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Primary hyperoxaluria type 1 is caused by hepatic overproduction of oxalate, leading to kidney stones, nephrocalcinosis, kidney failure, and systemic oxalosis. This trial tested whether an oligonucleotide drug can reduce the production of hepatic oxalate.

Janus kinase (JAK) inhibitors approved for myelofibrosis provide spleen and symptom improvements but do not meaningfully improve anaemia. Momelotinib, a first-in-class inhibitor of activin A receptor type 1 as well as JAK1 and JAK2, has shown symptom, spleen, and anaemia benefits in myelofibrosis. We aimed to confirm the differentiated clinical benefits of momelotinib versus the active comparator danazol in JAK-inhibitor-exposed, symptomatic patients with anaemia and intermediate-risk or high-risk myelofibrosis. MOMENTUM is an international, double-blind, randomised, controlled, phase 3 study that enrolled patients at 107 sites across 21 countries worldwide. Eligible patients were 18 years or older with a confirmed diagnosis of primary myelofibrosis or post-polycythaemia vera or post-essential thrombocythaemia myelofibrosis. Patients were randomly assigned (2:1) to receive momelotinib (200 mg orally once per day) plus danazol placebo (ie, the momelotinib group) or danazol (300 mg orally twice per day) plus momelotinib placebo (ie, the danazol group), stratified by total symptom score (TSS; <22 vs ≥22), spleen size (<12 cm vs ≥12 cm), red blood cell or whole blood units transfused in the 8 weeks before randomisation (0 units vs 1–4 units vs ≥5 units), and study site. The primary endpoint was the Myelofibrosis Symptom Assessment Form (MFSAF) TSS response rate at week 24 (defined as ≥50% reduction in mean MFSAF TSS over the 28 days immediately before the end of week 24 compared with baseline). MOMENTUM is registered with ClinicalTrials.gov, number NCT04173494, and is active but not recruiting. 195 patients were randomly assigned to either the momelotinib group (130 [67%]) or danazol group (65 [33%]) and received study treatment in the 24-week randomised treatment period between April 24, 2020, and Dec 3, 2021. A significantly greater proportion of patients in the momelotinib group reported a 50% or more reduction in TSS than in the danazol group (32 [25%] of 130 vs six [9%] of 65; proportion difference 16% [95% CI 6–26], p=0·0095). The most frequent grade 3 or higher treatment-emergent adverse events with momelotinib and danazol were haematological abnormalities by laboratory values: anaemia (79 [61%] of 130 vs 49 [75%] of 65) and thrombocytopenia (36 [28%] vs 17 [26%]). The most frequent non-haematological grade 3 or higher treatment-emergent adverse events with momelotinib and danazol were acute kidney injury (four [3%] of 130 vs six [9%] of 65) and pneumonia (three [2%] vs six [9%]). Treatment with momelotinib, compared with danazol, resulted in clinically significant improvements in myelofibrosis-associated symptoms, anaemia measures, and spleen response, with favourable safety. These findings support the future use of momelotinib as an effective treatment in patients with myelofibrosis, especially in those with anaemia. Sierra Oncology.

\"This book provides an invaluable resource for scholars, students, and political observers who want a comprehensive picture of the past and present of the U.S. presidential nominating system across every state\"-- Provided by publisher.

Patients with metastatic melanoma, 50% of whose tumours harbour a BRAF mutation, have a poor prognosis. Selumetinib, a MEK1/2 inhibitor, has shown antitumour activity in patients with BRAF-mutant melanoma and in preclinical models when combined with chemotherapy. This study was designed to look for a signal of improved efficacy by comparing the combination of selumetinib and dacarbazine with dacarbazine alone. This double-blind, randomised, placebo-controlled phase 2 study investigated selumetinib plus dacarbazine versus placebo plus dacarbazine as first-line treatment in patients older than 18 years with histologically or cytologically confirmed advanced BRAF-mutant cutaneous or unknown primary melanoma. Patients were randomly assigned by central interactive voice response system (1:1 ratio, block size four) to take either oral selumetinib (75 mg twice daily in a 21-day cycle) or placebo; all patients received intravenous dacarbazine (1000 mg/m2 on day 1 of a 21-day cycle). Patients, investigators, and the study team were masked to the treatment assigned. The primary endpoint was overall survival analysed by intention to treat. This study is registered at ClinicalTrials.gov, NCT00936221. Between July 20, 2009, and April 8, 2010, 91 patients were randomly assigned to receive dacarbazine in combination with selumetinib (n=45) or placebo (n=46). Overall survival did not differ significantly between groups (median 13·9 months, 80% CI 10·2–15·6, in the selumetinib plus dacarbazine group and 10·5 months, 9·6–14·7, in the placebo plus dacarbazine group; hazard ratio [HR] 0·93, 80% CI 0·67–1·28, one-sided p=0·39). However, progression-free survival was significantly improved in the selumetinib plus dacarbazine group versus the placebo plus dacarbazine group (HR 0·63, 80% CI 0·47–0·84, one-sided p=0·021), with a median of 5·6 months (80% CI 4·9–5·9) versus 3·0 months (2·8–4·6), respectively. The most frequent adverse events included nausea (28 [64%] of 44 patients on selumetinib vs 25 [56%] of 45 on placebo), acneiform dermatitis (23 [52%] vs one [2%]), diarrhoea (21 [48%] vs 13 [29%]), vomiting (21 [48%] vs 15 [33%]), and peripheral oedema (19 [43%] vs three [7%]). The most common grade 3–4 adverse event was neutropenia (six [14%] patients in the selumetinib plus dacarbazine group vs four [9%] in the placebo plus dacarbazine group). Selumetinib plus dacarbazine showed clinical activity in patients with BRAF-mutant cutaneous or unknown primary melanoma, reflected by a significant benefit in progression-free survival compared with placebo plus dacarbazine group, although no significant change in overall survival was noted. The tolerability of this combination was generally consistent with monotherapy safety profiles. AstraZeneca.

To carry out an economic evaluation of a task-shifting intervention for the treatment of depressive and anxiety disorders in primary-care settings in Goa, India. Cost-utility and cost-effectiveness analyses based on generalized linear models were performed within a trial set in 24 public and private primary-care facilities. Subjects were randomly assigned to an intervention or a control arm. Eligible subjects in the intervention arm were given psycho-education, case management, interpersonal psychotherapy and/or antidepressants by lay health workers. Subjects in the control arm were treated by physicians. The use of health-care resources, the disability of each subject and degree of psychiatric morbidity, as measured by the Revised Clinical Interview Schedule, were determined at 2, 6 and 12 months. Complete data, from all three follow-ups, were collected from 1243 (75.4%) and 938 (81.7%) of the subjects enrolled in the study facilities from the public and private sectors, respectively. Within the public facilities, subjects in the intervention arm showed greater improvement in all the health outcomes investigated than those in the control arm. Time costs were also significantly lower in the intervention arm than in the control arm, whereas health system costs in the two arms were similar. Within the private facilities, however, the effectiveness and costs recorded in the two arms were similar. Within public primary-care facilities in Goa, the use of lay health workers in the care of subjects with common mental disorders was not only cost-effective but also cost-saving.

Reflecting on 2016, it might seem that the national parties have little control over how the presidential nominations unfold and who becomes their presidential candidate. Yet the parties wield more influence than voters in determining who prevails at the National Conventions. Although the reforms of the late 1960s and 1970s gave rank-and-file party members a clear voice in the selection of presidential candidates, the parties retain influence through their ability to set the electoral rules. Despite this capability, party elites do not always fully understand the consequences of the rules and therefore often promote a system that undermines their goals. The Primary Rules illuminates the balance of power that the parties, states, and voters assert on the process. By utilizing an original, comprehensive data set that details the electoral rules each party employed in each state during every nomination from 1976 to 2016, Caitlin E. Jewitt uncovers the effects of the rules on the competitiveness of the nomination, the number of voters who participate, and the nomination outcomes. This reveals how the parties exert influence over their members and limit the impact of voters. The Primary Rules builds on prior analyses and extends work highlighting the role of the parties in the invisible primary stage, as it investigates the parties' influence once the nominations begin. The Primary Rules provides readers with a clearer sense of what the rules are, how they have changed, their consequences, and practical guidance on how to modify the rules of the nomination system to achieve their desired outcomes in future elections.

Exploring how to save primary care by giving family doctors a fighting chance to become the generalists we need in our lives, Searching for the Family Doctor is required reading for anyone interested in the troubled state of modern medicine.