Search

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.

Objective: Registries are important data sources for randomised controlled trials (RCTs), but reporting of how they are used may be inadequate. The objective was to describe the current adequacy of reporting of RCTs using registries. Study Design and Setting: We used a database of trials using registries from a scoping review supporting the development of the 2021 CONSORT extension for Trials Conducted Using Cohorts and Routinely Collected Data (CONSORT-ROUTINE). Reporting completeness of 13 CONSORT-ROUTINE items was assessed. Results: We assessed reports of 47 RCTs that used a registry, published between 2011 and 2018. Of the 13 CONSORT-ROUTINE items, 6 were adequately reported in at least half of reports (2 in at least 80%). The 7 other items were related to routinely collected data source eligibility (32% adequate), data linkage (8% adequate), validation and completeness of data used for outcome assessment (8% adequate), validation and completeness of data used for participant recruitment (0% adequate), participant flow (9% adequate), registry funding (6% adequate) and interpretation of results in consideration of registry use (25% adequate). Conclusion: Reporting of trials using registries was often poor, particularly details on data linkage and quality. Better reporting is needed for appropriate interpretation of the results of these trials. Keywords: registries, CONSORT, CONSORT-ROUTINE, randomised controlled trials, reporting guideline, routinely collected data Running Title: Completeness and Transparency of Reporting of RCTs using Registries

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

Objective Clinicians may use implicit or explicit motor learning approaches to facilitate motor learning of patients with stroke. Implicit motor learning approaches have shown promising results in healthy populations. The purpose of this study was to assess whether an implicit motor learning walking intervention is more effective compared with an explicit motor learning walking intervention delivered at home regarding walking speed in people after stroke in the chronic phase of recovery. Methods This randomized, controlled, single-blind trial was conducted in the home environment. The 79 participants, who were in the chronic phase after stroke (age = 66.4 [SD = 11.0] years; time poststroke = 70.1 [SD = 64.3] months; walking speed = 0.7 [SD = 0.3] m/s; Berg Balance Scale score = 44.5 [SD = 9.5]), were randomly assigned to an implicit (n = 38) or explicit (n = 41) group. Analogy learning was used as the implicit motor learning walking intervention, whereas the explicit motor learning walking intervention consisted of detailed verbal instructions. Both groups received 9 training sessions (30 minutes each), for a period of 3 weeks, targeted at improving quality of walking. The primary outcome was walking speed measured by the 10-Meter Walk Test at a comfortable walking pace. Outcomes were assessed at baseline, immediately after intervention, and 1 month postintervention. Results No statistically or clinically relevant differences between groups were obtained postintervention (between-group difference was estimated at 0.02 m/s [95% CI = −0.04 to 0.08] and at follow-up (between-group difference estimated at −0.02 m/s [95% CI = −0.09 to 0.05]). Conclusion Implicit motor learning was not superior to explicit motor learning to improve walking speed in people after stroke in the chronic phase of recovery. Impact To our knowledge, this is the first study to examine the effects of implicit compared with explicit motor learning on a functional task in people after stroke. Results indicate that physical therapists can use (tailored) implicit and explicit motor learning strategies to improve walking speed in people after stroke who are in the chronic phase of recovery.

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

Exercise can reduce the incidence of stress-related mental diseases, such as depression and anxiety. Control group was neither exposed to CVMS nor TRE (noCVMS/noTRE). Females were tested and levels of serum17-beta-oestradiol (E2), estrogen receptors α immunoreactive neurons (ERα-IRs), estrogen receptors β immunoreactive neurons (ERβ-IRs) and oxytocin immunoreactive neurons (OT-IRs) were measured. The results showed there’s increased anxiety-like behaviors for mice from CVMS/noTRE, CVMS/higher speed TRE (CVMS/HTRE) and noCVMS/HTRE groups when they were put in open field and elevated maze tests. They had lower serum E2 levels than mice from CVMS/low-moderate speed TRE (CVMS/LMTRE), noCVMS/LMTRE and noCVMS/noTRE groups. The three groups of CVMS/noTRE, CVMS/HTRE and noCVMS/HTRE mice had more ERα-IRs and less ERβ-IRs in the medial preoptic area (mPOA), bed nucleus of the stria terminalis (BNST) and medial amygdala (MeA), hypothalamic paraventricular nucleus (PVN) and supraoptic nucleus (SON). The number of OT-IRs in PVN and SON of CVMS/noTRE, CVMS/HTRE and noCVMS/HTRE mice was also lower than that of mice from CVMS/LMTRE, noCVMS/LMTRE and noCVMS/noTRE groups. Interestingly, CVMS/LMTRE and noCVMS/LMTRE mice were similar to noCVMS/noTRE mice in that they did not show anxiety, while CVMS/HTRE and noCVMS/HTRE mice did not, which were similar to the mice in CVMS/noTRE. We propose that LMTRE instead of HTRE changes the serum concentration of E2. ERβ/ERα ratio and OT level in the brain may be responsible for the decrease in anxiety-like behavior in female mice exposed to anxiety-inducing stress conditions., Highlights • CVMS/LMTRE did not show anxiety. • noCVMS/LMTRE did not show anxiety. • ERβ/ERα ratio decreas anxiety. • OT decreas anxiety.

Probiotics that regulate the microbiome-gut-brain axis and provide mental health benefits to the host are referred to as psychobiotics. Preclinical studies have demonstrated psychobiotic effects on early life stress-induced anxiety- and depression-related behavior in rodents; however, the specific mechanisms remain ill-defined. In the current study, we investigated the effects of probiotic supplementation on neurobiological responses to chronic stress in adult male Long-Evans rats. Twenty-four rats were randomly assigned to probiotic (PB) or vehicle control (VEH) groups, then to either chronic unpredictable stress (CUS) or no-stress control (CON) conditions within each group (n = 6/subgroup). We hypothesized that PB supplementation would reduce markers of anxiety and enhance emotional resilience, especially in the CUS animals. In the cognitive uncertainty task, a nonsignificant trend was observed indicating that the PB-supplemented animals spent more time oriented toward the food reward than VEH animals. In the open-field task, CUS-PB animals spent more time in the center of the arena than CUS-VEH animals, an effect not observed between the two CON groups. In the swim task, the PB animals, regardless of stress assignment, exhibited increased floating, suggesting a conserved response in a challenging context. Focusing on the endocrine measures, higher dehydroepiandrosterone (DHEA)-to-corticosterone fecal metabolite ratios, a correlate of emotional resilience, were observed in PB animals. Further, PB animals exhibited reduced microglia immunoreactivity in the basolateral amygdala, possibly indicating a neuroprotective effect of PB supplements in this rodent model. These results provide evidence that PB supplementation interacts with stress exposure to influence adaptive responses associated with endocrine, neural, and behavioral indices of anxiety.

Purpose The purpose of this study is to examine the effects of fatigue on muscular performance, oxygenation saturation, and cognition following acute hypoxic exposure at Normoxia, Moderate Hypoxia (MH), and Severe Hypoxia (SH). Methods Twelve males performed 3 sets of leg extensions to failure under Normoxia (FiO2: 21%), MH (Fi02: 15.4%), and SH (Fi02: 12.9%). Heart rate, peripheral oxygenation saturation, total saturation index, psychomotor vigilance testing reaction time, psychomotor vigilance error rate, maximum strength, and repetitions to failure were measured throughout each visit. Results The primary findings indicated that MH and SH resulted in significant decreases in psychomotor vigilance test performance (MH: 388.25–427.17 ms, 0.41–0.33 error rate; SH: 398.17–445.42 ms reaction time, 0.25–1.00 error rate), absolute muscle tissue oxygen saturation (Abs-StO2) (MH:67.22% compared to SH:57.56%), but similar muscular strength, heart rate, and patterns of muscle tissue oxygen saturation responses (StO2%) during fatigue when compared to Normoxia. There was an acute decrease in the ability to remain vigilant and/or respond correctly to visual stimuli as indicated by the worsened reaction time (PVTRT) during MH (FiO2: 15.4%) and increased PVTRT and error rate (PVTE) during SH (FiO2: 12.9%) conditions. Conclusions Acute hypoxic exposure in the current study was not a sufficient stimuli to elicit hypoxic-related changes in HR, muscular strength (1-RM), or repetitions to failure. The SpO2 responses were hypoxic-level dependent with increasing levels of hypoxia resulting in greater and more sustained reductions in SpO2. The combined SpO2 and StO2 responses at MH and SH suggested a balance between the muscles metabolic demand remaining lower than the muscle oxygen diffusion capacity. During the SH condition, Abs-StO2 suggested greater metabolic stress than Normoxia and MH conditions during the fatiguing leg extensions. The patterns of responses for StO2% during the three sets of leg press to failure indicated that exercise is a more potent influencer to muscle oxygenation status than hypoxic conditions (FiO2: 15.4 and 12.9%)., Graphical abstract Image 1, Highlights • Moderate Hypoxia (FiO2: 15.4%) coupled with fatigue resulted in a decrease in reaction time. • Severe Hypoxia (FiO2: 12.9%) coupled with fatigue resulted in increased error rate and a decrease in reaction time. • Fatigue was the primary influencer on heart rate, muscular strength, and muscular endurance and not hypoxic exposure. • Severe Hypoxia (FiO2: 12.9%) resulted in greatly reduced muscle tissue oxygenation saturation before and after fatigue.

In the current study, we aimed to investigate the network structure of COVID-19 symptoms and its related psychiatric symptoms, using a network approach. Specifically, we examined how COVID-19 symptoms relate to psychiatric symptoms and highlighted potential pathways between COVID-19 severity and psychiatric symptoms. With a sample of six hundred seventy-five recovered COVID-19 patients recruited 1 month after hospital discharge, we respectively integrated COVID-19 symptoms with PTSD, depression, and anxiety symptoms and analyzed the three network structures. In all three networks, COVID-19 severity and ICU admission are not linked directly to COVID-19 symptoms after hospitalization, while COVID-19 severity (but not ICU admission) is linked directly to one or more psychiatric symptoms. Specific pathways between COVID-19 symptoms and psychiatric symptoms were discussed. Finally, we used directed acyclic graph estimation to show potential causal effects between COVID-19 related variables and demographic characteristics.

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.

Objective Sprint-interval training (SIT) and intermittent fasting are effective independent methods in achieving clinical health outcomes. However, the impact of both modalities when performed concurrently is unclear. The aim of this study was to compare the effects of 6 weeks of SIT performed in the fasted versus fed state on physiological and clinical health markers in healthy adults. Methods. Thirty recreationally-active participants were equally randomised into either the fasted (FAS; 4 males, 11 females) or the fed (FED; 6 males, 9 females) group. For all exercise sessions, FAS participants had to fast ≥10 h prior to exercising while FED participants had to consume food within 3 h to exercise. All participants underwent three sessions of SIT per week for 6 weeks. Each session consists of repeated bouts of 30-s Wingate Anaerobic cycle exercise. Pre- and post-training peak oxygen uptake (VO2peak), isokinetic leg strength, insulin sensitivity, blood pressure and serum lipid levels were assessed. Results. There were no differences in baseline physiological and clinical measures between both groups (all p > 0.05). VO2peak improved by 6.0 ± 8.8% in the FAS group and 5.3 ± 10.6% in the FED group (both p 0.05). A similar pattern of results was seen for knee flexion maximum voluntary contraction at 300°·s−1. SIT training in either fasted or fed state had no impact on insulin sensitivity (both p > 0.05). There was significant reduction in diastolic blood pressure (8.2 ± 4.2%) and mean arterial pressure (7.0 ± 3.2%) in the FAS group (both p 0.05). Conclusion. VO2peak and leg strength improved with SIT regardless of whether participants trained in the fasted or fed state. Chronic SIT in the fasted state may potentially reduce blood pressure to a greater extent than the same chronic SIT in the fed state., Highlights • SIT in the fasted state leads to a significant decrease in blood pressure. • VO2peak and leg strength improves with SIT, regardless of nutrition status. • SIT, performed in fasted or fed state, does not improve insulin sensitivity, body fat percentage or lipid profile.

Purpose The present study examined acute normobaric hypoxic exposure on the number of repetitions to failure, electromyographic (EMG) repetition duration (Time), EMG root mean square (RMS) and EMG mean power frequency (MPF) during biceps brachii (BB) dynamic constant external resistance (DCER) exercise. Methods Thirteen subjects performed two sets of fatiguing DCER arm curl repetitions to failure at 70% of their one repetition maximum under normoxic (NH), moderate hypoxia FiO2 = 15% (MH) and severe hypoxia FiO2 = 13% (SH). Electromyography of the BB was analyzed for EMG Time, EMG RMS, and EMG MPF. Repetitions were selected as 25%, 50%, 75%, and 100% of total repetitions (%Fail) completed. Pulse oximetry (SpO2) was measured pre-and post-fatigue. Results There was no significant three-way (Condition x Set x %Fail) or two-way (Condition x Set) interaction for any variable. The number of repetitions to failure significantly decreased from (mean ± SEM) 18.2 ± 1.4 to 9.5 ± 1.0 with each Set. In addition, EMG Time increased (25% 75%>100%), and EMG MPF decreased (75% > 100%) as a result of fatiguing exercise. SpO2 was lower during MH (Δ5.3%) and SH (Δ9.2%) compared to NH and as a result of fatiguing exercise increased only in MH (Δ2.1%) and SH (Δ5.7%). Conclusion The changes in BB EMG variables indicated exercise caused myoelectric manifestations of fatigue, however, acute moderate or severe hypoxia had no additional influence on the rate of fatigue development or neuromuscular parameters., Highlights • Acute MH (FiO2 15%) and SH (FiO2 14%) did not alter the muscle contractile process. • Arm curl repetitions to failure decreased MU recruitment and conduction velocity. • EMG fatigue analysis, hypoxia and arm curls to failure, EMG RMS, EMG MPF and Time. • SpO2 was lower at MH and SH which increased following fatiguing exercise.

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.

Most studies examining sleep in mammals are done under controlled conditions in laboratory/zoological facilities with few studies being conducted in their natural environment. It is not always possible to record sleep polysomnographically (PSG) from animals in their natural environments, as PSG is invasive, requiring the surgical implantation of electrodes on the surface of the brain. In contrast, actigraphy (ACT) has been shown to be a minimally-invasive method to objectively measure overall sleep times in some mammals, although not revealing specific sleep states. The aim of this study is two-fold, first, to measure sleep polysomnographically in free-roaming blue wildebeest (Connochaetes taurinus) under the most natural conditions possible, and second, to establish the degree of concordance between ACT and PSG recordings undertaken simultaneously in the same individuals. Here we examined sleep in the blue wildebeest, in a naturalistic setting, using both polysomnography (PSG) and actigraphy (ACT). PSG showed that total sleep time (TST) in the blue wildebeest for a 24-h period was 4.53 h (±0.12 h), 4.26 h (±0.11 h) spent in slow wave (non-REM) sleep and 0.28 h (±0.01 h) spent in rapid eye movement (REM) sleep, with 19.47 h (±0.12 h) spent in Wake. ACT showed that the blue wildebeest spent 19.23 h (±0.18 h) Active and 4.77 h (±0.18 h) Inactive. For both animals studied, a fair agreement between the two techniques for sleep scoring was observed, with approximately 45% of corresponding epochs analyzed being scored as both sleep (using PSG) and inactive (using ACT)., Graphical Abstract Flow diagram illustrating the occurrence of state transitions (represented as a percentage) between Wake, non-REM sleep and REM sleep states with the pooled data from both blue wildebeest studied over a 72 h recording period.ga1, Highlights • We recorded sleep in two free-roaming adult blue wildebeest using two techniques. • On average these wildebeest spend around 4.5 h sleeping each day. • This sleep is comprised of both non-REM (4.2 h) and REM (0.28 h). • Actigraphy recordings show fair agreement with polysomnography. • This data contributes towards our understanding of sleep evolution.

Porpose The aim of this study was to evaluate, through a meta-analysis, the predictability of Regenerative Endodontic therapies with antibiotic pastes and calcium hydroxide [Ca(OH)2], related to four variables as follows: root dentin wall thickening, apical closure, apical repair and root lengthening. Methods Literature electronic searches were performed in Pubmed - MEDLINE, Scopus and Lilacs-BVS platforms using appropriate search terms, Mesh (Medical Subject Headings), DeCS (Health Sciences Descriptors) and Boolean operators comprising articles published between 2009 and 2020. Thirty-two original indexed papers were included making a total of 758 regenerative endodontic procedures. A descriptive meta-analysis was performed. Results Dentin wall thickening was present in 66% (CI95: 58%–73%) of the cases treated with antibiotic paste, while when Ca(OH)2 was used, a percentage of 53% (CI95: 26%–78%), was obtained. When antibiotic paste was used, apical closure was found in the 66% (CI95: 58%–73%) of the regenerative endodontic procedures, while when Ca(OH)2 was used, 88% (CI95: 80%–93%) of the cases were found to reach apical closure. Root lengthening and apical repair were found satisfactory for both disinfection protocols. Conclusions There could be differences between the two treatments since a higher percentage of root dentin wall thickening was found when using antibiotic pastes, while a higher percentage of apical closure was found when calcium hydroxide was used. Development of more clinical studies would be necessary in order to confirm the observed differences. The proposed approach could provide a useful contribution for endodontists when planning regenerative endodontic procedures, so as to guide decision-making to the best elective treatment and to select the appropriate disinfection method in accordance with preoperative radiographic diagnosis of root development stage, then increasing the predictability of regenerative endodontic treatment and reducing potential risk of root fractures.

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 The longitudinal trajectories of cardiopulmonary abnormalities and symptoms following infection with coronavirus disease (COVID-19) are unclear. We sought to describe their natural history in previously hospitalised patients, compare this with controls, and assess the relationship between symptoms and cardiopulmonary impairment at 6 months post-COVID-19. Methods Fifty-eight patients and thirty matched controls (single visit), recruited between 14th March - 25th May 2020, underwent symptom-questionnaires, cardiac and lung magnetic resonance imaging (CMR), cardiopulmonary exercise test (CPET), and spirometry at 3 months following COVID-19. Of them, forty-six patients returned for follow-up assessments at 6 months. • View related content for this article Findings At 2-3 months, 83% of patients had at least one cardiopulmonary symptom versus 33% of controls. Patients and controls had comparable biventricular volumes and function. Native cardiac T1 (marker of fibroinflammation) and late gadolinium enhancement (LGE, marker of focal fibrosis) were increased in patients at 2-3 months. Sixty percent of patients had lung parenchymal abnormalities on CMR and 55% had reduced peak oxygen consumption (pV̇O2) on CPET. By 6 months, 52% of patients remained symptomatic. On CMR, indexed right ventricular (RV) end-diastolic volume (-4·3 mls/m2, P=0·005) decreased and RV ejection fraction (+3·2%, P=0·0003) increased. Native T1 and LGE improved and was comparable to controls. Lung parenchymal abnormalities and peak V̇O2, although better, were abnormal in patients versus controls. 31% had reduced pV̇O2 secondary to symptomatic limitation and muscular impairment. Cardiopulmonary symptoms in patients did not associate with CMR, lung function, or CPET measures. Interpretation In patients, cardiopulmonary abnormalities improve over time, though some measures remain abnormal relative to controls. Persistent symptoms at 6 months post-COVID-19 did not associate with objective measures of cardiopulmonary health. Funding The authors’ work was supported by the NIHR Oxford Biomedical Research Centre, Oxford British Heart Foundation (BHF) Centre of Research Excellence (RE/18/3/34214), United Kingdom Research Innovation and Wellcome Trust. This project is part of a tier 3 study (C-MORE) within the collaborative research programme entitled PHOSP-COVID Post-hospitalization COVID-19 study: a national consortium to understand and improve long-term health outcomes, funded by the Medical Research Council and Department of Health and Social Care/National Institute for Health Research Grant (MR/V027859/1) ISRCTN number 10980107.

Background Since 2020 SARS-CoV-2 spreads pandemically, infecting more than 119 million people, causing >2·6 million fatalities. Symptoms of SARS-CoV-2 infection vary greatly, ranging from asymptomatic to fatal. Different populations react differently to the disease, making it very hard to track the spread of the infection in a population. Measuring specific anti-SARS-CoV-2 antibodies is an important tool to assess the spread of the infection or successful vaccinations. To achieve sufficient sample numbers, alternatives to venous blood sampling are needed not requiring medical personnel or cold-chains. Dried-blood-spots (DBS) on filter-cards have been used for different studies, but not routinely for serology. Methods We developed a semi-automated protocol using self-sampled DBS for SARS-CoV-2 serology. It was validated in a cohort of matched DBS and venous-blood samples (n = 1710). Feasibility is demonstrated with two large serosurveys with 10247 company employees and a population cohort of 4465 participants. Findings Sensitivity and specificity reached 99·20% and 98·65%, respectively. Providing written instructions and video tutorials, 99·87% (4465/4471) of the unsupervised home sampling DBS cards could be analysed. Interpretation DBS-sampling is a valid and highly reliable tool for large scale serosurveys. We demonstrate feasibility and accuracy with a large validation cohort including unsupervised home sampling. This protocol might be of big importance for surveillance in resource-limited settings, providing low-cost highly accurate serology data. Funding Provided by Bavarian State Ministry of Science and the Arts, LMU University-Hospital; Helmholtz-Centre-Munich, German Ministry for Education and Research (project01KI20271); University of Bonn; University of Bielefeld; the Medical Biodefense Research Program of Bundeswehr-Medical-Service; Euroimmun, RocheDiagnostics provided discounted kits and machines

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 The discipline of anaesthesiology in China has undergone historical changes and development during the past century. However, nationwide comprehensive data on the current status of each hospital department providing anaesthesia care has been lacking since the discipline was first established in China. This information is essential for effective regulation of healthcare policies by both the professional associations and the government health ministry. Therefore, a nationwide survey was set up in 2018 to investigate the current status of Chinese anaesthesiology. This paper reports the findings of the survey. Methods We performed a cross-sectional nationwide census survey of the current status of each hospital department providing anaesthesia care in 31 provinces across the Chinese mainland. The content of the survey included general information of the department, the hospital level and scale, the volume of the anaesthesiology department, the characteristics of anaesthesiologists, and the caseload of the anaesthesiology departments. Face-to-face interviews were performed by trained interviewers. The Chinese Anaesthesiology Department Tracking Database (CADTD) was established during the survey. Data quality control was undertaken by the investigation committee throughout the survey process. Findings The nationwide census survey was completed by 11,432 hospital departments providing anaesthesia care throughout mainland China from June 1, 2018 to June 30, 2019. Among the 11,432 departments, 4591 (40•16%) belonged to specialised hospitals, while 6841 (59•84%) were affiliated to general hospitals. The proportion of independent anaesthesiology departments was 45•15% in mainland China. There was a total of 92,726 anaesthesiologists, or 6•7 per 100,000 of the population. Regions with better economic conditions had more anaesthesiologists per 100,000 of the population. From 2015 to 2017, the workload of anaesthesiologists has increased by 10%. Interpretation The discipline of anaesthesiology in China has entered a rapid development phase. However, the current status of anaesthesiology is not well defined, which makes it difficult to meet the needs of the increasing Chinese healthcare demand. The evidence from this survey offers valuable information for policy makers and anaesthesiology associations to monitor the development of the discipline and regulate healthcare policies effectively. Funding National Key Research and Development Program of China (Grant No. 2018YFC2001900).

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.

Background: A childhood cancer diagnosis and late effects of treatment may affect survivors' possibilities of employment or highly skilled occupations later in life. In this study, we compared the employment and occupational status of childhood cancer survivors with population comparisons and siblings.Methods: In a cohort study based on Nordic registers, we identified 10 461 survivors of childhood cancer diagnosed before age 20 years in Denmark, Finland and Sweden since 1971. Survivors were compared with 48 928 population comparisons matched to survivors by age, sex and geographical region and 12 605 siblings of survivors. Annual outcome information on employment, unemployment, health-related unemployment and occupational position was obtained from the statistical institutes between 1980-2017 and assessed in multivariate logistic regression analyses from age 30 onwards.Findings: By 30 years of age, 9.2% (95% CI, 8.6-9.9%) of survivors were unemployed for health reasons. Childhood cancer survivors had considerably higher odds of health-related unemployment at ages 30, 40 and 50 than population comparisons (ORage30, 2.57; 95% CI, 2.35-2.81) and siblings (ORage30, 2.50; 95% CI, 2.15-2.90). We observed no large difference in unemployment unrelated to health or in occupational position. Health-related unemployment was particularly pronounced among survivors of central nervous system tumours and survivors diagnosed below 15 years of age.Interpretation: Survivors at risk of health-related unemployment should be offered comprehensive survivorship care and interventions for obtaining and maintaining suitable employment.Funding: NordForsk [76111], the Danish Childhood Cancer Foundation [2016-0293], Aarhus University [43239402], the Swedish Childhood Cancer Foundation [PR2020-0130] and [OB2019-0003], Tømrermester Jørgen Holm og Hustru Elisa F. Hansens Mindelegat [20088] and the Swiss National Science Foundation to LM [P2LUP3_175288].

Background and Objectives Performing cardiopulmonary resuscitation (CPR) on cardiac arrest patients with Do Not Resuscitate (DNR) orders does not respect patients’ autonomy. We aimed to 1) determine the frequency of patients who wished to be DNR prior to cardiac arrest; 2) determine what proportion received CPR; and 3) explain why DNR patients received CPR. Methods This was a retrospective chart review study of cardiac arrest patients at an emergency department. We reported the frequency and proportion of patients who 1) had valid DNR orders presented at the time of cardiac arrest; 2) had valid DNR orders that were unavailable at the time of arrest 3) had Advanced Directives but no DNR orders; 4) had their DNR orders rescinded; and 5) wished to be DNR but did not have any documents in place. Results Of 419 patients, 65 (15.51%) wished to be DNR. Out of these 65 patients, 38 (58.46 %) patients were resuscitated. Among the 38 patients, 23 (60.52%) received CPR accordingly and 15 (39.47%) patients were inappropriately resuscitated. Conclusion In our sample of 419 patients, 65 (15.51%) did not want CPR in the event of cardiac arrest and 38 (9.06%) received CPR against their wishes. This was due to failure to document DNR orders, lack of recognition of documented valid DNR orders, and use of non-actionable Advanced Directives to relay patients’ wishes.

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 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 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.

Background On 23 July 2018, the German Constitutional Court decided that mechanical restraint in psychiatric patients lasting longer than 30 minutes requires a judge's immediate decision. On the same day, the German Association for Psychiatry and Psychotherapy published its guideline on the prevention of coercion and violence. The registry for coercive measures in the federal state of Baden-Wuerttemberg, available since 2015 and comprising all 32 hospitals licensed to admit involuntary patients, has made it possible to evaluate the effect of the legal change, considered the strongest intervention ever in Germany to reduce coercion. Methods We analysed the mean percentage of patients subjected to coercive measures and the mean cumulative duration of these interventions in ICD-10 diagnostic groups in psychiatric hospitals from 2017 compared to 2019 among a total of 233,0273 admissions. Findings The percentage of patients subjected to any kind of freedom-restricting coercion decreased from 6·6% in 2017 to 5·8% in 2019 (p = 0·000). Accordingly, the percentage of patients subjected to mechanical restraint decreased from 4·8% to 3·6% in 2019 (p = 0·000). At the same time, the percentage of patients subjected to seclusion increased from 2·9% to 3·3% (p = 0·000). The median cumulated duration of restraint and seclusion per affected case decreased from 12·5 to 11·9 hrs (p = 0·001). Interpretation There is clear evidence that a strong legal intervention was effective in reducing the use of coercive measures under routine conditions. Funding The registry is funded by the Ministry of Social Welfare and Integration.

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.

Aim: To evaluate an algorithm that uses an end-tidal carbon dioxide (ETCO2) target of ≥ 30 torr to guide specific changes in chest compression rate and epinephrine administration during cardiopulmonary resuscitation (CPR) in paediatric swine. Methods: Swine underwent asphyxial cardiac arrest followed by resuscitation with either standard or ETCO2-guided algorithm CPR. The standard group received chest compressions at a rate of 100/min and epinephrine every 4 min during advanced life support consistent with the American Heart Association paediatric resuscitation guidelines. In the ETCO2-guided algorithm group, chest compression rate was increased by 10 compressions/min for every minute that the ETCO2 was < 30 torr, and the epinephrine administration interval was decreased to every 2 min if the ETCO2 remained < 30 torr. Short-term survival and physiologic data during active resuscitation were compared. Results: Short-term survival was significantly greater in the ETCO2-guided algorithm CPR group than in the standard CPR group (16/28 [57.1%] versus 4/28 [14.3%]; p = 0.002). Additionally, the algorithm group had higher predicted mean ETCO2, chest compression rate, diastolic and mean arterial pressure, and myocardial perfusion pressure throughout resuscitation. Swine in the algorithm group also exhibited significantly greater improvement in diastolic and mean arterial pressure and cerebral perfusion pressure after the first dose of epinephrine than did those in the standard group. Incidence of resuscitation-related injuries was similar in the two groups. Conclusions: Use of a resuscitation algorithm with stepwise guidance for changes in the chest compression rate and epinephrine administration interval based on a goal ETCO2 level improved survival and intra-arrest hemodynamics in this porcine cardiac arrest model.

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