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Background: Prognostic models combine several prognostic factors to provide an estimate of the likelihood (or risk) of future events in individual patients, conditional on their prognostic factor values. A fundamental part of evaluating prognostic models is undertaking studies to determine whether their predictive performance, such as calibration and discrimination, is reproduced across settings. Systematic reviews and meta-analyses of studies evaluating prognostic models’ performance are a necessary step for selection of models for clinical practice and for testing the underlying assumption that their use will improve outcomes, including patient's reassurance and optimal future planning. Methods: In this paper, we highlight key concepts in evaluating the certainty of evidence regarding the calibration of prognostic models. Results and Conclusion: Four concepts are key to evaluating the certainty of evidence on prognostic models’ performance regarding calibration. The first concept is that the inference regarding calibration may take one of two forms: deciding whether one is rating certainty that a model's performance is satisfactory or, instead, unsatisfactory, in either case defining the threshold for satisfactory (or unsatisfactory) model performance. Second, inconsistency is the critical GRADE domain to deciding whether we are rating certainty in the model performance being satisfactory or unsatisfactory. Third, depending on whether one is rating certainty in satisfactory or unsatisfactory performance, different patterns of inconsistency of results across studies will inform ratings of certainty of evidence. Fourth, exploring the distribution of point estimates of observed to expected ratio across individual studies, and its determinants, will bear on the need for and direction of future research. © 2021

Background The heterogeneity in symptomatology and phenotypic profile attributable to COVID-19 is widely unknown. The objective of this manuscript is to conduct a trans-ancestry genome wide association study (GWAS) meta-analysis of COVID-19 severity to improve the understanding of potentially causal targets for SARS-CoV-2. Methods This cross-sectional study recruited 646 participants in the UAE that were divided into two phenotypic groups based on the severity of COVID-19 phenotypes, hospitalized (n=482) and non-hospitalized (n=164) participants. Hospitalized participants were COVID-19 patients that developed acute respiratory distress syndrome (ARDS), pneumonia or progression to respiratory failure that required supplemental oxygen therapy or mechanical ventilation support or had severe complications such as septic shock or multi-organ failure. We conducted a trans-ancestry meta-analysis GWAS of European (n=302), American (n=102), South Asian (n=99), and East Asian (n=107) ancestry populations. We also carried out comprehensive post-GWAS analysis, including enrichment of SNP associations in tissues and cell-types, expression quantitative trait loci and differential expression analysis. Findings Eight genes demonstrated a strong association signal: VWA8 gene in locus 13p14·11 (SNP rs10507497; p=9·54 x10-7), PDE8B gene in locus 5q13·3 (SNP rs7715119; p=2·19 x10-6), CTSC gene in locus 11q14·2 (rs72953026; p=2·38 x10-6), THSD7B gene in locus 2q22·1 (rs7605851; p=3·07x10-6), STK39 gene in locus 2q24·3 (rs7595310; p=4·55 x10-6), FBXO34 gene in locus 14q22·3 (rs10140801; p=8·26 x10-6), RPL6P27 gene in locus 18p11·31 (rs11659676; p=8·88 x10-6), and METTL21C gene in locus 13q33·1 (rs599976; p=8·95 x10-6). The genes are expressed in the lung, associated to tumour progression, emphysema, airway obstruction, and surface tension within the lung, as well as an association to T-cell-mediated inflammation and the production of inflammatory cytokines. Interpretation We have discovered eight highly plausible genetic association with hospitalized cases in COVID-19. Further studies must be conducted on worldwide population genetics to facilitate the development of population specific therapeutics to mitigate this worldwide challenge. Funding This review was commissioned as part of a project to study the host cell receptors of coronaviruses funded by Khalifa University's CPRA grant (Reference number 2020-004).

Background: Low-dose aspirin can cause gastric and duodenal ulceration, hereafter called peptic ulcer disease (PUD). Predisposition is thought to be related to clinical and genetic factors; our aim was to identify genetic risk factors associated with aspirin-induced PUD. Methods: Patients (n=1478) were recruited from 15 UK hospitals. Cases (n=505) were defined as patients with endoscopically confirmed PUD within 2 weeks of using aspirin and non-aspirin Non-Steroidal Anti-Inflammatory Drugs (NSAIDs). They were compared to two control groups: patients with endoscopically confirmed PUD without any history of NSAID use within 3 months of diagnosis (n=495), and patients with no PUD on endoscopy (n=478). A genome-wide association study (GWAS) of aspirin-induced cases (n=247) was compared to 476 controls. The results were validated by replication in another 84 cases and 162 controls. Findings: The GWAS identified one variant, rs12678747 (p=1·65×10−7) located in the last intron of EYA1 on chromosome 8. The association was replicated in another sample of 84 PUD patients receiving aspirin (p=0·002). Meta-analysis of discovery and replication cohort data for rs12678747, yielded a genome-wide significant association (p=3·12×10−11; OR=2·03; 95% CI 1·65-2·50). Expression of EYA1 was lower at the gastric ulcer edge when compared with the antrum. Interpretation: Genetic variation in an intron of the EYA1 gene increases the risk of endoscopically confirmed aspirin-induced PUD. Reduced EYA1 expression in the upper gastrointestinal epithelium may modulate risk, but the functional basis of this association will need mechanistic evaluation. Funding: Department of Health Chair in Pharmacogenetics, MRC Centre for Drug Safety Science and the Barts Cardiovascular NIHR Biomedical Research Centre, British Heart Foundation (BHF)

Background Metabolic syndrome (MetS) is a cluster of multiple cardiometabolic risk factors that increase the risk of type 2 diabetes and cardiovascular diseases. Identifying novel biomarkers of MetS and their genetic associations could provide insights into the mechanisms of cardiometabolic diseases. Methods Potential MetS-associated metabolites were screened and internally validated by untargeted metabolomics analyses among 693 patients with MetS and 705 controls. External validation was conducted using two well-established targeted metabolomic methods among 149 patients with MetS and 253 controls. The genetic associations of metabolites were determined by linear regression using our previous genome-wide SNP data. Causal relationships were assessed using a one-sample Mendelian Randomization (MR) approach. Findings Nine metabolites were ultimately found to be associated with MetS or its components. Five metabolites, including LysoPC(14:0), LysoPC(15:0), propionyl carnitine, phenylalanine, and docosapentaenoic acid (DPA) were selected to construct a metabolite risk score (MRS), which was found to have a dose-response relationship with MetS and metabolic abnormalities. Moreover, MRS displayed a good ability to differentiate MetS and metabolic abnormalities. Three SNPs (rs11635491, rs7067822, and rs1952458) were associated with LysoPC(15:0). Two SNPs, rs1952458 and rs11635491 were found to be marginally correlated with several MetS components. MR analyses showed that a higher LysoPC(15:0) level was causally associated with the risk of overweight/obesity, dyslipidaemia, high uric acid, high insulin and high HOMA-IR. Interpretation We identified five metabolite biomarkers of MetS and three SNPs associated with LysoPC(15:0). MR analyses revealed that abnormal LysoPC metabolism may be causally linked the metabolic risk. Funding This work was supported by grants from the National Key Research and Development Program of China (2017YFC0907004).

Background Little is known about chronic cannabis smoking-associated oral microbiome and its effects on central nervous system (CNS) functions. Methods In the current study, we have analyzed the saliva microbiome in individuals who chronically smoked cannabis with cannabis use disorder (n = 16) and in non-smoking controls (n = 27). The saliva microbiome was analyzed using microbial 16S rRNA sequencing. To investigate the function of cannabis use-associated oral microbiome, mice were orally inoculated with live Actinomyces meyeri, Actinomyces odontolyticus, or Neisseria elongata twice per week for six months, which mimicked human conditions. Findings We found that cannabis smoking in humans was associated with oral microbial dysbiosis. The most increased oral bacteria were Streptococcus and Actinomyces genus and the most decreased bacteria were Neisseria genus in chronic cannabis smokers compared to those in non-smokers. Among the distinct species bacteria in cannabis smokers, the enrichment of Actinomyces meyeri was inversely associated with the age of first cannabis smoking. Strikingly, oral exposure of Actinomyces meyeri, an oral pathobiont, but not the other two control bacteria, decreased global activity, increased macrophage infiltration, and increased β-amyloid 42 protein production in the mouse brains. Interpretation This is the first study to reveal that long-term oral cannabis exposure is associated oral enrichment of Actinomyces meyeri and its contributions to CNS abnormalities.

Background The dynamic monitoring of perioperative carcinoembryonic antigen (CEA) is recommended by current colorectal cancer (CRC) guidelines, while the benefits of additional measurements of carbohydrate antigen 19-9 (CA19-9) and carbohydrate antigen 125 (CA125) have remained controversial. Methods This retrospective longitudinal cohort included 3539 CRC patients who underwent curative resection. Distinct trajectory groups were identified by the latent class growth mixed model. Patients were grouped into subgroups jointly by CEA, CA19-9, and CA125 according to preoperative levels and longitudinal trajectories, respectively. The end points were overall survival (OS) and recurrence-free survival (RFS). Findings Three distinct trajectory groups were characterized for serum CEA, CA19-9, and CA125: low-stable, early-rising, and later-rising. Jointly, patients were grouped into six preoperative (trajectory) joint groups. Compared with the three-low group, the adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) associated with death were 1.87 (1.29-2.70), 3.82 (2.37-6.17), 1.87 (0.97-3.61), 2.81 (1.93-4.11), and 4.99 (2.80-8.86) for the CEA-high, CA19-9-high, CA125-high, two-high, and three-high group, respectively. And compared with the three-stable trajectory group, the corresponding HRs (95% CIs) were 1.59 (1.10-2.30), 1.55 (0.77-3.10), 6.25 (4.02-9.70), 4.05 (2.73-6.02), and 12.40 (5.77-26.70) for the five rising trajectory groups, respectively. Similar associations between joint groups and RFS were observed. Notably, the trajectory joint group still had prognostic significance after adjusting for preoperative levels. The CA19-9-high group (HR: 3.82, 95% CI: 2.37-6.17) was associated with higher risk of death than the two-high group (HR: 2.81, 95% CI: 1.93-4.11). Likewise, for the CA125-rising trajectory group and two-rising trajectory group, the HRs (95% CIs) were 6.13 (3.75-10.00) and 3.99 (2.63-6.05) for death, and 3.08 (2.07-4.58) and 2.10 (1.52-2.90) for recurrence. Interpretation In addition to CEA, the dynamic measurements of CA19-9 and CA125 are recommended to monitor the prognosis of CRC patients. Funding National Natural Science Foundation of China [81973147, 82001986, 81960592, 82073569, 81660545].

Background: Preoperative determination of breast cancer molecular subtypes facilitates individualized treatment plan-making and improves patient prognosis. We aimed to develop an assembled convolutional neural network (ACNN) model for the preoperative prediction of molecular subtypes using multimodal ultrasound (US) images. Methods: This multicentre study prospectively evaluated a dataset of greyscale US, colour Doppler flow imaging (CDFI), and shear-wave elastography (SWE) images in 807 patients with 818 breast cancers from November 2016 to February 2021. The St. Gallen molecular subtypes of breast cancer were confirmed by postoperative immunohistochemical examination. The monomodal ACNN model based on greyscale US images, the dual-modal ACNN model based on greyscale US and CDFI images, and the multimodal ACNN model based on greyscale US and CDFI as well as SWE images were constructed in the training cohort. The performances of three ACNN models in predicting four- and five-classification molecular subtypes and identifying triple negative from non-triple negative subtypes were assessed and compared. The performance of the multimodal ACNN was also compared with preoperative core needle biopsy (CNB). Finding: The performance of the multimodal ACNN model (macroaverage area under the curve [AUC]: 0.89–0.96) was superior to that of the dual-modal ACNN model (macroaverage AUC: 0.81–0.84) and the monomodal ACNN model (macroaverage AUC: 0.73–0.75) in predicting four-classification breast cancer molecular subtypes, which was also better than that of preoperative CNB (AUC: 0.89–0.99 vs. 0.67–0.82, p

Background: Atherosclerosis-related cardiovascular diseases (CVDs) are the leading cause of mortality worldwide. Cholesterol crystals (CCs) induce inflammation in atherosclerosis and are associated with unstable plaques and poor prognosis, but no drug can remove CCs in the clinic currently. Methods: We generated a phospholipid-based and high-density lipoprotein (HDL)-like nanoparticle, miNano, and determined CC-dissolving capacity, cholesterol efflux property, and anti-inflammation effects of miNano in vitro. Both normal C57BL/6J and Apoe-deficient mice were used to explore the accumulation of miNano in atherosclerotic plaques. The efficacy and safety of miNano administration to treat atherosclerosis were evaluated in the Ldlr-deficient atherosclerosis model. The CC-dissolving capacity of miNano was also detected using human atherosclerotic plaques ex vivo. Findings: We found that miNano bound to and dissolved CCs efficiently in vitro, and miNano accumulated in atherosclerotic plaques, co-localized with CCs and macrophages in vivo. Administration of miNano inhibited atherosclerosis and improved plaque stability by reducing CCs and macrophages in Ldlr-deficient mice with favorable safety profiles. In macrophages, miNano prevented foam cell formation by enhancing cholesterol efflux and suppressed inflammatory responses via inhibiting TLR4-NF-κB pathway. Finally, in an ex vivo experiment, miNano effectively dissolved CCs in human aortic atherosclerotic plaques. Interpretation: Together, our work finds that phospholipid-based and HDL-like nanoparticle, miNano, has the potential to treat atherosclerosis by targeting CCs and stabilizing plaques. Funding: This work was supported by the National Institutes of Health HL134569, HL109916, HL136231, and HL137214 to Y.E.C, HL138139 to J.Z., R21NS111191 to A.S., by the American Heart Association 15SDG24470155, Grant Awards (U068144 from Bio-interfaces and G024404 from M-BRISC) at the University of Michigan to Y.G., by the American Heart Association 19PRE34400017 and Rackham Helen Wu award to M.Y., NIH T32 GM07767 to K. H., Barbour Fellowship to D.L.

International audience; Background: Familial Hypercholesterolemia (FH) is an underdiagnosed condition with an increased cardiovascular risk. It is unknown whether lipid accumulation plays a role in structural myocardial changes. Cardiovascular Magnetic Resonance (CMR) is the reference technique for the morpho-functional evaluation of heart chambers through cine sequences and for myocardial tissue characterization through late gadolinium enhancement (LGE) and T1 mapping images. We aimed to assess the prevalence of myocardial fibrosis in FH patients.Methods: Seventy-two asymptomatic subjects with genetically confirmed FH (mean age 49·24, range 40 to 60 years) were prospectively recruited along with 31 controls without dyslipidaemia matched for age, sex, BMI, and other cardiovascular risk factors. All underwent CMR including cine, LGE, pre- and post-contrast T1 mapping. Extracellular volume (ECV) and enhancement rate of the myocardium (ERM = difference between pre- and post-contrast myocardial T1, normalized by pre-contrast myocardial T1) were calculated.Findings: Five FH patients and none of the controls had intramyocardial LGE (p= 0·188). While no changes in Native T1 and ECV were found, post-contrast T1 was significantly lower (430·6 ± 55ms vs. 476·1 ± 43ms, p

s: Background: During pregnancy a feto-maternal exchange of cells through the placenta conducts to maternal microchimerism (Mc) in the child and fetal Mc in the mother. Because of this bidirectional traffic of cells, pregnant women have also acquired maternal cells in utero from their mother and could transfer grandmaternal (GdM) cells to their child through the maternal bloodstream during pregnancy. Thus, cord blood (CB) samples could theoretically carry GdMMc. Nevertheless this has never been demonstrated. Methods: Using Human Leukocyte Antigen (HLA)-specific quantitative PCR assays on three-generation families, we were able to test 28 CB samples from healthy primigravid women for GdMMc in whole blood (WB) and isolated cells (PBMC, T, B, granulocytes, stem cells). Findings: Five CB samples (18%) had GdMMc which could not be confounded with maternal source, with quantities 100 fold lower than maternal Mc in WB and PBMC. Risk of aneuploidies and/or related invasive prenatal procedures significantly correlated with the presence of GdMMc in CB (p=0.024). Significantly decreased HLA compatibility was observed in three-generation families from CB samples carrying GdMMc (p=0.019). Interpretation: Transgenerational transfer of cells could have implications in immunology and evolution. Further analyses will be necessary to evaluate whether GdMMc in CB is a passive or immunologically active transfer and whether invasive prenatal procedures could trigger GdMMc. Funding: Provence-Alpes-Côte d'Azur APEX grant # 2012_06549E, 2012_11786F and 2014_03978) and the Foundation for Medical Research (FRM Grant #ING20140129045).

Background: The survival time of amyotrophic lateral sclerosis (ALS) is greatly variable and protective or risk effects of the potential survival predictors are controversial. Thus, we aim to undertake a comprehensive meta-analysis of studies investigating non-genetic prognostic and survival factors in patients with ALS. Methods: A search of relevant literature from PubMed, Embase, Cochrane library and other citations from 1st January 1966 to 1st December 020 was conducted. Random-effects models were conducted to pool the multivariable or adjusted hazard ratios (HR) by Stata MP 16.0. PROSPERO registration number: CRD42021256923. Findings: A total of 5717 reports were identified, with 115 studies meeting pre-designed inclusion criteria involving 55,169 ALS patients. Five dimensions, including demographic, environmental or lifestyle, clinical manifestations, biochemical index, therapeutic factors or comorbidities were investigated. Twenty-five prediction factors, including twenty non-intervenable and five intervenable factors, were associated with ALS survival. Among them, NFL (HR:3.70, 6.80, in serum and CSF, respectively), FTD (HR:2.98), ALSFRS-R change (HR:2.37), respiratory subtype (HR:2.20), executive dysfunction (HR:2.10) and age of onset (HR:1.03) were superior predictors for poor prognosis, but pLMN or pUMN (HR:0.32), baseline ALSFRS-R score (HR:0.95), duration (HR:0.96), diagnostic delay (HR:0.97) were superior predictors for a good prognosis. Our results did not support the involvement of gender, education level, diabetes, hypertension, NIV, gastrostomy, and statins in ALS survival. Interpretation: Our study provided a comprehensive and quantitative index for assessing the prognosis for ALS patients, and the identified non-intervenable or intervenable factors will facilitate the development of treatment strategies for ALS. Funding: This study was supported by the National Natural Science Fund of China (Grant No. 81971188), the 1.3.5 project for disciplines of excellence, West China Hospital, Sichuan University (Grant No. 2019HXFH046), and the Science and Technology Bureau Fund of Sichuan Province (No. 2019YFS0216).

Highlights • In a sample of recurrently depressed women, 12.8% had elevated ADHD symptoms. • 3.4% met ADHD diagnostic criteria; none had a diagnosis from a medical professional. • ADHD was associated with earlier-onset, more impairing and recurrent depression. • Recurrently depressed women with ADHD symptoms were more likely to be hospitalised. • ADHD symptoms were associated with taking non-first-line antidepressant medication., Background Depression is highly heterogeneous in its clinical presentation. Those with attention deficit/hyperactivity disorder (ADHD) may be at risk of a more chronic and impairing depression compared to those with depression alone according to studies of young people. However, no studies to date have examined ADHD in recurrently depressed adults in mid-life. Method In a sample of women in mid-life (n=148) taken from a UK based prospective cohort of adults with a history of recurrent depression, we investigated the prevalence of ADHD and the association of ADHD with clinical features of depression. Results 12.8% of the recurrently depressed women had elevated ADHD symptoms and 3.4% met DSM-5 diagnostic criteria for ADHD. None of the women reported having a diagnosis of ADHD from a medical professional. ADHD symptoms were associated with earlier age of depression onset, higher depression associated impairment, a greater recurrence of depressive episodes and increased persistence of subthreshold depression symptoms over the study period, higher levels of irritability and increased risk of self-harm or suicide attempt. ADHD symptoms were associated with increased risk of hospitalisation and receiving non-first-line antidepressant medication. Limitations ADHD was measured using a questionnaire measure. We focussed on mothers in a longitudinal study of recurrent depression, so the findings may not apply to males or other groups. Conclusions Higher ADHD symptoms appear to index a worse clinical presentation for depression. Clinical implications include that in women with early onset, impairing and recurrent depression, the possibility of underlying ADHD masked by depression needs to be considered.

Background White blood cells (WBC) are commonly measured to investigate suspected infection and inflammation in pregnant women, but the pregnancy-specific reference interval is variably reported, increasing diagnostic uncertainty in this high-risk population. It is essential that clinicians can interpret WBC results in the context of normal pregnant physiology, given the huge global burden of infection on maternal mortality. Methods We performed a longitudinal, repeated measures population study of 24,318 pregnant women in Oxford, UK, to map the trajectory of WBC between 8-40 weeks of gestation. We defined 95% reference intervals (RI) for total WBC, neutrophils, lymphocytes, eosinophils, basophils, and monocytes for the antenatal and postnatal periods. Findings WBC were measured 80,637 times over five years. The upper reference limit for total WBC was elevated by 36% in pregnancy (RI 5.7-15.0×109/L), driven by a 55% increase in neutrophils (3.7-11.6×109/L) and 38% increase in monocytes (0.3-1.1×109/L), which remained stable between 8-40 weeks. Lymphocytes were reduced by 36% (1.0-2.9×109/L), while eosinophils and basophils were unchanged. Total WBC was elevated significantly further from the first day after birth (similar regardless of the mode of delivery), which resolved to pre-delivery levels by an average of seven days, and to pre-pregnancy levels by day 21. Interpretation There are marked changes in WBC in pregnancy, with substantial differences between cell subtypes. WBC are measured frequently in pregnant women in obstetric and non-obstetric settings, and results should be interpreted using a pregnancy-specific RI until delivery, and between days 7-21 after childbirth. Funding None.

Background SARS-CoV-2 has been responsible for considerable mortality worldwide, owing in particular to pulmonary failures such as ARDS, but also to other visceral failures and secondary infections. Recent progress in the characterization of the immunological mechanisms that result in severe organ injury led to the emergence of two successive hypotheses simultaneously tested here: hyperinflammation with cytokine storm syndrome or dysregulation of protective immunity resulting in immunosuppression and unrestrained viral dissemination. Methods In a prospective observational monocentric study of 134 patients, we analysed a panel of plasma inflammatory and anti-inflammatory cytokines and measured monocyte dysregulation via their membrane expression of HLA-DR. We first compared the results of patients with moderate forms hospitalized in an infectious disease unit with those of patients with severe forms hospitalized in an intensive care unit. In the latter group of patients, we then analysed the differences between the surviving and non-surviving groups and between the groups with or without secondary infections. Findings Higher blood IL-6 levels, lower quantitative expression of HLA-DR on blood monocytes and higher IL-6/mHLA-DR ratios were statistically associated with the risk of severe forms of the disease and among the latter with death and the early onset of secondary infections. Interpretation The unique immunological profile in patients with severe COVID-19 corresponds to a moderate cytokine inflammation associated with severe monocyte dysregulation. Individuals with major CSS were rare in our cohort of hospitalized patients, especially since the use of corticosteroids, but formed a very severe subgroup of the disease. Funding None.

Objective and hypothesis Klotho is an aging-suppressor gene. Mutation of Klotho gene causes hyperphosphatemia and acute heart failure. However, the relationship of hyperphosphatemia and acute heart failure is unclear. We hypothesize that hyperphosphatemia mediates Klotho deficiency-induced acute heart failure and further that therapeutic reduction of hyperphosphatemia prevents acute heart failure in Klotho mutant (KL(−/−)) mice. Methods and results A significant elevation of serum phosphorus levels and a large reduction of heart function were found in KL(−/−) mice by six weeks of age. Normalization of serum phosphorus levels by low phosphate diet (LPD) rescued Klotho deficiency-induced heart failure and extended lifespan in male mice. Klotho deficiency impaired cardiac mitochondrial respiratory enzyme function and increased superoxide production, oxidative stress, and cardiac cell apoptosis in male KL(−/−) mice which can be eliminated by LPD. LPD, however, did not rescue hyperphosphatemia or heart failure in female KL(−/−) mice. LPD did not affect estrogen depletion in female KL(−/−) mice. Normalization of serum estrogen levels by treatment with 17β-estradiol prevented hyperphosphatemia and heart failure in female KL(−/−) mice. Mechanistically, treatment with 17β-estradiol rescued hyperphosphatemia via inhibiting renal Na-Pi co-transporter expression. Normalization of serum phosphorus levels by treatment with 17β-estradiol also abolished cardiac mitochondrial respiratory enzyme dysfunction, ROS overproduction, oxidative stress and cardiac cell apoptosis in female KL(−/−) mice. Conclusion Klotho deficiency causes acute heart failure via hyperphosphatemia in male mice which can be prevented by LPD. 17β-estradiol prevents Klotho deficiency-induced hyperphosphatemia and heart failure by eliminating upregulation of renal Na-Pi co-transporter expression in female mice., Graphical abstract Image 1

Background: To assess potential roles for tumor-associated autoantibodies (TAAs) in esophageal squamous cell carcinoma (ESCC) screening: detecting early-stage malignancy, and predicting future cancer risk. Methods: Thirteen candidate autoantibodies identified in previous literatures were measured using multiplex serological assays in sera from cases and matched controls nested in two population-level screening cohorts in China. To evaluate the role of TAAs in detecting prevalent esophageal malignant lesions, an identification set (150 cases vs. 560 controls) and an external validation set (34 cases vs. 121 controls) were established with pre-screening sera collected ≤ 12 months prior to screening-related diagnosis. To explore the role of TAAs in predicting future ESCC risk, an exploration set (105 cases vs. 416 controls) with pre-diagnostic sera collected > 12 months before clinical diagnosis was established. Two models, the questionnaire-based model and full model additionally incorporating TAA markers, were constructed. Area under the receiver operating characteristic curve (AUC) and net reclassification improvement (NRI) were calculated to compare the performance of the two models. Findings: In the identification set, NY-ESO-1 (OR=2·12, 95% CI=1·02-4·40) and STIP1 (OR=1·83, 95% CI=1·10-3·05) were positively associated with higher risk of esophageal malignancy. Elevated MMP-7 was associated with higher risk of malignancy in females (ORfemale=5·07, 95% CI=1·30-19·71). The estimates in validation set were consistent with these results, but were close to null in exploration set. Integration of selected TAAs improved the performance of questionnaire-based models in detecting prevalent esophageal malignancy (female: AUCfull model=0·745, 95% CI=0·675-0·814, AUCquestionnaire-based model=0·658, 95% CI=0·585-0·732, NRI=0·604, P

Background: Alzheimer's disease (AD) is generally thought to spare primary sensory function; however, such interpretations have drawn from a literature that has rarely taken into account the variable cognitive declines seen in patients with AD. As these cognitive domains are now known to modulate cortical somatosensory processing, it remains possible that abnormalities in somatosensory function in patients with AD have been suppressed by neuropsychological variability in previous research. Methods: In this study, we combine magnetoencephalographic (MEG) brain imaging during a paired-pulse somatosensory gating task with an extensive battery of neuropsychological tests to investigate the influence of cognitive variability on estimated differences in somatosensory function between biomarker-confirmed patients on the AD spectrum and cognitively-normal older adults. Findings: We show that patients on the AD spectrum exhibit largely non-significant differences in somatosensory function when cognitive variability is not considered (p-value range: .020–.842). However, once attention and processing speed abilities are considered, robust differences in gamma-frequency somatosensory response amplitude (p

Background: If a pregnant woman is overweight, this can evoke metabolic alterations that may have health consequences for both mother and child. Methods: Pregnant women with overweight/obesity (n = 358) received fish oil+placebo, probiotics+placebo, fish oil+probiotics or placebo+placebo from early pregnancy onwards. The serum metabolome was analysed from fasting samples with a targeted NMR-approach in early and late pregnancy. GDM was diagnosed by OGTT. Findings: The intervention changed the metabolic profile of the women, but the effect was influenced by their GDM status. In women without GDM, the changes in nine lipids (FDR

Background Nicaragua experienced a large Zika epidemic in 2016, with up to 50% of the population in Managua infected. With the domesticated Aedes aegypti mosquito as its vector, it is widely assumed that Zika virus transmission occurs within the household and/or via human mobility. We investigated these assumptions by using viral genomes to trace Zika transmission spatially. Methods We analysed serum samples from 119 paediatric Zika cases participating in the long-standing Paediatric Dengue Cohort Study in Managua, which was expanded to include Zika in 2015. An optimal spanning directed tree was constructed by minimizing the differences in viral sequence diversity composition between patient nodes, where low-frequency variants were used to increase the resolution of the inferred Zika outbreak dynamics. Findings Out of the 18 houses where pairwise difference in sample collection dates among all the household members was within 30 days, we only found two where viruses from individuals within the same household were up to 10th-most closely linked to each other genetically. We also identified a substantial number of transmission events involving long geographical distances (n=30), as well as potential super-spreading events in the estimated transmission tree. Interpretation Our finding highlights that community transmission, often involving long geographical distances, played a much more important role in epidemic spread than within-household transmission. Funding This study was supported by an NUS startup grant (OMS) and grants R01 AI099631 (AB), P01 AI106695 (EH), P01 AI106695-03S1 (FB), and U19 AI118610 (EH) from the US National Institutes of Health.

Background Persistent carriage of pneumococcal vaccine serotypes has occurred after introduction of PCV13 vaccination in Africa but the mechanisms are unclear. We tested the feasibility of using a human pneumococcal challenge model in Malawi to understand immune correlates of protection against carriage and to trial alternative vaccine candidates. We aimed to identify a dose of Streptococcus pneumoniae serotype 6B sufficient to establish nasopharyngeal carriage in 40% of those nasally inoculated and evaluate nasal mucosal immunity before and after experimental inoculation. Methods Healthy student volunteers were recruited and inoculated with saline, 20,000 CFU/naris or 80,000 CFU/naris of Streptococcus pneumoniae serotype 6B Post inoculation carriage was determined by nasal sampling for bacterial culture and lytA PCR. Immunological responses were measured in serum and nasal mucosal biopsies before and after bacterial inoculation. Findings Twenty-four subjects completed the feasibility protocol with minimal side effects. pneumococcal carriage was established in 0/6, 3/9 and 4/9 subjects in the saline, 20,000 CFU/naris and 80,000 CFU/naris groups, respectively. Incidental (natural) serotype carriage was common (7/24 participants carried non-6B strains, 29.2%. Experimentally induced type 6B pneumococcal carriage was associated with pro-inflammatory nasal mucosal responses prior to inoculation and altered mucosal recruitment of immune cells post bacterial challenge. There was no association with serum anti-capsular antibody. Interpretation The serotype 6B experimental human pneumococcal carriage model is feasible in Malawi and can now be used to determine the immunological correlates of protection against carriage and vaccine efficacy in this population.

Background: Easily accessible biomarkers enabling the identification of those patients with multiple sclerosis (MS) who will accumulate irreversible disability in the long term are essential to guide early therapeutic decisions. We here examine the utility of serum neurofilament light chain (sNfL) for forecasting relapse-free disability progression and conversion to secondary progressive MS (SPMS) in the prospective Neurofilament and longterm outcome in MS (NaloMS) cohort. Methods: The predictive ability of sNfL at Baseline and sNfL follow-up (FU)/ Baseline (BL) ratio with regard to disability progression was assessed within a development cohort (NaloMS, n=196 patients with relapsing-remitting MS (RRMS) or clinically isolated syndrome) and validated with an external independent cohort (Düsseldorf, Essen, n=204). Both relapse-free EDSS-progression (RFP: inflammatory-independent EDSS-increase 12 months prior to FU) and SPMS-transition (minimum EDSS-score of 3.0) were investigated. Findings: During the study period, 17% (n=34) of NaloMS patients suffered from RFP and 14% (n=27) converted to SPMS at FU (validation cohort RFP n=42, SPMS-conversion n=24). sNfL at BL was increased in patients with RFP (10.8 pg/ml (interquartile range (IQR) 7.7-15.0) vs. 7.2 pg/ml (4.5-12.5), p

BACKGROUND: Circadian and multiday rhythms are found across many biological systems, including cardiology, endocrinology, neurology, and immunology. In people with epilepsy, epileptic brain activity and seizure occurrence have been found to follow circadian, weekly, and monthly rhythms. Understanding the relationship between these cycles of brain excitability and other physiological systems can provide new insight into the causes of multiday cycles. The brain-heart link has previously been considered in epilepsy research, with potential implications for seizure forecasting, therapy, and mortality (i.e., sudden unexpected death in epilepsy). METHODS: We report the results from a non-interventional, observational cohort study, Tracking Seizure Cycles. This study sought to examine multiday cycles of heart rate and seizures in adults with diagnosed uncontrolled epilepsy (N=31) and healthy adult controls (N=15) using wearable smartwatches and mobile seizure diaries over at least four months (M=12.0, SD=5.9; control M=10.6, SD=6.4). Cycles in heart rate were detected using a continuous wavelet transform. Relationships between heart rate cycles and seizure occurrence were measured from the distributions of seizure likelihood with respect to underlying cycle phase. FINDINGS: Heart rate cycles were found in all 46 participants (people with epilepsy and healthy controls), with circadian (N=46), about-weekly (N=25) and about-monthly (N=13) rhythms being the most prevalent. Of the participants with epilepsy, 19 people had at least 20 reported seizures, and 10 of these had seizures significantly phase locked to their multiday heart rate cycles. INTERPRETATION: Heart rate cycles showed similarities to multiday epileptic rhythms and may be comodulated with seizure likelihood. The relationship between heart rate and seizures is relevant for epilepsy therapy, including seizure forecasting, and may also have implications for cardiovascular disease. More broadly, understanding the link between multiday cycles in the heart and brain can shed new light on endogenous physiological rhythms in humans. FUNDING: This research received funding from the Australian Government National Health and Medical Research Council (investigator grant 1178220), the Australian Government BioMedTech Horizons program, and the Epilepsy Foundation of America's 'My Seizure Gauge' grant. ispartof: EBIOMEDICINE vol:72 ispartof: location:Netherlands status: published

Multiple sclerosis (MS) is an autoimmune disease characterized by the demyelination of mature oligodendrocytes induced by dysregulated immune cells in the central nervous system (CNS). Recently, several studies have indicated the vital roles of fatty acid-binding proteins (FABPs) 5 and 7 in regulating the immune response via T cells and astrocytes, respectively, in experimental autoimmune encephalomyelitis (EAE) mice. We verified a novel FABP5/FABP7 inhibitor, FABP ligand 6 (MF 6), as a potential therapeutic drug for MS therapy in EAE mice. We demonstrated that MF 6 reduced myelin loss and clinical symptoms of EAE both pretreatment and posttreatment. Furthermore, we found decreased oxidative stress levels and decreased GFAP-positive and Iba-1-positive cells in the spinal cord of MF 6-treated mice. In astrocyte primary culture, MF 6 attenuated IL-1β and TNF-α accumulation, stimulated by LPS via inhibition of both FABP5 and FABP7. Moreover, MF 6 also suggested a powerful protective function of mitochondria in oligodendrocytes of EAE mice by blocking voltage-dependent anion channel-1-dependent mitochondrial macropore formation through FABP5 inhibition. Overall, we identified a novel FABP inhibitor, MF 6, which has potent therapeutic benefits for MS via both immune inhibition and oligodendrocyte protection. Funding Information: We thank the Uehara Memorial Foundation for their financial support. This work was supported in part by the Strategic Research Program for Brain Sciences from Japan Agency for Medical Research and Development (JP17dm0107071, JP18dm0107071, JP19dm0107071, and JP20dm0107071, awarded to K.F. Declaration of Interests: The authors have declared that no conflict of interest exists. Ethics Approval Statement: Ethical approval was obtained from the Institutional Animal Care and Use Committee of the Tohoku University Environmental and Safety Committee (2019PhLM0-021 and 2019PhA-024).

Background HIV infection promotes the expansion of immunosuppressive regulatory T-cells (Tregs), contributing to immune dysfunction, tissue fibrosis and disease progression. Early antiretroviral treatment (ART) upon HIV infection improves CD4 count and decreases immune activation. However, Treg dynamics and their epigenetic regulation following early ART initiation remain understudied. Methods Treg subsets were characterized by flow cytometry in 103 individuals, including untreated HIV-infected participants in acute and chronic phases, ART-treated in early infection, elite controllers (ECs), immunological controllers (ICs), and HIV-uninfected controls. The methylation status of six regulatory regions of the foxp3 gene was assessed using MiSeq technology. Findings Total Treg frequency increased overtime during HIV infection, which was normalized in early ART recipients. Tregs in untreated individuals expressed higher levels of activation and immunosuppressive markers (CD39, and LAP(TGF-β1)), which remained unchanged following early ART. Expression of gut migration markers (CCR9, Integrin-β7) by Tregs was elevated during untreated HIV infection, while they declined with the duration of ART but not upon early ART initiation. Notably, gut-homing Tregs expressing LAP(TGF-β1) and CD39 remained higher despite early treatment. Additionally, the increase in LAP(TGF-β1)+ Tregs overtime were consistent with higher demethylation of conserved non-coding sequence (CNS)-1 in the foxp3 gene. Remarkably, LAP(TGF-β1)-expressing Tregs in ECs were significantly higher than in uninfected subjects, while the markers of Treg activation and gut migration were not different. Interpretation Early ART initiation was unable to control the levels of immunosuppressive Treg subsets and their gut migration potential, which could ultimately contribute to gut tissue fibrosis and HIV disease progression. Funding This study was funded by the Canadian Institutes of Health Research (CIHR, grant MOP 142294) and in part by the AIDS and Infectious Diseases Network of the Reseau SIDA et maladies infectieuses du Fonds de recherche du Quebec-Sante (FRQ-S).

BACKGROUND: Several SARS-CoV-2 lineages with spike receptor binding domain (RBD) N501Y mutation have spread globally. We evaluated the impact of N501Y on neutralizing activity of COVID-19 convalescent sera and on anti-RBD IgG assays. METHODS: The susceptibility to neutralization by COVID-19 patients' convalescent sera from Hong Kong were compared between two SARS-CoV-2 isolates (B117-1/B117-2) from the α variant with N501Y and 4 non-N501Y isolates. The effect of N501Y on antibody binding was assessed. The performance of commercially-available IgG assays was determined for patients infected with N501Y variants. FINDINGS: The microneutralization antibody (MN) titers of convalescent sera from 9 recovered COVID-19 patients against B117-1 (geometric mean titer[GMT],80; 95% CI, 47-136) were similar to those against the non-N501Y viruses. However, MN titer of these serum against B117-2 (GMT, 20; 95% CI, 11-36) was statistically significantly reduced when compared with non-N501Y viruses (P

Background Patients with breast cancer presenting with single lymph node metastasis (from a sentinel node) experience prolonged survival compared to patients with multiple lymph node metastases (≥3). However, little information is available on the genetic and immunological characteristics of breast cancer metastases within the regional lymph nodes as they progress from the sentinel lymph node (SLN) downstream to multiple regional lymph nodes (MLNs). Methods Genomic profiling was performed using a next-generation sequencing panel covering 520 cancer-related genes in the primary tumour and metastatic lymph nodes of 157 female patients with breast cancer. We included primary tumours, metastatic lymph nodes and adjacent clinically normal lymph nodes (20 patients from the SLN group and 28 patients from the MLNs group) in the whole transcriptome analysis. Findings The downstream metastatic lymph nodes (P = 0.029) and the primary breast tumours (P = 0.011) had a higher frequency of PIK3CA mutations compared to the SLN metastasis. We identified a distinct group of 14 mutations from single sentinel node metastasis and a different group of 15 mutations from multiple nodal metastases. Only 4 distinct mutations (PIK3CA, CDK4, NFKBIA and CDKN1B) were conserved in metastases from both lymph node settings. The tumour mutational burden (TMB) was significantly lower in single nodal metastasis compared to the paired primary breast cancer (P = 0.0021), while the decline in TMB did not reach statistical significance in the MLNs group (P = 0.083). In the gene set enrichment analysis, we identified 4 upregulated signatures in both primary tumour and nodal metastases from the MLNs group, including 3 Epithelial-mesenchymal transition(EMT) signatures and 1 angiogenesis signature. Both the CD8/Treg ratio and the CD8/EMT ratio were significantly higher in adjacent normal lymph nodes from patients with a single metastasis in the SLN compared with samples from the MLNs group (P = 0.045 and P = 0.023, respectively). This suggests that the immune defence from the MLNs patients might have a less favourable microenvironment, thus permitting multiple lymph nodes metastasis. Interpretation Single lymph node metastases and multiple lymph node metastases have significant differences in their molecular profiles and immune profiles. The findings are associated with more aggressive tumour characteristics and less favourable immune charactoristics in patients with multiple nodal metastases compared to those with a single metastasis in the sentinel node. Funding This work was supported by funds from High-level Hospital Construction Project (DFJH201921), the National Natural Science Foundation of China (81902828 and 82002928), the Fundamental Research Funds for the Central Universities (y2syD2192230), and the Medical Scientific Research Foundation of Guangdong Province (B2019039).

The trace element selenium is of essential importance for the synthesis of a set of redox active proteins. We investigated three complementary serum selenium status biomarkers in relation to overall survival and recurrence following diagnosis of primary invasive breast cancer in a large prospective cohort study. The Sweden Cancerome Analysis Network – Breast Initiative (SCAN-B) is a prospective population-based study including multiple participating hospitals. Main analyses included 1996 patients with a new diagnosis of primary invasive breast cancer, with blood sampling at the time of diagnosis. In sera of the patients, total serum selenium, selenoprotein P (SELENOP), and glutathione peroxidase 3 (GPx3) activity was analysed. All three biomarkers showed a positive correlation (p, Graphical abstract Image 1, Highlights • Three different serum biomarkers of selenium status are inversely associated with all-cause mortality following breast cancer diagnosis. • Lower serum glutathione peroxidase 3 activity is associated with more recurrences following breast cancer. • Patients in the lowest quintile regarding all three serum biomarkers have a particularly high all-cause mortality.

Background The most common B-cell cancers, chronic lymphocytic leukemia/lymphoma (CLL), follicular and diffuse large B-cell (FL, DLBCL) lymphomas, have distinct clinical courses, yet overlapping “cell-of-origin”. Dynamic changes to the epigenome are essential regulators of B-cell differentiation. Therefore, we reasoned that these distinct cancers may be driven by shared mechanisms of disruption in transcriptional circuitry. Methods We compared purified malignant B-cells from 52 patients with normal B-cell subsets (germinal center centrocytes and centroblasts, naive and memory B-cells) from 36 donor tonsils using >325 high-resolution molecular profiling assays for histone modifications, open chromatin (ChIP-, FAIRE-seq), transcriptome (RNA-seq), transcription factor (TF) binding, and genome copy number (microarrays). Findings From the resulting data, we identified gains in active chromatin in enhancers/super-enhancers that likely promote unchecked B-cell receptor signaling, including one we validated near the immunoglobulin superfamily receptors FCMR and PIGR. More striking and pervasive was the profound loss of key B-cell identity TFs, tumor suppressors and their super-enhancers, including EBF1, OCT2(POU2F2), and RUNX3. Using a novel approach to identify transcriptional feedback, we showed that these core transcriptional circuitries are self-regulating. Their selective gain and loss form a complex, iterative, and interactive process that likely curbs B-cell maturation and spurs proliferation. Interpretation Our study is the first to map the transcriptional circuitry of the most common blood cancers. We demonstrate that a critical subset of B-cell TFs and their cognate enhancers form self-regulatory transcriptional feedback loops whose disruption is a shared mechanism underlying these diverse subtypes of B-cell lymphoma. Funding National Institute of Health, Siteman Cancer Center, Barnes-Jewish Hospital Foundation, Doris Duke Foundation.

Aberrant placental angiogenesis is associated with fetal intrauterine growth restriction (IUGR), but the mechanism underlying abnormal placental angiogenesis remains largely unknown. Here, lower vessel density and higher expression of NADPH oxidases 2 (Nox2) were observed in the placentae for low birth weight (LBW) fetuses versus normal birth weight (NBW) fetuses, with a negative correlation between Nox2 and placental vessel density. Moreover, it was revealed for the first time that Nox2 deficiency facilitates angiogenesis in vitro and in vivo, and vascular endothelial growth factor-A (VEGF-A) has an essential role in Nox2-controlled inhibition of angiogenesis in porcine vascular endothelial cells (PVECs). Mechanistically, Nox2 inhibited phospho-signal transducer and activator of transcription 3 (p-STAT3) in the nucleus by inducing the production of mitochondrial reactive oxygen species (ROS). Dual-luciferase assay confirmed that knockdown of Nox2 reduces the expression of VEGF-A in an STAT3 dependent manner. Our results indicate that Nox2 is a potential target for therapy by increasing VEGF-A expression to promote angiogenesis and serves as a prognostic indicator for fetus with IUGR.

Potassium channels are important regulators of cellular homeostasis and targeting these proteins pharmacologically is unveiling important mechanisms in cancer cell biology. Here we demonstrate that pharmacological stimulation of the Kv11.1 potassium channel activity results in mitochondrial reactive oxygen species (ROS) production and fragmentation in breast cancer cell lines and patient-derived organoids independent of breast cancer subtype. mRNA expression profiling revealed that Kv11.1 activity significantly altered expression of genes controlling the production of ROS and endoplasmic-reticulum (ER) stress. Characterization of the transcriptional signature of breast cancer cells treated with Kv11.1 potassium channel activators strikingly revealed an adaptive response to the potentially lethal augmentation of ROS by increasing Nrf2-dependent transcription of antioxidant genes. Nrf2 in this context was shown to promote survival in breast cancer, whereas knockdown of Nrf2 lead to Kv11.1-induced cell death. In conclusion, we found that the Kv11.1 channel activity promotes oxidative stress in breast cancer cells and that suppression of the Nrf2-mediated anti-oxidant survival mechanism strongly sensitized breast cancer cells to a lethal effect of pharmacological activation of Kv11.1.

“Categorical thinking” in social science research has been widely criticised by feminist scholars for conceptualising social categories as natural, de-contextualised, and internally homogeneous. This paper develops and applies a mixed-methods approach to the study of healthinequalities, using social categories meaningfully in order to challenge categorical thinking. The approach is demonstrated through a case study of socio-economic (SES) inequalities in maternal healthcare access in Zambia. This paper's approach responds to the research agenda set by intersectional social epidemiologists by considering potential heterogeneity within categories, but also by exploring the context-specific meaning of categories, examining explanations at multiple levels, and interpreting results according to mutually constitutive social processes. The study finds that meso-level institutions, “health service environments”, explain a large share of SES inequalities in maternal healthcare access. Women's work, marital status, and levels of “autonomy” have heterogeneous implications for healthcare access across SES categories. Disadvantaged categories and their reproductive behaviours are stigmatised as 'backwards', in contrast to advantaged categories and their behaviours, which are associated with 'modernity’ and 'development’. Challenging categorical thinking has important implications for social justice and health, by rejecting framings of a specific category as problematic or non-compliant, highlighting the possibility of change, and emphasising the political and structural nature of progress.

Summary: Background: Health worker compliance with clinical guidelines is enhanced by digital clinical decision support at the point of care. The Palestinian public health system is implementing a digital maternal and child health eRegistry with clinical decision support. We aimed to compare the quality of antenatal care between clinics using the eRegistry and those using paper-based records. Methods: The eRegQual cluster-randomised controlled trial was done in primary health-care clinics offering routine antenatal care in the West Bank, Palestine. The intervention was the eRegistry with clinical decision support for antenatal care, implemented in District Health Information Systems 2 (DHIS2) Tracker software. 133 clinics forming 120 clusters were included and randomised; clusters were randomly assigned (1:1) to either the control (paper-based documentation) or intervention (eRegistry with clinical decision support) groups. The primary process outcomes were appropriate screening and management of anaemia, hypertension, and diabetes during pregnancy and foetal growth monitoring. The primary health outcome at delivery was a composite of moderate or severe anaemia; severe hypertension; large-for-gestational-age baby; malpresentation and small-for-gestational-age baby undetected before delivery. Data were analysed with mixed-effects logistic regression, accounting for clustering within clinics and pregnancies as appropriate. This trial is registered with the ISRCTN registry (ISRCTN18008445). Findings: Between Jan 15 and Sept 15, 2017, 3219 pregnant women received care in the intervention clinics (n=60 clusters) and 3148 pregnant women received care in the control primary health-care clinics (n=59 clusters). Compared with the control group, the intervention led to higher guideline adherence for screening and management of anaemia (1535 [28·9%] of 5320 vs 2297 [44·3%] of 5182; adjusted odds ratio [OR] 1·88 [95% CI 1·52–2·32]), hypertension (7555 [94·7%] of 7982 vs 7314 [96·6%] of 7569; adjusted OR 1·62 [95% CI 1·29–2·05]), and gestational diabetes (1726 (39·7%) of 4348 vs 2189 (50·7%) of 4321; adjusted OR 1·45 [95% CI 1·14–1·83]) at eligible antenatal contacts. Only 599 (9·4%) of 6367 women attended the full antenatal care schedule, and better care provision did not translate to fewer adverse health outcomes in the intervention clusters (700 cases; 21·7%) compared to the control clusters (688 cases; 21·9%; adjusted OR 0·99; 95% CI 0·87–1·12). Interpretation: Clinical decision support for antenatal care in the eRegistry was superior for most process outcomes but had no effect on the adverse health outcomes. The improvements in process outcomes strengthen the evidence for the WHO guideline for digital client tracking with clinical decision support in lower-middle-income settings. Digital health interventions to address gaps in attendance might help achieve effective coverage of antenatal care. Funding: European Research Council and Research Council of Norway. Translation: For the Arabic translation of the abstract see Supplementary Materials section.

There has been a huge interest in studying human brain connectomes inferred from different imaging modalities and exploring their relationships with human traits, such as cognition. Brain connectomes are usually represented as networks, with nodes corresponding to different regions of interest (ROIs) and edges to connection strengths between ROIs. Due to the high-dimensionality and non-Euclidean nature of networks, it is challenging to depict their population distribution and relate them to human traits. Current approaches focus on summarizing the network using either pre-specified topological features or principal components analysis (PCA). In this paper, building on recent advances in deep learning, we develop a nonlinear latent factor model to characterize the population distribution of brain graphs and infer their relationships to human traits. We refer to our method as Graph AuTo-Encoding (GATE). We applied GATE to two large-scale brain imaging datasets, the Adolescent Brain Cognitive Development (ABCD) study and the Human Connectome Project (HCP) for adults, to study the structural brain connectome and its relationship with cognition. Numerical results demonstrate huge advantages of GATE over competitors in terms of prediction accuracy, statistical inference, and computing efficiency. We found that the structural connectome has a stronger association with a wide range of human cognitive traits than was apparent using previous approaches. 16 NIH Institutes and Centers that support the NIH Blueprint for Neuroscience Research [1U54MH091657]; McDonnell Center for Systems Neuroscience at Washington University; National Institutes of Health [U01DA041022, U01DA041028, U01DA041048, U01DA041089, U01DA041106, U01DA041117, U01DA041120, U01DA041134, U01DA041148, U01DA041156, U01DA041174, U24DA041123, U24DA041147, U01DA041093, U01DA041025] Published version Data used in the preparation of this article were obtained from the Human Connectome Project (https://www.humanconnectome.org/) and Adolescent Brain Cognitive Development (ABCD) Study (https://abcdstudy.org).The HCP WU-Minn Consortium (Principal Investigators: David Van Essen and Kamil Ugurbil; 1U54MH091657) were funded by the 16 NIH Institutes and Centers that support the NIH Blueprint for Neuroscience Research; and by the McDonnell Center for Systems Neuroscience at Washington University. The ABCD study is supported by the National Institutes of Health and additional federal partners under award numbers U01DA041022, U01DA041028, U01DA041048, U01DA041089, U01DA041106, U01DA041117, U01DA041120, U01DA041134, U01DA041148, U01DA041156, U01DA041174, U24DA041123, U24DA041147, U01DA041093, and U01DA041025. A full list of supporters is available at https://abcdstudy.org/federal-partners.html.A listing of participating sites and a complete listing of the study investigators can be found at https://abcdstudy.org/scientists/workgroups/.ABCD consortium investigators designed and implemented the study and/or provided data but did not necessarily participate in the analysis or writing of this report. This paper reflects the views of the authors and may not reflect the opinions or views of the NIH or ABCD consortium investigators.; Dunson and Zhang want to acknowledge support from the National Institutes of Health (NIH) of the United States under award number MH118927. We also want to acknowledge the support from the NVIDIA Corporation with their donation of the Titan-V GPU.

Investigations within the Human Connectome Project have expanded to include studies focusing on brain disorders. This paper describes one of the investigations focused on psychotic psychopathology: The psychosis Human Connectome Project (P-HCP). The data collected as part of this project were multimodal and derived from clinical assessments of psychopathology, cognitive assessments, instrument-based motor assessments, blood specimens, and magnetic resonance imaging (MRI) data. The dataset will be made publicly available through the NIMH Data Archive. In this report we provide specific information on how the sample of participants was obtained and characterized and describe the experimental tasks and procedures used to probe neural functions involved in psychotic disorders that may also mark genetic liability for psychotic psychopathology. Our goal in this paper is to outline the data acquisition process so that researchers intending to use these publicly available data can plan their analyses. MRI data described in this paper are limited to data acquired at 3 Tesla. A companion paper describes the study's 7 Tesla image acquisition protocol in detail, which is focused on visual perceptual functions in psychotic psychopathology.

Highlights • WHO and ILO are developing joint estimates of work-related burden of disease and injury. • This paper synthesizes evidence on prevalence of occupational noise exposure. • 65 studies were included (157,370 participants, 54 countries, six WHO regions). • The prevalence of occupational noise exposure in workers was 0.17., Background The World Health Organization (WHO) and the International Labour Organization (ILO) are developing joint estimates of the work-related burden of disease and injury (WHO/ILO Joint Estimates), with contributions from a large network of individual experts. Evidence from mechanistic and human data suggests that occupational exposure to noise may cause cardiovascular disease. In this paper, we present a systematic review and meta-analysis of the prevalence of occupational exposure to noise for estimating (if feasible) the number of deaths and disability-adjusted life years from cardiovascular disease that are attributable to exposure to this risk factor, for the development of the WHO/ILO Joint Estimates. Objectives We aimed to systematically review and meta-analyse estimates of the prevalence of occupational exposure to noise. Data sources We searched electronic academic databases for potentially relevant records from published and unpublished studies, including Ovid Medline, PubMed, EMBASE, and CISDOC. We also searched electronic grey literature databases, Internet search engines, and organizational websites; hand-searched reference list of previous systematic reviews and included study records; and consulted additional experts. Study eligibility and criteria We included working-age (≥15 years) workers in the formal and informal economies in any WHO Member and/or ILO member State, but excluded children (

Ultrasound-based assistive tools are aimed at reducing the high skill needed to interpret a scan by providing automatic image guidance. This may encourage uptake of ultrasound (US) clinical assessments in rural settings in low- and middle-income countries (LMICs), where well-trained sonographers can be scarce. This paper describes a new method that automatically generates an assistive video overlay to provide image guidance to a user to assess placenta location. The user captures US video by following a sweep protocol that scans a U-shape on the lower maternal abdomen. The sweep trajectory is simple and easy to learn. We initially explore a 2-D embedding of placenta shapes, mapping manually segmented placentas in US video frames to a 2-D space. We map 2013 frames from 11 videos. This provides insight into the spectrum of placenta shapes that appear when using the sweep protocol. We propose classification of the placenta shapes from three observed clusters: complex, tip and rectangular. We use this insight to design an effective automatic segmentation algorithm, combining a U-Net with a CRF-RNN module to enhance segmentation performance with respect to placenta shape. The U-Net + CRF-RNN algorithm automatically segments the placenta and maternal bladder. We assess segmentation performance using both area and shape metrics. We report results comparable to the state-of-the-art for automatic placenta segmentation on the Dice metric, achieving 0.83 ± 0.15 evaluated on 2127 frames from 10 videos. We also qualitatively evaluate 78,308 frames from 135 videos, assessing if the anatomical outline is correctly segmented. We found that addition of the CRF-RNN improves over a baseline U-Net when faced with a complex placenta shape, which we observe in our 2-D embedding, up to 14% with respect to the percentage shape error. From the segmentations, an assistive video overlay is automatically constructed that (i) highlights the placenta and bladder, (ii) determines the lower placenta edge and highlights this location as a point and (iii) labels a 2-cm clearance on the lower placenta edge. The 2-cm clearance is chosen to satisfy current clinical guidelines. We propose to assess the placenta location by comparing the 2-cm region and the bottom of the bladder, which represents a coarse localization of the cervix. Anatomically, the bladder must sit above the cervix region. We present proof-of-concept results for the video overlay.

AIMS: This paper reviewed the literature on diabetes prevalence and risk factors associated with diabetes among first-generation Chinese international migrants. METHODS: MEDLINE, Scopus, Web of Science, CINAHL and Maternity and Infant Care were searched until March 2022, for articles written in English. The quality of the included articles was assessed using the Newcastle-Ottawa Scale. RESULTS: In total, 17 articles were included (nine for gestational diabetes, six for type 2 diabetes, and none for type 1 diabetes). The average crude prevalence rate for type 2 diabetes and gestational diabetes was 12.1% and 9.3% respectively. Risk factors contributing to the occurrence of type 2 diabetes included older age, sex, family history of type 2 diabetes, higher BMI/waist circumference, longer time since migration, alcohol consumption, smoker, hypertension, and high triglycerides. Risk factors contributing to the occurrence of gestational diabetes included older maternal age, history of gestational diabetes, higher weight/pre-pregnancy BMI, longer time since migration, and Chinese ethnicity. CONCLUSIONS: We identified a research gap in the diabetes health of Chinese migrants, particularly for type 1 diabetes, highlighting the need for ethnic-specific diabetes research and care, including for subsequent generations of migrants and those living in developing countries.

Objective Postoperative cognitive dysfunction may result from worsening in a condition of previous impairment. It causes greater difficulty in recovery, longer hospital stays, and consequent delay in returning to work activities. Digital games have a potential neuromodulatory and rehabilitation effect. In this study, a digital game was used as a neuropsychological test to assess postoperative cognitive dysfunction, with preoperative patient performance as control. Methods It was a non-controlled study, with patients selected among candidates for elective non-cardiac surgery, evaluated in the pre- and postoperative periods. The digital game used has six phases developed to evaluate selective attention, alternating attention, visuoperception, inhibitory control, short-term memory, and long-term memory. The digital game takes about 25 minutes. Scores are the sum of correct answers in each cognitive domain. Statistical analysis compared these cognitive functions pre- and post-surgery using a generalized linear mixed model (ANCOVA). Results Sixty patients were evaluated, 40% male and 60% female, with a mean age of 52.7 ± 13.5 years. Except for visuoperception, a reduction in post-surgery scores was found in all phases of the digital game. Conclusion The digital game was able to detect decline in several cognitive functions postoperatively. As its completion is faster than in conventional tests on paper, this digital game may be a potentially recommended tool for assessing patients, especially the elderly and in the early postoperative period.

Purpose Neoadjuvant chemotherapy (NACT) is increasingly adopted in the therapy of breast cancer (BC) patients with positive axillary nodes (cN+), but the reliability and feasibility of sentinel lymph node biopsy (SLNB) following NACT are still controversial. The objective of the present study is to conduct an updated meta-analysis on this issue. Methods A literature search was performed using PubMed, Cochrane, Embase, and Web of Science to identify papers published from January 1, 2000 to October 22, 2020 to research SLNB after NACT in BC patients. Studies that met the quality standard were enrolled for this meta-analysis. Results A total of 3578 participants from 27 trials were included in this meta-analysis. The pooled estimate of the identification rate (IR) for SLNB was 91 %, and the false negative rate (FNR) was 15 %. The pooled negative prediction value (NPV), accuracy, specificity, and sensitivity were 82 %, 89 %, 97 %, and 85 %, respectively. In subgroup analysis, the application of dual mapping could clearly decrease the FNR. The FNR was significantly high in the luminal types, and it declined as more sentinel lymph nodes (SLNs) were removed. Conclusion SLNB following NACT is now technically feasible for BC with cN+. However, it must be emphasized that the FNR is unacceptable high., Highlights • We performed a meta-analysis to provide a consensus regarding the application of SLNB post-NACT in cN + patients. • One comprehensive database search yielded 27 studies (3578 patients). • The pooled estimate of IR for SLNB was 91 %, and FNR was 15 %. • The application of dual mapping could clearly decrease the FNR.

Background: As daily engagement with social networking sites (SNS) increases globally, identifying and understanding the risk factors associated with problematic SNS use is of utmost importance. Researchers are interested in understanding internalizing symptoms as both a risk factor and a negative consequence of problematic SNS use. Prior research has proposed rumination alongside internalizing symptoms as a risk factor, though limited research has examined these associations across different cultures. Objective: The present study examined the indirect associations between internalizing symptoms (specifically depressive and social anxiety symptoms) and problematic SNS use via rumination among a cross-cultural sample. Method: Participants were 8,912 (70.8 % female; Mean age = 20.25, SD = 3.95) college students recruited across seven countries (U.S., Canada, Spain, England, Argentina, Uruguay, and South Africa) who completed measures of internalizing symptoms, rumination, weekly SNS use, and problematic SNS use. Results: We found that higher internalizing symptoms were associated with more problematic SNS use via higher ruminative thinking. Specifically, problem-focused thoughts (a rumination subtype) uniquely accounted for 22.89% and 28.15% of the total effect of depressive and social anxiety symptoms on problematic SNS use, respectively. Other rumination subtypes (i.e., anticipatory thoughts and repetitive thinking) also demonstrated significant indirect effects, though weaker effects than for problem-focused thoughts. Findings were invariant across countries. Conclusions: These findings provide support for further exploring the role rumination plays in determining and comparing problematic SNS use cross-culturally in longitudinal and experimental work. Dr. Bravo was supported by a training grant (T32-AA018108) from the National Institute on Alcohol Abuse and Alcoholism (NIAAA) in the United States during the duration of data collection for this project. Data collection was supported, in part, by grant T32-AA018108. NIAAA had no role in the study design, collection, analysis or interpretation of the data, writing the manuscript, or the decision to submit the paper for publication. Data collection in Spain was also supported by grants UJIA2019-08 from the Universitat Jaume I and grant PSI2015-67766-R from the Spanish Ministry of Economy and Competitiveness (MINECO). Data collection in Argentina was also supported by grants from the National Secretary of Science and Technology (FONCYT, Grant No PICT 2018–03170) and by grants from the Secretary of Science and Technology- National University of Cordoba (SECyT-UNC).

Objectives\ud Maternity health professionals (MHPs) caring for women may witness or be involved in traumatic births. This can be associated with MHPs experiencing secondary traumatic stress (STS) or probable post-traumatic stress disorder (PTSD), which may impact MHPs emotionally and physically. The aims of this review were therefore to determine: (i) the prevalence of STS and PTSD in maternity health professionals; and (ii) the impact of witnessing birth trauma on maternity health professionals.\ud \ud Methods\ud A mixed-methods systematic review was carried out by conducting literature searches on CINAHL, MEDLINE, PsychARTICLES, PsychINFO and PsychTESTS databases. Searches were conducted from the inception of databases up to February 2022 using search terms on MHPs and birth trauma combined. Methodological quality and bias were assessed. Data were synthesised using thematic synthesis.\ud \ud Results\ud A total of 18 studies were included in the review. Sample size ranged from 9-2,165 (total N =8,630). Participants included midwives, nurses and obstetricians aged 18-77 years. Many MHPs had witnessed a traumatic birth event (45% - 96.9%) with the prevalence of STS ranging from 12.6%-38.7% and the proportion of participants meeting diagnostic criteria for PTSD ranging from 3.1%-46%. MHPs reported positive and negative effects associated with witnessing traumatic birth events. Synthesis of quantitative and qualitative papers identified five themes: Negative emotions and symptoms; Responsibility and regret; Impact on practice and care; Challenging professional identity; and Team support being essential.\ud \ud Discussion\ud Witnessing traumatic birth events is associated with profound emotional and physical impacts on MHPs, signifying the importance of acknowledging and addressing this in the maternity workforce.\ud It is important to raise awareness of the impact of birth trauma on MHPs. Effective education and training guidelines, a supervisory network, ways to change practice and policy, and support and treatment should be provided to assist and improve the outcomes and work-life of MHPs’ who witness traumatic births.

Evidence shows interventions can improve positive body image in adult women. This systematic review examined the evidence of efficacy of interventions that aimed to increase positive body image in children and young people aged under 18 years. The authors followed PRISMA guidelines for the review. Searches of CINAHL Plus, Medline, PsychINFO, Wiley Online Library, SCOPUS and grey literature were conducted up to February 2021 and identified 4171 papers. Thirteen studies evaluating 12 interventions, designed for children/adolescents aged 9-18 years, were eligible and evaluated using the Effective Public Health Practice Project (EPHPP) Quality Assessment Tool. The studies evaluated body appreciation, body-esteem, and embodiment. Studies using cognitive dissonance, peer support, and psychoeducation had evidence of improving body appreciation and body-esteem in adolescent girls. However, evidence of efficacy for younger children and boys was lacking and the studies ranged in methodological quality. Further research should rigorously evaluate positive body image interventions using second-generation measures that assess specific components of positive body image and consider how to promote positive body image in young children and boys.

Background-\ud \ud The aim of the present study was to investigate associations between food insecurity with suicidal ideation and suicide attempts in adults aged ≥50 years from six low- and middle-income countries (LMICs).\ud \ud Methods-\ud \ud Cross-sectional, community-based data from the World Health Organisation's Study on Global Aging and Adult Health were analyzed. Self-reported information on past 12-month suicidal ideation and suicide attempts was collected. Past 12-month food insecurity was assessed with two questions on frequency of eating less and hunger due to lack of food. Multivariable logistic regression analysis was conducted to assess the association between food insecurity and suicidal ideation or suicide attempts.\ud \ud Results-\ud \ud The final analytical sample included 34,129 individuals aged ≥50 years [mean (SD) age 62.4 (16.0) years; 52.1% females]. Compared to no food insecurity, severe food insecurity was associated with a significant 2.78 (95%CI = 1.73–4.45) times higher odds for suicidal ideation, while moderate and severe food insecurity were associated with 2.59 (95%CI = 1.35–4.97) and 5.15 (95%CI = 2.52–10.53) times higher odds for suicide attempts, respectively.\ud \ud Limitations-\ud \ud The cross-sectional design, the use of self-reported wish to die as a measure of suicide ideation, and that suicidal ideation and suicide attempts were only assessed among those who had depressive symptoms, could be considered limitations of our study.\ud \ud Conclusions-\ud \ud Food insecurity was positively associated with suicidal ideation and suicide attempts. Targeting food insecurity among older adults in LMICs may lead to reduction in suicidal ideation and suicide attempts, although future longitudinal studies are warranted to confirm this.

Objective\ud To explore the experiences of women during pregnancy with mild to moderate mental health problems and describe the barriers to receiving support in relation to their mental health.\ud \ud Research design and participants\ud This paper reports part of a larger project which recruited women and midwives in one hospital in Wales. Participants completed questionnaires in early pregnancy in an antenatal clinic, and the characteristics of women with and without symptoms of anxiety and depression compared. All women were invited to express interest in a follow up interview in late pregnancy. Women identified to have depression and anxiety in early pregnancy, but not under the care of perinatal mental health services, were eligible for interview. Interviews were conducted with 20 women using a visual timeline to aid discussion and were thematically analysed.\ud \ud Findings\ud In late pregnancy mental health disorders were reported by nine women, of which five were diagnosed during adulthood. EPDS scores found 15 women had symptoms of mild to moderate depression and GAD-7 scores indicating 15 women with mild to moderate anxiety. Three themes were identified: moods and emotions - past, present and future; expectations and control; knowledge and conversations.\ud \ud Key conclusions and implications for practice\ud Due to limited access to specialist perinatal mental health services women relied on support networks and self-care to maintain their mental health. More time and better continuity at antenatal appointments along with improved mental health literacy may increase discussions regarding women's mental health during pregnancy. In addition investment is required to develop strategies and improve access to mental health services for women with mild to moderate mental health problems.

Background Uncertainty remains regarding the validity of screening tools to detect common mental disorders (CMDs) during perinatal periods. This umbrella review aims to provide an up-to-date summary of psychometric properties of tools for the identification of perinatal CMDs. Methods Reviews were identified via Ovid MEDLINE, PsychINFO, EMBASE, Global Health and Cochrane Database of Systematic Reviews electronic databases with no date or language restriction. Pooled sensitivity and specificity estimates and ranges were extracted and summarised using forest plots. Quality assessment was conducted using Measurement Tool to Assess Systematic Reviews (AMSTAR-2). Results Of 7,891 papers identified, 31 reviews met inclusion criteria. 76 screening tools were identified; most frequently validated were Edinburgh Postnatal Depression Scale (EPDS) (n=28 reviews), Beck's Depression Inventory (BDI) (n=13 reviews) and Patient Health Questionnaire (PHQ) (n=12 reviews). Forest plots demonstrated a pattern of decreasing sensitivity and increasing specificity with increasing cut-off scores. Sub-group analysis of data extracted from low quality reviews demonstrated wider 95% CIs and overall lower specificity. Validity also varied according to ethnicity, socio-economic background and age. Limitations Despite a low Covered Corrected Area (CCA) score the primary studies included within reviews overlapped; therefore we were unable perform meta-analysis. Conclusions The evidence suggests that the EPDS, PHQ and BDI are useful across a range of diverse settings but the context of tool application is a key factor determining validity. This review highlights that utilizing screening tools in clinical practice is complex and requires careful consideration of the population, context, and health system it will be used in.

PURPOSE Patient shielding during medical X-ray imaging has been increasingly criticized in the last years due to growing evidence that it often provides minimal benefit and may even compromise image quality. In Europe, and as also shown in a short assessment in Switzerland, the use of patient shielding is inhomogeneous. The aim of this study was to systematically review recent literature in order to assess benefits and appraise disadvantages related to the routine use of patient shielding. METHODS To evaluate benefits and disadvantages related to the application of patient shielding in radiological procedures, a systematic literature review was performed for CT, radiography, mammography and fluoroscopy-guided medical X-ray imaging. In addition, reports from medical physics societies and authorities of different countries were considered in the evaluation. RESULTS The literature review revealed 479 papers and reports on the topic, from which 87 qualified for closer analysis. The review considered in- and out-of-plane patient shielding as well as shielding for pregnant and pediatric patients. Dose savings and other dose and non-dose related effects of patient shielding were considered in the evaluation. CONCLUSIONS Although patient shielding has been used in radiological practice for many years, its use is no longer undisputed. The evaluation of the systematic literature review of recent studies and reports shows that dose savings are rather minimal while significant dose- and non-dose-related detrimental effects are present. Consequently, the routine usage of patient protection shielding in medical X-ray imaging can be safely discontinued for all modalities and patient groups.