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Background: During the COVID-19 pandemic, opioid-related overdose deaths increased. Although Medication-Assisted Treatment or Recovery (MAT or MAR) is available, initiation and retention rates vary. The goal of this study was to evaluate clinical, demographic, and Social Determinant of Health factors affecting MAR initiation, on-time initiation of medications, and successful retention in the program. The secondary goal was to evaluate the impact of a novel interprofessional practice model incorporating pharmacists. Methods: A retrospective analysis was conducted using electronic health record data from a pilot MAR Program initiated within a California Federally Qualified Healthcare Center. Results: From September 2019 to August 2020, 48 patients enrolled into the program. On-time initiation of medications occurred in 68% of patients and average program retention was 96.4 ± 95.8 days. Patients currently using opioids (p = 0.005) and those receiving supportive medications (p = 0.049) had lower odds of on-time MAR initiation. There were no statistically significant factors associated with successful retention in the program. The number of visits with members of the interprofessional team did not significantly affect on-time initiation or successful retention. Conclusions: Current opioid use and receipt of supportive medications were associated with lower on-time medication initiation. Further studies are warranted to explore additional factors which may affect initiation and retention.

Abstract Background AVATAR therapy is a novel intervention targeting distressing auditory verbal hallucinations (henceforth ‘voices’). A digital simulation (avatar) of the voice is created and used in a three-way dialogue between participant, avatar and therapist. To date, therapy has been delivered over 6 sessions, comprising an initial phase, focusing on standing up to a hostile avatar, and a second phase in which the avatar concedes and focus shifts to individualised treatment targets, including beliefs about voices. The first fully powered randomised trial found AVATAR therapy resulted in a rapid and substantial fall in voice frequency and associated distress that was superior to supportive counselling at 12 weeks. The main objective of this AVATAR2 trial is to test the efficacy of two forms of AVATAR therapy in reducing voice-related distress: AVATAR-brief (standardised focus on exposure, assertiveness and self-esteem) and AVATAR-extended (phase 1 mirroring AVATAR-brief augmented by a formulation-driven phase 2). Secondary objectives include the examination of additional voice, wellbeing and mood outcomes, the exploration of mediators and moderators of therapy response, and examining cost-effectiveness of both forms of therapy compared with usual treatment (TAU). Methods This multi-site parallel group randomised controlled trial will independently randomise 345 individuals to receive AVATAR-brief (6 sessions) plus TAU or AVATAR-extended (12 sessions) plus TAU or TAU alone (1:1:1 allocation). Participants will be people with a diagnosis of schizophrenia spectrum and other psychotic disorders who have heard distressing voices for more than 6 months. The primary outcome is the PSYRATS Auditory Hallucinations Distress dimension score at 16 and 28 weeks, conducted by blinded assessors. Statistical analysis will follow the intention-to-treat principle and data will be analysed using linear mixed models. Mediation and moderation analyses using contemporary causal inference methods will be conducted as secondary analyses. Service costs will be calculated, and cost-effectiveness assessed in terms of quality-adjusted life years accrued. Discussion This study will clarify optimal therapy delivery, test efficacy in a multi-site study and enable the testing of the AVATAR software platform, therapy training and provision in NHS settings. Trial registration ISRCTN registry ISRCTN55682735 . Registered on 22 January 2020. The trial is funded by the Wellcome Trust (WT).

Abstract Background Cannabis is the most commonly used illicit substance amongst people with psychosis. Continued cannabis use following the onset of psychosis is associated with poorer functional and clinical outcomes. However, finding effective ways of intervening has been very challenging. We examined the clinical and cost-effectiveness of adjunctive contingency management (CM), which involves incentives for abstinence from cannabis use, in people with a recent diagnosis of psychosis. Methods CIRCLE was a pragmatic multi-centre randomised controlled trial. Participants were recruited via Early Intervention in Psychosis (EIP) services across the Midlands and South East of England. They had had at least one episode of clinically diagnosed psychosis (affective or non-affective); were aged 18 to 36; reported cannabis use in at least 12 out of the previous 24 weeks; and were not currently receiving treatment for cannabis misuse, or subject to a legal requirement for cannabis testing. Participants were randomised via a secure web-based service 1:1 to either an experimental arm, involving 12 weeks of CM plus a six-session psychoeducation package, or a control arm receiving the psychoeducation package only. The total potential voucher reward in the CM intervention was £240. The primary outcome was time to acute psychiatric care, operationalised as admission to an acute mental health service (including community alternatives to admission). Primary outcome data were collected from patient records at 18 months post-consent by assessors masked to allocation. The trial was registered with the ISRCTN registry, number ISRCTN33576045. Results Five hundred fifty-one participants were recruited between June 2012 and April 2016. Primary outcome data were obtained for 272 (98%) in the CM (experimental) group and 259 (95%) in the control group. There was no statistically significant difference in time to acute psychiatric care (the primary outcome) (HR 1.03, 95% CI 0.76, 1.40) between groups. By 18 months, 90 (33%) of participants in the CM group, and 85 (30%) of the control groups had been admitted at least once to an acute psychiatric service. Amongst those who had experienced an acute psychiatric admission, the median time to admission was 196 days (IQR 82, 364) in the CM group and 245 days (IQR 99, 382) in the control group. Cost-effectiveness analyses suggest that there is an 81% likelihood that the intervention was cost-effective, mainly resulting from higher mean inpatient costs for the control group compared with the CM group; however, the cost difference between groups was not statistically significant. There were 58 adverse events, 27 in the CM group and 31 in the control group. Conclusions Overall, these results suggest that CM is not an effective intervention for improving the time to acute psychiatric admission or reducing cannabis use in psychosis, at least at the level of voucher reward offered.

Background: Cannabis is the most prevalent illicit substance among people with psychosis, and its use is associated with poorer clinical and social outcomes. However, so far, there has been limited evidence that any treatment is effective for reducing use. Contingency management (CM) is an incentive-based intervention for substance misuse that has a substantial evidence base across a range of substances and cohorts. However, to date there have been no randomised controlled trials (RCTs) of CM as a treatment for cannabis use specifically in psychosis. Objective: To conduct a RCT investigating the clinical effectiveness and cost-effectiveness of CM in reducing cannabis use among Early Intervention in Psychosis (EIP) service users. Design: The CIRCLE (Contingency Intervention for Reduction of Cannabis in Early Psychosis) trial was a rater-blinded, multicentre RCT with two arms. Participants were randomised 1 : 1 to either an CM arm, in which participants received CM for cannabis use alongside an optimised treatment-as-usual programme including structured psychoeducation, or a control arm in which participants received the treatment as usual only. Setting: EIP services across the Midlands and the south-east of England. Participants: The main eligibility criteria were EIP service users with a history of psychosis, aged 18–36 years, and having used cannabis at least once per week during 12 of the previous 24 weeks. Intervention: The CM intervention offered financial incentives (i.e. shopping vouchers) for cannabis abstinence over 12 once-weekly sessions, confirmed using urinalysis. The maximum value in vouchers that participants could receive was £240. Main outcome measures: The main outcome was time to relapse, operationalised as admission to an acute mental health service or hospital. The primary outcome was assessed at 18 months post inclusion using electronic patient records. Secondary outcomes assessed the clinical effectiveness and cost-effectiveness of the intervention, for which data were collected at 3 and 18 months. Results: A total of 278 participants were randomised to the CM arm and 273 were randomised to the control arm. In total, 530 (96%) participants were followed up for the primary outcome. There was no significant difference in time to admission between trial arms by 18 months following consent (hazard ratio 1.03, 95% confidence interval 0.76 to 1.40). There were no statistically significant differences in most secondary outcomes, including cannabis use, at either follow-up assessment. There were 58 serious adverse events, comprising 52 inpatient episodes, five deaths and one arrest. Limitations: Participant retention was low at 18 months, limiting the assessment of secondary outcomes. A different CM intervention design or reward level may have been effective. Conclusions: The CM intervention did not appear to be effective in reducing cannabis use and acute relapse among people with early psychosis and problematic cannabis use. Future work: Cannabis use is still a significant clinical concern in this population. A pressing need remains to identify suitable treatments. A wider perspective on the social circumstances of young people with psychosis may be needed for a successful intervention to be found. Trial registration: Current Controlled Trials ISRCTN33576045. Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 45. See the NIHR Journals Library website for further project information.

Background: Effective interventions are needed to prevent cardiovascular disease (CVD) in people with severe mental illnesses (SMI) because their risk of CVD is higher than that of the general population. Objectives: (1) Develop and validate risk models for predicting CVD events in people with SMI and evaluate their cost-effectiveness, (2) develop an intervention to reduce levels of cholesterol and CVD risk in SMI and (3) test the clinical effectiveness and cost-effectiveness of this new intervention in primary care. Design: Mixed methods with patient and public involvement throughout. The mixed methods were (1) a prospective cohort and risk score validation study and cost-effectiveness modelling, (2) development work (focus groups, updated systematic review of interventions, primary care database studies investigating statin prescribing and effectiveness) and (3) cluster randomised controlled trial (RCT) assessing the clinical effectiveness and cost-effectiveness of a new practitioner-led intervention, and fidelity assessment of audio-recorded appointments. Setting: General practices across England. Participants: All studies included adults with SMI (schizophrenia, bipolar disorder or other non-organic psychosis). The RCT included adults with SMI and two or more CVD risk factors. Interventions: The intervention consisted of 8–12 appointments with a practice nurse/health-care assistant over 6 months, involving collaborative behavioural approaches to CVD risk factors. The intervention was compared with routine practice with a general practitioner (GP). Main outcome measures: The primary outcome for the risk score work was CVD events, in the cost-effectiveness modelling it was quality-adjusted life-years (QALYs) and in the RCT it was level of total cholesterol. Data sources: Databases studies used The Health Improvement Network (THIN). Intervention development work included focus groups and systematic reviews. The RCT collected patient self-reported and routine NHS GP data. Intervention appointments were audio-recorded. Results: Two CVD risk score models were developed and validated in 38,824 people with SMI in THIN: the Primrose lipid model requiring cholesterol levels, and the Primrose body mass index (BMI) model with no blood test. These models performed better than published Cox Framingham models. In health economic modelling, the Primrose BMI model was most cost-effective when used as an algorithm to drive statin prescriptions. Focus groups identified barriers to, and facilitators of, reducing CVD risk in SMI including patient engagement and motivation, staff confidence, involving supportive others, goal-setting and continuity of care. Findings were synthesised with evidence from updated systematic reviews to create the Primrose intervention and training programme. THIN cohort studies in 16,854 people with SMI demonstrated that statins effectively reduced levels of cholesterol, with similar effect sizes to those in general population studies over 12–24 months (mean decrease 1.2 mmol/l). Cluster RCT: 76 GP practices were randomised to the Primrose intervention (n = 38) or treatment as usual (TAU) (n = 38). The primary outcome (level of cholesterol) was analysed for 137 out of 155 participants in Primrose and 152 out of 172 in TAU. There was no difference in levels of cholesterol at 12 months [5.4 mmol/l Primrose vs. 5.5 mmol/l TAU; coefficient 0.03; 95% confidence interval (CI) –0.22 to 0.29], nor in secondary outcomes related to cardiometabolic parameters, well-being or medication adherence. Mean cholesterol levels decreased over 12 months in both arms (–0.22 mmol/l Primrose vs. –0.39 mmol/l TAU). There was a significant reduction in the cost of inpatient mental health attendances (–£799, 95% CI –£1480 to –£117) and total health-care costs (–£895, 95% CI –£1631 to –£160; p = 0.012) in the intervention group, but no significant difference in QALYs (–0.011, 95% CI –0.034 to 0.011). A total of 69% of patients attended two or more Primrose appointments. Audiotapes revealed moderate fidelity to intervention delivery (67.7%). Statin prescribing and adherence was rarely addressed. Limitations: RCT participants and practices may not represent all UK practices. CVD care in the TAU arm may have been enhanced by trial procedures involving CVD risk screening and feedback. Conclusions: SMI-specific CVD risk scores better predict new CVD if used to guide statin prescribing in SMI. Statins are effective in reducing levels of cholesterol in people with SMI in UK clinical practice. This primary care RCT evaluated an evidence-based practitioner-led intervention that was well attended by patients and intervention components were delivered. No superiority was shown for the new intervention over TAU for level of cholesterol, but cholesterol levels decreased over 12 months in both arms and the intervention showed fewer inpatient admissions. There was no difference in cholesterol levels between the intervention and TAU arms, which might reflect better than standard general practice care in TAU, heterogeneity in intervention delivery or suboptimal emphasis on statins. Future work: The new risk score should be updated, deployed and tested in different settings and compared with the latest versions of CVD risk scores in different countries. Future research on CVD risk interventions should emphasise statin prescriptions more. The mechanism behind lower costs with the Primrose intervention needs exploring, including SMI-related training and offering frequent support to people with SMI in primary care. Trial registration: Current Controlled Trials ISRCTN13762819. Funding: This project was funded by the National Institute for Health Research (NIHR) Programme Grants for Applied Research programme and will be published in full in Programme Grants for Applied Research; Vol. 7, No. 2. See the NIHR Journals Library website for further project information. Professor David Osborn is supported by the University College London Hospital NIHR Biomedical Research Centre and he was also in part supported by the NIHR Collaboration for Leadership in Applied Health Research and Care (CLAHRC) North Thames at Barts Health NHS Trust.

Background: Despite the movement towards care in the community, 40% of the NHS budget on mental health care is still attributed to inpatient services. However, long before the Francis Report highlighted grave shortcomings in inpatient care, there were reports by service user groups on the poor quality of these services in mental health. The programme provides a particular focus on the inclusion of the patient’s perspective in the development and evaluation of evidence. Objectives: To understand how changes to inpatient care affect the perceptions of the ward by service users and staff by using stakeholder participatory methods. Design: The programme consisted of four work packages (WPs). (1) Lasting Improvements for Acute Inpatient SEttings (LIAISE): using participatory methods we developed two new scales [Views On Therapeutic Environment (VOTE) for staff and Views On Inpatient CarE (VOICE) for service users]. (2) Client Services Receipt Inventory – Inpatient (CITRINE): working with nurses and service users we developed a health economic measure of the amount of contact service users have with staff. The self-report measure records interactions with staff as well as the number of therapeutic activities attended. (3) Delivering Opportunities for Recovery (DOORWAYS): a stepped-wedge randomised controlled trial to test if training ward nurses to deliver therapeutic group activities would improve the perception of the ward by service users and staff. A total of 16 wards were progressively randomised and we compared the VOICE, VOTE and CITRINE measures before and after the intervention. A total of 1108 service users and 539 staff participated in this trial. (4) Bringing Emergency TreatmenT to Early Resolution (BETTER PATHWAYS) was an observational study comparing two service systems. The first was a ‘triage’ system in which service users were admitted to the triage ward and then either transferred to their locality wards or discharged back into the community within 7 days. The second system was routine care. We collected data from 454 service users and 284 nurses on their perceptions of the wards. Main outcome measures: The main outcomes for the DOORWAYS and BETTER project were service user and staff perceptions of the ward (VOICE and VOTE, respectively) and the health economic measure was CITRINE. All were developed in WPs 1 and 2. Results: We developed reliable and valid measures of (1) the perceptions of inpatient care from the perspectives of service users and nurses (VOICE and VOTE) and (2) costs of interactions that were valued by service users (CITRINE). In the DOORWAYS project, after adjusting for legal status, we found weak evidence for benefit (standardised effect of –0.18, 95% CI 0.38 improvement to 0.01 deterioration; p = 0.062). There was only a significant benefit for involuntary patients following the staff training (N582, standardised effect of –0.35, 95% CI –0.57 to –0.12; p = 0.002; interaction p-value 0.006). VOTE scores did not change over time (standardised effect size of 0.04, 95% CI –0.09 to 0.18; p = 0.54). We found no evidence of an improvement in cost-effectiveness (estimated effect of £33, 95% CI –£91 to £146; p = 0.602), but resource allocation did change towards patient-perceived meaningful contacts by an average of £12 (95% CI –£76 to £98; p = 0·774). There were no significant differences between the triage and routine models of admission in terms of better perceptions by service users (estimated effect 0.77-point improvement in VOICE score on the triage ward; p = 0.68) or nurses (estimated effect of 1.68-point deterioration in VOTE on the triage ward; p = 0.38) or in terms of the cost of the length of care provided (£391 higher on triage; p = 0.77). Strengths and limitations: We have developed measures using methods involving both service users and staff from mental health services. The measures were developed specifically for acute inpatient services and, therefore, cannot be assumed to be useful for other services. For instance, extensions of the measures are under construction for use in mother and baby units. The strength of the BETTER PATHWAYS and DOORWAYS projects is the large-scale data collection. However, we were testing specific services based in inner city areas and stretching to inner urban areas. It may be that different effects would be found in more rural communities or in different types of inpatient care. Future work: Our database will be used to develop an understanding of the mediating and moderating factors for improving care quality. Trial registration: Current Controlled Trials ISRCTN06545047. Funding: This project was funded by the NIHR Programme Grants for Applied Research programme and will be published in full in Programme Grants for Applied Research; Vol. 6, No. 7. See the NIHR Journals Library website for further project information.

Uveal melanoma (UM) is the most prevalent cancer of the eye in adults, driven by activating mutation of GNAQ/GNA11; however, there are limited therapies against UM and metastatic UM (mUM). Here, we perform a high-throughput chemogenetic drug screen in GNAQ-mutant UM contrasted with BRAF-mutant cutaneous melanoma, defining the druggable landscape of these distinct melanoma subtypes. Across all compounds, darovasertib demonstrates the highest preferential activity against UM. Our investigation reveals that darovasertib potently inhibits PKC as well as PKN/PRK, an AGC kinase family that is part of the "dark kinome." We find that downstream of the Gαq-RhoA signaling axis, PKN converges with ROCK to control FAK, a mediator of non-canonical Gαq-driven signaling. Strikingly, darovasertib synergizes with FAK inhibitors to halt UM growth and promote cytotoxic cell death in vitro and in preclinical metastatic mouse models, thus exposing a signaling vulnerability that can be exploited as a multimodal precision therapy against mUM.

The bowhead whale (Balaena mysticetus) is estimated to live over 200 years and is possibly the longest-living mammal. These animals should possess protective molecular adaptations relevant to age-related diseases, particularly cancer. Here, we report the sequencing and comparative analysis of the bowhead whale genome and two transcriptomes from different populations. Our analysis identifies genes under positive selection and bowhead-specific mutations in genes linked to cancer and aging. In addition, we identify gene gain and loss involving genes associated with DNA repair, cell-cycle regulation, cancer, and aging. Our results expand our understanding of the evolution of mammalian longevity and suggest possible players involved in adaptive genetic changes conferring cancer resistance. We also found potentially relevant changes in genes related to additional processes, including thermoregulation, sensory perception, dietary adaptations, and immune response. Our data are made available online (http://www.bowhead-whale.org) to facilitate research in this long-lived species.

Background Mobile health technology's impact on cardiovascular risk factor control is not fully understood. This study evaluates the association between interaction with a mobile health application and change in cardiovascular risk factors. Methods and Results Participants with hypertension with or without dyslipidemia enrolled in a workplace‐deployed mobile health application‐based cardiovascular risk self‐management program between January 2018 and December 2022. Retrospective evaluation explored the influence of application engagement on change in blood pressure (BP), total cholesterol (TC), low‐density lipoprotein cholesterol (LDL‐C), and weight. Multiple regression analyses examined the influence of guideline‐based, nonpharmacological lifestyle‐based digital coaching on outcomes adjusting for confounders. Of 102 475 participants, 49.1% were women. Median age was 53 (interquartile range, 43–61) years, BP was 134 (interquartile range, 124–144)/84 (interquartile range, 78–91) mm Hg, TC was 183 (interquartile range, 155–212) mg/dL, LDL‐C was 106 (82–131) mg/dL, and body mass index was 30 (26–35) kg/m2. At 2 years, participants with baseline systolic BP ≥140 mm Hg reduced systolic BP by 18.6 (SEM, 0.3) mm Hg. At follow up, participants with baseline TC ≥240 mg/dL reduced TC by 65.7 (SEM, 4.6) mg/dL, participants with baseline LDL‐C≥160 mg/dL reduced LDL‐C by 66.6 (SEM, 6.2) mg/dL, and participants with baseline body mass index ≥30 kg/m2 lost 12.0 (SEM, 0.3) pounds, or 5.1% of body weight. Interaction with digital coaching was associated with greater reduction in all outcomes. Conclusions A mobile health application‐based cardiovascular risk self‐management program was associated with favorable reductions in BP, TC, LDL‐C, and weight, highlighting the potential use of this technology in comprehensive cardiovascular risk factor control.

Cancer mortality is primarily a consequence of its metastatic spread. Here, we report that methionine sulfoxide reductase A (MSRA), which can reduce oxidized methionine residues, acts as a suppressor of pancreatic ductal adenocarcinoma (PDA) metastasis. MSRA expression is decreased in the metastatic tumors of PDA patients, whereas MSRA loss in primary PDA cells promotes migration and invasion. Chemoproteomic profiling of pancreatic organoids revealed that MSRA loss results in the selective oxidation of a methionine residue (M239) in pyruvate kinase M2 (PKM2). Moreover, M239 oxidation sustains PKM2 in an active tetrameric state to promote respiration, migration, and metastasis, whereas pharmacological activation of PKM2 increases cell migration and metastasis in vivo. These results demonstrate that methionine residues can act as reversible redox switches governing distinct signaling outcomes and that the MSRA-PKM2 axis serves as a regulatory nexus between redox biology and cancer metabolism to control tumor metastasis.

Dietary restriction (DR), limiting nutrient intake from diet without causing malnutrition, delays the aging process and extends lifespan in multiple organisms. The conserved life-extending effect of DR suggests the involvement of fundamental mechanisms, although these remain a subject of debate. To help decipher the life-extending mechanisms of DR, we first compiled a list of genes that if genetically altered disrupt or prevent the life-extending effects of DR. We called these DR-essential genes and identified more than 100 in model organisms such as yeast, worms, flies, and mice. In order for other researchers to benefit from this first curated list of genes essential for DR, we established an online database called GenDR (http://genomics.senescence.info/diet/). To dissect the interactions of DR-essential genes and discover the underlying lifespan-extending mechanisms, we then used a variety of network and systems biology approaches to analyze the gene network of DR. We show that DR-essential genes are more conserved at the molecular level and have more molecular interactions than expected by chance. Furthermore, we employed a guilt-by-association method to predict novel DR-essential genes. In budding yeast, we predicted nine genes related to vacuolar functions; we show experimentally that mutations deleting eight of those genes prevent the life-extending effects of DR. Three of these mutants (OPT2, FRE6, and RCR2) had extended lifespan under ad libitum, indicating that the lack of further longevity under DR is not caused by a general compromise of fitness. These results demonstrate how network analyses of DR using GenDR can be used to make phenotypically relevant predictions. Moreover, gene-regulatory circuits reveal that the DR-induced transcriptional signature in yeast involves nutrient-sensing, stress responses and meiotic transcription factors. Finally, comparing the influence of gene expression changes during DR on the interactomes of multiple organisms led us to suggest that DR commonly suppresses translation, while stimulating an ancient reproduction-related process.

BackgroundRegular physical activity is critical for health and disease prevention. Yet, health care providers and patients face barriers to implement evidence-based lifestyle recommendations. The potential to augment care with the increased availability of artificial intelligence (AI) technologies is limitless; however, the suitability of AI-generated exercise recommendations has yet to be explored. ObjectiveThe purpose of this study was to assess the comprehensiveness, accuracy, and readability of individualized exercise recommendations generated by a novel AI chatbot. MethodsA coding scheme was developed to score AI-generated exercise recommendations across ten categories informed by gold-standard exercise recommendations, including (1) health condition–specific benefits of exercise, (2) exercise preparticipation health screening, (3) frequency, (4) intensity, (5) time, (6) type, (7) volume, (8) progression, (9) special considerations, and (10) references to the primary literature. The AI chatbot was prompted to provide individualized exercise recommendations for 26 clinical populations using an open-source application programming interface. Two independent reviewers coded AI-generated content for each category and calculated comprehensiveness (%) and factual accuracy (%) on a scale of 0%-100%. Readability was assessed using the Flesch-Kincaid formula. Qualitative analysis identified and categorized themes from AI-generated output. ResultsAI-generated exercise recommendations were 41.2% (107/260) comprehensive and 90.7% (146/161) accurate, with the majority (8/15, 53%) of inaccuracy related to the need for exercise preparticipation medical clearance. Average readability level of AI-generated exercise recommendations was at the college level (mean 13.7, SD 1.7), with an average Flesch reading ease score of 31.1 (SD 7.7). Several recurring themes and observations of AI-generated output included concern for liability and safety, preference for aerobic exercise, and potential bias and direct discrimination against certain age-based populations and individuals with disabilities. ConclusionsThere were notable gaps in the comprehensiveness, accuracy, and readability of AI-generated exercise recommendations. Exercise and health care professionals should be aware of these limitations when using and endorsing AI-based technologies as a tool to support lifestyle change involving exercise.

Abstract Background The recently approved anti-AIDS drug rilpivirine (TMC278, Edurant) is a nonnucleoside inhibitor (NNRTI) that binds to reverse transcriptase (RT) and allosterically blocks the chemical step of DNA synthesis. In contrast to earlier NNRTIs, rilpivirine retains potency against well-characterized, clinically relevant RT mutants. Many structural analogues of rilpivirine are described in the patent literature, but detailed analyses of their antiviral activities have not been published. This work addresses the ability of several of these analogues to inhibit the replication of wild-type (WT) and drug-resistant HIV-1. Results We used a combination of structure activity relationships and X-ray crystallography to examine NNRTIs that are structurally related to rilpivirine to determine their ability to inhibit WT RT and several clinically relevant RT mutants. Several analogues showed broad activity with only modest losses of potency when challenged with drug-resistant viruses. Structural analyses (crystallography or modeling) of several analogues whose potencies were reduced by RT mutations provide insight into why these compounds were less effective. Conclusions Subtle variations between compounds can lead to profound differences in their activities and resistance profiles. Compounds with larger substitutions replacing the pyrimidine and benzonitrile groups of rilpivirine, which reorient pocket residues, tend to lose more activity against the mutants we tested. These results provide a deeper understanding of how rilpivirine and related compounds interact with the NNRTI binding pocket and should facilitate development of novel inhibitors.