Explore the vast range of titles available.

A sequential Rh(III)-catalyzed C-H activation/annulation of N-hydroxybenzamides with propargylic acetates leading to the formation of NH-free isoquinolones is described. This reaction proceeds through a sequential C-H activation/alkyne insertion/intramolecular annulation/N-O bond cleavage procedure, affording a broad spectrum of products with diverse substituents in moderate-to-excellent yields. Notably, this protocol features the simultaneous formation of two new C-C/C-N bonds and one heterocycle in one pot with the release of water as the sole byproduct.

Effective treatments for patients with primary biliary cholangitis are limited. Seladelpar, a peroxisome proliferator-activated receptor delta agonist, has potential benefits. In this phase 3, 12-month, double-blind, placebo-controlled trial, we randomly assigned (in a 2:1 ratio) patients who had had an inadequate response to or who had a history of unacceptable side effects with ursodeoxycholic acid to receive oral seladelpar at a dose of 10 mg daily or placebo. The primary end point was a biochemical response, which was defined as an alkaline phosphatase level less than 1.67 times the upper limit of the normal range, with a decrease of 15% or more from baseline, and a normal total bilirubin level at month 12. Key secondary end points were normalization of the alkaline phosphatase level at month 12 and a change in the score on the pruritus numerical rating scale (range, 0 [no itch] to 10 [worst itch imaginable]) from baseline to month 6 among patients with a baseline score of at least 4 (indicating moderate-to-severe pruritus). Of the 193 patients who underwent randomization and treatment, 93.8% received ursodeoxycholic acid as standard-of-care background therapy. A greater percentage of the patients in the seladelpar group than in the placebo group had a biochemical response (61.7% vs. 20.0%; difference, 41.7 percentage points; 95% confidence interval [CI], 27.7 to 53.4, P<0.001). Normalization of the alkaline phosphatase level also occurred in a greater percentage of patients who received seladelpar than of those who received placebo (25.0% vs. 0%; difference, 25.0 percentage points; 95% CI, 18.3 to 33.2, P<0.001). Seladelpar resulted in a greater reduction in the score on the pruritus numerical rating scale than placebo (least-squares mean change from baseline, -3.2 vs. -1.7; least-squares mean difference, -1.5; 95% CI, -2.5 to -0.5, P = 0.005). Adverse events were reported in 86.7% of the patients in the seladelpar group and in 84.6% in the placebo group, and serious adverse events in 7.0% and 6.2%, respectively. In this trial involving patients with primary biliary cholangitis, the percentage of patients who had a biochemical response and alkaline phosphatase normalization was significantly greater with seladelpar than with placebo. Seladelpar also significantly reduced pruritus among patients who had moderate-to-severe pruritus at baseline. The incidence and severity of adverse events were similar in the two groups. (Funded by CymaBay Therapeutics; RESPONSE ClinicalTrials.gov number, NCT04620733; EudraCT number, 2020-004348-27.).

Acetate-capped hydrophilic cubic phase NaYF.sub.4:Yb/Er upconversion nanophosphors were effectively synthesized in a single step employing a facile microwave-assisted synthesis route by applying relatively low temperatures in a short span of time compared to the conventional synthetic methods. The nanoparticles having a size of about 25 nm exhibit good upconversion luminescence property and can be well dispersed in aqueous solvents as-synthesized. These upconversion nanoparticles were examined for their cytotoxicity and demonstrated to be an effective material for cancer cell imaging using near-infrared radiation.

The addition of abiraterone, a drug that blocks endogenous androgen synthesis, to standard androgen-deprivation therapy in patients with newly diagnosed, metastatic prostate cancer significantly increased overall survival, with a low rate of adverse effects.

CMV infection is a common complication in patients undergoing hematopoietic-cell transplantation. The incidence of CMV infection was 23 percentage points lower with prophylactic letermovir, a CMV–terminase complex inhibitor, than with placebo, with only low-level toxic effects.

Transgender people with sex recorded male at birth desiring feminization commonly use cyproterone acetate or spironolactone as antiandrogens with estradiol, but the optimal antiandrogen is unclear. We aimed to assess the effect of antiandrogens on breast development. We hypothesized this would be greater in those treated with cyproterone acetate than spironolactone due to more potent androgen receptor antagonism and suppression of serum total testosterone concentrations. A randomized clinical trial was conducted between 2020-2022 at an outpatient endocrinology clinic. Transgender people aged 18+ years old commencing feminizing gender affirming hormone therapy were included. The intervention was standardized estradiol therapy plus either spironolactone 100 mg daily or cyproterone acetate 12.5 mg daily for 6 months. The primary outcome was breast development as measured by the breast-chest distance. Secondary outcomes included estimated breast volume, suppression of serum total testosterone concentration <2 nmol/L, and Gender Preoccupation and Stability Questionnaire (GPSQ). Sixty-three people (median age 25 years) were enrolled, randomized, and included in intention to treat analysis (cyproterone acetate n = 32, spironolactone n = 31). At 6 months, there was no between-group difference in breast-chest distance (mean difference 0.27 cm, 95% CI -0.82 to 1.35, P = .6) or estimated breast volume (mean difference 17.26 mL, 95% CI -16.94 to 51.47, P = .3). Cyproterone acetate was more likely to suppress serum testosterone concentration to <2 nmol/L (odds ratio 9.01, 95% CI 1.83 to 4.44, P = .008). Changes in GPSQ were similar between groups. Antiandrogen choice should be based on clinician and patient preference with consideration of side effects. Further research is needed to optimize breast development in transgender people.

Letermovir is an antiviral with activity against CMV. In patients undergoing allogeneic hematopoietic-cell transplantation, the rate of prophylaxis failure with letermovir (240 mg per day) was 29%, as compared with 64% with placebo. Toxicity was similar for letermovir and placebo. Cytomegalovirus (CMV) disease that results from CMV replication through reactivation or new infection is a serious, potentially life-threatening condition in immunocompromised patients. This is especially true for recipients of allogeneic hematopoietic-cell transplants 1 , 2 ; CMV viremia occurs in 50 to 60% of these patients and may progress to CMV disease. 3 The standard of care for treatment of CMV infection or disease has typically been intravenous ganciclovir or its oral prodrug, valganciclovir, or alternatively, intravenous foscarnet or cidofovir. 4 Although efficacious, these therapies are associated with clinically significant drug-specific effects, including myelosuppression (neutropenia or thrombocytopenia with ganciclovir, valganciclovir, and cidofovir) and renal . . .

Men with high-risk non-metastatic prostate cancer are treated with androgen-deprivation therapy (ADT) for 3 years, often combined with radiotherapy. We analysed new data from two randomised controlled phase 3 trials done in a multiarm, multistage platform protocol to assess the efficacy of adding abiraterone and prednisolone alone or with enzalutamide to ADT in this patient population. These open-label, phase 3 trials were done at 113 sites in the UK and Switzerland. Eligible patients (no age restrictions) had high-risk (defined as node positive or, if node negative, having at least two of the following: tumour stage T3 or T4, Gleason sum score of 8–10, and prostate-specific antigen [PSA] concentration ≥40 ng/mL) or relapsing with high-risk features (≤12 months of total ADT with an interval of ≥12 months without treatment and PSA concentration ≥4 ng/mL with a doubling time of <6 months, or a PSA concentration ≥20 ng/mL, or nodal relapse) non-metastatic prostate cancer, and a WHO performance status of 0–2. Local radiotherapy (as per local guidelines, 74 Gy in 37 fractions to the prostate and seminal vesicles or the equivalent using hypofractionated schedules) was mandated for node negative and encouraged for node positive disease. In both trials, patients were randomly assigned (1:1), by use of a computerised algorithm, to ADT alone (control group), which could include surgery and luteinising-hormone-releasing hormone agonists and antagonists, or with oral abiraterone acetate (1000 mg daily) and oral prednisolone (5 mg daily; combination-therapy group). In the second trial with no overlapping controls, the combination-therapy group also received enzalutamide (160 mg daily orally). ADT was given for 3 years and combination therapy for 2 years, except if local radiotherapy was omitted when treatment could be delivered until progression. In this primary analysis, we used meta-analysis methods to pool events from both trials. The primary endpoint of this meta-analysis was metastasis-free survival. Secondary endpoints were overall survival, prostate cancer-specific survival, biochemical failure-free survival, progression-free survival, and toxicity and adverse events. For 90% power and a one-sided type 1 error rate set to 1·25% to detect a target hazard ratio for improvement in metastasis-free survival of 0·75, approximately 315 metastasis-free survival events in the control groups was required. Efficacy was assessed in the intention-to-treat population and safety according to the treatment started within randomised allocation. STAMPEDE is registered with ClinicalTrials.gov, NCT00268476, and with the ISRCTN registry, ISRCTN78818544. Between Nov 15, 2011, and March 31, 2016, 1974 patients were randomly assigned to treatment. The first trial allocated 455 to the control group and 459 to combination therapy, and the second trial, which included enzalutamide, allocated 533 to the control group and 527 to combination therapy. Median age across all groups was 68 years (IQR 63–73) and median PSA 34 ng/ml (14·7–47); 774 (39%) of 1974 patients were node positive, and 1684 (85%) were planned to receive radiotherapy. With median follow-up of 72 months (60–84), there were 180 metastasis-free survival events in the combination-therapy groups and 306 in the control groups. Metastasis-free survival was significantly longer in the combination-therapy groups (median not reached, IQR not evaluable [NE]–NE) than in the control groups (not reached, 97–NE; hazard ratio [HR] 0·53, 95% CI 0·44–0·64, p<0·0001). 6-year metastasis-free survival was 82% (95% CI 79–85) in the combination-therapy group and 69% (66–72) in the control group. There was no evidence of a difference in metatasis-free survival when enzalutamide and abiraterone acetate were administered concurrently compared with abiraterone acetate alone (interaction HR 1·02, 0·70–1·50, p=0·91) and no evidence of between-trial heterogeneity (I2 p=0·90). Overall survival (median not reached [IQR NE–NE] in the combination-therapy groups vs not reached [103–NE] in the control groups; HR 0·60, 95% CI 0·48–0·73, p<0·0001), prostate cancer-specific survival (not reached [NE–NE] vs not reached [NE–NE]; 0·49, 0·37–0·65, p<0·0001), biochemical failure-free-survival (not reached [NE–NE] vs 86 months [83–NE]; 0·39, 0·33–0·47, p<0·0001), and progression-free-survival (not reached [NE–NE] vs not reached [103–NE]; 0·44, 0·36–0·54, p<0·0001) were also significantly longer in the combination-therapy groups than in the control groups. Adverse events grade 3 or higher during the first 24 months were, respectively, reported in 169 (37%) of 451 patients and 130 (29%) of 455 patients in the combination-therapy and control groups of the abiraterone trial, respectively, and 298 (58%) of 513 patients and 172 (32%) of 533 patients of the combination-therapy and control groups of the abiraterone and enzalutamide trial, respectively. The two most common events more frequent in the combination-therapy groups were hypertension (abiraterone trial: 23 (5%) in the combination-therapy group and six (1%) in control group; abiraterone and enzalutamide trial: 73 (14%) and eight (2%), respectively) and alanine transaminitis (abiraterone trial: 25 (6%) in the combination-therapy group and one (<1%) in control group; abiraterone and enzalutamide trial: 69 (13%) and four (1%), respectively). Seven grade 5 adverse events were reported: none in the control groups, three in the abiraterone acetate and prednisolone group (one event each of rectal adenocarcinoma, pulmonary haemorrhage, and a respiratory disorder), and four in the abiraterone acetate and prednisolone with enzalutamide group (two events each of septic shock and sudden death). Among men with high-risk non-metastatic prostate cancer, combination therapy is associated with significantly higher rates of metastasis-free survival compared with ADT alone. Abiraterone acetate with prednisolone should be considered a new standard treatment for this population. Cancer Research UK, UK Medical Research Council, Swiss Group for Clinical Cancer Research, Janssen, and Astellas.

The addition of abiraterone and prednisolone to standard androgen-deprivation therapy as the first treatment for patients with locally advanced or metastatic prostate cancer improved overall and failure-free survival, with a small increase in high-grade toxic effects.

This randomized, double-blind trial involving critically ill patients compared balanced multielectrolyte solution with saline as fluid therapy in the ICU. There was no evidence that the risk of death or acute kidney injury was lower with the use of BMES than with saline.