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IMPORTANCE:. The interhospital transfer (IHT) of patients with sepsis to higher-capability hospitals may improve outcomes. Little is known about patient and hospital factors associated with sepsis IHT. OBJECTIVES:. We evaluated patterns of hospitalization and IHT and determined patient and hospital factors associated with the IHT of adult patients with sepsis. DESIGN:. Retrospective cohort study. SETTING AND PARTICIPANTS:. A total of 349,938 adult patients with sepsis at 329 nonfederal hospitals in California, 2018–2019. MAIN OUTCOMES AND MEASURES:. We evaluated patterns of admission and outward IHT between low sepsis-, intermediate sepsis-, and high sepsis-capability hospitals. We estimated odds of IHT using generalized estimating equations logistic regression with bootstrap stepwise variable selection. RESULTS:. Among the cohort, 223,202 (66.4%) were initially hospitalized at high-capability hospitals and 10,870 (3.1%) underwent IHT. Nearly all transfers (98.2%) from low-capability hospitals were received at higher-capability hospitals. Younger age (< 65 yr) (adjusted odds ratio [aOR] 1.54; 95% CI, 1.40–1.69) and increasing organ dysfunction (aOR 1.22; 95% CI, 1.19–1.25) were associated with higher IHT odds, as were admission to low-capability (aOR 2.79; 95% CI, 2.33–3.35) or public hospitals (aOR 1.35; 95% CI, 1.09–1.66). Female sex (aOR 0.88; 95% CI, 0.84–0.91), Medicaid insurance (aOR 0.59; 95% CI, 0.53–0.66), home to admitting hospital distance less than or equal to 10 miles (aOR 0.92; 95% CI, 0.87–0.97) and do-not-resuscitate orders (aOR 0.48; 95% CI, 0.45–0.52) were associated with lower IHT odds, as was admission to a teaching hospital (aOR 0.83; 95% CI, 0.72–0.96). CONCLUSIONS AND RELEVANCE:. Most patients with sepsis are initially hospitalized at high-capability hospitals. The IHT rate for sepsis is low and more likely to originate from low-capability and public hospitals than from high-capability and for-profit hospitals. Transferred patients with sepsis are more likely to be younger, male, sicker, with private medical insurance, and less likely to have care limitation orders. Future studies should evaluate the comparative benefits of IHT from low-capability hospitals.

Record-breaking high temperatures were experienced across the United Kingdom during summer 2022. The impacts of these extreme climatic conditions were felt across the food system, including increased energy costs for cold storage, the failure of refrigeration systems in numerous retail facilities, and impacts on livestock including heat stress. Future climate projections indicate an increased likelihood and duration of extreme high temperatures like those experienced in 2022. Learning from the impacts of the 2022 heatwave on the United Kingdom food system can help identify adaptations that build resilience to climate change. We explore the impacts through two case studies (United Kingdom poultry and wheat sectors), discuss potential adaptation options required for a climate-resilient, net-zero United Kingdom food system and consider future research needs. United Kingdom chicken meat production was 9% lower in July 2022 than July 2021; in contrast, energy costs increased for both production and refrigeration. Potential heatwave adaptation measures for poultry include transitioning to heat tolerant chicken breeds, lower stocking density, dehumidification cooling and misting systems, nutritional supplements, and improving retail refrigeration resilience and efficiency. United Kingdom wheat yields were 8% higher in 2022 than the 2017–2021 average. Increases were observed in every United Kingdom region but were least in the South and East where the heatwave intensity was strongest. Future adaptation measures to avoid negative impacts of summer heat stress on winter wheat could include earlier maturing and heat/drought tolerant varieties, earlier autumn sowing, targeted irrigation for drought around anthesis, and soil and water conservation measures.

Background: The use of surrogate endpoints may expedite the reporting of study outcomes of clinical trials. The validity of disease-free survival (DFS) as a surrogate for overall survival (OS) in the neoadjuvant treatment of esophageal (E) or gastroesophageal junctional (GEJ) carcinomas remains uncertain., Objective: To evaluate DFS as a surrogate end-point for OS in E/GEJ using the meta-analytical approach DESIGN, SETTING, AND PARTICIPANTS: individual patient data from an international meta-analysis on operable locally advanced E/GEJ, which including randomized trials comparing at least two of the neo-adjuvant treatment strategies: upfront surgery (S), chemotherapy followed by surgery (CS), and/or chemoradiotherapy followed by surgery (CRS)., Main Outcomes and Measures: Individual (Kendall's tau) and trial-level (R2) correlations between DFS and OS were estimated using a Clayton copula., Results: DFS and OS data were available for a total of 4518 pts: 2222 pts included in CS vs S, 1908 pts in CRS vs S, and 388 in CS vs CRS comparisons. 3440 patients had a DFS event and 3303 patients died. Kendall's tau was 0.73 [95 % CI 0.71 - 0.75] and R2 trial-level correlation was 0.95 [0.84 - 0.99] for CS vs S, Kendall's tau was 0.76 [0.74 - 0.77] and R2 was 0.96 [0.87 - 0.99] for CRS vs S, Kendall's tau was 0.87 [0.78 - 0.92] and R2 was 0.93 [0.43 - 1] for CRS vs CS. In a multistate model, the median time in the recurrence state was shorter in older vs more recent trials: mean time of 10.8 [10.2 - 11.4] vs 16.5 months [15.4-17.6]., Conclusions and Relevance: DFS is a validated surrogate endpoint for OS in trials evaluating neoadjuvant chemotherapy or chemoradiotherapy in E/GEJ. DFS may be more useful as an endpoint when delays between recurrences and death become larger., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: FL: institutional grants from: Astra Zeneca, Beigene, BMS, Daiichi Sankyo and Gilead, and personal fees from: Amgen, ArtTempi. Astellas, Astra Zeneca, Bayer, Biontech, BMS, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, Gilead, Elsevier, Incyte, Medscape, MedUpdate, Merck Serono, MSD, PAGE, Roche, Servier, StreamedUp!, VJ Oncology, all outside the scope of the submitted work. SM: personal fees for Scientific Committee Study member: Roche, for Data and safety monitoring member of clinical trials: IQVIA, Kedrion, Biophytis, Servier, Yuhan, outside the scope of the submitted work The other authors reported no COI., (Copyright © 2025 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Tonsillectomy is a frequently performed otolaryngological procedure and is associated with significant postoperative pain and bleeding. A number of studies have investigated methods to reduce pain and bleeding. Coblation and BiZact devices have both been claimed to have favourable pain outcomes following tonsillectomy. This study was designed to investigate these two techniques in a direct comparison of postoperative pain and bleeding., Methods: In this single blinded, randomized control trial, 61 patients were randomly assigned to undergo tonsillectomy with either the BiZact or Coblation device. Pain scores were collected for 14 days postoperatively using a Visual Analogue Score scale. Secondary outcome data was collected for duration of surgery, intra-operative bleeding, return to normal, and secondary bleeding rates., Results: Coblation was found to have lower postoperative pain on day 1 (P < 0.05). BiZact was found to have lower postoperative pain on day 7 (P < 0.05) and day 11 (P < 0.05). Pain scores for other days were not significant. There was no significant difference in set-up time, procedural time and return to normal activities. The BiZact group had a longer time to achieve haemostasis (P < 0.001) and greater intraoperative blood loss (P < 0.01). There was a trend towards more significant secondary bleeding in the BiZact arm, however, this study was not adequately powered to assess this finding., Conclusion: Both Coblation and BiZact devices appear to provide a safe and effective method for tonsillectomy in adults. Reduced pain on day 1 may make Coblation more suitable for day-case surgery., (© 2024 Royal Australasian College of Surgeons.)

Aims: We explored trends in gabapentinoid prescribing, drug seizures and postmortem toxicology using a national pharmacy claims database, law enforcement drug seizures data and a population-based postmortem toxicology database., Methods: Gabapentinoid prescribing rates per 100 000 eligible population (2010-2020), annual number of drug seizures involving gabapentinoids (2012-2020) and gabapentinoid detection (positive) rates per 100 postmortem toxicology case (2013-2020) were calculated. Negative binomial regression models were used to evaluate longitudinal trends for gabapentin and pregabalin separately., Results: Gabapentin (adjusted rate ratio [RR] 1.06, 95% confidence interval [CI] 1.05-1.06, P < .001) and pregabalin (adjusted RR 1.08, 95% CI 1.08-1.09, P < .001) prescribing increased annually, with higher rates of pregabalin (vs. gabapentin) observed every year. Drug seizures involving pregabalin also increased over time (RR 1.54 95% CI 1.25-1.90, P < .0001). Of the 26 317 postmortem toxicology cases, 0.92% tested positive for gabapentin, and 6.37% for pregabalin. Detection rates increased for both gabapentin (RR 1.28, 95% CI 1.11-1.48, P < .001) and pregabalin (RR 1.13, 95% CI 1.11-1.48, P < .001) between 2013 and 2020. A total of 1901 cases (7.2%) tested positive for heroin/methadone; this sub-group had a higher detection rate for pregabalin (n = 528, 27.8%) and gabapentin (n = 41, 2.2%) over the study period, with a high burden of codetections for pregabalin with benzodiazepines (peaking at 37.3% in 2018), and pregabalin with prescription opioids (peaking at 28.9% in 2020)., Conclusion: This study raises concerns regarding the wide availability of pregabalin in Ireland, including a growing illicit supply, and the potential for serious harm arising from poly drug use involving pregabalin among people who use heroin or methadone., (© 2023 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Background: Cementless hip stems are widely used for total hip arthroplasty (THA) and have demonstrated excellent survivorship. This study aimed to investigate the effects of stem size and calcar collars on rates of revision due to periprosthetic fracture., Methods: All primary THA procedures recorded by the Australian Orthopaedic Association National Joint Replacement Registry (AOANJRR) from September 1999 to December 2021 for a diagnosis of osteoarthritis using a single cementless hip stem with modern bearings were included. The primary outcome measure was revision due to periprosthetic fracture. Stems were divided into 2 groups for comparison, large (size 14 to 20) and small-medium (6 to 13). A subanalysis was performed for collared stems. A total of 59,518 primary THA procedures were included., Results: The cumulative percent revision for periprosthetic fracture was significantly higher for large stems compared to small-medium stems (hazard ratio [HR] = 1.57 [95% confidence interval {CI} 1.18, 2.09] P = .002). Furthermore, collared stems had significantly lower revision rates due to late periprosthetic fracture compared to collarless variants (2 week + HR = 4.55 [95% CI 3.23, 6.42], P < .001). Large collarless stems were found to have greater revision rates due to fracture compared to small-medium collarless stems (HR = 1.55 [95% CI 1.13, 2.12] P = .006), but no difference was found between collared groups (HR = 1.37 [95% CI 0.68, 2.78] P = .382)., Conclusion: Large cementless hip stems have a higher rate of revision due to periprosthetic fracture compared to small-medium stems. Using a collared stem reduces the rate of periprosthetic fracture., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

This publication describes the outcome of a project to develop a replacement European Pharmacopoeia (Ph. Eur.) Biological Reference Preparation (BRP) for Human tetanus immunoglobulin (TIg) as well as for the World Health Organization (WHO) International Standard (IS) for Tetanus Immunoglobulin, Human. Bulk TIg was kindly provided by a European manufacturer and was used to prepare the candidate standard. The candidate standard was freeze-dried and calibrated in an international collaborative study jointly co-ordinated by the Medicines & Healthcare products Regulatory Agency (MHRA) and the European Directorate for the Quality of Medicines & HealthCare (EDQM, Council of Europe). The results of this study show that there was good agreement between laboratories for the potency estimates obtained for the candidate standard relative to the current WHO IS/Ph. Eur. BRP. The study also demonstrated that the candidate standard is suitable for use in Ph. Eur. assays for potency testing of TIg products and there was good agreement in the potency estimates obtained using the different assay methods included in the study. Accelerated degradation studies performed at the MHRA over a period of 4 years suggest that the freeze-dried candidate standard will be very stable. The candidate standard was established as Ph. Eur. BRP for Human tetanus immunoglobulin, batch 2 with an assigned potency of 45 IU/ampoule. The same preparation was also adopted by the WHO Expert Committee on Biological Standardization (ECBS) to serve as the WHO 2 nd IS for Tetanus Immunoglobulin, Human (13/240)., (© Council of Europe 2024.)

Purpose: The optimal neoadjuvant treatment for resectable carcinoma of the thoracic esophagus (TE) or gastroesophageal junction (GEJ) remains a matter of debate. We performed an individual participant data (IPD) network meta-analysis (NMA) of randomized controlled trials (RCTs) to study the effect of chemotherapy or chemoradiotherapy, with a focus on tumor location and histology subgroups., Patients and Methods: All, published or unpublished, RCTs closed to accrual before December 31, 2015 and having compared at least two of the following strategies were eligible: upfront surgery (S), chemotherapy followed by surgery (CS), and chemoradiotherapy followed by surgery (CRS). All analyses were conducted on IPD obtained from investigators. The primary end point was overall survival (OS). The IPD-NMA was analyzed by a one-step mixed-effect Cox model adjusted for age, sex, tumor location, and histology. The NMA was registered in PROSPERO (CRD42018107158)., Results: IPD were obtained for 26 of 35 RCTs (4,985 of 5,807 patients) corresponding to 12 comparisons for CS-S, 12 for CRS-S, and four for CRS-CS. CS and CRS led to increased OS when compared with S with hazard ratio (HR) = 0.86 (0.75 to 0.99), P = .03 and HR = 0.77 (0.68 to 0.87), P < .001 respectively. The NMA comparison of CRS versus CS for OS gave a HR of 0.90 (0.74 to 1.09), P = .27 (consistency P = .26, heterogeneity P = .0038). For CS versus S, a larger effect on OS was observed for GEJ versus TE tumors ( P = .036). For the CRS versus S and CRS versus CS, a larger effect on OS was observed for women ( P = .003, .012, respectively)., Conclusion: Neoadjuvant chemotherapy and chemoradiotherapy were consistently better than S alone across histology, but with some variation in the magnitude of treatment effect by sex for CRS and tumor location for CS. A strong OS difference between CS and CRS was not identified.

Introduction: There is an increasing concern about the misuse of prescription drugs. Misuse refers to the intentional repurposing of prescribed drugs and/or the use of illicitly sourced prescription drugs, which may be counterfeit or contaminated. Drugs with the greatest potential for misuse are prescription opioids, gabapentinoids, benzodiazepines, Z-drugs and stimulants., Objective: The aim of this study is to provide a comprehensive analysis of the supply, patterns of use and health burden associated with prescription drugs with potential for misuse (PDPM) in Ireland between 2010 and 2020. Three inter-related studies will be carried out. The first study will describe trends in supply of PDPM using law enforcement drug seizures data and national prescription records from national community and prison settings. The second study aims to estimate trends in the detection of PDPM across multiple early warning systems using national forensic toxicology data. The third study aims to quantify the health burden associated with PDPM nationally, using epidemiological indicators of drug-poisoning deaths, non-fatal intentional drug overdose presentations to hospitals and drug treatment demand., Methods and Analysis: A retrospective observational study design, with repeated cross-sectional analyses, using negative binomial regression models or, where appropriate, joinpoint regression., Ethics and Dissemination: The study has received approval from the RCSI Ethics Committee (REC202202020). Results will be disseminated in peer-reviewed journals, scientific and drug policy meetings and with key stakeholders via research briefs., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Previously we developed a murine model in which postinjury stimulation of an injured area triggers a transition to a nociplastic pain state manifesting as persistent mechanical hypersensitivity outside of the previously injured area. This hypersensitivity was maintained by sex-specific mechanisms; specifically, activated spinal microglia maintained the hypersensitivity only in males. Here we investigated whether spinal microglia drive the transition from acute injury-induced pain to nociplastic pain in males, and if so, how they are activated by normally innocuous stimulation after peripheral injury. Using intraplantar capsaicin injection as an acute peripheral injury and vibration of the injured paw as postinjury stimulation, we found that inhibition of spinal microglia prevents the vibration-induced transition to a nociplastic pain state. The transition was mediated by the ATP-P2X4 pathway, but not BDNF-TrkB signaling. Intrathecally injected GABA receptor agonists after intraplantar capsaicin injection prevented the vibration-induced transition to a nociplastic pain state. Conversely, in the absence of intraplantar capsaicin injection, intrathecally injected GABA receptor antagonists allowed the vibration stimulation of a normal paw to trigger the transition to a spinal microglia-mediated nociplastic pain state only in males. At the spinal level, TNF-α, IL-1β, and IL-6, but not prostaglandins, contributed to the maintenance of the nociplastic pain state in males. These results demonstrate that in males, the transition from acute injury-induced pain to nociplastic pain is driven by spinal microglia causing neuroinflammation and that peripheral injury-induced spinal GABAergic disinhibition is pivotal for normally innocuous stimulation to activate spinal microglia., (Copyright © 2022 Elsevier Inc. All rights reserved.)

There is a general consensus that the doctor-patient interview should be as productive and efficient as possible. This is becoming increasingly difficult in a health care insurance system that demands shorter appointment times. Clinicians must therefore find ways to condense the clinical encounter without sacrificing quality. The purposes of this study were: (1) to facilitate shared decision-making between psychiatrist and patient via pre-visit patient agenda-setting, (2) to evaluate the effectiveness and ease of use of the agenda-setting tool, and (3) to determine patient and clinician satisfaction with the clinical encounter. Patients completed questionnaires to assist in agenda-setting via an electronic tablet while in the waiting area before seeing the psychiatrist. Both patients and psychiatrists then completed post-visit questionnaires to assess their satisfaction with the encounter. We measured patient satisfaction and the extent to which the psychiatrist addressed concerns before and after the visit, as well as ease of use for the patient, psychiatrist satisfaction, and clinical helpfulness to the treating psychiatrist. Additional analyses also indicated that there was a significant increase in patient satisfaction scores, compared with an average of all previous visits, and a significant increase in the number of concerns addressed during the current visit when compared with the average number of previous concerns addressed. Patients reported little difficulty using the tablet. Similarly, psychiatrists reported that the device was helpful in the clinical setting and they expressed high levels of satisfaction with the visit. We hope our work will encourage others to use this agenda-setting tool in their practices to facilitate better patient care., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction Rezum is a minimally invasive, outpatient procedure using convective water vapor to relieve outlet obstruction from benign prostatic hyperplasia (BPH). Evidence on the technical approach of Rezum therapy, particularly pain control, is lacking. The purpose of this study was to evaluate the efficacy of utilizing a local anesthetic prostate block for postoperative pain control during Rezum therapy for BPH. A multimodal approach is typically utilized for pain control during and after Rezum. However, little is known about which elements are most critical. Methods This is a single-center retrospective study of 109 patients who underwent Rezum for BPH. Patients were then divided into two groups: Local anesthetic prostatic block verse no local anesthetic prostatic block for the procedure. A phone survey was performed to assess the patients' subjective pain scores and postoperative analgesics usage. A comparison of reported pain scores on a 0-10 Likert scale as well as usage of prescription and non-prescription analgesics medications was performed. Results There were 109 patients who underwent Rezum therapy, and 86 (79%) of patients responded to phone surveys. There was no significant difference in postoperative pain scores between patients who received local anesthetic prostatic block vs those who did not (2.10 vs 3.03). Similarly, there were no significant differences in postoperative narcotics or non-prescription analgesic medications usage. Conclusion Our data suggest that when performing Rezum using conscious sedation in the operating room or cystoscopy suite, it is unnecessary to perform a local anesthetic prostate block as it has no significant effect on patient-reported pain or the use of analgesics in the postoperative period., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Gilpin et al.)

The protection provided by natural versus hybrid immunity from COVID-19 is unclear. We reflect on the challenges from trying to conduct a randomized post-SARS-CoV-2 infection vaccination trial study with rapidly evolving scientific data, vaccination guidelines, varying international policies, difficulties with vaccine availability, vaccine hesitancy, and a constantly evolving virus., Competing Interests: Declaration of interests D.L.B is on the advisory boards of Gilead, MerckSharpe & Dohme, Pfizer, and ViiV, and receives travel grants from ViiV Healthcare. G.M. receives research grants from Gilead, AbbvieInc., ViiV Healthcare, and Janssen, and is on the advisory boards of Gileadand AstraZeneca. The other authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The Rho kinase (ROCK) pathway is implicated in the pathogenesis of several conditions, including neurological diseases. In Huntington's disease (HD), ROCK is implicated in mutant huntingtin (HTT) aggregation and neurotoxicity, and members of the ROCK pathway are increased in HD mouse models and patients. To validate this mode of action as a potential treatment for HD, we sought a potent, selective, central nervous system (CNS)-penetrant ROCK inhibitor. Identifying a compound that could be dosed orally in mice with selectivity against other AGC kinases, including protein kinase G (PKG), whose inhibition could potentially activate the ROCK pathway, was paramount for the program. We describe the optimization of published ligands to identify a novel series of ROCK inhibitors based on a piperazine core. Morphing of the early series developed in-house by scaffold hopping enabled the identification of a compound exhibiting high potency and desired selectivity and demonstrating a robust pharmacodynamic (PD) effect by the inhibition of ROCK-mediated substrate (MYPT1) phosphorylation after oral dosing.

Purpose: In response to the opioid crisis, opioid analgesic guidelines and prescribing limits have proliferated. The purpose of this narrative review is to examine evidence from studies evaluating the patient or public health impact of federal and state opioid analgesic prescribing guidelines and laws, describe gaps and challenges in current research, and highlight opportunities for improving future research., Methods: We focused on evidence from a literature review covering 2013 through 2019. We identified 30 studies evaluating opioid analgesic thresholds based on federal policies and guidelines, state laws, and Medicaid state plans that attempt to influence the course of patient care at or when the limit is exceeded (e.g., prior authorization)., Results: Most studies evaluated changes in prescribing or dispensing patterns of opioid analgesics, largely finding decreases in prescribing after policy enactment. Fewer studies evaluated patient or public health outcomes beyond changes in prescribing and dispensing patterns; results were infrequently stratified by potentially important sociodemographic and clinical factors. No studies assessed the potential for adverse patient outcomes for which we have emerging evidence of harms., Conclusions: We describe knowledge gaps and propose opportunities for future research to sufficiently assess the potential impact and unintended consequences of opioid analgesic prescribing laws, regulations, guidelines, and policies., (Published 2022. This article is a U.S. Government work and is in the public domain in the USA.)