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Patients with the dual burden of chronic kidney disease (CKD) and cardiovascular disease (CVD) experience unacceptably high rates of morbidity and mortality, which also entail unfavorable effects on healthcare systems. Currently, concerted efforts to identify, prevent and treat CVD in CKD patients are lacking at the institutional level, with emphasis still being placed on individual specialty views on this topic. The authors of this position paper endorse the need for a dedicated interdisciplinary team of subspecialists in cardio-nephrology that manages appropriate clinical interventions across the inpatient and outpatient settings. There is a critical need for training programs, guidelines and best clinical practice models, and research funding from nephrology, cardiology and other professional societies, to support the development of the subspecialty of cardio-nephrology. This position paper from the coordinating committee from the Working Group for Cardiorenal Medicine of the Spanish Society of Nephrology (S.E.N.) is intended to be the starting point to develop the subspecialty of cardio-nephrology within the S.E.N.. The implementation of the subspecialty in day-to-day nephrological practice will help to diagnose, treat, and prevent CVD in CKD patients in a precise, clinically effective, and health cost-favorable manner. Resumen: Los pacientes con enfermedad renal crónica (ERC) que presentan enfermedad cardiovascular (ECV) tienen índices de morbilidad y mortalidad inaceptablemente elevados, que impactan desfavorablemente sobre los sistemas de salud. En la actualidad, se requieren actuaciones multidisciplinares para identificar, prevenir y tratar la ECV en los pacientes con ERC, debiendo pues superarse la época de las actuaciones de las especialidades individuales. Los autores de este artículo respaldan la necesidad de un equipo interdisciplinar de subespecialistas en cardionefrología que gestione las intervenciones clínicas adecuadas en el entorno hospitalario y en el ambulatorio. Existe una gran necesidad de programas de formación, de guías y modelos de práctica clínica, y de fondos para la investigación en las sociedades de nefrología, cardiología y otras, para apoyar el desarrollo de la subespecialidad de cardio-nefrología. Este documento de opinión del comité coordinador del Grupo de Trabajo de Medicina Cardiorenal de la Sociedad Española de Nefrología (S.E.N.) pretende ser el inicio del desarrollo de la subespecialidad de Cardionefrología en el marco de la S.E.N. La implementación de la subespecialidad en la práctica nefrológica diaria contribuirá a diagnosticar, tratar y prevenir la ECV en los pacientes con ERC de una manera precisa, clínicamente efectiva y sanitariamente rentable.

© 2021 Sociedade Portuguesa de Cardiologia. Published by Elsevier España, S.L.U. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/), Heart failure (HF) with reduced ejection fraction (HFrEF) is associated with high rates of hospitalization and death. It also has a negative impact on patients' functional capacity and quality of life, as well as on healthcare costs. In recent years, new HFrEF prognosis-modifying drugs have emerged, leading to intense debate within the international scientific community toward a paradigm shift for the management of HFrEF. In this article, we report the contribution of a Portuguese HF expert panel to the ongoing debate. Based on the most recently published clinical evidence, and the panel members' clinical judgment, three key principles are highlighted: (i) sacubitril/valsartan should be preferred as first-line therapy for HFrEF, instead of an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker; (ii) the four foundation HFrEF drugs are the angiotensin receptor/neprilysin inhibitor, beta-adrenergic blocking agents, mineralocorticoid receptor antagonists, and sodium-glucose co-transporter 2 inhibitors, regardless of the presence of type-2 diabetes mellitus; (iii) these four HFrEF drug classes should be introduced over a short-term period of four to six weeks, guided by a safety protocol, followed by a dose up-titration period of 8 weeks., A insuficiência cardíaca (IC) com fração de ejeção reduzida (ICFEr) está associada a níveis elevados de hospitalização e mortalidade. A ICFEr também tem um impacto negativo na capacidade funcional e na qualidade de vida dos doentes, bem como na despesa em saúde. Nos últimos anos, surgiram novos medicamentos modificadores do prognóstico da ICFEr, originando um intenso debate na comunidade científica internacional em relação a uma mudança de paradigma para o tratamento da ICFEr. Neste artigo, relatamos a contribuição de um painel de especialistas portugueses em IC para o debate em curso. Com base na evidência clínica publicada mais recentemente e no julgamento clínico dos membros do painel, três princípios-chave são destacados: (i) sacubitril/valsartan deve ser preferido como terapia de primeira linha para a ICFEr, em vez de um inibidor da enzima de conversão da angiotensina ou um bloqueador do recetor da angiotensina; (ii) os quatro medicamentos básicos para a ICFEr são o inibidor do recetor da angiotensina e da neprilisina, os agentes bloqueadores beta-adrenérgicos, os antagonistas do recetor mineralocorticoide e os inibidores do cotransportador sódio-glucose 2, independentemente da presença de diabetes mellitus tipo 2; (iii) essas quatro classes de medicamentos para a ICFEr devem ser rapidamente introduzidas num período curto de 4-6 semanas, seguindo um protocolo de segurança, e depois tituladas durante as oito semanas seguintes.

Background: \ud Nutrition related publications in pediatric population cover wide range of topics and therefore it is usually difficult for clinicians to get an overview of recent nutrition related guidelines or recommendations.\ud \ud Methods: \ud The Special Interest Group (SIG) of Pediatrics of European Society for Clinical Nutrition and Metabolism (ESPEN) performed a literature search to capture publications in the last five years aiming to provide the latest information concerning nutritional issues in children in general and in specific diseases and to discuss progression in the field of pediatric nutrition evidence-based practice.\ud \ud Results: \ud Eight major topics were identified as the most frequently reported including allergy, critical illness, neonatal nutrition, parenteral and enteral nutrition, micronutrients, probiotics and malnutrition. Furthermore, it was noted that many reports were disease focused or included micronutrients and were, therefore, represented as tables.\ud \ud Conclusion: \ud Overall, it has been shown that most reports on nutrition topics in pediatrics were systematic reviews or guidelines/position papers of relevant societies, but many of them basing the conclusion on a limited number of high-quality randomized controlled trials or large observational cohort studies.

IMPORTANCE: Exercise therapies are advocated in osteoarthritis (OA) clinical guidelines. However, challenges to accessing exercise may be limiting widespread uptake. OBJECTIVE: To evaluate the effects of a self-directed web-based strengthening exercise and physical activity program supported by automated behavior-change text messages on knee pain and function for people with knee OA. DESIGN, SETTING, AND PARTICIPANTS: The participant-blinded and assessor-blinded randomized clinical trial enrolled 206 people who met clinical criteria for knee OA in communities across Australia from July 2018 to August 2019, with follow-up taking place at 24 weeks. INTERVENTIONS: The control group was given access to a custom-built website with information on OA and the importance of exercise and physical activity. The intervention group was given access to the same information plus a prescription for a 24-week self-directed strengthening regimen and guidance to increase physical activity, supported by automated behavior-change text messages encouraging exercise adherence. MAIN OUTCOMES AND MEASURES: Primary outcomes were change in overall knee pain (numeric rating scale, 0-10) and difficulty with physical function (Western Ontario and McMaster Universities Osteoarthritis Index, 0-68) over 24 weeks. Secondary outcomes were another knee pain measure, sport and recreation function, quality of life, physical activity, self-efficacy, overall improvement, and treatment satisfaction. RESULTS: Of 206 participants, 180 (87%; mean [SD] age, 60 [8.4] years; 109 [61%] women) completed both 24-week primary outcomes. The intervention group showed greater improvements in overall knee pain (mean difference, 1.6 units; 95% CI, 0.9-2.2 units; P

Rheumatoid arthritis (RA) is a common autoimmune disease characterized by joint inflammation and immune dysfunction. Although various therapeutic approaches have been utilized for the treatment of RA in clinical applications, the low responsiveness of RA patients and undesired systemic toxicity are still unresolved problems. Targeting the resolution pathway of inflammation with pro-resolving mediators would evoke the protective actions of patient for combating the inflammation. Ac2–26, a 25-amino acid peptide derived from Annexin A (a pro-resolving mediator), has shown good efficacy in the treatment of inflammatory disorders. However, the low bioavailability of Ac2–26 peptides hinders their efficacy in vivo. In this paper, we formed PEGylated lipid nanoparticles (LDNPs) by the co-assembly of l-ascorbyl palmitate (L-AP) and N-(carbonyl methoxypolyethylene glycol-2000)-1,2-distearoyl-sn‑glycero-3-phosphoethanolamine (DSPE-PEG2k) to encapsulate and deliver Ac2–26 peptides to the arthritic rats. They showed good stability and biocompatibility. After being intravenously administrated, Ac2–26 peptide-loaded PEGylated lipid nanoparticles (ADNPs) showed the prolonged in vivo circulation time and enhanced accumulation in inflamed sites. In vivo therapeutic evaluations revealed that ADNPs could attenuate synovial inflammation and improve joint pathology. Therefore, the pro-resolving therapeutic strategy using ADNPs is effective in RA treatment., Graphical abstract The fabrication of ADNPs and their in vivo performances in arthritic rats.Image, graphical abstract

Familial Adenomatous Polyposis (FAP) is an autosomal dominant disorder caused by mutation of the APC gene presenting with numerous colorectal adenomatous polyps and a near 100% risk of colon cancer. Preliminary research findings from our group indicate that FAP patients experience significant deficits across many cognitive domains. In the current study, fMRI brain metrics in a FAP population and matched controls were used to further the mechanistic understanding of reported cognitive deficits. This research identified and characterized any possible differences in resting brain networks and associations between neural network changes and cognition from 34 participants (18 FAP patients, 16 healthy controls). Functional connectivity analysis was performed using FSL with independent component analysis (ICA) to identify functional networks. Significant differences between cases and controls were observed in 8 well-established resting state networks. With the addition of an aggregate cognitive measure as a covariate, these differences were virtually non-existent, indicating a strong correlation between cognition and brain activity at the network level. The data indicate robust and pervasive effects on functional neural network activity among FAP patients and these effects are likely involved in cognitive deficits associated with this disease.

Background Analysis of fluid metabolites has the potential to provide insight into the neuropathophysiology of injury in patients with traumatic brain injury (TBI). Objective Using a 1H nuclear magnetic resonance (NMR)-based quantitative metabolic profiling approach, this study determined (1) if urinary metabolites change during recovery in patients with mild to severe TBI; (2) whether changes in urinary metabolites correlate to injury severity; (3) whether biological pathway analysis reflects mechanisms that mediate neural damage/repair throughout TBI recovery. Methods Urine samples were collected within 7 days and at 6-months post-injury in male participants (n = 8) with mild-severe TBI. Samples were analyzed with NMR-based quantitative spectroscopy for metabolomic profiles and analyzed with multivariate statistical and machine learning-based analyses. Results Lower levels of homovanillate (R = −0.74, p ≤ 0.001), L-methionine (R = −0.78, p, Highlights • NMR-based metabolomics of urine can identify metabolic fingerprints associated with functional recovery following TBI. • Metabolic profiles in urine correlate to injury severity. • Biological pathway analysis reflects mechanisms that mediate neural damage and repair processes throughout recovery. • Metabolomics provides insight into the neuropathophysiology of injury in TBI patients.

Highlights • Contact with stigmatized groups is a promising mechanism for reducing bias. • The nature of contact with patients who misuse opioids matters significantly. • Contact with patients who misuse opioids can have negative consequences for physicians. • Consequences occur in physicians who are experiencing stress, burnout, and bias. • Interventions need to consider factors that may reduce the effectiveness of contact., Introduction Prior research suggests that some physicians hold negative attitudes toward patients who misuse opioids and that this serves as a barrier which limits the availability and effectiveness of health care services. Interventions which improve physicians’ attitudes have thus garnered attention, many of which have focused on increasing contact between physicians and patients who misuse opioids. However, drawing on recent literature on intergroup contact, the current paper argues that contact may not have uniformly positive effects on prejudice. Methods We surveyed 408 board-certified physicians in the state of Ohio where many opioid overdose deaths have been concentrated. We used regression to test for interactions between contact and three focal variables, bias, burnout, and stress, on physician willingness to work with patients who misuse opioids. Results The negative relationships between bias, physician burnout, and stress induced by working with patients who misuse opioids and physicians’ willingness to work with this patient population are each exacerbated when contact with patients who misuse opioids is high. Conclusions Although intervention studies have shown promise for the role that increased contact may have in reducing stigma toward patients who misuse opioids, these interventions may not be appropriate for physicians who are experiencing strain or who hold preexisting negative attitudes toward this patient population. Future interventions may need to target bias, burnout, and stress, in addition to facilitating contact, to increase physician willingness to work with these patients.

Psychosis is a chronic neuropsychiatric disorder that affects millions of individuals worldwide and impairs the quality of life and productivity of the patients. Terminalia macroptera Guill & Perr. (Combrataceae) is a plant that is used in the management of anxiety related disorders. The present study investigates the antipsychotic effects of ethyl acetate fraction of T. macroptera (EFTM) leaf in ketamine-induced psychosis in mice. Acute toxicity of EFTM was determine using Lorke’s method. Ketamine (25 mg/kg) was injected once daily for 7 consecutive days in Swiss albino mice to induce psychosis. The effect of the extracts (100, 200 and 400 mg/kg) was evaluated against psychotic-like behaviors induced by ketamine including locomotor activity and stereotypy in the open field test, immobility duration in the forced swim test, and memory impairment using the Y- maze test. The acute antipsychotic effect of EFTM was evaluated on apomorphine climbing test, while woodblock test was performed to assess its extrapyramidal side effects. The LD50 was found to be 3807 mg/kg p.o. which is considered safe. EFTM (100, 200 and 400 mg/kg) exhibited significant antipsychotic effect by reducing ketamine-induced hyperactivity, immobility, and memory deficit in mice, EFTM also suppressed stereotypic climbing behavior due to apomorphine. Accordingly, the antipsychotic activity of EFTM was not associated with extrapyramidal side effects as evidenced by lack of catalepsy. The study revealed that EFTM ameliorated psychotic-like symptoms and is devoid of extrapyramidal side effects in mice, underscoring its antipsychotic-like effect.

It has been demonstrated that adult born granule cells are generated after traumatic brain injury (TBI). There is evidence that these newly generated neurons are aberrant and are poised to contribute to poor cognitive function after TBI. Yet, there is also evidence that these newly generated neurons are important for cognitive recovery. Pattern separation is a cognitive task known to be dependent on the function of adult generated granule cells. Performance on this task and the relation to dentate gyrus dysfunction after TBI has not been previously studied. Here we subjected Sprague Dawley rats to lateral fluid percussion injury or sham and tested them on the dentate gyrus dependent task pattern separation. At 2 weeks after injury, we examined common markers of dentate gyrus function such as GSK3ß phosphorylation, Ki-67 immunohistochemistry, and generation of adult born granule cells. We found that injured animals have deficits in pattern separation. We additionally found a decrease in proliferative capacity at 2 weeks indicated by decreased phosphorylation of GSK3ß and Ki-67 immunopositivity as compared to sham animals. Lastly we found an increase in numbers of new neurons generated during the pattern separation task. These findings provide evidence that dentate gyrus dysfunction may be an important contributor to TBI pathology.

Background Arterial stiffness is important because it is associated with adverse cardiovascular events including stroke. Methods that are based on pulse wave velocity have significant limitations in estimating arterial stiffness. The purpose of this paper is to present a novel easy to apply non-invasive method to estimate arterial stiffness that is based on pulse pressure. Methods Two indices to estimate arterial stiffness, (1) arterial stiffness 1 (AS1) and (2) arterial stiffness 2 (AS2) were developed and applied in two National Institutes of Health funded clinical trials, the Systolic Hypertension in the Elderly Program and the Systolic Blood Pressure Intervention Trial. These indices were developed by fitting individual survival models for selected predictor variables to the response, i.e. time to stroke, by selecting the coefficients that were statistically significant at the 0.05 α level after adjusting the variable weights. The indices were derived as the weighted linear combination of the coefficients. Results AS1 and AS2 performed well in two goodness of fit criteria i.e. overall model p-value and concordance correlation. Comparison of Cox models using indices AS1 and AS2 and chronological age indicated that AS1 and AS2 independently predicted the occurrence of stroke at five years better than chronological age. Nearly identical effects were observed when the analyses were limited to Black participants in SPRINT with a concordance correlation of 0.80 and log rank test p-value of 0.007. Conclusion These indices that are derived from pulse pressure predict the occurrence of stroke better than either pulse pressure or chronological age alone and may be used in designing new randomized clinical trials, and possibly incorporated in hypertension and stroke guidelines.

ObjectivesTo estimate the absolute risk of cerebral venous thrombosis (CVT) and portal vein thrombosis (PVT) in the two weeks following a diagnosis of COVID-19, and to assess the relative risks (RR) compared to influenza or the administration of an mRNA vaccine against COVID-19.DesignRetrospective cohort study based on an electronic health records networkSettingLinked records between primary and secondary care centres within 59 healthcare organisations, primarily in the USAParticipantsAll patients with a confirmed diagnosis of COVID-19 between January 20, 2020 and March 25, 2021 were included (N=537,913, mean [SD] age: 46.2 [21.4] years; 54.9% females). Cohorts (matched for age, sex, and race) of participants diagnosed with influenza (N=392,424) or receiving the BNT162b2 or mRNA-1273 vaccine (N=366,869) were used for comparison.Main outcome measuresDiagnosis of CVT (ICD-10 code I67.6) or PVT (ICD-10 code I81) within 2 weeks after a diagnosis of COVID-19.ResultsThe incidence of CVT after COVID-19 diagnosis was 42.8 per million people (95% CI 28.5–64.2) including 35.3 per million (95% CI 22.6–55.2) first diagnoses. This was significantly higher than the CVT incidence in a matched cohort of patients with influenza (RR=3.83, 95% CI 1.56–9.41, PConclusionsThe incidence of CVT and PVT is significantly increased after COVID-19. The data highlight the risk of serious thrombotic events in COVID-19 and can help contextualize the risks and benefits of vaccination in this regard.What is known‐A systematic review of cohort studies suggested an incidence of CVT among hospitalised patients with COVID-19 to be about 800 per million patients. There was evidence of selection, ascertainment, and reporting bias in all included studies.‐The incidence of CVT and PVT among both hospitalised and non-hospitalised patients with COVID-19 is unknown.‐It is unknown if COVID-19 increases the risk of CVT and PVT.What this study addsOur study estimates that the absolute risk of CVT and PVT are respectively 42.8 and 392.3 per million patients (both hospitalised and non-hospitalised) in the 2 weeks after a diagnosis of COVID-19. COVID-19 increases the risk of CVT and PVT compared to patients diagnosed with influenza, and to people who have received a COVID-19 mRNA vaccine.

Background: COVID-19 prevention and control policies have entailed lockdowns and confinement. This study aimed to summarize the global research evidence describing the effect of COVID-19 isolation measures on the health of people living with dementia. Methods: We searched Pubmed, PsycINFO and CINAHL up to 27th of February 2021 for peer-reviewed quantitative studies about the effects of isolation during COVID-19 on the cognitive, psychological and functional symptoms of people with dementia or mild cognitive impairment. The Joanna Briggs Institute critical appraisal tool was used to conduct the quality assessment. PROSPERO registration: CRD42021229259. Findings: 15 eligible papers were identified, examining a total of 6442 people with dementia. 13/15 studies investigated people living in the community and 2 in care homes. Out of 15 studies, 9 (60%) reported changes in cognition and 14 (93%) worsening or new onset of behavioral and psychological symptoms. Six studies (46%) reported a functional decline in daily activities in a variable proportion of the population analyzed. Interpretation: COVID-19 isolation measures have damaged the cognitive and mental health of people with dementia across the world. It is urgent to issue guidance that balances infection control measures against the principles of non-maleficence to guarantee fair and appropriate care during pandemic times for this population. Funding: ASG receives funding from a grant jointly funded by the Economic and Social Research Council (UK) and the National Institute for Health Research (UK) (ES/S010467/1). GL is supported by UCLH National Institute for Health Research (NIHR) Biomedical Research Centre, and by NIHR North Thames ARC as a NIHR senior investigator. JR is supported by a UK Research and Innovation's Global Challenges Research Fund (UKRI GCRF) (ES/P0109381).

Background Guillain-Barre syndrome (GBS) is the most prevalent acute autoimmune polyneuropathy, however, the incidence of GBS across China remains undetermined. We conducted the first nationwide study to extrapolate the incidence and mortality rates of GBS across all age groups at a national scale. Methods This study analyzed patient metrics from the National Hospital Quality Monitoring System, a comprehensive administrative database of which incorporate all 1665 tertiary hospitals in mainland China. For all study patients the "Medical Record Homepage" encompasses 346 distinct variables such as demographic characteristics, diagnoses, procedures, expenses, etc., that are systematically recorded from these hospitals by standard protocol. All GBS diagnoses adhered to the National Institute of Neurologic and Communicative Disorders and Stroke (NINCDS) diagnostic criteria and were identified with ICD-10 code (G61•0). Findings From 2016 to 2019, 75,548 hospital admissions for 38,861 GBS patients were identified. The age- and sex-adjusted incidence per 100,000 person-years is 0•698 (95% confidence interval [CI], 0•691-0•705), 0•233(0•225-0•242) in children and 0•829(0•820-0•837) in adults. The male-to-female ratio is 1•49. Peak disease onset was detected in the 70–74 years age group with an incidence of 1•806/100, 000 (95% CI, 1•741-1•870). Recognizable GBS distribution patterns were recognized in the southeastern coastal areas, where the cases of GBS were concentrated in the summer and autumn seasons. Prevalent comorbidities include hypertension (28•8%) and stroke (14•3%). The median length of hospitalization was 13•0 (8•0–18•0) days with a median hospitalization cost of $2371•60 ($1281•80–5463•60). Covering 69•9% of study patients, the Basic Medical Insurance was the most common payment mechanism. From 2016-2019, 426 adults and 13 children died in this study pool, with a hospital mortality rate of 11•2 per 1,000 person-years. Interpretation For the first time, we obtained a national incidence for GBS at 0•233 in children and 0•829 in adults per 100,000 in China. A differential spatiotemporal incidence is presented most southeast coastal areas in the summer and autumn seasons. Funding National Science Foundation of China (91949208, 91642205, and 81830038); Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing.

Summary: Background: The high rate of infections among patients admitted to critical care units (CCUs) is associated with high rate of antibiotic consumption, especially broad-spectrum antibiotics. This study is to describe the antibiotics use in CCUs in primary and secondary hospitals in Vietnam, a setting with high burden of antibiotic resistance. Methods: This was a 7-day observational study in 51 CCUs in hospitals from 5 provinces in Vietnam from March to July 2019. Patients aged ≥ 18 years admitted to the participating CCUs was enrolled consecutively. We collected data on patient's demographics, initial diagnosis and antibiotic therapy within the first 24 hours. Antibiotic therapy was classified by the Anatomical Therapeutic Chemical (ATC) Index and the 2019 WHO Access, Watch, Reserve (AWaRe) groups. Findings: Out of 1747 enrolled patients, empirical antibiotic treatments were initiated in 1112 (63.6%) patients. The most frequently prescribed antibiotics were cefotaxime (22.3%), levofloxacin (19%) and ceftazidime (10.8%). Antibiotics were given in 31.5% of patients without diagnosis of infection. Watch and/or Reserve group antibiotic were given in 87.3% of patients and associated with patient's age (aOR 1.01 per 1-year increment, 95%CI 1.00-1.02) and the presence of SIRS on admission (aOR 2.1, 95%CI 1.38-3.2). Interpretation: We observed a high frequency use and a substantial variation in patterns of empirical antibiotic use in the CCUs in Vietnam. It highlights the importance of continuous monitoring antibiotic consumption in CCUs. Funding: None.

Highlights • Among PWH, cocaine use vs no-use was associated with worse HIV treatment outcomes. • Powder cocaine only users were more likely to be younger, Hispanic, and employed. • Users of powder + crack cocaine had lower viral suppression than users of either alone. • Harm reduction efforts addressing substance use should be a key component of HIV care., Introduction Cocaine (including powder and crack) use is common among people with HIV (PWH). We identified socio-demographic and behavioral factors associated with cocaine use (overall and various forms) among PWH; we also examined differences in HIV treatment outcomes across cocaine exposure groups. Methods The study sample (N = 1166) was derived from two cohorts of PWH in Florida between 2014 and 2020. Baseline data were linked to the Enhanced HIV/AIDS Reporting System (eHARS) which tracks HIV viral load. Socio-demographics and polysubstance use were compared by cocaine use and the three cocaine use groups (powder only n = 101, crack only n = 91, or both n = 65). The association between the three cocaine use groups, ART adherence, and HIV viral suppression (

Background Atrial fibrillation (AF) is a heterogeneous condition caused by various underlying disorders and comorbidities. A cluster analysis is a statistical technique that attempts to group populations by shared traits. Applied to AF, it could be useful in classifying the variables and complex presentations of AF into phenotypes of coherent, more tractable subpopulations. Objectives This study aimed to characterize the clinical phenotypes of AF using a national AF patient registry using a cluster analysis. Methods We used data of an observational cohort that included 7406 patients with non-valvular AF enrolled from 158 sites participating in a nationwide AF registry (J-RHYTHM). The endpoints analyzed were all-cause mortality, thromboembolisms, and major bleeding. Results The optimal number of clusters was found to be 4 based on 40 characteristics. They were those with (1) a younger age and low rate of comorbidities (n = 1876), (2) a high rate of hypertension (n = 4579), (3) high bleeding risk (n = 302), and (4) prior coronary artery disease and other atherosclerotic comorbidities (n = 649). The patients in the younger/low comorbidity cluster demonstrated the lowest risk for all 3 endpoints. The atherosclerotic comorbidity cluster had significantly higher adjusted risks of total mortality (odds ratio [OR], 3.70; 95% confidence interval [CI], 2.37–5.80) and major bleeding (OR, 5.19; 95% CI, 2.58–10.9) than the younger/low comorbidity cluster. Conclusions A cluster analysis identified 4 distinct groups of non-valvular AF patients with different clinical characteristics and outcomes. Awareness of these groupings may lead to a differentiated patient management for AF.

Objectives Metabolic syndrome (MetS) is the constellation of cardio-metabolic risk factors, and it can illustrate the coming burden of cardiovascular diseases and diabetes mellitus. Myanmar faces larger pressure from cardio-metabolic diseases and there is no existing data to understand the magnitude of MetS in adult population. This study aimed to investigate the extent of existing people with MetS in the community and to know the related lifestyle factors to MetS. Methods A community based cross-sectional study was performed in convenient sample of 302 Myanmar adult people. Prevalence of MetS and associated risk factors were identified by collecting sociodemographic information, anthropometric measurements, and blood investigation of glucose and lipid profiles. Logistic regression analysis was performed for developing statistical models to estimate the odd ratios (OR) and confidence intervals (CI). Results Prevalence of MetS is 29.1%, and there is no significant difference between male and female prevalence. Abdominal obesity is the highest component of MetS (OR: 28.37, CI: 12.41–64.85, p, Highlights • Prevalence of Metabolic Syndrome in Myanmar adult people is 29.1%. • Abdominal obesity is the commonest component. • Aging, obesity, diabetes, and hypertensive conditions are risk factors. • Practice of midday nap is a potential risky behavior. • Myanmar needs more attention to public health.

Background: Country-specific evidence is needed to guide decisions regarding whether and how to implement lung cancer screening in different settings. For this study, we estimated the potential numbers of individuals screened and lung cancer deaths prevented in Brazil after applying different strategies to define screening eligibility. Methods: We applied the Lung Cancer Death Risk Assessment Tool (LCDRAT) to survey data on current and former smokers (ever-smokers) in 15 Brazilian state capital cities that comprise 18% of the Brazilian population. We evaluated three strategies to define eligibility for screening: (1) pack-years and cessation time (≥30 pack-years and

Background: The effect of beta-blockade (BB) on response to vagus nerve stimulation (VNS) has not been reported in patients with heart failure and reduced ejection fraction (HFrEF). In the ANTHEM-HF Study, 60 patients received chronic cervical VNS. Background pharmacological therapy remained unchanged during the study, and VNS intensity was stable once up-titrated. Significant improvement from baseline occurred in resting 24-hour heart rate (HR), 24-hour HR variability (SDNN), left ventricular EF (LVEF), 6-minute walk distance (6MWD), and quality of life (MLWHFS) at 6 months post-titration. We evaluated whether response to VNS was related to percentage of target BB dose (PTBBD) at baseline. Methods: Patients were categorized by baseline PTBBD, then analyzed for changes from baseline in symptoms and function at 6 months after VNS titration. Results: All patients received BB, either PTBBD ≥ 50 % (16 patients, 27 %; group 1) or PTBBD

Background Reducing the alcohol-attributable cancer burden in the WHO European Region is a public health priority. This study aims to estimate the number of potentially avoidable cancers in countries of the WHO European Region in 2019 for three scenarios in which current excise duties on alcoholic beverages were increased by 20%, 50%, or 100%. Methods Mean prices and excise duties for beer, wine, and spirits in the Member States of the WHO European Region in 2020 were used as the baseline scenario. We assumed that increases in excise duties (20%, 50%, and 100%) were fully incorporated into the consumer price. Beverage-specific price elasticities of demand, with lower elasticities for heavy drinkers, were obtained from a meta-analysis. Model estimates were applied to alcohol exposure data for 2009 and cancer incidence and mortality rates for 2019, assuming a 10-year lag time between alcohol intake and cancer development and mortality. Findings Of 180,887 (95% Confidence interval [CI]: 160,595-201,705) new alcohol-attributable cancer cases and 85,130 (95% CI: 74,920-95,523) deaths in the WHO European Region in 2019, 5·9% (95% CI: 5·6-6·4) and 5·7% (95% CI: 5·4-6·1), respectively, could have been avoided by increasing excise duties by 100%. According to our model, alcohol-attributable female breast cancer and colorectal cancer contributed most to the avoidable cases and deaths. Interpretation Doubling current alcohol excise duties could avoid just under 6% (or 10,700 cases and 4,850 deaths) of new alcohol-attributable cancers within the WHO European Region, particularly in Member States of the European Union where excise duties are in many cases very low. Funding None.

Graphical abstract, Highlights • Concurrent capecitabine with radiotherapy in painful bone metastases was safe. • It was effective in palliation of pain from bone metastases in breast cancer patients. • It associated with higher overall response rates regarding pain control. • This decreased analgesic consumption and improved the quality of life., Background In breast cancer, painful bone metastases are common. Local radiotherapy is the standard treatment of painful bone metastases. Pain control and overall response rateswere low in radiotherapy alone. The objectives of this study were to compare the safety and efficacy of external beam radiotherapy with concurrent capecitabine vs. external beam radiotherapy alone in pain control of painful bone metastases in breast cancer patients. Materials and methods Eighty-four patients with painful bone metastases from breast cancer participated in this prospective study. We randomized the patients into two groups: group A treated with radiotherapy 30 Gy in 10 fractions and group B treated with capecitabine 825 mg/m2 every 12 hrs. concurrently with the same radiotherapy dose. Results There was no statistically significant difference between the two groups regarding early treatment toxicity. Most of the toxicity was gastrointestinal (diarrhea and nausea) and mild (grade I or II). The median pain score decreased from week one, and there was a marked response at week4. The difference in median pain score between both groups was statistically significant with p-value = 0.045. The median analgesic score in both groups was statistically significant with a p-value = 0.032 at week 12. A complete response to pain at week 4 was 19% and 42.9% in groups A and B, respectively. Conclusion Concurrent chemoradiation in painful bone metastases from breast cancer origin was tolerable and safe; it had a higher overall response rate and pain palliation than radiotherapy alone.

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 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

Highlights • Adoption of adjuvant bisphosphonates for early breast cancer into standard clinical practice. • UK and Australian experience of adjuvant bisphosphonates in early breast cancer. • Pathway taken for adjuvant bisphosphonates implementation in the UK. • Steps to increase update of adjuvant bisphosphonates in early breast cancer. • Improve the care of women with early breast cancer., International guidelines recommend adjuvant bisphosphonates (BPs) for post-menopausal women with early breast cancer to reduce recurrence and mortality. However, globally, wide variation exists in their adoption. In the UK, adjuvant BPs were a recommendation in the breast cancer Clinical Reference Group service specification and were included as a priority for implementation by the national oncologists group UK Breast Cancer Group in November 2015, promoting national uptake, guidance and funding arrangements. In 2018, adjuvant BPs were recommended by the UKs National Institute for Health and Care Excellence. In Australia, adjuvant BPs are still ‘off-label’ and do not receive national reimbursement or endorsement. To date there has been no research into the prescribing habits of these agents in Australia. With the aim to gather data on adjuvant BPs prescribing practices, online surveys were developed and disseminated to breast oncologists in both countries between December 2018 and June 2019. Almost all of the UK oncologists prescribed adjuvant BPs, demonstrating that education, endorsement from professional bodies, presence of national guidelines and funding decisions have been critical to implementation. In contrast, only 48% of the Australian responders prescribed adjuvant BPs, while 83% reported that they would prescribe them if funding was available. Lack of local protocol guidance was also seen as a major barrier. This study was intended to assess the pathway taken for adjuvant BP implementation in the UK and how it might inform changes in Australian practice and also guide other countries with similar issues with the ultimate aim of improving the care of women with early breast cancer globally.

Background Dihydrolipoamide dehydrogenase deficiency (DLDD) is a rare metabolic disorder inherited in an autosomal recessive manner. This heterogeneous disease has a variable clinical presentation, onset, and biochemical markers. Materials and methods We retrospectively reviewed the clinical and molecular diagnosis of eight cases with DLDD from four referral centers in Saudi Arabia. Results Remarkably, we found hepatic involvement ranging from acute hepatic failure to chronic hepatitis in five patients. In addition, neurological disorders in the form of seizures, developmental delay, ataxia, hypotonia and psychomotor symptoms were found in five patients, two of them with a combination of hepatic and neurological symptoms. In addition, only one patient had recurrent episodes of hypoglycemia. While most patients had the hepatic form of homozygous variant c.685G > T in the DLD gene, one patient was found to have a novel variant c.623C > T that had neurological and hepatic symptoms. Conclusions We describe the largest reported DLDD cohort in the Saudi population. Clinical, biochemical, radiological, and molecular characterization was reviewed and no clear genotype-phenotype correlation was found in this cohort.

Growing evidence suggests that oxytocin (OT) plays an important factor for the control of food intake, body weight, and energy metabolism in human and non-human animals. It has reported previously, the downregulation in oxytocin receptors (OTRs) expression is linked with the development of obesity, but exogenous OT reverse body weight and food intake in obese animal model. It is important to know that, whether intraperitoneal administration crosses blood brain barrier. Therefore, in the present experiment, we study the impact of intraperitoneal administration of synthetic OT 0.0116 mg/kg and antagonist atosiban (OTA) 1 mg/kg on food intake, and body weight of female mice, Mus musculus for different duration i.e. 30, 60, and 90 days. In this study, it was observed that there was significant decrease (p

Elevated serum chitotriosidase (CHITO) is an indication of macrophage activation, and its capacity have been explored as a marker of inflammation in a number of disease states. For over a decade, CHITO plasma levels have been used by clinicians as a biomarker of inflammation in the lysosomal disease, Gaucher disease, including monitoring response to therapies in patients with Gaucher disease type I. Although it is becoming increasingly recognized that inflammation is a prominent component of many lysosomal diseases, the relation of CHITO levels to disease burden has not been well-characterized in the large majority of lysosomal diseases. Moreover, the role of CHITO in lysosomal diseases that affect the central nervous system (CNS) has not been systematically studied. In this study, one hundred and thirty-four specimens of CSF and serum were collected from 34 patients with lysosomal diseases affecting the CNS. This study included patients with GM1-gangliosidosis, GM2-gangliosidosis, mucopolysaccharidoses (MPS), multiple sulfatase deficiency and Gaucher disease. CHITO levels in the CSF were significantly higher in patients with more rapidly progressing severe neurological impairment: GM1-gangliosidosis vs MPS (p

The burden of anemia in Senegal is high, particularly in children and women in rural households. The main objectives of the study reported here were (i) to measure and compare the prevalence of anemia and intestinal parasitic infections in farmers and family members and sheep in two agro-ecological zones in Senegal and (ii) to examine the association between anemia and age or sex in farmers and family members. The study was conducted in Mpal (250 km from Dakar, the capital city) and Diawara (700 km from Dakar, a remote location near the Malian border). In humans, the prevalence of anemia was higher in Diawara (64/86 = 74%), compared to Mpal (13/29 = 45%) (p

International audience; Mitochondrial malate dehydrogenase (MDH2) deficiency (MDH2D) is an ultra-rare disease with only three patients described in literature to date. MDH2D leads to an interruption of the tricarboxylic acid (TCA) cycle and malate-aspartate shuttle (MAS) and results in severe early onset encephalopathy. Affected infants suffer from psychomotor delay, muscular hypotonia and frequent seizures. Laboratory findings are unspecific, including elevated lactate in blood and cerebrospinal fluid. Brain magnetic resonance imaging reveals delayed myelination and brain atrophy. Currently there is no curative therapy to treat this devastating disease.Here, we present a female patient diagnosed with MDH2D after a stroke-like episode at 18 months. Trio-whole exome sequencing revealed compound heterozygous missense variants in the MDH2 gene: c.398C>T, p.(Pro133Leu) and c.445delinsACA, p.(Pro149Hisfs*22). MDH2 activity assay and oxygraphic analysis in patient's fibroblasts confirmed the variants were pathogenic. At the age of 36 months, a drug trial with triheptanoin was initiated and well tolerated. The patient's neurologic and biochemical phenotype improved and she had no further metabolic decompensations during the treatment period suggesting a beneficial effect of triheptanoin on MDH2D.Further preclinical and clinical studies are required to evaluate triheptanoin treatment for MDH2D and other TCA cycle and MAS defects.

COVID-19; Mortality comparison; Pneumonia COVID-19; Comparación de la mortalidad; Neumonía COVID-19; Comparació de la mortalitat; Pneumònia Background It is unclear whether the changes in critical care throughout the pandemic have improved the outcomes in coronavirus disease 2019 (COVID-19) patients admitted to the intensive care units (ICUs). Methods We conducted a retrospective cohort study in adults with COVID-19 pneumonia admitted to 73 ICUs from Spain, Andorra and Ireland between February 2020 and March 2021. The first wave corresponded with the period from February 2020 to June 2020, whereas the second/third waves occurred from July 2020 to March 2021. The primary outcome was ICU mortality between study periods. Mortality predictors and differences in mortality between COVID-19 waves were identified using logistic regression. Findings As of March 2021, the participating ICUs had included 3795 COVID-19 pneumonia patients, 2479 (65·3%) and 1316 (34·7%) belonging to the first and second/third waves, respectively. Illness severity scores predicting mortality were lower in the second/third waves compared with the first wave according with the Acute Physiology and Chronic Health Evaluation system (median APACHE II score 12 [IQR 9–16] vs 14 [IQR 10–19]) and the organ failure assessment score (median SOFA 4 [3–6] vs 5 [3–7], p

Objective: To determine point prevalence of postpartum depression (PPD) and whether quarantine policies required in postpartum COVID-19 suspects increased the risk of depressive symptoms when compared COVID -19 non suspects in early postpartum period. Methods: A cross-sectional study conducted in the postnatal ward of Lady Hardinge Medical College and Smt. Sucheta Kriplani Hospital, New Delhi from August 2020 to February 2021 using Edinburgh Postnatal Depression Scale (EPDS) to estimate point prevalence of postpartum depression (PPD) in the stratified zones (suspect and nonsuspect) of the hospital. Results: Total of 408 postpartum women,204 each (COVID-19 suspects, and nonsuspects zone) were enrolled. Prevalence of Postpartum depression using an EDPS score of >9 was 11.9%. Prevalence of depression (17.9%; vs 4.85%, p

Background: Previous studies showed that caregivers of children with autism spectrum disorder (ASD) and other developmental disorders had higher levels of parenting stress, anxiety and depression. In the present study, the author examined the caregivers' mental health and investigated the mediating role of social support between symptoms severity and parenting stress during COVID-19. Methods: During 20 March to 8 April 2020, 1932 caregivers of children and adolescents with ASD and other developmental disorders from China were enrolled to fill in a sociodemographic questionnaire, Depression, Anxiety and Stress Scale and Social Support Rating Scale. The author also collected children's disability severity symptoms and behavioral problems. Results: The results showed that 46.01% of the caregivers reported symptoms of depression, 44.67% showed anxiety and 44.62% showed stress during COVID-19 pandemic. Fathers were found to get more subjective support than mothers (P

Highlights • In older AF patients, representative AF-related outcomes compete, causing difficulty in decision making. • We proposed cluster analysis using risk probability for four AF-related outcomes. • Older adults with AF were classified into 3 clusters. • The clusters could possibly identify older adults with AF with good/poor responses to AF-related treatment., Background Older adults with atrial fibrillation (AF) have highly diverse risk levels for mortality, heart failure (HF), thromboembolism (TE), and major bleeding (MB), thus an integrated risk-pattern algorithm is warranted. Methods We analyzed 573 AF patients aged ≥ 75 years from our single-center cohort (Shinken Database 2010–2018). The 3-year risk scores (risk probability) for mortality (M-score), HF (HF-score), TE (TE-score), and MB (MB-score) were estimated for each patient by logistic regression analysis. Using the four risk scores, cluster analysis was performed with Ward’s linkage hierarchical algorithm. Results Three clusters were identified: Clusters 1 (n = 429, 74%), 2 (n = 24, 5%), and 3 (n = 120, 21%). The clusters were characterized as standard risk (Cluster 1), high TE- and MB-risk (Cluster 2), and high M- and HF-risk (Cluster 3). Oral anticoagulants were prescribed for over 80% of the patients in each cluster. Catheter ablation for AF was performed only in Cluster 1 (8.9%). Compared with Cluster 1, Cluster 2 was more closely associated with males, asymptomatic AF, history of cerebral infarction or transient ischemic attack, history of intracranial hemorrhage, high HAS-BLED score (≥3), and low body mass index (

Background Clinical scores for sepsis have been primarily developed for, and applied in High-Income Countries. This systematic review and meta-analysis examined the performance of the quick Sequential Organ Failure Assessment (qSOFA), Systemic Inflammatory Response Syndrome (SIRS), Modified Early Warning Score (MEWS), and Universal Vital Assessment (UVA) scores for diagnosis and prediction of mortality in patients with suspected infection in Low-and-Middle-Income Countries. Methods PubMed, Science Direct, Web of Science, and the Cochrane Central Register of Controlled Trials databases were searched until May 18, 2021. Studies reporting the performance of at least one of the above-mentioned scores for predicting mortality in patients of 15 years of age and older with suspected infection or sepsis were eligible. The Quality Assessment of Diagnostic Accuracy Studies tool was used for risk-of-bias assessment. PRISMA guidelines were followed (PROSPERO registration: CRD42020153906). The bivariate random-effects regression model was used to pool the individual sensitivities, specificities and areas-under-the-curve (AUC). Findings Twenty-four articles (of 5669 identified) with 27,237 patients were eligible for inclusion. qSOFA pooled sensitivity was 0·70 (95% confidence interval [CI] 0·60–0·78), specificity 0·73 (95% CI 0·67–0·79), and AUC 0·77 (95% CI 0·72–0·82). SIRS pooled sensitivity, specificity and AUC were 0·88 (95% CI 0·79 -0·93), 0·34 (95% CI 0·25–0·44), and 0·69 (95% CI 0·50–0·83), respectively. MEWS pooled sensitivity, specificity and AUC were 0·70 (95% CI 0·57 -0·81), 0·61 (95% CI 0·42–0·77), and 0·72 (95% CI 0·64–0·77), respectively. UVA pooled sensitivity, specificity and AUC were 0·49 (95% CI 0·33 -0·65), 0·91(95% CI 0·84–0·96), and 0·76 (95% CI 0·44–0·93), respectively. Significant heterogeneity was observed in the pooled analysis. Interpretation Individual score performances ranged from poor to acceptable. Future studies should combine selected or modified elements of different scores. Funding Partially funded by the UK National Institute for Health Research (NIHR) (17/63/42).

Adropin is a highly-conserved peptide that has been shown to preserve endothelial barrier function. Blood-brain barrier (BBB) disruption is a key pathological event in cerebral ischemia. However, the effects of adropin on ischemic stroke outcomes remain unexplored. Hypothesizing that adropin exerts neuroprotective effects by maintaining BBB integrity, we investigated the role of adropin in stroke pathology utilizing loss- and gain-of-function genetic approaches combined with pharmacological treatment with synthetic adropin peptide. Long-term anatomical and functional outcomes were evaluated using histology, MRI, and a battery of sensorimotor and cognitive tests in mice subjected to ischemic stroke. Brain ischemia decreased endogenous adropin levels in the brain and plasma. Adropin treatment or transgenic adropin overexpression robustly reduced brain injury and improved long-term sensorimotor and cognitive function in young and aged mice subjected to ischemic stroke. In contrast, genetic deletion of adropin exacerbated ischemic brain injury, irrespective of sex. Mechanistically, adropin treatment reduced BBB damage, degradation of tight junction proteins, matrix metalloproteinase-9 activity, oxidative stress, and infiltration of neutrophils into the ischemic brain. Adropin significantly increased phosphorylation of endothelial nitric oxide synthase (eNOS), Akt, and ERK1/2. While adropin therapy was remarkably protective in wild-type mice, it failed to reduce brain injury in eNOS-deficient animals, suggesting that eNOS is required for the protective effects of adropin in stroke. These data provide the first causal evidence that adropin exerts neurovascular protection in stroke through an eNOS-dependent mechanism. We identify adropin as a novel neuroprotective peptide with the potential to improve stroke outcomes., Graphical abstract Image 1, Highlights • Ischemic stroke decreases endogenous adropin levels in the brain and plasma. • Adropin treatment improves stroke outcomes in young and aged mice. • Adropin genetic deletion exacerbates stroke injury. • Stroke-induced blood-brain barrier disruption is prevented by adropin. • Mechanistically, adropin reduces stroke damage through an eNOS-dependent pathway.

Objectives The purpose of this study was to identify a relationship between the background environment, bystander and emergency medical services intervention, and favourable neurological outcomes (CPC1-2) one-month after out-of-hospital cardiac arrest (OHCA) occurred at Tokyo train and subway stations. Methods This retrospective observational study used OHCA data between 2014 and 2018 that occurred at train stations in Tokyo. The eligible 954 patients were analysed for correlation between background, time frame, and location. Multivariable logistic regression models were used to estimate factors associated with CPC1-2 in patients with cardiogenic OHCA. Results A total of 886 OHCA cases, cardiogenic (n=562) and non-cardiogenic (n=324), met the inclusion criteria. Of the cardiogenic cases, 71.9% occurred at the platform and on-a-train. One-month CPC1-2 was achieved in 32.0% of cardiogenic OHCAs, which included 47.3% during morning rush hour, 24.7% during daytime hours, 40.2% during evening rush hour, and 20.5% during night-time/early morning hours. CPC1-2 had significant correlation with morning rush hour (adjusted odds ratio [AOR],4.52; 95% confidence interval [CI], 1.09–18.78), evening rush hour (AOR, 6.85; 95% CI, 1.51–31.15), public access defibrillation (AOR, 5.19; 95% CI, 1.38–19.51), and ventricular fibrillation or pulseless ventricular tachycardia (AOR, 7.56; 95% CI, 1.35–42.43). Conclusion A total of 71.9% of cardiogenic OHCAs occurred at platforms and on trains. To improve neurological outcomes of OHCAs at stations, AED installations on train platforms are necessary. Additionally, using artificial intelligence-based platform monitoring for early detection of OHCAs and offering CPR training are required.

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.

Highlights • Medical students are a risk population for many infectious diseases, which leads to their being included in health-staff vaccination recommendations. • There is an increasing noncompliance with vaccination programs, especially in the last decade, which can have also affected medical students’ immunization status and personal beliefs about this theme. Few studies have gauged student awareness of these programs and their effect in vaccination status along the medical course. • After being submitted to an electronic questionnaire, 74,7% Brazilian students were found to have incomplete vaccination in some way, with Pertussis, Varicella, and Influenza as the highest noncompliance rates. There was an increase in vaccination status toward the end of the course, though still far from optimal. • Main reasons given not to vaccinate were vaccination hesitancy (for influenza and varicella), and lack of awareness of the need to vaccinate (for pertussis)., Health workers are a risk population for many infectious diseases, which leads to a number of vaccines being routinely recommended for health care staff. Medical students are also prone to such hazards. This study accesses undergraduate medicine students’ compliance to recommended health-staff vaccination, and their reasons for noncompliance. Method An online questionnaire was sent to all undergraduates in a major public medical school in Brazil, asking about vaccination status to Hepatitis B, Measle-mumps-rubella, Varicella, Pertussis and Influenza, and reasons in case of noncompliance Results 146 students answered the questionnaire, (response rate 14,6%). Overall vaccination status showed 74,7% of students with incomplete vaccination in some way, with an increase in vaccination status toward the end of the course. The highest noncompliance rates were Pertussis (49,3%), Varicella (47,3%) and Influenza (30,1%) vaccines. The vaccine with the lowest noncompliance rate was measles (9,6%). During the course, the greatest increases in adequate vaccination status were Hepatitis B, from 53,2% in first-years to 93,2% by the end sixth year (chi-sq 21, p

Gaucher disease is renowned for extreme phenotypic diversity that does not show consistent genotype/phenotype correlations. In Argentina, a national collaborative group, Grupo Argentino de Diagnóstico y Tratamiento de la Enfermedad de Gaucher, GADTEG, delineated uniformly severe type 1 Gaucher disease manifestations presenting in childhood with large burden of irreversible skeletal disease. Here using Long-Read Single Molecule Real-Time (SMRT) Sequencing of GBA1 locus, we show that the RecNciI allele is highly prevalent and it is associated with severe skeletal manifestations with onset in childhood or in young adults. Additionally, we described novel GBA1 variants not previously described.

Background: It is important to identify further predictors of outcome after successful transcatheter mitral valve repair (TMVR), as optimal patient selection remains difficult. Objective: The study investigates the prognostic benefit of the mean arterial pressure (MAP) to right atrial pressure (RAP) ratio (MAP/RAP ratio) after successful TMVR in patients with congestive heart failure (CHF) and severe mitral regurgitation (MR). Method: Patients with CHF and severe MR were enrolled after successful TMVR (MR ≤ 2+ at discharge). The primary endpoint was a composite of all-cause mortality or hospitalisation for heart failure. The median follow-up time was 16 ± 9 months. Receiver Operating Characteristic (ROC) analysis was applied to assess the discriminatory power of the MAP/RAP ratio. The predictive value of the MAP/RAP ratio threshold was investigated using a Kaplan-Meier analysis. Multivariable logistic regression analysis was conducted to evaluate independent risk factors for the combined primary endpoint. Results: 145 patients (median age 76 [69–80 years], 60.3% male) were included. ROC curve analysis showed that MAP/RAP ratio was associated with an area under the curve of 0.62 (95% confidence interval (CI) 0.53–0.71; p = 0.01). A MAP/RAP ratio threshold of 7.13 was associated with 67.4% sensitivity and 57.0% specificity for the combined primary endpoint. Event-free survival was significantly lower in the MAP/RAP ratio

Globally, effective emergency response to disease outbreaks is usually affected by weak coordination. However, coordination using an incident management system (IMS) in line with a One Health approach involving human, environment, and animal health with collaborations between government and non-governmental agencies result in improved response outcome for zoonotic diseases such as Lassa fever (LF). We provide an overview of the 2019 LF outbreak response in Nigeria using the IMS and One Health approach. The response was coordinated via ten Emergency Operation Centre (EOC) response pillars. Cardinal response activities included activation of EOC, development of an incident action plan, deployment of One Health rapid response teams to support affected states, mid-outbreak review and after-action review meetings. Between 1st January and 29th December 2019, of the 5057 people tested for LF, 833 were confirmed positive from 23 States, across 86 Local Government Areas. Of the 833 confirmed cases, 650 (78%) were from hotspot States of Edo (36%), Ondo (26%) and Ebonyi (16%). Those in the age-group 21–40 years (47%) were mostly affected, with a male to female ratio of 1:1. Twenty healthcare workers were affected. Two LF naive states Kebbi and Zamfara, reported confirmed cases for the first time during this period. The outbreak peaked earlier in the year compared to previous years, and the emergency phase of the outbreak was declared over by epidemiological week 17 based on low national threshold composite indicators over a period of six consecutive weeks. Multisectoral and multidisciplinary strategic One Health EOC coordination at all levels facilitated the swift containment of Nigeria's large LF outbreak in 2019. It is therefore imperative to embrace One Health approach embedded within the EOC to holistically address the increasing LF incidence in Nigeria.

Background: \ud Understanding the mental health consequences of child maltreatment at different life stages is important in accurately quantifying the burden of maltreatment. This study investigated the association between child maltreatment and incident mental disorders in middle and older age as well as the potential mediators and moderators.\ud \ud Methods: \ud This is a retrospective cohort study of 56,082 participants from UK Biobank. Child maltreatment was recalled using the Childhood Trauma Screener. Incident mental disorders, including depressive, anxiety and affective disorders, behavioural syndromes, post-traumatic stress disorder (PTSD), schizophrenia, substance abuse, and dementia, after baseline assessment were ascertained through linkage to primary care records.\ud \ud Findings: \ud There was a dose-response relationship between child maltreatment and mental disorder. Those who experienced three or more maltreatment types had the highest risk of all mental disorders (HR 1.85, 95% CI: 1.67-2.06) followed by those who experienced two (HR 1.48, 95% CI: 1.35-1.63) and then one (HR 1.26, 95% CI: 1.19-2.35). Child maltreatment was most strongly associated with PTSD (HR 1.59, 95% CI: 1.20-2.10 P=0.001). The excess risk was largely unexplained by the included mediators. The association between child maltreatment and all mental disorders were stronger among participants who binge drank (Pinteraction=0.003) or had few social visits (Pinteraction=0.003).\ud \ud Interpretation: \ud The mental health consequence of child maltreatment could last decades, even among those who had no recorded mental disorders in early adulthood. In the absence of strong mediators, prevention of child maltreatment remains the priority.\ud \ud Funding: \ud Wellcome Trust Institutional Strategic Support Fund.

Highlights • Applicability of GAIA definitions were assessed using medical records in LMICs. • LBW, preterm birth and neonatal death definitions were applicable in the field. • SGA, stillbirth, neonatal infection, congenital microcephaly definitions were less applicable. • Suggestions to the improvement in GAIA definitions were made. • Better documentation of maternal immunization is suggested for vaccine-safety studies., Standardized case definitions strengthen post-marketing safety surveillance of new vaccines by improving generated data, interpretation and comparability across surveillance systems. The Global Alignment of Immunization Safety Assessment in Pregnancy (GAIA) project developed standardized case definitions for 21 key obstetric and neonatal terms following the Brighton Collaboration (BC) methodology. In this prospective cohort study, we assessed the applicability of GAIA definitions for maternal immunization exposure and for low birth weight (LBW), preterm birth, small for gestational age (SGA), stillbirth, neonatal death, neonatal infection, and congenital microcephaly. We identified the missing data elements that prevented identified cases and exposures from meeting the case definition (level 1–3 of BC diagnostic certainty). Over a one-year period (2019–2020), all births occurring in 21 sites (mostly secondary and tertiary hospitals) in 6 Low Middle Income Countries and 1 High Income Country were recorded and the 7 perinatal and neonatal outcome cases were identified from routine medical records. Up to 100 cases per outcome were recruited sequentially from each site. Most cases recruited for LBW, preterm birth and neonatal death met the GAIA case definitions. Birth weight, a key parameter for all three outcomes, was routinely recorded at all sites. The definitions for SGA, stillbirth, neonatal infection (particularly meningitis and respiratory infection) and congenital microcephaly were found to be less applicable. The main barrier to obtaining higher levels of diagnostic certainty was the lack of sonographic documentation of gestational age in first or second trimester. The definition for maternal immunization exposure was applicable, however, the highest level of diagnostic certainty was only reached at two sites. Improved documentation of maternal immunization will be important for vaccine safety studies. Following the field-testing of these 8 GAIA definitions, several improvements are suggested that may lead to their easier implementation, increased standardization and hence comparison across studies.

Background Neoadjuvant chemoradiotherapy (NCRT) or neoadjuvant chemotherapy (NCT) followed by surgery are two standard strategies in treating locally advanced esophageal cancer (EC). We aim to compare NCRT and NCT in the management of locally advanced EC patients. Methods MEDLINE, Embase, CENTRAL, and conferences were systematically searched for clinical trials published up to September 2021. Pairwise comparisons and Bayesian network meta-analyses were conducted to compare overall survival (OS) and disease-free survival (DFS) by reporting the hazard ratio (HR) and 95% credible intervals (CrIs). The study was registered at PROSPERO (CRD42020170619). Findings 25 trials with 4563 EC patients met inclusion criteria. NCRT improved OS (HR: 0·72, 95%CrI: 0·63–0·82) and DFS (HR: 0·72, 95%CrI: 0·63–0·81) compared to surgery alone. NCRT improved OS (HR: 0·83, 95%CrI: 0·69–0·99) and DFS (HR: 0·83, 95%CI: 0·69–0·99) compared to NCT. Subgroup analysis demonstrated that both NCRT (HR: 0·77, 95%CrI: 0·65–0·90) and NCT (HR: 0·81, 95%CrI: 0·67–0·99) improved OS than surgery in esophageal squamous cell carcinoma (ESCC) patients. No significant differences were observed between NCRT and NCT regarding OS (HR: 0·95, 95%CrI: 0·75–1·19) and DFS (HR: 0·90, 95%CrI: 0·50–1·62) in ESCC. The short-term outcomes were similar between NCRT and NCT. The three treatment strategies were comparable in esophageal adenocarcinoma (EAC) subpopulations. Interpretation The study corroborated current guidelines in addressing the importance of analysing EC according to histopathological types. The analysis suggested that in locally advanced ESCC patients, both NCRT and NCT improved OS as compared to surgery alone, whereas no clear evidence supported the optimal strategies between NCRT and NCT. More RCTs comparing different therapeutic strategies in EAC patients are warranted. Funding Koln Fortune Program, University of Cologne.

Background Cognitive function among apparently healthy adolescents has been associated with cardiovascular morbidity and mortality. We examined the relationship between global and subdomain cognitive scores in adolescence and early-onset type 2 diabetes (T2D) in men and women. Methods A nationwide, population-based study of 971,677 Israeli born adolescents (56% men; mean age 17.4 years) who were medically examined and their cognitive performance was assessed before compulsory military service during 1992–2010. Data included global and subdomain cognitive Z-scores (problem-solving, verbal abstraction and categorization, verbal comprehension, and mathematical abilities). Data were linked to the Israeli National Diabetes Registry. The relations between global and subdomain scores and incident T2D was determined using Cox proportional hazard models and logistic regression models. Analyses were conducted separately for men and women. Findings During 16,095,122 person-years, 3,570 individuals developed T2D. After adjustment, those in the low compared to the high quintile of global cognitive Z-score had the highest risk for T2D; HR 2.46, (95% CI 2.10–2.88) for men and 2.33 (95% CI 1.88–2.89) for women. A one-unit lower global cognitive Z-score was associated with 1.41 (95% CI 1.34–1.48) and 1.46 (95% CI 1.36–1.56) increased risks for men and women, respectively. The relationship was noted for the cognitive subdomains scores as well as for the global cognitive score, with no heterogeneity across cognitive subdomains. Interpretation This large nationally representative cohort suggests relationship between global, as well as subdomain cognitive scores in late adolescence, and incident early onset T2D in both sexes, which was independent of socioeconomic status. Funding None.

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.