Transdiagnostic phenotyping of psychopathology in a help-seeking population (PhenoNetz): a study protocol for an experience sampling study Prevention in psychiatry provides a promising way to address the burden by mental illness. However, established approaches focus on specific diagnoses and do not address the heterogeneity and manifold potential outcomes of help-seeking populations that present at early recognition services. Conceptualizing psychopathology manifested in help-seeking populations from a network perspective of interacting symptoms allows transdiagnostic investigations beyond binary disease categories. Furthermore, modern technologies such as smartphones facilitate the application of Experience Sampling Methods (ESM). A combination of ESM with network analyses provides valid insights beyond established assessment instruments. We will examine n = 75 individuals (age 18-40 years) of the help-seeking population of the Cologne early recognition centre (FETZ). For a maximally naturalistic sample, only minimal exclusion criteria will be applied. We will collect data for 14 days utilizing a mobile application to assess ten transdiagnostic symptoms, i.e., depressive, anxious and psychotic symptoms as well as distress level. With these data, we will generate average group-level symptom networks and personalized symptom networks using a two-step multilevel vector autoregressive model. Additionally, we will explore associations between symptom networks and sociodemographic, risk and resilience factors, as well as psychosocial functioning. Our study will provide insights about feasibility and utility of ESM in a help-seeking population. Providing a first explorative phenotyping of the transdiagnostic help-seeking population, this study will contribute to innovation of early recognition in psychiatry. Results will help to pave the way for prevention and targeted early intervention in a broader patient group and thus, enable greater intended effects in alleviating the burden of psychiatric disorders.
One Year of Evidence on Mental Health Disorders in China during the COVID-19 Crisis - A Systematic Review and Meta-Analysis This paper provides a systematic review and meta-analysis on the prevalence rate of mental health issues of general population, general and frontline healthcare workers (HCWs) in China over one year of the COVID-19 crisis. We systematically searched PubMed, Embase, Web of Science, and Medrxiv at November 16th, 2020, pooled data using random-effects meta-analyses to estimate the prevalence rates, and ran meta-regression to tease out the heterogeneity. The meta-regression results uncovered several predictors of the prevalence rates, including severity, type of mental issues, population, sampling location, and study quality. Pooled prevalence rates are significantly different from, yet largely between, the findings of previous meta-analyses, suggesting the results of our larger study are consistent with yet more accurate than the findings of the smaller, previous meta-analyses. The prevalence rates of distress and insomnia and those of frontline HCWs are higher suggest future research and interventions should pay more attention to those mental outcomes and populations. Our findings suggest a need to examine the prevalence rates at varying levels of severity. The one-year cumulative evidence on sampling locations (Wuhan vs. non-Wuhan) corroborates the typhoon eye effect theory.

Trial registrationCRD4202022059
Non-Markovian modelling highlights the importance of age structure on Covid-19 epidemiological dynamics The Covid-19 pandemic outbreak was followed by a huge amount of modelling studies in order to rapidly gain insights to implement the best public health policies. Most of these compartmental models involved ordinary differential equations (ODEs) systems. Such a formalism implicitly assumes that the time spent in each compartment does not depend on the time already spent in it, which is at odds with the clinical data. To overcome this "memoryless" issue, a widely used solution is to increase and chain the number of compartments of a unique reality (e.g. have infected individual move between several compartments). This allows for greater heterogeneity and thus be closer to the observed situation, but also tends to make the whole model more difficult to apprehend and parameterize. We develop a non-Markovian alternative formalism based on partial differential equations (PDEs) instead of ODEs, which, by construction, provides a memory structure for each compartment thereby allowing us to limit the number of compartments. We apply our model to the French 2021 SARS-CoV-2 epidemic and, while accounting for vaccine-induced and natural immunity, we analyse and determine the major components that contributed to the Covid-19 hospital admissions. The results indicate that the observed vaccination rate alone is not enough to control the epidemic, and a global sensitivity analysis highlights a huge uncertainty attributable to the age-structured contact matrix. Our study shows the flexibility and robustness of PDE formalism to capture national COVID-19 dynamics and opens perspectives to study medium or long-term scenarios involving immune waning or virus evolution. The Addiction Risk Factor: A Unitary Genetic Vulnerability Characterizes Substance Use Disorders and Their Associations with Common Correlates Substance use disorders commonly co-occur with one another and with other psychiatric disorders. They share common features including high impulsivity, negative affect, and lower executive function. We tested whether a common genetic factor undergirds liability to problematic alcohol use (PAU), problematic tobacco use (PTU), cannabis use disorder (CUD), and opioid use disorder (OUD) by applying genomic structural equation modelling to genome-wide association study summary statistics for individuals of European ancestry (Total N = 1,019,521; substance specific Ns range: 82,707-435,563), while adjusting for the genetics of substance use (Ns = 184,765-632,802). We also tested whether shared liability across SUDs is associated with behavioral constructs (risk taking, executive function, neuroticism; Ns = 328,339-427,037) and non-substance use psychopathology (psychotic, compulsive, and early neurodevelopmental disorders). Shared genetic liability to PAU, PTU, CUD, and OUD was characterized by a unidimensional addiction risk factor (termed The Addiction-Risk-Factor, independent of substance use. OUD and CUD demonstrated the largest loadings, while problematic tobacco use showed the lowest loading. The Addiction-Risk-Factor was associated with risk taking, neuroticism, executive function, and non-substance psychopathology, but retained specific variance before and after accounting for genetics of substance use. Thus, a common genetic factor partly explains susceptibility for alcohol, tobacco, cannabis, and opioid use disorder. The Addiction-Risk-Factor has a unique genetic architecture that is not shared with normative substance use or non-substance psychopathology, suggesting that addiction is not the linear combination of substance use and psychopathology. Serum proteome analysis of systemic JIA and related pulmonary alveolar proteinosis identifies distinct inflammatory programs and biomarkers ObjectivesRecent observations in systemic Juvenile Idiopathic Arthritis (sJIA) suggest an increasing incidence of high-mortality interstitial lung disease, characterized by a variant of pulmonary alveolar proteinosis (PAP). Co-occurrence of macrophage activation syndrome (MAS) and PAP in sJIA suggested a shared pathology, but sJIA-PAP patients also commonly experience features of drug reaction such as atypical rashes and eosinophilia. We sought to investigate immunopathology and identify biomarkers in sJIA, MAS, and sJIA-PAP.

MethodsWe used SOMAscan to measure >1300 analytes in sera from healthy controls and patients with sJIA, MAS, sJIA-PAP and other related diseases. We verified selected findings by ELISA and lung immunostaining. Because the proteome of a sample may reflect multiple states (sJIA, MAS, sJIA-PAP), we used regression modeling to identify subsets of altered proteins associated with each state. We tested key findings in a validation cohort.

ResultsProteome alterations in active sJIA and MAS overlapped substantially, including known sJIA biomarkers like SAA and S100A9, and novel elevations of heat shock proteins and glycolytic enzymes. IL-18 was elevated in all sJIA groups, particularly MAS and sJIA-PAP. We also identified an MAS-independent sJIA-PAP signature notable for elevated ICAM5, MMP7, and allergic/eosinophilic chemokines, which were all previously associated with lung damage. Immunohistochemistry localized ICAM5 and MMP7 in sJIA-PAP lung. ICAM5s ability to distinguish sJIA-PAP from sJIA/MAS was independently validated.

ConclusionsSerum proteins support an sJIA-to-MAS continuum, help distinguish sJIA, sJIA/MAS, and sJIA-PAP, and suggest etiologic hypotheses. Select biomarkers, such as ICAM5, could aid in early detection and management of sJIA-PAP. Complementary frailty and mortality prediction models on older patients as a tool for assessing palliative care needs BackgroundPalliative care (PC) has demonstrated benefits for life-limiting illnesses. Cancer patients have mainly accessed these services, but there is growing consensus about the importance of promoting access for patients with non-malignant disease. Bad survival prognosis and patients frailty are usual dimensions to decide PC inclusion.

ObjectivesThe main aim of this work is to design and evaluate three quantitative models based on machine learning approaches to predict frailty and mortality on older patients in the context of supporting PC decision making: one-year mortality, survival regression and one-year frailty classification.

MethodsThe dataset used in this study is composed of 39,310 hospital admissions for 19,753 older patients (age >= 65) from January 1st, 2011 to December 30th, 2018. All prediction models were based on Gradient Boosting Machines. From the initial pool of variables at hospital admission, 20 were selected by a recursive feature elimination algorithm based on the random forests GINI importance criterion. Besides, we run an independent grid search to find the best hyperparameters in each model. The evaluation was performed by 10-fold cross-validation and area under the receiver operating characteristic curve and mean absolute error were reported. The Cox proportional-hazards model was used to compare our proposed approach with classical survival methods.

ResultsThe one-year mortality model achieved an AUC ROC of 0.87 {+/-} 0.01; the mortality regression model achieved an MAE of 329.97 {+/-} 5.24 days. The one-year frailty classification reported an AUC ROC of 0.9 {+/-} 0.01. The Spearmans correlation between the admission frailty index and the survival time was -0.1, while the point-biserial correlation between one-year frailty index and survival time was -0.16.

ConclusionsOne-year mortality model performance is at a state-of-the-art level. Frailty Index used in this study behaves coherently with other works in the literature. One-year frailty classifier demonstrated that frailty status within the year could be predicted accurately. To our knowledge, this is the first study predicting one-year frailty status based on a frailty index. We found mortality and frailty as two weakly correlated and complementary PC needs assessment criteria. Predictive models are available online at http://demoiapc.upv.es. Colorectal Cancer Disparities Across the Continuum of Cancer Care with a Focus on Surgery and Black Patients: A Systematic Review and Meta-Analysis ImportanceDespite increases in screening among vulnerable populations, colorectal cancer disparities persist.

ObjectiveTo direct future efforts towards high impact opportunities in addressing these disparities, we performed a systematic review and meta-analysis of the colorectal cancer disparities literature with a focus on the utilization of Surgery, the primary treatment for colorectal cancer.

Data SourcesTwo electronic databases (PubMed and SCOPUS) were searched for prospective and retrospective studies reporting on colorectal cancer disparities between 2011 and March 29, 2021.

Study SelectionStudies for the systematic review were selected if: (1) reported on disparities within colorectal, colon, or rectal cancer (2) articles were published in the English language (3) articles used only United States-sourced data.

Studies for the meta-analysis were selected if: (1) reported on at least one of three utilization of surgery outcomes: receipt of colorectal, colon, or rectal surgery, refusal of surgery, or receipt of laparoscopic versus open surgery (2) Outcomes were reported as Odds ratio according to multivariate analysis.

Data Extraction and SynthesisQuality appraisal and data extraction were performed independently by 2 reviewers using the Newcastle-Ottawa Scale for quality assessment. For the meta-analysis, pooled multivariate odds ratios for the three outcomes regarding utilization of surgery were separately calculated according to fixed or random-effects models. Reporting followed the Preferred Reporting Items for Systematic Review and Meta-analyses guidelines.

Main Outcomes and MeasuresSystematic Review: The volume of publications attributed to the following sectors of the colorectal cancer care continuum: (1) Prevention, Screening, or Diagnosis (2) Treatment (3) Survivorship (4) End-of-life Care. Meta-analysis: Receipt of Colorectal, Colon, or Rectal Surgery and Black Race, Refusal of Surgery and Black Race, or Receipt of Laparoscopic versus Open Surgery and Black Race.

ResultsThe systematic review included 1,199 relevant publications. Among them, 60% were focused on Prevention, Screening, or Diagnosis, followed by Survivorship (20%), Treatment (15%), and End-of-Life Care (1%). Within the studies reporting on treatment disparities, 46% were focused on Race/Ethnicity, followed by Socioeconomic Status (28%), Age (17%), Gender (6%), Disabilities/Comorbidities (3%), and LGBTQI+ (0%). A total of 16 studies, including 1,110,674 patients, were applied to three separate meta-analyses regarding utilization of Surgery. Patients of black race were less likely to receive colorectal, or colon, or rectal surgery (OR 0.75, 95% CI 0.67-0.83), less likely to receive laparoscopic versus open colorectal cancer surgery (OR 0.91, 95% CI 0.88-0.94), and twice as likely to refuse colon surgery (OR 2.41, 95% CI 1.91-3.06).

Conclusions and RelevanceThe majority of research, to date, related to colorectal cancer disparities is focused on prevention, screening, or diagnosis and a minimal amount is dedicated to treatment. Additionally, all of the limited publications related to colorectal cancer surgery, as a treatment modality, are observational in nature. The application of this knowledge of past efforts and current continuing adverse outcomes is required in order to shift the focus of the research community towards treatment. In particular, research addressing surgical disparities is necessary, as surgery remains the primary treatment for colorectal cancer. How Informative Were Early SARS-CoV-2 Treatment and Prevention Trials? A longitudinal cohort analysis of trials registered on clinicaltrials.gov BackgroundEarly in the SARS-CoV-2 pandemic, commentators warned that some COVID trials were inadequately conceived, designed and reported. Here, we retrospectively assess the prevalence of informative COVID trials launched in the first 6 months of the pandemic.

MethodsWe created a cohort of SARS-CoV-2 treatment and prevention efficacy trials that were initiated from 2020-01-01 to 2020-06-30 using ClinicalTrials.gov registration records. We evaluated trials on 3 criteria of informativeness: potential redundancy, design quality and feasibility of patient-participant recruitment. The study protocol was prospectively registered with the Open Science Framework (https://osf.io/fp726/).

ResultsWe included 500 trials in our cohort, 58% of which were Phase 2 and 84.8% were directed towards the treatment of SARS-CoV-2. Close to one third of trials met all three criteria and were deemed informative (29.0% (95% Confidence Interval 23.7 - 36.9)). The proportion of potentially redundant trials in our cohort was 4.1%. Over half of the trials in our cohort (56.2%) did not meet our criteria for high quality trial design. The proportion of trials with infeasible patient-participant recruitment was 22.6%.

ConclusionsLess than one third of COVID-19 trials registered on ClinicalTrials.gov during the first six months met all three criteria for informativeness. Shortcomings in trial design, recruitment feasibility and redundancy reflect longstanding weaknesses in the clinical research enterprise that were likely amplified by the exceptional circumstances of a pandemic. The Outcome of Gynecologic Cancer Patients With Covid-19 Infection: A Systematic Review And Meta-Analysis ObjectiveCancer is a comorbidity that leads to progressive worsening of Covid-19 with increased mortality. This is a systematic review and meta-analysis to yield evidence of adverse outcomes of Covid-19 in gynecologic cancer.

MethodsSearches through PubMed, Google Scholar, ScienceDirect, and medRxiv to find articles on the outcome of gynecologic cancer with Covid-19 (24 July 2021-19 February 2022). Newcastle-Ottawa Scale tool is used to evaluate the quality of included studies. Pooled odds ratio (OR), 95% confidence interval (CI), random-effects model were presented. This study was registered to PROSPERO (CRD42021256557).

ResultsWe accepted 51 studies (1991 gynecologic cancer with Covid-19). Covid-19 infection was lower in gynecologic cancer vs hematologic cancer (OR 0.71, CI 0.56-0.90, p 0.005). Severe Covid and death were lower in gynecologic cancer vs lung and hematologic cancer (OR 0.36, CI 0.16-0.80, p 0.01), (OR 0.52, CI 0.44-0.62, p <0.0001), (OR 0.26, CI 0.10-0.67 p 0.005), (OR 0.63, CI 0.47-0.83, p 0.001) respectively. Increased Covid death is seen in gynecologic cancer vs breast, non-covid cancer, and non-cancer covid (OR 1.50, CI 1.20-1.88, p 0.0004), (OR 11.83, CI 8.20-17.07, p <0.0001), (OR 2.98, CI 2.23-3.98, p <0.0001) respectively.

ConclusionGynecologic cancer has higher Covid-19 adverse outcomes compared to non-cancer, breast cancer, non-metastatic, and Covid-19 negative population. Gynecologic cancer has fewer Covid-19 adverse outcomes compared to other cancer types, lung cancer, and hematologic cancer. These findings may aid health policies and services during the ongoing global pandemic. Potential impacts of Washington State's wildfire worker protection rule on construction workers Driven by climate change, wildfires are increasing in frequency, duration, and intensity across the Western United States. Outdoor workers are being exposed to increasing wildfire-related particulate matter and smoke. Recognizing this emerging risk, Washington adopted an emergency rule and is presently engaged in creating a permanent rule to protect outdoor workers from wildfire smoke exposure. While there are growing bodies of literature on the exposure to and health effects of wildfire smoke in the general public and wildland firefighters, there is a gap in knowledge about wildfire smoke exposure among outdoor workers generally, and construction workers specifically, a large category of outdoor workers in Washington totaling 200,000 people. In this study, several data sources were linked including state-collected employment data and national ambient air quality data to gain insight into the risk of PM2.5 exposure among construction workers and evaluate the impacts of different air quality thresholds that would have triggered a new Washington emergency wildfire smoke rule aimed at protecting workers from high PM2.5 exposure. Results indicate the number of poor air quality days has increased in August and September in recent years. Over the last decade these months with the greatest potential for particulate matter exposure coincided with an annual peak in construction employment that was typically 9.4 to 42.7% larger across Washington counties (one county was 75.8%). Lastly, the "encouraged" threshold of the Washington emergency rule (20.5 g/m3) would have resulted in 5.5 times more days subject to the wildfire rule on average across all Washington counties compared to its "required" threshold (55.5 g/m3), and in 2020 the rule could have created demand for 1.35 million N-95 filtering facepiece respirators among construction workers. These results have important implications for both employers and policy makers as rules are developed. The potential policy implications of wildfire smoke exposure, exposure control strategies, and data gaps that would improve understanding of construction worker exposure to wildfire smoke are also discussed. Inflammasome-related markers at the ICU admission are not associated with outcome in the critically ill COVID-19 patients. PurposeDevelopment of targeted biological therapies for COVID-19 requires reliable biomarkers that could help indicate the responding patients. Hyperactivation of the inflammasome by SARS-CoV2 virus is hypothesized to contribute to severe course of the COVID-19 disease. Therefore, we aimed to evaluate the prognostic value of several inflammasome-related cytokines and proteins at the admission to the intensive care unit (ICU).

Patients and methodsPlasma samples were obtained from 45 critically ill COVID-19 patients and from 10 patients any without any signs of infection (TBI, traumatic brain injury) on admission to the ICU. The concentration of IL-1, IL-1{beta}, IL-18, IL-1RA, galectin-1, ASC, LDH, ferritin, and gasdermin D were analyzed. A novel cell-free caspase-1 plasma assay was developed by inhibitor-based immunoprecipitation followed by Western Blot. Demographic and clinical characteristics were recorded.

ResultsIn-hospital mortality in COVID-19 patients reached 62%. Galectin-1 was 1.8-fold lower in COVID-19 than in TBI patients (17101.84 vs. 30764.20 pg/ml, p=0.007), but other inflammasome-related biomarkers were at similar concentrations. Patients with SOFA score of >9 on admission who were at high risk of death had significantly higher galectin-1 but lower IL-1RA in comparison to low-risk patients (25551.3 pg/ml vs 16302.7 pg/ml, p=0.014; 14.5 pg/ml vs 39.4 pg/ml, p=0.04, respectively). Statistically significant correlations were observed between: IL-1 and platelets (r=-0.37), IL-1{beta} and platelets (r=-0.36), ferritin and INR (r=0.39). Activated caspase-1 p35 was detectable in 12/22 COVID-19 patients but in none of the TBI patients. Its presence was related with higher fibrinogen and lower D-dimers. Moreover, the densitometric analysis showed a significantly higher amount of p35 in patients with SOFA> 9.

ConclusionOur results indicate that the systemic markers of activation of the inflammasome in critically ill COVID-19 patients is not directly related with outcome. Therefore, potential interventions aimed at the inflammasome pathway in this group of patients may be of limited effectiveness and should be biomarker-guided. Reports of myocarditis and pericarditis following mRNA COVID-19 vaccines: A systematic review of spontaneously reported data from the UK, Europe, and the US and of the literature ObjectivesTo bring together spontaneously reported data from around the world to estimate the reporting rate in different countries and better understand the risk factors for myocarditis and pericarditis following exposure to COVID-19 mRNA vaccines.

DesignSystematic review of the literature and systematic review of spontaneously reported data from the United Kingdom (UK), United States (US), and European Union/European Economic Area (EU/EEA).

Data sourcesSpontaneously reported data for COVID-19 Vaccine Pfizer/BioNTech (Comirnaty) and COVID-19 Vaccine Moderna (Spikevax) were obtained using outputs from the UKs Yellow Card scheme (covering the period 09/12/2020 - 20/10/2021), the Vaccine Adverse Event Reporting System (VAERS; US; covering the period 23/08/2021 - 21/10/2021), and EudraVigilance (EU/EEA; covering the period 21/12/2020 - 21/10/2021). Systematic searches of PubMed and Embase literature databases were performed with a datalock point of 11 October 2021.

Eligibility criteriaAll publicly available spontaneous reporting data from the three regions of interest were included. Data on events labelled "Myocarditis" and "Pericarditis" were included. No restrictions on age or gender were applied. For the systematic literature review, all pharmacoepidemiological studies of observational design investigating myocarditis and pericarditis following mRNA COVID-19 vaccines identified by our search were included. No restrictions on language or date were applied. Pre-print manuscripts were included if no peer-reviewed version was available. Studies of non-observational design, case reports, and case series were excluded. Study quality was assessed using relevant Critical Appraisal Skills Programme (CASP) tools. All studies were considered of sufficient quality for inclusion.

Data extraction and synthesisOne researcher extracted data from spontaneous reporting systems and published pharmacoepidemiological studies. Spontaneously reported events of myocarditis and pericarditis were presented for each individual data source, and stratified by vaccine, age, sex, and dose where this information was available. Vaccination data were obtained to the same date, and reporting rates were calculated for the events of myocarditis and pericarditis for each population of interest. For published pharmacoepidemiological studies, the study design, participant characteristics, and study results were tabulated.

ResultsOverall, there were 435 reports of myocarditis and 327 reports of pericarditis reported to the UKs Yellow Card scheme up to 20 October 2021. To 21 October 2021, in the US, 1936 reports of myocarditis and 1271 reports of pericarditis had been submitted to VAERS; there had been 2924 reports of myocarditis and 1855 reports of pericarditis submitted to EudraVigilance to the same date. Most reports (73.3%) had been submitted following Comirnaty (Pfizer/BioNTech). Males represented 74.9% of reports of myocarditis and 56.9% of pericarditis overall (for US and EU/EEA populations only), and the majority of reports concerned vaccinees ages under 40 years. Reports were more frequent following the second dose of mRNA COVID-19 vaccine. Reporting rates of myocarditis and pericarditis were consistent between the data sources. Seven pharmacoepidemiological studies were included; results of these studies were largely consistent with results of our spontaneous report analyses.

ConclusionsThis study provides evidence that younger vaccinees more frequently report myocarditis and pericarditis following mRNA COVID-19 vaccines compared with older vaccinees. These events had mild clinical course followed by full recovery in most cases. Results from published literature supported the results of our analyses.

Strengths and Limitations of the StudyO_LIThis is the first study to bring together spontaneously reported data from the United Kingdom, United States, and Europe on myocarditis and pericarditis following mRNA COVID-19 vaccines.
C_LIO_LIResults from this study provide evidence on the frequency of reported events of myocarditis and pericarditis following mRNA vaccines in different age groups, and by sex and vaccine dose. Analyses of spontaneous reports were consolidated with results of published literature, identified by systematic review.
C_LIO_LIResults may have been influenced by biases including different vaccination policies in each region examined, and publicity on events of myocarditis and pericarditis following mRNA vaccines.
C_LIO_LIThe study relied on outputs from spontaneous reporting systems in which the level of detail differed between the systems examined; furthermore, it is not possible to estimate incidence rates using spontaneous reports due to the lack of data on the exposed population, and there is no unvaccinated comparison group.
C_LIO_LIThere is an urgent need for further pharmacoepidemiological studies to be conducted to provide more accurate estimates of the frequency, clinical course, long term outcome, effects of treatment and impact on quality of life, to address many of the limitations of spontaneous reporting.
C_LI Analysis of MRI-derived spleen iron in the UK Biobank identifies genetic variation linked to iron homeostasis and erythrocyte morphology Aging, and the pathogenesis of many common diseases, involves iron homeostasis. A key role in iron homeostasis is played by the spleen, which is the largest filter of the blood and performs iron reuptake from old or damaged erythrocytes. Despite this important role, spleen iron content has not been measured previously in a large, population-based cohort. In this study, we quantify spleen iron in 41,764 participants of the UK Biobank using magnetic resonance imaging (MRI). We find that epidemiologic and environmental factors such as increased age, higher red meat consumption and lower alcohol intake correlate with higher spleen iron. Through genome-wide association study, we identify genetic associations between spleen iron and common variation at seven loci, including in two hereditary spherocytosis (HS) genes, ANK1 and SPTA1. HS-causing mutations in these genes are associated with lower reticulocyte volume and increased reticulocyte percentage, while our common alleles are associated with increased expression of ANK1 and SPTA1 in blood and with larger reticulocyte volume and reduced reticulocyte percentage. As genetic modifiers, these common alleles may explain mild spherocytosis phenotypes observed in some HS allele carriers. Further, we identify an association between spleen iron and MS4A7, which colocalizes with a quantitative trait locus for MS4A7 alternative splicing in whole blood, and with monocyte count and fraction. Through quantification of spleen iron in a large human cohort, we extend our understanding of epidemiological and genetic factors associated with iron recycling and erythrocyte morphology. Comparative profiles of SARS-CoV-2 Spike-specific human milk antibodies elicited by mRNA- and adenovirus-based COVID-19 vaccines Numerous COVID-19 vaccines are authorized globally. To date, [~]71% of doses are comprised of the Pfizer/BioNTech vaccine, and [~]17% the Moderna/NIH vaccine, both of which are mRNA-based. The chimpanzee Ad-based Oxford/AstraZeneca (AZ) vaccine comprises [~]9%, while the Johnson & Johnson/Janssen (J&J) human adenovirus (Ad26) vaccine ranks 4th at [~]2% [1]. No COVID-19 vaccines are yet available for children 0-4. One method to protect this population may be passive immunization via antibodies (Abs) provided in the milk of a lactating vaccinated person. Our early work [2] and other reports [3-5] have demonstrated that unlike the post-SARS-CoV-2 infection milk Ab profile, which is rich in specific secretory (s)IgA, the vaccine response is highly IgG-dominant. In this report, we present a comparative assessment of the milk Ab response elicited by Pfizer, Moderna, J&J, and AZ vaccines. This analysis revealed 86% -100% of mRNA vaccine recipient milk exhibited Spike-specific IgG endpoint titers, which were 12 - 28-fold higher than those measured for Ad vaccine recipient milk. Ad-based vaccines elicited Spike-specific milk IgG in only 33%-38% of recipients. Specific IgA was measured in 52%-71% of mRNA vaccine recipient milk and 17%-23% of Ad vaccine recipient milk. J&J recipient milk exhibited significantly lower IgA than Moderna recipients, and AZ recipients exhibited significantly lower IgA titers than Moderna and Pfizer. <50% of milk of any group exhibited specific secretory Ab, with Moderna recipient IgA titers measuring significantly higher than AZ. Moderna appeared to most frequently elicit >2-fold increases in specific secretory Ab titer relative to pre-vaccine sample. These data indicate that current Ad-based COVID-19 vaccines poorly elicit Spike-specific Ab in milk compared to mRNA-based vaccines and that mRNA vaccines are preferred for immunizing the lactating population. This study highlights the need to design vaccines better aimed at eliciting an optimal milk Ab response. The effects of modifiable maternal pregnancy risk factors on molar-incisor hypomineralisation: A negative control study ObjectivesO_LITo explore the associations between modifiable maternal pregnancy exposures: pre-pregnancy body mass index (BMI), pregnancy smoking and alcohol consumption with offspring molar-incisor hypomineralisation (MIH).
C_LIO_LITo explore for the presence of residual confounding using negative control analyses.
C_LI

MethodsThis study used data from Avon Longitudinal Study of Parents and Children (ALSPAC), a UK prospective birth cohort. We defined offspring MIH using prospectively collected questionnaire data. We used logistic regression to explore confounder adjusted associations between maternal pre-pregnancy BMI and smoking and alcohol consumption during pregnancy with MIH. We included negative control exposure (paternal BMI, smoking and alcohol around the time of pregnancy) and outcome (offspring dental trauma) analyses to explore for the presence of residual confounding.

Results5536 mother/offspring pairs were included (297 MIH cases [5.4%]). We found a positive association between maternal mean BMI and offspring MIH (OR per 1-kg/m2 difference in maternal BMI: 1.04, 95% CI: 1.00, 1.08). In subsequent analyses, we found evidence that this effect was non-linear and being driven by women in the highest BMI quintiles. In negative control analyses, we found no evidence of association between paternal BMI and offspring MIH (OR: 0.94, 95% CI: 0.89, 1.00) and maternal BMI and offspring dental trauma (OR: 0.99, 95% CI: 0.96, 1.02). There was no clear evidence of an association for maternal pregnancy smoking (OR: 0.76, 95%CI: 0.46, 1.22) and alcohol consumption (OR: 0.79, 95% CI: 0.56, 1.21) with offspring MIH with results imprecisely estimated.

ConclusionIn summary we found evidence of a possible intrauterine effect of high maternal pre-pregnancy BMI on offspring MIH. We did not find robust evidence for an intrauterine effect of maternal pregnancy smoking or alcohol consumption on offspring MIH. Our findings provide further support for women of reproductive age to maintain a healthy weight. Future studies are warranted to explore possible mechanisms on how the pregnancy environment may relate to offspring MIH. Characteristic and Sex Differences in Auditory Function and Cochlear Pathophysiology in a Noise-exposed Cohort: A Cross-sectional Study BackgroundTo determine the characteristics and sex differences of auditory perception and cochlear function in individuals with long-term occupational noise exposure.

MethodsYoung workers with long-term occupational noise exposure from a shipyard were recruited in the current study as the hidden hearing loss (HHL) risk group. Age-matched office workers in the same shipyard who had no occupational noise-exposure history were enrolled in the control group. The auditory processing ability of speech-in-noise (SIN) score and gap detection threshold (GDT) were further examined by sex. The cochlear function of action potential (AP) and summating potential (SP)/AP values were tested and compared by sex and side. The correlation between the SIN score and cochlear function was studied by sex. The correlation between either auditory processing ability or cochlear function and occupational-noise working length (OWL) was also analysed in the HHL risk group.

ResultsSignificantly decreased SIN scores and a higher GDT of the 4 kHz gap marker were only found in men in the HHL risk group. Although the hearing thresholds of the women in the HHL risk group were slightly but significantly worse than those of the women in the control group, no significant defects in auditory processing or temporal resolution were found between the two groups. Significantly decreased cochlear function and increased SP/AP values in the left ear were only found in men in the HHL risk group. Neither the AP amplitude nor the AP latency differed significantly between the two groups by sex. A correlation study indicated that only the correlation between the SIN score and the AP amplitude of the right ear in men was significant. No significant difference was found between the SIN score and cochlear function in women. The AP latency of the right ear was only significantly correlated with OWL in men.

ConclusionIn long-term occupational working exposure individuals with normal hearing, defects in auditory processing, temporal resolution and cochlear function showed sex differences, none of which were significant in women. In men, a weak correlation between the SIN score and the AP amplitude of the right ear was found. There was only a weak correlation between OWL and the AP latency of the right ear in men. Our findings indicate men are more vulnerable to occupational noise than women. Considering the noise-exposure dose differences between the control and HHL risk groups, our measures are insensitive to cochlear synaptopathy in humans. Humoral immune responses to COVID-19 vaccination in people living with HIV receiving suppressive antiretroviral therapy Humoral responses to COVID-19 vaccines in people living with HIV (PLWH) remain incompletely understood. We measured circulating antibodies against the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein, ACE2 displacement and live viral neutralization activities one month following the first and second COVID-19 vaccine doses in 100 adult PLWH and 152 controls. All PLWH were receiving suppressive antiretroviral therapy, with median CD4+ T-cell counts of 710 (IQR 525-935) cells/mm3. Nadir CD4+ T-cell counts ranged as low as <10 (median 280; IQR 120-490) cells/mm3. After adjustment for sociodemographic, health and vaccine-related variables, HIV infection was significantly associated with 0.2 log10 lower anti-RBD antibody concentrations (p=0.03) and [~]11% lower ACE2 displacement activity (p=0.02), but not lower viral neutralization (p=0.1) after one vaccine dose. Following two doses however, HIV was no longer significantly associated with the magnitude of any response measured. Rather, older age, a higher burden of chronic health conditions, and having received two ChAdOx1 doses (versus a heterologous or dual mRNA vaccine regimen) were independently associated with lower responses. After two vaccine doses, no significant correlation was observed between the most recent or nadir CD4+ T-cell counts and vaccine responses in PLWH. These results suggest that PLWH with well-controlled viral loads on antiretroviral therapy and CD4+ T-cell counts in a healthy range will generally not require a third COVID-19 vaccine dose as part of their initial immunization series, though other factors such as older age, co-morbidities, vaccine regimen type, and durability of vaccine responses will influence when this group may benefit from additional doses. Further studies of PLWH who are not receiving antiretroviral treatment and/or who have low CD4+ T-cell counts are needed. Survey of Contaminated Percutaneous Injuries in Anesthesia Practitioners BackgroundAnesthesia practitioners are at inherent risk for percutaneous injuries by blood-contaminated needles and sharp objects. These exposures may result in transmission of HIV and hepatitis viruses. Data about this occupational hazard from contaminated needles and sharp devices is limited and decades old. We conducted a web-based survey to assess the occurrence, reporting, characteristics, and outcome of contaminated percutaneous injuries (CPI) in anesthesia residents, fellows, and attendings.

MethodsAfter institutional research board approval, an email was sent to 217 anesthesia practitioners requesting their participation in an online survey about contaminated percutaneous injuries. Responses were collected from February through March 2020. Results are reported as absolute numbers and proportions with 95% confidence interval (CI).

ResultsThe overall survey response rate was 51% (110/217). 59% (65/110) (95% CI, 50-68) of participants reported having one or more contaminated percutaneous injury during their years of anesthesia practice (42% (21/50) of residents, 50% (4/8) of fellows, 77% (40/52) of anesthesia attendings). Prevalence of injuries related to attendings years of anesthesia practice was 69% (95% CI, 44-94) for 5-10 years, 62.5% (95% CI, 29-96) for 10-15 years, and 79% (95% CI, 63- 95) for greater than 15 years of practice.

35% (95% CI, 26-44) of participants reported having one or more CPI within the last 5 years (40% of residents, 50% of fellows, 29% of attendings). Occurrence of CPI within the last 5 years based on attending anesthesiologist years of practice was 57% for less than 5 years, 37.5% for 10-15 years, and 20% for 15-20 years of practice. 75% (95% CI, 65-85) reported the incident at the time of injury. 59% (95% CI, 48-70) of injuries were due to hollow bore needles. 50% (95% CI, 39-61) of total injuries were high risk. 26% of injured anesthesia practitioners received post-exposure prophylaxis and there were zero seroconversions.

ConclusionMost anesthesiologists will sustain a contaminated percutaneous injury during their careers. Incidence of these injuries decreases with years of practice. Occurrence of these injuries is high among anesthesia residents, with the majority reporting their injuries. Half of the injuries are high risk with a quarter requiring postexposure prophylaxis. More education and interventions are needed to reduce percutaneous injuries and improve reporting. Why one size fits all is not enough when designing covid-19 immunity certificates for domestic use: a UK wide cross-sectional online survey ObjectivesThe present study explored publics willingness to use COVID-19 immunity certificates across six different domestic scenarios.

DesignCross-sectional online survey.

SettingUK representative survey conducted on the 3rd of August 2021.

Participants534 UK residents over 18 years old.

InterventionsParticipants replied to the same set of questions.

Primary and secondary outcome measuresThe primary outcome measure was willingness to use immunity certificates across three different domestic settings (1. Visiting the GP for a non-urgent health issue, 2. Dining in a restaurant, and 3. Attending a performance in a theatre). For each setting two options, one prioritising convenience (option A) and the other privacy (option B), were offered. Our secondary outcome measures were computed indices from items adapted from the Health Belief Model; Attitudes towards sharing immunity status with service providers; Prior to COVID-19 lifestyle. In addition, we recorded data about respondents socio-demographic characteristics.

ResultsRespondents were more willing to use immunity certificates that prioritised convenience, rather than privacy, when visiting their GP (92%). However, privacy was more favorable (84%) in the other two settings (dining in a restaurant and going to a theatre) compared to convenience (39%). Personal beliefs about COVID-19 and immunity certificates were associated with variations in willingness to use these across all scenarios. No variations were observed across socio-demographics and lifestyle.

ConclusionsThe findings of this survey suggest that there is not one size fits all solution for designing immunity certificates. Immunity certificates are complex socio-technical systems, any attempt to implement these for domestic use should be tailored to different settings and user needs. The design of certification services requires a more evidence-based approach and further research is needed to understand how different settings, design elements (like convenience or privacy) and personal beliefs about the pandemic should inform their design.

Strengths and limitations of this studyO_LIThis study presents unique knowledge about the publics willingness to use immunity certificates for domestic purposes where there is very little published research at the moment.
C_LIO_LIThe study reports knowledge about the interaction between individual characteristics, domestic settings, and types of immunity certificate design on willingness to use these certificates.
C_LIO_LIUK nationally representative sample for age, gender, and ethnic background, but limited to people who have the means and capacity to use digital technologies (survey administered using Prolific.co).
C_LIO_LIWe present evidence-based recommendations for Public Health services and policy makers about the use of immunity certificates in different domestic settings.
C_LIO_LISince, as to the writing of this paper, COVID-19 certification has not been mandated in the UK, the scenarios used in the survey were hypothetical.
C_LI A general computational framework for COVID-19 modelling with applications to testing varied interventions in education environments We construct a spatially-compartmental individual-based model of the spread of Covid-19 in indoor spaces. The model can be used to predict the infection rates in a variety of locations when various non-pharmaceutical interventions (NPIs) are introduced. Tasked by the Welsh Government, we apply the model to secondary schools and Further and Higher Education environments. Specifically, we consider student populations mixing in a classroom and in halls of residence. We focus on assessing the potential efficacy of Lateral Flow Devices (LFDs) when used in broad-based screens for asymptomatic infection or in  test-to-release scenarios in which individuals who have been exposed to infection are released from isolation given a negative result. LFDs are also compared to other NPIs; we find that, although LFD testing can be used to mitigate the spread of Covid-19, it is more effective to invest in personal protective equipment, e.g. masks, and in increasing ventilation quality. In addition, we provide an open-access and user-friendly online applet that simulates the individual-based model, complete with user tutorials to encourage the use of the model to aid educational policy decisions as input infection data evolves (https://bit.ly/CV19_INTER_IBM). Macronutrient mass intake explains deferential weight and fat loss in isocaloric diets Differential weight and fat losses under isocaloric diets of distinct macronutrient composition are well-documented findings in obesity research.1-6 Such data are considered a result of inadequate methodology as it disagree with the energy balance theory.7 A recent mathematical analysis of this paradigm has found, however, serious analytical contradictions in its foundations.8 As an alternative, a mass balance model was proposed to explain the aforesaid body composition alterations. Here, we expand on this observation by contrasting both models. We show that mass balance explains a wide range of fending experiments including those concurring with the energy balance principle. The latter, however, is less flexible and results in poor forecasts in settings consistent with mass balance. The energy balance theory is thus an unsatisfactory model of body composition changes. Consequently, by shifting to a mass balance paradigm of obesity a much deeper understanding of this disease may follow in the near future. Correlates of patient-reported cognitive performance with regard to disability ObjectivesThe patient-reported Multiple Sclerosis Neuropsychological Questionnaire (MSNQ) is inconsistently related to objective cognitive tests in multiple sclerosis (MS), while being strongly correlated with depression. In this study we test whether the relation between subjective and objective cognitive performance is moderated by physical disability, assessed by the Expanded Disability Status Scale (EDSS).

Materials & MethodsFrom 275 MS patients who completed the patient-report MSNQ and the two-question screening tool for depression, we collected Symbol Digit Modalities Test (SDMT) and EDSS scores, indicators of respectively objective cognitive performance and physical disability. We analysed correlations between these variables in the total group and in three EDSS subgroups: Low 0.0 - 3.0, Medium 3.5 - 6.0 and High 6.5 - 9.0. We also investigated the use of a composite measure of cognitive impairment and depression.

ResultsWe found no significant correlations between patient-reported MSNQ and SDMT scores in the total group or the EDSS subgroups. MSNQ scores correlated significantly with depression in all subgroups. After correcting for several variables, MSNQ scores contributed adversely to SDMT scores in the total group, not in any subgroup. MSNQ scores contributed significantly to the prediction of the composite measure of impairment in the total group and in all EDSS subgroups.

ConclusionsThe relationship between measures of subjective and objective cognitive performance is not influenced by the patients level of physical disability. MSNQ scores are substantially influenced by depression, and reflect cognitive function to some degree. The patient-report MSNQ can be useful to identify patients requiring further (neuro)psychological assessment. Macular vascular complexity analysis of diabetes mellitus by swept-source optical coherence tomographic angiography PurposeTo evaluate the associations of retinal vascular complexity features, including fractal dimension (FD) and blood vessel tortuosity (BVT), with the severity of diabetic retinopathy (DR) by using noninvasive optical coherence tomographic angiography (OCTA).

MethodsThis prospective cross-sectional study recruited ocular-treatment-naive patients with type 2 diabetes mellitus (DM) registered in the community of Guangzhou, China. OCTA was used to obtain the measurements of FD and BVT in the superficial capillary plexus (SCP) and the deep capillary plexus (DCP). Univariate and multivariate linear regression was used to analyse the correlation of FD and BVT in different layers with DR severity.

ResultsA total of 1282 patients with DM (1282 eyes), with a mean age of 64.2{+/-}7.8 years, were included. FD in the DCP decreased and BVT in the DCP increased in DR patients compared to non-DR patients, even after adjusting for confounding factors (P< 0.05). Trend analysis showed a significant decrease in the FD values as the DR progressed, while the BVT progressively increased with worsening DR severity (P< 0.01). The FD in DCP had a statistically significant positive correlation with FD in SCP and a negative correlation with BVT in SCP and BVT in DCP in all of the participants, including the non-DR group, moderate DR group and severe DR group (P< 0.01).

ConclusionFD and BVT determined using OCTA might be useful parameters for objectively distinguishing DR from non-DR and indicating DR progression.