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Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. No potential conflicts of interest were disclosed.

Propylthiouracil (PTU) has been identified as a known cause of anti-neutrophil cytoplasmic antibodies-associated vasculitis. However, the association between PTU and immunoglobulin A (IgA) vasculitis remains uncertain due to its rarity and diverse clinical presentation. Here, we report the case of a 57-year-old female with a past medical history of chronic leukopenia and Graves' disease treated with PTU that presented with pancytopenia and widespread non-blanching ecchymoses on the bilateral legs. A punch biopsy of the medial leg demonstrated IgA vasculitis and autoimmune antibody analysis revealed increased levels of anti-proteinase 3 antibodies compared to anti-myeloperoxidase antibodies. These findings led to the diagnosis of PTU-induced IgA vasculitis. Following the discontinuation of PTU, there was marked improvement in the appearance of the patient's cutaneous manifestations and hematological indices., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Custer et al.)

Background: Anthracyclines such as doxorubicin (Dox) are highly effective anti-tumor agents, but their use is limited by dose-dependent cardiomyopathy and heart failure. Our laboratory previously reported that induction of cytochrome P450 family 1 (Cyp1) enzymes contributes to acute Dox cardiotoxicity in zebrafish and in mice, and that potent Cyp1 inhibitors prevent cardiotoxicity. However, the role of Cyp1 enzymes in chronic Dox cardiomyopathy, as well as the mechanisms underlying cardioprotection associated with Cyp1 inhibition, have not been fully elucidated., Methods: The Cyp1 pathway was evaluated using a small molecule Cyp1 inhibitor in wild-type (WT) mice, or Cyp1-null mice ( Cyp1a1/1a2 -/- , Cyp1b1 -/- , and Cyp1a1/1a2/1b1 -/- ). Low-dose Dox was administered by serial intraperitoneal or intravenous injections, respectively. Expression of Cyp1 isoforms was measured by RT-qPCR, and myocardial tissue was isolated from the left ventricle for RNA sequencing. Cardiac function was evaluated by transthoracic echocardiography., Results: In WT mice, Dox treatment was associated with a decrease in Cyp1a2 and increase in Cyp1b1 expression in the heart and in the liver. Co-treatment of WT mice with Dox and the novel Cyp1 inhibitor YW-130 protected against cardiac dysfunction compared to Dox treatment alone. Cyp1a1/1a2 -/- and Cyp1a1/1a2/1b1 -/- mice were protected from Dox cardiomyopathy compared to WT mice. Male, but not female, Cyp1b1 -/- mice had increased cardiac dysfunction following Dox treatment compared to WT mice. RNA sequencing of myocardial tissue showed upregulation of Fundc1 and downregulation of Ccl21c in Cyp1a1/1a2 -/- mice treated with Dox, implicating changes in mitophagy and chemokine-mediated inflammation as possible mechanisms of Cyp1a-mediated cardioprotection., Conclusions: Taken together, this study highlights the potential therapeutic value of Cyp1a inhibition in mitigating anthracycline cardiomyopathy.

Purpose: Targeted radionuclide therapy (TRT), whereby a tumor-targeted molecule is linked to a therapeutic beta- or alpha-emitting radioactive nuclide, is a promising treatment modality for patients with metastatic cancer, delivering radiation systemically. However, patients still progress due to suboptimal dosing, driven by the large patient-to-patient variability. Therefore, the ability to continuously monitor the real-time dose deposition in tumors and organs at risk provides an additional dimension of information during clinical trials that can enable insights into better strategies to personalize TRT., Methods and Materials: Here, we present a single beta-particle sensitive dosimeter consisting of a 0.27-mm 3 monolithic silicon chiplet directly implanted into the tumor. To maximize the sensitivity and have enough detection area, minimum-size diodes (1 μm 2 ) are arrayed in 64 × 64. Signal amplifiers, buffers, and on-chip memories are all integrated in the chip. For verification, PC3-PIP (prostate-specific membrane antigen [PSMA]+) and PC3-flu (PSMA-) cell lines are injected into the left and right flanks of the mice, respectively. The devices are inserted into each tumor and measure activities at 5 different time points (0-2 hours, 7-9 hours, 12-14 hours, 24-26 hours, and 48-50 hours) after 177 Lu-PSMA-617 injections. Single-photon emission computed tomography/computed tomography scans are used to verify measured data., Results: With a wide detection range from 0.013 to 8.95 MBq/mL, the system is capable of detecting high tumor uptake as well as low doses delivered to organs at risk in real time. The measurement data are highly proportional (R 2 > 0.99) to the 177 Lu-PSMA-617 activity. The in vivo measurement data agree well with the single-photon emission computed tomography/computed tomography results within acceptable errors (±1.5%ID/mL)., Conclusions: Given the recent advances in clinical use of TRT in prostate cancer, the proposed system is verified in a prostate cancer mouse model using 177 Lu-PSMA-617., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Cancer radiopharmaceutical therapies (RPTs) have demonstrated great promise in the treatment of neuroendocrine and prostate cancer, giving hope to late-stage metastatic cancer patients with currently very few treatment options. These therapies have sparked a large amount of interest in pre-clinical research due to their ability to target metastatic disease, with many research efforts focused towards developing and evaluating targeted RPTs for different cancer types in in vivo models. Here we describe a method for monitoring real-time in vivo binding kinetics for the pre-clinical evaluation of cancer RPTs. Recognizing the significant heterogeneity in biodistribution of RPTs among even genetically identical animal models, this approach offers long-term monitoring of the same in vivo organism without euthanasia in contrast to ex vivo tissue dosimetry, while providing high temporal resolution with a low-cost, easily assembled platform, that is not present in small-animal SPECT/CTs. The method utilizes the developed optical fiber-based γ-photon biosensor, characterized to have a wide linear dynamic range with Lutetium-177 ( 177 Lu) activity (0.5-500 μCi/mL), a common radioisotope used in cancer RPT. The probe's ability to track in vivo uptake relative to SPECT/CT and ex vivo dosimetry techniques was verified by administering 177 Lu-PSMA-617 to mouse models bearing human prostate cancer tumors (PC3-PIP, PC3-flu). With this method for monitoring RPT uptake, it is possible to evaluate changes in tissue uptake at temporal resolutions <1 min to determine RPT biodistribution in pre-clinical models and better understand dose relationships with tumor ablation, toxicity, and recurrence when attempting to move therapies towards clinical trial validation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: We explored the feasibility of a large-scale UK ambulance services trial of optimal defibrillation shock energy for out-of-hospital cardiac arrest. The primary objective of this feasibility study was to establish the number of eligible patients and the number recruited. Secondary outcomes were adherence to allocated treatment and data completeness., Methods: We conducted a three-arm parallel group cluster randomised controlled feasibility study in a single ambulance service in southern England. Adult patients in out-of-hospital cardiac arrest treated for a shockable rhythm were included. Zoll X series defibrillators (clusters) were randomised to deliver 120-150-200 J, 150-200-200 J, or 200-200-200 J shock strategies., Results: Between March 2022 and February 2023, we randomised 38 eligible patients (120-150-200 J (n = 12), 150-200-200 J (n = 10), 200-200-200 J (n = 16)) to the study. The recruitment rate per cluster was 0.07 per month. The median patient age was 71 years (IQR 59-81 years); 79% were male. Twenty-eight cardiac arrests (74%) occurred in a private residence, 29 (76%) were witnessed and 32 (84%) patients received bystander CPR. Treatment adherence was 93% and completeness of clinical and electrical outcomes was 86%. At 30 days, 3/36 (8.3%) patients survived; we were unable to collect survival outcomes for two patients. Defibrillation data collection became difficult when defibrillators became separated from their allocated vehicles., Conclusion: We have demonstrated the feasibility of a cluster randomised controlled trial of optimal shock energy for defibrillation in a UK ambulance service. We have identified possible solutions to issues relating to trial design., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: HP is a member of the International Liaison Committee on Resuscitation (ILCOR) Advanced Life Support task force committee. She holds a grant from the National Institute for Health and Social Care Research (NIHR)/Health Education England. GDP is Editor for Resuscitation and Resuscitation Plus and holds grants from the NIHR, British Heart Foundation, Resuscitation Council UK (RCUK) and Laerdal. He is an employee of University of Warwick, University Hospital of Coventry and Warwick, University Hospital Birmingham and West Midlands Ambulance Service and holds Leadership roles with ILCOR, the European Resuscitation Council, and RCUK. CDD, RL, DS, CS, FM, CH, JR, KS, MB, IR: Nil., (© 2024 The Author(s).)

Aims: The PARAMEDIC-3 trial evaluates the clinical and cost-effectiveness of an intraosseous first strategy, compared with an intravenous first strategy, for drug administration in adults who have sustained an out-of-hospital cardiac arrest., Methods: PARAMEDIC-3 is a pragmatic, allocation concealed, open-label, multi-centre, superiority randomised controlled trial. It will recruit 15,000 patients across English and Welsh ambulance services. Adults who have sustained an out-of-hospital cardiac arrest are individually randomised to an intraosseous access first strategy or intravenous access first strategy in a 1:1 ratio through an opaque, sealed envelope system. The randomised allocation determines the route used for the first two attempts at vascular access. Participants are initially enrolled under a deferred consent model.The primary clinical-effectiveness outcome is survival at 30-days. Secondary outcomes include return of spontaneous circulation, neurological functional outcome, and health-related quality of life. Participants are followed-up to six-months following cardiac arrest. The primary health economic outcome is incremental cost per quality-adjusted life year gained., Conclusion: The PARAMEDIC-3 trial will provide key information on the clinical and cost-effectiveness of drug route in out-of-hospital cardiac arrest.Trial registration: ISRCTN14223494, registered 16/08/2021, prospectively registered., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: GDP is co-chair of the International Liaison Committee on Resuscitation (ILCOR). CD and JPN are emeritus members of the ILCOR Advanced Life Support task force. KC and HP are current members of the ILCOR Advanced Life Support task force. GDP is editor-in-chief and JPN is founding editor of Resuscitation Plus. KC is associate editor of Resuscitation Plus and guest editor for the research methodology special edition., (© 2023 The Authors.)

Background: Cancer is one of the leading causes of morbidity and mortality in India. Clinical trials are critical for driving innovation in cancer therapy, diagnosis, and prevention. This study aims to depict the evolving landscape of cancer clinical trials in India by analysing the clinical trials registered in Clinical Trial Registry-India (CTRI)., Methods: We identified cancer trials registered in CTRI (between 2007 and 2021) using search terms adapted from the cancer types defined by the National Cancer Institute (USA). We then collated and analysed the publicly available information from CTRI (cancer subtypes, type of trial, treatment intent, type of intervention, sponsor type, recruitment countries) and used descriptive statistics to illustrate the overall as well as year-to-year trend., Findings: In total, we identified 1988 cancer trials, the majority of which focused on treating cancer (63%) and rest of the trials aimed at optimising the operational aspects of surgery (19%), mitigating treatment-related toxicity (10.6%), or treating cancer-related symptoms (7.8%). Focusing on trials with the intent of treating cancer, we found that most were investigating solid tumours as opposed to haematological malignancies with the most prominent cancer subtypes being breast cancer (17%), head and neck cancer (9.8%), lung cancer (9.6%), and cervical cancer (6.6%). The number of trials conducted in a given cancer subtype from our analysis overall correlated to the incidence, mortality, and 5-year prevalence of the respective cancer subtype in India; however, head and neck cancer and cervical cancer were underrepresented in trials as compared with the disease burden. The most common type of intervention was investigational drugs. The most common sponsor types were global pharmaceutical industry (26%) and research institution and hospital (26%). Despite a relatively high cancer burden, the availability of cancer trials in the Northeastern states of India was limited., Interpretation: There is a pressing need for clinical cancer research in India to be better aligned with the nation's healthcare needs and disease burden, focusing on prevalent and deadly cancers while ensuring the availability of clinical trials across geographic regions and underserved populations., Funding: Pi Health USA, a fully owned subsidiary of BeiGene Ltd., Competing Interests: PG, JC, ZH, MC, AM, RL, CL, GK and BR are employees of Pi Health USA, which is a fully owned subsidiary of BeiGene Ltd. PG, JC, ZH, MC, AM, RL, GK and BR report having received BGNE stock grants for employment. JC is an AACR-AstraZeneca Clinical Immuno-Oncology Research Training Program grant recipient, funded from October 2020 to September 2021. JC received speaker honoraria from University of California, Davis and the Association of Northern California Oncologists. JC received support from BeiGene for attending the American Association for Cancer Research (AACR) annual meeting, the American Society of Clinical Oncology (ASCO) annual meeting, and the HLTH (health) conference in 2022. All authors report no other conflicts of interest., (© 2023 Pi Health USA.)

Importance: Patients with septic shock undergo adrenergic stress, which affects cardiac, immune, inflammatory, and metabolic pathways. β-Blockade may attenuate the adverse effects of catecholamine exposure and has been associated with reduced mortality., Objectives: To assess the efficacy and safety of landiolol in patients with tachycardia and established septic shock requiring prolonged (>24 hours) vasopressor support., Design, Setting, and Participants: An open-label, multicenter, randomized trial involving 126 adults (≥18 years) with tachycardia (heart rate ≥95/min) and established septic shock treated for at least 24 hours with continuous norepinephrine (≥0.1 μg/kg/min) in 40 UK National Health Service intensive care units. The trial ran from April 2018 to December 2021, with early termination in December 2021 due to a signal of possible harm., Intervention: Sixty-three patients were randomized to receive standard care and 63 to receive landiolol infusion., Main Outcomes and Measures: The primary outcome was the mean Sequential Organ Failure Assessment (SOFA) score from randomization through 14 days. Secondary outcomes included mortality at days 28 and 90 and the number of adverse events in each group., Results: The trial was stopped prematurely on the advice of the independent data monitoring committee because it was unlikely to demonstrate benefit and because of possible harm. Of a planned 340 participants, 126 (37%) were enrolled (mean age, 55.6 years [95% CI, 52.7 to 58.5 years]; 58.7% male). The mean (SD) SOFA score in the landiolol group was 8.8 (3.9) compared with 8.1 (3.2) in the standard care group (mean difference [MD], 0.75 [95% CI, -0.49 to 2.0]; P = .24). Mortality at day 28 after randomization in the landiolol group was 37.1% (23 of 62) and 25.4% (16 of 63) in the standard care group (absolute difference, 11.7% [95% CI, -4.4% to 27.8%]; P = .16). Mortality at day 90 after randomization was 43.5% (27 of 62) in the landiolol group and 28.6% (18 of 63) in the standard care group (absolute difference, 15% [95% CI, -1.7% to 31.6%]; P = .08). There were no differences in the number of patients having at least one adverse event., Conclusion and Relevance: Among patients with septic shock with tachycardia and treated with norepinephrine for more than 24 hours, an infusion of landiolol did not reduce organ failure measured by the SOFA score over 14 days from randomization. These results do not support the use of landiolol for managing tachycardia among patients treated with norepinephrine for established septic shock., Trial Registration: EU Clinical Trials Register Eudra CT: 2017-001785-14; isrctn.org Identifier: ISRCTN12600919.

Aim: To describe the protocol for a multi-centre randomised controlled trial to determine whether treatment protocols monitoring daily CRP (C-reactive protein) or PCT (procalcitonin) safely allow a reduction in duration of antibiotic therapy in hospitalised adult patients with sepsis., Design: Multicentre three-arm randomised controlled trial., Setting: UK NHS hospitals., Target Population: Hospitalised critically ill adults who have been commenced on intravenous antibiotics for sepsis., Health Technology: Three protocols for guiding antibiotic discontinuation will be compared: (a) standard care; (b) standard care + daily CRP monitoring; (c) standard care + daily PCT monitoring. Standard care will be based on routine sepsis management and antibiotic stewardship. Measurement of outcomes and costs. Outcomes will be assessed to 28 days. The primary outcomes are total duration of antibiotics and safety outcome of all-cause mortality. Secondary outcomes include: escalation of care/re-admission; infection re-lapse/recurrence; antibiotic dose; length and level of critical care stay and length of hospital stay. Ninety-day all-cause mortality rates will also be collected. An assessment of cost effectiveness will be performed., Conclusion: In the setting of routine NHS care, if this trial finds that a treatment protocol based on monitoring CRP or PCT safely allows a reduction in duration of antibiotic therapy, and is cost effective, then this has the potential to change clinical practice for critically ill patients with sepsis. Moreover, if a biomarker-guided protocol is not found to be effective, then it will be important to avoid its use in sepsis and prevent ineffective technology becoming widely adopted in clinical practice., Competing Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: A.C.G. reports that outside of this work he has received speaker fees from Orion Corporation Orion Pharma and Amomed Pharma. He has consulted for Ferring Pharmaceuticals, Tenax Therapeutics, Baxter Healthcare, Bristol-Myers Squibb and GSK, and received grant support from Orion Corporation Orion Pharma, Tenax Therapeutics and HCA International with funds paid to his institution. Authors otherwise declare no conflicts of interest., (© The Intensive Care Society 2023.)

Background: Fractures are rare events and can occur because of a fall. Fracture counts are distinct from other count data in that these data are positively skewed, inflated by excess zero counts, and events can recur over time. Analytical methods used to assess fracture data and account for these characteristics are limited in the literature., Methods: Commonly used models for count data include Poisson regression, negative binomial regression, hurdle regression, and zero-inflated regression models. In this paper, we compare four alternative statistical models to fit fracture counts using data from a large UK based clinical trial evaluating the clinical and cost-effectiveness of alternative falls prevention interventions in older people (Prevention of Falls Injury Trial; PreFIT)., Results: The values of Akaike information criterion and Bayesian information criterion, the goodness-of-fit statistics, were the lowest for negative binomial model. The likelihood ratio test of no dispersion in the data showed strong evidence of dispersion (chi-square = 225.68, p-value < 0.001). This indicates that the negative binomial model fits the data better compared to the Poisson regression model. We also compared the standard negative binomial regression and mixed effects negative binomial models. The LR test showed no gain in fitting the data using mixed effects negative binomial model (chi-square = 1.67, p-value = 0.098) compared to standard negative binomial model., Conclusions: The negative binomial regression model was the most appropriate and optimal fit model for fracture count analyses., Trial Registration: The PreFIT trial was registered as ISRCTN71002650., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background : Sex and gender are vitally important in the study of epigenetic mechanisms for various types of cancer. However, little has been done to assess the state of sex and gender-based analyses (SGBA) in this field. The aim was to undertake a critical evaluation of sex and gender representation, discussion, and data analysis within the cancer epigenetics field since 2010. Methods : A PRISMA-ScR scoping review was conducted with 111 peer-reviewed studies comprising of colorectal, gastric, head and neck, hepatocellular carcinoma, and lung cancers. Data extraction and a quality appraisal were performed by a team of epidemiologists and bioethicists. Results : Of the 111 included studies, only 17 studies (15.3%) explicitly stated sex and gender analysis to be their primary aim. A total of 103 studies (92.8%) provided a detailed analysis of sex/gender as a biological or social variable, while the remaining 8 studies (7.2%) only stratified results by sex/gender. Although sex and gender were a key facet in all the eligible studies, only 7 studies (6.3%) provided an explicit definition of the terms "sex" or "gender", while the remaining 104 studies (93.7%) used the words "sex" or "gender" without providing a definition. A total of 84 studies (75.7%) conflated the concepts of "sex" and "gender", while 44 studies (39.6%) were inconsistent with their usage of the "sex" and "gender" terms. Conclusions : Very few studies offered a robust analysis of sex/gender data according to SAGER guidelines. We call for clear and directed guidelines regarding the use of sex/gender as a variable in epigenetics research.

Survival from in-hospital cardiac arrest is approximately 18%, but for patients who require advanced airway management survival is lower. Those who do survive are often left with significant disability. Traditionally, resuscitation of cardiac arrest patients has included tracheal intubation, however insertion of a supraglottic airway has gained popularity as an alternative approach to advanced airway management. Evidence from out-of-hospital cardiac arrest suggests no significant differences in mortality or morbidity between these two approaches, but there is no randomised evidence for airway management during in-hospital cardiac arrest. The aim of the AIRWAYS-3 randomised trial, described in this protocol paper, is to determine the clinical and cost effectiveness of a supraglottic airway versus tracheal intubation during in-hospital cardiac arrest. Patients will be allocated randomly to receive either a supraglottic airway or tracheal intubation as the initial advanced airway management. We will also estimate the relative cost-effectiveness of these two approaches. The primary outcome is functional status, measured using the modified Rankin Scale at hospital discharge or 30 days post-randomisation, whichever occurs first. AIRWAYS-3 presents ethical challenges regarding patient consent and data collection. These include the enrolment of unconscious patients without prior consent in a way that avoids methodological bias. Other complexities include the requirement to randomise patients efficiently during a time-critical cardiac arrest. Many of these challenges are encountered in other emergency care research; we discuss our approaches to addressing them. Trial registration: ISRCTN 17720457. Prospectively registered on 29/07/2022., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: GDP is Editor-in-Chief, and JPN, KC and JS are Editors of the journal Resuscitation Plus., (© 2023 The Author(s).)

Objective: To adapt an existing surveillance system to monitor the collateral impacts of the COVID-19 pandemic on health outcomes in New York City across 6 domains: access to care, chronic disease, sexual/reproductive health, food/economic insecurity, mental/behavioral health, and environmental health., Design: Epidemiologic assessment. Public health surveillance system., Setting: New York City., Participants: New York City residents., Main Outcome Measures: We monitored approximately 30 indicators, compiling data from 2006 to 2022. Sources of data include clinic visits, surveillance surveys, vital statistics, emergency department visits, lead and diabetes registries, Medicaid claims, and public benefit enrollment., Results: We observed disruptions across most indicators including more than 50% decrease in emergency department usage early in the pandemic, which rebounded to prepandemic levels by late 2021, changes in reporting levels of probable anxiety and depression, and worsening birth outcomes for mothers who identified as Asian/Pacific Islander or Black. Data are processed in SAS and analyzed using the R Surveillance package to detect possible inflections. Data are updated monthly to an internal Tableau Dashboard and shared with agency leadership., Conclusions: As the COVID-19 pandemic continues into its third year, public health priorities are returning to addressing non-COVID-19-related diseases and conditions, their collateral impacts, and postpandemic recovery needs. Substantial work is needed to return even to a suboptimal baseline across multiple health topic areas. Our surveillance framework offers a valuable starting place to effectively allocate resources, develop interventions, and issue public communications., Competing Interests: The authors have no financial or material support to declare. The authors have indicated that they have no potential conflicts of interest to disclose., (Copyright © 2023 The Authors. Published by Wolters Kluwer Health, Inc.)

Importance: Opioid use for chronic nonmalignant pain can be harmful., Objective: To test whether a multicomponent, group-based, self-management intervention reduced opioid use and improved pain-related disability compared with usual care., Design, Setting, and Participants: Multicentered, randomized clinical trial of 608 adults taking strong opioids (buprenorphine, dipipanone, morphine, diamorphine, fentanyl, hydromorphone, methadone, oxycodone, papaveretum, pentazocine, pethidine, tapentadol, and tramadol) to treat chronic nonmalignant pain. The study was conducted in 191 primary care centers in England between May 17, 2017, and January 30, 2019. Final follow-up occurred March 18, 2020., Intervention: Participants were randomized 1:1 to either usual care or 3-day-long group sessions that emphasized skill-based learning and education, supplemented by 1-on-1 support delivered by a nurse and lay person for 12 months., Main Outcomes and Measures: The 2 primary outcomes were Patient-Reported Outcomes Measurement Information System Pain Interference Short Form 8a (PROMIS-PI-SF-8a) score (T-score range, 40.7-77; 77 indicates worst pain interference; minimal clinically important difference, 3.5) and the proportion of participants who discontinued opioids at 12 months, measured by self-report., Results: Of 608 participants randomized (mean age, 61 years; 362 female [60%]; median daily morphine equivalent dose, 46 mg [IQR, 25 to 79]), 440 (72%) completed 12-month follow-up. There was no statistically significant difference in PROMIS-PI-SF-8a scores between the 2 groups at 12-month follow-up (-4.1 in the intervention and -3.17 in the usual care groups; between-group difference: mean difference, -0.52 [95% CI, -1.94 to 0.89]; P = .15). At 12 months, opioid discontinuation occurred in 65 of 225 participants (29%) in the intervention group and 15 of 208 participants (7%) in the usual care group (odds ratio, 5.55 [95% CI, 2.80 to 10.99]; absolute difference, 21.7% [95% CI, 14.8% to 28.6%]; P < .001). Serious adverse events occurred in 8% (25/305) of the participants in the intervention group and 5% (16/303) of the participants in the usual care group. The most common serious adverse events were gastrointestinal (2% in the intervention group and 0% in the usual care group) and locomotor/musculoskeletal (2% in the intervention group and 1% in the usual care group). Four people (1%) in the intervention group received additional medical care for possible or probable symptoms of opioid withdrawal (shortness of breath, hot flushes, fever and pain, small intestinal bleed, and an overdose suicide attempt)., Conclusions and Relevance: In people with chronic pain due to nonmalignant causes, compared with usual care, a group-based educational intervention that included group and individual support and skill-based learning significantly reduced patient-reported use of opioids, but had no effect on perceived pain interference with daily life activities., Trial Registration: isrctn.org Identifier: ISRCTN49470934.

Complexes of curcumin with metals have shown much-improved stability, solubility, antioxidant capability, and efficacy when compared to curcumin. The present research investigates the relative bioavailability, antioxidant, and ability to inhibit inflammatory cytokine production of a curcuminoid metal chelation complex of tetrahydrocurcumin-zinc-curcuminoid termed TurmiZn. In vitro uptake assay using pig intestinal epithelial cells showed that TurmiZn has an ~3-fold increase ( p ≤ 0.01) in uptake compared to curcumin and a ~2-fold increase ( p ≤ 0.01) over tetrahydrocurcumin (THC). In a chicken model, an oral 1-g dose of TurmiZn showed a ~2.5-fold increase of a specific metabolite peak compared to curcumin ( p = 0.004) and a ~3-fold increase compared to THC ( p = 0.001). Oral doses (5 g/Kg) of TurmiZn in rats also showed the presence of curcumin and THC metabolites in plasma, indicating bioavailability across cell membranes in animals. Determination of the antioxidant activity by a 2,2-diphenyl-1-picryl-hydrazyl-hydrate (DPPH) radical scavenging assay indicated that TurmiZn was about 13x better ( p ≤ 0.0001) than curcumin and about 4X better ( p ≤ 0.0001) than THC, in reducing free radicals. In vitro experiments further showed significant ( p ≤ 0.01) reductions of lipopolysaccharide (LPS)-induced proinflammatory cytokines such as interleukin (IL) IL-6, IL-8, IL-15, IL-18, and tumor necrosis factor (TNF)-alpha, while showing a significant ( p ≤ 0.01) increase of granulocyte-macrophage colony-stimulating factor (GM-CSF) in dog kidney cells. In vivo cytokine modulations were also observed when TurmiZn was fed for 6 weeks to newborn chickens. TurmiZn reduced IL-1 and IL-6, but significantly reduced ( p ≤ 0.01) IL-10 levels while there was a concurrent significant ( p = 0.02) increase in interferon gamma compared to controls. Overall, these results indicate that TurmiZn has better bioavailability and antioxidant capability than curcumin or THC and has the ability to significantly modulate cytokine levels. Thus, TurmiZn could be an excellent candidate for a novel ingredient that can be incorporated into food and supplements to help overall health during the aging process.

Background: Postal screening has not previously been validated as a method for identifying fall and fracture risk in community-dwelling populations. We examined prognostic performance of a postal risk screener used in the UK Prevention of Falls Injury Trial (PreFIT; ISRCTN71002650), to predict any fall, recurrent falls, and fractures over 12 months. We tested whether adding variables would improve screener performance., Methods: Nine thousand eight hundred and eight community-dwelling participants, aged 70 years and older, and 63 general practices in the UK National Health Service (NHS) were included in a large, pragmatic cluster randomised trial comparing screen and treat fall prevention interventions. The short postal screener was sent to all participants in the trial intervention arms as an A4 sheet to be completed and returned to the GP (n = 6,580). The postal screener items were embedded in the baseline pre-randomisation postal questionnaire for all arms of the trial (n = 9,808). We assessed discrimination and calibration using area under the curve (AUC). We identified additional predictors using data from the control arm and applied these coefficients to internal validation models in the intervention arm participants. We used logistic regression to identify additional predictor variables., Findings: A total of 10,743 falls and 307 fractures were reported over 12 months. Over one third of participants 3,349/8,136 (41%) fell at least once over 12 month follow up. Response to the postal screener was high (5,779/6,580; 88%). Prediction models showed similar discriminatory ability in both control and intervention arms, with discrimination values for any fall AUC 0.67 (95% CI 0.65 to 0.68), and recurrent falls (AUC 0.71; 95% CI 0.69, 0.72) but poorer discrimination for fractures (AUC 0.60; 95% CI 0.56, 0.64). Additional predictor variables improved prediction of falls but had modest effect on fracture, where AUC rose to 0.71 (95% CI 0.67 to 0.74). Calibration slopes were very close to 1., Conclusion: A short fall risk postal screener was acceptable for use in primary care but fall prediction was limited, although consistent with other tools. Fracture and fall prediction were only partially reliant on fall risk although were improved with the additional variables., (© 2023. The Author(s).)

The tumor microenvironment (TME) is a complex network of cellular and non-cellular components surrounding the tumor. The cellular component includes fibroblasts, adipocytes, endothelial cells, and immune cells, while non-cellular components are tumor vasculature, extracellular matrix and signaling molecules. The tumor cells have constant close interaction with their surrounding TME components that facilitate their growth, survival, and metastasis. Targeting a complex TME network and its interaction with the tumor can offer a novel strategy to disrupt cancer cell progression. Curcumin, from turmeric rhizome, is recognized as a safe and effective natural therapeutic agent against multiple diseases including cancer. Here the effects of curcumin and its metabolites on tumor-TME interaction modulating ability have been described. Curcumin and its metabolites regulate TME by inhibiting the growth of its cellular components such as cancer-associated adipocytes, cancer-associated fibroblast, tumor endothelial cells, tumor-stimulating immune cells, and inducing anticancer immune cells. They also inhibit the interplay of tumor cells to TME by suppressing non-cellular components such as extracellular matrix, and associated tumor promoting signaling-pathways. In addition, curcumin inhibits the inflammatory environment, suppresses angiogenic factors, and increases antioxidant status in TME. Overall, curcumin has the capability to regulate TME components and their interaction with tumor cells.

Background: Parkinson disease (PD) has been recognized as responsible for concurrent spinal disorders. Surgical correction may be necessary, but the complexity of such fragile patients may require specific considerations. We systematically reviewed the literature on degenerative spine surgery in patients with PD., Methods: PubMed, Scopus, Web of Science, and Cochrane were searched according to the PRISMA guidelines to include studies reporting clinical data of patients with PD undergoing degenerative spine surgery. Clinical characteristics, treatment protocols, and outcomes were analyzed., Results: We included 22 articles comprising 442 patients (61.5% female). Mean age was 66.9 ± 3.5 years (range, 41-83 years). Mean PD duration and modified Hoehn and Yahr stage were 4.46 ± 2.39 years and 2.3 ± 0.8, respectively. Operation types included fusion (55.3%) and decompression (41.6%). Mean operated spine levels were 6.0 ± 5.08. A total of 377 postoperative complications occurred in 34.6% patients, categorized into mechanical failure (58.0%), infection (15.1%), or neurologic (10.7%). Of patients, 31.8% required surgical revisions, with an average of 1.88 ± 1.03 revisions per patient. The average normalized presurgery, postsurgery, and final aggregate numeric patient outcome scores were 0.37 ± 0.13, 0.63 ± 0.18, and 0.61 ± 0.19, respectively, with a score of 0 and 1 representing the worst and best possible score., Conclusions: Degenerative spine surgery in patients with PD is challenging, with complications and revisions occurring in up to a third of treated patients. Surgery should be offered when other treatment options have proved ineffective and is typically reserved for patients with myelopathy or significant disability. Successful outcomes depend on strong interdisciplinary support to control the movement disorder before and after surgery., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Anthracyclines such as doxorubicin (Dox) are effective chemotherapies, but their use is limited by cardiac toxicity. We hypothesized that plasma proteomics in women with breast cancer could identify new mechanisms of anthracycline cardiac toxicity. We measured changes in 1317 proteins in anthracycline-treated patients ( n  = 30) and replicated key findings in a second cohort ( n  = 31). An increase in the heme-binding protein hemopexin (Hpx) 3 months after anthracycline initiation was associated with cardiac toxicity by echocardiography. To assess the functional role of Hpx, we administered Hpx to wild-type (WT) mice treated with Dox and observed improved cardiac function. Conversely, Hpx -/- mice demonstrated increased Dox cardiac toxicity compared to WT mice. Initial mechanistic studies indicate that Hpx is likely transported to the heart by circulating monocytes/macrophages and that Hpx may mitigate Dox-induced ferroptosis to confer cardioprotection. Together, these observations suggest that Hpx induction represents a compensatory response during Dox treatment.

Introduction: Sepsis is characterised by a dysregulated immune response to infection, with exaggerated pro-inflammatory and anti-inflammatory responses. A predominant immunosuppressive profile affecting both innate and adaptive immune responses is associated with increased hospital-acquired infection and reduced infection-free survival. While hospital-acquired infection leads to additional antibiotic use, the role of the immunosuppressive phenotype in guiding complex decisions, such as those affecting antibiotic stewardship, is uncertain. This study is a mechanistic substudy embedded within a multicentre clinical and cost-effectiveness trial of biomarker-guided antibiotic stewardship. This mechanistic study aims to determine the effect of sepsis-associated immunosuppression on the trial outcome measures., Methods and Analysis: RISC-sepsis is a prospective, multicentre, exploratory, observational study embedded within the ADAPT-sepsis trial. A subgroup of 180 participants with antibiotics commenced for suspected sepsis, enrolled in the ADAPT-sepsis trial, will be recruited. Blood samples will be collected on alternate days until day 7. At each time point, blood will be collected for flow cytometric analysis into cell preservation tubes. Immunophenotyping will be performed at a central testing hub by flow cytometry. The primary outcome measures are monocyte human leucocyte antigen-DR; neutrophil CD88; programmed cell death-1 on monocytes, neutrophils and T lymphocytes and the percentage of regulatory T cells. Secondary outcome measures will link to trial outcomes from the ADAPT-sepsis trial including antibiotic days; occurrence of hospital-acquired infection and length of ICU-stay and hospital-stay., Ethics and Dissemination: Ethical approval has been granted (IRAS 209815) and RISC-sepsis is registered with the ISRCTN (86837685). Study results will be disseminated by peer-reviewed publications, presentations at scientific meetings and via patient and public participation groups and social media., Competing Interests: Competing interests: DFMcA is NIHR/MRC EME programme director and has previously sat on NIHR HTA funding committees., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Introduction: Large-for-gestational age (LGA) fetuses have an increased risk of shoulder dystocia. This can lead to adverse neonatal outcomes and death. Early induction of labour in women with a fetus suspected to be macrosomic may mitigate the risk of shoulder dystocia. The Big Baby Trial aims to find if induction of labour at 38 +0 -38 +4 weeks' gestation, in pregnancies with suspected LGA fetuses, reduces the incidence of shoulder dystocia., Methods and Analysis: The Big Baby Trial is a multicentre, prospective, individually randomised controlled trial of induction of labour at 38 +0 to 38 +4 weeks' gestation vs standard care as per each hospital trust (median gestation of delivery 39 +4 ) among women whose fetuses have an estimated fetal weight >90th customised centile according to ultrasound scan at 35 +0 to 38 +0 weeks' gestation. There is a parallel cohort study for women who decline randomisation because they opt for induction, expectant management or caesarean section. Up to 4000 women will be recruited and randomised to induction of labour or to standard care. The primary outcome is the incidence of shoulder dystocia; assessed by an independent expert group, blind to treatment allocation, from delivery records. Secondary outcomes include birth trauma, fractures, haemorrhage, caesarean section rate and length of inpatient stay. The main trial is ongoing, following an internal pilot study. A qualitative reporting, health economic evaluation and parallel process evaluation are included., Ethics and Dissemination: The study received a favourable opinion from the South West-Cornwall and Plymouth Health Research Authority on 23/03/2018 (IRAS project ID 229163). Study results will be reported in the National Institute for Health Research journal library and published in an open access peer-reviewed journal. We will plan dissemination events for key stakeholders., Trial Registration Number: ISRCTN18229892., Competing Interests: Competing interests: JG is the director of the Perinatal Institute, a not for profit organisation, limited by guarantee, and a qualified provider of maternity support services to the NHS. It derives its income from some of its products and services, including the award-winning GAP programme mentioned in this protocol, through which they have been able to implement training, e-learning and protocols in the majority of Trusts and Health Boards in the UK. GAP includes the standardised, RCOG endorsed customised GROW charts which will be used to identify large-for-gestational age as the entry point for this trial. MU is chief investigator or coinvestigator on multiple previous and current research grants from the UK National Institute for Health Research, Arthritis Research UK and is a coinvestigator on grants funded by the Australian NHMRC. He is an NIHR Senior Investigator. He has received travel expenses for speaking at conferences from the professional organisations hosting the conferences. He is a director and shareholder of Clinvivo Ltd http://www.clinvivo.com that provides electronic data collection for health services research. He is part of an academic partnership with Serco Ltd, funded by the European Social Fund, related to return to work initiatives. He is a coinvestigator on two NIHR funded studies receiving additional support from Stryker Ltd. He has accepted honoraria for teaching/lecturing from consortium for advanced research training in Africa. He was until March 2020 an editor of the NIHR journal series, and a member of the NIHR Journal Editors Group, for which he received a fee., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Existing public health surveillance systems that rely on predefined symptom categories, or syndromes, are effective at monitoring known illnesses, but there is a critical need for innovation in "presyndromic" surveillance that detects biothreats with rare or previously unseen symptomology. We introduce a data-driven, automated machine learning approach for presyndromic surveillance that learns newly emerging syndromes from free-text emergency department chief complaints, identifies localized case clusters among subpopulations, and incorporates practitioner feedback to automatically distinguish between relevant and irrelevant clusters, thus providing personalized, actionable decision support. Blinded evaluations by New York City's Department of Health and Mental Hygiene demonstrate that our approach identifies more events of public health interest and achieves a lower false-positive rate compared to a state-of-the-art baseline.

Background: Dural venous sinus stenting (VSS) is an effective intervention for patients with idiopathic intracranial hypertension (IIH) refractory to medical treatment. Our goal was to evaluate the efficacy by utilizing a large multi-institutional sample., Methods: Five hundred forty-one patients >18 years old who underwent VSS within 3 years of IIH diagnosis were queried using Current Procedural Terminology and International Classification of Diseases, Tenth Revision codes from the TriNetX Analytics Network. Patient demographics, baseline symptoms, procedures, and clinical outcomes were evaluated within 1 year postoperatively. Outcomes examined were headache, tinnitus, blindness/low vision, optic nerve sheath fenestration (ONSF), cerebrospinal fluid (CSF) shunt, and use of medications (acetazolamide, methazolamide, furosemide, topiramate, tricyclic antidepressants, and valproate) for IIH. Prestent and poststent data were compared using Fisher exact test, and the odds ratios were computed using the Baptista-Pike method., Results: The mean age at VSS was 36.7 ± 10.6; 92% were female, 65% of patients were Caucasian, 25% were Black/African American, 1% were Asian, and 9% were of other/unknown race. Within the 1-year follow-up, acetazolamide and topiramate use were significantly reduced post-VSS (P < 0.0001∗; odds ratio, 0.45; confidence interval, 0.35-0.57 and P = 0.03∗; odds ratio, 0.71; confidence interval, 0.52-0.95, respectively). Also, headaches, visual disturbance, dizziness/giddiness, and tinnitus significantly improved post-VSS (P < 0.005∗). Finally, the number of CSF shunt procedures and ONSF procedures demonstrated no significant change post-VSS (P > 0.05)., Conclusions: VSS is an effective and safe procedure resulting in significant improvement of headaches, visual impairment, dizziness, and tinnitus, acetazolamide and topiramate usage were lower after VSS in patients with IIH. The paucity of pre-VSS and post-VSS CSF shunt and ONSF procedure data does not provide enough evidence to establish significance., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Aims: The Prehospital Optimal Shock Energy for Defibrillation (POSED) study will assess the feasibility of conducting a cluster randomised controlled study of clinical effectiveness in UK ambulance services to identify the optimal shock energy for defibrillation., Methods: POSED is a pragmatic, allocation concealed, open label, cluster randomised, controlled feasibility study. Defibrillators within a single UK ambulance service will be randomised in an equal ratio to deliver one of three shock strategies 120-150-200 J, 150-200-200 J, 200-200-200 J. Consecutive adults (≥18 years) presenting with out of hospital cardiac arrest requiring defibrillation will be eligible. The study plans to enrol 90 patients (30 in each group). Patients (or their relatives for non-survivors) will be informed about trial participation after the initial emergency has resolved. Survivors will be invited to consent to participate in follow-up (i.e., at 30 days or discharge).The primary feasibility outcome is the proportion of eligible patients who receive the randomised study intervention. Secondary feasibility outcomes will include recruitment rate, adherence to allocated treatment and data completeness. Clinical outcomes will include Return of an Organised Rhythm (ROOR) at 2 minutes post-shock, refibrillation rate, Return of Spontaneous Circulation (ROSC) at hospital handover, survival and neurological outcome at 30 days ., Conclusion: The POSED study will assess the feasibility of a large-scale trial and explore opportunities to optimise the trial protocol. Trial registration: ISRCTN16327029., Competing Interests: HP reports research funding from National Institute for Health and Care Research. CDD, RL, FM, AC, MAS, PK, AD, DES report no conflicts of interest. GDP reports research funding from National Institute for Health and Care Research, British Heart Foundation and Resuscitation Council UK. He has volunteer roles with Resuscitation Council UK, European Resuscitation Council and the International Liaison Committee on Resuscitation. He is an editor for the journals Resuscitation and Resuscitation Plus., (© 2022 The Author(s).)

Curcumin, a polyphenolic compound isolated from turmeric rhizome, displays antioxidant, anti-inflammatory, anticancer, anti-microbial, antiviral, antidiabetic, neuroprotective, immune boosting and other chemopreventive and therapeutic properties. However, the efficacy of curcumin is confined due to its aqueous insolubility, instability, low intestinal absorption, poor bioavailability, and systemic elimination. Therefore, to overcome these issues and enhance pharmacological activities of curcumin, a complex of curcumin with metals such as zinc have been synthesized. Curcumin acts as a ligand and forms a stable complex with zinc. In this review, the improved protective, and therapeutic activities of zinc-curcumin complexes are discussed. Zinc-curcumin conjugates have exhibited enhanced antioxidant, anti-inflammatory, anticancer, antimicrobial and antidiabetic properties. Zinc-curcumin complexes have also displayed hepatoprotective, gastroprotective, neuroprotective, cardioprotective and osteogenesis efficacy. These protective and therapeutic efficacies of zinc-curcumin conjugates were associated with modulation of multiple molecular mechanisms including decreased inflammatory cytokines, increased antioxidant enzymes, quenched free radicals, decreased blood glucose levels, decreased insulin resistance, induced apoptosis markers, and restored function of tumor suppressor protein p53 in cancer cells. Overall, applications of zinc-curcumin complex could be a new approach against various diseases and could also be helpful in improvement of health., (Copyright © 2022 Elsevier GmbH. All rights reserved.)

Aim: To determine the optimal first-shock energy level for biphasic defibrillation and whether fixed or escalating protocols for subsequent shocks are most effective., Methods: We searched Medline, Embase, Cochrane CENTRAL, CINAHL, the Web of Science and national and international trial registry databases for papers published from database inception to January 2022. We reviewed reference lists of key papers to identify additional references. The population included adults sustaining non traumatic out-of-hospital cardiac arrest subject to attempted defibrillation. Studies of internal or monophasic defibrillation and studies other than randomised controlled trials or prospective cohorts were excluded. Two reviewers assessed study relevance. Data extraction and risk of bias assessment, using the ROBINS-I tool, were conducted by one reviewer and checked by a second reviewer. Data underwent intention-to-treat analysis., Results: We identified no studies evaluating first shock energy. Only one study ( n  = 738) comparing fixed versus escalating energy met eligibility criteria: a prospective cohort analysis of a randomised controlled trial of manual versus mechanical CPR. High fixed (360 J) energy was compared with an escalating (200-200/300-360 J) strategy. Researchers found 27.5% (70/255) of patients in the escalating energy group and 27.61% (132/478) in the fixed high energy group survived to hospital discharge (unadjusted risk ratio 0.99, 95% CI 0.73, 1.23). Results were of very low certainty as the study was at serious risk of bias., Conclusion: This systematic review did not identify an optimal first-shock energy for biphasic defibrillation. We identified no survival advantage at 30 days when comparing 360 J fixed with 200 J escalating strategy., (© 2022 The Author(s).)

Hyperosmolar solutions are widely used to treat raised intracranial pressure following severe traumatic brain injury. Although mannitol has historically been the most frequently administered, hypertonic saline solutions are increasingly being used. However, definitive evidence regarding their comparative effectiveness is lacking. The Sugar or Salt Trial is a UK randomised, allocation concealed open label multicentre pragmatic trial designed to determine the clinical and cost-effectiveness of hypertonic saline compared with mannitol in the management of patients with severe traumatic brain injury. Patients requiring intensive care unit admission and intracranial pressure monitoring post-traumatic brain injury will be allocated at random to receive equi-osmolar boluses of either mannitol or hypertonic saline following failure of routine first-line measures to control intracranial pressure. The primary outcome for the study will be the Extended Glasgow Outcome Scale assessed at six months after randomisation. Results will inform current clinical practice in the routine use of hyperosmolar therapy as well as assess the impact of potential side effects. Pre-planned longer term clinical and cost effectiveness analyses will further inform the use of these treatments., Competing Interests: Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Intensive Care Society 2020.)

Background: Continuous positive airways pressure (CPAP) and high-flow nasal oxygen (HFNO) are considered 'aerosol-generating procedures' in the treatment of COVID-19., Objective: To measure air and surface environmental contamination with SARS-CoV-2 virus when CPAP and HFNO are used, compared with supplemental oxygen, to investigate the potential risks of viral transmission to healthcare workers and patients., Methods: 30 hospitalised patients with COVID-19 requiring supplemental oxygen, with a fraction of inspired oxygen ≥0.4 to maintain oxygen saturation ≥94%, were prospectively enrolled into an observational environmental sampling study. Participants received either supplemental oxygen, CPAP or HFNO (n=10 in each group). A nasopharyngeal swab, three air and three surface samples were collected from each participant and the clinical environment. Real-time quantitative polymerase chain reaction analyses were performed for viral and human RNA, and positive/suspected-positive samples were cultured for the presence of biologically viable virus., Results: Overall 21/30 (70%) participants tested positive for SARS-CoV-2 RNA in the nasopharynx. In contrast, only 4/90 (4%) and 6/90 (7%) of all air and surface samples tested positive (positive for E and ORF1a) for viral RNA respectively, although there were an additional 10 suspected-positive samples in both air and surfaces samples (positive for E or ORF1a). CPAP/HFNO use or coughing was not associated with significantly more environmental contamination than supplemental oxygen use. Only one nasopharyngeal sample was culture positive., Conclusions: The use of CPAP and HFNO to treat moderate/severe COVID-19 did not appear to be associated with substantially higher levels of air or surface viral contamination in the immediate care environment, compared with the use of supplemental oxygen., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Importance: Continuous positive airway pressure (CPAP) and high-flow nasal oxygen (HFNO) have been recommended for acute hypoxemic respiratory failure in patients with COVID-19. Uncertainty exists regarding the effectiveness and safety of these noninvasive respiratory strategies., Objective: To determine whether either CPAP or HFNO, compared with conventional oxygen therapy, improves clinical outcomes in hospitalized patients with COVID-19-related acute hypoxemic respiratory failure., Design, Setting, and Participants: A parallel group, adaptive, randomized clinical trial of 1273 hospitalized adults with COVID-19-related acute hypoxemic respiratory failure. The trial was conducted between April 6, 2020, and May 3, 2021, across 48 acute care hospitals in the UK and Jersey. Final follow-up occurred on June 20, 2021., Interventions: Adult patients were randomized to receive CPAP (n = 380), HFNO (n = 418), or conventional oxygen therapy (n = 475)., Main Outcomes and Measures: The primary outcome was a composite of tracheal intubation or mortality within 30 days., Results: The trial was stopped prematurely due to declining COVID-19 case numbers in the UK and the end of the funded recruitment period. Of the 1273 randomized patients (mean age, 57.4 [95% CI, 56.7 to 58.1] years; 66% male; 65% White race), primary outcome data were available for 1260. Crossover between interventions occurred in 17.1% of participants (15.3% in the CPAP group, 11.5% in the HFNO group, and 23.6% in the conventional oxygen therapy group). The requirement for tracheal intubation or mortality within 30 days was significantly lower with CPAP (36.3%; 137 of 377 participants) vs conventional oxygen therapy (44.4%; 158 of 356 participants) (absolute difference, -8% [95% CI, -15% to -1%], P = .03), but was not significantly different with HFNO (44.3%; 184 of 415 participants) vs conventional oxygen therapy (45.1%; 166 of 368 participants) (absolute difference, -1% [95% CI, -8% to 6%], P = .83). Adverse events occurred in 34.2% (130/380) of participants in the CPAP group, 20.6% (86/418) in the HFNO group, and 13.9% (66/475) in the conventional oxygen therapy group., Conclusions and Relevance: Among patients with acute hypoxemic respiratory failure due to COVID-19, an initial strategy of CPAP significantly reduced the risk of tracheal intubation or mortality compared with conventional oxygen therapy, but there was no significant difference between an initial strategy of HFNO compared with conventional oxygen therapy. The study may have been underpowered for the comparison of HFNO vs conventional oxygen therapy, and early study termination and crossover among the groups should be considered when interpreting the findings., Trial Registration: isrctn.org Identifier: ISRCTN16912075.

Background: Upper limb problems are common after breast cancer treatment., Objectives: To investigate the clinical effectiveness and cost-effectiveness of a structured exercise programme compared with usual care on upper limb function, health-related outcomes and costs in women undergoing breast cancer surgery., Design: This was a two-arm, pragmatic, randomised controlled trial with embedded qualitative research, process evaluation and parallel economic analysis; the unit of randomisation was the individual (allocated ratio 1 : 1)., Setting: Breast cancer centres, secondary care., Participants: Women aged ≥ 18 years who had been diagnosed with breast cancer and were at higher risk of developing shoulder problems. Women were screened to identify their risk status., Interventions: All participants received usual-care information leaflets. Those randomised to exercise were referred to physiotherapy for an early, structured exercise programme (three to six face-to-face appointments that included strengthening, physical activity and behavioural change strategies)., Main Outcome Measures: The primary outcome was upper limb function at 12 months as assessed using the Disabilities of Arm, Hand and Shoulder questionnaire. Secondary outcomes were function (Disabilities of Arm, Hand and Shoulder questionnaire subscales), pain, complications (e.g. wound-related complications, lymphoedema), health-related quality of life (e.g. EuroQol-5 Dimensions, five-level version; Short Form questionnaire-12 items), physical activity and health service resource use. The economic evaluation was expressed in terms of incremental cost per quality-adjusted life-year and incremental net monetary benefit gained from an NHS and Personal Social Services perspective. Participants and physiotherapists were not blinded to group assignment, but data collectors were blinded., Results: Between 2016 and 2017, we randomised 392 participants from 17 breast cancer centres across England: 196 (50%) to the usual-care group and 196 (50%) to the exercise group. Ten participants (10/392; 3%) were withdrawn at randomisation and 32 (8%) did not provide complete baseline data. A total of 175 participants (89%) from each treatment group provided baseline data. Participants' mean age was 58.1 years (standard deviation 12.1 years; range 28-88 years). Most participants had undergone axillary node clearance surgery (327/392; 83%) and 317 (81%) had received radiotherapy. Uptake of the exercise treatment was high, with 181 out of 196 (92%) participants attending at least one physiotherapy appointment. Compliance with exercise was good: 143 out of 196 (73%) participants completed three or more physiotherapy sessions. At 12 months, 274 out of 392 (70%) participants returned questionnaires. Improvement in arm function was greater in the exercise group [mean Disabilities of Arm, Hand and Shoulder questionnaire score of 16.3 (standard deviation 17.6)] than in the usual-care group [mean Disabilities of Arm, Hand and Shoulder questionnaire score of 23.7 (standard deviation 22.9)] at 12 months for intention-to-treat (adjusted mean difference Disabilities of Arm, Hand and Shoulder questionnaire score of -7.81, 95% confidence interval -12.44 to -3.17; p  = 0.001) and complier-average causal effect analyses (adjusted mean difference -8.74, 95% confidence interval -13.71 to -3.77; p  ≤ 0.001). At 12 months, pain scores were lower and physical health-related quality of life was higher in the exercise group than in the usual-care group (Short Form questionnaire-12 items, mean difference 4.39, 95% confidence interval 1.74 to 7.04; p  = 0.001). We found no differences in the rate of adverse events or lymphoedema over 12 months. The qualitative findings suggested that women found the exercise programme beneficial and enjoyable. Exercise accrued lower costs (-£387, 95% CI -£2491 to £1718) and generated more quality-adjusted life years (0.029, 95% CI 0.001 to 0.056) than usual care over 12 months. The cost-effectiveness analysis indicated that exercise was more cost-effective and that the results were robust to sensitivity analyses. Exercise was relatively cheap to implement (£129 per participant) and associated with lower health-care costs than usual care and improved health-related quality of life. Benefits may accrue beyond the end of the trial., Limitations: Postal follow-up was lower than estimated; however, the study was adequately powered. No serious adverse events directly related to the intervention were reported., Conclusions: This trial provided robust evidence that referral for early, supported exercise after breast cancer surgery improved shoulder function in those at risk of shoulder problems and was associated with lower health-care costs than usual care and improved health-related quality of life., Future Work: Future work should focus on the implementation of exercise programmes in clinical practice for those at highest risk of shoulder problems., Trial Registration: This trial is registered as ISRCTN35358984., 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. 26, No. 15. See the NIHR Journals Library website for further project information.

To characterize the epidemiological properties of the B.1.526 SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) variant of interest, here we used nine epidemiological and population datasets and model-inference methods to reconstruct SARS-CoV-2 transmission dynamics in New York City, where B.1.526 emerged. We estimated that B.1.526 had a moderate increase (15 to 25%) in transmissibility, could escape immunity in 0 to 10% of previously infected individuals, and substantially increased the infection fatality risk (IFR) among adults 65 or older by >60% during November 2020 to April 2021, compared to estimates for preexisting variants. Overall, findings suggest that new variants like B.1.526 likely spread in the population weeks before detection and that partial immune escape (e.g., resistance to therapeutic antibodies) could offset prior medical advances and increase IFR. Early preparedness for and close monitoring of SARS-CoV-2 variants, their epidemiological characteristics, and disease severity are thus crucial to COVID-19 (coronavirus disease 2019) response.

Aims: Bystander cardiopulmonary resuscitation and defibrillation can double survival to hospital discharge in out-of-hospital cardiac arrest. Mobile phone applications, such as GoodSAM, alerting nearby volunteer first-responders about out-of-hospital cardiac arrest could potentially improve bystander cardiopulmonary resuscitation and defibrillation, leading to better patient outcomes. The aim of this study was to determine GoodSAM's effect on survival to hospital discharge following out-of-hospital cardiac arrest., Methods and Results: We collected data from the Out-of-Hospital Cardiac Arrest Outcomes Registry (University of Warwick, UK) submitted by the London Ambulance Service (1 April 2016 to 31 March 2017) and East Midlands Ambulance Service (1 January 2018 to 17 June 2018) and matched out-of-hospital cardiac arrests to GoodSAM alerts. We constructed logistic regression models to determine if there was an association between a GoodSAM first-responder accepting an alert and survival to hospital discharge, adjusting for location type, presenting rhythm, age, gender, ambulance service response time, cardiac arrest witnessed status, and bystander actions. Survival to hospital discharge was 9.6% (393/4196) in London and 7.2% (72/1001) in East Midlands. A GoodSAM first-responder accepted an alert for out-of-hospital cardiac arrest in 1.3% (53/4196) cases in London and 5.4% (51/1001) cases in East Midlands. When a responder accepted an alert, the adjusted odds ratio for survival to hospital discharge was 3.15 (95% CI: 1.19-8.36, P = 0.021) in London and 3.19 (95% CI: 1.17-8.73, P = 0.024) in East Midlands., Conclusion: Alert acceptance was associated with improved survival in both ambulance services. Alert acceptance rates were low, and challenges remain to maximize the potential benefit of GoodSAM., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Coronavirus disease 2019 (COVID-19) was first officially diagnosed in the city of Wuhan, China in January 2020. In reality, the disease was identified in December 2019 in the same city where patients began showing symptoms of pneumonia of unidentified origin. Very soon the disease became a global pandemic due to the suppression of information in the country of origin and inadequate testing for the COVID-19 virus. Currently, > 101 million people have been found positive for this virus and > 2.17 million people have died. There are no signs that COVID-19 is slowing down. This deadly virus affects multiple vital organs (lungs, heart, nervous system, blood, and immune system), yet its exact mechanism of pathophysiology remains obscure. Depending on the viral load, sick people often show symptoms of fever, cough, shortness of breath, coagulopathy, cardiac abnormalities, fatigue, and death. Great strides have been made in COVID-19 testing, thereby allowing timely therapeutic intervention. Currently, vaccines are on the market from Pfizer, Moderna and Astra Zeneca with limited supply. Phase III clinical trials are also underway from other manufacturers. In the current scenario, nutraceuticals and other phyto-mineral supplements appear to be promising alternative solutions for the prevention and treatment of COVID-19.

Objective: To evaluate whether a structured exercise programme improved functional and health related quality of life outcomes compared with usual care for women at high risk of upper limb disability after breast cancer surgery., Design: Multicentre, pragmatic, superiority, randomised controlled trial with economic evaluation., Setting: 17 UK National Health Service cancer centres., Participants: 392 women undergoing breast cancer surgery, at risk of postoperative upper limb morbidity, randomised (1:1) to usual care with structured exercise (n=196) or usual care alone (n=196)., Interventions: Usual care (information leaflets) only or usual care plus a physiotherapy led exercise programme, incorporating stretching, strengthening, physical activity, and behavioural change techniques to support adherence to exercise, introduced at 7-10 days postoperatively, with two further appointments at one and three months., Main Outcome Measures: Disability of Arm, Hand and Shoulder (DASH) questionnaire at 12 months, analysed by intention to treat. Secondary outcomes included DASH subscales, pain, complications, health related quality of life, and resource use, from a health and personal social services perspective., Results: Between 26 January 2016 and 31 July 2017, 951 patients were screened and 392 (mean age 58.1 years) were randomly allocated, with 382 (97%) eligible for intention to treat analysis. 181 (95%) of 191 participants allocated to exercise attended at least one appointment. Upper limb function improved after exercise compared with usual care (mean DASH 16.3 (SD 17.6) for exercise (n=132); 23.7 (22.9) usual care (n=138); adjusted mean difference 7.81, 95% confidence interval 3.17 to 12.44; P=0.001). Secondary outcomes favoured exercise over usual care, with lower pain intensity at 12 months (adjusted mean difference on numerical rating scale -0.68, -1.23 to -0.12; P=0.02) and fewer arm disability symptoms at 12 months (adjusted mean difference on Functional Assessment of Cancer Therapy-Breast+4 (FACT-B+4) -2.02, -3.11 to -0.93; P=0.001). No increase in complications, lymphoedema, or adverse events was noted in participants allocated to exercise. Exercise accrued lower costs per patient (on average -£387 (€457; $533) (95% confidence interval -£2491 to £1718; 2015 pricing) and was cost effective compared with usual care., Conclusions: The PROSPER exercise programme was clinically effective and cost effective and reduced upper limb disability one year after breast cancer treatment in patients at risk of treatment related postoperative complications., Trial Registration: ISRCTN Registry ISRCTN35358984., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: support from the UK National Institute for Health Research (NIHR) Technology Assessment Programme; JB received grants from the UK NIHR during the conduct of this study and is a member of the NIHR Research for Patient Benefit board; SL reports membership of the UK NIHR Health Technology Assessment (HTA) Additional Capacity Funding Board, HTA End of Life Care and Add-on Studies Board, HTA Prioritisation Group Board, and HTA Trauma Board; no other relationships or activities that could appear to have influenced the submitted work., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. No commercial re-use. See rights and permissions. Published by BMJ.)

The novel coronavirus disease (COVID-19), the reason for worldwide pandemic, has already masked around 220 countries globally. This disease is induced by Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2). Arising environmental stress, increase in the oxidative stress level, weak immunity and lack of nutrition deteriorates the clinical status of the infected patients. Though several researches are at its peak for understanding and bringing forward effective therapeutics, yet there is no promising solution treating this disease directly. Medicinal plants and their active metabolites have always been promising in treating many clinical complications since time immemorial. Mother nature provides vivid chemical structures, which act multi-dimensionally all alone or synergistically in mitigating several diseases. Their unique antioxidant and anti-inflammatory activity with least side effects have made them more effective candidate for pharmacological studies. These medicinal plants inhibit attachment, encapsulation and replication of COVID-19 viruses by targeting various signaling molecules such as angiotensin converting enzyme-2, transmembrane serine protease 2, spike glycoprotein, main protease etc. This property is re-examined and its potency is now used to improve the existing global health crisis. This review is an attempt to focus various antiviral activities of various noteworthy medicinal plants. Moreover, its implications as prophylactic or preventive in various secondary complications including neurological, cardiovascular, acute kidney disease, liver disease are also pinpointed in the present review. This knowledge will help emphasis on the therapeutic developments for this novel coronavirus where it can be used as alone or in combination with the repositioned drugs to combat COVID-19.

Background: Using straight-line distance to estimate the proximity of public-access Automated External Defibrillators (AEDs) or volunteer first-responders to potential out-of-hospital cardiac arrests (OHCAs) does not reflect real-world travel distance. The difference between estimates may be an important consideration for bystanders and first-responders responding to OHCAs and may potentially impact patient outcome., Objectives: To explore how calculating real-world travel routes instead of using straight-line distance estimates might impact the community response to OHCA., Methods: We mapped 4355 OHCA (01/04/2016-31/03/2017) and 2677 AEDs in London (UK), and 1263 OHCA (18/06/2017-17/06/2018) and 4704 AEDs in East Midlands (UK) using ArcGIS mapping software. We determined the distance from OHCAs to the nearest AED using straight-line estimates and real-world travel routes. We mapped locations of potential OHCAs (London: n = 9065, 20/09/2019-22/03/2020; East Midlands: n = 7637, 20/09/2019-17/03/2020) for which volunteer first-responders were alerted by the GoodSAM mobile-phone app, and calculated response distance using straight-line estimates and real-world travel routes. We created Receiver Operating Characteristic (ROC) curves and calculated the Area Under the Curve (AUC) to determine if travel distance predicted whether or not a responder accepted an alert., Results: Real-world travel routes to the nearest AED were (median) 219 m longer (623 m vs 406 m) than straight-line estimates in London, and 211 m longer (568 m vs 357 m) in East Midlands. The identity of the nearest AED changed on 26% occasions in both areas when calculating real-world travel routes. GoodSAM responders' real-world travel routes were (median) 222 m longer (601 m vs 379 m) in London, and 291 m longer (814 m vs 523 m) in East Midlands. AUC statistics for both areas demonstrated that neither straight-line nor real-world travel distance predicted whether or not a responder accepted an alert., Conclusions: Calculating real-world travel routes increases the estimated travel distance and time for those responding to OHCAs. Calculating straight-line distance may overestimate the benefit of the community response to OHCA., (© 2021 The Author(s).)

Chronic joint inflammatory disorders like osteoarthritis and rheumatoid arthritis, which are manifested by joint dysfunction, show an upsurge in inflammation and oxidative stress. Although conventional anti-arthritic drugs are being used to relieve pain from arthritic symptoms, they usually cause severe side effects. Traditionally used Ayurvedic medicinal plants are a promising alternative for the management of arthritic symptoms, as they are safe and effective. Ayurvedic medicinal plants improve arthritic symptoms by reducing joint tenderness, joint pain, swelling, bone and cartilage damage, and increasing knee flexion, walking distance and sports activities. These beneficial effects of Ayurvedic medicinal plants on arthritis are mediated through various cellular mechanisms including inhibition of the inflammatory markers NF-κB, cytokines, adipokines, PGE2, NO, iNOS, COX-2, and MMPs and induction of antioxidant status by decreasing free radicals, lipid peroxidation, and myeloperoxidase, and increasing antioxidant enzymes, Nrf2, and HO-1. Thus, a strategy requires using these Ayurvedic medicinal plants to treat arthritis. This article describes the status of inflammation and oxidative stress in arthritic conditions. We also provide evidence that Ayurvedic medicinal plants and their bioactive components are highly effective in improving arthritic symptoms.

Background: More than 90% of antibiotics are prescribed in primary care, but 50% may be unnecessary. Reducing unnecessary antibiotic overuse is needed to limit antimicrobial resistance. We conducted a pragmatic trial of a primary care provider-focused antimicrobial stewardship intervention to reduce antibiotic prescriptions in primary care., Methods: Primary care practitioners from six primary care clinics in Toronto, Ontario were assigned to intervention or control groups to evaluate the effectiveness of a multi-faceted intervention for reducing antibiotic prescriptions to adults with respiratory and urinary tract infections. The intervention included provider education, clinical decision aids, and audit and feedback of antibiotic prescribing. The primary outcome was total antibiotic prescriptions for these infections. Secondary outcomes were delayed prescriptions, prescriptions longer than 7 days, recommended antibiotic use, and outcomes for individual infections. Generalized estimating equations were used to estimate treatment effects, adjusting for clustering by clinic and baseline differences., Results: There were 1682 encounters involving 54 primary care providers from January until May 31, 2019. In intervention clinics, the odds of any antibiotic prescription was reduced 22% (adjusted Odds Ratio (OR) = 0.78; 95% Confidence Interval (CI) = 0.64.0.96). The odds that a delay in filling a prescription was recommended was increased (adjusted OR=2.29; 95% CI=1.37, 3.83), while prescription durations greater than 7 days were reduced (adjusted OR=0.24; 95% CI=0.13, 0.43). Recommended antibiotic use was similar in control (85.4%) and intervention clinics (91.8%, p=0.37)., Conclusions: A community-based, primary care provider-focused antimicrobial stewardship intervention was associated with a reduced likelihood of antibiotic prescriptions for respiratory and urinary infections, an increase in delayed prescriptions, and reduced prescription durations., Trial Registration: clinicaltrials.gov ( NCT03517215 )., (© 2021. The Author(s).)

Background: The optimal airway management strategy for in-hospital cardiac arrest is unknown., Methods: An online survey and telephone interviews with anaesthetic and intensive care trainee doctors identified by the United Kingdom Research and Audit Federation of Trainees. Questions explored in-hospital cardiac arrest frequency, grade and specialty of those attending, proportion of patients receiving advanced airway management, airway strategies immediately available, and views on a randomised trial of airway management strategies during in-hospital cardiac arrest., Results: Completed surveys were received from 128 hospital sites (76% response rate). Adult in-hospital cardiac arrests were attended by anaesthesia staff at 40 sites (31%), intensive care staff at 37 sites (29%) and a combination of specialties at 51 sites (40%). The majority (123/128, 96%) of respondents reported immediate access to both tracheal intubation and supraglottic airways. A bag-mask technique was used 'very frequently' or 'frequently' during in-hospital cardiac arrest by 111/128 (87%) of respondents, followed by supraglottic airways (101/128, 79%) and tracheal intubation (69/128, 54%). The majority (60/100, 60%) of respondents estimated that ≤30% of in-hospital cardiac arrest patients undergo tracheal intubation, while 34 (34%) estimated this to be between 31% and 70%. Most respondents (102/128, 80%) would be 'likely' or 'very likely' to recruit future patients to a trial of alternative airway management strategies during in-hospital cardiac arrest. Interview data identified several barriers and facilitators to conducting research on airway management in in-hospital cardiac arrest., Conclusions: There is variation in airway management strategies for adult in-hospital cardiac arrest across the UK. Most respondents would be willing to take part in a randomised trial of airway management during in-hospital cardiac arrest., (© The Intensive Care Society 2020.)

Curcumin, an active component of the rhizome turmeric, has gained much attention as a plant-based compound with pleiotropic pharmacological properties. It possesses anti-inflammatory, antioxidant, hypoglycemic, antimicrobial, neuroprotective, and immunomodulatory activities. However, the health-promoting utility of curcumin is constrained due to its hydrophobic nature, water insolubility, poor bioavailability, rapid metabolism, and systemic elimination. Therefore, an innovative stride was taken, and complexes of metals with curcumin have been synthesized. Curcumin usually reacts with metals through the β-diketone moiety to generate metal-curcumin complexes. It is well established that curcumin strongly chelates several metal ions, including boron, cobalt, copper, gallium, gadolinium, gold, lanthanum, manganese, nickel, iron, palladium, platinum, ruthenium, silver, vanadium, and zinc. In this review, the pharmacological, chemopreventive, and therapeutic activities of metal-curcumin complexes are discussed. Metal-curcumin complexes increase the solubility, cellular uptake, and bioavailability and improve the antioxidant, anti-inflammatory, antimicrobial, and antiviral effects of curcumin. Metal-curcumin complexes have also demonstrated efficacy against various chronic diseases, including cancer, arthritis, osteoporosis, and neurological disorders such as Alzheimer's disease. These biological activities of metal-curcumin complexes were associated with the modulation of inflammatory mediators, transcription factors, protein kinases, antiapoptotic proteins, lipid peroxidation, and antioxidant enzymes. In addition, metal-curcumin complexes have shown usefulness in biological imaging and radioimaging. The future use of metal-curcumin complexes may represent a new approach in the prevention and treatment of chronic diseases.

Background: Falls and fractures are a major problem., Objectives: To investigate the clinical effectiveness and cost-effectiveness of alternative falls prevention interventions., Design: Three-arm, pragmatic, cluster randomised controlled trial with parallel economic analysis. The unit of randomisation was the general practice., Setting: Primary care., Participants: People aged ≥ 70 years., Interventions: All practices posted an advice leaflet to each participant. Practices randomised to active intervention arms (exercise and multifactorial falls prevention) screened participants for falls risk using a postal questionnaire. Active treatments were delivered to participants at higher risk of falling., Main Outcome Measures: The primary outcome was fracture rate over 18 months, captured from Hospital Episode Statistics, general practice records and self-report. Secondary outcomes were falls rate, health-related quality of life, mortality, frailty and health service resource use. Economic evaluation was expressed in terms of incremental cost per quality-adjusted life-year and incremental net monetary benefit., Results: Between 2011 and 2014, we randomised 63 general practices (9803 participants): 21 practices (3223 participants) to advice only, 21 practices (3279 participants) to exercise and 21 practices (3301 participants) to multifactorial falls prevention. In the active intervention arms, 5779 out of 6580 (87.8%) participants responded to the postal fall risk screener, of whom 2153 (37.3%) were classed as being at higher risk of falling and invited for treatment. The rate of intervention uptake was 65% (697 out of 1079) in the exercise arm and 71% (762 out of 1074) in the multifactorial falls prevention arm. Overall, 379 out of 9803 (3.9%) participants sustained a fracture. There was no difference in the fracture rate between the advice and exercise arms (rate ratio 1.20, 95% confidence interval 0.91 to 1.59) or between the advice and multifactorial falls prevention arms (rate ratio 1.30, 95% confidence interval 0.99 to 1.71). There was no difference in falls rate over 18 months (exercise arm: rate ratio 0.99, 95% confidence interval 0.86 to 1.14; multifactorial falls prevention arm: rate ratio 1.13, 95% confidence interval 0.98 to 1.30). A lower rate of falls was observed in the exercise arm at 8 months (rate ratio 0.78, 95% confidence interval 0.64 to 0.96), but not at other time points. There were 289 (2.9%) deaths, with no differences by treatment arm. There was no evidence of effects in prespecified subgroup comparisons, nor in nested intention-to-treat analyses that considered only those at higher risk of falling. Exercise provided the highest expected quality-adjusted life-years (1.120), followed by advice and multifactorial falls prevention, with 1.106 and 1.114 quality-adjusted life-years, respectively. NHS costs associated with exercise (£3720) were lower than the costs of advice (£3737) or of multifactorial falls prevention (£3941). Although incremental differences between treatment arms were small, exercise dominated advice, which in turn dominated multifactorial falls prevention. The incremental net monetary benefit of exercise relative to treatment valued at £30,000 per quality-adjusted life-year is modest, at £191, and for multifactorial falls prevention is £613. Exercise is the most cost-effective treatment. No serious adverse events were reported., Limitations: The rate of fractures was lower than anticipated., Conclusions: Screen-and-treat falls prevention strategies in primary care did not reduce fractures. Exercise resulted in a short-term reduction in falls and was cost-effective., Future Work: Exercise is the most promising intervention for primary care. Work is needed to ensure adequate uptake and sustained effects., Trial Registration: Current Controlled Trials ISRCTN71002650., 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. 25, No. 34. See the NIHR Journals Library website for further project information.

Background: Adrenaline has been used as a treatment for cardiac arrest for many years, despite uncertainty about its effects on long-term outcomes and concerns that it may cause worse neurological outcomes., Objectives: The objectives were to evaluate the effects of adrenaline on survival and neurological outcomes, and to assess the cost-effectiveness of adrenaline use., Design: This was a pragmatic, randomised, allocation-concealed, placebo-controlled, parallel-group superiority trial and economic evaluation. Costs are expressed in Great British pounds and reported in 2016/17 prices., Setting: This trial was set in five NHS ambulance services in England and Wales., Participants: Adults treated for an out-of-hospital cardiac arrest were included. Patients were ineligible if they were pregnant, if they were aged < 16 years, if the cardiac arrest had been caused by anaphylaxis or life-threatening asthma, or if adrenaline had already been given., Interventions: Participants were randomised to either adrenaline (1 mg) or placebo in a 1 : 1 allocation ratio by the opening of allocation-concealed treatment packs., Main Outcome Measures: The primary outcome was survival to 30 days. The secondary outcomes were survival to hospital admission, survival to hospital discharge, survival at 3, 6 and 12 months, neurological outcomes and health-related quality of life through to 6 months. The economic evaluation assessed the incremental cost per quality-adjusted life-year gained from the perspective of the NHS and Personal Social Services. Participants, clinical teams and those assessing patient outcomes were masked to the treatment allocation., Results: From December 2014 to October 2017, 8014 participants were assigned to the adrenaline ( n  = 4015) or to the placebo ( n  = 3999) arm. At 30 days, 130 out of 4012 participants (3.2%) in the adrenaline arm and 94 out of 3995 (2.4%) in the placebo arm were alive (adjusted odds ratio for survival 1.47, 95% confidence interval 1.09 to 1.97). For secondary outcomes, survival to hospital admission was higher for those receiving adrenaline than for those receiving placebo (23.6% vs. 8.0%; adjusted odds ratio 3.83, 95% confidence interval 3.30 to 4.43). The rate of favourable neurological outcome at hospital discharge was not significantly different between the arms (2.2% vs. 1.9%; adjusted odds ratio 1.19, 95% confidence interval 0.85 to 1.68). The pattern of improved survival but no significant improvement in neurological outcomes continued through to 6 months. By 12 months, survival in the adrenaline arm was 2.7%, compared with 2.0% in the placebo arm (adjusted odds ratio 1.38, 95% confidence interval 1.00 to 1.92). An adjusted subgroup analysis did not identify significant interactions. The incremental cost-effectiveness ratio for adrenaline was estimated at £1,693,003 per quality-adjusted life-year gained over the first 6 months after the cardiac arrest event and £81,070 per quality-adjusted life-year gained over the lifetime of survivors. Additional economic analyses estimated incremental cost-effectiveness ratios for adrenaline at £982,880 per percentage point increase in overall survival and £377,232 per percentage point increase in neurological outcomes over the first 6 months after the cardiac arrest., Limitations: The estimate for survival with a favourable neurological outcome is imprecise because of the small numbers of patients surviving with a good outcome., Conclusions: Adrenaline improved long-term survival, but there was no evidence that it significantly improved neurological outcomes. The incremental cost-effectiveness ratio per quality-adjusted life-year exceeds the threshold of £20,000-30,000 per quality-adjusted life-year usually supported by the NHS., Future Work: Further research is required to better understand patients' preferences in relation to survival and neurological outcomes after out-of-hospital cardiac arrest and to aid interpretation of the trial findings from a patient and public perspective., Trial Registration: Current Controlled Trials ISRCTN73485024 and EudraCT 2014-000792-11., 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. 25, No. 25. See the NIHR Journals Library website for further project information.

Aims: We recently reported early outcomes in patients enrolled in a randomised trial of adrenaline in out-of-hospital cardiac arrest: the PARAMEDIC2 (Prehospital Assessment of the Role of Adrenaline: Measuring the Effectiveness of Drug Administration in Cardiac Arrest) trial. The purpose of the present paper is to report long-term survival, quality of life, functional and cognitive outcomes at 3, 6 and 12-months., Methods: PARAMEDIC2 was a pragmatic, individually randomised, double blind, controlled trial with an economic evaluation. Patients were randomised to either adrenaline or placebo. This paper reports results on the modified Rankin Scale scores at 6-months, survival at 6 and 12-months, as well as other cognitive, functional and quality of life outcomes collected at 3 and 6 months (Two Simple Questions, the Mini Mental State Examination, the Informant Questionnaire on Cognitive Decline Evaluation for Cardiac Arrest, Hospital Anxiety and Depression Scale, the Post Traumatic Stress Disorder Checklist - Civilian Version, Short-Form 12-item Health Survey and the EuroQoL EQ-5D-5L)., Results: 8014 patients were randomised with confirmed trial drug administration. At 6-months, 78 (2.0%) of the patients in the adrenaline group and 58 (1.5%) of patients in the placebo group had a favourable neurological outcome (adjusted odds ratio 1.35 [95% confidence interval: 0.93, 1.97]). 117 (2.9%) patients were alive at 6-months in the adrenaline group compared with 86 (2.2%) in the placebo group (1.43 [1.05, 1.96], reducing to 107 (2.7%) and 80 (2.0%) respectively at 12-months (1.38 [1.00, 1.92]). Measures of 3 and 6-month cognitive, functional and quality of life outcomes were reduced, but there was no strong evidence of differences between groups., Conclusion: Adrenaline improved survival through to 12-months follow-up. The study did not find evidence of improvements in favourable neurological outcomes. (ISCRTN 73485024)., (Copyright © 2021. Published by Elsevier B.V.)

Introduction: In 2013, a single-centre study reported the safe use of esmolol in patients with septic shock and tachycardia who required vasopressor therapy for more than 24 hours. Although not powered to detect a change in mortality, marked improvements were seen in survival (adjusted HR, 0.39; 95% CI, 0.26 to 0.59; p<0.001). Beta blockers are one of the most studied groups of drugs but their effect in septic shock is poorly understood; proposed mechanisms include not only the modulation of cardiac function but also immunomodulation., Methods and Analysis: STRESS-L is a randomised, open-label, non-blinded clinical trial which is enrolling a total of 340 patients with septic shock as defined by Sepsis-3 consensus definition and a tachycardia (heart rate ≥95 beats per minute (bpm)) after vasopressor treatment of at least 24 hours. Standard randomisation (1:1 ratio) allocates patients to receive usual care (according to international standards) versus usual care and a continuous landiolol infusion to reduce the heart rate between 80 and 94 bpm. The primary endpoint is the mean Sequential Organ Failure Assessment score over 14 days from entry into the trial and while in intensive care unit. Results will inform current clinical practice guidelines., Ethics and Dissemination: This trial has clinical trial authorisation from the UK competent authority, the Medicines and Healthcare products Regulatory Agency, and has been approved by the East of England-Essex Research Ethics Committee (reference: 17/EE/0368).The results of the trial will be reported first to trial collaborators. The main report will be drafted by the trial coordinating team, and the final version will be agreed by the Trial Steering Committee before submission for publication, on behalf of the collaboration., Registration: The trial is funded by the National Institute for Health Research Efficacy and Mechanism Evaluation (EME) (Project Number: EME-14/150/85) and registered ISRCTN12600919 and EudraCT: 2017-001785-14., Competing Interests: Competing interests: TW reports grants from NIHR Efficacy and Mechanism Evaluation for the funding of STRESS-L (Project Number: EME-14/150/85) and during the conduct of the study; personal fees and non-financial support from AOP Orphan, manufacturer of Landiolol, outside the submitted work. MS has received travel expenses from AOP Orphan for delivering lectures. MS reports grants and other from NewB, grants from DSTL, other from Amormed, other from Biotest, other from GE, other from Baxter, grants from Critical Pressure, grants from Apollo Therapeutics, other from Roche, other from Bayer, other from Shionogi, outside the submitted work. ACG reports receiving grants from the NIHR and the NIHR Research Professorship; non-financial support from the NIHR Clinical Research Network and the NIHR Imperial Biomedical Research Centre during the conduct of the study; and personal fees from GlaxoSmithKline and Bristol-Myers Squibb outside the submitted work. DFM reports a grant from the NIHR EME programme for this study. Outside the submitted work, DFM reports personal fees from consultancy for GlaxoSmithKline, Boehringer Ingelheim, Bayer, Novartis and Eli Lilly. In addition, his institution has received funds from grants from the NIHR, Wellcome Trust, Innovate-UK and others. In addition, DFM has a patent issued to his institution for a treatment for ARDS. DFM is a director of the Research for the Intensive Care Society and NIHR EME programme director. GP reports grants from National Institute for Health Research, during the conduct of the study; and he is a director of the Research for the Intensive Care Society. All other authors declare they have no competing interests., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)