Conclusion PrEP has gained an important and irreplaceable position in the prevention of HIV infection. New models of care need to be studied, preferably in close collaboration with the users, to make this intervention sustainable for the health system in which it is introduced.Purpose Pembrolizumab monotherapy has shown antitumor activity in patients with small-cell lung cancer (SCLC). The randomized, double-blind, phase III KEYNOTE-604 study compared pembrolizumab plus etoposide and platinum (EP) with placebo plus EP for patients with previously untreated extensive-stage (ES) SCLC. Methods Eligible patients were randomly assigned 11 to pembrolizumab 200 mg once every 3 weeks or saline placebo for up to 35 cycles plus 4 cycles of EP. Primary end points were progression-free survival (PFS; RECIST version 1.1, blinded central review) and overall survival (OS) in the intention-to-treat population. Objective response rate (ORR) and duration of response were secondary end points. Prespecified efficacy boundaries were one-sided P = .0048 for PFS and .0128 for OS. Results Of the 453 participants, 228 were randomly assigned to pembrolizumab plus EP and 225 to placebo plus EP. Pembrolizumab plus EP significantly improved PFS (hazard ratio [HR], 0.75; 95% CI, 0.61 to 0.91; P = .0023). Twelve-month PFS estimates were 13.6% with pembrolizumab plus EP and 3.1% with placebo plus EP. Although pembrolizumab plus EP prolonged OS, the significance threshold was not met (HR, 0.80; 95% CI, 0.64 to 0.98; P = .0164). Twenty-four-month OS estimates were 22.5% and 11.2%, respectively. ORR was 70.6% in the pembrolizumab plus EP group and 61.8% in the placebo plus EP group; the estimated proportion of responders remaining in response at 12 months was 19.3% and 3.3%, respectively. In the pembrolizumab plus EP and placebo plus EP groups, respectively, any-cause adverse events were grade 3-4 in 76.7% and 74.9%, grade 5 in 6.3% and 5.4%, and led to discontinuation of any drug in 14.8% and 6.3%. Conclusion Pembrolizumab plus EP significantly improved PFS compared with placebo plus EP as first-line therapy for patients with ES-SCLC. No unexpected toxicities were seen with pembrolizumab plus EP. These data support the benefit of pembrolizumab in ES-SCLC.Purpose In the HER2CLIMB study, patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer with brain metastases (BMs) showed statistically significant improvement in progression-free survival (PFS) with tucatinib. We describe exploratory analyses of intracranial efficacy and survival in participants with BMs. Patients and methods Patients were randomly assigned 21 to tucatinib or placebo, in combination with trastuzumab and capecitabine. https://www.selleckchem.com/products/A014418.html All patients underwent baseline brain magnetic resonance imaging; those with BMs were classified as active or stable. Efficacy analyses were performed by applying RECIST 1.1 criteria to CNS target lesions by investigator assessment. CNS-PFS (intracranial progression or death) and overall survival (OS) were evaluated in all patients with BMs. Confirmed intracranial objective response rate (ORR-IC) was evaluated in patients with measurable intracranial disease. Results There were 291 patients with BMs 198 (48%) in the tucatinib arm and 93 (46%) in the control arm. The risk of intracranial progression or death was reduced by 68% in the tucatinib arm (hazard ratio [HR], 0.32; 95% CI, 0.22 to 0.48; P less then .0001). Median CNS-PFS was 9.9 months in the tucatinib arm versus 4.2 months in the control arm. Risk of death was reduced by 42% in the tucatinib arm (OS HR, 0.58; 95% CI, 0.40 to 0.85; P = .005). Median OS was 18.1 versus 12.0 months. ORR-IC was higher in the tucatinib arm (47.3%; 95% CI, 33.7% to 61.2%) versus the control arm (20.0%; 95% CI, 5.7% to 43.7%; P = .03). Conclusion In patients with HER2-positive breast cancer with BMs, the addition of tucatinib to trastuzumab and capecitabine doubled ORR-IC, reduced risk of intracranial progression or death by two thirds, and reduced risk of death by nearly half. To our knowledge, this is the first regimen to demonstrate improved antitumor activity against BMs in patients with HER2-positive breast cancer in a randomized, controlled trial.There is an increasing awareness that polypharmacy - the use of multiple medicines by one individual - may bring harm as well as benefit. This has been termed 'problematic polypharmacy' and is associated with increased risk of admission to hospital, decreased quality of life and psychological harm. This article addresses the factors that may be contributing to the global rise of polypharmacy (the whys), the problems it can cause (the so whats), and some opportunities and strategies for improving and avoiding problematic polypharmacy in the future (the what nexts).Compartment syndrome of the limb is a true orthopaedic emergency that warrants prompt evaluation and treatment. Acute compartment syndrome of the limb is not uncommon and has the potential to cause devastating morbidity and mortality. Failure to provide urgent surgical intervention once established can lead to irreversible tissue damage within hours of onset. Compartment syndrome can occur across all limbs, the buttocks and even the abdomen, but this article focuses solely on the diagnosis of acute compartment syndrome of the limb. Acute compartment syndrome can have a wide range of causes, with trauma representing approximately 70% of cases.Neoplasm of the spinal column in children is rare, but can involve either benign or malignant tumours. Early detection of malignant tumours is key to successful clinical outcome and long-term prognosis. In such cases, back pain is a common presenting symptom, but often has a non-neoplastic cause. Therefore, it is important for GPs and trainees who encounter paediatric patients to be aware of the clinical entity to be able to thoroughly assess them in clinical practice. This article discusses the types of paediatric spinal neoplasms, anatomical-based classification, clinical red flags, imaging modalities and outlines brief management options.The numbers of clinical trials have increased exponentially over the last decade, amplifying the pressure to select an appropriate study design to obtain reliable and valid evidence. The ability to find, critically appraise and use evidence to develop new interventions is fundamental to evidence-based medicine. Different study designs have their own advantages and disadvantages, and provide different evidentiary value. This article provides an overview of clinical trials, illustrating that, ultimately, the study design chosen needs to meet experimental and funding limitations, while minimising error.