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Presents a letter to the editor on the use of tar-based shampoo with 50 mg/ml calcipotriol solution in scalp psoriasis.

Background: The real-world consequences of a Philips Respironics recall for positive airway pressure (PAP) devices distributed between 2009 and 2021 are unknown., Methods: We conducted a retrospective population-based study using health administrative databases (Ontario, Canada) on all new adult PAP users identified through the provincial funding system, free of cancer at baseline, who initiated (claimed) PAP treatment between 2012 and 2018. Everyone was followed from the PAP claim date to the earliest of incident cancer diagnosis, death or end of follow-up (March 2022). We used inverse probability of treatment weighting to balance baseline characteristics between individuals on recalled devices and those on devices from other manufacturers. Weighted hazard ratios of incident cancer were compared between groups., Results: Of 231 692 individuals identified, 58 204 (25.1%) claimed recalled devices and 173 488 (74.9%) claimed devices from other manufacturers. A meaningful baseline difference between groups (standardised difference ≥0.10) was noted only by location-relevant covariates; other variables were mostly equally distributed (standardised differences ≤0.06). Over a median (interquartile range) follow-up of 6.3 (4.9-8.0) years, 11 166 (4.8%) developed cancer: unadjusted rates per 10 000 person-years of 78.8 (95% CI 76.0-81.7) in the recall group versus 74.0 (95% CI 72.4-75.6) in others (p=0.0034). Propensity score weighting achieved excellent balance in baseline characteristics between groups (standardised differences ≤0.07). On a weighted sample, there was no statistical difference in the hazard of incident cancer between groups: cause-specific hazard ratio (recalled versus others) 0.97 (95% CI 0.89-1.06)., Conclusion: In our real-world population study, compared to other manufacturers and adjusting for confounders, recalled Philips Respironics PAP devices do not appear to be independently associated with developing cancer., Competing Interests: Conflict of interest: All authors declare they have no potential conflicts of interest. T. Kendzerska and A.S. Gershon are supported by the PSI (Physicians’ Services Incorporated) Foundation. Outside of the submitted work, S.R. Pendharkar has received honoraria from Jazz Pharmaceuticals, Paladin Labs and the International Centre for Professional Development in Health and Medicine for participation in educational activities, and grant funding from Jazz Pharmaceuticals. Outside of the submitted work, M. Povitz has received a fellowship grant from Paladin Labs and contract research from Jazz Pharmaceuticals. Outside of the submitted work, N. Ayas has received a speaker honorarium from ResMed, and has been a consultant with EISAI, Jazz and Powell Mansfield. Outside of the submitted work, M. Kaminska is a consultant for Biron Soins du Sommeil and reports a Philips investigator-initiated research grant (pending). Outside of the submitted work, the University of California San Diego (UCSD) Sleep Medicine Center received a donation from ResMed., (Copyright ©The authors 2024. For reproduction rights and permissions contact permissions@ersnet.org.)

Background: Despite extensive research on the relationship between psychological factors and aerobic training, there remains a gap in understanding these relationships within resistance training (RT), particularly barbell-based RT. This study aimed to examine the associations between basic psychological needs, behavioral regulation, self-efficacy, and a longitudinal barbell-based RT program for adults., Methods: Forty-three adults ( M age = 45.09 ± 10.72) were recruited from the Competitive Edge resistance training program at a medical fitness center in Northwest Montana. The study followed an 18-week schedule: 8 weeks of training, 1 week of active recovery, and 8 additional weeks of training., Results: The results reveal several significant findings. First, the basic psychological need for competence significantly increased from baseline ( M  = 5.06) to post-program ( M  = 5.30), ( p = 0.017). Second, the composite score of the BREQ-3 significantly predicting muscular strength improvements in the deadlift ( β  = 3.64, p  = 0.039). Third, both mastery ( p  = 0.021) and resilience ( p  = 0.007) self-efficacy subscales increased from baseline to post-program. Fourth, exploratory analyses indicated that the reasons to exercise scale predicted increases in muscular endurance with the weight management ( β  = 10.016, p  = 0.046) and solitude ( β  = 6.792, p  = 0.037) subscales., Conclusion: These findings highlight the importance of psychological factors in predicting strength outcomes and muscular endurance, suggesting that psychological interventions may complement physical training to maximize benefits. This research contributes valuable insights into how psychological factors influence training outcomes, potentially guiding future interventions and program designs to better support strength development and endurance in resistance training contexts., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Martinez Kercher, Watkins, Goss, Phillips, Roy, Blades, Dobson and Kercher.)

Antimicrobial resistance is a global issue, and the investigation of alternative therapies that are not traditional antibiotics are warranted. Novel bacterial type II topoisomerase inhibitors (NBTIs) have recently emerged as a novel class of antibiotics with reduced potential for cross-resistance to fluoroquinolones due to their novel mechanism of action. This study investigated the in vitro activity of a series of cyclohexyl-oxazolidinone bacterial topoisomerase inhibitors against type strains of Francisella tularensis and Burkholderia pseudomallei . Broth microdilution, time-kill, and cell infection assays were performed to determine activity against these biothreat pathogens. Two candidates were identified that demonstrated in vitro activity in multiple assays that in some instances was equivalent to ciprofloxacin and doxycycline. These data warrant the further evaluation of these novel NBTIs and future iterations in vitro and in vivo .

There is an increasingly urgent and unmet medical need for novel antibiotic drugs that tackle infections caused by multidrug-resistant (MDR) pathogens. Novel bacterial type II topoisomerase inhibitors (NBTIs) are of high interest due to limited cross-resistance with fluoroquinolones, however analogues with Gram-negative activity often suffer from hERG channel inhibition. A novel series of bicyclic-oxazolidinone inhibitors of bacterial type II topoisomerase were identified which display potent broad-spectrum anti-bacterial activity, including against MDR strains, along with an encouraging in vitro safety profile. In vivo proof of concept was achieved in a A. baumannii mouse thigh infection model., (Copyright © 2022. Published by Elsevier Ltd.)

Background: The evidence surrounding the impact of COVID-19 on medical learners remains anecdotal and highly speculative despite the anticipated impact and potential consequences of the current pandemic on medical training. The purpose of this study was to explore the extent that COVID-19 initially impacted medical learners around the world and examine global trends and patterns across geographic regions and levels of training., Methods: A cross-sectional survey of medical learners was conducted between March 25-June 14, 2020, shortly after the World Health Organization declared COVID-19 a pandemic., Results: 6492 learners completed the survey from 140 countries. Most medical schools removed learners from the clinical environment and adopted online learning, but students reported concerns about the quality of their learning, training progression, and milestone fulfillment. Residents reported they could be better utilized and expressed concerns about their career timeline. Trainees generally felt under-utilized and wanted to be engaged clinically in meaningful ways; however, some felt that contributing to healthcare during a pandemic was beyond the scope of a learner. Significant differences were detected between levels of training and geographic regions for satisfaction with organizational responses as well as the impact of COVID-19 learner wellness and state-trait anxiety., Conclusions: The disruption to the status quo of medical education is perceived by learners across all levels and geographic regions to have negatively affected their training and well-being, particularly amongst postgraduate trainees. These results provide initial empirical insights into the areas that warrant future research as well as consideration for current and future policy planning., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare., (© 2021 Brown, Kassam, Paget, Blades, Mercia, Kachra; licensee Synergies Partners.)

Study Objectives: Difficulties in providing timely access to care have prompted interest in primary care delivery models for obstructive sleep apnea (OSA). Sustainable implementation of such models requires codesign with input from key stakeholders. The purpose of this study was to identify patient and provider perspectives on barriers and facilitators to optimal, patient-centered management of OSA in a primary care setting., Methods: This study was conducted in Alberta, Canada. Data from key stakeholders were collected through an online survey of primary care providers (n = 119), focus groups and interviews with patients living with OSA (n = 28), and workshops with primary care and sleep providers (n = 36). Quantitative survey data were reported using descriptive statistics, and qualitative data were analyzed using an inductive thematic approach., Results: Several barriers were identified, including poor specialist access, variable primary care providers knowledge of OSA, and lack of clarity about provider roles for OSA management. Barriers contributed to patients being poorly informed about OSA, leading them to separate OSA from their overall health and eroding trust in the system. Suggestions for improvement included integration of care providers in a comprehensive model of care, facilitated by improved system navigation and more effective use of technology. Themes were consistent across data collection methods and between stakeholder groups., Conclusions: Although primary care delivery models may improve access to OSA management, stakeholders identified important challenges in the current system. Innovative models of care, developed with input from patients and providers, may mitigate barriers and support optimal primary care management of OSA., (© 2021 American Academy of Sleep Medicine.)

Rationale, Aims, and Objectives: Family participation in Intensive Care Unit (ICU) bedside rounds has been advocated as a way to improve communication between families and health care providers; however, the associated impact and modulators have not been fully described. The purpose of this study was to explore benefits, drawbacks, barriers, and facilitators to family participation in ICU rounds in order to inform ways to improve how families are integrated into rounds., Methods: This was a qualitative exploratory study of ICU patients' family members (n = 29) and health care providers (n = 35) who work in ICU settings. Interviews and focus groups were conducted, and thematic analysis was used for data analysis., Results: Benefits and drawbacks for families were related to knowledge and emotional impact and for health care providers were related to knowledge and transparency, with rapport as an additional benefit and logistical impact as a drawback. Barriers and facilitators during rounds and outside of rounds were identified, and suggestions for improvement included preparing and orienting families, summarizing, teaching modifications, follow-up, and organizational culture., Conclusions: Our study provides insight into the multiple processes involved in family participation in ICU rounds, along with suggestions for improvement. Our findings may help guide development of a structured approach to family participation in ICU rounds that can be adapted to local contexts., (© 2020 John Wiley & Sons, Ltd.)

Aims: There is very little published literature on Enhanced Recovery Principles (ERP) used in primary joint replacements applied to revision hip and knee arthroplasty (rTHA, rTKA)., Methods: Retrospective series of 268 rTHA and rTKA surgeries from 2010 -2018, treated with ERP, focusing on multimodal pain management, blood management and early functional recovery., Results: No patients from the latest cohort required readmission within 6 weeks. Only 20 patients (7.5%) required a blood transfusion. Surgical site local anaesthetic infiltration was associated with lower PCA use in aseptic rTHA and rTKA (p<0.001; p<0.001). Revisions for infection had a longer length of stay (LOS) and increased PCA usage in both rTHA (6.5 vs. 5.2 days) and rTKA (10.1 vs. 5.3 days), similar to our previous study. 1 Use of an intra-articular catheter for analgesia in rTKA showed reduced PCA use. Tourniquets were not beneficial for blood loss in rTKA and had greater PCA use post-operatively (p<0.001)., Conclusion: The application of ERP to revision THA and TKA surgery is safe and effective., (Crown Copyright © 2020 Published by Elsevier B.V. on behalf of Professor P K Surendran Memorial Education Foundation. All rights reserved.)

The kinase ataxia telangiectasia mutated and rad3 related (ATR) is a key regulator of the DNA-damage response and the apical kinase which orchestrates the cellular processes that repair stalled replication forks (replication stress) and associated DNA double-strand breaks. Inhibition of repair pathways mediated by ATR in a context where alternative pathways are less active is expected to aid clinical response by increasing replication stress. Here we describe the development of the clinical candidate 2 (AZD6738), a potent and selective sulfoximine morpholinopyrimidine ATR inhibitor with excellent preclinical physicochemical and pharmacokinetic (PK) characteristics. Compound 2 was developed improving aqueous solubility and eliminating CYP3A4 time-dependent inhibition starting from the earlier described inhibitor 1 (AZ20). The clinical candidate 2 has favorable human PK suitable for once or twice daily dosing and achieves biologically effective exposure at moderate doses. Compound 2 is currently being tested in multiple phase I/II trials as an anticancer agent.

Introduction: This is the first study reporting the application of Enhanced Recovery Principles (ERP) to revision arthroplasty., Method: Retrospective series of 132 revision hip and knee replacements treated with ERP., Results: Infiltration was associated with reduced LOS in knees (6 vs 8.5 days), lower PCA usage and incidence of transfusion in knees (2 vs 3 days) and hips (1 vs 6 days). Revisions for infection had a longer LOS (5.4 vs 11.5 days p = 0.001), a greater use of PCA and a higher incidence of transfusion (5 vs 0) in both knees and hips., Discussion: The application of ERPs to revision arthroplasty is safe. Infiltration appears to be an important factor in improving outcome measures.

Inhibition of the protein-protein interaction between B-cell lymphoma 6 (BCL6) and corepressors has been implicated as a therapeutic target in diffuse large B-cell lymphoma (DLBCL) cancers and profiling of potent and selective BCL6 inhibitors are critical to test this hypothesis. We identified a pyrazolo[1,5-a]pyrimidine series of BCL6 binders from a fragment screen in parallel with a virtual screen. Using structure-based drug design, binding affinity was increased 100000-fold. This involved displacing crystallographic water, forming new ligand-protein interactions and a macrocyclization to favor the bioactive conformation of the ligands. Optimization for slow off-rate constant kinetics was conducted as well as improving selectivity against an off-target kinase, CK2. Potency in a cellular BCL6 assay was further optimized to afford highly selective probe molecules. Only weak antiproliferative effects were observed across a number of DLBCL lines and a multiple myeloma cell line without a clear relationship to BCL6 potency. As a result, we conclude that the BCL6 hypothesis in DLBCL cancer remains unproven.

Background: Increased demand and escalating costs necessitate innovation in health care. The challenge is to implement complex innovations-those that require coordinated use across the adopting organization to have the intended benefits., Purpose: We wanted to understand why and how two of five similar hospitals associated with the same health care authority made more progress with implementing a complex inpatient discharge innovation whereas the other three experienced more difficulties in doing so., Methodology: We conducted a qualitative comparative case study of the implementation process at five comparable urban hospitals adopting the same inpatient discharge innovation mandated by their health care authority. We analyzed documents and conducted 39 interviews of the health care authority and hospital executives and frontline managers across the five sites over a 1-year period while the implementation was ongoing., Findings: In two and a half years, two of the participating hospitals had made significant progress with implementing the innovation and had begun to realize benefits; they exemplified an integrated implementation mode. Three sites had made minimal progress, following a fragmented implementation mode. In the former mode, a semiautonomous health care organization developed a clear overall purpose and chose one umbrella initiative to implement it. The integrative initiative subsumed the rest and guided resource allocation and the practices of hospital executives, frontline managers, and staff who had bought into it. In contrast, in the fragmented implementation mode, the health care authority had several overlapping, competing innovations that overwhelmed the sites and impeded their implementation., Practice Implications: Implementing a complex innovation across hospital sites required (a) early prioritization of one initiative as integrative, (b) the commitment of additional (traded off or new) human resources,, ((c) deliberate upfront planning and continual support for and evaluation of implementation, and (d) allowance for local customization within the general principles of standardization.)

Aims and Objectives: Discharge prediction is designed to streamline inpatient flow and reduce hospital overcrowding without adding capacity. This study's objective was to describe the literature on discharge prediction and assess its usefulness in evaluating the implementation and outcomes of discharge prediction projects., Methods: The authors reviewed the current peer-reviewed and grey literature on discharge prediction projects in acute care hospitals. Project descriptions were analyzed using Donabedian's structure-process-outcome model for evaluating complex healthcare innovations., Results: The review revealed a paucity of literature on the use and effectiveness of discharge prediction. There is high variation in its use and generally poor reporting of both implementation and outcomes., Conclusions: The literature on discharge prediction generally lacks the descriptive detail that would be useful to parties considering or planning a discharge prediction initiative. Further study is required to determine how best to integrate these prediction tools into acute care hospitals., (Copyright © 2016 Longwoods Publishing.)

Group I p21-activated kinase (PAK) inhibitors are indicated as important in cancer progression, but achieving high kinase selectivity has been challenging. A bis-anilino pyrimidine PAK1 inhibitor was identified and optimized through structure-based drug design to improve PAK1 potency and achieve high kinase selectivity, giving in vitro probe compound AZ13705339 ( 18 ). Reduction of lipophilicity to lower clearance afforded AZ13711265 ( 14 ) as an in vivo probe compound with oral exposure in mouse. Such probes will allow further investigation of PAK1 biology.

High throughput screening followed by a lead generation campaign uncovered a novel series of urea containing morpholinopyrimidine compounds which act as potent and selective dual inhibitors of mTORC1 and mTORC2. We describe the continued compound optimization campaign for this series, in particular focused on identifying compounds with improved cellular potency, improved aqueous solubility, and good stability in human hepatocyte incubations. Knowledge from empirical SAR investigations was combined with an understanding of the molecular interactions in the crystal lattice to improve both cellular potency and solubility, and the composite parameters of LLE and pIC50-pSolubility were used to assess compound quality and progress. Predictive models were employed to efficiently mine the attractive chemical space identified resulting in the discovery of 42 (AZD3147), an extremely potent and selective dual inhibitor of mTORC1 and mTORC2 with physicochemical and pharmacokinetic properties suitable for development as a potential clinical candidate.

Constitutively active mutant KRas displays a reduced rate of GTP hydrolysis via both intrinsic and GTPase-activating protein-catalyzed mechanisms, resulting in the perpetual activation of Ras pathways. We describe a fragment screening campaign using X-ray crystallography that led to the discovery of three fragment binding sites on the Ras:SOS complex. The identification of tool compounds binding at each of these sites allowed exploration of two new approaches to Ras pathway inhibition by stabilizing or covalently modifying the Ras:SOS complex to prevent the reloading of Ras with GTP. Initially, we identified ligands that bound reversibly to the Ras:SOS complex in two distinct sites, but these compounds were not sufficiently potent inhibitors to validate our stabilization hypothesis. We conclude by demonstrating that covalent modification of Cys118 on Ras leads to a novel mechanism of inhibition of the SOS-mediated interaction between Ras and Raf and is effective at inhibiting the exchange of labeled GDP in both mutant (G12C and G12V) and wild type Ras.

A new synthetic route to 3-(heteroaryl) tetrahydropyrazolo[3,4-c]pyridines has been developed that uses the Suzuki-Miyaura cross-coupling of a triflate 6 with (hetero)aryl boronic acids or esters. Using Pd(OAc)2 and XPhos or an XPhos precatalyst, a diverse range of substituents at the C3 position of the tetrahydropyrazolo[3,4-c]pyridine skeleton were prepared. The use of pivaloyloxymethyl and benzyl protection also offers the potential to differentially functionalize the pyrazole and tetrahydropyridine nitrogens.

ATR is an attractive new anticancer drug target whose inhibitors have potential as chemo- or radiation sensitizers or as monotherapy in tumors addicted to particular DNA-repair pathways. We describe the discovery and synthesis of a series of sulfonylmorpholinopyrimidines that show potent and selective ATR inhibition. Optimization from a high quality screening hit within tight SAR space led to compound 6 (AZ20) which inhibits ATR immunoprecipitated from HeLa nuclear extracts with an IC50 of 5 nM and ATR mediated phosphorylation of Chk1 in HT29 colorectal adenocarcinoma tumor cells with an IC50 of 50 nM. Compound 6 potently inhibits the growth of LoVo colorectal adenocarcinoma tumor cells in vitro and has high free exposure in mouse following moderate oral doses. At well tolerated doses 6 leads to significant growth inhibition of LoVo xenografts grown in nude mice. Compound 6 is a useful compound to explore ATR pharmacology in vivo.

A directed screen of a relatively small number of compounds, selected for kinase ATP pocket binding potential, yielded a novel series of hit compounds (1). Hit explosion on two binding residues identified compounds 27 and 43 as the best leads for an optimization program having reduced secondary metabolism, as measured by in vitro rat hepatocytes incubation, leading to oral bio-availability. Structure-activity relationships and molecular modeling have suggested a binding mode for the most potent inhibitor 12., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

The development of a novel series of imidazole pyrimidine amides as cyclin-dependent kinase (CDK) inhibitors is described. The series was found to have much improved CDK2 inhibition and potent in vitro anti-proliferative effects against cancer cell lines. Control of overall lipophilicity was important to achieve good in vitro potency along with acceptable physiochemical properties and margins against inhibition of both CYP isoforms and the hERG potassium ion channel. A compound with an attractive overall balance of properties was profiled in vivo and possessed suitable physiochemical and pharmacokinetic profiles for oral dosing.

The development of a novel series of imidazole pyrimidine amides as cyclin-dependent kinase (CDK) inhibitors is described. Optimisation of inhibitory potency against multiple CDK's (1, 2 and 9) resulted in imidazole pyrimidine amides with potent in vitro anti-proliferative effects against a range of cancer cell lines. Excellent physiochemical properties and large margins against inhibition of CYP isoforms and the hERG ion channel were achieved by modification of lipophilicity and amine basicity. A candidate with disease model activity in human cancer cell line xenografts and with suitable physiochemical and pharmacokinetic profiles for intravenous (i.v.) dosing was selected for further development as AZD5597.