METHODS: In a phase 2 trial, we randomly assigned patients with a GPP flare in a 2:1 ratio to receive a single 900-mg intravenous dose of spesolimab or placebo. Patients in both groups could receive an open-label dose of spesolimab on day 8, an open-label dose of spesolimab as a rescue medication after day 8, or both and were followed to week 12. The primary end point was a Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) pustulation subscore of 0 (range, 0 [no visible pustules] to 4 [severe pustulation]) at the end of week 1. The key secondary end point was a GPPGA total score of 0 or 1 (clear or almost clear skin) at the end of week 1; scores range from 0 to 4, with higher scores indicating greater disease severity.

RESULTS: A total of 53 patients were enrolled: 35 were assigned to receive spesolimab and 18 to receive placebo. At baseline, 46% of the patients in the spesolimab group and 39% of those in the placebo group had a GPPGA pustulation subscore of 3, and 37% and 33%, respectively, had a pustulation subscore of 4. At the end of week 1, a total of 19 of 35 patients (54%) in the spesolimab group had a pustulation subscore of 0, as compared with 1 of 18 patients (6%) in the placebo group (difference, 49 percentage points; 95% confidence interval [CI], 21 to 67; P<0.001). A total of 15 of 35 patients (43%) had a GPPGA total score of 0 or 1, as compared with 2 of 18 patients (11%) in the placebo group (difference, 32 percentage points; 95% CI, 2 to 53; P = 0.02). Drug reactions were reported in 2 patients who received spesolimab, in 1 of them concurrently with a drug-induced hepatic injury. Among patients assigned to the spesolimab group, infections occurred in 6 of 35 (17%) through the first week; among patients who received spesolimab at any time in the trial, infections had occurred in 24 of 51 (47%) at week 12. Antidrug antibodies were detected in 23 of 50 patients (46%) who received at least one dose of spesolimab.

OBJECTIVES: To conduct a systematic review of RCTs involving topical drugs published in the Archives of Dermatology, Journal of the American Academy of Dermatology and British Journal of Dermatology for correct classification of studies as vehicle versus placebo-controlled.

METHODS: RCTs involving topical drugs published in the Archives of Dermatology, Journal of the American Academy of Dermatology and British Journal of Dermatology from January 1999 to November 2008 were identified through PubMed, supplemented by citation lists from the individual journals' web pages. Only original studies that involved using a topical control or used the term topical "vehicle" or "placebo" were selected. The studies were examined for correct classification as vehicle-controlled, the year of publication, country of origin, sample size, funding source and nature of study center.

RESULTS: Out of 132, 64 (49%) correctly classified their studies as vehicle-controlled. Pharmaceutical-funded studies (55%, P=0.01) were significantly associated with the use of correct classification.

LIMITATIONS: As only three peer-reviewed dermatology journals were studied, findings may not be generalized to other dermatology journals and other types of publications.

OBJECTIVES: To assess the efficacy and safety of umeclidinium bromide versus placebo for people with stable COPD.

SEARCH METHODS: We searched the Cochrane Airways Group Specialised Register (CAGR), ClinicalTrials.gov, the World Health Organization (WHO) trials portal, and the GlaxoSmithKline (GSK) Clinical Study Register, using prespecified terms, as well as the reference lists of all identified studies. Searches are current to April 2017.

SELECTION CRITERIA: We included randomised controlled trials (RCTs) of parallel design comparing umeclidinium bromide versus placebo in people with COPD, for at least 12 weeks.

DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodological procedures. If we noted significant heterogeneity in the meta-analyses, we subgrouped studies by umeclidinium dose.

MAIN RESULTS: We included four studies of 12 to 52 weeks' duration, involving 3798 participants with COPD. Mean age of participants ranged from 60.1 to 64.6 years; most were males with baseline mean smoking pack-years of 39.2 to 52.3. They had moderate to severe COPD and baseline mean post-bronchodilator forced expiratory volume in one second (FEV1) ranging from 44.5% to 55.1% of predicted normal. As all studies were systematically conducted according to prespecified protocols, we assessed risk of selection, performance, detection, attrition, and reporting biases as low.Compared with those given placebo, participants in the umeclidinium group had a lesser likelihood of developing moderate exacerbations requiring a short course of steroids, antibiotics, or both (odds ratio (OR) 0.61, 95% confidence interval (CI) 0.46 to 0.80; four studies, N = 1922; GRADE: high), but not specifically requiring hospitalisations due to severe exacerbations (OR 0.86, 95% CI 0.25 to 2.92; four studies, N = 1922, GRADE: low). The number needed to treat for an additional beneficial outcome (NNTB) to prevent an acute exacerbation requiring steroids, antibiotics, or both was 18 (95% CI 13 to 37). Quality of life was better in the umeclidinium group (mean difference (MD) -4.79, 95% CI -8.84 to -0.75; three studies, N = 1119), and these participants had a significantly higher chance of achieving a minimal clinically important difference of at least four units in St George's Respiratory Questionnaire (SGRQ) total score compared with those in the placebo group (OR 1.45, 95% CI 1.16 to 1.82; three studies, N = 1397; GRADE: moderate). The NNTB to achieve one person with a clinically meaningful improvement was 11 (95% CI 7 to 29). The likelihood of all-cause mortality, non-fatal serious adverse events (OR 1.33; 95% CI 0.89 to 2.00; four studies, N = 1922, GRADE: moderate), and adverse events (OR 1.06, 95% CI 0.85 to 1.31; four studies, N = 1922; GRADE: moderate) did not differ between umeclidinium and placebo groups. The umeclidinium group demonstrated significantly greater improvement in change from baseline in trough FEV1 compared with the placebo group (MD 0.14, 95% CI 0.12 to 0.17; four studies, N = 1381; GRADE: high). Symptomatic improvement was more likely in the umeclidinium group than in the placebo group, as determined by Transitional Dyspnoea Index (TDI) focal score (MD 0.76, 95% CI 0.43 to 1.09; three studies, N = 1193), and the chance of achieving a minimal clinically important difference of at least one unit improvement was significantly higher with umeclidinium than with placebo (OR 1.71, 95% CI 1.37 to 2.15; three studies, N = 1141; GRADE: high). The NNTB to attain one person with clinically important symptomatic improvement was 8 (95% CI 5 to 14). The likelihood of rescue medication usage (change from baseline in the number of puffs per day) was significantly less for the umeclidinium group than for the placebo group (MD -0.45, 95% CI -0.76 to -0.14; four studies, N = 1531).

OBJECTIVES: To assess the efficacy and adverse effects of D-cycloserine compared with placebo for social and communication skills in individuals with ASD.

SEARCH METHODS: In November 2020, we searched CENTRAL, MEDLINE, Embase, six other databases and two trials registers. We also searched the reference lists of relevant publications and contacted the authors of the included study, Minshawi 2016, to identify any additional studies. In addition, we contacted pharmaceutical companies, searched manufacturers' websites and sources of reports of adverse events.  SELECTION CRITERIA: All randomised controlled trials (RCTs) of any duration and dose of D-cycloserine, with or without adjunct treatment, compared to placebo in individuals with ASD.

DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies for inclusion, extracted relevant data, assessed the risk of bias, graded the certainty of the evidence using the GRADE approach, and analysed and evaluated the data. We provide a narrative report of the findings as only one study is included in this review.

OBJECTIVES: To assess the comparative efficacy and safety of different types of systemic immunosuppressive treatments for moderate to severe eczema using NMA and to generate rankings of available systemic immunosuppressive treatments for eczema according to their efficacy and safety.

SEARCH METHODS: We searched the following databases up to August 2019: the Cochrane Skin Specialised Register, CENTRAL, MEDLINE, and Embase.

SELECTION CRITERIA: All randomised controlled trials (RCTs) of systemic immunosuppressive agents for moderate to severe atopic eczema when compared against placebo or any other eligible eczema treatment.

DATA COLLECTION AND ANALYSIS: We synthesised data using pair-wise analysis and NMA to compare treatments and rank them according to their effectiveness. Effectiveness was assessed primarily by determining the proportion of participants who achieved at least 75% improvement in the Eczema Area and Severity Index (EASI75) and improvement in the Patient-Oriented Eczema Measure (POEM). Safety was evaluated primarily by considering the proportion of participants with serious adverse events (SAEs) and infection. We deemed short-term follow-up as ≤ 16 weeks and long-term follow-up as > 16 weeks. We assessed the certainty of the body of evidence from the NMA for these primary outcomes using six domains of CiNEMA grading.

MAIN RESULTS: We included a total of 74 studies, with 8177 randomised participants. Approximately 55% of participants were male, with average age of 32 years (range 2 to 84 years), although age and gender were unreported for 419 and 902 participants, respectively. Most of the included trials were placebo controlled (65%), 34% were head-to-head studies (15% assessed the effects of different doses of the same drug), and 1% were multi-armed studies with both an active comparator and a placebo. All trials included participants with moderate to severe eczema, but 62% of studies did not separate data by severity; 38% of studies assessed only severe eczema. The total duration of included trials ranged from 2 weeks to 60 months, whereas treatment duration varied from a single dose (CIM331, KPL-716) to 60 months (methotrexate (MTX)). Seventy studies were available for quantitative synthesis; this review assessed 29 immunosuppressive agents from three classes of interventions. These included (1) conventional treatments, with ciclosporin assessed most commonly; (2) small molecule treatments, including phosphodiesterase (PDE)-4 inhibitors, tyrosine kinase inhibitors, and Janus kinase (JAK) inhibitors; and (3) biological treatments, including anti-CD31 receptors, anti-interleukin (IL)-22, anti-IL-31, anti-IL-13, anti-IL-12/23p40, anti-OX40, anti-TSLP, anti-CRTH2, and anti-immunoglobulin E (IgE) monoclonal antibodies, but most commonly dupilumab. Most trials (73) assessed outcomes at a short-term duration ranging from 2 to 16 weeks, whereas 33 trials assessed long-term outcomes, with duration ranging from 5 to 60 months. All participants were from a hospital setting. Fifty-two studies declared a source of funding, and of these, pharmaceutical companies funded 88%. We rated 37 studies as high risk; 21, unclear risk, and 16, low risk of bias, with studies most commonly at high risk of attrition bias. Network meta-analysis suggests that dupilumab ranks first for effectiveness when compared with other biological treatments. Dupilumab is more effective than placebo in achieving EASI75 (risk ratio (RR) 3.04, 95% confidence interval (CI) 2.51 to 3.69) and improvement in POEM score (mean difference 7.30, 95% CI 6.61 to 8.00) at short-term follow-up (high-certainty evidence). Very low-certainty evidence means we are uncertain of the effects of dupilumab when compared with placebo, in terms of the proportion of participants who achieve EASI75 (RR 2.59, 95% CI 1.87 to 3.60) at longer-term follow-up. Low-certainty evidence indicates that tralokinumab may be more effective than placebo in achieving short-term EASI75 (RR 2.54, 95% CI 1.21 to 5.34), but there was no evidence for tralokinumab to allow us to assess short-term follow-up of POEM or long-term follow-up of EASI75. We are uncertain of the effect of ustekinumab compared with placebo in achieving EASI75 (long-term follow-up: RR 1.17, 95% CI 0.40 to 3.45; short-term follow-up: RR 0.91, 95% CI 0.28 to 2.97; both very low certainty). We found no evidence on ustekinumab for the POEM outcome. We are uncertain whether other immunosuppressive agents that targeted our key outcomes influence the achievement of short-term EASI75 compared with placebo due to low- or very low-certainty evidence. Dupilumab and ustekinumab were the only immunosuppressive agents evaluated for longer-term EASI75. Dupilumab was the only agent evaluated for improvement in POEM during short-term follow-up. Low- to moderate-certainty evidence indicates a lower proportion of participants with SAEs after treatment with QAW039 and dupilumab compared to placebo during short-term follow-up, but low- to very low-certainty evidence suggests no difference in SAEs during short-term follow-up of other immunosuppressive agents compared to placebo. Evidence for effects of immunosuppressive agents on risk of any infection during short-term follow-up and SAEs during long-term follow-up compared with placebo was of low or very low certainty but did not indicate a difference. We did not identify differences in other adverse events (AEs), but dupilumab is associated with specific AEs, including eye inflammation and eosinophilia.

MATERIALS AND METHODS: This randomized, double-blind, sham controlled study was performed in 120 female subjects at least 21 years old with stress urinary incontinence. Treatment involved pulsed magnetic stimulation for 2 sessions per week for 2 months (16 sessions). After 2 months, subjects could opt for 16 additional sessions regardless of initial randomization. The primary response criterion was a 5-point reduction in the ICIQ-UI SF (International Consultation on Incontinence Questionnaire for Urinary Incontinence-Short Form) score. Key secondary response criteria included objective and subjective cure, supplemented by other secondary criteria. Followups were performed at months 1, 2, 5, 8 and 14.

RESULTS: At 2 months 45 of 60 subjects (75%) in the active arm vs 13 of 60 (21.7%) in the sham arm were treatment responders (p <0.001). After 2 months 24 subjects (40%) in the active arm and 41 (68%) in the sham arm elected additional active pulsed magnetic stimulation. At 14 months, subjects who received 32 sessions of active pulsed magnetic stimulation had the highest percentage of treatment responders (18 of 24 or 75.0%), followed by those who received 16 sessions (26 of 36 or 72.2% and 28 of 41 or 68.3%) and those who did not receive any active pulsed magnetic stimulation (4 of 19 or 21.1%) (p <0.001).

METHODS: In this randomised, placebo-controlled, double-blind, phase 3 trial, done in 209 sites in 29 countries, we randomly assigned patients 2:1 with untreated locally recurrent inoperable or metastatic triple-negative breast cancer using a block method (block size of six) and an interactive voice-response system with integrated web-response to pembrolizumab (200 mg) every 3 weeks plus chemotherapy (nab-paclitaxel; paclitaxel; or gemcitabine plus carboplatin) or placebo plus chemotherapy. Randomisation was stratified by type of on-study chemotherapy (taxane or gemcitabine-carboplatin), PD-L1 expression at baseline (combined positive score [CPS] ≥1 or <1), and previous treatment with the same class of chemotherapy in the neoadjuvant or adjuvant setting (yes or no). Eligibility criteria included age at least 18 years, centrally confirmed triple-negative breast cancer; at least one measurable lesion; provision of a newly obtained tumour sample for determination of triple-negative breast cancer status and PD-L1 status by immunohistochemistry at a central laboratory; an Eastern Cooperative Oncology Group performance status score 0 or 1; and adequate organ function. The sponsor, investigators, other study site staff (except for the unmasked pharmacist), and patients were masked to pembrolizumab versus saline placebo administration. In addition, the sponsor, the investigators, other study site staff, and patients were masked to patient-level tumour PD-L1 biomarker results. Dual primary efficacy endpoints were progression-free survival and overall survival assessed in the PD-L1 CPS of 10 or more, CPS of 1 or more, and intention-to-treat populations. The definitive assessment of progression-free survival was done at this interim analysis; follow-up to assess overall survival is continuing. For progression-free survival, a hierarchical testing strategy was used, such that testing was done first in patients with CPS of 10 or more (prespecified statistical criterion was α=0·00411 at this interim analysis), then in patients with CPS of 1 or more (α=0·00111 at this interim analysis, with partial alpha from progression-free survival in patients with CPS of 10 or more passed over), and finally in the intention-to-treat population (α=0·00111 at this interim analysis). This study is registered with ClinicalTrials.gov, NCT02819518, and is ongoing.

FINDINGS: Between Jan 9, 2017, and June 12, 2018, of 1372 patients screened, 847 were randomly assigned to treatment, with 566 patients in the pembrolizumab-chemotherapy group and 281 patients in the placebo-chemotherapy group. At the second interim analysis (data cutoff, Dec 11, 2019), median follow-up was 25·9 months (IQR 22·8-29·9) in the pembrolizumab-chemotherapy group and 26·3 months (22·7-29·7) in the placebo-chemotherapy group. Among patients with CPS of 10 or more, median progression-free survival was 9·7 months with pembrolizumab-chemotherapy and 5·6 months with placebo-chemotherapy (hazard ratio [HR] for progression or death, 0·65, 95% CI 0·49-0·86; one-sided p=0·0012 [primary objective met]). Median progression-free survival was 7·6 and 5·6 months (HR, 0·74, 0·61-0·90; one-sided p=0·0014 [not significant]) among patients with CPS of 1 or more and 7·5 and 5·6 months (HR, 0·82, 0·69-0·97 [not tested]) among the intention-to-treat population. The pembrolizumab treatment effect increased with PD-L1 enrichment. Grade 3-5 treatment-related adverse event rates were 68% in the pembrolizumab-chemotherapy group and 67% in the placebo-chemotherapy group, including death in <1% in the pembrolizumab-chemotherapy group and 0% in the placebo-chemotherapy group.

INTERPRETATION: Pembrolizumab-chemotherapy showed a significant and clinically meaningful improvement in progression-free survival versus placebo-chemotherapy among patients with metastatic triple-negative breast cancer with CPS of 10 or more. These findings suggest a role for the addition of pembrolizumab to standard chemotherapy for the first-line treatment of metastatic triple-negative breast cancer.

METHODS: Twenty postmenopausal women with a mean age of 54.59 +/- 1.22 years participated in this randomized, crossover, double-blind, placebo-controlled clinical trial. All women received 400 IU of tocopherol daily for 10 weeks or a placebo capsule, before being crossed over for treatment. At intervals of 5 weeks, subjects attended sessions where measurements of arterial stiffness, blood pressure and plasma vitamin E level were taken. Pulse wave velocity measurement, using the automated Complior machine, was used as an index of arterial stiffness.

RESULTS: Plasma vitamin E level was 30.38 +/- 1.56 micromol/l at baseline, after treatment it was 59.01 +/- 3.30 micromol/l and 31.17 +/- 1.37 micromol/l with vitamin E and placebo, respectively (p < 0.001). There was no significant difference in pulse wave velocity after 10-week treatment with placebo and vitamin E (9.14 +/- 0.29 versus 9.04 +/- 0.29 m/s, respectively). Similarly, no difference in systolic and diastolic blood pressure was seen between placebo and vitamin E at the end of 10 weeks.