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SIGNIFICANCE We provide a preclinical model of ICI-associated myocarditis which recapitulates this clinical syndrome. Using this model, we demonstrate that CTLA4 and PD-1 (ICI targets) functionally interact for myocarditis development and that intervention with CTLA4-Ig (abatacept) attenuates myocarditis, providing mechanistic rationale and preclinical support for therapeutic clinical studies.See related commentary by Young and Bluestone, p. 537.This article is highlighted in the In This Issue feature, p. 521.Current guidelines recommend angiotensin receptor blocker neprilysin inhibitors (ARNI) (sacubitril/valsartan) as a replacement for angiotensin-converting-enzymeinhibitor (ACE-I) in heart failure with reduced ejection fraction (HFrEF) who remain symptomatic despite optimal medical therapy. The effects of ARNIs have not previously been assessed in a systematic review. We searched for relevant trials until October 2019 in CENTRAL, MEDLINE, Embase, LILACS, BIOSIS, CNKI, VIP, WanFang and CBM. Our primary outcomes were all-cause mortality and serious adverse events. We systematically assessed the risks of random errors and systematic errors. PROSPERO registration CRD42019129336. 48 trials randomising 19 086 participants were included. The ARNI assessed in all trials was sacubitril/valsartan. ACE-I or ARB were used as control interventions. Trials randomising HFrEF participants (27 trials) and heart failure with preserved ejection fraction (HFpEF) participants (four trials) were analysed separately. In HFrEF participants, meta-analyses and Trial Sequential Analyses showed evidence of a beneficial effect of sacubitril/valsartan when assessing all-cause mortality (risk ratio (RR), 0.86; 95% CI, 0.79 to 0.94) and serious adverse events (RR, 0.89; 95% CI, 0.86 to 0.93); and the results did not differ between the guideline recommended target population and HFrEF participants in general. https://www.selleckchem.com/products/Eloxatin.html We found no evidence of an effect of sacubitril/valsartan in HFpEF participants. Sacubitril/valsartan compared with either ACE-I or ARB seems to have a beneficial effect in patients with HFrEF. Our results indicate that sacubitril/valsartan might be beneficial in a wider population of patients with heart failure than the guideline recommended target population. Sacubitril/valsartan does not seem to show evidence of a difference compared with valsartan in patients with HFpEF. Early intervention in people with an at-risk mental state for psychosis can decrease the rates of transition to psychosis. GPs play a key role in the identification of this patient group but very few studies have explored GPs' awareness of patients who are at risk of psychosis. To explore GPs' views and experiences of identifying patients with an at-risk mental state for psychosis, and the barriers and facilitators to identification. In-depth semi-structured interviews were held with GPs working in South West England primary care. The interviews were conducted between March and July 2019. A topic guide was used to ensure consistency across interviews. This guide was revised to incorporate a definition of the at-risk mental state for psychosis, as after conducting a few interviews it became clear that some GPs were not familiar with this construct. Interviews were audiorecorded and analysed thematically. A total of 20 GPs were interviewed. Some GPs were not familiar with the concept of being at risk of developing psychosis, and perceived that they may not have the right skills to identify this patient group. Other barriers related to patients not presenting or disclosing psychotic symptoms, and limitations imposed by scarce resources on the structure and provision of NHS services, such as lack of continuity of care and high thresholds for accessing specialised services. Identifying people at risk of psychosis in primary care is difficult. Provision of GP training, development of policies that support continuity of care, and improved access to specialised services could help improve the identification of this patient group. Identifying people at risk of psychosis in primary care is difficult. Provision of GP training, development of policies that support continuity of care, and improved access to specialised services could help improve the identification of this patient group. One can assume a relatively high prevalence of urinary incontinence (UI) in people with multimorbidity. However, literature in this area is scarce. There is a need for further robust research to aid GPs to identify patients at a particular risk for UI, and to initiate the early treatment and multidisciplinary management of this condition. To examine the association between multimorbidity and UI in 23 089 individuals aged ≥15 years and residing in Spain. This study used data from the Spanish National Health Survey 2017, a cross-sectional sample of 23 089 participants aged ≥15 years residing in Spain (54.1% female; mean [standard deviation] age = 53.4 [18.9] years). UI and 30 other physical and mental chronic conditions were self-reported. Multimorbidity was defined as the presence of ≥2 physical and/or mental chronic conditions (excluding UI). Control variables included sex, age, marital status, education, smoking, and alcohol consumption. Multivariable logistic regression analyses were conducted to assess the association between multimorbidity and UI. The prevalence of UI was 5.9% in this sample. UI was more frequent in the presence than in the absence of each one of the 30 chronic conditions ( <0.001). The proportion of people with UI was also higher in the multimorbidity than in the no-multimorbidity group (9.8% versus 0.7%, <0.001). After adjusting for several potential confounders (that is, sex, age, marital status, education, smoking, and alcohol), there was a significant and positive relationship between multimorbidity and UI (odds ratio = 5.02, 95% confidence interval [CI] = 3.89 to 6.59, <0.001). In this large sample of Spanish individuals aged ≥15 years, suffering from multimorbidity was associated with a significantly higher level of UI. In this large sample of Spanish individuals aged ≥15 years, suffering from multimorbidity was associated with a significantly higher level of UI.
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