Explore the vast range of titles available.

The lidocaine/tetracaine heated patch is typically applied to the skin for 20 to 30 minutes to provide local dermal analgesia prior to venous access or minor dermatologic procedures. The potential exists for the use of multiple heated patches for longer application times, but the pharmacokinetic properties and tolerability of these multiple and/or longer applications have not been assessed. The aim of this study was to assess the effects of heat and application time on the pharmacokinetic properties and tolerability of the patch after the application of 4 lidocaine/tetracaine (70/70 mg) heated patches applied at the same time in healthy volunteers for up to 12 hours. In this randomized, open-labeled, controlled study, healthy subjects underwent 4 treatment periods (2-, 4-, or 12-hour application of 4 heated patches, or 4-hour application of 4 unheated patches), each separated by a 1-week washout period. Twelve subjects were enrolled (8 women, 4 men; mean age, 31.8 years; mean body mass index, 24.1 kg/m2). No tetracaine was detected in the plasma of any subject. Plasma concentrations of lidocaine increased rapidly during the first 2 hours of application in each heated-patch group, and with mean (SD) Cmax values of 18.2 (5.1), 25.7 (5.9), and 30.3 (8.1) ng/mL in the 2-, 4-, and 12-hour groups, respectively. Estimates of application time–normalized AUC0–t were not significantly different between the 2- and 4-hour applications of the heated patches, but were 25% lower during the 12-hour application time, suggesting continued but diminished drug delivery between 4 and 12 hours. Compared with subjects who received the unheated patch, those who received the heated patch had plasma lidocaine concentrations 5- and 3-fold higher after 30 and 60 minutes, respectively. Fifteen mild to moderate adverse events (AEs) were reported in 7 subjects, and none of the subjects discontinued the study due to treatment-related AEs. The heated patch continuously delivered drug for up to 12 hours and was generally well tolerated in these healthy subjects. ClinicalTrials.gov identifier: NCT01602757.

Pain control is an important first step in the treatment of shoulder impingement syndrome (SIS) because fear of pain must be removed as an obstacle to participation in an appropriate physical therapy program. Adult patients with SIS-associated pain of at least 2 weeks' duration and who had an average pain score of ≥4 on the zero- to ten-point Numeric Pain Rating Scale were eligible to enroll in this 2-week pilot study. Patients were treated with the heated lidocaine/tetracaine (70 mg/70 mg) patch (HLT patch) placed over the site of shoulder tenderness each morning and evening for a period of 2 to 4 hours. Average and worst pain during the previous 24 hours and shoulder range of motion were assessed at baseline and on Day 14. Results were expressed as change and percent change from baseline to Day 14. This pilot study was not powered for rigorous statistical analysis. Twenty patients (seven male, 13 female; average age 51.2 ± 10.8 years [mean ± standard deviation]) enrolled in this study, and 18 patients completed the protocol. The mean average pain score at baseline was 5.5 ± 1.1 (range 4 to 8). In the per-protocol population, average and worst pain scores declined by 2.4 ± 2.0 and 3.7 ± 2.7 points, respectively. Two-thirds of the patients demonstrated a clinically meaningful ≥30% decline in average pain score, and half of the patients demonstrated a ≥50% decline in average pain score. Shoulder internal rotation increased by 29.7° ± 21.8° and abduction increased by 40.0° ± 44.2°. Application-site erythema was reported by ten patients at some time during the study. Patients treated with the HLT patch for 14 days demonstrated clinically meaningful improvement in pain intensity and range of motion. Further controlled research is necessary to characterize the efficacy and tolerability of the HLT patch in the treatment of SIS.

The pain of patellar tendinopathy (PT) may be mediated by neuronal glutamate and sodium channels. Lidocaine and tetracaine block both of these channels. This study tested the self-heated lidocaine-tetracaine patch (HLT patch) in patients with PT confirmed by physical examination to determine if the HLT patch might relieve pain and improve function. Thirteen patients with PT pain of ≥14 days' duration and baseline average pain scores ≥4 (on a 0-10 scale) enrolled in and completed this prospective, single-center pilot study. Patients applied one HLT patch to the affected knee twice daily for 2-4 hours for a total of 14 days. Change in average pain intensity and interference (Victorian Institute of Sport Assessment [VISA]) scores from baseline to day 14 were assessed. No statistical inference testing was performed. Average pain scores declined from 5.5 ± 1.3 (mean ± standard deviation) at baseline to 3.8 ± 2.5 on day 14. Similarly, VISA scores improved from 45.2 ± 14.4 at baseline to 54.3 ± 24.5 on day 14. A clinically important reduction in pain score (≥30%) was demonstrated by 54% of patients. The results of this pilot study suggest that topical treatment that targets neuronal sodium and glutamate channels may be useful in the treatment of PT.

Most patients with primary hyperparathyroidism in the United States are asymptomatic. 1 – 3 Although the usual treatment for this disorder is surgical removal of the abnormal parathyroid gland or glands, the need for surgery has been questioned because of the absence of symptoms and absence of progression of the disorder. 4 – 7 At this time, however, there are no alternatives to surgery that can reduce both serum parathyroid hormone and serum calcium concentrations in these patients. An effective medical therapy would provide an option not only for asymptomatic patients but also for those in whom parathyroid surgery is contraindicated because of intercurrent . . .

SIR,-The most, interesting intelligence you can convey to me is, an assurance that you adore a gracious Providence, which has preserved your life to this day; that. you receive the truths of the Christian religion, obey its precepts, and associate with good people.

SIR,-The most, interesting intelligence you can convey to me is, an assurance that you adore a gracious Providence, which has preserved your life to this day; that. you receive the truths of the Christian religion, obey its precepts, and associate with good people.

Concomitant administration of COVID-19 and influenza vaccines could reduce burden on health-care systems. We aimed to assess the safety of concomitant administration of ChAdOx1 or BNT162b2 plus an age-appropriate influenza vaccine. In this multicentre, randomised, controlled, phase 4 trial, adults in receipt of a single dose of ChAdOx1 or BNT162b2 were enrolled at 12 UK sites and randomly assigned (1:1) to receive concomitant administration of either an age-appropriate influenza vaccine or placebo alongside their second dose of COVID-19 vaccine. 3 weeks later the group who received placebo received the influenza vaccine, and vice versa. Participants were followed up for 6 weeks. The influenza vaccines were three seasonal, inactivated vaccines (trivalent, MF59C adjuvanted or a cellular or recombinant quadrivalent vaccine). Participants and investigators were masked to the allocation. The primary endpoint was one or more participant-reported solicited systemic reactions in the 7 days after first trial vaccination(s), with a difference of less than 25% considered non-inferior. Analyses were done on an intention-to-treat basis. Local and unsolicited systemic reactions and humoral responses were also assessed. The trial is registered with ISRCTN, ISRCTN14391248. Between April 1 and June 26, 2021, 679 participants were recruited to one of six cohorts, as follows: 129 ChAdOx1 plus cellular quadrivalent influenza vaccine, 139 BNT162b2 plus cellular quadrivalent influenza vaccine, 146 ChAdOx1 plus MF59C adjuvanted, trivalent influenza vaccine, 79 BNT162b2 plus MF59C adjuvanted, trivalent influenza vaccine, 128 ChAdOx1 plus recombinant quadrivalent influenza vaccine, and 58 BNT162b2 plus recombinant quadrivalent influenza vaccine. 340 participants were assigned to concomitant administration of influenza and a second dose of COVID-19 vaccine at day 0 followed by placebo at day 21, and 339 participants were randomly assigned to concomitant administration of placebo and a second dose of COVID-19 vaccine at day 0 followed by influenza vaccine at day 21. Non-inferiority was indicated in four cohorts, as follows: ChAdOx1 plus cellular quadrivalent influenza vaccine (risk difference for influenza vaccine minus placebos −1·29%, 95% CI −14·7 to 12·1), BNT162b2 plus cellular quadrivalent influenza vaccine (6·17%, −6·27 to 18·6), BNT162b2 plus MF59C adjuvanted, trivalent influenza vaccine (–12·9%, −34·2 to 8·37), and ChAdOx1 plus recombinant quadrivalent influenza vaccine (2·53%, −13·3 to 18·3). In the other two cohorts, the upper limit of the 95% CI exceeded the 0·25 non-inferiority margin (ChAdOx1 plus MF59C adjuvanted, trivalent influenza vaccine 10·3%, −5·44 to 26·0; BNT162b2 plus recombinant quadrivalent influenza vaccine 6·75%, −11·8 to 25·3). Most systemic reactions to vaccination were mild or moderate. Rates of local and unsolicited systemic reactions were similar between the randomly assigned groups. One serious adverse event, hospitalisation with severe headache, was considered related to the trial intervention. Immune responses were not adversely affected. Concomitant vaccination with ChAdOx1 or BNT162b2 plus an age-appropriate influenza vaccine raises no safety concerns and preserves antibody responses to both vaccines. Concomitant vaccination with both COVID-19 and influenza vaccines over the next immunisation season should reduce the burden on health-care services for vaccine delivery, allowing for timely vaccine administration and protection from COVID-19 and influenza for those in need. National Institute for Health Research Policy Research Programme

Background Depressive episodes are common after first-episode psychosis (FEP), affecting more than 40% of people, adding to individual burden, poor outcomes, and healthcare costs. If the risks of developing depression were lower, this could have a beneficial effect on morbidity and mortality, as well as improving outcomes. Sertraline is a selective serotonin reuptake inhibitor and a common first-line medication for the treatment of depression in adults. It has been shown to be safe when co-prescribed with antipsychotic medication, and there is evidence that it is an effective treatment for depression in established schizophrenia. We present a protocol for a multi-centre, double-blind, randomised, placebo-controlled clinical trial called ADEPP that aims to investigate the efficacy and cost-effectiveness of sertraline in preventing depression after FEP. Methods The recruitment target is 452 participants between the ages of 18 and 65 years who are within 12 months of treatment initiation for FEP. Having provided informed consent, participants will be randomised to receive either 50 mg of sertraline daily or matched placebo for 6 months, in addition to treatment as usual. The primary outcome measure will be a comparison of the number of new cases of depression between the treatment and placebo arms over the 6-month intervention phase. Secondary outcomes include suicidal behaviour, anxiety, rates of relapse, functional outcome, quality of life, and resource use. Discussion The ADEPP trial will test whether the addition of sertraline following FEP is a clinically useful, acceptable, and cost-effective way of improving outcomes following FEP. Trial registration ISRCTN12682719 registration date 24/11/2020.

IntroductionThis study aims to clarify the role(s) of endogenous sex hormones to influence health outcomes in men, specifically to define the associations of plasma testosterone with incidence of cardiovascular events, cancer, dementia and mortality risk, and to identify factors predicting testosterone concentrations. Data will be accrued from at least three Australian, two European and four North American population-based cohorts involving approximately 20 000 men.Methods and analysisEligible studies include prospective cohort studies with baseline testosterone concentrations measured using mass spectrometry and 5 years of follow-up data on incident cardiovascular events, mortality, cancer diagnoses or deaths, new-onset dementia or decline in cognitive function recorded. Data for men, who were not taking androgens or drugs suppressing testosterone production, metabolism or action; and had no prior orchidectomy, are eligible. Systematic literature searches were conducted from 14 June 2019 to 31 December 2019, with no date range set for searches. Aggregate level data will be sought where individual participant data (IPD) are not available. One-stage IPD random-effects meta-analyses will be performed, using linear mixed models, generalised linear mixed models and either stratified or frailty-augmented Cox regression models. Heterogeneity in estimates from different studies will be quantified and bias investigated using funnel plots. Effect size estimates will be presented in forest plots and non-negligible heterogeneity and bias investigated using subgroup or meta-regression analyses.Ethics and disseminationEthics approvals obtained for each of the participating cohorts state that participants have consented to have their data collected and used for research purposes. The Androgens In Men Study has been assessed as exempt from ethics review by the Human Ethics office at the University of Western Australia (file reference number RA/4/20/5014). Each of the component studies had obtained ethics approvals; please refer to respective component studies for details. Research findings will be disseminated to the scientific and broader community via the publication of four research articles, with each involving a separate set of IPD meta-analyses (articles will investigate different, distinct outcomes), at scientific conferences and meetings of relevant professional societies. Collaborating cohort studies will disseminate findings to study participants and local communities.PROSPERO registration numberCRD42019139668.

Abstract Rationale The role of NADPH oxidase activation in pneumonia is complex because reactive oxygen species contribute to both microbial killing and regulation of the acute pulmonary infiltrate. The relative importance of each role remains poorly defined in community-acquired pneumonia. Objectives We evaluated the contribution of NADPH oxidase–derived reactive oxygen species to the pathogenesis of pneumococcal pneumonia, addressing both the contribution to microbial killing and regulation of the inflammatory response. Methods Mice deficient in the gp91phox component of the phagocyte NADPH oxidase were studied after pneumococcal challenge. Measurements and Main Results gp91phox−/− mice demonstrated no defect in microbial clearance as compared with wild-type C57BL/6 mice. A significant increase in bacterial clearance from the lungs of gp91phox−/− mice was associated with increased numbers of neutrophils in the lung, lower rates of neutrophil apoptosis, and enhanced activation. Marked alterations in pulmonary cytokine/chemokine expression were also noted in the lungs of gp91phox−/− mice, characterized by elevated levels of tumor necrosis factor-α, KC, macrophage inflammatory protein-2, monocyte chemotactic protein-1, and IL-6. The greater numbers of neutrophils in gp91phox−/− mice were not associated with increased lung injury. Levels of neutrophil elastase in bronchoalveolar lavage were not decreased in gp91phox−/− mice. Conclusions During pneumococcal pneumonia, NADPH oxidase–derived reactive oxygen species are redundant for host defense but limit neutrophil recruitment and survival. Decreased NADPH oxidase–dependent reactive oxygen species production is well tolerated and improves disease outcome during pneumococcal pneumonia by removing neutrophils from the tight constraints of reactive oxygen species–mediated regulation.