iRHOM2 is a highly conserved, catalytically inactive member of the Rhomboid family, which has recently been shown to regulate the maturation of the multi-substrate ectodomain sheddase enzyme ADAM17 (TACE) in macrophages. Dominant iRHOM2 mutations are the cause of the inherited cutaneous and oesophageal cancer-susceptibility syndrome tylosis with oesophageal cancer (TOC), suggesting a role for this protein in epithelial cells. Here, using tissues derived from TOC patients, we demonstrate that TOC-associated mutations in iRHOM2 cause an increase in the maturation and activity of ADAM17 in epidermal keratinocytes, resulting in significantly upregulated shedding of ADAM17 substrates, including EGF-family growth factors and pro-inflammatory cytokines. This activity is accompanied by increased EGFR activity, increased desmosome processing and the presence of immature epidermal desmosomes, upregulated epidermal transglutaminase activity and heightened resistance to Staphylococcal infection in TOC keratinocytes. Many of these features are consistent with the presence of a constitutive wound-healing-like phenotype in TOC epidermis, which may shed light on a novel pathway in skin repair, regeneration and inflammation.

Background and Aims Previous studies have shown low rates of diagnosis and treatment of hepatitis C virus (HCV) infection in people who inject drugs (PWID). Our aims were to test the effect of a complex intervention [Hepatitis C Awareness Through to Treatment (HepCATT)] in drug and alcohol clinics-primarily, on engagement of HCV-positive PWID with therapy and, secondarily, on testing for HCV, referral to hepatology services and start of HCV treatment. Design and setting A non-randomized pilot study in three specialist addiction clinics in England comparing an intervention year (starting between September 2015 and February 2016) with a baseline year (2014), together with three control clinics.Participants Analysis included all attendees at the intervention and control specialist addiction clinics identified as PWID.Intervention The intervention comprised the placement of a half-time facilitator in each clinic for 12 months with the brief to increase diagnosis of HCV infection within clients at those services and the engagement of diagnosed individuals with an appropriate care pathway. The facilitator undertook various activities, which could include training of key workers, direct interaction with clients, streamlining and support for hepatology appointments and introduction of dried blood-spot testing. Measurements For each clinic and period, we obtained the total number of clients and, as relevant, their status as PWID, tested for HCV, known HCV-positive, engaged with HCV therapy or treated. Findings Compared with baseline, there was strong evidence that engagement with HCV therapy in the intervention year increased (P < 0.001) more in the HepCATT centres than controls, up + 31 percentage points [95% confidence interval (CI) = 19-43] versus À12 (CI = -31 to + 6) and odds ratio (OR) = 9.99 (CI = 4.42-22.6) versus 0.35 (CI = 0.08-1.56). HepCATT centres also had greater increases in HCV testing (OR = 3.06 versus 0.78, P < 0.001), referral to hepatology (OR = 9.60 versus 0.56, P < 0.001) and treatment initiation (OR = 9.5 versus 0.74, P < 0.001). Conclusions Introducing a half-time facilitator into drug and alcohol clinics in England increased engagement of HCV-positive people who inject drugs with hepatitis C virus care pathways, with increased uptake also of testing, referral to hepatology and initiation of treatment.

Escherichia coli, including enteropathogenic E. coli (EPEC), represents the most common cause of diarrhoea worldwide and is therefore a serious public health burden. Treatment for gastrointestinal pathogens is hindered by the emergence of multiple antibiotic resistance, leading to the requirement for the development of new therapies. A variety of mechanisms act in combination to mediate gastrointestinal-bacterial-associated diarrhoea development. For example, EPEC infection of enterocytes induces attaching and effacing lesion formation and the disruption of tight junctions. An alternative enteric pathogen, Shigella flexneri, manipulates the expression of Connexin 26 (Cx26), a gap junction protein. S. flexneri can open Cx26 hemichannels allowing the release of ATP, whereas HeLa cells expressing mutant gap-junction-associated Cx26 are less susceptible to cellular invasion by S. flexneri than cells expressing wild-type (WT) Cx26. We have investigated further the link between Cx26 expression and gastrointestinal infection by using EPEC and S. flexneri as in vitro models of infection. In this study, a significant reduction in EPEC adherence was observed in cells expressing mutant Cx26 compared with WT Cx26. Furthermore, a significant reduction in both cellular invasion by S. flexneri and adherence by EPEC was demonstrated in human intestinal cell lines following treatment with Cx26 short interfering RNA. These in vitro results suggest that the loss of functional Cx26 expression provides improved protection against gastrointestinal bacterial pathogens. Thus, Cx26 represents a potential therapeutic target for gastrointestinal bacterial infection.

BackgroundManagement of acute psychotic episodes in schizophrenic patients remains a significant challenge for clinicians. Despite treatment guidelines recommending that second-generation antipsychotics (SGAs) should be used as monotherapy, first-generation antipsychotics, polypharmacy, and lower than recommended doses are frequently administered in clinical practice. Minimal data exist regarding the use of SGAs in the Middle East. The objective of this study was to examine the discrepancies between current clinical practice and guideline recommendations in the region.MethodsRECONNECT-S Beta was a multicenter, noninterventional study conducted in Egypt, Kuwait, Saudi Arabia, and the United Arab Emirates to observe the management of schizophrenic patients who were hospitalized due to an acute psychotic episode. Patients underwent one visit on the day of discharge. Demographic and medical history, together with data on antipsychotic treatment and concomitant medication during the hospitalization period and medication recommendations at discharge were recorded.ResultsOf the 1,057 patients, 180 (17.0%) and 692 (65.5%) received SGAs as monotherapy and in combination therapy, respectively. Overall, the most frequently administered medications were given orally, and included risperidone (40.3%), olanzapine (32.5%), and quetiapine (24.6%); the doses administered varied between countries and deviated from the recommended guidelines. Upon discharge, 93.9% of patients were prescribed SGAs as maintenance therapy, and 84.8% were prescribed the same medication(s) as during hospitalization.ConclusionCurrent clinical practice in the Middle East differs from guideline recommendations. Patients frequently received antipsychotics in combination therapy, by various methods of administration, and at doses above and below the recommended guidelines for the management of their acute psychotic episodes.

Purpose The prevalence of obesity in secure mental health units is higher than in the general population, having a negative impact on the physical health and mental well-being of people with severe mental health illness (SMI). The purpose of this study was to describe the feasibility of a programme aimed to help people with SMI to eat healthily and be physically active. Design/methodology/approach A mixed-methods approach was used. A questionnaire administered to patients in both wards measured acceptability, demand, implementation and practicality of the project. Individual semi-structured interviews and focus groups were used to explore staff and patients’ perceptions of the project; as well as the barriers and enablers towards an effective implementation and participation in the project’s activities. Findings Patients were, overall, satisfied with the activities implemented. Successful activities were easy to implement, had staff actively engaged and did not require logistic or administrative planning beforehand. Barriers included unawareness around funding mechanisms of activities, staff capacity issues or lack of patients’ permission to leave the ward. Originality/value Few studies have assessed the feasibility of real-life interventions aimed to improve healthy eating and physical activity in secure mental health units. The results of this study can inform commissioners and providers of mental health services to design and implement new interventions and programmes.