Structure- and Property-Based Optimization of Efficient Pan-Bromodomain and Extra Terminal Inhibitors to Identify Oral and Intravenous Candidate I-BET787.

The bromodomain and extra terminal (BET) family of bromodomain-containing proteins are important epigenetic regulators that elicit their effect through binding histone tail N-acetyl lysine (KAc) post-translational modifications. Recognition of such markers has been implicated in a range of oncology and immune diseases and, as such, small-molecule inhibition of the BET family bromodomain-KAc protein-protein interaction has received significant interest as a therapeutic strategy, with several potential medicines under clinical evaluation. This work describes the structure- and property-based optimization of a ligand and lipophilic efficient pan-BET bromodomain inhibitor series to deliver candidate I-BET787 (70) that demonstrates efficacy in a mouse model of inflammation and suitable properties for both oral and intravenous (IV) administration. This focused two-phase explore-exploit medicinal chemistry effort delivered the candidate molecule in 3 months with less than 100 final compounds synthesized.

Fostering integration among students with different backgrounds using an orthotic community service program.

BACKGROUND: In this globalization era, institutions are developing strategies including international service-learning pedagogies to integrate global perspectives and dimensions into the learning and teaching processes to develop students' capacity in intercultural competence. OBJECTIVE: This study aimed to assess the students' intercultural learning outcome through provision of orthotic community service to the less-privileged children. METHODS: A Hong Kong-based university collaborated with 2 American universities to conduct an orthotic community service program for the children with cerebral palsy in mainland China. In the process of service delivery, the students with different backgrounds worked closely and students' professional knowledge, intercultural understanding, and communication skills were evaluated. A mixed-method approach was adopted to investigate on how this international program could facilitate meaningful interactions in clinical practices. Preprogram and postprogram surveys and focus group interviews were conducted. Statistical analyses were performed on the quantitative data, while interview data were analyzed thematically. RESULTS: A comparison of preprogram and postprogram surveys showed that the students perceived this community service program important for enhancement of their capabilities to communicate with people from other cultures (n = 39, p < 0.05). It also showed an increase in local students' willingness to work with people from other cultures. Some themes related to intercultural competences were identified from the interview: "intercultural awareness, understanding, and communication" as well as openness to work/socialize with people from other cultures." CONCLUSIONS: This study demonstrated that an international community service program could initiate positive changes in students' intercultural communication capability and interest to work with culturally different people.

Teaching psychiatry to medical students in the time of COVID-19: experiences from UK medical schools.

AIMS AND METHOD: Education leads for undergraduate psychiatry in UK medical schools completed questionnaires on adaptations made to undergraduate psychiatry education, their impact and what lessons could be learnt for the future. RESULTS: Respondents from 24 medical schools across the UK reported a major shift to online teaching delivery, with reduced workplace learning and increased use of teleconferencing, online tasks and self-directed learning. Changes were implemented with some faculty training provided, but little additional funding or resources from medical schools or National Health Service trusts. A variety of challenges and opportunities were reported. CLINICAL IMPLICATIONS: Despite the extraordinary efforts of education leads to maintain undergraduate psychiatry education, the pandemic may affect the development of students' professional competencies and recruitment into psychiatry. Individual clinicians, trusts and medical and foundation schools have much to offer, and need to work with students to replace what has been lost during the pandemic.

A real-time light-scattering technique for tailings solids measurement.

This study presents the concept of an economic in situ light-scattering sensor for real-time measurement of the solid content in tailings facilities. An experimental setup using a blue (405 nm wavelength) laser diode and silicon photodiodes was constructed to measure the angular distribution of the intensity of scattered light. It was found that the angular intensity of scattered light for tailing samples follows a cosn (θ) relation with n ≈ 1.5, where θ is the angle between the laser beam and the photodiode. An angular value of θ = 20° was chosen for the sensor design based on a high signal-to-noise ratio. The setup was used to determine the relation between scattered light intensity and solids content using a thickened tailings underflow from an oil sands facility and Kaolin as a model material. It was observed that the intensity of scattered light tends to increase with an increase in solids content, with qualitatively similar settling behavior for the two materials but at largely different time scales. An insertion-based prototype was built and tested in a large (2.7 m height) settling column with treated mature fine tailings, and the light-scattering data were verified by standard gravimetric method and gamma-ray measurements. In general, good agreement was established between these measurements in the absence of optical fouling, which demonstrates the potential of the sensor as an effective tool for tailings management.

Decreased mean perfusion pressure as an independent predictor of acute kidney injury after cardiac surgery.

Acute kidney injury after cardiac surgery (AKICS) is common. Previous studies examining the role that mean arterial pressure (MAP) during cardiopulmonary bypass (CPB) may have on AKICS have not taken into account how baseline central venous pressure (CVP) and mean perfusion pressure (MPP) (i.e. MAP - CVP) can influence its evolution. To assess whether the change in MPP to the kidneys (i.e. delta MPP or DMPP) during CPB compared to baseline is an independent predictor of AKICS. After ethical approval, a retrospective observational study was performed on all patients undergoing CPB between October 2013 and June 2015 at a university-affiliated hospital. Known risk factors for the development of AKICS were recorded, as were the MPP values at baseline and during CPB. From this, statistical modelling was performed to identify predictors of postoperative AKICS. 664 patients were identified. Analysis was performed on 513 patients after exclusion. On logistic regression, significant and independent predictors of AKICS included: d20DMPP (cumulative duration of MPP values during CPB that were 20% below baseline and exceeded three consecutive minutes) (P = 0.010); baseline CVP; age; pre-operative creatinine level; and left ventricular (LV) dysfunction (ejection fraction (EF) < 45%). On alternative modelling, the cumulative number of MPP values during CPB that were 10% below baseline was also independently associated with AKICS (P = 0.003). Modelling without taking into account CVP also supported this association. The duration of differences in perfusion pressure to the kidneys during CPB compared to baseline is an independent predictor of AKICS.