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Analysis of data from clinical cohorts, and more recently from human pancreatic tissue, indicates that reduced prohormone processing is an early and persistent finding in type 1 diabetes. In this article, we review the current state of knowledge regarding alterations in islet prohormone expression and processing in type 1 diabetes and consider the clinical impact of these findings. Lingering questions, including pathologic etiologies and consequences of altered prohormone expression and secretion in type 1 diabetes, and the natural history of circulating prohormone production in health and disease, are considered. Finally, key next steps required to move forward in this area are outlined, including longitudinal testing of relevant clinical populations, studies that probe the genetics of altered prohormone processing, the need for combined functional and histologic testing of human pancreatic tissues, continued interrogation of the intersection between prohormone processing and autoimmunity, and optimal approaches for analysis. Successful resolution of these questions may offer the potential to use altered prohormone processing as a biomarker to inform therapeutic strategies aimed at personalized intervention during the natural history of type 1 diabetes and as a pathogenic anchor for identification of potential disease-specific endotypes.Primary sclerosing cholangitis and colitis are known predisposing factors for bile duct cancer, but their exact pro-oncogenic mechanisms are unclear. In this issue of Cancer Discovery, Zhang and colleagues identify intestinal barrier impairment as a key mechanism, resulting in gut microbes spilling into the portal vein, in turn recruiting immunosuppressive myeloid-derived suppressor cells and promoting cholangiocarcinoma.See related article by Zhang et al. p. 1248.In this issue of Cancer Discovery, Welti and colleagues demonstrate a positive correlation between the expression of the histone acetyltransferase paralogs CBP and p300 with increased androgen receptor (AR) signaling and androgen deprivation therapy resistance in advanced prostate cancer. CCS1477, a selective inhibitor of p300/CBP bromodomain, disrupts AR- and MYC-regulated gene expression, suppresses tumor growth in vivo in multiple castration-resistant prostate cancer xenograft models, and modulates biomarker expression in early clinical evaluation, providing a novel therapeutic approach for AR-addicted advanced prostate cancer.See related article by Welti et al., p. 1118.Although combination anti-PD-1 and anti-CTLA4 mAbs have revolutionized outcomes for many cancers, their utility has been limited due to significant immune-related toxicities and the emergence of resistance. In this issue of Cancer Discovery, Dovedi and colleagues describe the development and preclinical testing of MEDI5752, a bispecific anti-PD-1/CTLA4 antibody designed to optimize therapeutic response by maximizing CTLA4 blockade on antigen-experienced T cells, thereby increasing efficacy and potentially minimizing toxicity.See related article by Dovedi et al., p. 1100.

Following the disruption of normal paediatric inflammatory bowel disease (IBD) services during the peak of the COVID-19 pandemic, we prospectively audited the first-time use of home faecal calprotectin testing. We aimed to provide an alternative to laboratory tests and to assess the value of home testing as part of our regular services going forward.

Home test kits as well as accompanying user instructions were made available to our patients with paediatric IBD that required faecal calprotectin test between 17 April and 12 August 2020. Once the user completed the test, results were automatically uploaded to the result portal and clinical staff were alerted. A user feedback questionnaire was sent to users that had completed the home test.

Of the 54 patients, 41 (76%) aged between 4.7 and 18.1 years used the home test. A total of 45 home tests were done, one of which produced an invalid result. The decision to modify management was made in 12 (29%) of the patients, while 14 (34%) had no changes made and 15 (37%) required further assessment. Twenty (48.8%) responded to the questionnaire and 85% stated that they preferred the home test to the laboratory testing method.

Home calprotectin tests were useful in guiding clinical management during a time when laboratory testing was less available. BOS172722 cost They may offer benefits as part of routine paediatric IBD monitoring to help target appointments and reduce unnecessary hospital attendances in the future.

Home calprotectin tests were useful in guiding clinical management during a time when laboratory testing was less available. They may offer benefits as part of routine paediatric IBD monitoring to help target appointments and reduce unnecessary hospital attendances in the future.

Percutaneousendoscopic gastrostomy is a commonly used endoscopic technique where a tube isplaced through the abdominal wall mainly to administer fluids, drugs and/orenteral nutrition. Several placement techniques are described in the literaturewith the 'pull' technique (Ponsky-Gardener) as the most popular one.Independent of the method used, placement includes a 'blind' perforation of thestomach through a small acute surgical abdominal wound. It is a generally safetechnique with only few major complications. Nevertheless these complicationscan be sometimes life-threatening or generate serious morbidity.

Anarrative review of the literature of major complications in percutaneousendoscopic gastrostomy.

This review was written from a clinical viewpoint focussing on prevention andmanagement of major complications and documentedscientific evidence with real cases from more than 20 years of clinical practice.

Majorcomplications are rare but prevention, early recognition and popper management areimportant.

Majorcomplications are rare but prevention, early recognition and popper management areimportant.Since early 2020, global stakeholders have highlighted the significant gendered consequences of the COVID-19 pandemic, including increases in the risk of gender-based violence (GBV). Researchers have sought to inform the pandemic response through a diverse set of methodologies, including early efforts modelling anticipated increases in GBV. For example, in April 2020, a highly cited modelling effort by the United Nations Population Fund (UNFPA) and partners projected headline global figures of 31 million additional cases of intimate partner violence due to 6 months of lockdown, and an additional 13 million child marriages by 2030. In this paper, we discuss the rationale for using modelling to make projections about GBV, and use the projections released by UNFPA to draw attention to the assumptions and biases underlying model-based projections. We raise five key critiques (1) reducing complex issues to simplified, linear cause-effect relationships, (2) reliance on a small number of studies to generate global estimates, (3) assuming that the pandemic results in the complete service disruption for existing interventions, (4) lack of clarity in indicators used and sources of estimates, and (5) failure to account for margins of uncertainty.