MIDA boronates are hydrolysed fast and slow by two different mechanisms

MIDA boronates (N-methylimidodiacetic boronic acid esters) serve as an increasingly general platform for small-molecule construction based on building blocks, largely because of the dramatic and general rate differences with which they are hydrolysed under various basic conditions. Yet the mechanistic underpinnings of these rate differences have remained unclear, which has hindered efforts to address the current limitations of this chemistry. Here we show that there are two distinct mechanisms for this hydrolysis: one is base mediated and the other neutral. The former can proceed more than three orders of magnitude faster than the latter, and involves a rate-limiting attack by a hydroxide at a MIDA carbonyl carbon. The alternative 'neutral' hydrolysis does not require an exogenous acid or base and involves rate-limiting B-N bond cleavage by a small water cluster, (H2O)n. The two mechanisms can operate in parallel, and their relative rates are readily quantified by (18)O incorporation. Whether hydrolysis is 'fast' or 'slow' is dictated by the pH, the water activity and the mass-transfer rates between phases. These findings stand to enable, in a rational way, an even more effective and widespread utilization of MIDA boronates in synthesis

Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial

Background Non-alcoholic steatohepatitis (NASH) is a common type of chronic liver disease that can lead to cirrhosis. Obeticholic acid, a farnesoid X receptor agonist, has been shown to improve the histological features of NASH. Here we report results from a planned interim analysis of an ongoing, phase 3 study of obeticholic acid for NASH. Methods In this multicentre, randomised, double-blind, placebo-controlled study, adult patients with definite NASH,non-alcoholic fatty liver disease (NAFLD) activity score of at least 4, and fibrosis stages F2–F3, or F1 with at least oneaccompanying comorbidity, were randomly assigned using an interactive web response system in a 1:1:1 ratio to receive oral placebo, obeticholic acid 10 mg, or obeticholic acid 25 mg daily. Patients were excluded if cirrhosis, other chronic liver disease, elevated alcohol consumption, or confounding conditions were present. The primary endpointsfor the month-18 interim analysis were fibrosis improvement (≥1 stage) with no worsening of NASH, or NASH resolution with no worsening of fibrosis, with the study considered successful if either primary endpoint was met. Primary analyses were done by intention to treat, in patients with fibrosis stage F2–F3 who received at least one dose of treatment and reached, or would have reached, the month 18 visit by the prespecified interim analysis cutoff date. The study also evaluated other histological and biochemical markers of NASH and fibrosis, and safety. This study is ongoing, and registered with ClinicalTrials.gov, NCT02548351, and EudraCT, 20150-025601-6. Findings Between Dec 9, 2015, and Oct 26, 2018, 1968 patients with stage F1–F3 fibrosis were enrolled and received at least one dose of study treatment; 931 patients with stage F2–F3 fibrosis were included in the primary analysis (311 in the placebo group, 312 in the obeticholic acid 10 mg group, and 308 in the obeticholic acid 25 mg group). The fibrosis improvement endpoint was achieved by 37 (12%) patients in the placebo group, 55 (18%) in the obeticholic acid 10 mg group (p=0·045), and 71 (23%) in the obeticholic acid 25 mg group (p=0·0002). The NASH resolution endpoint was not met (25 [8%] patients in the placebo group, 35 [11%] in the obeticholic acid 10 mg group [p=0·18], and 36 [12%] in the obeticholic acid 25 mg group [p=0·13]). In the safety population (1968 patients with fibrosis stages F1–F3), the most common adverse event was pruritus (123 [19%] in the placebo group, 183 [28%] in the obeticholic acid 10 mg group, and 336 [51%] in the obeticholic acid 25 mg group); incidence was generally mild to moderate in severity. The overall safety profile was similar to that in previous studies, and incidence of serious adverse events was similar across treatment groups (75 [11%] patients in the placebo group, 72 [11%] in the obeticholic acid 10 mg group, and 93 [14%] in the obeticholic acid 25 mg group). Interpretation Obeticholic acid 25 mg significantly improved fibrosis and key components of NASH disease activity among patients with NASH. The results from this planned interim analysis show clinically significant histological improvement that is reasonably likely to predict clinical benefit. This study is ongoing to assess clinical outcomes

SUBMISSION TO The Joint Standing committee on Migration Inquiry into immigration treatment of disability

The focus of our submission is on the healthcare of people with intellectual disability although we will make reference to people with disabilities in genera

Characteristics influencing attendance at a primary care health check for people with intellectual disability: an individual participant data meta-analysis

Background: Health checks benefit adolescents and adults with intellectual disability, however uptake is low despite government-funded incentives

Health care for people with an intellectual disability: General practitioners' attitudes, and provision of care

The aim of this study was to investigate general practitioners' (GPs) beliefs about the importance of addressing nine health care issues for people with intellectual disabilities, and their roles in providing this care. GPs' current level and intended future level of addressing these health care issues were also determined Questionnaires were mailed to 912 GPs Australia wide, with a 58% response rate. The vast majority of respondents agreed that the nine issues are important health care issues for people with an intellectual disability. Most respondents also agreed that it is the GPs' role to facilitate or ensure these health issues are addressed. Although having broad attitudes about their roles, GPs indicated significant deficiencies in their current level of health care provision for many of the health issues. However they also indicated their intentions to increase the frequency of addressing these health issues in the future as a result of issues raised in previous questions on the questionnaire. This response to simply increasing GPs' awareness of their practice behaviour has a variety of important implications for training and ongoing education

Drop-out during a randomized trial with adolescents with intellectual disability was associated with participant burden, while drop-out at study exit was associated with carer and household characteristics

Background: People with intellectual disability are difficult to retain in longitudinal studies. Research on determinants of study retention for individual-carer dyads, and their reasons for drop-out, are limited

Health actions prompted by health assessments for people with intellectual disability exceed actions recorded in general practitioners' records

People with intellectual disability experience inadequate health care and have unmet health needs that can go unidentified or be poorly managed. Health assessments have been shown to significantly increase short-term clinical activity for people with intellectual disability. The aim of this study was to more accurately quantify the effect of health assessments for people with intellectual disability by comparing health actions recorded in health assessment booklets to actions recorded in general practitioners’ (GPs) records in the 12-month period following the health assessment. Participants were people with intellectual disability who had received a Comprehensive Health Assessment Program (CHAP), living in the community. The CHAP is a health assessment that is demonstrated to significantly increase health actions, compared with usual care, for people with intellectual disability. Data collected from three randomised controlled trials conducted in South-East Queensland, Australia, from 2000 to 2010 were pooled and analysed. The health assessment booklet contained significantly more information on health actions than GPs’ records. Notably, hearing tests (risk ratio (RR) = 5.9; 95% confidence interval (CI) = 4.7–7.4), breast checks (RR = 3.9; 95% CI = 2.7–5.7), and skin examinations (RR = 7.9; 95% CI = 5.9–10.7) were more likely to be recorded in the CHAP booklet. Health assessments increase health actions for people with intellectual disability to a significantly greater extent than previously demonstrated