Antibiotics for treatment of leptospirosis.

BACKGROUND: Leptospirosis is a disease transmitted from animals to humans through water, soil, or food contaminated with the urine of infected animals, caused by pathogenic Leptospira species. Antibiotics are commonly prescribed for the management of leptospirosis. Despite the widespread use of antibiotic treatment for leptospirosis, there seems to be insufficient evidence to determine its effectiveness or to recommend antibiotic use as a standard practice. This updated systematic review evaluated the available evidence regarding the use of antibiotics in treating leptospirosis, building upon a previously published Cochrane review. OBJECTIVES: To evaluate the benefits and harms of antibiotics versus placebo, no intervention, or another antibiotic for the treatment of people with leptospirosis. SEARCH METHODS: We identified randomised clinical trials following standard Cochrane procedures. The date of the last search was 27 March 2023. SELECTION CRITERIA: We searched for randomised clinical trials of various designs that examined the use of antibiotics for treating leptospirosis. We did not impose any restrictions based on the age, sex, occupation, or comorbidities of the participants involved in the trials. Our search encompassed trials that evaluated antibiotics, regardless of the method of administration, dosage, and schedule, and compared them with placebo or no intervention, or compared different antibiotics. We included trials regardless of the outcomes reported. DATA COLLECTION AND ANALYSIS: During the preparation of this review, we adhered to the Cochrane methodology and used Review Manager. The primary outcomes were all-cause mortality and serious adverse events (nosocomial infection). Our secondary outcomes were quality of life, proportion of people with adverse events considered non-serious, and days of hospitalisation. To assess the risk of bias of the included trials, we used the RoB 2 tool, and for evaluating the certainty of evidence we used GRADEpro GDT software. We presented dichotomous outcomes as risk ratios (RR) and continuous outcomes as mean differences (MD), both accompanied by their corresponding 95% confidence intervals (CI). We used the random-effects model for all our main analyses and the fixed-effect model for sensitivity analyses. For our primary outcome analyses, we included trial data from the longest follow-up period. MAIN RESULTS: We identified nine randomised clinical trials comprising 1019 participants. Seven trials compared two intervention groups and two trials compared three intervention groups. Amongst the trials comparing antibiotics versus placebos, four trials assessed penicillin and one trial assessed doxycycline. In the trials comparing different antibiotics, one trial evaluated doxycycline versus azithromycin, one trial assessed penicillin versus doxycycline versus cefotaxime, and one trial evaluated ceftriaxone versus penicillin. One trial assessed penicillin with chloramphenicol and no intervention. Apart from two trials that recruited military personnel stationed in endemic areas or military personnel returning from training courses in endemic areas, the remaining trials recruited people from the general population presenting to the hospital with fever in an endemic area. The participants' ages in the included trials was 13 to 92 years. The treatment duration was seven days for penicillin, doxycycline, and cephalosporins; five days for chloramphenicol; and three days for azithromycin. The follow-up durations varied across trials, with three trials not specifying their follow-up periods. Three trials were excluded from quantitative synthesis; one reported zero events for a prespecified outcome, and two did not provide data for any prespecified outcomes. Antibiotics versus placebo or no intervention The evidence is very uncertain about the effect of penicillin versus placebo on all-cause mortality (RR 1.57, 95% CI 0.65 to 3.79; I2 = 8%; 3 trials, 367 participants; very low-certainty evidence). The evidence is very uncertain about the effect of penicillin or chloramphenicol versus placebo on adverse events considered non-serious (RR 1.05, 95% CI 0.35 to 3.17; I2 = 0%; 2 trials, 162 participants; very low-certainty evidence). None of the included trials assessed serious adverse events. Antibiotics versus another antibiotic The evidence is very uncertain about the effect of penicillin versus cephalosporin on all-cause mortality (RR 1.38, 95% CI 0.47 to 4.04; I2 = 0%; 2 trials, 348 participants; very low-certainty evidence), or versus doxycycline (RR 0.93, 95% CI 0.13 to 6.46; 1 trial, 168 participants; very low-certainty evidence). The evidence is very uncertain about the effect of cefotaxime versus doxycycline on all-cause mortality (RR 0.18, 95% CI 0.01 to 3.78; 1 trial, 169 participants; very low-certainty evidence). The evidence is very uncertain about the effect of penicillin versus doxycycline on serious adverse events (nosocomial infection) (RR 0.62, 95% CI 0.11 to 3.62; 1 trial, 168 participants; very low-certainty evidence) or versus cefotaxime (RR 1.01, 95% CI 0.15 to 7.02; 1 trial, 175 participants; very low-certainty evidence). The evidence is very uncertain about the effect of doxycycline versus cefotaxime on serious adverse events (nosocomial infection) (RR 1.01, 95% CI 0.15 to 7.02; 1 trial, 175 participants; very low-certainty evidence). The evidence is very uncertain about the effect of penicillin versus cefotaxime (RR 3.03, 95% CI 0.13 to 73.47; 1 trial, 175 participants; very low-certainty evidence), versus doxycycline (RR 2.80, 95% CI 0.12 to 67.66; 1 trial, 175 participants; very low-certainty evidence), or versus chloramphenicol on adverse events considered non-serious (RR 0.74, 95% CI 0.15 to 3.67; 1 trial, 52 participants; very low-certainty evidence). Funding Six of the nine trials included statements disclosing their funding/supporting sources and three trials did not mention funding source. Four of the six trials mentioning sources received funds from public or governmental sources or from international charitable sources, and the remaining two, in addition to public or governmental sources, received support in the form of trial drug supply directly from pharmaceutical companies. AUTHORS' CONCLUSIONS: As the certainty of evidence is very low, we do not know if antibiotics provide little to no effect on all-cause mortality, serious adverse events, or adverse events considered non-serious. There is a lack of definitive rigorous data from randomised trials to support the use of antibiotics for treating leptospirosis infection, and the absence of trials reporting data on clinically relevant outcomes further adds to this limitation.

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.

Anticoagulation versus placebo for heart failure in sinus rhythm.

BACKGROUND: People with chronic heart failure (HF) are at risk of thromboembolic events, including stroke, pulmonary embolism, and peripheral arterial embolism; coronary ischaemic events also contribute to the progression of HF. The use of long-term oral anticoagulation is established in certain populations, including people with HF and atrial fibrillation (AF), but there is wide variation in the indications and use of oral anticoagulation in the broader HF population. OBJECTIVES: To determine whether long-term oral anticoagulation reduces total deaths and stroke in people with heart failure in sinus rhythm. SEARCH METHODS: We updated the searches in CENTRAL, MEDLINE, and Embase in March 2020. We screened reference lists of papers and abstracts from national and international cardiovascular meetings to identify unpublished studies. We contacted relevant authors to obtain further data. We did not apply any language restrictions. SELECTION CRITERIA: Randomised controlled trials (RCT) comparing oral anticoagulants with placebo or no treatment in adults with HF, with treatment duration of at least one month. We made inclusion decisions in duplicate, and resolved any disagreements between review authors by discussion, or a third party. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion, and assessed the risks and benefits of antithrombotic therapy by calculating odds ratio (OR), accompanied by the 95% confidence intervals (CI). MAIN RESULTS: We identified three RCTs (5498 participants). One RCT compared warfarin, aspirin, and no antithrombotic therapy, the second compared warfarin with placebo in participants with idiopathic dilated cardiomyopathy, and the third compared rivaroxaban with placebo in participants with HF and coronary artery disease. We pooled data from the studies that compared warfarin with a placebo or no treatment. We are uncertain if there is an effect on all-cause death (OR 0.66, 95% CI 0.36 to 1.18; 2 studies, 324 participants; low-certainty evidence); warfarin may increase the risk of major bleeding events (OR 5.98, 95% CI 1.71 to 20.93, NNTH 17). 2 studies, 324 participants; low-certainty evidence). None of the studies reported stroke as an individual outcome. Rivaroxaban makes little to no difference to all-cause death compared with placebo (OR 0.99, 95% CI 0.87 to 1.13; 1 study, 5022 participants; high-certainty evidence). Rivaroxaban probably reduces the risk of stroke compared to placebo (OR 0.67, 95% CI 0.47 to 0.95; NNTB 101; 1 study, 5022 participants; moderate-certainty evidence), and probably increases the risk of major bleeding events (OR 1.65, 95% CI 1.17 to 2.33; NNTH 79; 1 study, 5008 participants; moderate-certainty evidence). AUTHORS' CONCLUSIONS: Based on the three RCTs, there is no evidence that oral anticoagulant therapy modifies mortality in people with HF in sinus rhythm. The evidence is uncertain if warfarin has any effect on all-cause death compared to placebo or no treatment, but it may increase the risk of major bleeding events. There is no evidence of a difference in the effect of rivaroxaban on all-cause death compared to placebo. It probably reduces the risk of stroke, but probably increases the risk of major bleedings. The available evidence does not support the routine use of anticoagulation in people with HF who remain in sinus rhythm.

Ginseng for erectile dysfunction.

BACKGROUND: Dietary supplements with ginseng, or ginseng alone, are widely used for a broad range of conditions, including erectile dysfunction. Ginseng is particularly popular in Asian countries. Individual studies assessing its effects are mostly small, of uneven methodological quality and have unclear results. OBJECTIVES: To assess the effects of ginseng on erectile dysfunction. SEARCH METHODS: We conducted systematic searches on multiple electronic databases, including CENTRAL, MEDLINE, Embase, CINAHL, AMED, and loco-regional databases of east Asia, from their inceptions to 30 January 2021 without restrictions on language and publication status. Handsearches included conference proceedings. SELECTION CRITERIA: We included randomized or quasi-randomized controlled trials that evaluated the use of any type of ginseng as a treatment for erectile dysfunction compared to placebo or conventional treatment. DATA COLLECTION AND ANALYSIS: Two authors independently classified studies and three authors independently extracted data and assessed risk of bias in the included studies. We rated the certainty of evidence according to the GRADE approach. MAIN RESULTS: We included nine studies with 587 men with mild to moderate erectile dysfunction, aged from 20 to 70 years old. The studies all compared ginseng to placebo. We found only short-term follow-up data (up to 12 weeks).  Primary outcomes Ginseng appears to have a trivial effect on erectile dysfunction when compared to placebo based on the Erectile Function Domain of the International Index of Erectile Function (IIEF)-15 instrument (scale: 1 to 30, higher scores imply better function; mean difference [MD] 3.52, 95% confidence interval [CI] 1.79 to 5.25; I² = 0%; 3 studies; low certainty evidence) assuming a minimal clinically important difference (MCID) of 4.  Ginseng probably also has a trivial effect on erectile function when compared to placebo based on the IIEF-5 instrument (scale: 1 to 25, higher scores imply better function; MD 2.39, 95% CI 0.89 to 3.88; I² = 0%; 3 studies; moderate certainty evidence) assuming a MCID of 5. Ginseng may have little to no effect on adverse events compared to placebo (risk ratio [RR] 1.45, 95% CI 0.69 to 3.03; I² = 0%; 7 studies; low certainty evidence). Based on 86 adverse events per 1000 men in the placebo group, this would correspond to 39 more adverse events per 1000 (95% CI 27 fewer to 174 more). Secondary outcomes Ginseng may improve men's self-reported ability to have intercourse (RR 2.55, 95% CI 1.76 to 3.69; I² = 23%; 6 studies; low certainty evidence). Based on 207 per 1000 men self-reporting the ability to have intercourse in the placebo group, this would correspond to 321 more men (95% CI 158 more to 558 more) per 1000 self-reporting the ability to have intercourse. Ginseng may have a trivial effect on men's satisfaction with intercourse based on the Intercourse Satisfaction Domain of the IIEF-15 (scale: 0 to 15, higher scores imply greater satisfaction; MD 1.19, 95% CI 0.41 to 1.97; I²=0%; 3 studies; low certainty evidence) based on a MCID of 25% improvement from baseline. It may also have a trivial effect on men's satisfaction with intercourse based on item 5 of the IIEF-5 (scale: 0 to 5, higher scores imply more satisfaction; MD 0.60, 95% CI 0.02 to 1.18; 1 study; low certainty evidence) based on a MCID of 25% improvement from baseline. No study reported quality of life as an outcome. We found no trial evidence to inform comparisons to other treatments for erectile dysfunction, such as phosphodiesterase-5 inhibitors. We were unable to conduct any predefined subgroup analyses. AUTHORS' CONCLUSIONS: Based on mostly low certainty evidence, ginseng may only have trivial effects on erectile function or satisfaction with intercourse compared to placebo when assessed using validated instruments. Ginseng may improve men's self-reported ability to have intercourse. It may have little to no effect on adverse events. We found no trial evidence comparing ginseng to other agents with a more established role in treating erectile dysfunction, such as phosphodiesterase-5 inhibitors.

Comparación del bloqueo periprostático con lidocaina y supositorio de diclofenac y placebo en la biopsia prostática / Comparison of periprostatic block with lidocaine and diclofenac suppository and placebo in prostate biopsy

El bloqueo del nervio peri prostático con lidocaína, proporciona un buen alivio del dolor en la realización de la biopsia prostática guiada por ultrasonido, pero el dolor post-procedimiento, puede llegar a ser significativo, la adición del supositorio de diclofenac, podría proporcionar alivio adicional. Se asignaron al azar pacientes en 2 grupos el grupo 1 bloqueo con lidocaína del plexo peri prostático + supositorio de diclofenac sódico y el grupo 2 bloqueo con lidocaína del plexo peri prostático + supositorio de placebo, realizando biopsia doble sextante, el dolor a varios intervalos después del procedimiento se registró en una escala visual análoga (EVA) de 0 a 10. Los 2 grupos fueron similares en cuanto a edad, volumen de próstata, antígeno prostático específico, diagnóstico histopatológico. Los pacientes que recibieron diclofenac tuvieron puntajes de dolor significativamente más bajos que los que recibieron placebo (2 frente a 3,35) p 0,02. La administración rectal de diclofenac antes de la realización de la biopsia de próstata es un procedimiento simple que alivia significativamente el dolor experimentado sin aumento en la morbilidad(AU)

The peri-prostatic nerve block with lidocaine, provides good pain relief in performing ultrasoundguided prostate biopsy, but the postprocedure pain can be significant, the addition of diclofenac suppository, could provide additional relief. Patients were randomly assigned in 2 groups to group 1 blockade with lidocaine of the prostatic peri plexus + suppository of diclofenac sodium and group 2 blockade with lidocaine of the prostatic peri plexus + placebo suppository, performing double sextant biopsy, pain at several intervals after the procedure was recorded on a visual analog scale (EVA) from 0 to 10. Thee 2 groups were similar in terms of age, prostate volume, prostate-specific antigen, histopathological diagnosis. Patients who received diclofenac had pain scores significantly lower than those who received placebo (2 vs. 3.35) p 0.02. Rectal administration of diclofenac before performing a prostate biopsy is a simple procedure that relieves significantly pain experienced without increased morbidity(AU)

Multicenter randomized phase II study comparing docetaxel plus curcumin versus docetaxel plus placebo in first-line treatment of metastatic castration-resistant prostate cancer.

BACKGROUND: Metastatic castration-resistant prostate cancer (mCRPC) patients have a poor prognosis, and curcumin is known to have antineoplastic properties. On the basis of previous phase I and phase II studies, we investigated whether the association of curcumin with docetaxel could improve prognosis among mCRPC patients. METHODS: A total of 50 mCRPC patients (included from June 2014 to July 2016) treated with docetaxel in association with oral curcumin (6 g/d for 7 days every 3 weeks) versus placebo were included in this double-blind, randomized, phase II study. The primary endpoint was to evaluate the time to progression. Among the secondary endpoints, compliance, overall survival, prostate-specific antigen (PSA) response, safety, curcumin absorption, and quality of life were investigated. An interim analysis was planned in the modified intention-to-treat population with data at 6 months (22 patients per arm). RESULTS: Despite good compliance and a verified absorption of curcumin, no difference was shown for our primary endpoint: progression-free survival (PFS) between the placebo and curcumin groups was, respectively, 5.3 months versus 3.7 months, p = 0.75. Similarly, no difference was observed for the secondary objectives: PSA response rate (p = 0.88), overall survival (p = 0.50), and quality of life (p = 0.49 and p = 0.47). CONCLUSION: Even though our previous studies and data in the literature seemed to support an association between curcumin and cancer therapies in order to improve patient outcome and prognosis, the results from this interim analysis clearly showed that adding curcumin to mCRPC patients' treatment strategies was not efficacious. The study was discontinued on the grounds of futility.

Second-generation antidepressants for treatment of seasonal affective disorder.

BACKGROUND: Seasonal affective disorder (SAD) is a seasonal pattern of recurrent depressive episodes that is often treated with second-generation antidepressants (SGAs), light therapy, or psychotherapy. OBJECTIVES: To assess the efficacy and safety of second-generation antidepressants (SGAs) for the treatment of seasonal affective disorder (SAD) in adults in comparison with placebo, light therapy, other SGAs, or psychotherapy. SEARCH METHODS: This is an update of an earlier review first published in 2011. We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2020, Issue 1) in the Cochrane Library (all years), Ovid MEDLINE, Embase, and PsycINFO (2011 to January 2020), together with the Cochrane Common Mental Disorders Controlled Trials Register (CCMDCTR) (all available years), for reports of randomised controlled trials (RCTs). We hand searched the reference lists of all included studies and other systematic reviews. We searched ClinicalTrials.gov for unpublished/ongoing trials. We ran a separate update search for reports of adverse events in the Ovid databases.  SELECTION CRITERIA: For efficacy we included RCTs of SGAs compared with other SGAs, placebo, light therapy, or psychotherapy in adult participants with SAD. For adverse events we also included non-randomised studies. DATA COLLECTION AND ANALYSIS: Two review authors independently screened abstracts and full-text publications against the inclusion criteria. Data extraction and 'Risk of bias' assessment were conducted individually. We pooled data for meta-analysis where the participant groups were similar, and the studies assessed the same treatments with the same comparator and had similar definitions of outcome measures over a similar duration of treatment. MAIN RESULTS: In this update we identified no new RCT on the effectiveness of SGAs in SAD patients. We included 2 additional single-arm observational studies that reported on adverse events of SGAs.  For efficacy we included three RCTs of between five and eight weeks' duration with a total of 204 participants. For adverse events we included two RCTs and five observational (non-randomised) studies of five to eight weeks' duration with a total of 249 participants. All participants met the DSM (Diagnostic and Statistical Manual of Mental Disorders) criteria for SAD. The average age ranged from 34 to 42 years, and the majority of participants were female (66% to 100%). Results from one trial with 68 participants showed that fluoxetine (20/36) was numerically superior to placebo (11/32) in achieving clinical response; however, the confidence interval (CI) included both a potential benefit as well as no benefit of fluoxetine (risk ratio (RR) 1.62, 95% CI 0.92 to 2.83, very low-certainty evidence). The number of adverse events was similar in both groups (very low-certainty evidence). Two trials involving a total of 136 participants compared fluoxetine versus light therapy. Meta-analysis showed fluoxetine and light therapy to be approximately equal in treating seasonal depression: RR of response 0.98 (95% CI 0.77 to 1.24, low-certainty evidence), RR of remission 0.81 (95% CI 0.39 to 1.71, very low-certainty evidence). The number of adverse events was similar in both groups (low-certainty evidence). We did not identify any eligible study comparing SGA with another SGA or with psychotherapy. Two RCTs and five non-randomised studies reported adverse event data on a total of 249 participants who received bupropion, fluoxetine, escitalopram, duloxetine, nefazodone, reboxetine, light therapy, or placebo. We were only able to obtain crude rates of adverse events, therefore caution is advised regarding interpretation of this information. Between 0% and 100% of participants who received an SGA suffered an adverse event, and between 0% and 25% of participants withdrew from the study due to adverse events. AUTHORS' CONCLUSIONS: Evidence for the effectiveness of SGAs is limited to one small trial of fluoxetine compared with placebo showing a non-significant effect in favour of fluoxetine, and two small trials comparing fluoxetine against light therapy suggesting equivalence between the two interventions. The lack of available evidence precluded us from drawing any overall conclusions on the use of SGAs for SAD. Further, larger RCTs are required to expand and strengthen the evidence base on this topic, and should also include comparisons with psychotherapy and other SGAs. Data on adverse events were sparse, and a comparative analysis was not possible. The data we obtained on adverse events is therefore not robust, and our confidence in the data is limited. Overall, up to 25% of participants treated with SGAs for SAD withdrew from the study early due to adverse events.

Interventions for cutaneous disease in systemic lupus erythematosus.

BACKGROUND: Lupus erythematosus is an autoimmune disease with significant morbidity and mortality. Cutaneous disease in systemic lupus erythematosus (SLE) is common. Many interventions are used to treat SLE with varying efficacy, risks, and benefits. OBJECTIVES: To assess the effects of interventions for cutaneous disease in SLE. SEARCH METHODS: We searched the following databases up to June 2019: the Cochrane Skin Specialised Register, CENTRAL, MEDLINE, Embase, Wiley Interscience Online Library, and Biblioteca Virtual em Saude (Virtual Health Library). We updated our search in September 2020, but these results have not yet been fully incorporated. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of interventions for cutaneous disease in SLE compared with placebo, another intervention, no treatment, or different doses of the same intervention. We did not evaluate trials of cutaneous lupus in people without a diagnosis of SLE. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Primary outcomes were complete and partial clinical response. Secondary outcomes included reduction (or change) in number of clinical flares; and severe and minor adverse events. We used GRADE to assess the quality of evidence. MAIN RESULTS: Sixty-one RCTs, involving 11,232 participants, reported 43 different interventions. Trials predominantly included women from outpatient clinics; the mean age range of participants was 20 to 40 years. Twenty-five studies reported baseline severity, and 22 studies included participants with moderate to severe cutaneous lupus erythematosus (CLE); duration of CLE was not well reported. Studies were conducted mainly in multi-centre settings. Most often treatment duration was 12 months. Risk of bias was highest for the domain of reporting bias, followed by performance/detection bias. We identified too few studies for meta-analysis for most comparisons. We limited this abstract to main comparisons (all administered orally) and outcomes. We did not identify clinical trials of other commonly used treatments, such as topical corticosteroids, that reported complete or partial clinical response or numbers of clinical flares. Complete clinical response Studies comparing oral hydroxychloroquine against placebo did not report complete clinical response. Chloroquine may increase complete clinical response at 12 months' follow-up compared with placebo (absence of skin lesions) (risk ratio (RR) 1.57, 95% confidence interval (CI) 0.95 to 2.61; 1 study, 24 participants; low-quality evidence). There may be little to no difference between methotrexate and chloroquine in complete clinical response (skin rash resolution) at 6 months' follow-up (RR 1.13, 95% CI 0.84 to 1.50; 1 study, 25 participants; low-quality evidence). Methotrexate may be superior to placebo with regard to complete clinical response (absence of malar/discoid rash) at 6 months' follow-up (RR 3.57, 95% CI 1.63 to 7.84; 1 study, 41 participants; low-quality evidence). At 12 months' follow-up, there may be little to no difference between azathioprine and ciclosporin in complete clinical response (malar rash resolution) (RR 0.83, 95% CI 0.46 to 1.52; 1 study, 89 participants; low-quality evidence). Partial clinical response Partial clinical response was reported for only one key comparison: hydroxychloroquine may increase partial clinical response at 12 months compared to placebo, but the 95% CI indicates that hydroxychloroquine may make no difference or may decrease response (RR 7.00, 95% CI 0.41 to 120.16; 20 pregnant participants, 1 trial; low-quality evidence). Clinical flares Clinical flares were reported for only two key comparisons: hydroxychloroquine is probably superior to placebo at 6 months' follow-up for reducing clinical flares (RR 0.49, 95% CI 0.28 to 0.89; 1 study, 47 participants; moderate-quality evidence). At 12 months' follow-up, there may be no difference between methotrexate and placebo, but the 95% CI indicates there may be more or fewer flares with methotrexate (RR 0.77, 95% CI 0.32 to 1.83; 1 study, 86 participants; moderate-quality evidence). Adverse events Data for adverse events were limited and were inconsistently reported, but hydroxychloroquine, chloroquine, and methotrexate have well-documented adverse effects including gastrointestinal symptoms, liver problems, and retinopathy for hydroxychloroquine and chloroquine and teratogenicity during pregnancy for methotrexate. AUTHORS' CONCLUSIONS: Evidence supports the commonly-used treatment hydroxychloroquine, and there is also evidence supporting chloroquine and methotrexate for treating cutaneous disease in SLE. Evidence is limited due to the small number of studies reporting key outcomes. Evidence for most key outcomes was low or moderate quality, meaning findings should be interpreted with caution. Head-to-head intervention trials designed to detect differences in efficacy between treatments for specific CLE subtypes are needed. Thirteen further trials are awaiting classification and have not yet been incorporated in this review; they may alter the review conclusions.

Rationale and design for the study of rivaroxaban to reduce thrombotic events, hospitalization and death in outpatients with COVID-19: The PREVENT-HD study.

BACKGROUND: COVID-19 is associated with both venous and arterial thrombotic complications. While prophylactic anticoagulation is now widely recommended for hospitalized patients with COVID-19, the effectiveness and safety of thromboprophylaxis in outpatients with COVID-19 has not been established. STUDY DESIGN: PREVENT-HD is a double-blind, placebo-controlled, pragmatic, event-driven phase 3 trial to evaluate the efficacy and safety of rivaroxaban in symptomatic outpatients with laboratory-confirmed COVID-19 at risk for thrombotic events, hospitalization, and death. Several challenges posed by the pandemic have necessitated innovative approaches to clinical trial design, start-up, and conduct. Participants are randomized in a 1:1 ratio, stratified by time from COVID-19 confirmation, to either rivaroxaban 10 mg once daily or placebo for 35 days. The primary efficacy end point is a composite of symptomatic venous thromboembolism, myocardial infarction, ischemic stroke, acute limb ischemia, non-central nervous system systemic embolization, all-cause hospitalization, and all-cause mortality. The primary safety end point is fatal and critical site bleeding according to the International Society on Thrombosis and Haemostasis definition. Enrollment began in August 2020 and is expected to enroll approximately 4,000 participants to yield the required number of end point events. CONCLUSIONS: PREVENT-HD is a pragmatic trial evaluating the efficacy and safety of the direct oral anticoagulant rivaroxaban in the outpatient setting to reduce major venous and arterial thrombotic events, hospitalization, and mortality associated with COVID-19.

The Influence of Specific Bioactive Collagen Peptides on Knee Joint Discomfort in Young Physically Active Adults: A Randomized Controlled Trial.

First evidence indicates that the supplementation of specific collagen peptides is associated with a significant reduction in activity-related joint pain in young adults. The purpose of the current investigation was to confirm the efficacy of the same collagen peptides in a comparable study population. In total, 180 active men and women aged between 18 and 30 years with exercise-related knee pain but no diagnosed joint disease completed the trial over a period of 12 weeks. Participants were randomly assigned to the group receiving 5 g of specific collagen peptides (CP-G) or to the placebo group (P-G). For the primary outcome, changes in pain during or after exercise from pre- to post-intervention were assessed by the participants using the Visual Analog Scale (VAS). These changes were additionally evaluated by the examining physician by means of anamnesis and physical examination of the affected knee joint. As secondary outcomes, pain under resting conditions and after 20 squats were compared between the study groups. In addition, the mobility of the knee joint and the use of alternative therapies (e.g., ointments or physiotherapy) were recorded. The supplementation of specific collagen peptides derived from type I collagen with a mean molecular weight of 3 kDa led to a significantly (p = 0.024) higher reduction of exercise-induced knee pain (-21.9 ± 18.3 mm) compared with the placebo group (-15.6 ± 18.5 mm). These findings were consistent with the physician's evaluation (-23.0 ± 19.2 mm vs. -14.6 ± 17.9 mm, p = 0.003). The decrease in pain under resting conditions and after squats did not significantly differ between the groups, as only a small number of participants suffered from pain under these conditions. Due to the clinically unremarkable baseline values, the mobility of the knee joint did not change significantly after the intervention. In conclusion, the current investigation confirmed that the oral intake of bioactive collagen peptides used in the current investigation led to a statistically significant reduction of activity-related joint pain in young active adults suffering from knee joint discomfort.

Tyrosine supplementation for phenylketonuria.

BACKGROUND: Phenylketonuria is an inherited disease for which the main treatment is the dietary restriction of the amino acid phenylalanine. The diet has to be initiated in the neonatal period to prevent or reduce mental handicap. However, the diet is very restrictive and unpalatable and can be difficult to follow. A deficiency of the amino acid tyrosine has been suggested as a cause of some of the neuropsychological problems exhibited in phenylketonuria. Therefore, this review aims to assess the efficacy of tyrosine supplementation for phenylketonuria. This is an update of previously published versions of this review. OBJECTIVES: To assess the effects of tyrosine supplementation alongside or instead of a phenylalanine-restricted diet for people with phenylketonuria, who commenced on diet at diagnosis and either continued on the diet or relaxed the diet later in life. To assess the evidence that tyrosine supplementation alongside, or instead of a phenylalanine-restricted diet improves intelligence, neuropsychological performance, growth and nutritional status, mortality rate and quality of life. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Trials Register which is comprised of references identified from comprehensive electronic database searches, handsearches of relevant journals and abstract books of conference proceedings. Additional studies were identified from handsearches of the Journal of Inherited Metabolic Disease (from inception in 1978 to 1998). The manufacturers of prescribable dietary products used in the treatment of phenylketonuria were also contacted for further references. Date of the most recent search of the Group's Inborn Errors of Metabolism Trials Register: 07 December 2020. SELECTION CRITERIA: All randomised or quasi-randomised trials investigating the use of tyrosine supplementation versus placebo in people with phenylketonuria in addition to, or instead of, a phenylalanine-restricted diet. People treated for maternal phenylketonuria were excluded. DATA COLLECTION AND ANALYSIS: Two authors independently assessed the trial eligibility, methodological quality and extracted the data. MAIN RESULTS: Six trials were found, of which three trials reporting the results of a total of 56 participants, were suitable for inclusion in the review. The blood tyrosine concentrations were significantly higher in the participants receiving tyrosine supplements than those in the placebo group, mean difference 23.46 (95% confidence interval 12.87 to 34.05). No significant differences were found between any of the other outcomes measured. The trials were assessed as having a low to moderate risk of bias across several domains. AUTHORS' CONCLUSIONS: From the available evidence no recommendations can be made about whether tyrosine supplementation should be introduced into routine clinical practice. Further randomised controlled studies are required to provide more evidence. However, given this is not an active area of research, we have no plans to update this review in the future.

Randomized, double-blind, placebo-controlled clinical trial studying the effects of Turmeric in combination with mefenamic acid in patients with primary dysmenorrhoea.

Primary dysmenorrhea (PDM) is one of the common complaints in women. This study aimed to assess the effects of turmeric and mefenamic acid and a combination compared with placebo on PDM. This clinical trial was conducted on dormitory students with PDM. Subjects completed the visual analog scale (VAS) before randomization. One hundred twenty-eight patients, randomly assigned to one of following groups: Turmeric group (n=32), mefenamic acid group (n=32), turmeric and mefenamic acid group (n=32), and placebo group (n=32). Turmeric and mefenamic acid were administrated in 500mg and 250mg, respectively. Pain severity was assessed in the baseline and the end line by VAS. Statistical analysis was performed using SPSS software. The combination of turmeric and mefenamic acid, dramatically, alleviated pain in comparison to other groups. Our results illustrated that combination of turmeric and mefenamic acid would be better in pain alleviation in PDM.

Interventions for leg cramps in pregnancy.

BACKGROUND: Leg cramps are a common problem in pregnancy. Various interventions have been used to treat them, including drug, electrolyte and vitamin therapies, and non-drug therapies. This Cochrane Review is an update of a review first published in 2015. OBJECTIVES: To assess the effectiveness and safety of different interventions for treating leg cramps in pregnancy. SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (25 September 2019), and reference lists of retrieved studies. SELECTION CRITERIA: Randomised controlled trials (RCTs) of any intervention for the treatment of leg cramps in pregnancy compared with placebo, no treatment or other treatments. Quinine was excluded for its known adverse effects. Cluster-RCTS were eligible for inclusion. Quasi-RCTs and cross-over studies were excluded. DATA COLLECTION AND ANALYSIS: Three review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. The certainty of the evidence was assessed using the GRADE approach. MAIN RESULTS: We included eight small studies (576 women). Frequency of leg cramps was our primary outcome and secondary outcomes included intensity and duration of leg cramps, adverse outcomes for mother and baby and health-related quality of life. Overall, the studies were at low or unclear risk of bias. Outcomes were reported in different ways, precluding the use of meta-analysis and thus data were limited to single trials. Certainty of evidence was assessed as either low or very-low due to serious limitations in study design and imprecision. Oral magnesium versus placebo/no treatment The results for frequency of leg cramps were inconsistent. In one study, results indicated that women may be more likely to report never having any leg cramps after treatment (risk ratio (RR) 5.66, 95% confidence interval (CI) 1.35 to 23.68, 1 trial, 69 women, low-certainty evidence); whilst fewer women may report having twice-weekly leg cramps (RR 0.29, 95% CI 0.11 to 0.80, 1 trial, 69 women); and more women may report a 50% reduction in number of leg cramps after treatment (RR 1.42, 95% CI 1.09 to 1.86, 1 trial, 86 women, low-certainty evidence). However, other findings indicated that magnesium may make little to no difference in the frequency of leg cramps during differing periods of treatment. For pain intensity, again results were inconsistent. Findings indicated that magnesium may make little or no difference: mean total pain score (MD 1.80, 95% CI -3.10 to 6.70, 1 trial, 38 women, low-certainty evidence). In another study the evidence was very uncertain about the effects of magnesium on pain intensity as measured in terms of a 50% reduction in pain. Findings from another study indicated that magnesium may reduce pain intensity according to a visual analogue scale (MD -17.50, 95% CI -34.68 to -0.32,1 trial, 69 women, low-certainty evidence). For all other outcomes examined there may be little or no difference: duration of leg cramps (low to very-low certainty); composite outcome - symptoms of leg cramps (very-low certainty); and for any side effects, including nausea and diarrhoea (low certainty). Oral calcium versus placebo/no treatment The evidence is unclear about the effect of calcium supplements on frequency of leg cramps because the certainty was found to be very low: no leg cramps after treatment (RR 8.59, 95% CI 1.19 to 62.07, 1 study, 43 women, very low-certainty evidence). In another small study, the findings indicated that the mean frequency of leg cramps may be slightly lower with oral calcium (MD -0.53, 95% CI -0.72 to -0.34; 1 study, 60 women; low certainty). Oral vitamin B versus no treatment One small trial, did not report on frequency of leg cramps individually, but showed that oral vitamin B supplements may reduce the frequency and intensity (composite outcome) of leg cramps (RR 0.29, 95% CI 0.11 to 0.73; 1 study, 42 women). There were no data on side effects. Oral calcium versus oral vitamin C The evidence is very uncertain about the effect of calcium on frequency of leg cramps after treatment compared with vitamin C (RR 1.33, 95% CI 0.53 to 3.38, 1 study, 60 women, very low-certainty evidence). Oral vitamin D versus placebo One trial (84 women) found vitamin D may make little or no difference to frequency of leg cramps compared with placebo at three weeks (MD 2.06, 95% CI 0.58 to 3.54); or six weeks after treatment (MD 1.53, 95% CI 0.12 to 2.94). Oral calcium-vitamin D versus placebo One trial (84 women) found oral calcium-vitamin D may make little or no difference to frequency of leg cramps compared with placebo after treatment at three weeks (MD -0.30, 95% CI -1.55 to 0.95); and six weeks (MD 0.03, 95% CI -1.3 to 1.36). Oral calcium-vitamin D versus vitamin D One trial (84 women) found oral calcium-vitamin D may make little or no difference to frequency of leg cramps compared with vitamin D after treatment at three weeks (MD -1.35, 95% CI -2.84 to 0.14); and six weeks after treatment (MD -1.10, 95% CI -2.69 to 0.49). AUTHORS' CONCLUSIONS: It is unclear from the evidence reviewed whether any of the interventions provide an effective treatment for leg cramps. This is primarily due to outcomes being measured and reported in different, incomparable ways so that data could not be pooled. The certainty of evidence was found to be low or very-low due to design limitations and trials being too small to address the question satisfactorily. Adverse outcomes were not reported, other than side effects for magnesium versus placebo/no treatment. It is therefore not possible to assess the safety of these interventions. The inconsistency in the measurement and reporting of outcomes meant that meta-analyses could not be carried out. The development of a core outcome set for measuring the frequency, intensity and duration of leg cramps would address these inconsistencies and mean these outcomes could be investigated effectively in the future.

Effects of neuro-adaptive electrostimulation therapy on pain and disability in fibromyalgia: A prospective, randomized, double-blind study.

BACKGROUND: To evaluate the effectiveness of non-invasive neuro-adaptive electrostimulation (NAE) therapy for treating chronic pain and disability in patients with fibromyalgia. METHOD/DESIGN: A prospective, randomized, sham-controlled study was conducted in 37 women with fibromyalgia. Participants were randomly assigned to receive either active NAE (n = 20) or stimulation with a sham device (n = 17). Participants in the experimental arm received eight 30-minute sessions over 4 weeks (2 sessions per week). The sham group received eight 30-minute sessions of sham stimulation. Therapeutic effects on pain relief, disability, and quality of life were evaluated using outcome measures at baseline, at 4 weeks, and after 3 months' follow-up. RESULTS: The findings indicated a significant reduction of pain in the active NAE group compared with the sham group immediately post-intervention, with a difference on the Visual Analog Scale (VAS) of 3 points (P = .001), and at 3 months' follow-up (P = .02). There were significant intragroup differences between the groups (P < .05) at post-intervention. After the intervention, both groups presented significant reductions on the Fibromyalgia Impact Questionnaire (FIQ) with respect to baseline (P = .004), but not at the 3-month follow-up. In the conditioned pain modulation (CPM) in thumb variable we found significant differences between the groups at the 3-month follow-up (P = .02). No additional benefits for conditioned pain modulation and disability were observed between groups at the 3-month follow-up. Furthermore, anxiety/depression and catastrophizing improved in both groups, but no differences between groups were found. CONCLUSIONS: In this fibromyalgia cohort, NAE therapy significantly improved pain and quality of life at 4 weeks, but not at 3-month follow-up, compared with the sham stimulation group. Future investigations are needed in larger populations to confirm these findings.

Magnesium sulphate for treating acute bronchiolitis in children up to two years of age.

BACKGROUND: Acute bronchiolitis is a significant burden on children, their families and healthcare facilities. It mostly affects children younger than two years of age. Treatment involves adequate hydration, humidified oxygen supplementation, and nebulisation of medications, such as salbutamol, epinephrine, and hypertonic saline. The effectiveness of magnesium sulphate for acute bronchiolitis is unclear. OBJECTIVES: To assess the effects of magnesium sulphate in acute bronchiolitis in children up to two years of age. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, LILACS, CINAHL, and two trials registries to 30 April 2020. We contacted trial authors to identify additional studies. We searched conference proceedings and reference lists of retrieved articles. Unpublished and published studies were eligible for inclusion. SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs, comparing magnesium sulphate, alone or with another treatment, with placebo or another treatment, in children up to two years old with acute bronchiolitis. Primary outcomes were time to recovery, mortality, and adverse events. Secondary outcomes were duration of hospital stay, clinical severity score at 0 to 24 hours and 25 to 48 hours after treatment, pulmonary function test, hospital readmission within 30 days, duration of mechanical ventilation, and duration of intensive care unit stay. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. We used GRADE methods to assess the certainty of the evidence. MAIN RESULTS: We included four RCTs (564 children). One study received funding from a hospital and one from a university; two studies did not report funding sources. Comparator interventions differed among all four trials. Studies were conducted in Qatar, Turkey, Iran, and India. We assessed two studies to be at an overall low risk of bias, and two to be at unclear risk of bias, overall. The certainty of the evidence for all outcomes and comparisons was very low except for one: hospital re-admission rate within 30 days of discharge for magnesium sulphate versus placebo. None of the studies measured time to recovery, duration of mechanical ventilation, duration of intensive care unit stay, or pulmonary function. There were no events of mortality or adverse effects for magnesium sulphate compared with placebo (1 RCT, 160 children). The effects of magnesium sulphate on clinical severity are uncertain (at 0 to 24 hours: mean difference (MD) on the Wang score 0.13, 95% confidence interval (CI) -0.28 to 0.54; and at 25 to 48 hours: MD on the Wang score -0.42, 95% CI -0.84 to -0.00). Magnesium sulphate may increase hospital re-admission rate within 30 days of discharge (risk ratio (RR) 3.16, 95% CI 1.20 to 8.27; 158 children; low-certainty evidence). None of our primary outcomes were measured for magnesium sulphate compared with hypertonic saline (1 RCT, 220 children). Effects were uncertain on the duration of hospital stay in days (MD 0.00, 95% CI -0.28 to 0.28), and on clinical severity on the Respiratory Distress Assessment Instrument (RDAI) score at 25 to 48 hours (MD 0.10, 95% CI -0.39 to 0.59). There were no events of mortality or adverse effects for magnesium sulphate, with or without salbutamol, compared with salbutamol (1 RCT, 57 children). Effects on the duration of hospital stay were uncertain (magnesium sulphate: 24 hours (95% CI 25.8 to 47.4), magnesium sulphate + salbutamol: 20 hours (95% CI 15.3 to 39.0), and salbutamol: 24 hours (95% CI 23.4 to 76.9)). None of our primary outcomes were measured for magnesium sulphate + epinephrine compared with no treatment or normal saline + epinephrine (1 RCT,120 children). Effects were uncertain for the duration of hospital stay in hours (MD -0.40, 95% CI -3.94 to 3.14), and for RDAI scores (0 to 24 hours: MD -0.20, 95% CI -1.06 to 0.66; and 25 to 48 hours: MD -0.90, 95% CI -1.75 to -0.05). AUTHORS' CONCLUSIONS: There is insufficient evidence to establish the efficacy and safety of magnesium sulphate for treating children up to two years of age with acute bronchiolitis. No evidence was available for time to recovery, duration of mechanical ventilation and intensive care unit stay, or pulmonary function. There was no information about adverse events for some comparisons. Well-designed RCTs to assess the effects of magnesium sulphate for children with acute bronchiolitis are needed. Important outcomes, such as time to recovery and adverse events should be measured.

Souvenaid for Alzheimer's disease.

BACKGROUND: Souvenaid is a dietary supplement with a patented composition (Fortasyn Connect™)which is intended to be used by people with Alzheimer's disease (AD). It has been designed to support the formation and function of synapses in the brain, which are thought to be strongly correlated with cognitive function. If effective, it might improve symptoms of Alzheimer's disease and also prevent the progression from prodromal Alzheimer's disease to dementia. We sought in this review to examine the evidence for this proposition. OBJECTIVES: To assess the effects of Souvenaid on incidence of dementia, cognition, functional performance, and safety in people with Alzheimer's disease. SEARCH METHODS: We searched ALOIS, i.e. the specialised register of the Cochrane Dementia and Cognitive Improvement Group, MEDLINE (Ovid SP), Embase (Ovid SP), PsycINFO (Ovid SP), Web of Science (ISI Web of Science), Cinahl (EBSCOhost), Lilacs (BIREME), and clinical trials registries up to 24 June 2020. We also reviewed citations of reference lists of landmark papers, reviews, and included studies for additional studies and assessed their suitability for inclusion in the review. SELECTION CRITERIA: We included randomised, placebo-controlled trials which evaluated Souvenaid in people diagnosed with mild cognitive impairment (MCI) due to AD (also termed prodromal AD) or with dementia due to AD, and with a treatment duration of at least 16 weeks. DATA COLLECTION AND ANALYSIS: Our primary outcome measures were incidence of dementia, global and specific cognitive function, functional performance, combined cognitive-functional outcomes and adverse events. We selected studies, extracted data, assessed the quality of trials and intended to conduct meta-analyses according to the Cochrane Handbook for Systematic Reviews of Interventions. We rated the quality of the evidence using the GRADE approach. We present all outcomes grouped by stage of AD. MAIN RESULTS: We included three randomised, placebo-controlled trials investigating Souvenaid in 1097 community-dwelling participants with Alzheimer's disease. One study each included participants with prodromal AD, mild AD dementia and mild-to-moderate AD dementia. We rated the risks of bias of all trials as low. One study (in prodromal AD) was funded by European grants. The other two studies were funded by the manufacturer of Souvenaid. One trial investigated the incidence of dementia in people with prodromal AD at baseline, and found little to no difference between the Souvenaid group and the placebo group after 24 months (RR 1.09, 95% CI 0.82 to 1.43; 1 trial, 311 participants; moderate quality of evidence). In prodromal AD, and in mild and mild-to-moderate Alzheimer's disease dementia, Souvenaid probably results in little or no difference in global or specific cognitive functions (moderate quality of evidence). Everyday function, or the ability to perform activities of daily living, were measured in mild and mild-to-moderate AD dementia. Neither study found evidence of a difference between the groups after 24 weeks of treatment (moderate quality of evidence). Two studies investigated combined cognitive-functional outcomes with the Clinical Dementia Rating Sum of Boxes and observed conflicting results. Souvenaid probably results in slight improvement, which is below estimates of meaningful change, in participants with prodromal Alzheimer's disease after 24 months (moderate quality of evidence), but probably has little to no effect in mild-to-moderate Alzheimer's disease dementia after 24 weeks (moderate quality of evidence). Adverse effects observed were low in all trials, and the available data were insufficient to determine any connection with Souvenaid. AUTHORS' CONCLUSIONS: Two years of treatment with Souvenaid probably does not reduce the risk of progression to dementia in people with prodromal AD. There is no convincing evidence that Souvenaid affects other outcomes important to people with AD in the prodromal stage or mild-to-moderate stages of dementia. Conflicting evidence on combined cognitive-functional outcomes in prodromal AD and mild AD dementia warrants further investigation. Adverse effects of Souvenaid seem to be uncommon, but the evidence synthesised in this review does not permit us to make a definitive statement on the long-term tolerability of Souvenaid. The effects of Souvenaid in more severe AD dementia or in people with AD at risk of nutritional deficiencies remain unclear.

Pioglitazone for prevention or delay of type 2 diabetes mellitus and its associated complications in people at risk for the development of type 2 diabetes mellitus.

BACKGROUND: The term prediabetes is used to describe a population with an elevated risk of developing type 2 diabetes mellitus (T2DM). With projections of an increase in the incidence of T2DM, prevention or delay of the disease and its complications is paramount. It is currently unknown whether pioglitazone is beneficial in the treatment of people with increased risk of developing T2DM. OBJECTIVES: To assess the effects of pioglitazone for prevention or delay of T2DM and its associated complications in people at risk of developing T2DM. SEARCH METHODS: We searched CENTRAL, MEDLINE, Chinese databases, ICTRP Search Portal and ClinicalTrials.gov. We did not apply any language restrictions. Further, we investigated the reference lists of all included studies and reviews. We tried to contact all study authors. The date of the last search of databases was November 2019 (March 2020 for Chinese databases). SELECTION CRITERIA: We included randomised controlled trials (RCTs) with a minimum duration of 24 weeks, and participants diagnosed with intermediate hyperglycaemia with no concomitant diseases, comparing pioglitazone as monotherapy or part of dual therapy with other glucose-lowering drugs, behaviour-changing interventions, placebo or no intervention. DATA COLLECTION AND ANALYSIS: Two review authors independently screened abstracts, read full-text articles and records, assessed risk of bias and extracted data. We performed meta-analyses with a random-effects model and calculated risk ratios (RRs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes, with 95% confidence intervals (CIs) for effect estimates. We evaluated the certainty of the evidence with the GRADE. MAIN RESULTS: We included 27 studies with a total of 4186 randomised participants. The size of individual studies ranged between 43 and 605 participants and the duration varied between 6 and 36 months. We judged none of the included studies as having low risk of bias across all 'Risk of bias' domains. Most studies identified people at increased risk of T2DM by impaired fasting glucose or impaired glucose tolerance (IGT), or both. Our main outcome measures were all-cause mortality, incidence of T2DM, serious adverse events (SAEs), cardiovascular mortality, nonfatal myocardial infarction or stroke (NMI/S), health-related quality of life (QoL) and socioeconomic effects. The following comparisons mostly reported only a fraction of our main outcome set. Three studies compared pioglitazone with metformin. They did not report all-cause and cardiovascular mortality, NMI/S, QoL or socioeconomic effects. Incidence of T2DM was 9/168 participants in the pioglitazone groups versus 9/163 participants in the metformin groups (RR 0.98, 95% CI 0.40 to 2.38; P = 0.96; 3 studies, 331 participants; low-certainty evidence). No SAEs were reported in two studies (201 participants; low-certainty evidence). One study compared pioglitazone with acarbose. Incidence of T2DM was 1/50 participants in the pioglitazone group versus 2/46 participants in the acarbose group (very low-certainty evidence). No participant experienced a SAE (very low-certainty evidence).One study compared pioglitazone with repaglinide. Incidence of T2DM was 2/48 participants in the pioglitazone group versus 1/48 participants in the repaglinide group (low-certainty evidence). No participant experienced a SAE (low-certainty evidence). One study compared pioglitazone with a personalised diet and exercise consultation. All-cause and cardiovascular mortality, NMI/S, QoL or socioeconomic effects were not reported. Incidence of T2DM was 2/48 participants in the pioglitazone group versus 5/48 participants in the diet and exercise consultation group (low-certainty evidence). No participant experienced a SAE (low-certainty evidence). Six studies compared pioglitazone with placebo. No study reported on QoL or socioeconomic effects. All-cause mortality was 5/577 participants the in the pioglitazone groups versus 2/579 participants in the placebo groups (Peto odds ratio 2.38, 95% CI 0.54 to 10.50; P = 0.25; 4 studies, 1156 participants; very low-certainty evidence). Incidence of T2DM was 80/700 participants in the pioglitazone groups versus 131/695 participants in the placebo groups (RR 0.40, 95% CI 0.17 to 0.95; P = 0.04; 6 studies, 1395 participants; low-certainty evidence). There were 3/93 participants with SAEs in the pioglitazone groups versus 1/94 participants in the placebo groups (RR 3.00, 95% CI 0.32 to 28.22; P = 0.34; 2 studies, 187 participants; very low-certainty evidence). However, the largest study for this comparison did not distinguish between serious and non-serious adverse events. This study reported that 121/303 (39.9%) participants in the pioglitazone group versus 151/299 (50.5%) participants in the placebo group experienced an adverse event (P = 0.03). One study observed cardiovascular mortality in 2/181 participants in the pioglitazone group versus 0/186 participants in the placebo group (RR 5.14, 95% CI 0.25 to 106.28; P = 0.29; very low-certainty evidence). One study observed NMI in 2/303 participants in the pioglitazone group versus 1/299 participants in the placebo group (RR 1.97: 95% CI 0.18 to 21.65; P = 0.58; very low-certainty evidence). Twenty-one studies compared pioglitazone with no intervention. No study reported on cardiovascular mortality, NMI/S, QoL or socioeconomic effects. All-cause mortality was 11/441 participants in the pioglitazone groups versus 12/425 participants in the no-intervention groups (RR 0.85, 95% CI 0.38 to 1.91; P = 0.70; 3 studies, 866 participants; very low-certainty evidence). Incidence of T2DM was 60/1034 participants in the pioglitazone groups versus 197/1019 participants in the no-intervention groups (RR 0.31, 95% CI 0.23 to 0.40; P < 0.001; 16 studies, 2053 participants; moderate-certainty evidence). Studies reported SAEs in 16/610 participants in the pioglitazone groups versus 21/601 participants in the no-intervention groups (RR 0.71, 95% CI 0.38 to 1.32; P = 0.28; 7 studies, 1211 participants; low-certainty evidence). We identified two ongoing studies, comparing pioglitazone with placebo and with other glucose-lowering drugs. These studies, with 2694 participants. may contribute evidence to future updates of this review. AUTHORS' CONCLUSIONS: Pioglitazone reduced or delayed the development of T2DM in people at increased risk of T2DM compared with placebo (low-certainty evidence) and compared with no intervention (moderate-certainty evidence). It is unclear whether the effect of pioglitazone is sustained once discontinued. Pioglitazone compared with metformin neither showed advantage nor disadvantage regarding the development of T2DM in people at increased risk (low-certainty evidence). The data and reporting of all-cause mortality, SAEs, micro- and macrovascular complications were generally sparse. None of the included studies reported on QoL or socioeconomic effects.

Relief of pain due to uterine cramping/involution after birth.

BACKGROUND: Women may experience differing types of pain and discomfort following birth, including cramping pain (often called after-birth pain) associated with uterine involution, where the uterus contracts to reduce blood loss and return the uterus to its non-pregnant size. This is an update of a review first published in 2011. OBJECTIVES: To assess the effectiveness and safety of pharmacological and non-pharmacological pain relief/analgesia for the relief of after-birth pains following vaginal birth. SEARCH METHODS: For this update, we searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (31 October 2019), and reference lists of retrieved studies. SELECTION CRITERIA: Randomised controlled trials comparing two different types of analgesia or analgesia versus placebo or analgesia versus no treatment, for the relief of after-birth pains following vaginal birth. Types of analgesia included pharmacological and non-pharmacological. Quasi-randomised trials were not eligible for inclusion. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion, conducted 'Risk of bias' assessment, extracted data and assessed the certainty of the evidence using the GRADE approach. MAIN RESULTS: In this update, we include 28 studies (involving 2749 women). The evidence identified in this review comes from middle- to high-income countries. Generally the trials were at low risk of selection bias, performance bias and attrition bias, but some trials were at high risk of bias due to selective reporting and lack of blinding. Our GRADE certainty of evidence assessments ranged from moderate to very low certainty, with downgrading decisions based on study limitations, imprecision, and (for one comparison) indirectness. Most studies reported our primary outcome of adequate pain relief as reported by the women. No studies reported data relating to neonatal adverse events, duration of hospital stay, or breastfeeding rates. Almost half of the included studies (11/28) excluded breastfeeding women from participating, making the evidence less generalisable to a broader group of women. Non-steroidal anti-inflammatory drugs (NSAIDs) compared to placebo NSAIDs are probably better than placebo for adequate pain relief as reported by the women (risk ratio (RR) 1.66, 95% confidence interval (CI) 1.45 to 1.91; 11 studies, 946 women; moderate-certainty evidence). NSAIDs may reduce the need for additional pain relief compared to placebo (RR 0.15, 95% CI 0.07 to 0.33; 4 studies, 375 women; low-certainty evidence). There may be a similar risk of maternal adverse events (RR 1.05, 95% CI 0.78 to 1.41; 9 studies, 598 women; low-certainty evidence). NSAIDs compared to opioids NSAIDs are probably better than opioids for adequate pain relief as reported by the women (RR 1.33, 95% CI 1.13 to 1.57; 5 studies, 560 women; moderate-certainty evidence) and may reduce the risk of maternal adverse events (RR 0.62, 95% CI 0.43 to 0.89; 3 studies, 255 women; low-certainty evidence). NSAIDs may be better than opioids for the need for additional pain relief, but the wide CIs include the possibility that the two classes of drugs are similarly effective or that opioids are better (RR 0.37, 95% CI 0.12 to 1.12; 2 studies, 232 women; low-certainty evidence). Opioids compared to placebo Opioids may be better than placebo for adequate pain relief as reported by the women (RR 1.26, 95% CI 0.99 to 1.61; 5 studies, 299 women; low-certainty evidence). Opioids may reduce the need for additional pain relief compared to placebo (RR 0.48, 95% CI 0.28 to 0.82; 3 studies, 273 women; low-certainty evidence). Opioids may increase the risk of maternal adverse events compared with placebo, although the certainty of evidence is low (RR 1.59, 95% CI 0.99 to 2.55; 3 studies, 188 women; low-certainty evidence). Paracetamol compared to placebo Very low-certainty evidence means we are uncertain if paracetamol is better than placebo for adequate pain relief as reported by the women, the need for additional pain relief, or risk of maternal adverse events (2 studies, 123 women). Paracetamol compared to NSAIDs Very low-certainty evidence means we are uncertain if there are any differences between paracetamol and NSAIDs for adequate pain relief as reported by the women, or the risk of maternal adverse events. No data were reported about the need for additional pain relief comparing paracetamol and NSAIDs (2 studies, 112 women). NSAIDs compared to herbal analgesia We are uncertain if there are any differences between NSAIDs and herbal analgesia for adequate pain relief as reported by the women, the need for additional pain relief, or risk of maternal adverse events, because the certainty of evidence is very low (4 studies, 394 women). Transcutaneous nerve stimulation (TENS) compared to no TENS Very low-certainty evidence means we are uncertain if TENS is better than no TENS for adequate pain relief as reported by the women. No other data were reported comparing TENS with no TENS (1 study, 32 women). AUTHORS' CONCLUSIONS: NSAIDs may be better than placebo and are probably better than opioids at relieving pain from uterine cramping/involution following vaginal birth. NSAIDs and paracetamol may be as effective as each other, whereas opioids may be more effective than placebo. Due to low-certainty evidence, we are uncertain about the effectiveness of other forms of pain relief. Future trials should recruit adequate numbers of women and ensure greater generalisability by including breastfeeding women. In addition, further research is required, including a survey of postpartum women to describe appropriately their experience of uterine cramping and involution. We identified nine ongoing studies, which may help to increase the level of certainty of the evidence around pain relief due to uterine cramping in future updates of this review.

Long-term effects of hyperbaric oxygen therapy on visual acuity and retinopathy.

Hyperbaric oxygen (HBO2) therapy is an adjunct treatment for diabetic foot ulcers. Since plausible mechanisms of action for this treatment include increased angiogenesis and high tissue oxygen concentrations, concerns about deterioration of retinopathy have been raised. The aim of this study was to evaluate the effects of HBO2 on visual acuity (VA) and retinopathy in patients with chronic diabetic foot ulcers during a two-year follow-up period. This is a randomized, single-center, double-blinded and placebo-controlled clinical trial evaluating the effects of HBO2 in patients with diabetes mellitus and chronic foot ulcers. All study participants underwent an ophthalmological examination before the first study treatment and then at three, six, 12 and 24 months. Fifty patients with a median age of 67 years were included. Visual acuity was similar between groups and did not change during the two-year observation period. No differences in retinopathy were seen between groups; neither were any differences found in numbers or areas of bleedings, hard exudates, microaneurysms or edemas, nor between groups or visits. New clinically significant macular edema was identified in four eyes in the HBO2 group and in three eyes in the placebo group. In this population of diabetic foot ulcer patients HBO2 seems to be neutral in an ophthalmological perspective. From a retinal point of view, we could not identify any indication of harmful effects of HBO2 on the microvascular bed in the placebo group.

Magnesium for skeletal muscle cramps.

BACKGROUND: Skeletal muscle cramps are common and often occur in association with pregnancy, advanced age, exercise or motor neuron disorders (such as amyotrophic lateral sclerosis). Typically, such cramps have no obvious underlying pathology, and so are termed idiopathic. Magnesium supplements are marketed for the prophylaxis of cramps but the efficacy of magnesium for this purpose remains unclear. This is an update of a Cochrane Review first published in 2012, and performed to identify and incorporate more recent studies. OBJECTIVES: To assess the effects of magnesium supplementation compared to no treatment, placebo control or other cramp therapies in people with skeletal muscle cramps.   SEARCH METHODS: On 9 September 2019, we searched the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, Embase, LILACS, CINAHL Plus, AMED, and SPORTDiscus. We also searched WHO-ICTRP and ClinicalTrials.gov for registered trials that might be ongoing or unpublished, and ISI Web of Science for studies citing the studies included in this review. SELECTION CRITERIA: Randomized controlled trials (RCTs) of magnesium supplementation (in any form) to prevent skeletal muscle cramps in any patient group (i.e. all clinical presentations of cramp). We considered comparisons of magnesium with no treatment, placebo control, or other therapy. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion and extracted data. Two review authors assessed risk of bias. We attempted to contact all study authors when questions arose and obtained participant-level data for four of the included trials, one of which was unpublished. We collected all data on adverse effects from the included RCTs. MAIN RESULTS: We identified 11 trials (nine parallel-group, two cross-over) enrolling a total of 735 individuals, amongst whom 118 cross-over participants additionally served as their own controls. Five trials enrolled women with pregnancy-associated leg cramps (408 participants) and five trials enrolled people with idiopathic cramps (271 participants, with 118 additionally crossed over to control). Another study enrolled 29 people with liver cirrhosis, only some of whom suffered muscle cramps. All trials provided magnesium as an oral supplement, except for one trial which provided magnesium as a series of slow intravenous infusions. Nine trials compared magnesium to placebo, one trial compared magnesium to no treatment, calcium carbonate or vitamin B, and another trial compared magnesium to vitamin E or calcium. We judged the single trial in people with liver cirrhosis and all five trials in participants with pregnancy-associated leg cramps to be at high risk of bias. In contrast, we rated the risk of bias high in only one of five trials in participants with idiopathic rest cramps. For idiopathic cramps, largely in older adults (mean age 61.6 to 69.3 years) presumed to have nocturnal leg cramps (the commonest presentation), differences in measures of cramp frequency when comparing magnesium to placebo were small, not statistically significant, and showed minimal heterogeneity (I² = 0% to 12%). This includes the primary endpoint, percentage change from baseline in the number of cramps per week at four weeks (mean difference (MD) -9.59%, 95% confidence interval (CI) -23.14% to 3.97%; 3 studies, 177 participants; moderate-certainty evidence); and the difference in the number of cramps per week at four weeks (MD -0.18 cramps/week, 95% CI -0.84 to 0.49; 5 studies, 307 participants; moderate-certainty evidence). The percentage of individuals experiencing a 25% or better reduction in cramp rate from baseline was also no different (RR 1.04, 95% CI 0.84 to 1.29; 3 studies, 177 participants; high-certainty evidence). Similarly, no statistically significant difference was found at four weeks in measures of cramp intensity or cramp duration. This includes the number of participants rating their cramps as moderate or severe at four weeks (RR 1.33, 95% CI 0.81 to 2.21; 2 studies, 91 participants; moderate-certainty evidence); and the percentage of participants with the majority of cramp durations of one minute or more at four weeks (RR 1.83, 95% CI 0.74 to 4.53, 1 study, 46 participants; low-certainty evidence). We were unable to perform meta-analysis for trials of pregnancy-associated leg cramps. The single study comparing magnesium to no treatment failed to find statistically significant benefit on a three-point ordinal scale of overall treatment efficacy. Of the three trials comparing magnesium to placebo, one found no benefit on frequency or intensity measures, another found benefit for both, and a third reported inconsistent results for frequency that could not be reconciled. The single study in people with liver cirrhosis was small and had limited reporting of cramps, but found no difference in terms of cramp frequency or cramp intensity. Our analysis of adverse events pooled all studies, regardless of the setting in which cramps occurred. Major adverse events (occurring in 2 out of 72 magnesium recipients and 3 out of 68 placebo recipients), and withdrawals due to adverse events, were not significantly different from placebo. However, in the four studies for which it could be determined, more participants experienced minor adverse events in the magnesium group than in the placebo group (RR 1.51, 95% CI 0.98 to 2.33; 4 studies, 254 participants; low-certainty evidence). Overall, oral magnesium was associated with mostly gastrointestinal adverse events (e.g. diarrhoea), experienced by 11% (10% in control) to 37% (14% in control) of participants. AUTHORS' CONCLUSIONS: It is unlikely that magnesium supplementation provides clinically meaningful cramp prophylaxis to older adults experiencing skeletal muscle cramps. In contrast, for those experiencing pregnancy-associated rest cramps the literature is conflicting and further research in this population is needed. We found no RCTs evaluating magnesium for exercise-associated muscle cramps or disease-state-associated muscle cramps (for example amyotrophic lateral sclerosis/motor neuron disease) other than a single small (inconclusive) study in people with liver cirrhosis, only some of whom suffered cramps.