title: Episodic future thinking and compassion reduce public health guideline noncompliance urges: A randomised controlled trial

abstract:
BackgroundDuring the COVID-19 pandemic, public health departments have issued guidelines to limit viral transmission. In this environment, people will feel urges to engage in activities that violate these guidelines, but research on guideline adherence has been reliant on surveys asking people to self-report their typical behaviour, which may fail to capture these urges as they unfold. Guideline adherence could be improved through behaviour change interventions, but considering the wide range of behaviours that COVID-19 guidelines prescribe, there are few methods that allow observing changes of aggregate guideline adherence in the  wild.

MethodsIn order to administer interventions and to obtain contemporaneous data on a wide range of behaviours, we use ecological momentary assessment. In this preregistered parallel randomised trial, 95 participants aged 18-65 from the UK were assigned to three conditions using blinded block randomisation, and engage in episodic future thinking (n = 33), compassion exercises (n = 31), or a sham procedure (n = 31) and report regularly on the intensity of their occurrent urges (min. 1, max. 10) and their ability to control them. We investigate whether state impulsivity and vaccine attitudes predict guideline adherence, while assessing through which mechanism these predictors affect behaviour.

FindingsWe found that episodic future thinking (b = -1.60) and compassion exercises (b = -1.40) reduce the intensity of urges. State impulsivity is associated with stronger urges, but we found no evidence that vaccine hesitancy predicts lesser self-control.

InterpretationWe conclude that episodic future thinking exercises and compassion training may be used to stimulate compliance of individuals who are a risk for the community, such as those in voluntary self-isolation.


title: Molecular Programs of Glomerular Hyperfiltration in Early Diabetic Kidney Disease

abstract: Hyperfiltration (HF) is a state of high glomerular filtration rate (GFR) observed in early diabetes that damages glomeruli, resulting in an iterative process of increasing filtration load on fewer and fewer remaining functional glomeruli. To delineate underlying cellular mechanisms of damage induced by HF, transcriptional profiles of kidney biopsies from Pima Indians with type 2 diabetes with or without early-stage diabetic kidney disease (DKD) were grouped into two HF categories based on annual iothalamate GFR measurements. Twenty-six participants with a peak GFR measurement within two years of biopsy were categorized as the "HF group", and 26 in whom biopsy preceded peak GFR by >2 years were considered "pre-HF". The HF group had higher hemoglobin A1c, higher urine albumin-to-creatinine ratio, increased glomerular basement membrane width and lower podocyte density compared to the pre-HF group. A glomerular 1240-gene transcriptional signature identified in the HF group was enriched for endothelial stress response signaling genes, including from endothelin-1, tec-kinase and TGF-{beta}1 pathways, with the majority of the transcripts mapped to endothelial and inflammatory cell clusters in kidney single cell transcriptional data. This analysis reveals molecular pathomechanisms contributing to development of HF and early DKD and involving putative ligand-receptor pairs and downstream intracellular targets linked to cellular crosstalk between endothelial and mesangial cells.

category: nephrology


title: Early life predictors of cerebral small vessel disease in four prospective cohort studies.

abstract:
Development of cerebral small vessel disease, a major cause of stroke and dementia, may be influenced by early life factors. It is unclear whether these relationships are independent of each other, of adult socioeconomic status or of vascular risk factor exposures.

We examined associations between factors from birth (ponderal index, birth weight), childhood (IQ, education, socioeconomic status), adult small vessel disease, and brain volumes, using data from four prospective cohort studies: STratifying Resilience And Depression Longitudinally (STRADL) (n=1080; mean age=59 years); The Dutch Famine Birth cohort (n=118; mean age=68 years); the Lothian Birth Cohort 1936 (LBC1936; n=617; mean age=73 years), and the Simpsons cohort (n=110; mean age=78 years). We analysed each small vessel disease feature individually and summed to give a total small vessel disease score (range 1-4) in each cohort separately, then in meta-analysis, adjusted for vascular risk factors and adult socioeconomic status.

Higher birth weight was associated with fewer lacunes (OR per 100g, 0.93 95%CI=0.88-0.99), fewer infarcts (OR=0.94 95%CI=0.89-0.99), and fewer perivascular spaces (OR=0.95 95%CI=0.91-0.99). Higher childhood IQ was associated with lower white matter hyperintensity burden (OR per IQ point=0.99 95%CI 0.98-0.998), fewer infarcts (OR=0.98, 95%CI=0.97-0.998), fewer lacunes (OR=0.98, 95%CI=0.97-0.999), and lower total small vessel disease burden (OR=0.98, 95%CI=0.96-0.999). Low education was associated with more microbleeds (OR=1.90 95%CI=1.33-2.72) and lower total brain volume (MD=-178.86cm3, 95%CI=-325.07- -32.66). Low childhood socioeconomic status was associated with fewer lacunes (OR=0.62, 95%CI=0.40-0.95).

Early life factors are associated with worse small vessel disease in later life, independent of each other, vascular risk factors and adult socioeconomic status. Risk for small vessel disease may originate in early life and provide a mechanistic link between early life factors and risk of stroke and dementia. Policies investing in early child development may contribute to improve lifelong brain health to prevent dementia and stroke in older age.

category: neurology


title: High Seroconversion Rates Amongst Black and Hispanics With Hematologic Malignancies after SARS-CoV-2 Vaccination

abstract: It is well established that COVID-19 carries a higher risk of morbidity and mortality in patients with hematologic malignancies, however, very little data on ethnicity specific responses in this particular patient population currently exist. We established a program of rapid vaccination and evaluation of antibody-mediated response to all EUA COVID-19 vaccines in an inner city minority population to determine the factors that contribute to the poor seroconversion to COVID-19 vaccination in this population. We conducted a cross-sectional cohort study of 126 patients with hematologic malignancies in the outpatient practices of our institution who completed their vaccination series with one of the three FDA EUA COVID-19 vaccines, Moderna, Pfizer, or Johnson & Johnson (J&J). We qualitatively measured Spike IgG production in all patients using the AdviseDx SARS-CoV-2 IgG II assay and quantitatively in 106 patients who completed their vaccination series with at least 14 days after the 2nd dose of the Moderna or Pfizer vaccines or 28d after the single J&J vaccine. Patient characteristics were analyzed using standard descriptive statistics and associations between patient characteristics, cancer subtypes, treatments, and vaccine response were assessed using Fisher Exact test or Kruskal-Wallis Rank Sum test. The majority of patients (74%) were minorities. Seventy patients (60%) received Pfizer, 36 patients (31%) Moderna, and 10 patients (9%) J&J. We observed a high-rate of seropositivity (86%) with 16 pts (14%) having a negative Spike IgG. Of the 86 minority patients included, 94% Blacks (30/32) and 87% (39/45) Hispanics showed seropositivity. The factors that contributed to significantly lower seroconversion rates included patients with Non-Hodgkin lymphoma (p=0.005), those who received cytotoxic chemotherapy (p=0.002), IVIG (p=0.01), CAR-T cell therapy (p=0.00002), and CD20 monoclonal antibodies (Ab) (p=0.0000008). Plasma cell neoplasms (p=0.02), immunomodulatory agents (p=0.01), and proteasome inhibitors (p=0.01) had significantly higher seroconversion rates, and those with a history of prior COVID-19 (11%, 12/106) had significantly higher antibody titers (p=0.0003). The positivity rate was 86% (37 seropositive, 6 seronegative) for autologous HSCT and 75% (3 seropositive, 1 seronegative) for allogeneic HSCT. No life-threatening AE were observed. We show high seroconversion rates after SARS-CoV-2 vaccination in non-White patients with hematologic malignancies treated with a wide spectrum of therapeutic modalities. Vaccination is safe, effective, and should be encouraged in most patients with hematologic malignancies. Our minorities based study could be employed as an educational tool to dispel myths and provide data driven evidence to overcome vaccine hesitancy.

category: oncology


title: Potentially Inappropriate Medication Use and the Hospitalization Rate among Thai Elderly Patients: a Retrospective Cohort Study

abstract:
PurposeTo examine the association between potentially inappropriate medications (PIMs) use and the hospitalization rate in elderly Thai patients.

MethodsIn this retrospective cohort study, we collected the electronic medical data of elderly patients aged 60 years and older who visited the outpatient department (OPD) at Thammasat University Hospital in Thailand in 2015. The patients were categorized into PIM and non-PIM users according to the Beers 2019 criteria. We calculated descriptive statistics for demographic variables. We also examined the association between PIM use and various different factors with hospitalization rate during follow-up using log-binomial regression. We calculated the relative risk for association between PIM use and other factors with the hospitalization rate.

ResultsWe collected data for a total of 32,261 patients. The majority of participants were female (59.65%) and had a mean age of 70.21 years (SD=7.88). Overall, 63.98% of the patients (n=20,641) were PIM users and 49.45% (n=15,952) received polypharmacy ([≥]5 medications). The most common PIM prescription was proton-pump inhibitors, which were 27.51% of all medications prescribed. We found that PIM use increased the risk of hospitalization by 1.31 times (adjusted RR=1.31, 95% CI: 1.21 - 1.41, p-value < 0.001). Other factors associated with a higher rate of hospitalizations included older age, male gender, polypharmacy, and a higher number of OPD visits.

ConclusionPIMs were commonly prescribed to the elderly in the OPD, and were significantly associated with subsequent hospitalization. The provision of an alternative drug list can help physicians avoid prescribing PIMs to the elderly. If PIMs prescription is unavoidable, physicians should closely monitor patients for drug-related problems and deprescribe PIMs when they are no longer indicated.

category: geriatric medicine


title: Using Artificial Intelligence-based models to predict the risk of Mucormycosis among COVID-19 Survivors: An Experience from India

abstract:
IntroductionIndia reported a severe public health challenge not only due to the COVID-19 outbreak but also the increasing number of associated mucormycosis cases since 2021. This study aimed at developing artificial intelligence-based models to predict the risk of mucormycosis among the patients at the time of discharge from the hospital.

MethodsThe dataset included 1229 COVID-19 positive patients, and additional 214 inpatients, COVID-19 positive as well as infected with mucormycosis. We used logistic regression, decision tree, and random forest, and the extreme gradient boosting algorithm. All our models were evaluated with 5-fold validation to derive a reliable estimate of the model error.

ResultsThe logistic regression, XGBoost, and random forest performed equally well with AUROC 95.0, 94.0, and 94.0 respectively. This study also determined the top five variables namely obesity, anosmia, de novo diabetes, myalgia, and nasal discharge, which showed a positive impact on the risk of mucormycosis.

ConclusionThe developed model has the potential to predict the patients at high risk and thus, consequently initiating preventive care or aiding in early detection of mucormycosis infection. Thus, this study holds potential for early treatment and better management of patients suffering from COVID-19 associated mucormycosis.

category: health informatics


title: Social Capital Dimensions are Differentially Associated with COVID-19 Vaccinations, Masks, and Physical Distancing

abstract:
BackgroundSocial capital has been associated with health outcomes in communities and can explain variations in different geographic localities. Social capital has also been associated with behaviors that promote better health and reduce the impacts of diseases. During the COVID-19 pandemic, social distancing, face masking, and vaccination have all been essential in controlling contagion. These behaviors have not been uniformly adopted by communities in the United States. Using different facets of social capital to explain the differences in public behaviors among communities during pandemics is lacking.

ObjectiveThis study examines the relationship among public health behavior--vaccination, face masking, and physical distancing--during COVID-19 pandemic and social capital indices in counties in the United States.

MethodsWe used publicly available vaccination data as of June 2021, face masking data in July 2020, and mobility data from mobile phones movements from the end of March 2020. Then, correlation analysis was conducted with county-level social capital index and its subindices (family unity, community health, institutional health, and collective efficacy) that were obtained from the Social Capital Project by the United States Senate.

ResultsWe found the social capital index and its subindices differentially correlate with different public health behaviors. Vaccination is associated with institutional health: positively with fully vaccinated population and negatively with vaccination hesitancy. Also, wearing masks negatively associates with community health, whereases reduced mobility associates with better community health. Further, residential mobility positively associates with family unity. By comparing correlation coefficients, we find that social capital and its subindices have largest effect sizes on vaccination and residential mobility.

ConclusionOur results show that different facets of social capital are significantly associated with adoption of protective behaviors, e.g., social distancing, face masking, and vaccination. As such, our results suggest that differential facets of social capital imply a Swiss cheese model of pandemic control planning where, e.g., institutional health and community health, provide partially overlapping behavioral benefits.

category: health policy


title: Platelet polyphosphate and SARS-Cov-2 mRNA-vaccine-induced inflammatory side-effects: a pilot study

abstract:
BackgroundPlatelets have recently been recognized as immune cells. Platelets first contact invading pathogens and then induce immune reactions in cooperation with white blood cells. Platelet polyphosphate (polyP), which is classically recognized as a thrombotic and hemostatic biomolecule, has recently attracted attention as a  cytokine that modulates inflammation and is involved in intercellular communication between platelets and major immune cells.

ObjectiveTo determine the involvement of polyP in SARS-Cov-2-mRNA vaccine-induced immune responses, this pilot study examined the effects of mRNA vaccines on platelet polyP levels.

MethodsBefore and after vaccination (BNT162b2), blood samples were obtained from healthy, non-smoking individuals (relatively older male group, n=6 vs. younger female group, n=23), who did not have systemic diseases that required continuous treatment. Washed platelets were prepared and subjected to a fluorometric determination of platelet polyP levels using 4,6-diamidino-2-phenylindole. The side effects of vaccination were recorded as scores.

ResultsCompared with the male group, platelet polyP levels decreased in the relatively younger female group after the initial dose, while the side effect score increased in the female group after the second dose. Moderate correlation coefficients were observed between the reduction in polyP levels and the side effect scores or the original polyP levels.

ConclusionsDespite being a pilot study using a small sample size, this study suggests the possibility that platelet polyP may suppress the side effects induced by the mRNA vaccines after the initial dose, but not the second dose, in relatively young female subjects who generally have high immune responsiveness.

EssentialsO_LIThe COVID-19 mRNA vaccines (BNT162b2) reduced platelet polyP levels after the initial dose, but not after the 2nd dose, in relatively younger female subjects.
C_LIO_LIRelatively older male subjects did not respond to the vaccination by reducing platelet polyP.
C_LIO_LIThese findings suggest that platelets release polyP to suppress vaccine-induced reactions, for example, inflammation, which is usually recognized as a side effect.
C_LIO_LIHowever, such suppression could be observed in subjects with higher immune responses, generally in relatively younger female subjects.
C_LI

category: hematology


title: Aging-related cell type-specific pathophysiologic immune responses that exacerbate disease severity in aged COVID-19 patients

abstract: Coronavirus Disease 2019 (COVID-19) is especially severe in aged patients, defined as 65 years or older, for reasons that are currently unknown. To investigate the underlying basis for this vulnerability, we performed multimodal data analyses on immunity, inflammation, and COVID-19 incidence and severity as a function of age. Our analysis leveraged age-specific COVID-19 mortality and laboratory testing from a large COVID-19 registry, along with epidemiological data of [~]3.4 million individuals, large-scale deep immune cell profiling data, and single-cell RNA-sequencing data from aged COVID-19 patients across diverse populations. To begin, we confirmed a significantly increased rate of severe outcomes in aged COVID-19 patients. Furthermore, we identified increased inflammatory markers (C-reactive protein, D-dimer, and neutrophil-lymphocyte ratio), viral entry factors in secretory cells, and TGF{beta}-mediated immune-epithelial cell interactions, as well as reduction in both naive CD8 T cells and expression of interferon antiviral defense genes (i.e., IFITM3 and TRIM22), along with strong TGF-beta mediated immune-epithelial cell interactions (i.e., secretory - T regulatory cells), in aged severe COVID-19 patients. Taken together, our findings point to immuno-inflammatory factors that could be targeted therapeutically to reduce morbidity and mortality in aged COVID-19 patients.

category: infectious diseases


title: Adverse reactions to BNT162b2 mRNA COVID-19 vaccine in medical staffs with a history of allergy.

abstract:
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) vaccination is progressing globally. Several adverse reactions have been reported with vaccination against COVID-19. It is unknown whether adverse reactions to COVID-19 vaccination are severe in individuals with allergies. We administered the COVID-19 vaccine to the medical staff at Yamagata University Hospital from March to August 2021. Subsequently, we conducted an online questionnaire-based survey to investigate the presence of allergy and adverse reactions after vaccination and examined the association between allergy and adverse reactions after immunization.

Responses were collected from 1586 subjects after the first vaccination and 1306 subjects after the second administration of the BNT162b2 mRNA COVID-19 vaccine. Adverse reactions included injection site pain, injection site swelling, fever, fatigue or malaise, headache, chills, nausea, muscle pain outside the injection site, and arthralgia. The frequency and severity of most adverse reactions were higher after the second vaccination compared to the first. The frequency of some adverse reactions and their severity were higher, and the duration of symptoms was longer in subjects with allergies than in subjects without allergies. Although several participants visited the emergency room for treatment after the first and second vaccinations, nobody was diagnosed with anaphylaxis.

Given the serious consequence of COVID-19 and the reported high efficacy of this vaccine against this disease, we conclude that vaccination of allergic individuals is generally recommended.


title: Factors Influencing The First and Second Peak of COVID-19 Global Cases: A Survival Analysis

abstract:
ObjectivesThe number of reported cases continues to increase everyday, since the first case of COVID-19 was detected in Wuhan, China in December 2019. Using the global COVID-19 data of 188 countries extracted from the Our World in Data between January 22, 2020-January 18, 2021, this study attempts to explore the potential determinants of the number of days to reach the first and second peak of COVID-19 cases for all 188 countries.

MethodsA semi-parametric Cox proportional hazard (PH) model has been used to explore the covariates that are associated with the number of days to reach the first and second peak of global COVID-19 cases.

ResultsAs of January 18, 2021, the first and second peak were found in 175 and 59 countries, out of 188 countries, respectively. The median number of days to hit the first peak was 60 days for countries which have median age above 40 while the median number of days to hit the second peak was 267 days for countries which have population density above 500 per square kilometer. Countries having population density between 250 and 500 were 2.25 times more likely to experience the first peak of COVID-19 cases (95% CI: 1.15-4.45, P < 0.05) than countries which have population density below 25. Countries having population density between 100 and 250 were 67% less likely to get the second peak (95% CI: 0.119-0.908, P < 0.05) compared to countries which have population density below 25. Countries having cardiovascular death rates above 350 were 2.94 times more likely to get the first peak (95% CI: 1.59-5.43, P < 0.001). In contrast, countries having diabetes prevalence rate 3 to 12 were 85% less likely to experience the second peak of COVID-19 cases (95% CI: 0.036-0.680, P < 0.05) than countries which have diabetes prevalence rate below 3. Besides, highly significant difference is found in the Kaplan-Meier plots of the number of days to reach both peaks across different categories of the countrys Human Development Index.

ConclusionsThe number of days to the first peak was considerably small in Asian & European countries but that to the second peak in the countries where diabetes prevalence was very higher. Countrys life expectancy had a significant effect on determining the first peak and so was the case for two other variables-the cardiovascular death rate and hospital beds per thousand. A contrast result was found for Human Development Index factor under the second peak. Additionally, it was found that the second peak was more likely to occur in more densely populated countries.


title: Multi-trait genome-wide association study of opioid addiction: OPRM1 and Beyond

abstract: Opioid addiction (OA) has strong heritability, yet few genetic variant associations have been robustly identified. Only rs1799971, the A118G variant in OPRM1, has been identified as a genome-wide significant association with OA and independently replicated. We applied genomic structural equation modeling to conduct a GWAS of the new Genetics of Opioid Addiction Consortium (GENOA) data and published studies (Psychiatric Genomics Consortium, Million Veteran Program, and Partners Health), comprising 23,367 cases and effective sample size of 88,114 individuals of European ancestry. Genetic correlations among the various OA phenotypes were uniformly high (rg > 0.9). We observed the strongest evidence to date for OPRM1: lead SNP rs9478500 (p=2.56x10-9). Gene-based analyses identified novel genome-wide significant associations with PPP6C and FURIN. Variants within these loci appear to be pleiotropic for addiction and related traits.

category: addiction medicine


title: A linked mixture model of coronary atherosclerosis

abstract:
Background & ObjectivesCharacterizing the progression of coronary atherosclerosis is a critical public health goal. The most common quantitative summary, the CAC score, is modelled by a variety of statistical methods, both as a predictor of coronary events and as an outcome of behavioral and population-specific risk factors. Little attempt has been made, however, to ground these statistical models in the underlying physiology of arterial aging, which would allow us to describe the onset and growth of CAC over a patient's life.

MethodsUsing a generative growth model for arterial plaque accumulation, we identify severe under-estimation in the age of initial onset and rate of progression (doubling time) of CAC growth with standard ln(CAC + 1) or ln(CAC | CAC > 0) models, and use this growth model to motivate new statistical approaches to CAC using logistic and log-linear mixture regressions. We compare statistical models directly by computing their average parameter biases using 540 growth trajectory simulations (113,760 patients, 268,200 observations).

ResultsWhile all models used can successfully estimate the influence of risk factors with minimal bias, we demonstrate substantial improvements in predictive accuracy in the timing of CAC onset and progression with logistic regression and linked hurdle-lognormal mixture regression, compared with standard ln(CAC + 1) or ln(CAC | CAC > 0) models.

ConclusionsUsing models that can account for patient-specific onset and progression rates, accurate descriptions of CAC trajectories can be made even in cross-sectional (single scan per patient) designs, with substantial clinical and epidemiological utility.

category: cardiovascular medicine


title: mRNA COVID-19 Vaccination and Development of CMR-confirmed Myopericarditis

abstract:
During the process of open peer review on MedRxiv we quickly received a number of messages from reviewers concerned that there was a problem with our reported incidence of myocarditis post mRNA vaccination. Our reported incidence appeared vastly inflated by an incorrectly small denominator (ie number of doses administered over the time period of the study). We reviewed the data available at Open Ottawa and found that there had indeed been a major underestimation, with the actual number of administered doses being more than 800,000 (much higher than quoted in the paper).

In order to avoid misleading either colleagues or the general public and press, we the authors unanimously wish to withdraw this paper on the grounds of incorrect incidence data. We thank the many peer reviewers who went out of their way to contact us and point out our error. We apologize to anyone who may have been upset or disturbed by our report.

In summary, the authors have withdrawn this manuscript because of a major error pertaining to the quoted incidence data. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.


title: Misdiagnosis prevents accurate monitoring of transmission and burden for sub-critical pathogens: a case study of Plasmodium knowlesi malaria

abstract: Maintaining surveillance of emerging infectious diseases presents challenges for monitoring their transmission and burden. Incomplete observation of infections and imperfect diagnosis reduce the observed sizes of transmission chains relative to their true sizes. Previous studies have examined the effect of incomplete observation on estimates of pathogen transmission and burden. However, each study assumed that, if observed, each infection was correctly diagnosed. Here, I leveraged principles from branching process theory to examine how misdiagnosis could contribute to bias in estimates of transmission and burden for emerging infectious diseases. Using the zoonotic Plasmodium knowlesi malaria as a case study, I found that, even when assuming complete observation of infections, the number of misdiagnosed cases within a transmission chain for every correctly diagnosed case could range from 0 (0 - 4) when R0 was 0.1 to 86 (0 - 837) when R0 was 0.9. Data on transmission chain sizes obtained using an imperfect diagnostic could consistently lead to underestimates of R0, the basic reproduction number, and simulations revealed that such data on up to 1,000 observed transmission chains was not powered to detect changes in transmission. My results demonstrate that misdiagnosis may hinder effective monitoring of emerging infectious diseases and that sensitivity of diagnostics should be considered in evaluations of surveillance systems.

category: epidemiology


title: Efficacy of two doses of COVID-19 vaccine against severe COVID-19 in those with risk conditions and residual risk to the clinically extremely vulnerable: the REACT-SCOT case-control study

abstract:
ObjectivesTo determine whether COVID-19 efficacy varies with clinical risk category and to investigate risk factors for severe COVID-19 in those who have received two doses of vaccine.

DesignMatched case-control study (REACT-SCOT).

SettingPopulation of Scotland from 1 December 2020 to 8 September 2021.

Main outcome measureSevere COVID-19, defined as cases with entry to critical care or fatal outcome.

ResultsEfficacy against severe COVID-19 of two doses of vaccine was 94% (95 percent CI 93% to 96%) in those without designated risk conditions, 89% (95 percent CI 86% to 91%) in those with moderate risk conditions, but only 73% (95 percent CI 64% to 79%) in those designated as clinically extremely vulnerable (CEV) and eligible for shielding. Of the 641 cases of severe COVID-19 in double-vaccinated individuals, 47% had moderate risk conditions and 38% were CEV. In the double-vaccinated CEV group, the rate ratio for severe disease (with no risk condition as reference category) was highest in solid organ transplants at 101 (95% CI 47 to 214) but even in this subgroup the absolute risk of severe COVID-19 was low (35 cases in 23678 person-months of follow-up).

ConclusionsTwo doses of vaccine protect against severe COVID-19 in CEV individuals but the residual risk in double-vaccinated individuals remains far higher in those who are CEV than in those who are not. These results lay a basis for determining eligibility for additional measures including passive immunization to protect those at highest risk.


title: Severe Acute Respiratory Syndrome Coronavirus-2 seropositivity in South-central Uganda, during 2019 - 2021

abstract:
Globally, key subpopulations have a high risk of contracting SARS-CoV-2. In Uganda, limited access to personal protective equipment amidst lack of clarity on the extent of the community disease burden may exacerbate this situation.

We assessed SARS-CoV-2 antibody seroprevalence among high-risk sub-populations, including healthcare workers, persons within the general population previously reporting experiencing key COVID-19 like symptoms and archived plasma specimens collected prior to confirmation of COVID-19 in Uganda.

We collected venous blood from HCWs at selected health facilities and from population-cohort participants who reported specific COVID-19 like symptoms in a prior phone-based survey conducted during the first national lockdown (May-August 2020). Pre-lockdown plasma collected from individuals considered high risk for SARS-CoV-2 infection was retrieved. Specimens were tested for antibodies to SARS-CoV-2 using the CoronaChek rapid COVID-19 IgM/IgG lateral flow test assay. IgM only positive samples were confirmed using a chemiluminescent microparticle immunoassay (ARCHITECT AdviseDx SARS-CoV-2 IgM) which targets the spike. SARS-CoV-2 exposure was defined as either confirmed IgM, both IgM and IgG or sole IgG positivity.

The seroprevalence of antibodies to SARS-CoV-2 in HCWs was 21.1% [95%CI: 18.2-24.2]. Of the phone-based survey participants, 11.9% [95%CI: 8.0-16.8] had antibodies to SARS-CoV-2. Among 636 pre-lockdown plasma specimens, 1.7% [95%CI: 0.9-3.1] were reactive.

Findings suggest a high seroprevalence of antibodies to SARS-CoV-2 among HCWs and substantial exposure in persons presenting with specific COVID-19 like symptoms in the general population of South-central Uganda. Based on current limitations in serological test confirmation, it remains unclear whether pre-lockdown seropositivity implies prior SARS-CoV-2 exposure in Uganda.


title: Spread of SARS-CoV-2 Delta variant infections bearing the S:E484Q and S:T95I mutations in July and August 2021 in France

abstract: Analysing 92,598 variant screening tests performed on SARS-CoV-2 positive samples collected in France between 1 July and 31 August 2021 shows an increase of Kappa-like infections. Full genome sequencing reveals that these correspond to Delta variants bearing the S:E484Q mutation. Most of these sequences belong to a phylogenetic cluster and also bear the S:T95I mutation. Further monitoring is needed to determine if this trend is driven by undocumented superspreading events or an early signal of future viral evolutionary dynamics.


title: The natural history of TB disease - a synthesis of data to quantify progression and regression across the spectrum

abstract:
BackgroundPrevalence surveys have found a substantial burden of subclinical (asymptomatic but infectious) TB, from which individuals can progress, regress or even persist in a chronic disease state. We aimed to quantify these pathways across the spectrum of TB disease.

MethodsWe created deterministic framework of TB disease with progression and regression between three states of pulmonary TB disease: minimal (non-infectious), subclinical, and clinical (symptomatic and infectious) disease. We estimated ranges for each parameter by considering all data from a systematic review in a Bayesian framework, enabling quantitative estimation of TB disease pathways.

FindingsTwenty-four studies contributed data from 6030 individuals. Results suggested that, after five years, 24.7%(95% uncertainty interval, UI, 21.3%-28.6%) of individuals with prevalent subclinical disease at baseline had either progressed to clinical disease or died from TB, whereas 16.1%(95%UI, 13.8%-18.5%) had recovered after regressing to minimal disease. Over the course of five years 30% (95%UI, 27.2%-32.6%) of the subclinial cohort never developed symptoms. For those with clinical disease at baseline, 39%(95%UI, 35.8%-41.9%) and 10.3%(95%UI, 8.5%-12.4%) had died or recovered from TB, with the remainder in, or undulating between, the three disease states. The ten-year mortality of people with untreated prevalent infectious disease was 38%.

InterpretationOur results show that for people with subclinical disease, classic clinical disease is neither inevitable nor an irreversible outcome. As such, reliance on symptom-based screening means a large proportion of people with infectious disease may never be detected.

FundingTB Modelling and Analysis Consortium and European Research Council

Research in ContextO_ST_ABSEvidence before this studyC_ST_ABSIn recent years the existence of a spectrum of TB disease has been re-accepted. The classic paradigm of disease is one active state of symptomatic presentation with bacteriologically positive sputum, now referred to as clinical disease. Within the spectrum, a subclinical phase (where people do not report symptoms but have bacteriologically positive sputum) has been widely accepted, due to prevalence surveys using chest radiography screening in addition to symptom screening. On average these prevalence surveys have found around 50% of people with prevalent infectious TB had subclinical disease. There is also another state of minimal disease, or non-infectious disease, that is the earliest point on the disease spectrum after progression from infection. The likelihood or speed of natural progression, regression, or persistence of individuals across this spectrum remains unknown. As a consequence, the ability to accurately predict the impact of interventions has been limited. As individuals with bacteriologically-positive TB now receive treatment, contemporary data to inform the required transitions is highly limited. However, a large number of cohorts of patients were described in the pre-chemotherapy era. Until now, these data have not been synthesised to inform parameters to describe the natural history of TB disease.

Added value of this studyWe synthesised data from historical and contemporary literature to explore the expected trajectories of individuals across the spectrum of TB disease. We considered a cohort of people with prevalent bacteriologically positive disease, with a 50/50 split of people with subclinical and clinical disease at baseline. We found that within five years, 13.3% of people recover from TB, with no chance of progressing to active disease without reinfection. However, we also find that 26.3% are still spending time infectious at the end of the five years. Our estimates for 10 year mortality and duration of symptoms before treatment aligned with the known and accepted values.

We also show that regression from subclinical disease results in a large reservoir of people with minimal disease, from which they can permanently recover, but can also progress again to subclinical disease. The undulating pathways that lead to regression and progression mean that 30% (27.2%-32.6%) of individuals with prevalent subclinical disease do not experience symptoms over the course of five years. This shows that clinical disease is neither a rapid, nor inevitable outcome of subclinical disease.

Implications of the available evidenceWith these data-driven estimates of parameters, informed projections of the relative value of addressing minimal, subclinical, or clinical disease can now be provided. Given the known reservoir of prevalent subclinical disease and its contribution to transmission, efforts to diagnose and treat people with "earlier" stages of TB are likely to have a larger impact than strategies targeting clinical disease, particularly on individuals who never would have progressed to clinical disease.


title: The immunogenetics of viral antigen response is associated with sub-type specific glioma risk and survival

abstract:
Glioma is a highly fatal cancer with prognostically significant molecular subtypes and few known risk factors. Multiple studies have implicated infections in glioma susceptibility, but evidence remains inconsistent. Genetic variants in the human leukocyte antigen (HLA) region modulate host response to infection and have been linked to glioma risk. In this study we leveraged genetic predictors of antibody response to 10 viral antigens to investigate the relationship with glioma risk and survival.

Genetic reactivity scores (GRS) for each antigen were derived from genome-wide significant (p<5x10-8) variants associated with immunoglobulin G antibody response in the UK Biobank cohort. We conducted parallel analyses of glioma risk and survival for each GRS and HLA alleles imputed at two-field resolution using data from 3418 glioma patients subtyped by somatic mutations and 8156 controls.

Genetic reactivity scores to Epstein-Barr virus (EBV) ZEBRA and EBNA antigens and Merkel cell polyomavirus (MCV) VP1 antigen were associated with glioma risk and survival (Bonferroni-corrected p<0.01). GRSZEBRA and GRSMCV were associated in opposite directions with risk of IDH wild type gliomas (ORZEBRA=0.91, p=0.0099 / ORMCV=1.11, p=0.0054). GRSEBNA was associated with both increased risk for IDH mutated gliomas (OR=1.09, p=0.040) and improved survival (HR=0.86, p=0.010). HLA-DQA1*03:01 was significantly associated with decreased risk of glioma overall (OR=0.85, p=3.96x10-4) after multiple testing adjustment.

This first systematic investigation of the role of genetic determinants of viral antigen reactivity in glioma risk and survival provides insight into complex immunogenomic mechanisms of glioma pathogenesis. These results may inform applications of antiviral based therapies in glioma treatment.


title: Maternal childhood trauma and perinatal distress predict the development of attention in infants from 6 to 18 months in a Swedish cohort study

abstract: Maternal distress is repeatedly reported to have negative impacts on the cognitive development in children. Studies examining the association between maternal distress and the development of attention in infancy are few. This study investigated the longitudinal relationships between maternal distress (depressive symptoms, anxiety symptoms, and exposure to childhood trauma) and the development of attention in infancy in 118 mother-infant dyads. We found that maternal exposure to non-interpersonal traumatic events in childhood and a large degree of anxiety during the 2nd trimester was associated with less attention of the infants to audio-visual stimuli at 6, 10, and 18 months. In addition, exposure to interpersonal traumatic events in childhood was identified as a moderator of the negative effect of maternal anxiety during the 2nd trimester on the development of attention in infants. We discuss the possible mechanisms accounting for these cross-generational effects. Our findings underscore the importance of maternal mental health to the development of attention in infancy and address the need for early screening of maternal mental health during pregnancy.

category: psychiatry and clinical psychology


title: Monocytic Subsets and Their Signature Genes Differentially Impact Cortex and Cognition in First-Episode Schizophrenia

abstract:
Accumulating evidence supports involvement of innate immunity in the pathophysiology of schizophrenia. Monocytes are a highly heterogeneous population, subcategorized into classical (CD14++CD16-), intermediate (CD14++CD16+) and nonclassical subsets (CD14+CD16++). How monocytic subsets may shape brain structures and functions remains unclear. The primary goal of this cross-sectional study was to investigate the inter-relationships among monocytic subsets and their specific transcriptomic profiles, cerebral cortical thickness, and cognitive functions in first-episode schizophrenia (FES) patients. We performed whole-blood RNA sequencing (RNAseq) in 128 FES patients and 111 healthy controls (HCs) along with MATRICS Consensus Cognitive Battery (MCCB) measurement, as well as neuroimaging and flow cytometry among partial participants. RNAseq revealed significantly changed expressions of 54 monocytic signature genes in FES patients compared to HCs, especially for intermediate and nonclassical monocytic subsets, with the most outstanding alterations being downregulated S100 Calcium Binding Protein A (S100A) and upregulated Interferon Induced Transmembrane Protein (IFITM) family members, respectively. The percentage of nonclassical monocytes was decreased in FES patients. Cortical thicknesses and MCCB performance were expectantly reduced in FES patients too. Interestingly, negative inter-relationships of monocytic signature genes with both cortical thicknesses and cognition were found in HCs, which were weakened or even reversed in FES patients. Furthermore, the lateral occipital cortex fully mediated the negative effect of a classical monocytic gene Ribonuclease A Family Member 2 (RNASE2) on visual learning in patient group. This study suggests that monocytic dysfunctions play an essential role in cognitive deficit of schizophrenia, and their subtypes should be considered in future research.

One Sentence SummaryDysfunctions of monocytic subsets play an essential role in cortex and cognitive deficit of schizophrenia


title: Integrative multi-omics analysis of childhood aggressive behavior

abstract: This study introduces and illustrates the potential of an integrated multi-omics approach in investigating the underlying biology of complex traits such as childhood aggressive behavior. Using multivariate statistical methods, we integrated 45 polygenic scores (PGSs) based on genome-wide SNP data, 78,772 CpGs, and 90 metabolites for 645 twins (cases=42.0%, controls=58.0%). The single-omics models selected 31 PGSs, 1614 CpGs, and 90 metabolites, and the multi-omics biomarker panel comprised 44 PGSs, 746 CpGs, and 90 metabolites. The predictive accuracy in the test (N=277, cases=42.2%, controls=57.8%) and validation data (N=142 participants from a clinical cohort, cases=45.1%, controls=54.9%) ranged from 43.0% to 57.0% for the single- and multi-omics models. The average correlations across omics layers of omics traits selected for aggression in single-omics models ranged from 0.18 to 0.28. In the multi-omics model higher correlations were found and we describe five sets of correlational patterns with high absolute correlations (|r| [≥] 0.60) of aggression-related omics traits selected into the multi-omics model, providing novel biological insights.


title: Health systems performance for hypertension control using a cascade of care approach in South Africa, 2008-2017

abstract:
BackgroundHypertension is a major contributor to global morbidity and mortality. In South Africa, the government has employed a whole systems approach to address the growing burden of non-communicable diseases. We used a novel incident care cascade approach to measure changes in the South African health systems ability to manage hypertension between 2008 and 2017.

MethodsWe used data from Waves 1-5 of the National Income Dynamics Study (NIDS) to estimate trends in the hypertension care cascade and unmet treatment need across four successive cohorts with incident hypertension. We used a negative binomial regression to identify factors that may predict higher rates of hypertension control, controlling for socio-demographic and healthcare factors. The largest cascade attrition occurred prior to diagnosis.

ResultsIn 2011, 19{middle dot}6% (95%CI 14{middle dot}2, 26{middle dot}2) of individuals with incident hypertension were diagnosed, 15{middle dot}4% (95%CI 10{middle dot}8, 21{middle dot}4) were on treatment and 7.1% had controlled blood pressure. By 2017, the proportion of individuals with diagnosed incident hypertension had increased to 24{middle dot}4% (95%CI 15{middle dot}9, 35{middle dot}4) with increases in treatment (23{middle dot}3%, 95%CI 15{middle dot}0, 34{middle dot}3) and control (22{middle dot}1%, 95%CI 14{middle dot}1, 33{middle dot}.0) were also observed, translating to a decrease in unmet need from 92{middle dot}9% in 2011 to 77{middle dot}9% in 2017. Multivariable regression showed that participants with incident hypertension in 2017 were 3{middle dot}01 (95%CI 1{middle dot}77, 5{middle dot}13) times more likely to have a controlled blood pressure compared to those in 2011.

ConclusionsThe proportion of people with incident hypertension who successfully progressed to controlled blood pressure tripled between 2011 and 2017 in South Africa. Despite these improvements, a low absolute proportion of the population were able to control their blood pressure and a high burden of unmet need remains.

Summary BoxO_ST_ABSWhat is already knownC_ST_ABSO_LIPrevalent cascades provide insight to where losses in care cascades occur.
C_LIO_LIWhile mostly used in the management of HIV, recently they have also been adopted in studying the management of non-communicable diseases on a population level.
C_LIO_LIPrevalent hypertension cascades in South Africa showed a high burden of unmet need, with the biggest losses where lost between disease development and diagnosis.
C_LI

What are the new findingsO_LIIncident hypertension cascades improved from 2008 to 2017 in South Africa.
C_LI

What do the new findings implyO_LIIncident cascades provide an improved means to measure changes in management cascades as this allows us to distinguish between historical and current health system performance.
C_LIO_LIOur data show that while substantial improvements in the care cascade occurred between 2008 and 2017, a large burden of unmet need remains.
C_LI

category: public and global health


title: Detailed Overview of the Buildout and Integration of an Automated High-Throughput CLIA Laboratory for SARS-CoV-2 Testing on a Large Urban Campus

abstract: In 2019, the first cases of SARS-CoV-2 were detected in Wuhan, China, and by early 2020 the cases were identified in the United States. SARS-CoV-2 infections increased in the US causing many states to implement stay-at-home orders and additional safety precautions to mitigate potential outbreaks. As policies changed throughout the pandemic and restrictions lifted, there was an increase in demand for Covid-19 testing which was costly, difficult to obtain, or had long turn-around times. Some academic institutions, including Boston University, created an on-campus Covid-19 screening protocol as part of planning for the safe return of students, faculty, and staff to campus with the option for in-person classes. At BU, we stood up an automated high-throughput clinical testing lab with the capacity to run 45,000 individual tests weekly by fall of 2020, with a purpose-built clinical testing laboratory, a multiplexed RT-PCR test, robotic instrumentation, and trained CLIA certified staff. There were challenges to overcome, including the supply chain issues for PPE testing materials, and equipment that were in high demand. The Boston University Clinical Testing Laboratory was operational at the start of the fall 2020 academic year. The lab performed over 1 million SARS-CoV-2 RT-PCR tests during the 2020-2021 academic year.


title: The Impact of Non-Price In-premise Marketing on Food and Beverage Purchasing and Consumer Behaviour: A Systematic Review

abstract: In-premise marketing is commonly used to promote foods that are high in fat, sugar or salt. In order to inform development of public policy in this area, this systematic review sought to determine the quantity and quality of English-language evidence which examines the role and impact of in-premise advertising (e.g., signage, posters) and positional promotions (e.g., checkout displays) on consumer behaviour and diet-related outcomes in retail, out-of-home (i.e., cafes, restaurants, takeaways) and online purchasing environments. Sixty-two studies met inclusion criteria, of which 69% (n=42) were identified as being methodologically weak. The best-available evidence constitutes findings from four methodologically strong studies, and ten moderate studies which are not confounded by additional promotions such as price or availability. These studies predominantly found evidence that in-premise marketing is likely to be successful in influencing consumer behaviour towards targeted items, across retail and out-of-home settings. These findings provide a basis for authorities to consider acting to restrict in-premise marketing of unhealthy foods and encouraging the in-premise marketing of healthier products. This review identified gaps in the evidence available on non-sales outcomes, and on online purchase environments. These gaps, and identified methodological limitations of the extant evidence remain to be addressed by future research.


title: Should the family have a role in deceased organ donation decision-making? A systematic review of public knowledge and attitudes towards organ procurement policies in Europe

abstract:
GoalTo assess public knowledge and attitudes towards the role of the family in deceased organ donation in Europe.

MethodsA systematic search was conducted in CINHAL, MEDLINE, PAIS Index, Scopus, PsycINFO, and Web of Science. These databases were last searched on December 15th, 2017. Eligibility criteria were empirical studies conducted in Europe from 2008 to 2017 and addressing either knowledge or attitudes by the public towards the consent system, including the involvement of the family in the decision-making process, for post-mortem organ retrieval. Each record was screened by two or more independent reviewers in three phases. Data collection from each report was performed by two or more independent reviewers.

ResultsOf the 1,482 results, 467 reports were assessed in full-text form, and 33 were included in this synthesis. Studies show that a majority of the public support the familys involvement in organ retrieval decision-making and, in particular, their role as surrogate decision-maker when the deceased has expressed no preference.

ConclusionsA common conceptual framework and validated well-designed questionnaires are needed to address the role of the family in future studies. The findings should be considered in the development of Government policy and guidance regarding the role of families in deceased organ donation.

category: medical ethics


title: Factors associated with chemotherapy-induced peripheral neuropathy-related reduced taxane dose or premature discontinuation in women with early-stage breast cancer

abstract:
PurposeIn the absence of treatments for chemotherapy-induced peripheral neuropathy (CIPN), dose reductions (DR) and premature discontinuation (PD) are primary management strategies. However, decision-making guidance is insufficient and knowledge of factors associated with DR/PD is limited. We examined biopsychosocial factors associated with CIPN-related DR/PD in women undergoing taxane-based chemotherapy for early-stage breast cancer.

Patients and methodsAs part of a longitudinal study of CIPN measurement, women completed assessments before the first taxane infusion and at the final infusion or within the originally expected timeframe for the final infusion. Participants completed self-report measures of CIPN, pain, and physical and psychosocial wellbeing, and underwent physical testing of lower limb disability and Quantitative Sensory Testing for sensation and pain threshold to thermal, vibration, and touch stimuli in the feet and hands. Sociodemographic and clinical data were collected. Logistic regression was used to identify factors associated with neuropathy-related DR/PD.

ResultsAmong 121 participants, 66 (54.5%) received taxane-as-prescribed, 46 (38.0%) had neuropathy-related DR/PD, and 9 (7.4%) had DR/PD for other reasons. Factors associated with neuropathy-related DR/PD were receipt of paclitaxel (Odds Ratio [OR]=75.05, 95% Confidence Interval [CI] 2.56-2197.96]), lower pre-treatment pain catastrophizing (OR=0.72, 95% CI: 0.54 - 0.95), and higher post-treatment neuropathic pain (OR=10.77, 95% CI: 1.99 - 58.15) and sensitivity to cold pain in the hand (OR=1.64, 95% CI: 1.05 - 2.56).

ConclusionCIPN-related DR/PD is associated with paclitaxel treatment and post-treatment neuropathic pain and cold pain sensitivity in the hands. CIPN communication to healthcare providers may be influenced by pain catastrophizing, suggesting symptom appraisal may be an important factor in communication. Findings could contribute to clinical practice recommendations to facilitate treatment decision-making.

Lay summaryWe studied pre- and post-treatment factors associated with reduced taxane dose or early cessation due to chemotherapy-induced peripheral neuropathy in women undergoing chemotherapy for early-stage breast cancer. Reduced taxane dose or early cessation is associated with paclitaxel treatment, and high post-treatment neuropathic pain and sensitivity to cold pain stimuli in the hands. Communication of these experiences to healthcare providers may be influenced by pre-treatment thoughts and feelings about symptoms.

Precis for use in the Table of Contentstwo concise sentences that state the significant conclusion(s) or message of the manuscript; Chemotherapy-induced peripheral neuropathy-related reduced taxane dose or premature discontinuation is associated with paclitaxel treatment and high post-treatment neuropathic pain and cold pain sensitivity in the upper limbs. Reporting of these experiences may be influenced by pre-treatment symptom appraisal and communication style.


title: Age-Related Macular Degeneration, Cardiovascular Disease and Stroke

abstract:
ImportanceHigh-risk vascular diseases (HRVs) may remain undetected until catastrophe ensues. Detection from non-invasive retinal imaging would be highly significant.

ObjectiveTo demonstrate that certain lesions of Age-Related Macular Degeneration (AMD) found on retinal imaging correlate with co-existing HRVs.

DesignCross-sectional cohort study. Two years. Retinal image graders blinded to HRV status.

Setting2 retina referral clinics.

Participants151 consecutive AMD patients, ages 50-90, 97 females, 54 males, with lesions of soft drusen and/or subretinal drusenoid deposits (SDD). 12 others approached, 10 refused, 2 excluded.

MethodsPatients were classified by retinal imaging into SDD (SDD present, +/- drusen) or nonSDD (soft drusen only), and by history into HRV (cardiac pump defect (myocardial infarction (MI), coronary artery bypass grafting (CABG), congestive heart failure (CHF)), valve defect, and carotid stroke) or nonHRV, with serum risk factors and medical histories.

Main Outcome MeasuresCorrelations of HRV with SDD and other covariates (Univariate chi-square and multivariate regression). Performance of Machine Learning predicting HRV.

Results75 SDD subjects; 76 nonSDD subjects; HRV prevalence 19.2% (29/151).

O_LIHigh density lipoprotein (HDL) < 62 mg/Dl was found in 24/29 HRV, 42/122 nonHRV, OR 12.40, 95% Confidence Interval (CI) 5.125-30.014; p= 0.0002.
C_LIO_LI15 Pump defects, 14/15 SDD, 8 Valve defects, 6/8 SDD (4 severe aortic stenosis), 6 carotid strokes, 5/6 SDD. Total HRVs 29, 25/29 SDD, OR 9.0, 95% CI 2.95-27.46; p= 0.000012.
C_LIO_LIAdjusted multivariate correlations. HRV with SDD (p= 0.000333). SDD and HDL < 62 with HRV (p= 0.000098 and 0.021).
C_LIO_LIMachine Learning prediction of HRVs from SDD status and HDL level: specificity 87.4%, sensitivity 77.4%, accuracy 84.9%; 95% CIs(%) 79.0-93.3, 58.0-90.4, 77.5-90.7, respectively.
C_LI

Conclusions and RelevanceHigh-risk vascular diseases were accurately identified in a cohort of AMD patients from the presence of characteristic deposits (SDDs) on imaging and HDL levels. The SDDs are directly consequent to inadequate ocular perfusion resulting from the systemic vasculopathies. Further validation in larger cohorts of both vasculopathic and AMD subjects could bring this system into widespread medical practice, to reduce mortality and morbidity from vascular disease, particularly in women, where undiagnosed cardiac disease remains a serious issue.

Key PointsO_ST_ABSQuestionC_ST_ABSWhat is the relationship and driving mechanism between High Risk Vascular Diseases (HRVs) and Age-Related Macular Degeneration (AMD)?

FindingsThe specific AMD lesions of Subretinal Drusenoid Deposits (SDDs) were found to be highly correlated with and directly consequent to the inadequate ocular perfusion resulting from the HRVs of severe cardiac pump insufficiency or valve defect, and carotid occlusion, These vasculopathies could be predicted from the presence of SDDs on spectral domain optical coherence tomography (SD-OCT) imaging and serum HDL.

MeaningScreening for SDDs with SD-OCT imaging could reduce mortality and morbidity from severe vascular disease, particularly in women, where undiagnosed cardiac disease remains a serious issue.

category: ophthalmology


title: How do we measure the adequacy of cancer pain management? Testing the performance of 4 commonly used measures and steps towards measurement refinement

abstract:
Although pain is the most common and disabling cancer symptom requiring management, the best index of cancer pain management adequacy is unknown. While the Pain Management Index is most commonly used, other indices have included relief, satisfaction, and pain intensity. We evaluated their correlations and agreement, compared their biopsychosocial correlates, and investigated whether they represented a single construct reflecting the adequacy of cancer pain management in 269 people with advanced cancer and pain. Despite moderate-to-severe average pain in 52.8% of participants, 85.1% had PMI scores suggesting adequate analgesia, pain relief was moderate and satisfaction was high. Correlations and agreement were low-to-moderate, suggesting low construct validity. Although the correlates of pain management adequacy were multidimensional, including lower pain interference, neuropathic and nociceptive pain, and catastrophizing, shorter cancer duration, and greater physical symptoms, no single index captured this multidimensionality. Principal component analysis demonstrated a single underlying construct, thus we constructed the Adequacy of Cancer Pain Management from factor loadings. It had somewhat better agreement, however correlates were limited to pain interference and neuropathic pain. This study demonstrates the psychometric shortcomings of commonly used indices. We provide suggestions for future research to improve measurement, a critical step in optimizing cancer pain management.

PerspectiveThe Pain Management Index and other commonly used indices of cancer pain management adequacy have poor construct validity. This study provides suggestions to improve the measurement of the adequacy of cancer pain management.

category: pain medicine


title: Reduced levels of convalescent neutralizing antibodies against SARS-CoV-2 B.1+L249S+E484K lineage

abstract:
The E484K mutation at the SARS-CoV-2 Spike protein emerged independently in different variants around the world, probably as part of the ongoing adaptation of the virus to the human host, and has been widely associated with immune escape from neutralizing antibodies generated during previous infection or vaccination. In this work, the B.1+L249S+E484K lineage was isolated along with A.1, B.1.420 and B.1.111 SARS-CoV-2 lineages without the E484K mutation and the neutralizing titer of convalescent sera was compared using microneutralization assays. While no significant differences in the neutralizing antibody titers were found between A1 and B lineages without the E484K mutation, the neutralizing titers against B.1+L249S+E484K were 1.5, 1.9, 2.1, and 1.3-fold lower than against A.1, B.1.420, B.1.111-I, and B.1.111-II, respectively. However, molecular epidemiological data indicate that there is no increase in the transmissibility rate associated with this new lineage. Hence, although the evidence provided in this study support a Variant of Interest Status (VOI) for the B1+L249S+E484K lineage, enhanced laboratory characterization of this particular lineage and other emerging lineages with the E484K mutation should be carried out in individuals with immunity acquired by natural infection and vaccination. This study accentuated the capability of new variants with the E484K mutation to be resistant to neutralization by humoral immunity, and therefore the need to intensify surveillance programs.

HIGHLIGHT The E484K mutation in B.1+L249S+E484K appears not to affect the viral titer
 Sensitivity of lineages without E484K mutation to neutralizing antibodies did not change
 B.1+L249S+E484K lineage shows a reduction in its neutralizing capacity


title: Persistent oxidative stress and inflammasome activation in CD14highCD16- monocytes from COVID-19 patients

abstract: The poor outcome of the coronavirus disease-2019 (COVID-19), caused by SARS-CoV-2, is associated with systemic hyperinflammatory response and immunopathology. Although inflammasome and oxidative stress have independently been implicated in COVID-19, it is poorly understood whether these two pathways cooperatively contribute to disease severity. Herein, we found an enrichment of CD14highCD16- monocytes displaying inflammasome activation evidenced by caspase-1/ASC-speck formation in severe COVID-19 patients when compared to mild ones and healthy controls, respectively. Those cells also showed aberrant levels of mitochondrial superoxide (MitoSOX) and lipid peroxidation, both hallmarks of the oxidative stress response, which strongly correlated with caspase-1 activity. In addition, we found that NLRP3 inflammasome-derived IL-1{beta} secretion by SARS-CoV-2- exposed monocytes in vitro was partially dependent on lipid peroxidation. Importantly, altered inflammasome and stress responses persisted after short- term patient recovery. Collectively, our findings suggest oxidative stress/NLRP3 signaling pathway as a potential target for host-directed therapy to mitigate early COVID-19 hyperinflammation as well as its long-term outcomes.


title: Geographic and Phylodynamic Distribution of SARS-CoV-2 from Environmental Origin

abstract:
The coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread globally. Understanding the transmission dynamics of SARS-CoV-2 contamination in the environment is essential for infection control policies. This study aims to provide a phylodynamic analysis and distribution pattern of SARS-CoV-2 from the environment in terms of Source, clades, lineages, and their location. Ninety (90) retrieved whole-genome sequences of environmental sources from GISAID were investigated to determine the evolutionary process of SARS-CoV-2 and mutation in the isolated nucleotide sequences. The analysis was carried out using R, MAFFT, and MEGA X software. Out of the five countries studied, Austria has the highest distribution with sixty-five samples (72.2%), and the highest isolates of 68 (75.6%) were from raw sewage. The highest clade in circulation as obtained from the study is G with lineages B. The phylogeny of SARS-CoV-2 whole-genome sequences from Austria, the United States, China, Brazil, and Liechtenstein indicated that the SARS-CoV-2 viruses were all clustered together, irrespective of sequence geographic location. The study concluded by demonstrating a clear interconnection between the phylogeny of SARS-CoV-2 isolates from various geographic locations, all of which were locked in the same cluster regardless of their environment specimen. Thus, depicting the possibility of their origination from a common ancestor.

HighlightO_LIEnvironmental sources of specimen isolated from raw sewage have the highest occurring specimen sequence, while those from breathing air, door handle, and wastewater have the lowest sequence.
C_LIO_LIEnvironmental surveillance of SARS-CoV-2 is of great importance to control the spread of the virus. Untreated raw sewage should be of more priority for the environmental surveillance of the virus.
C_LIO_LIEighteen (18) nucleotide sequences from this studys multiple sequence alignment shared a 90% similarity with the Wuhan-Hu-1 reference genome, indicating a common evolutionary origin.
C_LI


title: SIGLEC1 enables straightforward assessment of type I interferon activity in idiopathic inflammatory myopathies

abstract:
ObjectiveTo evaluate SIGLEC1 expression on monocytes by flow cytometry as a type I interferon biomarker in idiopathic inflammatory myopathies (IIM).

MethodsWe performed a retrospective analysis of adult and pediatric patients with the diagnosis of IIM. SIGLEC1 expression was assessed by flow cytometry and was compared with Physician Global Assessment (PGA) or Childhood Myositis Assessment Scale (CMAS) disease activity scores. Mann Whitney-U test and receiver operating characteristic (ROC) curves were used for cross-sectional data analysis (n=96), two-level mixed-effects linear regression model for longitudinal analyses (n=26, 110 visits). Response to treatment was analyzed in 14 patients within 12 months, using Wilcoxon test. SIGLEC1 was compared to ISG15/MxA status by immunohistochemical staining of muscle biopsies (n=17).

Results96 patients with adult (a) and juvenile (j) dermatomyositis (DM, n=38), antisynthetase syndrome (AS, n=19), immune-mediated necrotizing myopathy (IMNM, n=8), inclusion body myositis (IBM, n=9), and overlap myositis (n=22) were included. SIGLEC1 distinguished significantly between active and inactive disease with an area under the curve (AUC) of 0.92 (95% CI: 0.83-1) in DM and correlated with disease activity longitudinally (aDM: standardized beta=0.54, p<0.001; jDM: standardized beta=-0.70, p<0.001). Response to treatment in DM was associated with a decreasing SIGLEC1 (p<0.01, Wilcoxon test). A positive ISG15/MxA stain was highly associated with a SIGLEC1 upregulation. SIGLEC1 was found upregulated in AS (42.1%) and IBM (22,2%) and not in IMNM.

ConclusionSIGLEC1 is a candidate biomarker to assess type I interferon activity in IIM and proved useful for monitoring disease activity and response to treatment in juvenile and adult DM.

Key messagesO_ST_ABSWhat is already known about this subject?C_ST_ABSO_LIThere is an unmet need for routine clinical biomarkers to assess type I interferon activity in rheumatic musculoskeletal diseases
C_LIO_LISIGLEC1 is part of the type I interferon signature and transcripts were found to be upregulated in various autoimmune diseases such as systemic lupus erythematosus (SLE), Sjoegren syndrome and dermatomyositis.
C_LIO_LISIGLEC1 is expressed on the surface of monocytes and thus is easily assessable by flow cytometry, which enables straightforward monitoring of type I interferon activity
C_LI

What does this study add?O_LIAn activation of the type I interferon system in IIM can be identified by flow cytometry analysing SIGLEC1 expression. SIGLEC1 correlated to disease activity and improvement under therapy in juvenile and adult dermatomyositis.
C_LI

How might this impact on clinical practice or future developments?O_LISIGLEC1 expression is a suitable biomarker for monitoring type I interferon activation in rheumatic musculoskeletal diseases, which has clinical implications for patient stratification and treatment decision making especially in the context of interferon inhibitory therapies.
C_LI

category: rheumatology


title: Prevalence, severity, and risk factors of disability among adults living with HIV accessing routine outpatient HIV care in London, United Kingdom (UK): A cross-sectional self-report study

abstract:
ObjectivesMeasure the prevalence and severity of disability, and examine disability risk factors among adults living with HIV in London, United Kingdom (UK).

MethodsWe conducted a quantitative cross-sectional study. The following self-reported questionnaires were administered: World Health Organization Disability Assessment Schedule 2.0 (WHODAS), HIV Disability Questionnaire (HDQ), a disability item using the Equality Act disability definition (EADD), and demographic and HIV questionnaire. We calculated the proportion (95% Confidence Interval; CI) of "severe" and "moderate" disability as measured using EADD and WHODAS scores [≥]2 respectively. We measured disability severity with HDQ domain severity scores. We used demographic and HIV characteristic questionnaire responses to assess potential risk factors of "severe" (EADD) and "moderate" (WHODAS scores [≥]2) disability using logistic regression analysis, and HDQ severity domain scores using linear regression analysis.

ResultsOf 201 participants, 176 (87.6%) identified as men, with median age 47 years, and 194 (96.5%) virologically suppressed. Severe disability prevalence was 39.5% (n=79/201), 95% CI [32.5%, 46.4%]. Moderate disability prevalence was 70.5% (n=141/200), 95% CI [64.2%, 76.8%]. Uncertainty was the most severe HDQ disability domain. The HIV characteristic of late HIV diagnosis was a risk factor for severe disability [Odds Ratio (OR) 2.71; CI 1.25, 5.87]. The social determinants of health economic inactivity [OR 2.79; CI 1.08, 7.21] and receiving benefits [OR 2.87; CI 1.05, 7.83] were risk factors for "severe" disability. Economic inactivity [OR 3.14; CI 1.00, 9.98] was a risk factor for "moderate" disability. Economic inactivity, receiving benefits, and having no fixed abode were risk factors (P[≤]0.05) across HDQ disability domains; physical, mental and emotional, difficulty with day-to-day activities, and challenges to social participation. Personal factors of identifying as a woman and being aged <50 years were risk factors (P[≤]0.05) for HDQ disability domains; mental and emotional, uncertainty, and challenges with social participation.

ConclusionsPeople living with well-controlled HIV in London UK experienced multi-dimensional and episodic disability. Results help to better understand the prevalence, severity, and risk factors of disability experienced by adults living with HIV, identify areas to target interventions, reduce disability, and optimise health and function.

category: hiv aids


title: Dysregulated immune responses in COVID-19 patients correlating with disease severity and invasive oxygen requirements

abstract:
The prognosis of severe COVID-19 patients has motivated research communities to uncover mechanisms of SARS-CoV-2 pathogenesis also on a regional level. In this work, we aimed to understand the immunological dynamics of severe COVID-19 patients with different degrees of illness, and upon long-term recovery.

We analyzed immune cellular subsets and SARS-CoV-2-specific antibody isotypes of 66 COVID-19 patients admitted to the Hospital Clinico Universidad de Chile, which were categorized according to the WHO ten-point clinical progression score. These included 29 moderate patients (score 4-5) and 37 severe patients under either high flow oxygen nasal cannula (18 patients, score 6), or invasive mechanical ventilation (19 patients, score 7-9), plus 28 convalescent patients and 28 healthy controls. Furthermore, six severe patients that recovered from the disease were longitudinally followed over 300 days.

Our data indicate that severe COVID-19 patients display increased frequencies of plasmablasts, activated T cells and SARS-CoV-2-specific antibodies compared to moderate and convalescent patients. Remarkably, within the severe COVID-19 group, patients rapidly progressing into invasive mechanical ventilation show higher frequencies of plasmablasts, monocytes, eosinophils, Th1 cells and SARS-CoV-2-specific IgG than patients under high flow oxygen nasal cannula. These findings demonstrate that severe COVID-19 patients progressing into invasive mechanical ventilation show a distinctive type of immunity. In addition, patients that recover from severe COVID-19 begin to regain normal proportions of immune cells 100 days after hospital discharge and maintain high levels of SARS-CoV-2-specific IgG throughout the study, which is an indicative sign of immunological memory. Thus, this work can provide a useful benchmark for improvement of disease outcomes.

category: allergy and immunology


title: Anopheles salivary antigens as serological biomarkers of vector exposure and malaria transmission: A systematic review with multilevel modelling

abstract:
BackgroundEntomological surveillance for malaria is inherently resource-intensive and produces crude population-level measures of vector exposure which are insensitive in low-transmission settings. Antibodies against Anopheles salivary proteins measured at the individual-level may serve as proxy biomarkers for vector exposure and malaria transmission, but their relationship is yet to be quantified.

MethodsA systematic review of studies measuring antibodies against Anopheles salivary antigens (PROSPERO: CRD42020185449). Multilevel modelling estimated associations between seroprevalence with Anopheles human biting rate (HBR) and malaria transmission measures.

ResultsFrom 3981 studies identified in literature searches, 42 studies across 16 countries were included contributing 393 meta-observations of anti-Anopheles salivary antibodies determined in 42,764 samples. A positive non-linear association between HBR and seroprevalence was found; overall a 50% increase in HBR was associated with a 13% increase in odds of seropositivity (OR: 1.13, 95%CI: 1.06-1.20, p<0.001). The association between HBR and Anopheles salivary antibodies was strongest with concordant, rather than discordant Anopheles species. Seroprevalence was also significantly positively associated with established epidemiological measures of malaria transmission: entomological inoculation rate, Plasmodium spp. prevalence, and malarial endemicity class.

ConclusionsAnopheles salivary antibody biomarkers can serve as a proxy measure for HBR and malaria transmission, and could monitor vectorial capacity and malaria receptivity of a population to sustain malaria transmission. Validation of Anopheles species-specific biomarkers are important given the global heterogeneity in the distribution of Anopheles species. Salivary biomarkers have the potential to transform surveillance by replacing impractical, inaccurate entomological investigations, especially in areas progressing towards malaria elimination.

FundingAustralian National Health and Medical Research Council, Wellcome Trust.


title: Widening Disparities in Online Information Access during the COVID-19 Pandemic

abstract:
The COVID-19 pandemic has stimulated a staggering increase in online information access (1, 2), but the extent to which different communities of internet users enlist digital resources to meet everyday needs varies (2-4). We analyze 55 billion everyday web search interactions across 25,150 US ZIP codes and demonstrate that there were disparate impacts of the pandemic on online information access across several information domains, including health and pandemic-relevant online resources (e.g., online learning, online food delivery). Among many findings, we show that ZIP codes associated with higher proportions of Black residents intensified their access to unemployment resources, and ZIP codes associated with lower income reduced their access to health information resources relative to their counterpart ZIP codes. Because these disparate impacts on the access to online information may result in downstream offline gaps in health, education, employment, and well-being (3), public health interventions should target potential barriers to accessing the necessary digital resources and provide adequate support to meet the intensified digital resource needs.

One Sentence SummaryLarge-scale web search logs reveal disparate impacts on online health, education, unemployment, and food information access.


title: Disparate Impacts on Online Information Access during the COVID-19 Pandemic


title: Predominance of Distinct Autoantibodies in Response to SARS-CoV-2 Infection

abstract:
BackgroundImproved knowledge regarding the prevalence and clinical significance of the broad spectrum of autoantibodies triggered by SARS-CoV2 infection can clarify the underlying pathobiology, enhance approaches to evaluating heterogeneity of COVID-19 clinical manifestations, and potentially guide options for targeting immunosuppressive therapy as the need for more effective interventions continues to evolve. In this study, we sought to determine the prevalence of autoimmune antibodies in diverse cohort of SARS-CoV-2 positive healthcare workers and measure the extent to which factors associated with triggered autoimmunity are activated even following mild and asymptomatic infection.

MethodsAntigen microarrays were used to profile reactivity of IgG autoantibodies against 91 proteins and cytokines based on autoantibody profiling studies in autoimmune diseases.

ResultsIn this discovery screening study, we found that 90% of the IgG positive individuals demonstrated reactivity to at least one autoantibody. When compared to results of the same assays conducted on samples from pre-COVID-19 controls, our primary cohort of individuals with SARS-CoV-2 IgG antibody positivity had significantly elevated IgG against twelve additional proteins including CHD3, CTLA4, HARS, IFNA4, INS, MIF, MX1, RNF41, S100A9, SRP19, TROVE2, and VEGFA. These findings confirmed that all severity levels of SARS-CoV-2 infection, even asymptomatic infections, trigger a robust and diverse autoimmune response; our results also highlight the utility of multiparametric autoantibody detection in this setting.

InterpretationTaken together, our findings underscore the serological diversity underlying the clinical heterogeneity of COVID-19 infection and its sequelae, including the long-Covid phenotypes.

FundingThis work was supported in part by Cedars-Sinai Medical Center (JEE; SC), the Erika J Glazer Family Foundation (JEE; JEVE; SC), CSMC Precision Health Grant (JFB), the F. Widjaja Family Foundation (JGB, GYM, DM), the Helmsley Charitable Trust (JGB, GYM, DM), and NIH grants K23-HL153888 (JEE) and DK062413 (DPBM).

RESEARCH IN CONTEXTO_ST_ABSEvidence before this studyC_ST_ABSCurrently, several studies have shown the possible involvement of autoimmunity in patients affected by coronavirus disease 2019 (COVID-19). In contrast to cytokine storms, which tend to cause systemic, short-duration problems, autoantibodies (AABs) are thought to result in targeted, longer-term damage and development of autoimmune diseases.

Added value of this studyAccording to our knowledge, we evaluated the largest number of protein antigens to characterize the prevalence and heterogeneity of the AABs signature in SARS-CoV-2 convalescent individuals. We examined autoimmune reactivity to SARS-CoV-2 in the absence of extreme clinical disease to acknowledge the existence of AABs even among those who had mild-to-moderate or no symptoms during their illness, as a hallmark of ongoing long-COVID syndrome. Through our analysis we suggest that VEGFA, MIF, IFNA4, SPP1 and APOH could be used as hallmark for SARS-CoV-2 infection and activation of the autoimmune system.

Implications of all the available evidenceOur study comprehensively characterized the heterogeneity of the AABs signature in SARS-CoV-2 convalescent individuals. The results established a list of diagnostic signatures and potential therapeutic targets for long-Covid-19 patients although follow-up long-term studies are required. We believe that our findings will serve as a valuable resource, to drive further exploration of long-COVID syndrome pathogenesis.


title: COVID-19 vaccine effectiveness against hospitalizations and ICU admissions in the Netherlands, April- August 2021

abstract: The objective of this study was to estimate vaccine effectiveness (VE) against COVID-19 hospitalization and ICU admission, per period according to dominating SARS-CoV-2 variant (Alpha and Delta), per vaccine and per time since vaccination. To this end, data from the national COVID-19 vaccination register was added to the national register of COVID-19 hospitalizations. For the study period 4 April - 29 August 2021, 15,571 hospitalized people with COVID-19 were included in the analysis, of whom 887 (5.7%) were fully vaccinated. Incidence rates of hospitalizations and ICU admissions per age group and vaccination status were calculated, and VE was estimated as 1-incidence rate ratio, adjusted for calendar date and age group in a negative binomial regression model. VE against hospitalization for full vaccination was 94% (95%CI 93-95%) in the Alpha period and 95% (95%CI 94-95%) in the Delta period. The VE for full vaccination against ICU admission was 93% (95%CI 87-96%) in the Alpha period and 97% (95%CI 97-98%) in the Delta period. VE was high in all age groups and did not show waning with time since vaccination up to 20 weeks after full vaccination.


title: Updating The Accuracy of Administrative Claims for Identifying Left Ventricular Ejection Fraction Among Patients with Heart Failure

abstract:
IntroductionLeft ventricular ejection fraction (EF) is an important factor for treatment decisions for heart failure. The EF is unavailable in administrative claims. We sought to evaluate the predictive accuracy of claims diagnoses for classifying heart failure with reduced ejection fraction (HFrEF) versus heart failure with preserved ejection fraction (HFpEF) with International Classification of Disease-Tenth Revision codes.

MethodsWe identified HF diagnoses for VA patients between 2017-2019 and extracted the EF from clinical notes and imaging reports using a VA natural language processing algorithm. We classified sets of codes as HFrEF-related, HFpEF-related, or non-specific based on the closest EF within 180 days. We selected a random heart failure diagnosis for each patient and tested the predictive accuracy of various algorithms for identifying HFrEF using the last 1 year of heart failure diagnoses. We performed sensitivity analyses on the EF thresholds, the cohort, and the diagnoses used.

ResultsBetween 2017-2019, we identified 358,172 patients and 1,671,084 diagnoses with an EF recording within 180 days. After dividing diagnoses into HFrEF-related, HFpEF-related, or non-specific, we found using the proportion of specific diagnoses classified as HFrEF-related had an AUC of 0.76 for predicting EF[≤]40% and 0.80 for predicting EF<50%. However, 23.3% of patients could not be classified due to only having non-specific codes. Predictive accuracy increased among patients with [≥]4 HF diagnoses over the preceding year.

DiscussionIn a VA cohort, administrative claims with ICD-10 codes had moderate accuracy for identifying reduced ejection fraction. This level of specificity is likely inadequate for performance measures. Administrative claims need to better align terminology with relevant clinical definitions.


title: Long-term Effects of Perceived Stress, Anxiety, and Anger on Hospitalizations or Death and Health Status in Heart Failure Patients

abstract:
BackgroundChronic and acute stress and emotion predict incidence/recurrence of CHD, but long-term effects on HF exacerbations are poorly understood. This study determined long-term chronic and episodic effects of stress, anxiety, and anger on hospitalizations or death, and worsened health status in HF.

Methods and Results147 patients with heart failure and reduced ejection fraction (HFrEF) completed measures of perceived stress (Perceived Stress Scale; PSS), state anxiety (STAI), recent anger (RA), and HF-related health status (Kansas City Cardiomyopathy Questionnaire; KCCQ) every 6 months for up to 39 months. Relationships of chronic (Mean) stress and emotion and episodic changes (Deviation) to subsequent hospitalizations or death and health status were determined utilizing Generalized Estimating Equation models. All-cause hospitalizations were predicted by chronic (Mean) PSS (OR=1.06, 95% CI 1.02-1.11, p=0.004), Mean STAI (OR=1.06, 95% CI=1.03, 1.10, p<0.001), and episodic (Deviation) PSS (OR=1.03, 95% CI 1.01-1.06, p=0.022). Mean PSS and Mean STAI also predicted cardiovascular hospitalizations. Each 1 standard deviation increase in Mean PSS and Mean STAI was associated, respectively, with a 61% and 79% increase in hospitalization or death. Anger was not associated with hospitalizations. Poorer KCCQ health status was related to higher Mean and Deviation PSS, STAI, and RA. Relationships to hospitalizations and health status were significant for Anxiety and Perceived Stress, independently of the other psychological measures.

ConclusionsIn HF patients, chronic perceived stress and anxiety and episodic stress increases are predictive of hospitalizations or death and worsened health status over a >3-year period. Mechanisms may involve sympathetic activation, and/or exacerbations of perceived symptoms or health behaviors.


title: Comparison of children and young people admitted with SARS-CoV-2 across the UK in the first and second pandemic waves: prospective multicentre observational cohort study

abstract:
BackgroundChildren and young people (CYP) were less affected than adults in the first wave of SARS-CoV-2 in the UK. We test the hypothesis that clinical characteristics of hospitalized CYP with SARS-CoV-2 in the UK second wave would differ from the first due to the combined impact of the alpha variant, school reopening and relaxation of shielding.

MethodsPatients <19 years hospitalised in the UK with clinician-reported SARS-CoV-2 were enrolled in a prospective multicentre observational cohort study between 17th January 2020 and 31st January 2021. Minimum follow up time was two weeks. Clinical characteristics were compared between the first (W1) and second wave (W2) of infections.

Findings2044 CYP aged <19 years were reported from 187 hospitals. 427/2044 (20.6%) had asymptomatic/incidental SARS-CoV-2 infection and were excluded from main analysis. 16.0% (248/1548) of symptomatic CYP were admitted to critical care and 0.8% (12/1504) died. 5.6% (91/1617) of symptomatic CYP had Multisystem Inflammatory Syndrome in Children (MIS-C).

Patients in W2 were significantly older (median age 6.5 years, IQR 0.3-14.9) than W1 (4.0 (0.4-13.6, p 0.015). Fever was more common in W1, otherwise presenting symptoms and comorbidities were similar across waves. After excluding CYP with MIS-C, patients in W2 had lower PEWS at presentation, lower antibiotic use and less respiratory and cardiovascular support compared to W1. There was no change in the proportion of CYP admitted to critical care between W1 and W2.

58.0% (938/1617) of symptomatic CYP had no reported comorbidity. Patients without co-morbidities were younger (42.4%, 398/938, <1 year old), had lower Paediatric Early Warning Scores (PEWS) at presentation, shorter length of hospital stay and received less respiratory support. MIS-C was responsible for a large proportion of critical care admissions, invasive and non-invasive ventilatory support, inotrope and intravenous corticosteroid use in CYP without comorbidities.

InterpretationSevere disease in CYP admitted with symptomatic SARS-CoV-2 in the UK remains rare. One in five CYP in this cohort had asymptomatic/incidental SARS-CoV-2 infection. We found no evidence of increased disease severity in W2 compared with W1.

FundingShort form: National Institute for Health Research, UK Medical Research Council, Wellcome Trust, Department for International Development and the Bill and Melinda Gates Foundation.

Long form: This work is supported by grants from the National Institute for Health Research (award CO-CIN-01) and the Medical Research Council (grant MC_PC_19059) and by the National Institute for Health Research Health Protection Research Unit (NIHR HPRU) in Emerging and Zoonotic Infections at University of Liverpool in partnership with Public Health England (PHE), in collaboration with Liverpool School of Tropical Medicine and the University of Oxford (NIHR award 200907), Wellcome Trust and Department for International Development (215091/Z/18/Z), and the Bill and Melinda Gates Foundation (OPP1209135). Liverpool Experimental Cancer Medicine Centre provided infrastructure support for this research (grant reference: C18616/A25153). JSN-V-T is seconded to the Department of Health and Social Care, England (DHSC). The views expressed are those of the authors and not necessarily those of the DHSC, DID, NIHR, MRC, Wellcome Trust, or PHE.

category: pediatrics


title: Population-based Cross-sectional Analysis of the Epidemiology of the Surgical Correction of Hyperhidrosis in 1216 Patients over 11 years.

abstract:
AO_SCPLOWBSTRACTC_SCPLOWO_ST_ABSBackgroundC_ST_ABSEndoscopic thoracic sympathectomy is the definitive surgical treatment for hyperhidrosis, and a nationwide study suggested that it has been performed in a higher rate than which could have been expected due to climate characteristics, comparing to the national statistics.

ObjectivesTo study the epidemiology of sympathectomy to treat hyperhidrosis in Sao Paulo, the largest city in the Southeast.

Design and settingpopulation-based cross-sectional study.

Methodsdata on sympathectomies to treat hyperhidrosis between 2008 and 2018 were assessed from the database of the Municipal Health Secretary of Sao Paulo, Brazil.

Results65.29% of the patients were female, 66.2% aged between 20 and 39 years and 37.59% had addresses registered outside Sao Paulo. 1216 procedures were performed in the city of Sao Paulo from 2008 to 2018, 78.45% of which in only two public hospitals. The number of procedures significantly declined over the years (p = 0.001). 71.63% of the procedures were associated with 2 to 3 days of hospital stay, only 78 intensive care unit days were billed and we did not observe any intra-hospital death.

Conclusionssympathectomies for the treatment of HH were widely performed in the city of Sao Paulo (1216 procedures), mainly in young (20 -39 years) and female patients, with more than one third of the patients having addresses registered outside the city. This is a very safe surgery, with low need for intensive care units and no mortality in our series. There was a decreasing trend in the number of surgeries over the years.

category: surgery


title: The equivalence of hydration status measured by the Fresenius BCM and the Cella Bioimpedance Spectroscopy devices on hemodialysis patients

abstract:
BackgroundFluid management is a serious challenge for patients undergoing hemodialysis therapy (HD). Bioimpedance spectroscopy (BIS) is a promising technique to help with clinical hydration (HYD) assessment. The Fresenius Medical Care (FMC) Body Composition Monitor (BCM) is the standard but is large and expensive. Cella Medical has introduced a small wireless BIS device. This study compared the HYD status predicted by the two devices.

MethodsFollowing the FMC BCM device manual guidelines, measurements of BIS were made wrist-ankle using typical ECG electrodes on the non-fistula side of HD patients pre dialysis while in their normal supine position. As usual, patients were measured before their normal time of therapy with the BCM. The Cella measurements were then performed within two minutes.

ResultsForty-two HD patients (M=64%, age=64{+/-}30 yrs.), were measured. One patient data was removed. The mean BCM HYD status was 1.86 l, SD 1.46 l, and SEM 0.22 l. Cella was 1.806 l, SD 1.36 l, and the SEM 0.21 l. The 95% difference confidence interval (CI) was -0.66 to 0.55 l. The Pearsons correlation (r) was r^2 = 0.85 (p<0.00001). There was no proportional bias: the offset was -0.056 l, and K=1.010. The limits of agreement (LOA) analysis showed a mean difference of 0.56 l, and limits d {+/-}2SD = (-1.192 l, 1.081 l), indicating 95% of the difference will lie within these limits. To evaluate equivalence, we performed two one-sided t-tests (TOST). When the bounds were reduced to the limit =0.47 l and -0.59 l, we obtained a 0.046 p-value (alpha =0.05), at 80% statistical power. For 26% of the subjects, the difference was <0.1 l, for 43% <0.25 l, for 71% <0.5 l, for 83% <0.75 l, for 90% <1.0 l, and for 9.5% (4 patients) more than 1 l. Only two cases (4.8%) were just over the {+/-}2SD limit.

ConclusionThis study suggests the BCM and Cella devices can be used interchangeably.

category: nephrology


title: Hospital-level work organization drives the spread of SARS-CoV-2 within hospitals: insights from a multi-ward model

abstract:
extensive protective measures, SARS-CoV-2 widely circulates within healthcare facilities, posing a significant risk to both patients and healthcare workers. Several control strategies have been proposed; however, the global efficacy of local measures implemented at the ward level may depend on hospital-level organizational factors. We aimed at better understanding the role of between-ward interactions on nosocomial outbreaks and their control in a multiward psychiatric hospital in Western France. We built a stochastic compartmental transmission model of SARS-CoV-2 in the 24-wards hospital, accounting for the various infection states among patients and staff, and between-ward connections resulting from staff sharing. We first evaluated the potential of hospital-wide diffusion of local outbreaks, depending on the ward they started in. We then assessed control strategies, including a screening area upon patient admission, an isolation ward for COVID-19 positive patients and changes in staff schedules to limit between-ward mixing. Much larger and more frequent outbreaks occurred when the index case originated in one of the most connected wards with up to four times more transmissions when compared to the more isolated ones. The number of wards where infection spreads was brought down by up to 53 % after reducing staff sharing. Finally, we found that setting up an isolation ward reduced the number of transmissions by up to 70 %, while adding a screening area before admission seemed ineffective.

Significance StatementHospital acquired COVID-19 poses a major problem to many countries. Despite extensive protective measures, transmission within hospitals still occurs regularly and threatens those essential to the fight against the pandemic while putting patients at risk. Using a stochastic compartmental model, we simulate the spread of SARS-CoV-2 in a multi-ward hospital, assessing the effect of different scenarios and infection control strategies. The novelty of our method resides in the consideration of staff sharing data to better reflect the field reality. Our results highlight the poor efficiency of implementing a screening area before hospital admission, while the setting up of an isolation ward dedicated to COVID-19 patients and the restriction of healthcare workers movements between wards significantly reduce epidemic spread.