The chemokine receptor CCR8 is not a high-affinity receptor for the human chemokine CCL18.

The primate-specific chemokine CCL18 is a potent chemoattractant for T cells and is expressed at elevated levels in several inflammatory diseases. However, the cognate receptor for CCL18 remains unconfirmed. Here, we describe attempts to validate a previous report that the chemokine receptor CCR8 is the human CCL18 receptor (Islam et al. J Exp Med. 2013, 210:1889-98). Two mouse pre-B cell lines (4DE4 and L1.2) exogenously expressing CCR8 exhibited robust migration in response to the known CCR8 ligand CCL1 but not to CCL18. Similarly, CCL1 but not CCL18 induced internalization of CCR8 on 4DE4 cells. CCR8 expressed on Chinese hamster ovarian (CHO) cells mediated robust G protein activation, inhibition of cAMP synthesis and ß-arrestin2 recruitment in response to CCL1 but not CCL18. Several N- and C-terminal variants of CCL18 also failed to stimulate CCR8 activation. On the other hand, and as previously reported, CCL18 inhibited CCL11-stimulated migration of 4DE4 cells expressing the receptor CCR3. These data suggest that CCR8, at least in the absence of unidentified cofactors, does not function as a high affinity receptor for CCL18.

Health Service Utilization Patterns Among Medicaid Enrollees With Intellectual and Developmental Disabilities Before and During the COVID-19 Pandemic: Implications for Pandemic Response and Recovery Efforts.

OBJECTIVES: To assess the impact of COVID-19 on health service utilization of adults with intellectual and developmental disabilities (IDDs) through an analysis of Medicaid claims data. DESIGN: Retrospective cohort study of Medicaid claims. SETTING AND PARTICIPANTS: Medicaid members aged 25 to 64 years from January 1, 2018, to March 31, 2021, from the states of Louisiana, Pennsylvania, and Wyoming. INTERVENTION: We analyzed data from two 12-month time periods (pre-COVID-19 and during COVID-19) and assessed the potential impact of the COVID-19 pandemic on health service utilization and service intensity for 3 cohorts: (1) IDD with preexisting mental health diagnoses, (2) IDD without mental health diagnoses, and (3) all other Medicaid members. MAIN OUTCOME MEASURE: Health service utilization determined by specific claims data classifications. RESULTS: The analysis showed reduced utilization for nonmental health service types with differing utilization patterns for IDD with preexisting mental health diagnoses, IDD without mental health diagnoses, and all other Medicaid members. Change in utilization varied, however, for mental health service types. Measures of service intensity showed decreased numbers of members utilizing services across most service types and increased Medicaid claims per person across most mental health service categories but decreased Medicaid claims per person for most nonmental health services. CONCLUSIONS: Results suggest a need for mental health services among all Medicaid members during the COVID-19 pandemic. By anticipating these needs, communities may be able to expand outreach to Medicaid members through enhanced case management, medication checks, and telemedicine options.

Photo-BQCA: Positive Allosteric Modulators Enabling Optical Control of the M1 Receptor.

The field of G protein-coupled receptor (GPCR) research has greatly benefited from the spatiotemporal resolution provided by light controllable, photoswitchable agents. Most of the developed tools have targeted the Rhodopsin-like family (Class A), the largest family of GPCRs. However, to date, all such Class A photoswitchable ligands were designed to act at the orthosteric binding site of these receptors. Herein, we report the development of the first photoswitchable allosteric modulators of Class A GPCRs, designed to target the M1 muscarinic acetylcholine receptor. The presented benzyl quinolone carboxylic acid (BQCA) derivatives, photo-BQCisA and photo-BQCtrAns, exhibit complementary photopharmacological behavior and allow reversible control over the receptor using light as an external stimulus. This makes them valuable tools to further investigate M1 receptor signaling and a proof of concept for photoswitchable allosteric modulators at Class A receptors.

A Systematic Review and Meta-Analysis of Therapeutic Hypothermia and Pharmacological Cotherapies in Animal Models of Ischemic Stroke.

Therapeutic hypothermia (TH) lessens ischemic brain injury. Cytoprotective agents can augment protection, although it is unclear which combinations are most effective. The objective of this study is to identify which cytoprotective drug works best with delayed TH. Following PRISMA guidelines, a systematic review (PubMed, Web of Science, MEDLINE, Scopus) identified controlled experiments that used an in vivo focal ischemic stroke model and evaluated the efficacy of TH (delay of ≥1 hour) coupled with cytoprotective agents. This combination was our main intervention compared with single treatments with TH, drug, or no treatment. Endpoints were brain injury and neurological impairment. The CAMARADES checklist for study quality and the SYRCLE's risk of bias tool gauged study quality. Twenty-five studies were included. Most used young, healthy male rats, with only one using spontaneously hypertensive rats. Two studies used mice models, and six used adult animals. Study quality was moderate (median score = 6), and risk of bias was high. Pharmacological agents provided an additive effect on TH for all outcomes measured. Magnesium coupled with TH had the greatest impact compared with other agent-TH combinations on all outcomes. Longer TH durations improved both behavioral and histological outcomes and had greater cytoprotective efficacy than shorter durations. Anti-inflammatories were the most effective in reducing infarction (standardized mean difference [SMD]: -1.64, confidence interval [CI]: [-2.13, -1.15]), sulfonylureas reduced edema the most (SMD: -2.32, CI: [-3.09, -1.54]), and antiapoptotic agents improved behavioral outcomes the most (normalized mean difference: 52.38, CI: [45.29, 59.46]). Statistically significant heterogeneity was observed (I2 = 82 - 98%, all p < 0.001), indicating that studies wildly differ in their effect size estimates. Our results support the superiority of adding cytoprotective therapies with TH (vs. individual or no therapy). Additional exploratory and confirmatory studies are required to identify and thoroughly assess combination therapies owing to limited work and inconsistent translational quality.

Leveraging Science to Advance Health Equity: Preliminary Considerations for Implementing Health Equity Science at State and Local Health Departments.

CONTEXT: In 2021, the Centers for Disease Control and Prevention (CDC) launched CORE, an agency-wide strategy to embed health equity as a foundational component across all areas of the agency's work. The CDC established a definition of health equity science (HES) and principles to guide the development, implementation, dissemination, and use of the HES framework to move beyond documenting inequities to investigating root causes and promoting actionable approaches to eliminate health inequities. The HES framework may be used by state and local health departments to advance health equity efforts in their jurisdictions. OBJECTIVE: Identify implementation considerations and opportunities for providing technical assistance and support to state and local public health departments in advancing HES. DESIGN: A series of implementation consultations and multi-jurisdictional facilitated discussions were held with state and local health departments and community partners in 5 states to gather feedback on the current efforts, opportunities, and support needs to advance HES at the state and local levels. The information shared during these activities was analyzed using inductive and deductive methods, validated with partners, and summarized into themes and HES implementation considerations. RESULTS: Five themes emerged regarding current efforts, opportunities, and support needed to implement HES at state and local health departments. These themes included the following criteria: (1) enhancing the existing health equity evidence base; (2) addressing interdisciplinary public health practice and data needs; (3) recognizing the value of qualitative data; (4) evaluating health equity programs and policies; and (5) including impacted communities in the full life cycle of health equity efforts. Within these themes, we identified HES implementation considerations, which may be leveraged to inform future efforts to advance HES at the state and local levels. CONCLUSION: Health equity efforts at state and local health departments may be strengthened by leveraging the HES framework and implementation considerations.

Conservative management versus invasive management of significant traumatic pneumothoraces in the emergency department (the CoMiTED trial): a study protocol for a randomised non-inferiority trial.

INTRODUCTION: Traumatic pneumothoraces are present in one of five victims of severe trauma. Current guidelines advise chest drain insertion for most traumatic pneumothoraces, although very small pneumothoraces can be managed with observation at the treating clinician's discretion. There remains a large proportion of patients in whom there is clinical uncertainty as to whether an immediate chest drain is required, with no robust evidence to inform practice. Chest drains carry a high risk of complications such as bleeding and infection. The default to invasive treatment may be causing potentially avoidable pain, distress and complications. We are evaluating the clinical and cost-effectiveness of an initial conservative approach to the management of patients with traumatic pneumothoraces. METHODS AND ANALYSIS: The CoMiTED (Conservative Management in Traumatic Pneumothoraces in the Emergency Department) trial is a multicentre, pragmatic parallel group, individually randomised controlled non-inferiority trial to establish whether initial conservative management of significant traumatic pneumothoraces is non-inferior to invasive management in terms of subsequent emergency pleural interventions, complications, pain, breathlessness and quality of life. We aim to recruit 750 patients from at least 40 UK National Health Service hospitals. Patients allocated to the control (invasive management) group will have a chest drain inserted in the emergency department. For those in the intervention (initial conservative management) group, the treating clinician will be advised to manage the participant without chest drain insertion and undertake observation. The primary outcome is a binary measure of the need for one or more subsequent emergency pleural interventions within 30 days of randomisation. Secondary outcomes include complications, cost-effectiveness, patient-reported quality of life and patient and clinician views of the two treatment options; participants are followed up for 6 months. ETHICS AND DISSEMINATION: This trial received approval from the Wales Research Ethics Committee 4 (reference: 22/WA/0118) and the Health Research Authority. Results will be submitted for publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: ISRCTN35574247.

Enantioselective de novo synthesis of 14-hydroxy-6-oxomorphinans.

The enantioselective de novo synthesis of pharmacologically important 14-hydroxy-6-oxomorphinans is described. 4,5-Desoxynaltrexone and 4,5-desoxynaloxone were prepared using this route and their biological activities against the opioid receptors were measured.

Prostate-Specific Antigen Screening and 15-Year Prostate Cancer Mortality: A Secondary Analysis of the CAP Randomized Clinical Trial.

Importance: The Cluster Randomized Trial of PSA Testing for Prostate Cancer (CAP) reported no effect of prostate-specific antigen (PSA) screening on prostate cancer mortality at a median 10-year follow-up (primary outcome), but the long-term effects of PSA screening on prostate cancer mortality remain unclear. Objective: To evaluate the effect of a single invitation for PSA screening on prostate cancer-specific mortality at a median 15-year follow-up compared with no invitation for screening. Design, Setting, and Participants: This secondary analysis of the CAP randomized clinical trial included men aged 50 to 69 years identified at 573 primary care practices in England and Wales. Primary care practices were randomized between September 25, 2001, and August 24, 2007, and men were enrolled between January 8, 2002, and January 20, 2009. Follow-up was completed on March 31, 2021. Intervention: Men received a single invitation for a PSA screening test with subsequent diagnostic tests if the PSA level was 3.0 ng/mL or higher. The control group received standard practice (no invitation). Main Outcomes and Measures: The primary outcome was reported previously. Of 8 prespecified secondary outcomes, results of 4 were reported previously. The 4 remaining prespecified secondary outcomes at 15-year follow-up were prostate cancer-specific mortality, all-cause mortality, and prostate cancer stage and Gleason grade at diagnosis. Results: Of 415 357 eligible men (mean [SD] age, 59.0 [5.6] years), 98% were included in these analyses. Overall, 12 013 and 12 958 men with a prostate cancer diagnosis were in the intervention and control groups, respectively (15-year cumulative risk, 7.08% [95% CI, 6.95%-7.21%] and 6.94% [95% CI, 6.82%-7.06%], respectively). At a median 15-year follow-up, 1199 men in the intervention group (0.69% [95% CI, 0.65%-0.73%]) and 1451 men in the control group (0.78% [95% CI, 0.73%-0.82%]) died of prostate cancer (rate ratio [RR], 0.92 [95% CI, 0.85-0.99]; P = .03). Compared with the control, the PSA screening intervention increased detection of low-grade (Gleason score [GS] ≤6: 2.2% vs 1.6%; P < .001) and localized (T1/T2: 3.6% vs 3.1%; P < .001) disease but not intermediate (GS of 7), high-grade (GS ≥8), locally advanced (T3), or distally advanced (T4/N1/M1) tumors. There were 45 084 all-cause deaths in the intervention group (23.2% [95% CI, 23.0%-23.4%]) and 50 336 deaths in the control group (23.3% [95% CI, 23.1%-23.5%]) (RR, 0.97 [95% CI, 0.94-1.01]; P = .11). Eight of the prostate cancer deaths in the intervention group (0.7%) and 7 deaths in the control group (0.5%) were related to a diagnostic biopsy or prostate cancer treatment. Conclusions and Relevance: In this secondary analysis of a randomized clinical trial, a single invitation for PSA screening compared with standard practice without routine screening reduced prostate cancer deaths at a median follow-up of 15 years. However, the absolute reduction in deaths was small. Trial Registration: isrctn.org Identifier: ISRCTN92187251.

Romosozumab in patients who experienced an on-study fracture: post hoc analyses of the FRAME and ARCH phase 3 trials.

Post hoc analysis of FRAME and ARCH revealed that on-study nonvertebral and vertebral fractures by Month 12 were less common in women initially treated with romosozumab versus placebo or alendronate. Recurrent fracture risk was also lower in romosozumab­treated patients, and there were no fracture­related complications. Results support continuing romosozumab treatment post­fracture. PURPOSE: Post hoc analysis evaluating efficacy and safety of romosozumab, administered in the immediate post­fracture period, in the FRAME and ARCH phase 3 trials. METHODS: In FRAME (NCT01575834) and ARCH (NCT01631214), postmenopausal women with osteoporosis were randomized 1:1 to romosozumab 210 mg monthly or comparator (FRAME, placebo; ARCH, alendronate 70 mg weekly) for 12 months, followed by antiresorptive therapy (FRAME, denosumab; ARCH, alendronate). In patients who experienced on-study nonvertebral or new/worsening vertebral fracture by Month 12, we report the following: fracture and treatment­emergent adverse event (TEAE) incidence through 36 months, bone mineral density changes (BMD), and romosozumab timing. Due to the sample sizes employed, meaningful statistical comparisons between treatments were not possible. RESULTS: Incidence of on-study nonvertebral and vertebral fractures by Month 12 was numerically lower in romosozumab- versus comparator-treated patients (FRAME, 1.6% and 0.5% versus 2.1% and 1.6%; ARCH, 3.4% and 3.3% versus 4.6% and 4.9%, respectively). In those who experienced on-study nonvertebral fracture by Month 12, recurrent nonvertebral and subsequent vertebral fracture incidences were numerically lower in patients initially treated with romosozumab versus comparator (FRAME, 3.6% [2/56] and 1.8% [1/56] versus 9.2% [7/76] and 3.9% [3/76]; ARCH, 10.0% [7/70] and 5.7% [4/70] versus 12.6% [12/95] and 8.4% [8/95], respectively). Among those with on-study vertebral fracture by Month 12, recurrent vertebral and subsequent nonvertebral fracture incidences were numerically lower with romosozumab versus comparator (FRAME, 0.0% [0/17] and 0.0% [0/17] versus 11.9% [7/59] and 8.5% [5/59]; ARCH, 9.0% [6/67] and 7.5% [5/67] versus 15.0% [15/100] and 16.0% [16/100], respectively). In patients with fracture by Month 12, no fracture­related complications were reported in romosozumab-treated patients. BMD gains were numerically greater with romosozumab than comparators. CONCLUSION: Data suggest support for the efficacy and safety of continuing romosozumab treatment following fracture. TRIAL REGISTRATIONS: NCT01575834; NCT01631214.

Lower urinary tract symptoms in men: the TRIUMPH cluster RCT.

Background: Conservative therapies are recommended as initial treatment for male lower urinary tract symptoms. However, there is a lack of evidence on effectiveness and uncertainty regarding approaches to delivery. Objective: The objective was to determine whether or not a standardised and manualised care intervention delivered in primary care achieves superior symptomatic outcome for lower urinary tract symptoms to usual care. Design: This was a two-arm cluster randomised controlled trial. Setting: The trial was set in 30 NHS general practice sites in England. Participants: Participants were adult men (aged ≥ 18 years) with bothersome lower urinary tract symptoms. Interventions: Sites were randomised 1 : 1 to deliver the TReatIng Urinary symptoms in Men in Primary Health care using non-pharmacological and non-surgical interventions trial intervention or usual care to all participants. The TReatIng Urinary symptoms in Men in Primary Health care using non-pharmacological and non-surgical interventions intervention comprised a standardised advice booklet developed for the trial from the British Association of Urological Surgeons' patient information sheets, with patient and expert input. Patients were directed to relevant sections by general practice or research nurses/healthcare assistants following urinary symptom assessment, providing the manualised element. The healthcare professional provided follow-up contacts over 12 weeks to support adherence to the intervention. Main outcome measures: The primary outcome was the validated patient-reported International Prostate Symptom Score 12 months post consent. Rather than the minimal clinically important difference of 3.0 points for overall International Prostate Symptom Score, the sample size aimed to detect a difference of 2.0 points, owing to the recognised clinical impact of individual symptoms. Results: A total of 1077 men consented to the study: 524 in sites randomised to the intervention arm (n = 17) and 553 in sites randomised to the control arm (n = 13). A difference in mean International Prostate Symptom Score at 12 months was found (adjusted mean difference of -1.81 points, 95% confidence interval -2.66 to -0.95 points), with a lower score in the intervention arm, indicating less severe symptoms. Secondary outcomes of patient-reported urinary symptoms, quality of life specific to lower urinary tract symptoms and perception of lower urinary tract symptoms all showed evidence of a difference between the arms favouring the intervention. No difference was seen between the arms in the proportion of urology referrals or adverse events. In qualitative interviews, participants welcomed the intervention, describing positive effects on their symptoms, as well as on their understanding of conservative care and their attitude towards the experience of lower urinary tract symptoms. The interviews highlighted that structured, in-depth self-management is insufficiently embedded within general practitioner consultations. From an NHS perspective, mean costs and quality-adjusted life-years were similar between trial arms. The intervention arm had slightly lower mean costs (adjusted mean difference of -£29.99, 95% confidence interval -£109.84 to £22.63) than the usual-care arm, and a small gain in quality-adjusted life-years (adjusted mean difference of 0.001, 95% confidence interval -0.011 to 0.014). Conclusions: The intervention showed a small, sustained benefit for men's lower urinary tract symptoms and quality of life across a range of outcome measures in a UK primary care setting. Qualitative data showed that men highly valued the intervention. Intervention costs were marginally lower than usual-care costs. Limitations of the study included that trial participants were unmasked, with limited diversity in ethnicity and deprivation level. Additional research is needed to assess the applicability of the intervention for a more ethnically diverse population.. Trial registration: This trial is registered as ISRCTN11669964. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 16/90/03) and is published in full in Health Technology Assessment; Vol. 28, No. 13. See the NIHR Funding and Awards website for further award information.

Urinary problems among men become more common with age. Nearly one-third of all men aged > 65 years experience some urinary symptoms, which can have a substantial effect on their daily lives. Symptoms include needing to pass urine more often, urgently or during the night, and difficulties in passing urine. Men are usually diagnosed and treated by their general practitioner, and should be offered advice on controlling their symptoms themselves (e.g. lifestyle changes and exercises) before trying tablets or surgery. However, it is not known how helpful such advice is, and how general practices can effectively provide it. Thirty general practices in the West of England and Wessex took part in the study. Practices were split into two groups, with each practice providing either the TReatIng Urinary symptoms in Men in Primary Health care using non-pharmacological and non-surgical interventions care package or the practice's usual care to all of its patients in the trial. The TReatIng Urinary symptoms in Men in Primary Healthcare using nonpharmacological and non-surgical interventions care package included a booklet of advice to help control urinary symptoms, with a nurse or healthcare assistant directing men to relevant sections according to their symptoms, and providing follow-up contacts. We mainly assessed the benefits of the TReatIng Urinary symptoms in Men in Primary Healthcare using nonpharmacological and non-surgical interventions care package, compared with usual care, by using a questionnaire on urinary symptoms completed by participants. A total of 1077 men with urinary symptoms that bothered them joined the study. The main result was that men reported greater improvement in urinary symptoms with the TRIUMPH care package than with usual care, 12 months after joining the study. We also found that men receiving the TRIUMPH care package had a slight improvement in quality of life and outlook on their urinary symptoms. There was no difference between the two groups in the number of patients referred to hospital for treatment, the type, number and severity of side effects or cost to the NHS. Overall, the TRIUMPH care package was more effective in treating men with urinary symptoms than usual care by their general practice.

Discovery of the First-in-Class Inhibitors of Hypoxia Up-Regulated Protein†1 (HYOU1) Suppressing Pathogenic Fibroblast Activation.

Fibroblasts are key regulators of inflammation, fibrosis, and cancer. Targeting their activation in these complex diseases has emerged as a novel strategy to restore tissue homeostasis. Here, we present a multidisciplinary lead discovery approach to identify and optimize small molecule inhibitors of pathogenic fibroblast activation. The study encompasses medicinal chemistry, molecular phenotyping assays, chemoproteomics, bulk RNA-sequencing analysis, target validation experiments, and chemical absorption, distribution, metabolism, excretion and toxicity (ADMET)/pharmacokinetic (PK)/in vivo evaluation. The parallel synthesis employed for the production of the new benzamide derivatives enabled us to a) pinpoint key structural elements of the scaffold that provide potent fibroblast-deactivating effects in cells, b) discriminate atoms or groups that favor or disfavor a desirable ADMET profile, and c) identify metabolic "hot spots". Furthermore, we report the discovery of the first-in-class inhibitor leads for hypoxia up-regulated protein 1 (HYOU1), a member of the heat shock protein 70 (HSP70) family often associated with cellular stress responses, particularly under hypoxic conditions. Targeting HYOU1 may therefore represent a potentially novel strategy to modulate fibroblast activation and treat chronic inflammatory and fibrotic disorders.

In Vitro Functional Profiling of Fentanyl and Nitazene Analogs at the µ-Opioid Receptor Reveals High Efficacy for Gi Protein Signaling.

Novel synthetic opioids (NSOs), including both fentanyl and non-fentanyl analogs that act as µ-opioid receptor (MOR) agonists, are associated with serious intoxication and fatal overdose. Previous studies proposed that G-protein-biased MOR agonists are safer pain medications, while other evidence indicates that low intrinsic efficacy at MOR better explains the reduced opioid side effects. Here, we characterized the in vitro functional profiles of various NSOs at the MOR using adenylate cyclase inhibition and ß-arrestin2 recruitment assays, in conjunction with the application of the receptor depletion approach. By fitting the concentration-response data to the operational model of agonism, we deduced the intrinsic efficacy and affinity for each opioid in the Gi protein signaling and ß-arrestin2 recruitment pathways. Compared to the reference agonist [d-Ala2,N-MePhe4,Gly-ol5]enkephalin, we found that several fentanyl analogs were more efficacious at inhibiting cAMP production, whereas all fentanyl analogs were less efficacious at recruiting ß-arrestin2. In contrast, the non-fentanyl 2-benzylbenzimidazole (i.e., nitazene) analogs were highly efficacious and potent in both the cAMP and ß-arrestin2 assays. Our findings suggest that the high intrinsic efficacy of the NSOs in Gi protein signaling is a common property that may underlie their high risk of intoxication and overdose, highlighting the limitation of using in vitro functional bias to predict the adverse effects of opioids. In addition, the extremely high potency of many NSOs now infiltrating illicit drug markets further contributes to the danger posed to public health.

Regulations and Funding to Create Enterprise Architecture for a Nationwide Health Data Ecosystem.

The COVID-19 pandemic highlighted the United States' lack of a nationwide infrastructure for collecting, sharing, and using health data, especially for secondary uses (e.g., population health management and public health). The federal government is taking several important steps to upgrade the nation's health data ecosystem-notably, the Centers for Disease Control and Prevention's Data Modernization Initiative and the Office of the National Coordinator for Health Information Technology's Trusted Exchange Framework and Common Agreement. However, substantial barriers remain. Inconsistent regulations, infrastructure, and governance across federal and state levels and between states significantly impede the exchange and analysis of health data. Siloed systems and insufficient funding block effective integration of clinical, public health, and social determinants data within and between states. In this analytic essay, we propose strategies to develop a nationwide health data ecosystem. We focus on providing federal guidance and incentives to develop state-designated entities responsible for the collection, integration, and analysis of clinical, public health, social determinants of health, claims, administrative, and other relevant data. These recommendations include a regulatory clearinghouse, federal guidance, model legislation and templated regulation, funding to incentive enterprise architecture, regulatory sandboxes, and a 3-pronged research agenda. (Am J Public Health. 2024;114(2):209-217. https://doi.org/10.2105/AJPH.2023.307477).

Predicting Prostate Surgery Outcomes from Standard Clinical Assessments of Lower Urinary Tract Symptoms To Derive Prognostic Symptom and Flowmetry Criteria.

BACKGROUND: Assessment of male lower urinary tract symptoms (LUTS) needs to identify predictors of symptom outcomes when interventional treatment is planned. OBJECTIVE: To develop a novel prediction model for prostate surgery outcomes and validate it using a separate patient cohort and derive thresholds for key clinical parameters. DESIGN, SETTING, AND PARTICIPANTS: From the UPSTREAM trial of 820 men seeking treatment for LUTS, analysis of bladder diary (BD), International Prostate Symptom Score (IPSS), IPSS-quality of life, and uroflowmetry data was performed for 176 participants who underwent prostate surgery and provided complete data. For external validation, data from a retrospective database of surgery outcomes in a Japanese urology department (n = 227) were used. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Symptom improvement was defined as a reduction in total IPSS of ≥3 points. Multiple logistic regression, classification tree analysis, and random forest models were generated, including versions with and without BD data. RESULTS AND LIMITATIONS: Multiple logistic regression without BD data identified age (p = 0.029), total IPSS (p = 0.0016), and maximum flow rate (Qmax; p = 0.066) as predictors of outcomes, with area under the receiver operating characteristic curve (AUC) of 77.1%. Classification tree analysis without BD data gave thresholds of IPSS <16 and Qmax ≥13 ml/s (AUC 75.0%). The random forest model, which included all clinical parameters except BD data, had an AUC of 94.7%. Internal validation using the bootstrap method showed reasonable AUCs (69.6-85.8%). Analyses using BD data marginally improved the model fits. External validation gave comparable AUCs for logistic regression, classification tree analysis, and random forest models (all without BD; 70.9%, 67.3%, and 68.5%, respectively). Limitations include the significant number of men with incomplete baseline data and limited assessments in the external validation cohort. CONCLUSIONS: Outcomes of prostate surgery can be predicted preoperatively using age, total IPSS, and uroflowmetry data, with prognostic thresholds of 16 for IPSS and 13 ml/s for Qmax. PATIENT SUMMARY: This study identified key preoperative factors that can predict outcomes of prostate surgery for bothersome urinary symptoms, including which patients are at risk of a poor outcome.

An Assessment of Physical and N6-Cyclohexyladenosine-Induced Hypothermia in Rodent Distal Focal Ischemic Stroke.

Therapeutic hypothermia (TH) mitigates damage in ischemic stroke models. However, safer and easier TH methods (e.g., pharmacological) are needed to circumvent physical cooling complications. This study evaluated systemic and pharmacologically induced TH using the adenosine A1 receptor agonist, N6-cyclohexyladenosine (CHA), with control groups in male Sprague-Dawley rats. CHA was administered intraperitoneally 10 minutes following a 2-hour intraluminal middle cerebral artery occlusion. We used a 1.5 mg/kg induction dose, followed by three 1.0 mg/kg doses every 6 hours for a total of 4 doses, causing 20-24 hours of hypothermia. Animals assigned to physical hypothermia and CHA-hypothermia had similar induction rates and nadir temperatures, but forced cooling lasted ∼6 hours longer compared with CHA-treated animals. The divergence is likely attributable to individual differences in CHA metabolism, which led to varied durations at nadir, whereas physical hypothermia was better regulated. Physical hypothermia significantly reduced infarction (primary endpoint) on day 7 (mean reduction of 36.8 mm3 or 39% reduction; p = 0.021 vs. normothermic animals; Cohen's d = 0.75), whereas CHA-induced hypothermia did not (p = 0.33). Similarly, physical cooling improved neurological function (physical hypothermia median = 0, physical normothermia median = 2; p = 0.008) and CHA-induced cooling did not (p > 0.99). Our findings demonstrate that forced cooling was neuroprotective compared with controls, but prolonged CHA-induced cooling was not neuroprotective.

Survival and Success Rates of Endodontically Treated Teeth Restored with Full Veneer Crowns or Full Cuspal Coverage onlays: A Systematic Review.

INTRODUCTION: The aim of this paper is to compare the survival and success rates of endodontically treated posterior teeth restored with full veneer crowns or full cuspal coverage onlays in vivo. METHODS: A literature search using PubMed, Medline and Embase via Ovid, and The Cochrane Library retrieved English and non-English language articles from 1946 to April 2022. Electronic searches were supplemented with the use of forward citation chaining via Google Scholar. RESULTS: A total of eleven studies met all predetermined search criteria. Data were extracted and tabulated. Survival rates for onlays ranged from 95% to 100% at two years and 90.7% to 100% at three years with success rates ranging from 86.6% - 96.6% at two years and 86.6% to 96% at three years. Survival results for full veneer crowns were reported at 87.8% at over two years, 95.1% at three years, and 84% - 97.73% at five to ten years. Success rates have been reported at 91.11% - 92.64% at five years and 60% at six years. CONCLUSIONS: The data suggest that the use of onlays instead of full veneer crowns in the restoration of endodontically treated posterior teeth is favourable in the short to midterm.

How surgical Trainee Research Collaboratives achieve success: a mixed methods study to develop trainee engagement strategies.

OBJECTIVES: This study aimed to understand the role of surgical Trainee Research Collaboratives (TRCs) in conducting randomised controlled trials and identify strategies to enhance trainee engagement in trials. DESIGN: This is a mixed methods study. We used observation of TRC meetings, semi-structured interviews and an online survey to explore trainees' motivations for engagement in trials and TRCs, including barriers and facilitators. Interviews were analysed thematically, alongside observation field notes. Survey responses were analysed using descriptive statistics. Strategies to enhance TRCs were developed at a workshop by 13 trial methodologists, surgical trainees, consultants and research nurses. SETTING: This study was conducted within a secondary care setting in the UK. PARTICIPANTS: The survey was sent to registered UK surgical trainees. TRC members and linked stakeholders across surgical specialties and UK regions were purposefully sampled for interviews. RESULTS: We observed 5 TRC meetings, conducted 32 semi-structured interviews and analysed 73 survey responses. TRCs can mobilise trainees thus gaining wider access to patients. Trainees engaged with TRCs to improve patient care, surgical evidence and to help progress their careers. Trainees valued the TRC infrastructure, research expertise and mentoring. Challenges for trainees included clinical and other priorities, limited time and confidence, and recognition, especially by authorship. Key TRC strategies were consultant support, initial simple rapid studies, transparency of involvement and recognition for trainees (including authorship policies) and working with Clinical Trials Units and research nurses. A 6 min digital story on YouTube disseminated these strategies. CONCLUSION: Trainee surgeons are mostly motivated to engage with trials and TRCs. Trainee engagement in TRCs can be enhanced through building relationships with key stakeholders, maximising multi-disciplinary working and offering training and career development opportunities.

Motor Rehabilitation Provides Modest Functional Benefits After Intracerebral Hemorrhage: a Systematic Review and Meta-Analysis of Translational Rehabilitation Studies.

Few certainties exist regarding the optimal type, timing, or dosage of rehabilitation after stroke. Despite differing injury mechanisms and recovery patterns following ischemic and hemorrhagic stroke, most translational stroke research is conducted after ischemia. As we enter the era of personalized medicine, exploring subtype-specific treatment efficacy is essential to optimizing recovery. Our objective was to characterize common rehabilitation interventions used after in vivo preclinical intracerebral hemorrhage (ICH) and assess the impact of post-ICH rehabilitation (vs. no-rehabilitation) on recovery of motor function. Following PRISMA guidelines, a systematic review (Academic Search Complete, CINAHL, EMBASE, Medline, PubMed Central) identified eligible articles published up to December 2022. Risk of bias (SYRCLE) and study quality (CAMARADES) were evaluated, and random-effects meta-analysis was used to assess treatment efficacy in recovery of forelimb and locomotor functions. Thirty articles met inclusion criteria, and 48 rehabilitation intervention groups were identified. Most used collagenase to model striatal ICH in young, male rodents. Aerobic exercise, enriched rehabilitation, and constraint-induced movement therapy represented ~ 70% of interventions. Study quality was low (median 4/10, range 2-8), and risk of bias was unclear. Rehabilitation provided modest benefits in skilled reaching, spontaneous impaired forelimb use, and locomotor function; however, effects varied substantially by endpoint, treatment type, and study quality. Rehabilitation statistically improves motor function after preclinical ICH, but whether these effects are functionally meaningful is unclear. Incomplete reporting and variable research quality hinder our capacity to analyze and interpret how treatment factors influence rehabilitation efficacy and recovery after ICH.

Treatment of lower urinary tract symptoms in men in primary care using a conservative intervention: cluster randomised controlled trial.

OBJECTIVE: To determine whether a standardised and manualised care intervention in men in primary care could achieve superior improvement of lower urinary tract symptoms (LUTS) compared with usual care. DESIGN: Cluster randomised controlled trial. SETTING: 30 National Health Service general practice sites in England. PARTICIPANTS: Sites were randomised 1:1 to the intervention and control arms. 1077 men (≥18 years) with bothersome LUTS recruited between June 2018 and August 2019: 524 were assigned to the intervention arm (n=17 sites) and 553 were assigned to the usual care arm (n=13 sites). INTERVENTION: Standardised information booklet developed with patient and expert input, providing guidance on conservative and lifestyle interventions for LUTS in men. After assessment of urinary symptoms (manualised element), general practice nurses and healthcare assistants or research nurses directed participants to relevant sections of the manual and provided contact over 12 weeks to assist with adherence. MAIN OUTCOME MEASURES: The primary outcome was patient reported International Prostate Symptom Score (IPSS) measured 12 months after participants had consented to take part in the study. The target reduction of 2.0 points on which the study was powered reflects the minimal clinically important difference where baseline IPSS is <20. Secondary outcomes were patient reported quality of life, urinary symptoms and perception of LUTS, hospital referrals, and adverse events. The primary intention-to-treat analysis included 887 participants (82% of those recruited) and used a mixed effects multilevel linear regression model adjusted for site level variables used in the randomisation and baseline scores. RESULTS: Participants in the intervention arm had a lower mean IPSS at 12 months (adjusted mean difference -1.81 points, 95% confidence interval -2.66 to -0.95) indicating less severe urinary symptoms than those in the usual care arm. LUTS specific quality of life, incontinence, and perception of LUTS also improved more in the intervention arm than usual care arm at 12 months. The proportion of urology referrals (intervention 7.3%, usual care 7.9%) and adverse events (intervention seven events, usual care eight events) were comparable between the arms. CONCLUSIONS: A standardised and manualised intervention in primary care showed a sustained reduction in LUTS in men at 12 months. The mean difference of -1.81 points (95% confidence interval -0.95 to -2.66) on the IPSS was less than the predefined target reduction of 2.0 points. TRIAL REGISTRATION: ISRCTN Registry ISRCTN11669964.

The in vitro functional profiles of fentanyl and nitazene analogs at the µ-opioid receptor - high efficacy is dangerous regardless of signaling bias.

Novel synthetic opioids (NSOs), including both fentanyl and non-fentanyl analogs that act as the µ-opioid receptor (MOR) agonists, are associated with serious intoxication and fatal overdose. Previous studies proposed that G protein biased MOR agonists are safer pain medications, while other evidence indicates that low intrinsic efficacy at MOR better explains reduced opioid side effects. Here, we characterized the in vitro functional profiles of various NSOs at MOR using adenylate cyclase inhibition and ß-arrestin2 recruitment assays, in conjunction with the application of the receptor depletion approach. By fitting the concentration-response data to the operational model of agonism, we deduced the intrinsic efficacy and affinity for each opioid in the Gi protein signaling and ß-arrestin2 recruitment pathways. Compared to the reference agonist DAMGO, we found that several fentanyl analogs were more efficacious at inhibiting cAMP production, whereas all fentanyl analogs were less efficacious at recruiting ß-arrestin2. In contrast, the non-fentanyl 2-benzylbenzimidazole (i.e., nitazene) analogs were highly efficacious and potent in both the cAMP and ß-arrestin2 assays. Our findings suggest that the high intrinsic efficacy of the NSOs in Gi protein signaling is a common property that may underlie their high risk of intoxication and overdose, highlighting the limitation of using in vitro functional bias to predict the adverse effects of opioids. Instead, our results show that, regardless of bias, opioids with sufficiently high intrinsic efficacy can be lethal, especially given the extremely high potency of many of these compounds that are now pervading the illicit drug market.