewy body related pathology.
C_LIO_LIHigh sensitivity and specificity of the Syn-SAA is confirmed in detecting alpha-synuclein seeds in spinal fluid and brain tissue in limbic and neocortical stage Lewy body stage pathology, but markedly decreased sensitivity is observed in detecting alpha-synuclein seeds in both spinal fluid and brain tissue in amygdala-predominant type Lewy body related pathology. A small number of these cases showed seeding capability from the amygdala that was not present in the frontal cortex, suggesting a topographic spread of alpha-synuclein seeds.
C_LIO_LIThe current generation of Syn-SAAs have a high sensitivity and specificity for detecting the most clinically relevant forms of Lewy body related pathology. Further study is needed to understand the differences in Lewy body related pathology between limbic/neocortical cases and amygdala-predominant cases that result in this difference in seeding capability.
C_LI

category: neurology


title: An Alzheimer's disease pathway uncovered by functional omics: the risk gene CELF1 regulates KLC1 splice variant E expression, which drives Aβ pathology

abstract: In an era when numerous disease-associated genes have been identified, determining the molecular mechanisms of complex diseases is still difficult. The CELF1 region was identified by genome-wide association studies as an Alzheimers disease (AD) risk locus. Using transcriptomics and cross-linking and immunoprecipitation sequencing (CLIP-seq), we found that CELF1, an RNA-binding protein, binds to KLC1 RNA and regulates its splicing. Analysis of two brain banks revealed that CELF1 expression is correlated with inclusion of KLC1 exons downstream of the CELF1-binding region identified by CLIP-seq. In AD, low CELF1 levels result in high levels of KLC1 splice variant E (KLC1_vE), an amyloid-{beta} (A{beta}) pathology-driving gene product. Cell culture experiments confirmed regulation of KLC1_vE by CELF1. Analysis of mouse strains with different propensities for A{beta} accumulation confirmed that Klc1_vE drives A{beta} pathology. Using omics methods, we revealedthe molecular pathway of a complex disease supported by human and mouse genetics.


title: Cost-effectiveness of implementing HIV and HIV/syphilis dual testing among key populations in Viet Nam: a modeling analysis

abstract:
ObjectivesKey populations, including sex workers, men who have sex with men, and people who inject drugs, have a high risk of HIV and sexually transmitted infections (STIs). We assessed the health and economic impacts of different HIV and syphilis testing strategies among three key populations in Viet Nam using a dual HIV/syphilis rapid diagnostic test (RDT).

SettingWe used the Spectrum AIDS Impact Model to simulate the HIV epidemic in key populations in Viet Nam and evaluated five testing scenarios. We used a 15-year time horizon and all costs are from the providers perspective.

ParticipantsWe include the entire population of Viet Nam in the model.

InterventionsWe model five testing scenarios among key populations: 1) annual testing with an HIV rapid diagnostic test (RDT), 2) annual testing with a dual RDT, 3) biannual testing using dual RDT and HIV RDT, 4) biannual testing using HIV RDT, and 5) biannual testing using dual RDTs.

Primary and secondary outcome measuresThe primary outcome is incremental cost-effectiveness ratios (ICERS). Secondary outcomes include HIV and syphilis cases and costs for each proposed intervention.

ResultsAnnual testing using a dual HIV/syphilis RDT was cost saving and averted 3,206 HIV cases and treated 7,719 syphilis cases compared to baseline over 15 years. Biannual testing using one dual test and one HIV RDT, or two dual tests both averted an additional 875 HIV cases and were cost-effective ($1,024 and $2,518 per DALY averted, respectively). Annual or biannual HIV testing using HIV RDTs and separate syphilis tests were more costly and less effective than using one or two dual RDTs.

ConclusionsAnnual or biannual HIV and syphilis testing using dual RDTs among key populations can be cost-effective and support countries in reaching global reduction goals for HIV and syphilis.

STRENGTHS AND LIMITATIONS OF THIS STUDYO_LIStrength: Our model presents novel cost-effectiveness estimates for the use of dual HIV/syphilis testing in key populations that can inform health planners
C_LIO_LIStrength: We include five testing scale up scenarios using both HIV RDT and dual HIV/syphilis RDT
C_LIO_LIStrength: Our model is informed by demographic, behavioral, and biological data from government sources, surveys, surveillance, publicly available reports, databases, and peer-reviewed literature
C_LIO_LILimitation: We made some assumptions regarding the timing and uptake of HIV and syphilis testing among key populations that may be inaccurate.
C_LIO_LILimitation: Our model assumes that increased syphilis testing and treatment will not impact syphilis prevalence, however, it is unknown whether increased testing will reduce or increase syphilis prevalence.
C_LI

category: health economics


title: Patients with CLL have similar high risk of death upon the omicron variant of COVID-19 as previously during the pandemic.

abstract:
Previous studies have shown that patients with chronic lymphocytic leukemia (CLL) and coronavirus disease 2019 (COVID-19) have high mortality rates. The omicron variant has been reported to give milder disease in the general population, but outcomes of infections with the omicron variant among immunocompromised patients have not previously been reported. In a population-based cohort we assessed rates of hospitalizations, ICU-admissions, and 30-day all-cause mortality among all patients with CLL from Eastern Denmark testing positive for severe adult respiratory syndrome coronavirus 2 (SARS-CoV-2) in time periods before and after dominance of the omicron variant. Rates of hospitalizations and ICU-admissions declined significantly, whereas 30-day mortality remained as high as 23% in the period with dominance of the omicron sublineage BA.2 variant. Thus, patients with CLL in general and in particular those above 70 years of age with one or more comorbidities should be considered for closer monitoring and pre-emptive antiviral therapy upon a positive SARS-CoV-2 test.

Key pointsO_LIThe omicron variant of COVID-19 leads to high fatality rates in CLL, despite milder disease in the background population
C_LIO_LIPatients with CLL who test positive for SARS-CoV-2 in the era of the omicron variant should be considered for pre-emptive antiviral therapy
C_LI

Explanation of noveltyThe omicron variant has been reported to give milder disease in the general population, but outcomes of infections with the omicron variant among immunocompromised patients have not previously been reported. These population-based data on outcome for patients with CLL upon infection with the omicron variant of SARS-CoV-2 warrants closer monitoring and pre-emptive antiviral therapy upon a positive SARS-CoV-2 test for patients with CLL.

category: hematology


title: Ammonium Sulfate Addition Reduces the Need for Guanidinium Isothiocyanate in the Denaturing Transport Medium Used for SARS-COV-2 RNA Detection

abstract: Rapid identification of SARS-CoV-2 infected individuals through viral RNA detection followed by effective personal isolation remains the most effective way to prevent the spread of this virus. Large-scale RNA detection involves mass specimen collection and transportation. For biosafety reasons, denaturing viral transport medium has been extensively used during the pandemic. But the high concentrations of guanidinium isothiocyanate (GITC) in such media have raised issues around sufficient GITC supply and laboratory safety. Here, we tested whether supplementing media containing low concentrations of GITC with ammonium sulfate (AS) would affect the throat-swab detection of SARS-CoV-2 pseudovirus or a viral inactivation assay targeting both enveloped and non-enveloped viruses. Adding AS to the denaturing transport media reduced the need for high levels of GITC and improved SARS-COV-2 RNA detection without compromising virus inactivation.


title: First detection of Powassan Virus lineage I in field-collected Dermacentor variabilis from New York, USA

abstract: Powassan virus (POWV) is a tick-borne flavivirus that can cause lethal or debilitating neurological illness. It is canonically transmitted by Ixodes genus ticks but may interact with sympatric Dermacentor species. Here, we report the first detection of POWV lineage I from a pool of field-collected D. variabilis in New York state.


title: Childhood meningitis in rural Gambia: 10 years of population-based surveillance

abstract:
BackgroundThe introduction in many countries of conjugate vaccines against Haemophilus influenzae type-b, Streptococcus pneumoniae, and Neisseria meningitidis has led to significant reductions in acute bacterial meningitis (ABM) in children. However, recent population-based data on ABM in sub-Saharan Africa are limited.

MethodsPopulation-based surveillance for meningitis was carried out in a rural area of The Gambia under demographic surveillance from 2008 to 2017, using standardised criteria for referral, diagnosis and investigation. We calculated incidence using population denominators.

ResultsWe diagnosed 1,599 patients with suspected meningitis and collected cerebrospinal fluid (n=1,121) and/or blood (n=1,070) from 1,427 (88%) of cases. We detected 169 cases of ABM, 209 cases of non-bacterial meningitis and 1,049 cases of clinically suspected meningitis. The estimated average annual incidence of ABM was high at 145 per 100,000 population in the <2-month age group, 56 per 100,000 in the 2-23-month age group, but lower at 5 per 100,000 in the 5-14-year age group. The most common causes of ABM were Streptococcus pneumoniae (n=44), Neisseria meningitidis (n=42), and Gram-negative coliform bacteria (n=26). Eighteen of 22 cases caused by pneumococcal serotypes included in PCV13 occurred prior to vaccine introduction and four afterwards. The overall case fatality ratio for ABM was 29% (49/169) and highest in the <2-month age group 37% (10/27). The fatality rate was 8.6% (18/209) for non-bacterial meningitis cases.

ConclusionsGambian children continue to experience substantial morbidity and mortality associated with suspected meningitis, especially acute bacterial meningitis. Such severely ill children in sub-Saharan Africa require improved diagnostics and clinical care.

Summary of the articles main pointPopulation-based surveillance in a health demographic surveillance area in Gambia showed a high incidence and mortality in clinically suspected, acute-bacterial, and non-bacterial meningitis among children 14-years of age. Findings revealed potential gaps in the diagnosis of meningitis in The Gambia requiring urgent attention.


title: Transcriptomic clustering of critically ill COVID-19 patients

abstract: Infections caused by SARS-CoV-2 may cause a severe disease, termed COVID-19, with significant mortality. Host responses to this infection, mainly in terms of systemic inflammation, have emerged as key pathogenetic mechanisms, and their modulation is the only therapeutic strategy that has shown a mortality benefit. Herein, we used peripheral blood transcriptomes of critically-ill COVID-19 patients obtained at admission in an Intensive Care Unit (ICU), to identify two transcriptomic clusters characterized by expression of either interferon-related or immune checkpoint genes, respectively. These profiles have different ICU outcome, in spite of no major clinical differences at ICU admission. A transcriptomic signature was used to identify these clusters in an external validation cohort, yielding similar results. These findings reveal different underlying pathogenetic mechanisms and illustrate the potential of transcriptomics to identify patient endotypes in severe COVID-19, aimed to ultimately personalize their therapies.

category: intensive care and critical care medicine


title: Dual Guidance in Regional Anesthesia Influence of Needle Electrode Configuration on Stimulation Success at Sciatic Nerve; A Randomized, Controlled Pilot Trial

abstract:
IntroductionIn contrast to ultrasound technology (US), peripheral nerve stimulation (PNS) for regional anesthesia was little improved in recent years. When using the combination of both techniques, PNS can give additional information for nerve localization to improve safety and success of regional anesthesia. There are influencing factors on the success rate of stimulation in PNS remaining uninvestigated in a clinical setting to date. This randomized controlled pilot trial evaluates the impact of shape and size of stimulation needles electrodes under dual guidance conditions.

MethodsIn a randomized controlled clinical trial 35 participants undergoing lower limb surgery received a preoperative proximal sciatic nerve block in dual guidance technique. Use of facet needles with point shaped electrodes (N=19, facet group) were compared with tuohy needles with large electroconductive tips (N=16, touhy group). Stimulation success at minimal distance between needle tip and nerve was recorded. Block success and complications of regional anesthesia were assessed.

ResultsIn 87% of successful stimulation (20 of 23) an ultrasound-proven contact of needle tip and sciatic nerve was necessary to elicit a motor response. More successful stimulations could performed using facet needles (84%, 16/19) compared to tuohy needles (44%, 7/16, p=0.03). If stimulation was successful the number of successful sensory blockades was increased (78%, 18/23, p=0.02). No serious complications of regional anesthesia were recorded.

DiscussionThis pilot trial suggests that stimulation needles with small electrodes may be more reliable in indicating a contact of needle and nerve, which may improve safety and success of proximal sciatic nerve blocks.

category: anesthesia


title: Blood-Based Brain Injury Biomarkers to Prognosticate Outcome after Pediatric Cardiac Arrest

abstract:
BackgroundPrognostication after cardiac arrest in children is challenging due to a lack of validated methods to evaluate direct brain injury. The objective of this multicenter study was to analyze biomarker accuracy to prognosticate outcome 1 year post-arrest.

MethodsFourteen U.S. centers enrolled 164 children ages 48 h - 17 years with pre-arrest Pediatric Cerebral Performance Category score of 1-3 who were admitted to an intensive care unit after cardiac arrest. Glial fibrillary acidic protein (GFAP), ubiquitin carboxyl-terminal esterase-L1 (UCH-L1), neurofilament light (NfL), and Tau concentrations were measured in blood samples from post-arrest days 1-3 using Quanterix Simoa 4-Plex assay, Billerica, MA. Unfavorable outcome was death or survival with Vineland Adaptive Behavioral Scale-Third Edition score < 70 at 1 year. We analyzed area under receiver operator curve (AUROC) and performed multivariate logistic regressions to determine the association of each biomarker with outcome on days 1-3.

ResultsFifty of 120 children with primary outcomes available had an unfavorable outcome, including 43 deaths. Compared to those with favorable outcomes, more children with unfavorable outcome had out-of-hospital (36% vs. 70%) and unwitnessed (7% vs. 46%) events, p<0.05. For days 1-3, concentrations of all four measured biomarkers were increased in children with an unfavorable vs. favorable outcome, p<0.05. On post-arrest day 1, NfL demonstrated the best outcome classification (AUROC 0.731 [95% confidence interval 0.642, 0.820]) while UCH-L1 performed best on days 2 (0.860 [0.785, 0.935]) and 3 (0.837 [0.747, 0.926]). After covariate adjustment, NfL concentrations on day 1 (odds ratio 5.9 [95% confidence interval 1.8, 19.2], day 2 (11.9 [3.8, 36.9]), and day 3 (10.2 [3.1, 33.3]), UCH-L1 on day 2 (11.3 [3.0, 42.4]) and day 3 (7.6 [2.1, 27.1]), GFAP on day 2 (2.3 [1.2, 4.5]) and day 3 (2.2 [1.2, 4.0]), and tau on day 1 (2.4 [1.1, 5.3]), day 2 (2.3 [1.3, 4.0]), and day 3 (2.0 [1.2, 3.6]) were associated with unfavorable outcome, p<0.05.

ConclusionsBlood-based brain injury biomarkers accurately prognosticated death or unfavorable adaptive behavior composite outcome at 1 year after pediatric cardiac arrest. Accuracy of biomarkers to predict neurodevelopmental outcomes beyond 1 year should be evaluated.

Clinical Trial RegistrationURL: https://www.clinicaltrials.gov: Unique identifier: NCT02861534

Clinical PerspectiveO_ST_ABSWhat is new?C_ST_ABSO_LIIn children who suffered a cardiac arrest, post-arrest blood levels of neurofilament light, ubiquitin carboxyl-terminal esterase-L1, glial fibrillary acidic protein, and tau predicted death or unfavorable adaptive behavior composite outcome at 1 year.
C_LIO_LINeurofilament light was the best performing biomarker to predict outcome on day 1 while ubiquitin carboxyl-terminal esterase-L1 performed best on days 1 and 2.
C_LI

What are the clinical implications?O_LIBlood-based brain injury biomarkers should be considered for clinical use to aid in prognostication after pediatric cardiac arrest.
C_LIO_LIBiomarker levels should be assessed as tools to aid in the prediction of neurodevelopmental outcomes beyond one year.
C_LI

category: pediatrics


title: Large-scale analysis of structural brain asymmetries in schizophrenia via the ENIGMA consortium

abstract:
BACKGROUNDLeft-right asymmetry is an important organizing feature of the healthy brain that may be altered in schizophrenia, but most studies have used relatively small samples and heterogeneous approaches, resulting in equivocal findings. We carried out the largest case-control study of structural brain asymmetries in schizophrenia (N = 11,095), using a single image analysis protocol.

METHODSWe included T1-weighted data from 46 datasets (5,080 affected individuals and 6,015 controls) from the ENIGMA Consortium. Asymmetry indexes were calculated for global and regional cortical thickness, surface area, and subcortical volume measures. Differences of asymmetry were calculated between affected individuals and controls per dataset, and effect sizes were meta-analyzed across datasets. Analyses were also performed with respect to the use of antipsychotic medication and other clinical variables, as well as age and sex. Case-control differences in a multivariate context were assessed in a subset of the data (N = 2,029).

RESULTSSmall average differences between cases and controls were observed for asymmetries in cortical thickness, specifically of the rostral anterior cingulate (d = -0.08, pFDR = 0.047) and the middle temporal gyrus (d = -0.07, pFDR = 0.048), both driven primarily by thinner cortices in the left hemisphere in schizophrenia. These asymmetries were not significantly associated with the use of antipsychotic medication or other clinical variables. Older individuals with schizophrenia showed a stronger average leftward asymmetry of pallidum volume than older controls (d = 0.08, pFDR = 9.0 x 10-3). The multivariate analysis revealed that 7% of the variance across all structural asymmetries was explained by case-control status (F = 1.87, p = 1.25 x 10-5).

CONCLUSIONSAltered trajectories of asymmetrical brain development and/or lifespan asymmetry may contribute to schizophrenia pathophysiology. Small case-control differences of brain macro-structural asymmetry may manifest due to more substantial differences at the molecular, cytoarchitectonic or circuit levels, with functional relevance for lateralized cognitive processes.


title: Person-specific Characteristics of People with Low Back Pain Moderate the Preferred Movement Pattern within Motor Skill Training and Strength and Flexibility Exercise

abstract:
BackgroundPeople with chronic low back pain (LBP) display an altered movement pattern where the lumbar spine moves more readily into its available range of motion relative to other joints when performing a movement. Recently a randomized controlled trial was completed to compare the effects of motor skill training (MST) to strength and flexibility exercise (SFE). MST improved the altered pattern to a greater extent than SFE. However, there was substantial variability in the baseline and the change over time in the pattern. Understanding factors that influence this variability may ultimately be used to better target treatment strategies to the person.

ObjectiveExamine if gender, age, LBP duration, and the movement pattern at baseline moderate the baseline movement pattern and the change over time in the pattern within MST and SFE. Design: Secondary analysis of kinematic data from a single-blind, randomized controlled clinical trial.

SettingInstitutional

Patients154 patients with chronic LBP.

InterventionsMotor skill training and strength and flexibility exercise.

Main outcome measureslumbar contribution (LC) to total movement.

ResultsThere was not a significant difference in baseline LC between MST and SFE ({beta}=-2.39, CI=[-7.74, 2.96], p=0.38). SFE did not change LC over time ({beta}=-0.11, CI=[-0.47, 0.24], p=0.53). However, there was a significant change over time in LC within MST ({beta}=-2.13, CI=[-2.54, -1.48], p<0.001). Irrespective of treatment group, there was a trend for gender ({beta}=-5.29, CI=[-10.34, 0.30], p=0.05) and age ({beta}=-0.22, CI=[-0.46, 0.00], p=0.05) to moderate baseline LC. Age ({beta}=0.01, CI=[0.00, 0.02], p = 0.04) and baseline LC ({beta}=-0.07, CI=[-0.10, -0.04], p<0.01) were associated with the change over time in LC within MST only.

ConclusionsPerson-specific characteristics moderate the baseline altered movement pattern within MST and SFE, as well as the change over time in the pattern within MST.

category: rehabilitation medicine and physical therapy


title: Viral cultures, Polymerase Chain Reaction Cycle Threshold Values and Viral Load Estimation for SARS-CoV-2 Infectious Potential Assessment in Hematopoietic Stem Cell and Solid Organ Transplant Patients: A Systematic Review

abstract:
BackgroundOrgan transplant recipients are at increased vulnerability to SARS-CoV-2 due to immunosuppression and may pose a continued transmission risk especially within hospital settings. Detailed case reports including symptoms, viral load and infectiousness, defined by the presence of replication-competent viruses in culture, provide an opportunity to examine the relationship between clinical course, burden and contagiousness, and provide guidance on release from isolation.

ObjectivesWe performed a systematic review to investigate the relationship in transplant recipients between serial SARS-CoV-2 RT-PCR cycle threshold (Ct) value or cycle of quantification value (Cq), or other measures of viral burden and the likelihood and duration of the presence of infectious virus based on viral culture including the influence of age, sex, underlying pathologies, degree of immunosuppression, and/or vaccination on this relationship.

MethodsWe searched LitCovid, medRxiv, Google Scholar and WHO Covid-19 databases, from 1 November 2019 until 31 December 2021. We included studies reporting relevant data for transplantees with SARS-CoV-2 infection: results from serial RT-PCR testing and viral culture data from the same respiratory samples. We assessed methodological quality using five criteria, and synthesised the data narratively and graphically.

ResultsWe included 9 case reports and case series reporting on 30 transplantees. We observed a relationship between proxies of viral burden and likelihood of shedding replication-competent SARS-CoV-2 particles. Two individuals shed replication-competent particles over 100 days after infection onset. Lack of standardisation of testing and reporting precludes establishing a viral burden cutoff. Most transplantees stopped shedding competent particles when the RT-PCR cycle threshold was above 30, but there are differences across platforms.

ConclusionsViral burden is a reasonable proxy for infectivity when considered within the context of the clinical status of each patient. Standardised study design and reporting are essential to avoid research waste and generate guidance based on an increasing evidence base.


title: Duration of viable virus shedding in SARS-CoV-2 omicron variant infection

abstract: Clinical features of SARS-CoV-2 Omicron variant infection, including incubation period and transmission rates, distinguish this variant from preceding variants. However, whether the duration of shedding of viable virus differs between omicron and previous variants is not well understood. To characterize how variant and vaccination status impact shedding of viable virus, we serially sampled symptomatic outpatients newly diagnosed with COVID-19. Anterior nasal swabs were tested for viral load, sequencing, and viral culture. Time to PCR conversion was similar between individuals infected with the Delta and the Omicron variant. Time to culture conversion was also similar, with a median time to culture conversion of 6 days (interquartile range 4-8 days) in both groups. There were also no differences in time to PCR or culture conversion by vaccination status.


title: Analysis of Y Chromosome Haplogroups in Parkinson's Disease

abstract: Parkinsons disease is a complex neurodegenerative disorder that is about 1.5 times more prevalent in males than females. Extensive work has been done to identify the genetic risk factors behind Parkinsons disease on autosomes and more recently on chromosome X, but work remains to be done on the male specific Y chromosome. In an effort to explore the role of the Y chromosome in Parkinsons disease we analyzed whole genome sequencing data from the Accelerating Medicines Partnership - Parkinsons disease initiative (1,466 cases and 1,664 controls), genotype data from NeuroX (3,491 cases and 3,232 controls) and genotype data from UKBiobank (182,517 controls, 1,892 cases, and 3,783 proxy cases) all consisting of male European ancestry samples. We classified sample Y chromosomes by haplogroup using three different tools for comparison (Snappy, Yhaplo, Y-LineageTracker), and meta-analyzed this data to identify haplogroups associated with Parkinsons disease. This was followed up with a Y chromosome association study to identify specific variants associated with disease. We also analyzed blood based RNASeq data obtained from the Accelerating Medicines Partnership - Parkinsons disease initiative (1,020 samples) and RNASeq data obtained from the North American Brain Expression Consortium (171 samples) to identify Y chromosome genes differentially expressed in cases, controls, specific haplogroups, and specific tissues. RNASeq analyses suggest Y chromosome gene expression differs between brain and blood tissues but does not differ significantly in cases, controls or specific haplogroups. Overall, we did not find any strong associations between Y chromosome genetics and Parkinsons disease, suggesting the explanation for increased prevalence in males may lie elsewhere.


title: High Viral Specific Antibody Convalescent Plasma Effectively Neutralizes SARS-CoV-2 Variants of Concern

abstract:
The ongoing evolution of SARS-Co-V2 variants to omicron severely limits available effective monoclonal antibody therapies. Effective drugs are also supply limited. Covid-19 convalescent plasma (CCP) qualified for high antibody levels effectively reduces immunocompetent outpatient hospitalization. The FDA currently allows outpatient CCP for the immunosuppressed. Viral specific antibody levels in CCP can range ten-to hundred-fold between donors unlike the uniform viral specific monoclonal antibody dosing. Limited data are available on the efficacy of polyclonal CCP to neutralize variants. We examined 108 pre-delta/pre-omicron donor units obtained before March 2021, 20 post-delta COVID-19/post-vaccination units and one pre-delta/pre-omicron hyperimmunoglobulin preparation for variant specific virus (vaccine-related isolate (WA-1), delta and omicron) neutralization correlated to Euroimmun S1 IgG antibody levels. We observed a 2-to 4-fold and 20-to 40-fold drop in virus neutralization from SARS-CoV-2 WA-1 to delta or omicron, respectively. CCP antibody levels in the upper 10% of the 108 donations as well as 100% of the post-delta COVID-19/post-vaccination units and the hyperimmunoglobulin effectively neutralized all three variants. High-titer CCP neutralizes SARS-CoV-2 variants despite no previous donor exposure to the variants.

Key pointsAll of the post-delta COVID-19/post vaccination convalescent plasma effectively neutralizes the omicron and delta variants.

High-titer CCP and hyperimmunoglobulin neutralizes SARS-CoV-2 variants despite no previous donor exposure to the variants.


title: Longitudinal monitoring of SARS-CoV-2 neutralizing antibody titers and its impact on employee personal wellness decisions

abstract: Virus neutralizing antibody (vnAb) titers are the strongest laboratory correlate of protection from SARS-CoV-2. Providing individuals with real-time measures of their vnAb titers is predicted to improve their ability to make personal wellness decisions. Yet, widespread commercial testing of SARS-CoV-2 vnAbs does not currently occur. Here, we examined whether knowing their vnAb titer impacted wellness decision-making among individuals. To this end, starting on January 1, 2021, we offered all employees from two companies free IMMUNO-COV testing and conducted a survey to assess their behaviors and decisions regarding booster vaccination. IMMUNO-COV is a clinically validated, surrogate virus assay that quantitates serum titers of SARS-CoV-2 vnAbs. To help participants gauge their level of protection based on their vnAb titer, we calibrated IMMUNO-COV titers to the World Health Organization (WHO) International Standard (IU/mL), making them comparable to published reports of correlates of protection, and we fit historical IMMUNO-COV vnAb titer values into predictive models of immune protection from COVID-19. As expected, data for the 56 program participants showed variability in vnAb titers post vaccination, rates vnAb decay, and fold-increases in vnAb titers after booster vaccination. Based on the participant survey, the majority (66%) of participants indicated that knowing their vnAb titer impacted their social behaviors and/or their decision on the timing of a booster vaccination. Several participants indicated that knowing their vnAb titer contributed to their peace of mind regarding their high level of protection from COVID-19. Together, these data demonstrate that regular determination of SARS-CoV-2 neutralizing antibody titers can significantly impact decisions regarding social interactions and timing of booster vaccinations.


title: Racial/Ethnic Disparities in the Observed COVID-19 Case Fatality Rate Among the U.S. Population

abstract:
PurposeDuring the initial 12 months of the pandemic, racial and ethnic disparities in COVID-19 death rates received considerable attention but it has been unclear whether disparities in death rates were due to disparities in case fatality rates (CFRs), incidence rates or both. We examined differences in observed COVID-19 case fatality rates (CFRs) between U.S. Whites, Blacks/African Americans and Latinx during this period.

MethodsUsing data from the COVID Tracking Project (CTP) and the CDCs COVID-19 Case Surveillance Public Use dataset, we calculated CFR ratios comparing minority groups to Whites, both overall and separately by age group. We also used a model of monthly COVID-19 deaths to estimate CFR ratios, adjusting for age, gender, and differences across states and time.

ResultsOverall Blacks and Latinx had lower CFRs than Whites. However, when adjusting for age, Blacks and Latinx had higher CFRs than Whites among those younger than 65. CFRs varied substantially across states and time.

ConclusionsDisparities in COVID-19 case fatality among U.S. Blacks and Latinx under age 65 were evident during the first year of the pandemic. Understanding racial/ethnic differences in COVID-19 CFRs is challenging due to limitations in available data.


title: In vitro Characterization of SARS-CoV-2 Protein Translated from the Moderna mRNA-1273 Vaccine

abstract: Extensive research around mRNA vaccines and their proposed utility during the current COVID-19 pandemic resulted in many publications concerning the SARS-Cov-2 spike protein and angiotensin converting enzyme-2 receptor-binding domain of the virus, but none describe the characteristics of the full-length protein obtained from the modified/synthetic mRNA that is part of the Moderna and Pfizer-BioNTech vaccines. In this paper, we provide the first data characterizing the actual proteins produced by mouse and human cells in culture that had been incubated up to 30 minutes with the commercial vaccine produced by Moderna (i.e., Spikevax). The mRNA vaccine continues to produce proteins up to 12-14 days after introduction to the cells. The molecular weight of the SARS-CoV-2 encoded protein ranges from 135-200 kilodaltons depending on the extent of glycosylation.


title: Variability in SARS-Cov-2 IgG Antibody Affinity To Omicron and Delta Variants in Convalescent and Community mRNA Vaccinated Individuals

abstract:
The emergence of Omicron and Delta variants of SARS-CoV-2 has begun a number of discussions regarding breakthrough infection, waning immunity, need and timing for vaccine boosters and whether existing mRNA vaccines for the wildtype strain are adequate. Our work leverages a biosensor-based technique to evaluate the binding efficacy of SARS-CoV-2 S1 specific salivary antibodies to the Omicron and Delta variants using a cohort of mRNA vaccinated (n=109) and convalescent (n=19) subjects. We discovered a wide range of binding efficacies to the variant strains, with a mean reduction of 60.5%, 26.7%, and 14.7% in measurable signal to the Omicron strain and 13.4%, 2.4%, and -6.4% percent mean reduction to the Delta Variant for convalescent, Pfizer, and Moderna vaccinated groups respectively. This assay may be an important tool in determining susceptibility to infection or need for booster immunization as the pandemic evolves.

Key PointsO_LIAMPERIAL assay developed to quantify salivary SARS-CoV-2 S1 IgG antibodies to Omicron and Delta variants
C_LIO_LIThere was a reduction in affinity to both Delta and Omicron Variants
C_LIO_LIThe reduction in affinity was more pronounced to Omicron than for Delta Variants
C_LIO_LIThere was a significant difference between IgG affinities in Individuals vaccinated with Pfizer versus Moderna Vaccines
C_LI


title: Association of the medical therapy with beta-blockers or inhibitors of renin-angiotensin system with clinical outcomes in patients with mildly reduced left ventricular ejection fraction after acute myocardial infarction

abstract: In the era of the initial optimal interventional and medical therapy for acute myocardial infarction (AMI), a number of patients with mildly reduced left ventricular ejection fraction (EF) (41 - 49%) have been increasing. This observational study aimed to investigate the association between the medical therapy with oral beta-blockers or inhibitors of renin-angiotensin system (RAS) and 2-year clinical outcomes in patients with mildly reduced EF after AMI. Among patients enrolled in the Korea Acute Myocardial Infarction Registry-National Institute of Health, propensity-score matched patients who survived the initial attack and had mildly reduced EF were selected according to beta-blocker or RAS inhibitor therapy at discharge. Beta-blocker therapy at discharge was associated with lower 2-year major adverse cardiac events which was a composite of cardiac death, myocardial infarction, revascularization and re-hospitalization due to heart failure (8.7 vs. 12.8/100 patient-years; hazard ratio [HR] 0.68; 95% confidence interval [CI] 0.50-0.93; P=0.015), and no significant interaction between EF [≤]45% and >45% was observed (Pinteraction=0.354). This association was mainly driven by lower myocardial infarction in patients with beta-blockers (HR 0.50; 95% CI 0.26-0.95; P=0.035). Inhibitors of RAS at discharge were associated with lower re-hospitalization due to heart failure (1.8 vs. 3.5/100 patient-years; HR 0.53; 95% CI 0.33-0.86; P=0.010) without a significant interaction between EF [≤]45% and >45% (Pinteraction=0.333). In patients with mildly reduced EF after AMI, the medical therapy with beta-blockers or RAS inhibitors at discharge was associated with better 2-year clinical outcomes.

category: cardiovascular medicine


title: Comparing Waves of COVID-19 in the US: Scale of response changes over time

abstract: Local response to the SARS-CoV-2 pandemic differed spatially across the United States but the drivers of this spatial variation remain unclear. We approach this open question by studying the relationship between the growth rate of subsequent waves of the pandemic at the county level during the first year of the pandemic, asking whether state or county demographics better explain variation in this relationship. We found clear spatiotemporal patterns in the relationship between the slopes of subsequent waves in a given county. Generally the standardized difference between the growth rates of waves 1 and 2 and waves 2 and 3 were strongly positively correlated over short distances and shifted to a weak negative correlation at intermediate distances. We also found that peer county health group (a categorization of counties by demographic information relevant to public health) explained variation in response better between wave 1 and 2, while state identity was most important between wave 2 and 3. Taken together, we suggest that there are identifiable spatial patterns in pandemic response across the US but that the nature of these patterns change over the course of the pandemic.

category: epidemiology


title: Understanding multimorbidity trajectories in Scotland: an application of sequence analysis.

abstract:
BACKGROUNDAlthough understanding how multiple conditions develop over time is of growing interest, there is currently little methodological development on the topic, especially in understanding how multimorbidity (the co-existence of at least two chronic conditions) develops longitudinally and in which order diseases occur. Therefore, we aim to describe how a longitudinal method, sequence analysis, can be used to understand the sequencing of common chronic diseases that lead to multimorbidity and the socio-demographic factors and health outcomes associated with typical disease trajectories.

METHODSWe use the Scottish Longitudinal Study (SLS) linking the Scottish census 2001 to disease registries, hospitalisation and mortality records. SLS participants aged 40-74 years at baseline were followed over a 10-year period (2001-2011) for the onset of three commonly occurring diseases: diabetes, cardiovascular disease (CVD), and cancer. We focused on participants who transitioned to at least two of these conditions over the follow-up period (N=6,300). We use sequence analysis with optimal matching and hierarchical cluster analysis to understand the process of disease sequencing and to distinguish typical multimorbidity trajectories. Socio-demographic differences between specific disease trajectories were evaluated using multinomial logistic regression. Poisson and Cox regressions were used to assess differences in hospitalisation and mortality outcomes between typical trajectories.

RESULTSIndividuals who transitioned to multimorbidity over 10 years were more likely to be older and living in more deprived areas than the rest of the population. We found seven typical trajectories: later fast transition to multimorbidity, CVD start with slow transition to multimorbidity, cancer start with slow transition to multimorbidity, diabetes start with slow transition to multimorbidity, fast transition to both diabetes and CVD, fast transition to multimorbidity and death, fast transition to both cancer and CVD. Those who quickly transitioned to multimorbidity and death were the most vulnerable, typically older, less educated, and more likely to live in more deprived areas. They also experienced higher number of hospitalisations and overnight stays while still alive.

CONCLUSIONSSequence analysis can strengthen our understanding of typical disease trajectories when considering a few key diseases. This may have implications for more active clinical review of patients beginning quick transition trajectories.


title: Describing a complex primary health care population in a learning health system to support future decision support and artificial intelligence initiatives

abstract:
BackgroundLearning health systems (LHS) use data to improve care. Descriptive epidemiology to reveal health states and needs of the LHS population is essential for informing LHS initiatives. To properly characterize complex populations, both simple statistical and artificial intelligence techniques, applied with an epidemiological lens, can be useful. We present the first large-scale description of the population served by one of the first primary care LHS in Canada.

MethodsWe use electronic health record data from 2009-2019 to describe sociodemographic, clinical, and health care use characteristics of adult primary care clients served by the Alliance for Healthier Communities. In addition to simple summary statistics, we apply unsupervised leaning techniques to explore patterns of common condition co-occurrence, care provider teams, and care frequency.

ResultsThere are 221 047 eligible clients. Clients at community health centres that primarily serve those most at risk (homeless, mental health, addictions) and clients with multimorbidity tended to have more social determinants of health and chronic conditions. Most care is provided by physician and nursing providers, with heterogeneous combinations of other provider types. A subset of clients have many issues addressed within single-visits and there is notable within- and between-client variability in care frequency.

ConclusionsThis population-level overview of clients served by the Alliance provides a foundation for future LHS initiatives. In addition to substantive findings, we demonstrate the use of methods from statistics and artificial intelligence to describe a complex primary care population. We discuss implications for future initiatives, including development of decision support tools.

Key messagesO_LIThe Alliance for Healthier Communities serves clients with barriers to care and complex health needs through Community Health Centres across Ontario; we provide the first large-scale description of sociodemographic, clinical, and health care use characteristics of their primary care population using electronic health record data.
C_LIO_LIWe demonstrate the use of both simple statistical techniques traditionally used in descriptive epidemiology and artificial intelligence techniques, applied with an epidemiological lens, to account for complexity.
C_LIO_LIImplications for future learning health system initiatives, including the development of decision support tools, are discussed.
C_LI

category: primary care research


title: Descriptive and Narrative Study of Long Covid Cases in General Practice and Diagnostic Value of Single Photon Emission Computed Tomography

abstract:
Primary care is under great pressure from patients with Covid -19 and those affected by Long Covid. The issue of Long Covid, its diagnosis and therapeutic approach are discussed here in detail. The Long Covid is described on the basis of a review of the literature and also on the basis of clinical experience in general practice. The main characteristics of thirty four cases (twenty five women) of Long Covid encountered in 2021 and early 2022 are outlined. The experience of six of them is reported on the basis of notes from their medical records. These six patients were interviewed and each was asked to reread and correct the texts concerning them. This is therefore a descriptive study based on clinical and narrative experience, verified by the patients.

Long Covid, the first disease in the history of medicine to be described first by patients themselves on social networks, is not yet precisely defined and the multi -systemic symptoms may be non-specific or vary according to the organs affected.

Diagnosis is based on careful listening to the patients history. Previously unknown irrepressible fatigue, brain fog, working memory disorders with possible anomia, anosmia, dysgeusia or other muli-systemic symptoms occurring after an acute Covid are varying characteristics of Long Covid. Biological evidence of Covid is missing in fourteen patients as PCRs may have been not done or came back negative in the acute phase of the disease. Anti-SARS-CoV-2 antibodies are not always present or are indistinguishable from post-vaccine antibodies. In fourteen severe cases presented, Single Photon Emission Computed Tomography (SPECT scan) after intravenous administration of Technetium-99m (Tc-99m HM-PAO) were able to demonstrate a disorder of cerebral perfusion. Two follow -up brain SPECT at three months showed significant improvement. Further genetic and immunologic study is ongoing for all patient with the help of the international consortium COVID Human Genetic Effort. A patient who presents after a Covid with medically unexplained symptoms may well be a Long Covid. Despite some interesting hypothesis, there is no known specific treatment. Neurocognitive revalidation and physiotherapy may help those patients who need long -term empathic support to cope with their condition.

Key messages{square} Long Covid is a recent onset, multi-systemic, long-term condition that can be very debilitating.
{square}The main symptoms are severe fatigue, exertional exhaustion, and cognitive and memory problems, among others.
{square}Patients who suffer from it may not realize it, may not talk about it, or may attribute their problem to other causes.
{square}Single Photon Emission Computed Tomography (SPECT CT) contributes to the hypothesis of a vascular perfusion disorder induced by SARS -coV-2 and should be validated as a diagnostic tool in neurological Long Covid.
{square}Tissue immunity should be available to prove Long Covid in case of humoral seronegativity
{square}There is no identified treatment that can be recommended yet. Careful listening, empathic support and cognitive and physical rehabilitation are suggested and should be organised or supported by the Belgian state.


title: Development and validation of a quantitative instrument for measuring temporal and social disorientation in the Covid-19 crisis

abstract: We developed a quantitative Instrument for measuring Temporal and Social Disorientation (ITSD), aimed at major crises such as the Covid-19 pandemic. Disorientation has been identified as one of the central elements of the psychological impact of the Covid-19 era on the general public, but so far, the question has only been approached qualitatively. This paper offers an empirical, quantitative approach to the multi-faceted disorientation of the Covid-19 pandemic by operationalising the issue with the help of the ITSD. The ITSD was developed through multiple stages involving a preliminary open-ended questionnaire followed by a coder-based thematic analysis. This paper establishes the reliability and validity of the resulting ITSD using a 3-step validation process on a sample size of 3306.

category: public and global health


title: Healthcare services access, use, and barriers among migrants in Europe: a systematic review

abstract:
BackgroundThe issue of migrants health and access to health services is dynamic and complex posing a challenge to health systems worldwide.

AimTo investigate migrants access to health services in European countries, the use of health services by migrants and the barriers encountered by migrants in the use of health services.

Material and methodsThe search was conducted in January 2022 in five databases; PubMed, Medline, Web of science, Scopus and Cinahl. We used the following keywords: migrants, immigrants, use, access, utilization, healthcare services, services, needs, health, difficulties, barriers. The inclusion criteria were the following: (a) the studies investigated the access of migrants to health services, the use of health services by migrants and the barriers encountered by migrants in using health services. (b) migrants self-assessed access, use and barriers. (c) studies were conducted in European countries. (d) studies included adult migrants. (e) the language of articles was English.

ResultsSixty-five studies were met our inclusion criteria. among studies, 89.2% were quantitative and 11.8% were qualitative. All quantitative studies were cross-sectional. for data collection, 58.5% of studies used questionnaires and 30.8% used historical files. Also, personal interviews were performed in 9.2% of studies and focus groups in 1.5% of studies. in our studies, 73.8% of natives stated that they had better access to health services and used health services better than migrants, while 26.2% found that migrants stated that they had better access to health services and used health services better. The most common barriers were the following: inability to understand the language and communicate, lack of insurance, lack of information and knowledge, lack of family support, low educational level, short duration of stay in the country of migration, low income, lack of a family doctor and high costs.

ConclusionsMigrants face several barriers both in accessing and using health services in Europe. Intensive efforts are needed to increase migrants knowledge, implement culturally sensitive interventions in migrant communities and better inform healthcare professionals so that they can approach migrants more effectively.