BACKGROUND:Approximately 10% of hospitalized patients globally report a penicillin allergy, leading to inappropriate antibiotic prescribing and inferior healthcare outcomes. Evidence supporting the effectiveness and widespread implementation of inpatient penicillin direct oral challenge (DOC) is limited. METHODS:A prospective, multicenter, international type 2 hybrid effectiveness-implementation study was conducted in 40 hospitals across 8 countries between November 2022 and May 2025. Adult inpatients with a penicillin allergy underwent assessment using a digital penicillin allergy toolkit (National Antibiotic Allergy Network [NAAN] App). According to site clinical practice, participants received penicillin DOC (effectiveness intervention) or assessment only. Participating sites received bimonthly audit and feedback at least 3 months after site activation (implementation strategy). Observational data were used to emulate a target trial to examine secondary effectiveness outcomes, including antibiotic prescribing at 90 days in DOC versus non-DOC participants. The primary implementation outcome was adoption of the NAAN App within 6 months of site activation. RESULTS:Among 5121 participants assessed, 1573 (30.7%) underwent DOC, of which 1502 (95.5%) were delabeled. Of 71 (4.5%) participants with a positive DOC, 6 (0.4%) had a serious adverse event. Of 1852 inpatients in the target trial analysis, 892 underwent DOC and 960 underwent assessment only. Participants who underwent DOC were more likely to be prescribed penicillin (risk ratio [RR], 13.25 [95% confidence interval {CI}, 7.82-22.46]), and less likely to be prescribed World Health Organization (WHO) "Watch" or "Reserve" antibiotics (RR, 0.73 [95% CI, .60-.89]) at 90 days post evaluation. Within 6 months of site activation, 77 clinicians adopted the NAAN App. CONCLUSIONS:Multidisciplinary adoption of inpatient penicillin DOC was safe and significantly improved penicillin prescribing and reduced use of WHO restricted antibiotics.
Cardiometabolic diseases, including hypertension, type 2 diabetes, dyslipidemia, and obesity, along with their cardiovascular complications, remain leading causes of morbidity and mortality worldwide, imposing significant public health, economic, and societal burdens. Conventional pharmacological therapies often show limited efficacy and increased adverse effects because they do not account for the body’s intrinsic circadian rhythms, which regulate organ function, drug absorption, and metabolism. Chronopharmacology, which aligns treatment timing with these biological rhythms, offers a strategy to enhance therapeutic outcomes. This review presents a comprehensive analysis of chronopharmacology principles applied to cardiometabolic disease management, integrating molecular, physiological, and clinical perspectives. It examines how core clock genes and tissue-specific circadian patterns influence drug action and absorption and summarizes evidence-based time-optimized interventions for hypertension, diabetes, dyslipidemia, obesity, and multimorbid patients. Furthermore, the review highlights emerging innovations, including artificial intelligence-guided dosing, circadian-biomarker-informed therapy selection, and wearable digital devices for real-time monitoring of biological rhythms. By synthesizing mechanistic and clinical insights, circadian-aligned treatment strategies are shown to improve drug efficacy, reduce adverse effects, and support the development of precision, rhythm-based therapeutics, offering a practical framework for personalized cardiometabolic disease care.
Lung cancer remains a leading cause of cancer mortality worldwide, with current treatments often limited by toxicity and resistance. Dysregulated kinase signaling particularly involving EGFR, PI3K/AKT/mTOR, MAPK, and ALK pathways drives tumor growth, survival, and metastasis. While synthetic kinase inhibitors have improved outcomes, their use is constrained by adverse effects and acquired resistance. Natural kinase inhibitors (NKIs) derived from plants, marine organisms, and microorganisms offer a promising alternative due to their multi-targeted action, lower toxicity, and potential to overcome resistance. This review aims to evaluate the molecular mechanisms, therapeutic potential, and clinical relevance of NKIs in lung cancer management. Key compounds such as curcumin, resveratrol, quercetin, genistein, and epigallocatechin gallate inhibit critical kinases, modulating pathways that regulate proliferation, apoptosis, angiogenesis, and metastasis. Preclinical studies demonstrate significant anticancer activity, while emerging clinical evidence supports their role as adjuncts or alternatives to conventional therapies. Strategies such as nanotechnology-based delivery systems and combination regimens further enhance bioavailability and efficacy. Despite these advantages, challenges persist, including poor solubility, rapid metabolism, and limited clinical validation. Future research should focus on optimizing formulations, elucidating pharmacokinetics, and conducting large-scale clinical trials to confirm safety and effectiveness. Integration of NKIs into personalized treatment paradigms could transform lung cancer therapy, offering cost-effective, less toxic, and multi-targeted approaches to improve patient outcomes.
Scaphoid fractures are a common but frequently missed wrist injury. Patients classically present following a fall onto an outstretched hand, with pain and tenderness in the anatomical snuffbox. When missed, scaphoid fractures can have serious complications such as avascular necrosis of the scaphoid and scaphoid non-union advanced collapse. The British Society for Surgery of the Hand has recently published guidelines on the management of suspected scaphoid fractures. Initial management involves radiographs and immobilisation with referral to a specialist within 7 days. Further management includes immobilisation for stable fractures and surgical intervention for cases with greater than 2 mm displacement, associated distal radial fractures, peri-lunate injuries, or proximal pole fractures with any displacement. Follow-up radiographs and computed tomography are used to monitor healing. This article aims to review recent advances in scaphoid fracture management, aligned with the latest British Society for Surgery of the Hand (BSSH) guidelines.
OBJECTIVES:In England, there is a 'hard stop' to weekly tocilizumab (qwTCZ) therapy for GCA; this is currently 12 months but was extended during the COVID-19 pandemic subject to certain criteria for GCA relapse risk. Taking advantage of variation in practice, we aimed to compare outcomes of GCA patients who tapered-TCZ vs those who stopped abruptly (non-taper patients). METHODS:Secondary analysis of an English multicentre service evaluation of relapse after stopping qwTCZ for GCA. Time to relapse was compared between taper and non-taper patients. We examined outcomes according to whether they had been 'adequate responders' during qwTCZ therapy, defined as those in remission and on ≤5 mg prednisolone at qwTCZ cessation, without relapse whilst taking qwTCZ. RESULTS:We analysed 336 patients from 40 centres. Time to relapse after qwTCZ cessation was significantly longer in adequate responders than non-adequate responders (P = 0.0004). 17.0% (57/336) patients tapered to fortnightly TCZ after qwTCZ cessation, for a median of 6 (IQR 2-13) months. For adequate responders, time to relapse whilst taking tapered-dose TCZ was significantly longer compared with those in the non-taper group (P = 0.0231) based on a relatively small number of flares. There was no difference between the taper and non-tapered groups after tapered-TCZ was stopped (P = 0.8346). In contrast, time to relapse for non-adequate responders was similar in taper patients compared with non-taper patients (P = 0.4892). CONCLUSION:Tapering TCZ after qwTCZ cessation delayed relapse only during the tapering period, but only in adequate responders to qwTCZ. No lasting benefit was seen after tapering ended.
