Exploring foundation doctors' self-reported confidence in the assessment and management of mental health conditions.

AIMS AND METHOD: This study assesses newly qualified doctors' confidence in practising clinical skills related to the assessment and management of mental health conditions and how this correlates with other areas of medicine. We conducted a national survey of 1311 Foundation Year 1 doctors in the UK. Survey items assessed confidence recognising mentally unwell patients, conducting a mental state examination, assessing cognition and mental capacity, formulating a psychiatric diagnosis and prescribing psychotropic medications. RESULTS: A substantial proportion of surveyed doctors lacked confidence in their clinical skills related to mental health and prescribing psychotropic medications. Network analysis revealed that items corresponding to mental health were highly correlated, suggesting a potential generalised lack of confidence in mental healthcare. CLINICAL IMPLICATIONS: We identify areas of lack of confidence in some newly qualified doctors' ability to assess and manage mental health conditions. Future research might explore how greater exposure to psychiatry, integrated teaching and clinical simulation might better support medical students for future clinical work.

Discovery of an In Vivo Chemical Probe for BCL6 Inhibition by Optimization of Tricyclic Quinolinones.

B-cell lymphoma 6 (BCL6) is a transcriptional repressor and oncogenic driver of diffuse large B-cell lymphoma (DLBCL). Here, we report the optimization of our previously reported tricyclic quinolinone series for the inhibition of BCL6. We sought to improve the cellular potency and in vivo exposure of the non-degrading isomer, CCT373567, of our recently published degrader, CCT373566. The major limitation of our inhibitors was their high topological polar surface areas (TPSA), leading to increased efflux ratios. Reducing the molecular weight allowed us to remove polarity and decrease TPSA without considerably reducing solubility. Careful optimization of these properties, as guided by pharmacokinetic studies, led to the discovery of CCT374705, a potent inhibitor of BCL6 with a good in vivo profile. Modest in vivo efficacy was achieved in a lymphoma xenograft mouse model after oral dosing.

Assisted gamete treatment to pinpoint acquired meiotic maturity and overcome oocyte activation deficiency contributed by both gametes.

Objective: To treat couples with total fertilization failure (TFF) based on a combined oocyte- and sperm-related oocyte activation deficiency by optimizing oocyte response to chemical activation with calcium ionophore. Design: Case report. Setting: Tertiary Hospital. Patients: Two couples with a history of TFF after intracytoplasmic sperm injection intracytoplasmic sperm injection (ICSI). Interventions: To overcome oocyte-related oocyte activation deficiency (OAD), extended in vivo/in vitro oocyte maturation was performed to enhance ooplasmic maturity; to address sperm-related OAD, assisted gamete treatment (AGT) was performed to trigger oocyte activation. Main outcome measures: Treatment cycle outcomes for the 2 couples undergoing ICSI with extended oocyte maturation (EOM) and AGT. Results: We identified 2 couples with TFF after ICSI because of a combined factor of OAD confirmed by phospholipase C zeta expression and genomic assessment. Initial AGT treatment alone failed to enhance fertilization, suggesting superimposed oocyte dysmaturity prohibiting oocytes from responding to chemical stimuli. To address this complex form of OAD, in couple 1, 27 oocytes out of 34 retrieved presented normal metaphase II spindles after EOM; ICSI with AGT yielded a fertilization rate of 63.0% (17/27). All 17 zygotes were cryopreserved initially. Two embryos were thawed and transferred, yielding a monochorionic diamniotic twin pregnancy. Couple 2 underwent 3 ICSI cycles with EOM and AGT; 91.4% (32/35) of oocytes displayed normal metaphase II spindle and achieved an overall fertilization rate of 43.8% (14/32). A total of 12 blastocysts were cryopreserved. A single 46XY blastocyst was thawed and transferred, resulting in a singleton pregnancy. Conclusions: Our study has demonstrated the usefulness of EOM by targeting spindle presence to enhance chemical responses to AGT.

Discovering cell-active BCL6 inhibitors: effectively combining biochemical HTS with multiple biophysical techniques, X-ray crystallography and cell-based assays.

By suppressing gene transcription through the recruitment of corepressor proteins, B-cell lymphoma 6 (BCL6) protein controls a transcriptional network required for the formation and maintenance of B-cell germinal centres. As BCL6 deregulation is implicated in the development of Diffuse Large B-Cell Lymphoma, we sought to discover novel small molecule inhibitors that disrupt the BCL6-corepressor protein-protein interaction (PPI). Here we report our hit finding and compound optimisation strategies, which provide insight into the multi-faceted orthogonal approaches that are needed to tackle this challenging PPI with small molecule inhibitors. Using a 1536-well plate fluorescence polarisation high throughput screen we identified multiple hit series, which were followed up by hit confirmation using a thermal shift assay, surface plasmon resonance and ligand-observed NMR. We determined X-ray structures of BCL6 bound to compounds from nine different series, enabling a structure-based drug design approach to improve their weak biochemical potency. We developed a time-resolved fluorescence energy transfer biochemical assay and a nano bioluminescence resonance energy transfer cellular assay to monitor cellular activity during compound optimisation. This workflow led to the discovery of novel inhibitors with respective biochemical and cellular potencies (IC50s) in the sub-micromolar and low micromolar range.

Improved Binding Affinity and Pharmacokinetics Enable Sustained Degradation of BCL6 In Vivo.

The transcriptional repressor BCL6 is an oncogenic driver found to be deregulated in lymphoid malignancies. Herein, we report the optimization of our previously reported benzimidazolone molecular glue-type degrader CCT369260 to CCT373566, a highly potent probe suitable for sustained depletion of BCL6 in vivo. We observed a sharp degradation SAR, where subtle structural changes conveyed the ability to induce degradation of BCL6. CCT373566 showed modest in vivo efficacy in a lymphoma xenograft mouse model following oral dosing.

Optimizing Shape Complementarity Enables the Discovery of Potent Tricyclic BCL6 Inhibitors.

To identify new chemical series with enhanced binding affinity to the BTB domain of B-cell lymphoma 6 protein, we targeted a subpocket adjacent to Val18. With no opportunities for strong polar interactions, we focused on attaining close shape complementarity by ring fusion onto our quinolinone lead series. Following exploration of different sized rings, we identified a conformationally restricted core which optimally filled the available space, leading to potent BCL6 inhibitors. Through X-ray structure-guided design, combined with efficient synthetic chemistry to make the resulting novel core structures, a >300-fold improvement in activity was obtained by the addition of seven heavy atoms.

Health and social outcomes in the Housing First model: Testing the theory of change.

Background: Homelessness continues to grow globally. The Housing First (HF) model offers immediate access to housing and support services without preconditions and has a growing body of evidence documenting its effectiveness at ending homelessness. HF has a robust theory of change that hypothesizes how unique program components (i.e., immediate access to housing, separation of services from housing, client choice, etc.) drive positive social and health changes over time. We advance the understanding of how HF causes client improvement by empirically testing this program's theory of change. Methods: Using a unique longitudinal quantitative data from the large Canadian At Home/Chez Soi Housing First trial we used path analysis to test the theory of change for Quality of Life, Crisis related events or service utilization, and Recovery.  Program pathways and health and social outcomes were measured at enrolment, 6-, 12- and 24-months post-enrolment. Findings: Most hypothesized pathways were confirmed with path analysis.  Confirmed pathways for two outcomes- Quality of Life (QOL) and Recovery - were similar. Health and social consultations at enrolment, health status at 6- and 12-months post enrolment, and social connectedness at 12-months were important predictors of the 24-month outcomes of Quality of Life and Recovery, but not for Crisis related events or service utilization. Interpretation: This analysis directly responds to recent calls for more empirical evidence about intervention mechanisms. Ensuring linkages to health and social service consultations for clients, supporting clients' engagement with family and community, and enabling clients to improve or maintain good health will drive better longer term client outcomes within Housing First. Funding: Funding Mental Health Commission of Canada.

Into Deep Water: Optimizing BCL6 Inhibitors by Growing into a Solvated Pocket.

We describe the optimization of modestly active starting points to potent inhibitors of BCL6 by growing into a subpocket, which was occupied by a network of five stably bound water molecules. Identifying potent inhibitors required not only forming new interactions in the subpocket but also perturbing the water network in a productive, potency-increasing fashion while controlling the physicochemical properties. We achieved this goal in a sequential manner by systematically probing the pocket and the water network, ultimately achieving a 100-fold improvement of activity. The most potent compounds displaced three of the five initial water molecules and formed hydrogen bonds with the remaining two. Compound 25 showed a promising profile for a lead compound with submicromolar inhibition of BCL6 in cells and satisfactory pharmacokinetic (PK) properties. Our work highlights the importance of finding productive ways to perturb existing water networks when growing into solvent-filled protein pockets.

Reproductive and obstetric outcomes in women of racial minorities aged 40 years and older undergoing IVF.

RESEARCH QUESTION: Do women of racial minorities aged 40 years or older have similar reproductive and obstetric outcomes as white women undergoing IVF? DESIGN: A retrospective cohort study conducted at a single academic university-affiliated centre. The study population included women aged 40 years or older undergoing their first IVF cycle with fresh cleavage-stage embryo transfer stratified by racial minority status: minority (black or Asian) versus white. Clinical intrauterine pregnancy and live birth rate were the primary outcomes. Preterm delivery (<37 weeks) and small for gestational age were the secondary outcomes. Odds ratios with 95% confidence intervals were estimated. P < 0.05 was considered to be statistically significant. RESULTS: A total of 2050 cycles in women over the age of 40 years were analysed, 561 (27.4%) of which were undertaken by minority women and 1489 (72.6%) by white women. Minority women were 30% less likely to achieve a pregnancy compared with their white (non-Hispanic) counterparts (adjusted OR 0.68, CI 0.54 to 0.87). Once pregnant, however, the odds of live birth were similar (adjusted OR 1.23, CI 0.91 to 1.67). Minority women were significantly more likely to have lower gestational ages at time of delivery (38.5 versus 39.2 weeks, P = 0.009) and were more likely to have extreme preterm birth delivery 24-28 weeks (5.5 versus 1.0%, P = 0.021). CONCLUSION: Minority women of advanced reproductive age are less likely to achieve a pregnancy compared with white (non-Hispanic) women. Once pregnancy is achieved, however, live birth rates are similar albeit with minority women experiencing higher rates of preterm delivery.

Achieving In Vivo Target Depletion through the Discovery and Optimization of Benzimidazolone BCL6 Degraders.

Deregulation of the transcriptional repressor BCL6 enables tumorigenesis of germinal center B-cells, and hence BCL6 has been proposed as a therapeutic target for the treatment of diffuse large B-cell lymphoma (DLBCL). Herein we report the discovery of a series of benzimidazolone inhibitors of the protein-protein interaction between BCL6 and its co-repressors. A subset of these inhibitors were found to cause rapid degradation of BCL6, and optimization of pharmacokinetic properties led to the discovery of 5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyrimidin-4-yl)amino)-3-(3-hydroxy-3-methylbutyl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (CCT369260), which reduces BCL6 levels in a lymphoma xenograft mouse model following oral dosing.

Outcomes in, and characteristics of, patients who undergo intrauterine insemination immediately after failed oocyte retrieval.

OBJECTIVE: To describe the patient and cycle characteristics of women who undergo intrauterine insemination (IUI) immediately after an unsuccessful oocyte retrieval. DESIGN: Retrospective case series. SETTING: University-affiliated center. PATIENTS: Women who underwent an oocyte retrieval procedure in which no oocytes were retrieved followed by an IUI on the same morning. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Live birth rate, subsequent live birth rate. RESULTS: From 2011 to 2019, 63 cycles in 57 patients were identified. The mean (SD) age was 39.6 (4.6) years, and diminished ovarian reserve (94.7%) was the most common diagnosis. The median (IQR) number of previous IVF cycles in this cohort was 3 (1-7), with 56.1% having had at least one previous canceled IVF cycle. The majority of patients had undergone either controlled ovarian hyperstimulation (COH) (64.9%) or modified natural cycles (21.1%). The mean (SD) number of follicles >14 mm at the time of trigger was 1.9 (1.4), with 38.9% of patients manifesting a drop in their estradiol levels after the trigger. One pregnancy resulting in a live birth was identified (1.8%). For patients who underwent subsequent IVF cycles, 60.7% had at least one subsequent cancelled cycle. Three patients went on to achieve a live birth using autologous oocytes (6.5%). CONCLUSIONS: Same-day IUI for patients who have no oocytes retrieved is associated with a <2% chance of achieving a live birth. Of patients who attempt subsequent IVF cycles, nearly two thirds will go on to have at least one subsequent cancelled cycle. In this poor-prognosis cohort, fewer than 10% will ultimately achieve a live birth by the use of autologous oocytes.

Sliding scale HCG trigger yields equivalent pregnancy outcomes and reduces ovarian hyperstimulation syndrome: Analysis of 10,427 IVF-ICSI cycles.

OBJECTIVE: To evaluate pregnancy outcomes and the incidence of ovarian hyperstimulation syndrome (OHSS) using a sliding scale hCG protocol to trigger oocyte maturity and establish a threshold level of serum b-hCG associated with optimal oocyte maturity. DESIGN: Retrospective cohort. SETTING: Academic medical center. PATIENTS: Fresh IVF cycles from 9/2004-12/2011. INTERVENTION: 10,427 fresh IVF-ICSI cycles met inclusion criteria. hCG was administered according to E2 level at trigger: 10,000IU vs. 5,000IU vs. 4,000IU vs. 3,300IU vs. dual trigger (2mg leuprolide acetate + 1,500IU hCG). Serum absorption of hCG was assessed according to dose and BMI. MAIN OUTCOME MEASURES: Oocyte maturity was analyzed according to post-trigger serum b-hCG. Fertilization, clinical pregnancy, live birth and OHSS rates were examined by hCG trigger dose. RESULTS: Post-trigger serum b-hCG 20-30, 30-40, and 40-50 mIU/mL was associated with reduced oocyte maturity as compared b-hCG >50 (67.8% vs. 71.4% vs. 73.3% vs. 78.9%, respectively, P<0.05). b-hCG 20-50 mIU/mL was associated with a 40.1% reduction in live birth (OR 0.59, 95% CI 0.41-0.87). No differences in IVF outcomes per retrieval were seen for varying doses of hCG or dual trigger when controlling for patient age. The incidence of moderate to severe OHSS was 0.13% (n = 14) and severe OHSS was 0.03% (n = 4) of cycles. CONCLUSIONS: Moderate stimulation with sliding scale hCG at trigger and fresh transfer is associated with low rates of OHSS and favorable pregnancy rates. Doses as low as 3,300IU alone or dual trigger with 1,500IU are sufficient to facilitate oocyte maturity.

Morphologic grading of euploid blastocysts influences implantation and ongoing pregnancy rates.

OBJECTIVE: To determine whether blastocyst grading can predict pregnancy outcomes in the frozen-thawed embryo transfer (FET) of euploid blastocysts. DESIGN: Retrospective cohort study. SETTING: Academic medical center. PATIENT(S): Women who underwent FET of euploid embryo(s) between January 2013 and December 2015, with blastocysts were divided into four groups based on their morphologic grading before cryopreservation: excellent (≥3AA), good (3-6AB, 3-6BA, 1-2AA), average (3-6BB, 3-6AC, 3-6CA, 1-2AB, 1-2BA), and poor (1-6BC, 1-6CB, 1-6CC, 1-2BB). INTERVENTION(S): FET. MAIN OUTCOMES MEASURE(S): Ongoing pregnancy rate (OPR). RESULT(S): A total of 417 FET cycles (477 embryos) were included. Excellent-quality embryos (n = 38) yielded a statistically significantly higher OPR than poor-quality embryos (n = 106) (84.2% vs. 35.8%; adjusted odds ratio 11.0; 95% confidence interval, 3.8-32.1) and average-quality embryos (n = 197) (84.2% vs. 55.8%; adjusted odds ratio 4.8; 95% confidence interval, 1.7-13.3). Good-quality embryos (n = 76) were associated with a statistically significantly higher OPR than poor-quality embryos (61.8% vs. 35.8%). These odds ratios were adjusted for patient's age, body mass index, number of transferred embryos, type of frozen cycle, peak endometrial thickness, day of trophectoderm biopsy (5 or 6), and total number of euploid embryos for each patient. An inner cell mass grade of A yielded a statistically significantly higher OPR than ICM grade C (76.2% vs. 13.5%) or grade B (76.2% vs. 53.6%) after controlling for all confounders. CONCLUSION(S): Contrary to prior published studies, the current data suggest that blastocyst morphologic grading and particularly inner cell mass grade is a useful predictor of OPR per euploid embryo. Morphologic grading should be used to help in the selection among euploid blastocysts.

Synthesis of Substituted 1,4-Dioxenes through O-H Insertion and Cyclization Using Keto-Diazo Compounds.

1,4-Dioxenes present interesting potential as synthetic intermediates and as unusual motifs for incorporation into biologically active compounds. Here, an efficient synthesis of functionalized 1,4-dioxenes is achieved in two steps. Using keto-diazo compounds, a ruthenium catalyzed O-H insertion with ß-halohydrins followed by treatment with base results in cyclization with excellent selectivity, through O-alkylation of the keto-enolate. A variety of halohydrins and anion-stabilizing groups in the diazo-component are tolerated, affording novel functionalized dioxenes. Enantioenriched ß-bromohydrins provide enantioenriched 1,4-dioxenes.

Oxetanes: Recent Advances in Synthesis, Reactivity, and Medicinal Chemistry.

The four-membered oxetane ring has been increasingly exploited for its contrasting behaviors: its influence on physicochemical properties as a stable motif in medicinal chemistry and its propensity to undergo ring-opening reactions as a synthetic intermediate. These applications have driven numerous studies into the synthesis of new oxetane derivatives. This review takes an overview of the literature for the synthesis of oxetane derivatives, concentrating on advances in the last five years up to the end of 2015. These methods are clustered by strategies for preparation of the ring and further derivatization of preformed oxetane-containing building blocks. Examples of the use of oxetanes in medicinal chemistry are reported, including a collation of oxetane derivatives appearing in recent patents for medicinal chemistry applications. Finally, examples of oxetane derivatives in ring-opening and ring-expansion reactions are described.

Keeping the Zika Virus Out of the Assisted Reproductive Technology Laboratory.

The Zika virus (ZIKV) epidemic spreading through South and Central America, as well as several U.S. territories has created worldwide concern as the linkage between ZIKV infection and microcephaly has been established. Both travel associated and sexually transmitted cases have put couples who live in nonendemic areas at risk of falling victim to effects of Zika. The presence of ZIKV within reproductive tissues may pose a significant threat to patients seeking fertility services and to safety of the tissues currently housed in assisted reproductive technology (ART) laboratories. There are still many unanswered questions regarding the mechanism of ZIKV sexual transmission. Just as strict guidelines have been set regarding the screening and handling of human immunodeficiency virus, hepatitis C virus, and hepatitis B virus-positive patient tissues, similar recommendations are needed to prevent contamination and inadvertent transmission within the ART laboratory.

Introduction: Access to fertility care.

Given that only an estimated 24% of infertile couples in the United States can fully engage in the medical care required to successfully conceive, the American Society for Reproductive Medicine (ASRM) has incorporated improved access to the full gamut of fertility therapies as an integral component of the Society's strategic plan that was launched in 2014. Toward this end, the ASRM hosted a two-day summit held in Washington D.C. in September 2015 that attracted thought leaders, both speakers and attendees, from around the world. This issue's Views and Reviews focuses on several key areas integral to this effort: an appreciation of the economic challenges to access, as well as the impact and interplay of racial, ethnic, emotional and gender-specific issues in the treatment of infertility. The potential to broaden access to care through modification of existing assisted reproductive techniques is also explored.

Do flexicurity policies protect workers from the adverse health consequences of temporary employment? A cross-national comparative analysis.

Flexicurity policies comprise a relatively novel approach to the regulation of work and welfare that aims to combine labour market flexibility with social security. Advocates of this approach argue that, by striking the right balance between flexibility and security, flexicurity policies allow firms to take advantage of loose contractual arrangements in an increasingly competitive economic environment while simultaneously protecting workers from the adverse health and social consequences of flexible forms of employment. In this study, we use multilevel Poisson regression models to test the theoretical claim of the flexicurity approach using data for 23 countries across three waves of the European Social Survey. We construct an institutional typology of labour market regulation and social security to evaluate whether inequalities in self-reported health and limiting longstanding illness between temporary workers and their permanent counterparts are smaller in countries that most closely approximate the ideal type described by advocates of the flexicurity approach. Our results indicate that, while the association between temporary employment and health varies across countries, institutional configurations of labour market regulation and social security do not provide a meaningful explanation for this cross-national variation. Contrary to the expectations of the flexicurity hypothesis, our data do not indicate that employment-related inequalities are smaller in countries that approximate the flexicurity approach. We discuss potential explanations for these findings and conclude that there remains a relative lack of evidence in support of the theoretical claims of the flexicurity approach.

Synthesis of diversely functionalised 2,2-disubstituted oxetanes: fragment motifs in new chemical space.

Di-, tri- and tetra-substituted oxetane derivatives with combinations of ester, amide, nitrile, aryl, sulfone and phosphonate substituents are prepared as fragments or building blocks for drug discovery. The synthesis of these novel oxetane functional groups, in new chemical space, is achieved via rhodium-catalysed O-H insertion and C-C bond forming cyclisation.