Background Lynch syndrome is a rare familial cancer syndrome caused by pathogenic variants in the mismatch repair genes MLH1, MSH2, MSH6, or PMS2, that cause predisposition to various cancers, predominantly colorectal and endometrial cancer. Data are emerging that pathogenic variants in mismatch repair genes increase the risk of earlyonset aggressive prostate cancer. The IMPACT study is prospectively assessing prostate-specific antigen (PSA) screening in men with germline mismatch repair pathogenic variants. Here, we report the usefulness of PSA screening, prostate cancer incidence, and tumour characteristics after the first screening round in men with and without these germline pathogenic variants. MethodsThe IMPACT study is an international, prospective study. Men aged 40-69 years without a previous prostate cancer diagnosis and with a known germline pathogenic variant in the MLH1, MSH2, or MSH6 gene, and age-matched male controls who tested negative for a familial pathogenic variant in these genes were recruited from 34 genetic and urology clinics in eight countries, and underwent a baseline PSA screening. Men who had a PSA level higher than 3•0 ng/mL were offered a transrectal, ultrasound-guided, prostate biopsy and a histopathological analysis was done. All participants are undergoing a minimum of 5 years' annual screening. The primary endpoint was to determine the incidence, stage, and pathology of screening-detected prostate cancer in carriers of pathogenic variants compared with non-carrier controls. We used Fisher's exact test to compare the number of cases, cancer incidence, and positive predictive values of the PSA cutoff and biopsy between carriers and non-carriers and the differences between disease types (ie, cancer vs no cancer, clinically significant cancer vs no cancer). We assessed screening outcomes and tumour characteristics by pathogenic variant status. Here we present results from the first round of PSA screening in the IMPACT study. This study is registered with ClinicalTrials.gov, NCT00261456, and is now closed to accrual.

The disabling nature and costly impact of mental disorders, such as schizophrenia, can cause significant burden to both person and society. It is also indicated that the negative outcomes associated with psychosis may, in part, be due to the delayed detection and initiation of treatment. Preventative interventions in several arenas of medicine have advanced; however have only come to the fore in psychiatry in the last two decades. It was long-known that a preclinical phase preceded psychosis, now commonly termed as ultra high-risk (UHR) status.The advent of specialized early intervention services provided the cornerstone in taking a preventative and timely endeavor to maximize the chance of positive outcomes in psychosis.Despite the potential, the current state of the UHR concept lacks consensus in how at-risk individuals should be approached. This chapter aims to provide an overview of how preventative medicine can intersect with psychiatry by focusing on the psychosis high risk state. It describes the current criteria and screening procedures used to prospectively detect UHR individuals, as well as discussing the validity of these tools. Whilst advocating the benefits of focused interventions, this chapter also recognizes current challenges and the controversy that leaves the psychosis high risk state on fertile ground for wavering opinions.The chapter concludes with an exploration and discussion that proposes an improved conceptualization of the high risk state and how this can direct intervention, as well as suggesting future lines of research in this area.2