Optimization of a series of novel, potent and selective Macrocyclic SYK inhibitors.

Spleen tyrosine kinase (SYK) is a non-receptor cytoplasmic kinase. Due to its pivotal role in B cell receptor and Fc-receptor signalling, inhibition of SYK has been a target of interest in a variety of diseases. Herein, we report the use of structure-based drug design to discover a series of potent macrocyclic inhibitors of SYK, with excellent kinome selectivity and in vitro metabolic stability. We were able to remove hERG inhibition through the optimization of physical properties, and utilized a pro-drug strategy to address permeability challenges.

Discovery of a Potent and Orally Bioavailable Zwitterionic Series of Selective Estrogen Receptor Degrader-Antagonists.

Herein, we report the optimization of a meta-substituted series of selective estrogen receptor degrader (SERD) antagonists for the treatment of ER+ breast cancer. Structure-based design together with the use of modeling and NMR to favor the bioactive conformation led to a highly potent series of basic SERDs with promising physicochemical properties. Issues with hERG activity resulted in a strategy of zwitterion formation and ultimately in the identification of 38. This compound was shown to be a highly potent SERD capable of effectively degrading ERα in both MCF-7 and CAMA-1 cell lines. The low lipophilicity and zwitterionic nature led to a SERD with a clean secondary pharmacology profile and no hERG activity. Favorable physicochemical properties resulted in good oral bioavailability in preclinical species and potent in vivo activity in a mouse xenograft model.

Biomechanical compensations during a stand-to-sit maneuver using transfemoral osseointegrated prostheses: A case series.

BACKGROUND: Patients with transfemoral amputation and socket prostheses are at a heightened risk of developing musculoskeletal overuse injuries, commonly due to altered joint biomechanics. Osseointegrated prostheses, which involve direct anchorage of the prosthesis to the residual limb through a bone anchored prosthesis, are a novel alternative to sockets yet their biomechanical effect is largely unknown. METHODS: Four patients scheduled to undergo unilateral transfemoral prosthesis osseointegration completed two data collections (baseline with socket prosthesis and 12-months after prosthesis osseointegration) in which whole-body kinematics and ground reaction forces were collected during stand-to-sit tasks. Trunk, pelvis, and hip kinematics, and the surrounding muscle forces, were calculated using subject-specific musculoskeletal models developed in OpenSim. Peak joint angles and muscle forces were compared between timepoints using Cohen's d effect sizes. FINDINGS: Compared to baseline with socket prostheses, patients with osseointegrated prostheses demonstrated reduced lateral trunk bending (d = 1.46), pelvic obliquity (d = 1.09), and rotation (d = 1.77) toward the amputated limb during the stand to sit task. This was accompanied by increased amputated limb hip flexor, abductor, and rotator muscle forces (d> > 0.8). INTERPRETATION: Improved lumbopelvic movement patterns and stabilizing muscle forces when using an osseointegrated prosthesis indicate that this novel prosthesis type likely reduces the risk of the development and/or progression of overuse injuries, such as low back pain and osteoarthritis. We attribute the increased muscle hip muscle forces to the increased load transmission between the osseointegrated prosthesis and residual limb, which allows a greater eccentric ability of the amputated limb to control lowering during the stand-to-sit task.

Analysis of Postoperative Gait, Hip Strength, and Patient-Reported Outcomes After OTA/AO 61-B and 61-C Pelvic Ring Injuries.

OBJECTIVES: To examine clinical gait parameters, hip muscle strength, pelvic functional outcomes, and psychological outcomes after surgical fixation of OTA/AO 61-B and 61-C pelvic ring injuries. DESIGN: Retrospective review identified 10 OTA/AO 61-B patients and 9 OTA/AO 61-C patients for recruitment who were between 1 and 5 years after pelvic fixation. Gait and strength assessments, and patient-reported outcome scores were performed/collected and analyzed. SETTING: Outpatient clinical motion performance laboratory. PATIENTS/PARTICIPANTS: Patients with OTA/AO 61-B and OTA/AO 61-C fractures who were between 1 and 5 years after pelvic fixation. MAIN OUTCOME MEASUREMENTS: Hip strength, kinetics, and spatial-temporal outcomes; Majeed Pelvic Outcome Score; Short Form 36; Hamilton Anxiety/Depression Rating Scales. RESULTS: There were no differences in age, body mass index, or time since definitive fixation between OTA/AO 61-B and 61-C groups. The OTA/AO 61-C group had higher median injury severity scores, longer length of stay, and greater postoperative pelvic fracture displacement. There was no difference in bilateral hip strength, bilateral peak hip moments, peak hip power, and walking speed between groups. Patients with OTA/AO 61-C fractures had lower scores on Short Form 36 General Health and Majeed Work, with a trend toward a lower Total Majeed score. There were no differences in self-reported total anxiety and depression symptoms. CONCLUSIONS: This study did not identify any gait, strength, or psychological differences between OTA/AO 61-B and 61-C injuries at 1-5 years of follow-up. However, increased injury severity in OTA/AO 61-C patients may have residual consequences on perceived general health and ability to work. This pilot study establishes a template for future research into functional recovery of patients with severe pelvic ring trauma. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Examining the impact of social distancing and methamphetamine use on sexual risk and intimate partner violence in sexual and gender minority young adults during the COVID-19 pandemic.

BACKGROUND: During the COVID-19 pandemic in 2020, concerns were raised about the potential impact of pandemic-related social distancing measures on existing health disparities among sexual and gender minority (SGM) young adults, including HIV transmission risk and intimate partner violence (IPV). Another concern was the potential for increased methamphetamine use during the pandemic, which is a known risk factor for HIV transmission and IPV. METHODS: The present analysis examines the impact of COVID-19 social distancing (social distancing and quarantining) and methamphetamine use on HIV risk and IPV in a combined dataset from 3 cohort studies of SGM young adults (two in Los Angeles and one in Chicago) from May 2020 to April 2021 (n = 1142). Bivariate analyses and multivariable logistic regressions were estimated. RESULTS: The median age was 26. All participants were assigned male at birth and most participants were men (93.8%). The largest racial groups were Hispanic/Latinx (44.6%) and Black (29.0%). In adjusted models methamphetamine use was consistently associated with having a new sex partner, higher numbers of sex partners, and experience of IPV, during the pandemic. Reporting no social distancing and reporting one social distancing behavior, were associated with experience of IPV relative to reporting 2 social distancing behaviors. Social distancing was not associated with sexual risk behavior or Pre-exposure Prophylaxis use. CONCLUSIONS: SGM young adults live at the intersection of multiple vulnerabilities during the COVID-19 pandemic. Addiction services, HIV prevention services, and violence support services should be prepared to support young adult SGM needs, particularly those who use methamphetamine.

Personality change in the Nottingham Study of Neurotic Disorder: 30-Year cohort study.

BACKGROUND: Persistence is said to be a feature of personality disorder, but there are few long-term prospective studies of the condition. A total of 200 patients with anxiety and depressive disorders involved in a randomised controlled trial initiated in 1983 had full personality status assessed at baseline. We repeated assessment of personality status on three subsequent occasions over 30 years. METHODS: Personality status was recorded using methods derived from the Personality Assessment Schedule, which has algorithms for allocating Diagnostic and Statistical Manual of Mental Disorders (DSM) and the 11th International Classification of Diseases (ICD-11) categories. The category and severity of personality diagnosis were recorded at baseline in the randomised patients with DSM-III anxiety and depressive diagnoses. The same methods of assessing personality status was repeated at 2, 12 and 30 years after baseline. RESULTS: Using the ICD-11 system, 47% of patients, mainly those with no personality disturbance at baseline, retained their personality status; of the others 16.8% improved and 20.4% worsened to more severe disorder. In DSM-III diagnosed patients, those diagnosed as Cluster A and Cluster C increased in frequency (from 14% to 40%, p < 0.001, and 21.5% to 36%, p < 0.001, respectively) over follow-up, while those with Cluster B showed little change in frequency (22% to 18%, p = 0.197). CONCLUSION: In this population of patients with common mental disorders, personality status showed many changes over time, inconsistent with the view that personality disorder is a persistent or stable condition. The increase in diagnoses within the Cluster A and C groups suggests personality disorder generally increases in frequency as people age.

Thirty-year outcome of anxiety and depressive disorders and personality status: comprehensive evaluation of mixed symptoms and the general neurotic syndrome in the follow-up of a randomised controlled trial.

BACKGROUND: Cohort studies of the long-term outcome of anxiety, depression and personality status rarely join together. METHODS: Two hundred and ten patients recruited with anxiety and depression to a randomised controlled trial between 1983 and 1987 (Nottingham Study of Neurotic Disorder) were followed up over 30 years. At trial entry personality status was assessed, together with the general neurotic syndrome, a combined diagnosis of mixed anxiety-depression (cothymia) linked to neurotic personality traits. Personality assessment used a procedure allowing conversion of data to the ICD-11 severity classification of personality disorder. After the original trial, seven further assessments were made. Observer and self-ratings of psychopathology and global outcome were also made. The primary outcome at 30 years was the proportion of those with no Diagnostic and Statistical Manual of Mental Disorders (DSM) diagnosis.Data were analysed using multilevel repeated measures models that adjusted for age and gender. Missing data were assumed to be missing at random, and the models allowed all subjects to be included in the analysis with missing data automatically handled in the model estimation. RESULTS: At 30 years, 69% of those with a baseline diagnosis of panic disorder had no DSM diagnosis compared to 37-47% of those with generalised anxiety disorder, dysthymia or mixed symptoms (cothymia) (p = 0.027). Apart from those with no personality dysfunction at entry all patients had worse outcomes after 30 years with regard to total psychopathology, anxiety and depression, social function and global outcome. CONCLUSIONS: The long-term outcome of disorders formerly called 'neurotic' is poor with the exception of panic disorder. Personality dysfunction accentuates poor recovery.

Improving metabolic stability and removing aldehyde oxidase liability in a 5-azaquinazoline series of IRAK4 inhibitors.

In this article, we report our efforts towards improving in vitro human clearance in a series of 5-azaquinazolines through a series of C4 truncations and C2 expansions. Extensive DMPK studies enabled us to tackle high Aldehyde Oxidase (AO) metabolism and unexpected discrepancies in human hepatocyte and liver microsomal intrinsic clearance. Our efforts culminated with the discovery of 5-azaquinazoline 35, which also displayed exquisite selectivity for IRAK4, and showed synergistic in vitro activity against MyD88/CD79 double mutant ABC-DLBCL in combination with the covalent BTK inhibitor acalabrutinib.

Novel potent and selective pyrazolylpyrimidine-based SYK inhibitors.

Hybridisation of amino-pyrimidine based SYK inhibitors (e.g. 1a) with previously reported diamine-based SYK inhibitors (e.g. TAK-659) led to the identification and optimisation of a novel pyrimidine-based series of potent and selective SYK inhibitors, where the original aminomethylene group was replaced by a 3,4-diaminotetrahydropyran group. The initial compound 5 achieved excellent SYK potency. However, it suffered from poor permeability and modest kinase selectivity. Further modifications of the 3,4-diaminotetrahydropyran group were identified and the interactions of those groups with Asp512 were characterised by protein X-ray crystallography. Further optimisation of this series saw mixed results where permeability and kinase selectivity were increased and oral bioavailability was achieved in the series, but at the expense of potent hERG inhibition.

Discovery of AZD9833, a Potent and Orally Bioavailable Selective Estrogen Receptor Degrader and Antagonist.

Herein we report the optimization of a series of tricyclic indazoles as selective estrogen receptor degraders (SERD) and antagonists for the treatment of ER+ breast cancer. Structure based design together with systematic investigation of each region of the molecular architecture led to the identification of N-[1-(3-fluoropropyl)azetidin-3-yl]-6-[(6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl]pyridin-3-amine (28). This compound was demonstrated to be a highly potent SERD that showed a pharmacological profile comparable to fulvestrant in its ability to degrade ERα in both MCF-7 and CAMA-1 cell lines. A stringent control of lipophilicity ensured that 28 had favorable physicochemical and preclinical pharmacokinetic properties for oral administration. This, combined with demonstration of potent in vivo activity in mouse xenograft models, resulted in progression of this compound, also known as AZD9833, into clinical trials.

Tricyclic Indazoles-A Novel Class of Selective Estrogen Receptor Degrader Antagonists.

Herein, we report the identification and synthesis of a series of tricyclic indazoles as a novel class of selective estrogen receptor degrader antagonists. Replacement of a phenol, present in our previously reported tetrahydroisoquinoline scaffold, with an indazole group led to the removal of a reactive metabolite signal in an in vitro glutathione trapping assay. Further optimization, guided by X-ray crystal structures and NMR conformational work, varied the alkyl side chain and pendant aryl group and resulted in compounds with low turnover in human hepatocytes and enhanced chemical stability. Compound 9 was profiled as a representative of the series in terms of pharmacology and demonstrated the desired estrogen receptor α degrader-antagonist profile and demonstrated activity in a xenograft model of breast cancer.

Estimating direction in brain-behavior interactions: Proactive and reactive brain states in driving.

Conventional neuroimaging analyses have ascribed function to particular brain regions, exploiting the power of the subtraction technique in fMRI and event-related potential analyses in EEG. Moving beyond this convention, many researchers have begun exploring network-based neurodynamics and coordination between brain regions as a function of behavioral parameters or environmental statistics; however, most approaches average evoked activity across the experimental session to study task-dependent networks. Here, we examined on-going oscillatory activity as measured with EEG and use a methodology to estimate directionality in brain-behavior interactions. After source reconstruction, activity within specific frequency bands (delta: 2-3Hz; theta: 4-7Hz; alpha: 8-12Hz; beta: 13-25Hz) in a priori regions of interest was linked to continuous behavioral measurements, and we used a predictive filtering scheme to estimate the asymmetry between brain-to-behavior and behavior-to-brain prediction using a variant of Granger causality. We applied this approach to a simulated driving task and examined directed relationships between brain activity and continuous driving performance (steering behavior or vehicle heading error). Our results indicated that two neuro-behavioral states may be explored with this methodology: a Proactive brain state that actively plans the response to the sensory information and is characterized by delta-beta activity, and a Reactive brain state that processes incoming information and reacts to environmental statistics primarily within the alpha band.

Cost-effectiveness of donepezil and memantine in moderate to severe Alzheimer's disease (the DOMINO-AD trial).

OBJECTIVE: Most investigations of pharmacotherapy for treating Alzheimer's disease focus on patients with mild-to-moderate symptoms, with little evidence to guide clinical decisions when symptoms become severe. We examined whether continuing donepezil, or commencing memantine, is cost-effective for community-dwelling, moderate-to-severe Alzheimer's disease patients. METHODS: Cost-effectiveness analysis was based on a 52-week, multicentre, double-blind, placebo-controlled, factorial clinical trial. A total of 295 community-dwelling patients with moderate/severe Alzheimer's disease, already treated with donepezil, were randomised to: (i) continue donepezil; (ii) discontinue donepezil; (iii) discontinue donepezil and start memantine; or (iv) continue donepezil and start memantine. RESULTS: Continuing donepezil for 52 weeks was more cost-effective than discontinuation, considering cognition, activities of daily living and health-related quality of life. Starting memantine was more cost-effective than donepezil discontinuation. Donepezil-memantine combined is not more cost-effective than donepezil alone. CONCLUSIONS: Robust evidence is now available to inform clinical decisions and commissioning strategies so as to improve patients' lives whilst making efficient use of available resources. Clinical guidelines for treating moderate/severe Alzheimer's disease, such as those issued by NICE in England and Wales, should be revisited. © 2016 The Authors. International Journal of Geriatric Psychiatry published by John Wiley & Sons Ltd.

Major Greenwood (1880-1949): the biography.

Background is provided on the discovery of an unpublished biography of Major Greenwood written by one of his sons. The motivation and preparation for online publication of the biography in Statistics in Medicine are outlined. © 2016 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd.

Major Greenwood (1880-1949): a biographical and bibliographical study.

Major Greenwood was the foremost medical statistician of the first half of the 20th century in the U.K. Trained in both medicine and statistics, his career extended over 45 years during which he published eight books, 23 extensive reports and over 200 papers. His classical education extended to Latin and Greek, and he was fluent in German and French. We provide an overview of his life including family background, training and his career subdivided according to the places where he worked. We describe in particular the key role he played with others in the development of medical statistics within the Medical Research Council, the General Register Office, the Department of Health and the Universities.

Nursing home placement in the Donepezil and Memantine in Moderate to Severe Alzheimer's Disease (DOMINO-AD) trial: secondary and post-hoc analyses.

BACKGROUND: Findings from observational studies have suggested a delay in nursing home placement with dementia drug treatment, but findings from a previous randomised trial of patients with mild-to-moderate Alzheimer's disease showed no effect. We investigated the effects of continuation or discontinuation of donepezil and starting of memantine on subsequent nursing home placement in patients with moderate-to-severe Alzheimer's disease. METHODS: In the randomised, double-blind, placebo-controlled Donepezil and Memantine in Moderate to Severe Alzheimer's Disease (DOMINO-AD) trial, community-living patients with moderate-to-severe Alzheimer's disease (who had been prescribed donepezil continuously for at least 3 months at a dose of 10 mg for at least the previous 6 weeks and had a score of between 5 and 13 on the Standardised Mini-Mental State Examination) were recruited from 15 secondary care memory centres in England and Scotland and randomly allocated to continue donepezil 10 mg per day without memantine, discontinue donepezil without memantine, discontinue donepezil and start memantine 20 mg per day, or continue donepezil 10 mg per day and start memantine 20 mg per day, for 52 weeks. After 52 weeks, choice of treatment was left to participants and their physicians. Place of residence was recorded during the first 52 weeks of the trial and then every 26 weeks for a further 3 years. A secondary outcome of the trial, reported in this study, was nursing home placement: an irreversible move from independent accommodation to a residential caring facility. Analyses restricted to risk of placement in the first year of follow-up after the patients had completed the double-blind phase of the trial were post-hoc. The DOMINO-AD trial is registered with the ISRCTN Registry, number ISRCTN49545035. FINDINGS: Between Feb 11, 2008, and March 5, 2010, 73 (25%) patients were randomly assigned to continue donepezil without memantine, 73 (25%) to discontinue donepezil without memantine, 76 (26%) to discontinue donepezil and start memantine, and 73 (25%) to continue donepezil and start memantine. 162 (55%) patients underwent nursing home placement within 4 years of randomisation, with similar numbers for all groups (36 [49%] in patients who continued donepezil without memantine, 42 [58%] who discontinued donepezil without memantine, 41 [54%] who discontinued donepezil and started memantine, and 43 [59%] who continued donepezil and started memantine). We noted significant (p=0·010) heterogeneity of treatment effect over time, with significantly more nursing home placements in the combined donepezil discontinuation groups during the first year (hazard ratio 2·09 [95% CI 1·29-3·39]) than in the combined donepezil continuation groups, and no difference during the next 3 years (0·89 [0·58-1·35]). We noted no effect of patients starting memantine compared with not starting memantine during the first year (0·92 [0·58-1·45]) or the next 3 years (1·23 [0·81-1·87]). INTERPRETATION: Withdrawal of donepezil in patients with moderate-to-severe Alzheimer's disease increased the risk of nursing home placement during 12 months of treatment, but made no difference during the following 3 years of follow-up. Decisions to stop or continue donepezil treatment should be informed by potential risks of withdrawal, even if the perceived benefits of continued treatment are not clear. FUNDING: Medical Research Council and UK Alzheimer's Society.

Complete Dentures: Designing Occlusal Registration Blocks to Save Clinical Time and Improve Accuracy.

The techniques described in this article are based on facial measurements and an analysis of the patient's existing dentures to provide measurements that will enable registration blocks to be constructed for individual patients rather than the arbitrarily produced block more commonly seen. Employing the methods shown will lead to a saving in clinical time and contribute to a more accurate registration. It is important to remember that the technician can only provide occlusal registration blocks of the appropriate dimensions if the clinician has assessed the patient and existing dentures and then passed this information to the laboratory. Clinical Relevances: Being able to assess the clinical suitability of a patient's existing dentures and then take measurements from those dentures will allow occlusal registration blocks to be constructed that have the correct dimensions and anatomical features for a particular patient. This will save time during the registration stage and help to improve accuracy.