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Ipilimumab is a fully human monoclonal antibody that binds cytotoxic T-lymphocyte antigen 4 to enhance antitumour immunity. Our aim was to assess the use of ipilimumab after radiotherapy in patients with metastatic castration-resistant prostate cancer that progressed after docetaxel chemotherapy. We did a multicentre, randomised, double-blind, phase 3 trial in which men with at least one bone metastasis from castration-resistant prostate cancer that had progressed after docetaxel treatment were randomly assigned in a 1:1 ratio to receive bone-directed radiotherapy (8 Gy in one fraction) followed by either ipilimumab 10 mg/kg or placebo every 3 weeks for up to four doses. Non-progressing patients could continue to receive ipilimumab at 10 mg/kg or placebo as maintenance therapy every 3 months until disease progression, unacceptable toxic effect, or death. Patients were randomly assigned to either treatment group via a minimisation algorithm, and stratified by Eastern Cooperative Oncology Group performance status, alkaline phosphatase concentration, haemoglobin concentration, and investigator site. Patients and investigators were masked to treatment allocation. The primary endpoint was overall survival, assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00861614. From May 26, 2009, to Feb 15, 2012, 799 patients were randomly assigned (399 to ipilimumab and 400 to placebo), all of whom were included in the intention-to-treat analysis. Median overall survival was 11·2 months (95% CI 9·5–12·7) with ipilimumab and 10·0 months (8·3–11·0) with placebo (hazard ratio [HR] 0·85, 0·72–1·00; p=0·053). However, the assessment of the proportional hazards assumption showed that it was violated (p=0·0031). A piecewise hazard model showed that the HR changed over time: the HR for 0–5 months was 1·46 (95% CI 1·10–1·95), for 5–12 months was 0·65 (0·50–0·85), and beyond 12 months was 0·60 (0·43–0·86). The most common grade 3–4 adverse events were immune-related, occurring in 101 (26%) patients in the ipilimumab group and 11 (3%) of patients in the placebo group. The most frequent grade 3–4 adverse events included diarrhoea (64 [16%] of 393 patients in the ipilimumab group vs seven [2%] of 396 in the placebo group), fatigue (40 [11%] vs 35 [9%]), anaemia (40 [10%] vs 43 [11%]), and colitis (18 [5%] vs 0). Four (1%) deaths occurred because of toxic effects of the study drug, all in the ipilimumab group. Although there was no significant difference between the ipilimumab group and the placebo group in terms of overall survival in the primary analysis, there were signs of activity with the drug that warrant further investigation. Bristol-Myers Squibb.

The combination of a CTLA-4 blocker and a PD-1 blocker produced responses in more than 60% of previously untreated patients with BRAF wild-type advanced melanoma, including complete responses in more than 20% of these patients. Recent approaches to the treatment of metastatic melanoma enhance antitumor immunity by blocking immune checkpoints, such as cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) and the programmed death 1 (PD-1) receptor. Ipilimumab, an anti–CTLA-4 antibody, is approved by the Food and Drug Administration (FDA) on the basis of improvement in overall survival among patients with advanced melanoma, with objective responses in approximately 11% of the patients. 1 , 2 Nivolumab, an anti–PD-1 monoclonal antibody, has recently been shown to improve overall survival, as compared with dacarbazine (objective response rate, 40% vs. 14%), among previously untreated patients with advanced BRAF wild-type melanoma. 3 Nivolumab is approved . . .

Results from phase 2 and 3 trials in patients with advanced melanoma have shown significant improvements in the proportion of patients achieving an objective response and prolonged progression-free survival with the combination of nivolumab (an anti-PD-1 antibody) plus ipilimumab (an anti-CTLA-4 antibody) compared with ipilimumab alone. We report 2-year overall survival data from a randomised controlled trial assessing this treatment in previously untreated advanced melanoma. In this multicentre, double-blind, randomised, controlled, phase 2 trial (CheckMate 069) we recruited patients from 19 specialist cancer centres in two countries (France and the USA). Eligible patients were aged 18 years or older with previously untreated, unresectable stage III or IV melanoma and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned 2:1 to receive an intravenous infusion of nivolumab 1 mg/kg plus ipilimumab 3 mg/kg or ipilimumab 3 mg/kg plus placebo, every 3 weeks for four doses. Subsequently, patients assigned to nivolumab plus ipilimumab received nivolumab 3 mg/kg every 2 weeks until disease progression or unacceptable toxicity, whereas patients allocated to ipilimumab alone received placebo every 2 weeks during this phase. Randomisation was done via an interactive voice response system with a permuted block schedule (block size of six) and stratification by BRAF mutation status. The study funder, patients, investigators, and study site staff were masked to treatment assignment. The primary endpoint, which has been reported previously, was the proportion of patients with BRAFV600 wild-type melanoma achieving an investigator-assessed objective response. Overall survival was an exploratory endpoint and is reported in this Article. Efficacy analyses were done on the intention-to-treat population, whereas safety was assessed in all treated patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01927419, and is ongoing but no longer enrolling patients. Between Sept 16, 2013, and Feb 6, 2014, we screened 179 patients and enrolled 142, randomly assigning 95 patients to nivolumab plus ipilimumab and 47 to ipilimumab alone. In each treatment group, one patient no longer met the study criteria following randomisation and thus did not receive study drug. At a median follow-up of 24·5 months (IQR 9·1–25·7), 2-year overall survival was 63·8% (95% CI 53·3–72·6) for those assigned to nivolumab plus ipilimumab and 53·6% (95% CI 38·1–66·8) for those assigned to ipilimumab alone; median overall survival had not been reached in either group (hazard ratio 0·74, 95% CI 0·43–1·26; p=0·26). Treatment-related grade 3–4 adverse events were reported in 51 (54%) of 94 patients who received nivolumab plus ipilimumab compared with nine (20%) of 46 patients who received ipilimumab alone. The most common treatment-related grade 3–4 adverse events were colitis (12 [13%] of 94 patients) and increased alanine aminotransferase (ten [11%]) in the combination group and diarrhoea (five [11%] of 46 patients) and hypophysitis (two [4%]) in the ipilimumab alone group. Serious grade 3–4 treatment-related adverse events were reported in 34 (36%) of 94 patients who received nivolumab plus ipilimumab (including colitis in ten [11%] of 94 patients, and diarrhoea in five [5%]) compared with four (9%) of 46 patients who received ipilimumab alone (including diarrhoea in two [4%] of 46 patients, colitis in one [2%], and hypophysitis in one [2%]). No new types of treatment-related adverse events or treatment-related deaths occurred in this updated analysis. Although follow-up of the patients in this study is ongoing, the results of this analysis suggest that the combination of first-line nivolumab plus ipilimumab might lead to improved outcomes compared with first-line ipilimumab alone in patients with advanced melanoma. The results suggest encouraging survival outcomes with immunotherapy in this population of patients. Bristol-Myers Squibb.

The safety, toxicity, and pharmacokinetics of intrapartum and early newborn nevirapine were evaluated in 17 human immunodeficiency virus type 1-infected women in labor and their newborns. No adverse effects of nevirapine were noted in any study mothers or infants. Following maternal dosing with 200 mg during labor, concentrations exceeding 100 ng/mL (10 times the in vitro IC50) were achieved in the newborns. Nevirapine elimination was prolonged in both mothers and infants, with median half-lives ranging from 36.8 to 65.7 h. Administration of 200 mg orally to the mothers in labor and of a single 2-mg/kg oral dose to the infants at 48–72 h after birth maintained serum concentrations in the infants >100 ng/mL through 7 days of life.

CombAT was a randomised, double-blind study in men (n=4844) aged 50 years with a clinical diagnosis of benign prostatic hyperplasia (BPH). Patients were randomised to daily tamsulosin 0.4 mg, dutasteride 0.5 mg or both for 4 years. The primary endpoint was time to acute urinary retention (AUR) or BPH-related surgery. Secondary endpoints included BPH clinical progression, symptoms and maximum urinary flow rate. A post-hoc analysis of data from the European subgroup was conducted. A total of 2925 men were randomised to treatment in Europe as part of CombAT (tamsulosin, n=972; dutasteride, n=970; combination, n=983). Combination therapy significantly reduced the relative risk of AUR or BPH-related surgery compared with either monotherapy at 4 years, and also significantly reduced the risk of BPH clinical progression. Combination therapy also provided significantly greater symptom improvement than either monotherapy at 4 years. Safety and tolerability of dutasteride plus tamsulosin was consistent with previous experience of this combination and with the monotherapies. These data provide further evidence to support the use of long-term combination therapy (dutasteride plus tamsulosin) in men with moderate-to-severe LUTS due to BPH and prostatic enlargement. The results in the European subgroup are generally consistent with those in the overall study population.

The use of microwaves as an alternative heating source has been growing for the past few decades. The utility as a rapid heating tool is known, but the overall impacts on chemistry and synthesis, still needs to be investigated. With growing reports of observed selective microwave effects, further understanding is required. This study investigates the use of additives both homogeneous and heterogeneous, and their impacts on synthetic microwave chemistry compared to traditional convective heating. The aryl-Clasien rearrangement is a well-studied unimolecular [3+3] sigmatropic rearrangement. Its use through out synthetic organic chemistry makes it a good candidate to study selective microwave heating. Here we investigated the addition of a chaperone molecule, in which a non-reactive but highly absorbing additive added the rearrangement under microwave irradiation but showed almost no improvement under conventional heating at comparable temperatures. Hydroalkoxylation is the reaction of an alcohol with either an alkene or alkyne to produce ethers. Recently, our group was studying the heterogeneous catalyzed aryl Claisen rearrangement of allyl phenyl ether, when the use of spinels as a catalyst afforded the 2-methylcoumaran as a byproduct. Under microwave conditions this byproduct was formed in higher yields when compared to that of the oil bath. It was then observed that the hydroalkoxylation of the 2-allylphenol produced the coumaran at a faster rate under microwave heating than conventional heating. In this study we investigated the utility of the spinel catalyzed hydroalkoxylation. Magnetite afforded the greatest conversion to the desired products in moderate to high yields.

Well-written and transparent case reports (1) reveal early signals of potential benefits, harms, and information on the use of resources; (2) provide information for clinical research and clinical practice guidelines, and (3) inform medical education. High-quality case reports are more likely when authors follow reporting guidelines. During 2011–2012, a group of clinicians, researchers, and journal editors developed recommendations for the accurate reporting of information in case reports that resulted in the CARE (CAse REport) Statement and Checklist. They were presented at the 2013 International Congress on Peer Review and Biomedical Publication, have been endorsed by multiple medical journals, and translated into nine languages. This explanation and elaboration document has the objective to increase the use and dissemination of the CARE Checklist in writing and publishing case reports. Each item from the CARE Checklist is explained and accompanied by published examples. The explanations and examples in this document are designed to support the writing of high-quality case reports by authors and their critical appraisal by editors, peer reviewers, and readers. This article and the 2013 CARE Statement and Checklist, available from the CARE website [www.care-statement.org] and the EQUATOR Network [www.equator-network.org], are resources for improving the completeness and transparency of case reports. •This article provides a step-by-step guide to writing case reports that address some of the historic limitations associated with case reports.•It follows the CARE reporting guidelines and includes examples of good case reporting that will support authors writing case reports for submission to medical journals.•Systematic data collection from the point of care can help improve the delivery of care to patients and provide useful information for:◦Clinical research,◦Clinical practice guidelines, and◦Medical education.

IntroductionLower limb conditions requiring reconstructive surgery can be either congenital or acquired from trauma, infection or other medical conditions. Patient-reported outcome measures (PROMs) are often used by healthcare professionals to assess the impact of a patient’s condition (and treatment) on quality of life. However, we are not aware of any measures developed specifically for people requiring lower limb reconstructive surgery. Consequently, it is not clear the extent to which current PROMs accurately and specifically measure the outcomes that are important to these patients.Methods and analysisThe ‘PROLLIT’ (Patient-Reported Outcome Measure for Lower Limb Reconstruction) involves three phases: to explore what is important to patients with regard to quality of life (phase 1), ascertain whether current measures adequately capture these experiences (phase 2) and if not begin, the development of a new PROM (phase 3). The population of interest is people requiring, undergoing or after undergoing reconstructive surgery for a lower limb condition. In this paper, we describe phase 1, which aims to develop a conceptual framework to identify and map what is important to this group with regard to social interactions, employment, perceived health and quality of life after condition onset/injury and throughout recovery. The conceptual framework will be developed through three steps: (step A) a qualitative evidence synthesis, (step B) a qualitative study with patients and staff to explore patient’s views and experiences of lower limb reconstructive surgery and (step C) a round table discussion with key stakeholders where findings from step A and step B will be brought together and used to finalise the conceptual framework.Ethics consideration and disseminationEthical approval has been granted for the qualitative data collection (step B) from South Central Berkshire Research Ethics committee (REF:20/SC/0114). Findings from steps A and B will be submitted for peer-reviewed publication in academic journals, and presented at academic conferences.PROSPERO registration numberCRD42019139587.ISRCTN registration numberISRCTN75201623.

Background A community-based research (CBR) approach is critical to redressing the exclusion of women—particularly, traditionally marginalized women including those who use substances—from HIV research participation and benefit. However, few studies have articulated their process of involving and engaging peers, particularly within large-scale cohort studies of women living with HIV where gender, cultural and linguistic diversity, HIV stigma, substance use experience, and power inequities must be navigated. Methods Through our work on the Canadian HIV Women’s Sexual and Reproductive Health Cohort Study (CHIWOS), Canada’s largest community-collaborative longitudinal cohort of women living with HIV ( n = 1422), we developed a comprehensive, regionally tailored approach for hiring, training, and supporting women living with HIV as Peer Research Associates (PRAs). To reflect the diversity of women with HIV in Canada, we initially hired 37 PRAs from British Columbia, Ontario, and Quebec, prioritizing women historically under-represented in research, including women who use or have used illicit drugs, and women living with HIV of other social identities including Indigenous, racialized, LGBTQ2S, and sex work communities, noting important points of intersection between these groups. Results Building on PRAs’ lived experience, research capacity was supported through a comprehensive, multi-phase, and evidence-based experiential training curriculum, with mentorship and support opportunities provided at various stages of the study. Challenges included the following: being responsive to PRAs’ diversity; ensuring PRAs’ health, well-being, safety, and confidentiality; supporting PRAs to navigate shifting roles in their community; and ensuring sufficient time and resources for the translation of materials between English and French. Opportunities included the following: mutual capacity building of PRAs and researchers; community-informed approaches to study the processes and challenges; enhanced recruitment of harder-to-reach populations; and stronger community partnerships facilitating advocacy and action on findings. Conclusions Community-collaborative studies are key to increasing the relevance and impact potential of research. For women living with HIV to participate in and benefit from HIV research, studies must foster inclusive, flexible, safe, and reciprocal approaches to PRA engagement, employment, and training tailored to regional contexts and women’s lives. Recommendations for best practice are offered.