Baru nuts reduce abdominal adiposity in type 2 diabetic adults: a randomized, placebo-controlled, crossover trial / Amêndoa de baru reduz a adiposidade abdominal de adultos com diabetes Mellitus tipo 2: um estudo randomizado, placebo-controlado, crossover

ABSTRACT Objective: This study aimed to evaluate the effect of baru nuts supplementation on body composition and metabolic profile in adults with type 2 diabetes. Methods: This is a randomized, placebo-controlled, crossover trial with 30 adults with type 2 diabetes. The assay had two periods of 12 weeks each, with a washout period of 12 weeks between treatments. The subjects were randomized and received the two treatments in alternate periods: supplementation of 30g baru nuts or placebo. Anthropometry, body composition, blood pressure, blood sampling, food intake, and physical activity data were analyzed. Results: Baru nut intake reduced waist circumference (p=0.032), compared to placebo group. In the intra-group analysis, baru nut intake reduced total cholesterol (p=0.012) and LDL-c (p=0.017). Conclusion: The daily intake of baru nuts improved abdominal adiposity. Therefore, these nuts should be included in the diet to improve the health status of adults with type 2 diabetes.

RESUMO: Objetivo: Avaliar o efeito da suplementação com amêndoa de baru sobre a composição corporal e perfil metabólico de adultos com diabetes Mellitus tipo 2. Métodos: Este é um estudo randomizado, placebo-controlado, crossover com 30 adultos com diabetes Mellitus tipo 2. O ensaio clínico foi dividido em dois períodos de 12 semanas cada, com um washout de 12 semanas entre os tratamentos. Os sujeitos foram randomizados e receberam dois tratamentos em períodos alternativos: suplementação com 30 g de amêndoa de baru ou placebo. Foram coletados dados referentes à antropometria, composição corporal, pressão arterial, amostras de sangue, ingestão de alimentos e práticas de atividade física. Resultados: A ingestão de amêndoa de baru reduziu a circunferência da cintura (p=0,032), em comparação com o grupo placebo. Na análise intragrupo, a ingestão de amêndoa de baru também reduziu o colesterol total (p=0,012) e LDL-c (p=0,017). Conclusão: A ingestão diária de amêndoa de baru melhorou a adiposidade abdominal, portanto, deve ser incluída na dieta para a melhora do estado de saúde de adultos com diabetes Mellitus tipo 2.

Remotely Provided Open-Label Placebo Reduces Frequency of and Impairment by Allergic Symptoms.

OBJECTIVE: Placebos being prescribed with full honesty and disclosure (i.e., open-label placebo [OLP]) have been shown to reduce symptom burden in a variety of conditions. With regard to allergic rhinitis, previous research provided inconclusive evidence for the effects of OLP, possibly related to a separate focus on either symptom severity or symptom frequency. Overcoming this limitation of previous research, the present study aimed to examine the effects of OLP on both the severity and frequency of allergic symptoms. METHODS: In a randomized-controlled trial, patients with allergic rhinitis ( N = 74) were randomized to OLP or treatment as usual (TAU). Because of the COVID-19 pandemic, OLP was administered remotely in a virtual clinical encounter. Participants took placebo tablets for 14 days. The primary outcomes were the severity and frequency of allergic symptoms. The secondary end point was allergy-related impairment. RESULTS: OLP did not significantly improve symptom severity over TAU ( F (1,71) = 3.280, p = .074, η2 = 0.044) but did reduce symptom frequency ( F (1,71) = 7.272, p = .009, η2 = 0.093) and allergy-related impairment more than TAU ( F (1,71) = 6.445, p = .013, η2 = 0.083), reflecting medium to large effects. The use of other antiallergic medication did not influence the results. CONCLUSIONS: Although OLP was able to lower the frequency of allergic symptoms and allergy-related impairment substantially, its effects on symptom severity were weaker. The remote provision of OLP suggests that physical contact between patients and providers might not be necessary for OLP to work.

Otitis media (acute): antimicrobial prescribing

This guideline sets out an antimicrobial prescribing strategy for acute otitis media (ear infection). It aims to limit antibiotic use and reduce antimicrobial resistance. Acute otitis media can be caused by viruses or bacteria. It lasts for about a week, and most children get better in 3 days without antibiotics. Serious complications are rare. In March 2022, we reviewed the evidence and added a recommendation on eardrops containing an anaesthetic and an analgesic because a licensed preparation is now available in the UK. For more information, see update information.

Association of Single-blind Placebo Run-in Periods With the Placebo Response in Randomized Clinical Trials of Antidepressants: A Systematic Review and Meta-analysis.

Importance: Single-blind placebo run-in (PRI) periods are common in randomized clinical trials (RCTs) of treatment for depression. They aim to increase sensitivity to detect drug effects; however, the association of PRI periods with study outcomes remains unclear. This is concerning given the costs of PRI periods to patients and investigators. Objective: To examine the association of the use of PRI periods with the placebo response, drug response, and drug-placebo difference among RCTs of antidepressants. Data Sources: MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and PsycINFO, as well as repositories of unpublished studies, were systematically searched up to July 2021. Study Selection: Included studies were double-blind, placebo-controlled RCTs of antidepressant medication among adults with depressive disorders. Data Extraction and Synthesis: Data were extracted into a coding sheet, including the characteristics of studies, the characteristics of PRI periods, and the outcomes of studies. Main Outcomes and Measures: Study outcomes were the primary depression symptom measure reported by the RCT. These outcomes were used to calculate effect sizes (Hedges g) of the within-group drug response and placebo response as well as the drug-placebo difference. Random-effects meta-analysis was used to calculate effect sizes, and subgroup analyses were used to compare outcomes depending on use of PRI periods. Results: A total of 347 trials (representing 89 183 participants) were included; 174 studies (50%) reported using a single-blind PRI period. Response outcome data were available for 189 studies. Studies using PRI periods reported a smaller placebo response (g = 1.05 [95% CI, 0.98-1.11]; I2 = 82%) than studies that did not use a PRI period (g = 1.15 [95% CI, 1.09-1.21]; I2 = 81%; P = .02). Subgroup analysis showed a larger drug response size among studies that did not use a PRI period (g = 1.55 [95% CI, 1.49-1.61]; I2 = 85%) than those that did use a PRI period (g = 1.42 [95% CI, 1.36-1.48]; I2 = 81%; P = .001). The drug-placebo difference did not differ by use of PRI periods (g = 0.33 [95% CI, 0.29-0.38]; I2 = 47% for use of a PRI period vs g = 0.34 [95% CI, 0.30-0.38]; I2 = 54% for no use of PRI periods; P = .92). The likelihood of response to drug vs placebo also did not differ between studies that used a PRI period (odds ratio, 1.89 [95% CI, 1.76-2.03]) and those that did not use a PRI period (odds ratio, 1.77 [95% CI, 1.65-1.89]; P = .18). Conclusions and Relevance: This study suggests that RCTs using PRI periods yield smaller within-group changes across both placebo and drug groups compared with RCTs without PRI periods. The reduction in effect size across groups was equivalent in magnitude. Consequently, PRI studies do not observe larger drug-placebo differences, suggesting that they do not increase trial sensitivity. As such, given the resources and probable deception required and risk to external validity, the practice of using PRI periods in RCTs of antidepressants should be ended.

Etrolizumab versus adalimumab or placebo as induction therapy for moderately to severely active ulcerative colitis (HIBISCUS): two phase 3 randomised, controlled trials.

BACKGROUND: Etrolizumab is a gut-targeted anti-ß7 integrin monoclonal antibody. In an earlier phase 2 induction study, etrolizumab significantly improved clinical remission relative to placebo in patients with moderately to severely active ulcerative colitis. The HIBISCUS studies aimed to compare the efficacy and safety of etrolizumab to adalimumab and placebo for induction of remission in patients with moderately to severely active ulcerative colitis. METHODS: HIBISCUS I and HIBISCUS II were identically designed, multicentre, phase 3, randomised, double-blind, placebo-controlled and active-controlled studies of etrolizumab, adalimumab, and placebo in adult (18-80 years) patients with moderately to severely active ulcerative colitis (Mayo Clinic total score [MCS] of 6-12 with an endoscopic subscore of ≥2, a rectal bleeding subscore of ≥1, and a stool frequency subscore of ≥1) who were naive to tumour necrosis factor inhibitors. All patients had an established diagnosis of ulcerative colitis for at least 3 months, corroborated by both clinical and endoscopic evidence, and evidence of disease extending at least 20 cm from the anal verge. In both studies, patients were randomly assigned (2:2:1) to receive subcutaneous etrolizumab 105 mg once every 4 weeks; subcutaneous adalimumab 160 mg on day 1, 80 mg at week 2, and 40 mg at weeks 4, 6, and 8; or placebo. Randomisation was stratified by baseline concomitant treatment with corticosteroids, concomitant treatment with immunosuppressants, and baseline disease activity. All patients and study site personnel were masked to treatment assignment. The primary endpoint was induction of remission at week 10 (defined as MCS of 2 or lower, with individual subscores of 1 or lower, and rectal bleeding subscore of 0) with etrolizumab compared with placebo. Pooled analyses of both studies comparing etrolizumab and adalimumab were examined for several clinical and endoscopic endpoints. Efficacy was analysed using a modified intent-to-treat population, defined as all randomly assigned patients who received at least one dose of study drug. These trials are registered with ClinicalTrials.gov, NCT02163759 (HIBISCUS I), NCT02171429 (HIBISCUS II). FINDINGS: Between Nov 4, 2014, and May 25, 2020, each study screened 652 patients (HIBISCUS I) and 613 patients (HIBISCUS II). Each study enrolled and randomly assigned 358 patients (HIBISCUS I etrolizumab n=144, adalimumab n=142, placebo n=72; HIBISCUS II etrolizumab n=143; adalimumab n=143; placebo n=72). In HIBISCUS I, 28 (19·4%) of 144 patients in the etrolizumab group and five (6·9%) of 72 patients in the placebo group were in remission at week 10, with an adjusted treatment difference of 12·3% (95% CI 1·6 to 20·6; p=0·017) in favour of etrolizumab. In HIBISCUS II, 26 (18·2%) of 143 patients in the etrolizumab group and eight (11·1%) of 72 patients in the placebo group were in remission at week 10, with an adjusted treatment difference of 7·2% (95% CI -3·8 to 16·1; p=0·17). In the pooled analysis, etrolizumab was not superior to adalimumab for induction of remission, endoscopic improvement, clinical response, histological remission, or endoscopic remission; however, similar numerical results were observed in both groups. In HIBISCUS I, 50 (35%) of 144 patients in the etrolizumab group reported any adverse event, compared with 61 (43%) of 142 in the adalimumab group and 26 (36%) of 72 in the placebo group. In HIBISCUS II, 63 (44%) of 143 patients in the etrolizumab group reported any adverse event, as did 62 (43%) of 143 in the adalimumab group and 33 (46%) in the placebo group. The most common adverse event in all groups was ulcerative colitis flare. The incidence of serious adverse events in the pooled patient population was similar for etrolizumab (15 [5%] of 287) and placebo (seven [5%] of 144) and lower for adalimumab (six [2%] of 285). Two patients in the etrolizumab group died; neither death was deemed to be treatment related. INTERPRETATION: Etrolizumab was superior to placebo for induction of remission in HIBISCUS I, but not in HIBISCUS II. Etrolizumab was well tolerated in both studies. FUNDING: F Hoffmann-La Roche.

B-cell depletion with obinutuzumab for the treatment of proliferative lupus nephritis: a randomised, double-blind, placebo-controlled trial.

OBJECTIVE: Randomised trials of type I anti-CD20 antibodies rituximab and ocrelizumab failed to show benefit in proliferative lupus nephritis (LN). We compared obinutuzumab, a humanised type II anti-CD20 monoclonal antibody that induces potent B-cell depletion, with placebo for the treatment of LN in combination with standard therapies. METHODS: Patients with LN receiving mycophenolate and corticosteroids were randomised to obinutuzumab 1000 mg or placebo on day 1 and weeks 2, 24 and 26, and followed through week 104. The primary endpoint was complete renal response (CRR) at week 52. Exploratory analyses through week 104 were conducted. The prespecified alpha level was 0.2. RESULTS: A total of 125 patients were randomised and received blinded infusions. Achievement of CRR was greater with obinutuzumab at week 52 (primary endpoint, 22 (35%) vs 14 (23%) with placebo; percentage difference, 12% (95% CI -3.4% to 28%), p=0.115) and at week 104 (26 (41%) vs 14 (23%); percentage difference, 19% (95% CI 2.7% to 35%), p=0.026). Improvements in other renal response measures, serologies, estimated glomerular filtration rate and proteinuria were greater with obinutuzumab. Obinutuzumab was not associated with increases in serious adverse events, serious infections or deaths. Non-serious infusion-related reactions occurred more frequently with obinutuzumab. CONCLUSIONS: Improved renal responses through week 104 were observed in patients with LN who received obinutuzumab plus standard therapies compared with standard therapies alone. Obinutuzumab was well tolerated and no new safety signals were identified. TRIAL REGISTRATION NUMBER: NCT02550652.

Trial of Spesolimab for Generalized Pustular Psoriasis.

BACKGROUND: Generalized pustular psoriasis (GPP) is a rare, life-threatening, inflammatory skin disease characterized by widespread eruption of sterile pustules. Interleukin-36 signaling is involved in the pathogenesis of this disorder. Spesolimab, a humanized anti-interleukin-36 receptor monoclonal antibody, is being studied for the treatment of GPP flares. 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. CONCLUSIONS: In a phase 2 randomized trial involving patients with GPP, the interleukin-36 receptor inhibitor spesolimab resulted in a higher incidence of lesion clearance at 1 week than placebo but was associated with infections and systemic drug reactions. Longer and larger trials are warranted to determine the effect and risks of spesolimab in patients with pustular psoriasis. (Funded by Boehringer Ingelheim; Effisayil 1 ClinicalTrials.gov number, NCT03782792.).

Giving and taking: ethical treatment assignment in controlled trials.

The current version of the Declaration of Helsinki states that 'the benefits, risks, burdens and effectiveness of a new intervention must be tested against those of the best current proven intervention(s) … '. This wording implies that it is acceptable for patients to be assigned to receive an unproven new intervention and to be denied a best current proven intervention. We assert that patients being invited to participate in controlled trials cannot, ethically, be expected to forego proven beneficial forms of care. Patients being treated in controlled trials should not knowingly be disadvantaged compared with similar patients being treated in usual clinical care, where they have access to beneficial care. In this article, we have tried to separate for discussion 'the withholding of effective care from trial participants', 'informed consent to treatment', 'blinding' and 'use of placebos'.

Effects of Combined Varenicline With Nicotine Patch and of Extended Treatment Duration on Smoking Cessation: A Randomized Clinical Trial.

Importance: Smoking cessation medications are routinely used in health care. Research suggests that combining varenicline with the nicotine patch, extending the duration of varenicline treatment, or both, may increase cessation effectiveness. Objective: To compare combinations of varenicline plus the nicotine or placebo patch vs combinations used for either 12 weeks (standard duration) or 24 weeks (extended duration). Design, Settings, and Participants: Double-blind, 2 × 2 factorial randomized clinical trial conducted from November 11, 2017, to July 9, 2020, at 1 research clinic in Madison, Wisconsin, and at 1 clinic in Milwaukee, Wisconsin. Of the 5836 adults asked to participate in the study, 1251 who smoked 5 cigarettes/d or more were randomized. Interventions: All participants received cessation counseling and were randomized to 1 of 4 medication groups: varenicline monotherapy for 12 weeks (n = 315), varenicline plus nicotine patch for 12 weeks (n = 314), varenicline monotherapy for 24 weeks (n = 311), or varenicline plus nicotine patch for 24 weeks (n = 311). Main Outcomes and Measures: The primary outcome was carbon monoxide-confirmed self-reported 7-day point prevalence abstinence at 52 weeks. Results: Among 1251 patients who were randomized (mean [SD] age, 49.1 [11.9] years; 675 [54.0%] women), 751 (60.0%) completed treatment and 881 (70.4%) provided final follow-up. For the primary outcome, there was no significant interaction between the 2 treatment factors of medication type and medication duration (odds ratio [OR], 1.03 [95% CI, 0.91 to 1.17]; P = .66). For patients randomized to 24-week vs 12-week treatment duration, the primary outcome occurred in 24.8% (154/622) vs 24.3% (153/629), respectively (risk difference, -0.4% [95% CI, -5.2% to 4.3%]; OR, 1.01 [95% CI, 0.89 to 1.15]). For patients randomized to varenicline combination therapy vs varenicline monotherapy, the primary outcome occurred in 24.3% (152/625) vs 24.8% (155/626), respectively (risk difference, 0.4% [95% CI, -4.3% to 5.2%]; OR, 0.99 [95% CI, 0.87 to 1.12]). Nausea occurrence ranged from 24.0% to 30.9% and insomnia occurrence ranged from 24.4% to 30.5% across the 4 groups. Conclusions and Relevance: Among adults smoking 5 cigarettes/d or more, there were no significant differences in 7-day point prevalence abstinence at 52 weeks among those treated with combined varenicline plus nicotine patch therapy vs varenicline monotherapy, or among those treated for 24 weeks vs 12 weeks. These findings do not support the use of combined therapy or of extended treatment duration. Trial Registration: ClinicalTrials.gov Identifier: NCT03176784.

Cancer Antigen 15-3/Mucin 1 Levels in CCTG MA.32: A Breast Cancer Randomized Trial of Metformin vs Placebo.

Background: Circulating levels of cancer antigen (CA) 15-3, a tumor marker and regulator of cellular metabolism, were reduced by metformin in a nonrandomized neoadjuvant study. We examined the effects of metformin (vs placebo) on CA 15-3 in participants of MA.32, a phase III randomized trial in early-stage breast cancer. Methods: A total of 3649 patients with T1-3, N0-3, M0 breast cancer were randomly assigned; pretreatment and 6-month on-treatment fasting plasma were centrally assayed for CA 15-3. Genomic DNA was analyzed for the rs11212617 single nucleotide polymorphism. Absolute and relative change of CA 15-3 (metformin vs placebo) were compared using Wilcoxon rank and t tests. Regression models adjusted for baseline differences and assessed key interactions. All statistical tests were 2-sided. Results: Mean (SD) age was 52.4 (10.0) years. The majority of patients had T2/3, node-positive, hormone receptor-positive, HER2-negative breast cancer treated with (neo)adjuvant chemotherapy and hormone therapy. Mean (SD) baseline CA 15-3 was 17.7 (7.6) and 18.0 (8.1 U/mL). At 6 months, CA 15-3 was statistically significantly reduced in metformin vs placebo arms (absolute geometric mean reduction in CA 15-3 = 7.7% vs 2.0%, P < .001; relative metformin: placebo level of CA 15-3 [adjusted for age, baseline body mass index, and baseline CA 15-3] = 0.94, 95% confidence interval = 0.92 to 0.96). This reduction was independent of tumor characteristics, perioperative systemic therapy, baseline body mass index, insulin, and the single nucleotide polymorphism status (all Ps > .11). Conclusions: Our observation that metformin reduces CA 15-3 by approximately 6% was corroborated in a large placebo-controlled randomized trial. The clinical implications of this reduction in CA 15-3 will be explored in upcoming efficacy analyses of breast cancer outcomes in MA.32.

Prevention of radiotherapy induced enteropathy by probiotics (PREP): protocol for a double-blind randomized placebo-controlled trial.

BACKGROUND: Radiation induced enteropathy is a common complication of radiotherapy for pelvic tumors and adversely affects patient quality of life. Probiotics are thought to restore bowel microflora to optimal levels and reinforce intestinal barrier capacity. Although probiotics are effective in the treatment of radiation induced enteropathy, less is known about their efficacy to prevent radiation induced enteropathy. METHODS: This double-blind randomized placebo-controlled study will investigate the efficacy of probiotics to prevent radiation-induced enteropathy in patients with gynecologic or urologic cancer who received pelvic radiotherapy. The study is designed to enroll 248 eligible patients, who will be randomized 1:1 to a probiotic or placebo group. Toxicities will be evaluated using Common Terminology Criteria for Adverse Events (CTCAE) v5.0. DISCUSSION: The primary aim of this study is to provide high level evidence for the ability of probiotics to prevent acute radiation induced enteropathy. The secondary aims are to determine the effects of probiotics on the incidence of chronic radiation induced enteropathy and the safety of probiotics in patients with gynecologic or urologic cancer. TRIAL REGISTRATION: ClinicalTrials.gov ( NCT03978949 , Registered on 7 June 2019).

Budesonide as induction therapy for incomplete microscopic colitis: A randomised, placebo-controlled multicentre trial.

BACKGROUND AND AIMS: Incomplete microscopic colitis (MCi) is a subtype of microscopic colitis (MC). Budesonide is recommended as a first-line treatment for MC. However, randomised trials on efficacy of treatment in MCi are missing. We therefore performed a randomised, placebo-controlled trial to evaluate budesonide as induction therapy for MCi. METHODS: Patients with active MCi were randomly assigned to either budesonide 9 mg once daily or placebo for 8 weeks in a double-blind, double-dummy design. The primary endpoint was clinical remission, defined as a mean of <3 stools/day and a mean of <1 watery stool/day in the 7 days before week 8. RESULTS: Due to insufficient patient recruitment, the trial was discontinued prematurely. The intention-to-treat analysis included 44 patients (21 budesonide and 23 placebo). The primary endpoint of clinical remission at week 8 was obtained by 71.4% on budesonide and 43.5% on placebo (p = 0.0582). All clinical secondary endpoints were in favour of budesonide. Budesonide decreased the number of soft or watery stools (16.3 vs. 7.7, p = 0.0186) and improved health-related quality of life for all four dimensions of the short health scale. Adverse events with a suspected relation to study drug were reported in one patient in the budesonide group and two patients in the placebo group. Neither serious nor severe adverse events occurred during the double-blind phase. CONCLUSIONS: Budesonide decreased the frequency of soft or watery stools and improved the patients' quality of life significantly in MCi, but the primary endpoint was not met due to the low sample size (type 2 error). Budesonide was safe and well tolerated during the 8-weeks treatment course.

Botulinum toxin type A for facial wrinkles.

BACKGROUND: Botulinum toxin type A (BontA) is the most frequent treatment for facial wrinkles, but its effectiveness and safety have not previously been assessed in a Cochrane Review. OBJECTIVES: To assess the effects of all commercially available botulinum toxin type A products for the treatment of any type of facial wrinkles. SEARCH METHODS: We searched the following databases up to May 2020: the Cochrane Skin Specialised Register, CENTRAL, MEDLINE, Embase, and LILACS. We also searched five trials registers, and checked the reference lists of included studies for further references to relevant randomised controlled trials (RCTs). SELECTION CRITERIA: We included RCTs with over 50 participants, comparing BontA versus placebo, other types of BontA, or fillers (hyaluronic acid), for treating facial wrinkles in adults. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Primary outcomes were participant assessment of success and major adverse events (AEs) (eyelid ptosis, eyelid sensory disorder, strabismus). Secondary outcomes included physician assessment of success; proportion of participants with at least one AE and duration of treatment effect. We used GRADE to assess the certainty of the evidence for each outcome. MAIN RESULTS: We included 65 RCTs, involving 14,919 randomised participants. Most participants were female, aged 18 to 65 years. All participants were outpatients (private office or day clinic). Study duration was between one week and one year. No studies were assessed as low risk of bias in all domains; the overall risk of bias was unclear for most studies. The most common comparator was placebo (36 studies). An active control was used in 19 studies. There were eight dose-ranging studies of onabotulinumtoxinA, and a small number of studies compared against fillers. Treatment was given in one cycle (54 studies), two cycles (three studies), or three or more cycles (eight studies). The treated regions were glabella (43 studies), crow's feet (seven studies), forehead (two studies), perioral (two studies), full face (one study), or more than two regions (nine studies). Most studies analysed moderate to severe wrinkles; mean duration of treatment was 20 weeks. The following results summarise the main comparisons, based on studies of one treatment cycle for the glabella. AEs were collected over the duration of these studies (over four to 24 weeks). Compared to placebo, onabotulinumtoxinA-20 U probably has a higher success rate when assessed by participants (risk ratio (RR) 19.45, 95% confidence interval (CI) 8.60 to 43.99; 575 participants; 4 studies; moderate-certainty evidence) or physicians (RR 17.10, 95% CI 10.07 to 29.05; 1339 participants; 7 studies; moderate-certainty evidence) at week four. Major AEs are probably higher with onabotulinumtoxinA-20 U (Peto OR 3.62, 95% CI 1.50 to 8.74; 1390 participants; 8 studies; moderate-certainty evidence), but there may be no difference in any AEs (RR 1.14, 95% CI 0.89 to 1.45; 1388 participants; 8 studies; low-certainty evidence). Compared to placebo, abobotulinumtoxinA-50 U has a higher participant-assessed success rate at week four (RR 21.22, 95% CI 7.40 to 60.56; 915 participants; 6 studies; high-certainty evidence); and probably has a higher physician-assessed success rate (RR 14.93, 95% CI 8.09 to 27.55; 1059 participants; 7 studies; moderate-certainty evidence). There are probably more major AEs with abobotulinumtoxinA-50 U (Peto OR 3.36, 95% CI 0.88 to 12.87; 1294 participants; 7 studies; moderate-certainty evidence). Any AE may be more common with abobotulinumtoxinA-50 U (RR 1.25, 95% CI 1.05 to 1.49; 1471 participants; 8 studies; low-certainty evidence). Compared to placebo, incobotulinumtoxinA-20 U probably has a higher participant-assessed success rate at week four (RR 66.57, 95% CI 13.50 to 328.28; 547 participants; 2 studies; moderate-certainty evidence), and physician-assessed success rate (RR 134.62, 95% CI 19.05 to 951.45; 547 participants; 2 studies; moderate-certainty evidence). Major AEs were not observed (547 participants; 2 studies; moderate-certainty evidence). There may be no difference between groups in any AEs (RR 1.17, 95% CI 0.90 to 1.53; 547 participants; 2 studies; low-certainty evidence). AbobotulinumtoxinA-50 U is no different to onabotulinumtoxinA-20 U in participant-assessed success rate (RR 1.00, 95% CI 0.92 to 1.08, 388 participants, 1 study, high-certainty evidence) and physician-assessed success rate (RR 1.01, 95% CI 0.95 to 1.06; 388 participants; 1 study; high-certainty evidence) at week four. Major AEs are probably more likely in the abobotulinumtoxinA-50 U group than the onabotulinumtoxinA-20 U group (Peto OR 2.65, 95% CI 0.77 to 9.09; 433 participants; 1 study; moderate-certainty evidence). There is probably no difference in any AE (RR 1.02, 95% CI 0.67 to 1.54; 492 participants; 2 studies; moderate-certainty evidence). IncobotulinumtoxinA-24 U may be no different to onabotulinumtoxinA-24 U in physician-assessed success rate at week four (RR 1.01, 95% CI 0.96 to 1.05; 381 participants; 1 study; low-certainty evidence) (participant assessment was not measured). One participant reported ptosis with onabotulinumtoxinA, but we are uncertain of the risk of AEs (Peto OR 0.02, 95% CI 0.00 to 1.77; 381 participants; 1 study; very low-certainty evidence). Compared to placebo, daxibotulinumtoxinA-40 U probably has a higher participant-assessed success rate (RR 21.10, 95% CI 11.31 to 39.34; 683 participants; 2 studies; moderate-certainty evidence) and physician-assessed success rate (RR 23.40, 95% CI 12.56 to 43.61; 683 participants; 2 studies; moderate-certainty evidence) at week four. Major AEs were not observed (716 participants; 2 studies; moderate-certainty evidence). There may be an increase in any AE with daxibotulinumtoxinA compared to placebo (RR 2.23, 95% CI 1.46 to 3.40; 716 participants; 2 studies; moderate-certainty evidence). Major AEs reported were mainly ptosis; BontA is also known to carry a risk of strabismus or eyelid sensory disorders. AUTHORS' CONCLUSIONS: BontA treatment reduces wrinkles within four weeks of treatment, but probably increases risk of ptosis. We found several heterogeneous studies (different types or doses of BontA, number of cycles, and different facial regions) hindering meta-analyses. The certainty of the evidence for effectiveness outcomes was high, low or moderate; for AEs, very low to moderate. Future RCTs should compare the most common BontA (onabotulinumtoxinA, abobotulinumtoxinA, incobotulinumtoxinA, daxibotulinumtoxinA, prabotulinumtoxinA) and evaluate long-term outcomes. There is a lack of evidence about the effects of multiple cycles of BontA, frequency of major AEs, duration of effect, efficacy of recently-approved BontA and comparisons with other treatments.

Interventions for preventing diarrhoea-associated haemolytic uraemic syndrome.

BACKGROUND: Haemolytic uraemic syndrome (HUS) is a common cause of acquired kidney failure in children and rarely in adults. The most important risk factor for development of HUS is a gastrointestinal infection by Shiga toxin-producing Escherichia coli (STEC). This review addressed the interventions aimed at secondary prevention of HUS in patients with diarrhoea who were infected with a bacteria that increase the risk of HUS. OBJECTIVES: Our objective was to evaluate evidence regarding secondary preventative strategies for HUS associated with STEC infections. In doing so, we sought to assess the effectiveness and safety of interventions as well as their potential to impact the morbidity and death associated with this condition. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies up to 12 November 2020 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: Studies were considered based on the methods, participants, and research goals. Only randomised controlled trials were considered eligible for inclusion. The participants of the studies were paediatric and adult patients with diarrhoeal illnesses due to STEC. The primary outcome of interest was incidence of HUS. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures as recommended by Cochrane. Summary estimates of effect were obtained using a random-effects model, and results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS: We identified four studies (536 participants) for inclusion that investigated four different interventions including antibiotics (trimethoprim-sulfamethoxazole), anti-Shiga toxin antibody-containing bovine colostrum, Shiga toxin binding agent (Synsorb Pk: a silicon dioxide-based agent), and a monoclonal antibody against Shiga toxin (urtoxazumab). The overall risk of bias was unclear for selection, performance and detection bias and low for attrition, reporting and other sources of bias. It was uncertain if trimethoprim-sulfamethoxazole reduced the incidence of HUS compared to no treatment (47 participants: RR 0.57, 95% CI 0.11-2.81, very low certainty evidence). Adverse events relative to this review, need for acute dialysis, neurological complication and death were not reported. There were no incidences of HUS in either the bovine colostrum group or the placebo group. It was uncertain if bovine colostrum caused more adverse events (27 participants: RR 0.92, 95% CI 0.42 to 2.03; very low certainty evidence). The need for acute dialysis, neurological complications or death were not reported. It is uncertain whether Synsorb Pk reduces the incidence of HUS compared to placebo (353 participants: RR 0.93, 95% CI 0.39 to 2.22; very low certainty evidence). Adverse events relevant to this review, need for acute dialysis, neurological complications or death were not reported. One study compared two doses of urtoxazumab (3.0 mg/kg and 1.0 mg/kg) to placebo. It is uncertain if either 3.0 mg/kg urtoxazumab (71 participants: RR 0.34, 95% CI 0.01 to 8.14) or 1.0 mg/kg urtoxazumab (74 participants: RR 0.95, 95% CI 0.79 to 1.13) reduced the incidence of HUS compared to placebo (very low certainty evidence). Low certainty evidence showed there may be little or no difference in the number of treatment-emergent adverse events with either 3.0 mg/kg urtoxazumab (71 participants: RR 1.00, 95% CI 0.84 to 1.18) or 1.0 mg/kg urtoxazumab (74 participants: RR 0.95, 95% CI 0.79 to 1.13) compared to placebo. There were 25 serious adverse events reported in 18 patients: 10 in the placebo group, and 9 and 6 serious adverse events in the 1.0 mg/kg and 3.0 mg/kg urtoxazumab groups, respectively. It is unclear how many patients experienced these adverse events in each group, and how many patients experienced more than one event. It is uncertain if either dose of urtoxazumab increased the risk of neurological complications or death (very low certainty evidence). Need for acute dialysis was not reported. AUTHORS' CONCLUSIONS: The included studies assessed antibiotics, bovine milk, and Shiga toxin inhibitor (Synsorb Pk) and monoclonal antibodies (Urtoxazumab) against Shiga toxin for secondary prevention of HUS in patients with diarrhoea due to STEC. However, no firm conclusions about the efficacy of these interventions can be drawn given the small number of included studies and the small sample sizes of those included studies. Additional studies, including larger multicentre studies, are needed to assess the efficacy of interventions to prevent development of HUS in patients with diarrhoea due to STEC infection.

Ivermectin for preventing and treating COVID-19.

BACKGROUND: Ivermectin, an antiparasitic agent used to treat parasitic infestations, inhibits the replication of viruses in vitro. The molecular hypothesis of ivermectin's antiviral mode of action suggests an inhibitory effect on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication in the early stages of infection. Currently, evidence on efficacy and safety of ivermectin for prevention of SARS-CoV-2 infection and COVID-19 treatment is conflicting. OBJECTIVES: To assess the efficacy and safety of ivermectin compared to no treatment, standard of care, placebo, or any other proven intervention for people with COVID-19 receiving treatment as inpatients or outpatients, and for prevention of an infection with SARS-CoV-2 (postexposure prophylaxis). SEARCH METHODS: We searched the Cochrane COVID-19 Study Register, Web of Science (Emerging Citation Index and Science Citation Index), medRxiv, and Research Square, identifying completed and ongoing studies without language restrictions to 26 May 2021. SELECTION CRITERIA: We included randomized controlled trials (RCTs) comparing ivermectin to no treatment, standard of care, placebo, or another proven intervention for treatment of people with confirmed COVID-19 diagnosis, irrespective of disease severity, treated in inpatient or outpatient settings, and for prevention of SARS-CoV-2 infection. Co-interventions had to be the same in both study arms.  We excluded studies comparing ivermectin to other pharmacological interventions with unproven efficacy. DATA COLLECTION AND ANALYSIS: We assessed RCTs for bias, using the Cochrane risk of bias 2 tool. The primary analysis excluded studies with high risk of bias. We used GRADE to rate the certainty of evidence for the following outcomes 1. to treat inpatients with moderate-to-severe COVID-19: mortality, clinical worsening or improvement, adverse events, quality of life, duration of hospitalization, and viral clearance; 2. to treat outpatients with mild COVID-19: mortality, clinical worsening or improvement, admission to hospital, adverse events, quality of life, and viral clearance; (3) to prevent SARS-CoV-2 infection: SARS-CoV-2 infection, development of COVID-19 symptoms, adverse events, mortality, admission to hospital, and quality of life. MAIN RESULTS: We found 14 studies with 1678 participants investigating ivermectin compared to no treatment, placebo, or standard of care. No study compared ivermectin to an intervention with proven efficacy. There were nine studies treating participants with moderate COVID-19 in inpatient settings and four treating mild COVID-19 cases in outpatient settings. One study investigated ivermectin for prevention of SARS-CoV-2 infection. Eight studies had an open-label design, six were double-blind and placebo-controlled. Of the 41 study results contributed by included studies, about one third were at overall high risk of bias.  Ivermectin doses and treatment duration varied among included studies.  We identified 31 ongoing and 18 studies awaiting classification until publication of results or clarification of inconsistencies. Ivermectin compared to placebo or standard of care for inpatient COVID-19 treatment We are uncertain whether ivermectin compared to placebo or standard of care reduces or increases mortality (risk ratio (RR) 0.60, 95% confidence interval (CI) 0.14 to 2.51; 2 studies, 185 participants; very low-certainty evidence) and clinical worsening up to day 28 assessed as need for invasive mechanical ventilation (IMV) (RR 0.55, 95% CI 0.11 to 2.59; 2 studies, 185 participants; very low-certainty evidence) or need for supplemental oxygen (0 participants required supplemental oxygen; 1 study, 45 participants; very low-certainty evidence), adverse events within 28 days (RR 1.21, 95% CI 0.50 to 2.97; 1 study, 152 participants; very low-certainty evidence), and viral clearance at day seven (RR 1.82, 95% CI 0.51 to 6.48; 2 studies, 159 participants; very low-certainty evidence). Ivermectin may have little or no effect compared to placebo or standard of care on clinical improvement up to 28 days (RR 1.03, 95% CI 0.78 to 1.35; 1 study; 73 participants; low-certainty evidence) and duration of hospitalization (mean difference (MD) -0.10 days, 95% CI -2.43 to 2.23; 1 study; 45 participants; low-certainty evidence). No study reported quality of life up to 28 days. Ivermectin compared to placebo or standard of care for outpatient COVID-19 treatment We are uncertain whether ivermectin compared to placebo or standard of care reduces or increases mortality up to 28 days (RR 0.33, 95% CI 0.01 to 8.05; 2 studies, 422 participants; very low-certainty evidence) and clinical worsening up to 14 days assessed as need for IMV (RR 2.97, 95% CI 0.12 to 72.47; 1 study, 398 participants; very low-certainty evidence) or non-IMV or high flow oxygen requirement (0 participants required non-IMV or high flow; 1 study, 398 participants; very low-certainty evidence). We are uncertain whether ivermectin compared to placebo reduces or increases viral clearance at seven days (RR 3.00, 95% CI 0.13 to 67.06; 1 study, 24 participants; low-certainty evidence). Ivermectin may have little or no effect compared to placebo or standard of care on the number of participants with symptoms resolved up to 14 days (RR 1.04, 95% CI 0.89 to 1.21; 1 study, 398 participants; low-certainty evidence) and adverse events within 28 days (RR 0.95, 95% CI 0.86 to 1.05; 2 studies, 422 participants; low-certainty evidence). None of the studies reporting duration of symptoms were eligible for primary analysis. No study reported hospital admission or quality of life up to 14 days. Ivermectin compared to no treatment for prevention of SARS-CoV-2 infection We found one study. Mortality up to 28 days was the only outcome eligible for primary analysis. We are uncertain whether ivermectin reduces or increases mortality compared to no treatment (0 participants died; 1 study, 304 participants; very low-certainty evidence). The study reported results for development of COVID-19 symptoms and adverse events up to 14 days that were included in a secondary analysis due to high risk of bias. No study reported SARS-CoV-2 infection, hospital admission, and quality of life up to 14 days. AUTHORS' CONCLUSIONS: Based on the current very low- to low-certainty evidence, we are uncertain about the efficacy and safety of ivermectin used to treat or prevent COVID-19. The completed studies are small and few are considered high quality. Several studies are underway that may produce clearer answers in review updates. Overall, the reliable evidence available does not support the use ivermectin for treatment or prevention of COVID-19 outside of well-designed randomized trials.

Laser therapy for dentinal hypersensitivity.

BACKGROUND: Dentinal hypersensitivity is characterized by short, sharp pain from exposed dentine that occurs in response to external stimuli such as cold, heat, osmotic, tactile or chemicals, and cannot be explained by any other form of dental defect or pathology. Laser therapy has become a commonly used intervention and might be effective for dentinal hypersensitivity. OBJECTIVES: To assess the effects of in-office employed lasers versus placebo laser, placebo agents or no treatment for relieving pain of dentinal hypersensitivity. SEARCH METHODS: Cochrane Oral Health's Information Specialist searched the following databases: Cochrane Oral Health's Trials Register (to 20 October 2020), the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library 2020, Issue 9), MEDLINE Ovid (1946 to 20 October 2020), Embase Ovid (1980 to 20 October 2020), CINAHL EBSCO (Cumulative Index to Nursing and Allied Health Literature; 1937 to 20 October 2020), and LILACS BIREME Virtual Health Library (Latin American and Caribbean Health Science Information database; from 1982 to 20 October 2020). Conference proceedings were searched via the ISI Web of Science and ZETOC, and OpenGrey was searched for grey literature. The US National Institutes of Health Ongoing Trials Register (ClinicalTrials.gov) and the World Health Organization International Clinical Trials Registry Platform were searched for ongoing trials. No restrictions were placed on the language or date of publication when searching the electronic databases. SELECTION CRITERIA: Randomized controlled trials (RCTs) in which in-office lasers were compared to placebo or no treatment on patients aged above 12 years with tooth hypersensitivity. DATA COLLECTION AND ANALYSIS: Two review authors independently and in duplicate screened the search results, extracted data, and assessed the risk of bias of the included studies. Disagreement was resolved by discussion. For continuous outcomes, we used mean differences (MD) and 95% confidence intervals (CI). We conducted meta-analyses only with studies of similar comparisons reporting the same outcome measures. We assessed the overall certainty of the evidence using GRADE. MAIN RESULTS: We included a total of 23 studies with 936 participants and 2296 teeth. We assessed five studies at overall low risk of bias, 13 at unclear, and five at high risk of bias. 17 studies contributed data to the meta-analyses. We divided the studies into six subgroups based on the type of laser and the primary outcome measure. We assessed the change in intensity of pain using quantitative pain scale (visual analogue scale (VAS) of 0 to 10 (no pain to worst possible pain)) when tested through air blast and tactile stimuli in three categories of short (0 to 24 hours), medium (more than 24 hours to 2 months), and long term (more than 2 months). Results demonstrated that compared to placebo or no treatment the application of all types of lasers combined may reduce pain intensity when tested through air blast stimuli at short term (MD -2.24, 95% CI -3.55 to -0.93; P = 0.0008; 13 studies, 978 teeth; low-certainty evidence), medium term (MD -2.46, 95% CI -3.57 to -1.35; P < 0.0001; 11 studies, 1007 teeth; very low-certainty evidence), and long term (MD -2.60, 95% CI -4.47 to -0.73; P = 0.006; 5 studies, 564 teeth; very low-certainty evidence). Similarly, compared to placebo or no treatment the application of all types of lasers combined may reduce pain intensity when tested through tactile stimuli at short term (MD -0.67, 95% CI -1.31 to -0.03; P = 0.04; 8 studies, 506 teeth; low-certainty evidence) and medium term (MD -1.73, 95% CI -3.17 to -0.30; P = 0.02; 9 studies, 591 teeth; very low-certainty evidence). However, there was insufficient evidence of a difference in pain intensity for all types of lasers when tested through tactile stimuli in the long term (MD -3.52, 95% CI -10.37 to 3.33; P = 0.31; 2 studies, 184 teeth; very low-certainty evidence). Most included studies assessed adverse events and reported that no obvious adverse events were observed during the trials. No studies investigated the impact of laser treatment on participants' quality of life. AUTHORS' CONCLUSIONS: Limited and uncertain evidence from meta-analyses suggests that the application of laser overall may improve pain intensity when tested through air blast or tactile stimuli at short, medium, or long term when compared to placebo/no treatment. Overall, laser therapy appears to be safe. Future studies including well-designed double-blinded RCTs are necessary to further investigate the clinical efficacy of lasers as well as their cost-effectiveness.

Stem cell therapy for dilated cardiomyopathy.

BACKGROUND: Stem cell therapy (SCT) has been proposed as an alternative treatment for dilated cardiomyopathy (DCM), nonetheless its effectiveness remains debatable. OBJECTIVES: To assess the effectiveness and safety of SCT in adults with non-ischaemic DCM. SEARCH METHODS: We searched CENTRAL in the Cochrane Library, MEDLINE, and Embase for relevant trials in November 2020. We also searched two clinical trials registers in May 2020. SELECTION CRITERIA: Eligible studies were randomized controlled trials (RCT) comparing stem/progenitor cells with no cells in adults with non-ischaemic DCM. We included co-interventions such as the administration of stem cell mobilizing agents. Studies were classified and analysed into three categories according to the comparison intervention, which consisted of no intervention/placebo, cell mobilization with cytokines, or a different mode of SCT. The first two comparisons (no cells in the control group) served to assess the efficacy of SCT while the third (different mode of SCT) served to complement the review with information about safety and other information of potential utility for a better understanding of the effects of SCT. DATA COLLECTION AND ANALYSIS: Two review authors independently screened all references for eligibility, assessed trial quality, and extracted data. We undertook a quantitative evaluation of data using random-effects meta-analyses. We evaluated heterogeneity using the I² statistic. We could not explore potential effect modifiers through subgroup analyses as they were deemed uninformative due to the scarce number of trials available. We assessed the certainty of the evidence using the GRADE approach. We created summary of findings tables using GRADEpro GDT. We focused our summary of findings on all-cause mortality, safety, health-related quality of life (HRQoL), performance status, and major adverse cardiovascular events. MAIN RESULTS: We included 13 RCTs involving 762 participants (452 cell therapy and 310 controls). Only one study was at low risk of bias in all domains. There were many shortcomings in the publications that did not allow a precise assessment of the risk of bias in many domains. Due to the nature of the intervention, the main source of potential bias was lack of blinding of participants (performance bias). Frequently, the format of the continuous data available was not ideal for use in the meta-analysis and forced us to seek strategies for transforming data in a usable format. We are uncertain whether SCT reduces all-cause mortality in people with DCM compared to no intervention/placebo (mean follow-up 12 months) (risk ratio (RR) 0.84, 95% confidence interval (CI) 0.54 to 1.31; I² = 0%; studies = 7, participants = 361; very low-certainty evidence). We are uncertain whether SCT increases the risk of procedural complications associated with cells injection in people with DCM (data could not be pooled; studies = 7; participants = 361; very low-certainty evidence). We are uncertain whether SCT improves HRQoL (standardized mean difference (SMD) 0.62, 95% CI 0.01 to 1.23; I² = 72%; studies = 5, participants = 272; very low-certainty evidence) and functional capacity (6-minute walk test) (mean difference (MD) 70.12 m, 95% CI -5.28 to 145.51; I² = 87%; studies = 5, participants = 230; very low-certainty evidence). SCT may result in a slight functional class (New York Heart Association) improvement (data could not be pooled; studies = 6, participants = 398; low-certainty evidence). None of the included studies reported major adverse cardiovascular events as defined in our protocol. SCT may not increase the risk of ventricular arrhythmia (data could not be pooled; studies = 8, participants = 504; low-certainty evidence). When comparing SCT to cell mobilization with granulocyte-colony stimulating factor (G-CSF), we are uncertain whether SCT reduces all-cause mortality (RR 0.46, 95% CI 0.16 to 1.31; I² = 39%; studies = 3, participants = 195; very low-certainty evidence). We are uncertain whether SCT increases the risk of procedural complications associated with cells injection (studies = 1, participants = 60; very low-certainty evidence). SCT may not improve HRQoL (MD 4.61 points, 95% CI -5.62 to 14.83; studies = 1, participants = 22; low-certainty evidence). SCT may improve functional capacity (6-minute walk test) (MD 140.14 m, 95% CI 119.51 to 160.77; I² = 0%; studies = 2, participants = 155; low-certainty evidence). None of the included studies reported MACE as defined in our protocol or ventricular arrhythmia. The most commonly reported outcomes across studies were based on physiological measures of cardiac function where there were some beneficial effects suggesting potential benefits of SCT in people with non-ischaemic DCM. However, it is unclear if this intermediate effects translates into clinical benefits for these patients. With regard to specific aspects related to the modality of cell therapy and its delivery, uncertainties remain as subgroup analyses could not be performed as planned, making it necessary to wait for the publication of several studies that are currently in progress before any firm conclusion can be reached. AUTHORS' CONCLUSIONS: We are uncertain whether SCT in people with DCM reduces the risk of all-cause mortality and procedural complications, improves HRQoL, and performance status (exercise capacity). SCT may improve functional class (NYHA), compared to usual care (no cells). Similarly, when compared to G-CSF, we are also uncertain whether SCT in people with DCM reduces the risk of all-cause mortality although some studies within this comparison observed a favourable effect that should be interpreted with caution. SCT may not improve HRQoL but may improve to some extent performance status (exercise capacity). Very low-quality evidence reflects uncertainty regarding procedural complications. These suggested beneficial effects of SCT, although uncertain due to the very low certainty of the evidence, are accompanied by favourable effects on some physiological measures of cardiac function. Presently, the most effective mode of administration of SCT and the population that could benefit the most is unclear. Therefore, it seems reasonable that use of SCT in people with DCM is limited to clinical research settings. Results of ongoing studies are likely to modify these conclusions.

Anthelmintics for people with neurocysticercosis.

BACKGROUND: Neurocysticercosis is a parasitic infection of the central nervous system by the larval stage of the pork tapeworm and is a common cause of seizures and epilepsy in endemic areas. Anthelmintics (albendazole or praziquantel) may be given alongside supportive treatment (antiepileptics/analgesia) with the aim of killing these larvae (cysticerci), with or without corticosteroid treatment. However, there are potential adverse effects of these drugs, and the cysticerci may eventually die without directed anthelminthic treatment. OBJECTIVES: To assess the effects of anthelmintics on people with neurocysticercosis. SEARCH METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, LILACS, the WHO ICTRP, and ClinicalTrials.gov, up to 21 October 2020. SELECTION CRITERIA: Randomized controlled trials comparing anthelmintics and supportive treatment (+/- corticosteroids) with supportive treatment alone (+/- corticosteroids) for people with neurocysticercosis. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the title and abstract of all articles identified by the search. We obtained full-text articles to confirm the eligibility of all studies that passed screening. One review author extracted data, which a second review author checked. Two review authors assessed the risk of bias of each trial and performed GRADE assessments. In cases of disagreement at consensus discussion stage between review authors, we consulted a third review author. We calculated risk ratios (RR) for dichotomous variables, with 95% confidence intervals (CIs) for pooled data from studies with similar interventions and outcomes. MAIN RESULTS: We included 16 studies in the review. Only two studies investigated praziquantel and did not report data in a format that could contribute to meta-analysis. Most results in this review are therefore applicable to albendazole versus placebo or no anthelmintic. The aggregate analysis across all participants with neurocysticercosis did not demonstrate a difference between groups in seizure recurrence, but heterogeneity was marked (RR 0.94, 95% CI 0.78 to 1.14; 10 trials, 1054 participants; I2 = 67%; low-certainty evidence). When stratified by participants with a single cyst or multiple cysts, pooled analysis suggests that albendazole probably improves seizure recurrence for participants with a single cyst (RR 0.61, 95% CI 0.4 to 0.91; 5 trials, 396 participants; moderate-certainty evidence). All studies contributing to this analysis recruited participants with non-viable, intraparenchymal cysts only, and most participants were children. We are uncertain whether or not albendazole reduces seizure recurrence in participants with multiple cysts, as the certainty of the evidence is very low, although the direction of effect is towards albendazole causing harm (RR 2.05, 95% CI 1.28 to 3.31; 2 trials, 321 participants; very low-certainty evidence). This analysis included a large study containing a highly heterogeneous population that received an assessment of unclear risk for multiple 'Risk of bias' domains. Regarding radiological outcomes, albendazole probably slightly improves the complete radiological clearance of lesions (RR 1.22, 95% CI 1.07 to 1.39; 13 trials, 1324 participants; moderate-certainty evidence) and the evolution of cysts (RR 1.27, 95% CI 1.10 to 1.47; 6 trials, 434 participants; moderate-certainty evidence). More adverse events appeared to be observed in participants treated with either albendazole or praziquantel compared to those receiving placebo or no anthelmintic. The most commonly reported side effects were headache, abdominal pain, and nausea/vomiting. AUTHORS' CONCLUSIONS: For participants with a single cyst, there was less seizure recurrence in the albendazole group compared to the placebo/no anthelmintic group. The studies contributing to this evidence only recruited participants with a non-viable intraparenchymal cyst. We are uncertain whether albendazole reduces seizure recurrence for participants with multiple cysts. We also found that albendazole probably increases radiological clearance and evolution of lesions. There were very few studies reporting praziquantel outcomes, and these findings apply to albendazole only.

Adjuvant Nivolumab versus Placebo in Muscle-Invasive Urothelial Carcinoma.

BACKGROUND: The role of adjuvant treatment in high-risk muscle-invasive urothelial carcinoma after radical surgery is not clear. METHODS: In a phase 3, multicenter, double-blind, randomized, controlled trial, we assigned patients with muscle-invasive urothelial carcinoma who had undergone radical surgery to receive, in a 1:1 ratio, either nivolumab (240 mg intravenously) or placebo every 2 weeks for up to 1 year. Neoadjuvant cisplatin-based chemotherapy before trial entry was allowed. The primary end points were disease-free survival among all the patients (intention-to-treat population) and among patients with a tumor programmed death ligand 1 (PD-L1) expression level of 1% or more. Survival free from recurrence outside the urothelial tract was a secondary end point. RESULTS: A total of 353 patients were assigned to receive nivolumab and 356 to receive placebo. The median disease-free survival in the intention-to-treat population was 20.8 months (95% confidence interval [CI], 16.5 to 27.6) with nivolumab and 10.8 months (95% CI, 8.3 to 13.9) with placebo. The percentage of patients who were alive and disease-free at 6 months was 74.9% with nivolumab and 60.3% with placebo (hazard ratio for disease recurrence or death, 0.70; 98.22% CI, 0.55 to 0.90; P<0.001). Among patients with a PD-L1 expression level of 1% or more, the percentage of patients was 74.5% and 55.7%, respectively (hazard ratio, 0.55; 98.72% CI, 0.35 to 0.85; P<0.001). The median survival free from recurrence outside the urothelial tract in the intention-to-treat population was 22.9 months (95% CI, 19.2 to 33.4) with nivolumab and 13.7 months (95% CI, 8.4 to 20.3) with placebo. The percentage of patients who were alive and free from recurrence outside the urothelial tract at 6 months was 77.0% with nivolumab and 62.7% with placebo (hazard ratio for recurrence outside the urothelial tract or death, 0.72; 95% CI, 0.59 to 0.89). Among patients with a PD-L1 expression level of 1% or more, the percentage of patients was 75.3% and 56.7%, respectively (hazard ratio, 0.55; 95% CI, 0.39 to 0.79). Treatment-related adverse events of grade 3 or higher occurred in 17.9% of the nivolumab group and 7.2% of the placebo group. Two treatment-related deaths due to pneumonitis were noted in the nivolumab group. CONCLUSIONS: In this trial involving patients with high-risk muscle-invasive urothelial carcinoma who had undergone radical surgery, disease-free survival was longer with adjuvant nivolumab than with placebo in the intention-to-treat population and among patients with a PD-L1 expression level of 1% or more. (Funded by Bristol Myers Squibb and Ono Pharmaceutical; CheckMate 274 ClinicalTrials.gov number, NCT02632409.).

Cilostazol for intermittent claudication.

BACKGROUND: Peripheral arterial disease (PAD) affects between 4% and 12% of people aged 55 to 70 years, and 20% of people over 70 years. A common complaint is intermittent claudication (exercise-induced lower limb pain relieved by rest). These patients have a three- to six-fold increase in cardiovascular mortality.  Cilostazol is a drug licensed for the use of improving claudication distance and, if shown to reduce cardiovascular risk, could offer additional clinical benefits. This is an update of the review first published in 2007. OBJECTIVES: To determine the effect of cilostazol on initial and absolute claudication distances, mortality and vascular events in patients with stable intermittent claudication. SEARCH METHODS: The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase, CINAHL, and AMED databases, and the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials registries, on 9 November 2020. SELECTION CRITERIA: We considered double-blind, randomised controlled trials (RCTs) of cilostazol versus placebo, or versus other drugs used to improve claudication distance in patients with stable intermittent claudication. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trials for selection and independently extracted data. Disagreements were resolved by discussion. We assessed the risk of bias with the Cochrane risk of bias tool. Certainty of the evidence was evaluated using GRADE. For dichotomous outcomes, we used odds ratios (ORs) with corresponding 95% confidence intervals (CIs) and for continuous outcomes we used mean differences (MDs) and 95% CIs. We pooled data using a fixed-effect model, or a random-effects model when heterogeneity was identified. Primary outcomes were initial claudication distance (ICD) and quality of life (QoL). Secondary outcomes were absolute claudication distance (ACD), revascularisation, amputation, adverse events and cardiovascular events. MAIN RESULTS: We included 16 double-blind, RCTs (3972 participants) comparing cilostazol with placebo, of which five studies also compared cilostazol with pentoxifylline. Treatment duration ranged from six to 26 weeks. All participants had intermittent claudication secondary to PAD. Cilostazol dose ranged from 100 mg to 300 mg; pentoxifylline dose ranged from 800 mg to 1200 mg. The certainty of the evidence was downgraded by one level for all studies because publication bias was strongly suspected. Other reasons for downgrading were imprecision, inconsistency and selective reporting. Cilostazol versus placebo Participants taking cilostazol had a higher ICD compared with those taking placebo (MD 26.49 metres; 95% CI 18.93 to 34.05; 1722 participants; six studies; low-certainty evidence). We reported QoL measures descriptively due to insufficient statistical detail within the studies to combine the results; there was a possible indication in improvement of QoL in the cilostazol treatment groups (low-certainty evidence). Participants taking cilostazol had a higher ACD compared with those taking placebo (39.57 metres; 95% CI 21.80 to 57.33; 2360 participants; eight studies; very-low certainty evidence). The most commonly reported adverse events were headache, diarrhoea, abnormal stools, dizziness, pain and palpitations. Participants taking cilostazol had an increased odds of experiencing headache compared to participants taking placebo (OR 2.83; 95% CI 2.26 to 3.55; 2584 participants; eight studies; moderate-certainty evidence).Very few studies reported on other outcomes so conclusions on revascularisation, amputation, or cardiovascular events could not be made. Cilostazol versus pentoxifylline There was no difference detected between cilostazol and pentoxifylline for improving walking distance, both in terms of ICD (MD 20.0 metres, 95% CI -2.57 to 42.57; 417 participants; one study; low-certainty evidence); and ACD (MD 13.4 metres, 95% CI -43.50 to 70.36; 866 participants; two studies; very low-certainty evidence). One study reported on QoL; the study authors reported no difference in QoL between the treatment groups (very low-certainty evidence). No study reported on revascularisation, amputation or cardiovascular events. Cilostazol participants had an increased odds of experiencing headache compared with participants taking pentoxifylline at 24 weeks (OR 2.20, 95% CI 1.16 to 4.17; 982 participants; two studies; low-certainty evidence). AUTHORS' CONCLUSIONS: Cilostazol has been shown to improve walking distance in people with intermittent claudication. However, participants taking cilostazol had higher odds of experiencing headache. There is insufficient evidence about the effectiveness of cilostazol for serious events such as amputation, revascularisation, and cardiovascular events. Despite the importance of QoL to patients, meta-analysis could not be undertaken because of differences in measures used and reporting. Very limited data indicated no difference between cilostazol and pentoxifylline for improving walking distance and data were too limited for any conclusions on other outcomes.