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Carnitine deficiency is common in patients with chronic kidney disease (CKD) who require dialysis. Several clinical studies have suggested that carnitine supplementation is beneficial for dialysis-related symptoms. However, the clinical effectiveness and potential adverse effects of carnitine supplementation in dialysis patients have not been determined.This review aimed to evaluate the effectiveness and safety of carnitine supplementation for the treatment of dialysis-related complications in CKD patients requiring dialysis.We searched the Cochrane Kidney and Transplant Register of Studies up to 16 August 2022 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.We included all randomised controlled trials (RCTs) and quasi-RCTs (RCTs in which allocation to treatment was obtained by alternation, use of alternate medical records, date of birth, or other predictable methods) that compared carnitine supplements with placebo or standard care in people with CKD requiring dialysis.Two authors independently extracted study data and assessed study quality. We used a random-effects model to perform a quantitative synthesis of the data. We used the I² statistic to measure heterogeneity amongst the studies in each analysis. We indicated summary estimates as a risk ratio (RR) for dichotomous outcomes, mean difference (MD) for continuous outcomes, or standardised mean differences (SMD) if different scales were used, with 95% confidence intervals (CI). We assessed the certainty of the evidence for each of the main outcomes using the GRADE (Grades of Recommendation, Assessment, Development, and Evaluation) approach.We included 52 studies (47 parallel RCTs and five cross-over RCTs) (3398 randomised participants). All studies compared L-carnitine with a placebo, other treatment, or no treatment. Standard care was continued as co-interventions in each group. Most studies were judged to have an unclear or high risk of bias. L-carnitine may have little or no effect on the quality of life (QoL) SF-36 physical component score (PCS) (4 studies, 134 participants: SMD 0.57, 95% CI -0.15 to 1.28; I² = 73%; low certainty of evidence), and the total QoL score (Kidney Disease Quality of Life (KDQOL), VAS (general well-being), or PedsQL) (3 studies, 230 participants: SMD -0.02, 95% CI -0.29 to 0.25; I² = 0%; low certainty of evidence). L-carnitine may improve SF-36 mental component score (MCS) (4 studies, 134 participants: SMD 0.70, 95% CI 0.22 to 1.18; I² = 42%; low certainty of evidence). L-carnitine may have little or no effect on fatigue score (2 studies, 353 participants: SMD 0.01, 95% CI -0.20 to 0.23; I² = 0%; low certainty of evidence), adverse events (12 studies, 1041 participants: RR, 1.14, 95% CI 0.86 to 1.51; I² = 0%; low certainty of evidence), muscle cramps (2 studies, 102 participants: RR, 0.44, 95% CI 0.18 to 1.09; I² = 23%; low certainty of evidence), and intradialytic hypotension (3 studies, 128 participants: RR, 0.76, 95% CI 0.34 to 1.69; I² = 0%; low certainty of evidence). L-carnitine may improve haemoglobin levels (26 studies, 1795 participants: MD 0.46 g/dL, 95% CI 0.18 to 0.74; I² = 86%; low certainty of evidence) and haematocrit values (14 studies, 950 participants: MD 1.78%, 95% CI 0.38 to 3.18; I² = 84%; low certainty of evidence).The available evidence does not currently support the use of carnitine supplementation in the treatment of dialysis-related carnitine deficiency. Although carnitine supplementation may slightly improve anaemia-related markers, carnitine supplementation makes little or no difference to adverse events. However, these conclusions are based on limited data and, therefore, should be interpreted with caution.

This study aimed to provide an updated and comprehensive review of the efficacy of psychosocial interventions for the employability of individuals with autism spectrum disorder (ASD). Ten studies (423 participants) were identified in the literature. Compared to control groups, the proportion of those who could work was significantly higher among those who had participated in employment support programs and higher, but not significantly, among those who had received communication skills training. The communication skills training group had an improved communication score on employment. This systematic review showed that psychosocial interventions could increase the number of individuals with ASD who are employable and improve their communication skills for employment.

Background Research has shown the efficacy of school-based programs for mental health problems in children. However, few studies have focused on the strengths of children, such as resilience, which is essential in preventing mental health problems. Moreover, no research has investigated the effect of a universal school-based program on children with increased autistic traits in mainstream classes. We examined the changes in children's self-efficacy, social skills, and general mental health after the implementation of a newly developed universal program, the Universal Unified Prevention Program for Diverse Disorders (Up2-D2), and whether similar changes occurred in children with and without higher autistic traits. Methods To assess possible changes associated with the program, questionnaires were collected from 396 children (207 boys and 189 girls) aged 9–12 years old before (T1), immediately after (T2), and three months after (T3) the implementation of the program. Results Results from a linear mixed-effects model showed a significant increase in children's self-efficacy at T2 (adjusted difference 0.49, 95% CI 0.03–0.94; p Conclusions Our pilot study suggests that a universal program has the potential to promote positive attitudes and mental health in both at-risk and not-at-risk children.

Long-term use of benzodiazepine (BZD) is not recommended for the treatment of anxiety disorders. Cognitive behavioral therapy (CBT) is an effective treatment option for discontinuation of BZDs in patients with anxiety disorders. This systematic review and meta-analysis sought to clarify whether CBT is effective for discontinuing BZD anxiolytics in patients with anxiety disorders. This study was preregistered with PROSPERO (registration number: CRD42019125263). A literature search of major electronic databases was conducted in December 2018. Three randomized controlled trials were included in this review, and meta-analyses were performed. The proportion of discontinuing BZD anxiolytics was significantly higher in the CBT plus gradual tapering group than in the gradual tapering alone group, both in the short term (3 months after allocation; number needed to treat [NNT]: 3.2, 95% confidence interval: 2.1 to 7.1; risk ratio: 1.96, 95% confidence interval: 1.29 to 2.98, p=0.002, three studies) and long term (6 to 12 months after allocation; NNT: 2.8, 95% confidence interval: 1.9 to 5.3; risk ratio: 2.16, 95% confidence interval: 1.41 to 3.32, p=0.0004, three studies). CBT may be effective for discontinuing BZD anxiolytics, both in the short term and in the long term after the allocation. Further studies with larger sample sizes are necessary to draw definitive conclusions regarding the efficacy and safety of CBT for discontinuing BZD anxiolytics in patients with anxiety disorders. This article is protected by copyright. All rights reserved.

Purpose:Nocturia has been reported as a risk factor for mortality. However, evidence is limited and has a high risk of bias. We evaluated the association between nocturia and mortality using longit...

Overall early improvement in depression after commencement of antidepressant treatment could be associated with subsequent response or remission, but its predictive ability is not adequate. We aimed to investigate whether early improvement of individual depressive symptoms and important baseline characteristics of patients including the number of previous depressive episodes and the duration of index episode, better predicts response or remission. We requested pharmaceutical companies in Japan for individual patient data from randomized placebo-controlled trials focusing on the efficacy of second-generation antidepressants. Primary and secondary outcomes were response and remission at week 6, respectively. We compared models that only included improvement in the overall depression severity at week 2 with models that also included improvement in individual symptoms and baseline characteristics, by conducting an individual patient data meta-analysis. We obtained data from three trials comprising 997 participants. For the response outcome, the model incorporating individual symptoms and baseline characteristics demonstrated better predictive values than those in the model including early improvement in overall depression only. However, the area under the receiver operating characteristic curve, and positive and negative predictive values were 0.65, 0.70, and 0.64, respectively, suggesting that 30% and 36% of the participants still had false-negative and false-positive predictions, respectively. For the remission outcome, the corresponding values in the latter model were 0.72, 0.62, and 0.68, respectively. We suggest that clinical judgement on early discontinuation of antidepressant from non-early improvement at week 2 should be carefully made.

Although the association between nocturia and depressive symptoms has been demonstrated, the causal direction remains unclear. We investigated the directional association between nocturia and depressive symptoms using longitudinal data from the general population.This longitudinal analysis was conducted as part of the Nagahama Cohort Project, a population based cohort study, with baseline and 5-year followup investigations. Nocturnal voiding frequency and mental health were measured with self-report questionnaires, the International Prostate Symptom Score and the 5-item Mental Health Inventory. Logistic regression analyses and a cross-lagged panel analysis were performed to analyze the bidirectional association between nocturia and depressive symptoms.With 9,764 participants at baseline, data from 8,285 were used in this analysis. Median age at baseline was 57.3 years and the proportion of men was 32.0%. New onset depressive symptoms and nocturia were observed among 369 and 793 participants, respectively. In adjusted logistic regression analyses we observed a clear dose-relationship between baseline nocturnal voiding frequency and new onset depressive symptoms (p for trend0.001) and a weak association between baseline 5-item Mental Health Inventory and new onset nocturia (p for trend=0.0087). In a cross-lagged panel analysis the path coefficient from nocturnal voiding frequency to 5-item Mental Health Inventory (β=-0.06, p0.001) was stronger than that from 5-item Mental Health Inventory to nocturnal voiding frequency (β=-0.02, p=0.047).This longitudinal study demonstrated a bidirectional association between nocturia and depressive symptoms. The cross-lagged path coefficient suggested that nocturia could more likely be a cause than a result of depressive symptoms.

Aim To describe the development and acceptability of a decision aid (DA) for chronic insomnia considering discontinuation of benzodiazepine (BZD) and benzodiazepine receptor agonist (BZRA) hypnotics, and if discontinuing, tapering with or without cognitive behavioral therapy for insomnia (CBT-I). Methods We reviewed relevant literature describing chronic insomnia to identify options. We used the results of the systematic review and meta-analysis conducted previously to determine the related outcomes of two options: discontinuation of BZD/BZRA hypnotics by gradual tapering alone and discontinuation of BZD/BZRA hypnotics by gradual tapering with CBT-I. We then developed a prototype of DA following the International Patient Decision Aid Standards. A mixed methods survey was conducted to assess the acceptability among patients and healthcare providers. Results The prototype consisted of a description of insomnia, options of continuing or discontinuing BZD/BRZA hypnotics (if discontinuing, the options of tapering hypnotics with or without CBT-I), pros and cons of each option, and a value clarification exercise. Patients (n = 24) reported that the DA had acceptable language (79%), adequate information (71%), and well-balanced presentation (91%). Healthcare providers (n = 20) also provided favorable feedback. Conclusion We developed a DA for chronic insomnia considering discontinuation of BZD/BRZA hypnotics, which was acceptable for stakeholders. The developed DA was designed to support patients and healthcare providers to make a decision about whether to discontinue BZD/BRZA hypnotics.

Background Gastric cancer is the fifth most common cancer diagnosed worldwide. Due to improved early detection rates of gastric cancer and technological advances in treatments, a significant improvement in survival rates has been achieved in people with cancer undergoing gastrectomy. Subsequently, there has been increasing emphasis on postgastrectomy syndrome (e.g. fullness, delayed emptying, and cold sweat, amongst others) and quality of life postsurgery. However, it is uncertain which types of reconstruction result in better outcomes postsurgery. Objectives To assess the evidence on health-related quality of life and safety outcomes of Roux-en-Y and Billroth-I reconstructions after distal gastrectomy for people with gastric cancer. Search methods We searched the Cochrane Library and the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase on 4 May 2021. We checked the reference lists of the included studies and contacted manufacturers and professionals in the field. There were no language restrictions. Selection criteria Randomised controlled trials (RCTs) allocating participants to Roux-en-Y reconstruction or Billroth-I reconstruction after distal gastrectomy for gastric cancer. Data collection and analysis Two review authors independently screened studies identified by the search for eligibility and extracted data. The primary outcomes were health-related quality of life after surgery and incidence of anastomotic leakage. The secondary outcomes included body weight loss, incidence of bile reflux, length of hospital stay, and overall morbidity. We used a random-effects model to conduct meta-analyses. We assessed risk of bias of the included studies in accordance with the Cochrane Handbook for Systematic Reviews of Interventions, and the certainty of the evidence using the GRADE approach. Main results We included eight RCTs (942 participants) in the review. One study included both cancer patients and benign disease patients such as stomach ulcers. Two studies compared Roux-en-Y, Billroth-I, and Billroth-II reconstructions, whilst the other studies compared Roux-en-Y and Billroth-I directly. For the primary outcomes, the evidence suggests that there may be little to no difference in health-related quality of life between Roux-en-Y and Billroth-I reconstruction (standardised mean difference 0.04, 95% confidence interval (CI) -0.11 to 0.18; I² = 0%; 6 studies; 695 participants; low-certainty evidence due to study limitations and imprecision). The evidence for the effect of Roux-en-Y versus Billroth-I reconstruction on the incidence of anastomotic leakage is very uncertain (risk ratio (RR) 0.63, 95% CI 0.16 to 2.53; I² = 0%; 5 studies; 711 participants; very low-certainty evidence). The incidence of anastomotic leakage was 0.6% and 1.4% in the Roux-en-Y and Billroth-I groups, respectively. For the secondary outcomes, the evidence suggests that Billroth-I reconstruction may result in little to no difference in loss of body weight compared to Roux-en-Y reconstruction (mean difference (MD) 0.41, 95% CI -0.77 to 1.59; I² = 0%; 4 studies; 541 participants; low-certainty evidence). Roux-en-Y reconstruction probably reduces the incidence of bile reflux compared to Billroth-I reconstruction (RR 0.40, 95% CI 0.25 to 0.63; I² = 22%; 4 studies; 399 participants; moderate-certainty evidence). Billroth-I reconstruction may shorten postoperative hospital stay, but the evidence for this outcome is very uncertain (MD 0.96, 95% CI 0.16 to 1.76; I² = 56%; 7 studies; 894 participants; very low-certainty evidence). Billroth-I reconstruction may reduce postoperative overall morbidity compared to Roux-en-Y reconstruction (RR 1.47, 95% CI 1.02 to 2.11; I² = 0%; 7 studies; 891 participants; low-certainty evidence). Authors' conclusions The evidence suggests that there is little to no difference between Roux-en-Y and Billroth-I reconstruction for the outcome health-related quality of life. The evidence for the effect of Roux-en-Y versus Billroth-I reconstruction on the incidence of anastomotic leakage is very uncertain as the incidence of this outcome was low. Although the certainty of evidence was low, we found some possibly clinically meaningful differences between Roux-en-Y and Billroth-I reconstruction for short-term outcomes. Roux-en-Y reconstruction probably reduces the incidence of bile reflux into the remnant stomach compared to Billroth-I reconstruction. Billroth-I reconstruction may shorten postoperative hospital stay compared to Roux-en-Y reconstruction, but the evidence is very uncertain. Billroth-I reconstruction may reduce postoperative overall morbidity compared to Roux-en-Y reconstruction. Future trials should include long-term follow-up of health-related quality of life and body weight loss.

Background Bipolar disorder is a chronic mental disorder with repetitive mania/hypomania as well as depressive episodes, which eventually results in marked impairment in overall functioning and health-related quality of life. A worldwide prevalence rate of 2.4% has been reported. The risk of suicide is higher in people with bipolar disorder than those with other mental disorders. Therefore, effective management of bipolar disorder in the maintenance period is warranted to minimize the risk of relapse or recurrence. Although lithium has been the standard treatment of bipolar disorder for many years, it is associated with adverse effects and teratogenicity. Lamotrigine is approved to be expected for prevention of recurrence for the maintenance treatment of bipolar disorder. In addition, lamotrigine is as effective as lithium. Therefore, we performed a systematic review to confirm the efficacy and safety of lamotrigine in the maintenance treatment of bipolar disorder. Objectives To assess the efficacy and tolerability of lamotrigine in the maintenance treatment of bipolar disorder. Search methods We searched Ovid MEDLINE, Embase, PsycINFO, the Cochrane Common Mental Disorders Group's Specialized Register (CCMDCTR) and the Cochrane Central Register of Controlled Trials (CENTRAL) from inception to 21 May 2021. We also searched international trial registries and contacted experts in the field. Selection criteria We included randomized controlled trials enrolling adults with bipolar disorder who were treated with lamotrigine, placebo or lithium. Data collection and analysis Two reviews authors independently checked the eligibility of studies and extracted data using a standardized form. Data extracted included study characteristics, participant characteristics, intervention details, settings, and outcome measures in the term of efficacy and tolerability. Study information were then entered into RevMan web. Main results We included 11 studies with a total of 2314 participants in this review; 1146 were randomized to lamotrigine, 869 were randomized to placebo and, 299 to lithium. We rated all studies as having an unclear risk of bias in at least one domain of Cochrane's tool for assessing risk of bias, with the most commonly observed weakness being selection bias (random sequence generation and allocation concealment). We judged five studies to be at a high risk of detection bias (blinding of outcome assessment). These potential biases pose as major threat to the validity of the included studies in this review. Outcomes of efficacy showed a possible advantage of lamotrigine over placebo. The estimated risk ratio (RR) for recurrence of manic symptom at one year as measured by the Young Mania Rating Scale (YMRS) was 0.67, (95% confidence interval (CI) 0.51 to 0.87; 3 studies, 663 participants; low-certainty evidence) in favor of lamotrigine. The RR of clinical worsening with the need for additional psychotropic treatment (RR 0.82, 95% CI 0.70 to 0.98; 4 studies, 756 participants) based on moderate-certainty evidence. The possible benefits of lamotrigine were also seen for the outcome of treatment withdrawal due to any reason at 6-12 months after treatment (RR 0.88, 95% CI 0.78 to 0.99; 4 studies, 700 participants; moderate-certainty evidence). Regarding tolerability, our analyses showed that the incidence rates of adverse effects were similar between the lamotrigine group and the placebo group (short-term effect: RR 1.07, 95% CI 0.81 to 1.42; 5 studies, 1138 participants; very low-certainty evidence; long-term effect: RR 0.97, 95% CI 0.77 to 1.23; 4 studies, 756 participants; moderate-certainty evidence). In the comparison between lamotrigine and lithium, efficacy was similar between groups except for recurrence of mania episode at one year. Recurrence of manic symptoms was higher in the lamotrigine group than that of the lithium group (RR 2.13, 95% CI 1.32 to 3.44; 3 studies, 602 participants; moderate-certainty evidence). Analysis of adverse effects at 6-12 months showed that a lower proportion of participants experienced at least one adverse effect when treated with lamotrigine compared to lithium (RR 0.70, 95% CI 0.51 to 0.96; 4 studies, 691 participants; moderate-certainty evidence). Authors' conclusions Low- to moderate-certainty evidence collectively suggests that lamotrigine may be superior to placebo as a treatment modality for bipolar disorder. In comparison to lithium, people with bipolar disorder seem to tolerate lamotrigine better in the long run; however, the demonstrated efficacy in the maintenance of bipolar disorder was similar between the two groups.

Background Chronic kidney disease (CKD) is an independent risk factor for osteoporosis and is more prevalent among people with CKD than among people who do not have CKD. Although several drugs have been used to effectively treat osteoporosis in the general population, it is unclear whether they are also effective and safe for people with CKD, who have altered systemic mineral and bone metabolism. Objectives To assess the efficacy and safety of pharmacological interventions for osteoporosis in patients with CKD stages 3-5, and those undergoing dialysis (5D). Search methods We searched the Cochrane Kidney and Transplant Register of Studies up to 25 January 2021 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 Randomised controlled trials comparing any anti-osteoporotic drugs with a placebo, no treatment or usual care in patients with osteoporosis and CKD stages 3 to 5D were included. Data collection and analysis Two review authors independently selected studies, assessed their quality using the risk of bias tool, and extracted data. The main outcomes were the incidence of fracture at any sites; mean change in the bone mineral density (BMD; measured using dual-energy radiographic absorptiometry (DXA)) of the femoral neck, total hip, lumbar spine, and distal radius; death from all causes; incidence of adverse events; and quality of life (QoL). 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, and mean difference (MD) for continuous outcomes. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Main results Seven studies involving 9164 randomised participants with osteoporosis and CKD stages 3 to 5D met the inclusion criteria; all participants were postmenopausal women. Five studies included patients with CKD stages 3-4, and two studies included patients with CKD stages 5 or 5D. Five pharmacological interventions were identified (abaloparatide, alendronate, denosumab, raloxifene, and teriparatide). All studies were judged to be at an overall high risk of bias. Among patients with CKD stages 3-4, anti-osteoporotic drugs may reduce the risk of vertebral fracture (RR 0.52, 95% CI 0.39 to 0.69; low certainty evidence). Anti-osteoporotic drugs probably makes little or no difference to the risk of clinical fracture (RR 0.91, 95% CI 0.79 to 1.05; moderate certainty evidence) and adverse events (RR 0.99, 95% CI 0.98 to 1.00; moderate certainty evidence). We were unable to incorporate studies into the meta-analyses for BMD at the femoral neck, lumbar spine and total hip as they only reported the percentage change in the BMD in the intervention group. Among patients with severe CKD stages 5 or 5D, it is uncertain whether anti-osteoporotic drug reduces the risk of clinical fracture (RR 0.33, 95% CI 0.01 to 7.87; very low certainty evidence). It is uncertain whether anti-osteoporotic drug improves the BMD at the femoral neck because the certainty of this evidence is very low (MD 0.01, 95% CI 0.00 to 0.02). Anti-osteoporotic drug may slightly improve the BMD at the lumbar spine (MD 0.03, 95% CI 0.03 to 0.04, low certainty evidence). No adverse events were reported in the included studies. It is uncertain whether anti-osteoporotic drug reduces the risk of death (RR 1.00, 95% CI 0.22 to 4.56; very low certainty evidence). Authors' conclusions Among patients with CKD stages 3-4, anti-osteoporotic drugs may reduce the risk of vertebral fracture in low certainty evidence. Anti-osteoporotic drugs make little or no difference to the risk of clinical fracture and adverse events in moderate certainty evidence. Among patients with CKD stages 5 and 5D, it is uncertain whether anti-osteoporotic drug reduces the risk of clinical fracture and death because the certainty of this evidence is very low. Anti-osteoporotic drug may slightly improve the BMD at the lumbar spine in low certainty evidence. It is uncertain whether anti-osteoporotic drug improves the BMD at the femoral neck because the certainty of this evidence is very low. Larger studies including men, paediatric patients or individuals with unstable CKD-mineral and bone disorder are required to assess the effect of each anti-osteoporotic drug at each stage of CKD.

Background Psychological problems during childhood and adolescence are highly prevalent, frequently comorbid, and incur severe social burden. A school-based universal prevention approach is one avenue to address these issues. Objective The first aim of this study was the development of a novel, transdiagnostic cognitive-behavioral universal prevention program: The Universal Unified Prevention Program for Diverse Disorders (Up2-D2). The second aim of this study was to examine the acceptability and fidelity of the Up2-D2. Methods Classroom teachers who attended a 1-day workshop implemented the Up2-D2 independently as a part of their regular curricula. To assess the acceptability of the Up2-D2, 213 children (111 boys and 102 girls) aged 9–12 years completed questionnaires about their enjoyment, comprehension, attainment, applicability, and self-efficacy after completing Lessons 1–12. For fidelity, research assistants independently evaluated audio files that were randomly selected and assigned (27.3%). Results Our preliminary evaluation revealed the program was highly enjoyable, clear, and applicable for students. In addition, self-efficacy demonstrated a trend of gradually increasing over the 12 sessions. The total fidelity observed in the two schools was sufficient (76.2%), given the length of the teacher training. Conclusions The results of this study supported the theory that the Up2-D2 could be feasible in real-world school settings when classroom teachers implement the program. We discussed current research and practical issues of using universal prevention to address mental health problems in school, based on implementation science for user-centered design.

Background This study examined the effects of the standard model of family psychoeducation (SM-FPE) in Japan on the mental health of relatives who care for young patients with a psychotic disorder. Methods Stratified by recent-onset/chronic psychosis, 74 caregivers of outpatients aged 30.1 years (mean) were randomly assigned to receive TAU (treatment as usual) alone or TAU plus SM-FPE. All outcomes were measured at baseline, at the end of the intervention (10 weeks), and 1 month post-intervention (14 weeks). The primary outcome was the trait anxiety of caregivers at 14 weeks. Secondary outcomes included caregivers’ state anxiety, psychological distress, care burden, and expressed emotion. Integrating these secondary outcomes, a conceptual framework of caregivers’ health state was assessed via structural equation modelling. Results Compared with TAU alone, SM-FPE plus TAU did not significantly improve all caregivers’ individual outcomes. Direct effects of the intervention were observed in the caregivers of chronic patients as significant improvements of their overall mental health state at 10 weeks, which indirectly continued until 14 weeks. However, such intervention effects were not observed in the caregivers of recent-onset patients. Conclusions The lack of effectiveness in the recent-onset stage suggests that the usefulness of the SM-FPE needs to be corroborated by further research. Trial registration The study protocol was retrospectively registered at ClinicalTrials.gov (registration number: NCT01731977; date of registration: 22 November 2012).

The third-wave cognitive behavioral therapies (CBTs), such as acceptance and commitment therapy (ACT) and dialectical behavior therapy (DBT), have been shown to be effective treatments for individuals with substance use disorders (SUD). Given their conceptual and methodological heterogeneity, however, it is difficult to categorize these third-wave CBTs and examine their clinical outcomes. One proposed method is to identify and categorize treatments based on their intended mechanisms of change, and then systematically examine their clinical effects. Psychological flexibility is theorized to be a potential process of change in many third-wave CBTs. In this study, we first identified third-wave CBTs that deliberately target psychological flexibility and categorized them as psychological flexibility–based interventions (PF interventions). PF interventions included ACT, DBT, mindfulness-oriented recovery enhancement, and distress tolerance therapy. We then conducted a meta-analysis of randomized controlled trials (RCT) that compared PF interventions to first-line psychosocial interventions. From a total of 2781 citations, our search identified 10 RCTs including a total of 658 participants. Compared to the first-line psychosocial interventions recommended for SUD treatment (e.g., brief motivational interventions, 12-step groups, and the like), PF interventions demonstrated a higher rate of substance discontinuation (33.6% vs 24.8%). There was no significant difference in dropout rate between the two groups of interventions. Third-wave CBT methods that target psychological flexibility are promising interventions for SUDs. Meta-analyses of this kind are a useful first step in taking a process-based therapy approach to the current evidence on psychosocial interventions.

Background The efficacy of the mindfulness-based stress management program for maintaining a better mental state has not been examined among working populations. We aimed to explore the effectiveness of the brief mindfulness-based stress management program for hospital nurses. Methods In a multi-center randomized trial, 80 junior nurses working in hospitals were randomly allocated either to the brief mindfulness-based stress management program or psychoeducation using a leaflet. The program consisted of four 30 min individual sessions conducted by trained senior nurses using a detailed manual. The primary outcome was the total score of the Hospital Anxiety and Depression Scale (HADS) at week 26. Secondary outcomes included presence of a major depressive episode; severity of depression, anxiety, insomnia, burnout, and presenteeism; utility scores; and adverse events up to 52 weeks. Results The mean HADS score of all the participants at baseline was 7.2. At 26 weeks, adjusted mean scores on the HADS score were 7.2 (95% confidence intervals: 5.9, 8. 5) in the program group and 6.0 (4.8, 7.2) in the leaflet group, respectively. The coefficient of the group by time interaction was not statistically significant at -1.41 (-3.35, 0.54; P = 0.156). No significant superiority or inferiority was observed on the other outcomes. Limitations We did not manage to recruit the number of participants we initially set out, although our post-hoc analyses showed that this did not lead to changes in our conclusions. Conclusions The additive value of the brief mindfulness-based stress management program was not confirmed in mental state and self-evaluated work efficiency.

Aim Whether patients with adult bipolar disorder (BD) who have been clinically stabilized with lithium or lamotrigine should continue this medication is not established fully. This systematic review and meta‐analysis evaluated the efficacy and safety of lithium and lamotrigine for maintenance treatment in clinically stable patients with adult BD. Methods This meta‐analysis included only double‐blind, randomized, placebo‐controlled trials with an enrichment design that selected patients who responded acutely to lithium or lamotrigine. Reports prior to November 15, 2018, were retrieved from the PubMed/Cochrane Library/Embase. The primary outcome was the relapse rate due to any mood episode at the study endpoint. Other outcomes were relapse rates due to a manic/hypomanic/mixed episode or depression at the study endpoint, discontinuation rate, death, and death by suicide. Risk ratios (RRs) (95% confidence intervals) were calculated. When the random‐effects model showed significant differences between groups, the number‐needed‐to‐treat (NNT) was estimated. Results The search retrieved two studies regarding lithium (N = 218) and four evaluating lamotrigine (N = 706). Both drugs were superior to placebo for reducing the relapse rate due to any mood episode [lithium: RR = 0.52 (0.41‐0.66), P, Study, patient, and treatment characteristics of the included double‐blinded, randomized placebo‐controlled trials of patients with bipolar disorder

Background: Many primary care facilities have dedicated significant resources to drug misuse screening and brief intervention (BI). However, the efficacy of BI for drug misuse in primary care has not been substantiated, revealing many non-significant findings. Thus, we aimed to determine the efficacy of BI for drug misuse, length of effects, and benefits among primary care subpopulations. Methods: We searched CENTRAL, EMBASE, MEDLINE, PsycINFO, and reference lists up to January 13, 2021. The population were patients receiving primary care-delivered BI for drug misuse compared with usual care. Primary outcomes were drug use frequency (days used) and severity on validated scales at 4-8 months. Analyses were conducted using random-effects models. This study was registered in PROSPERO (CRD42020157733). Results: We identified 27 studies and analyzed 20 (7471 patients) at three follow-up timepoints for frequency and severity. There was insufficient evidence to support the efficacy of BI for drug misuse in general primary care for use frequency (SMD = -0·07, 95% CI = -0·17, 0·02, p = 0·12, I2 = 37%, high certainty of evidence) and severity (SMD = -0·27, 95% CI = -0·78, 0·24, p = 0·30, I2= 98%, low certainty of evidence). However, subgroup analyses uncovered significant effects for frequency (interaction p = 0·004) with insufficient evidence for hospital/community primary care (SMD = 0·07, 95% CI = -0·03, 0·18, p = 0·08), but significant small effects among emergency department (SMD = -0·15, 95% CI = -0·25, -0·04, p < 0·01) and specialty primary care populations (SMD = -0·19, 95% CI = -0·36, -0·02, p < 0·05).Interpretation: BI for drug misuse is not indicated in general primary care. Department heads could consider continuing BI, noting the small positive effects and confidence intervals found only in emergency and specialty clinics. Funding : Japan Society for the Promotion of Science (P19110 and 19F19110). Declaration of Interest

It has been difficult to find robust brain structural correlates of the overall severity of major depressive disorder (MDD). We hypothesized that specific symptoms may better reveal correlates and investigated this for the severity of insomnia, both a key symptom and a modifiable major risk factor of MDD. Cortical thickness, surface area and subcortical volumes were assessed from T1-weighted brain magnetic resonance imaging (MRI) scans of 1053 MDD patients (age range 13-79 years) from 15 cohorts within the ENIGMA MDD Working Group. Insomnia severity was measured by summing the insomnia items of the Hamilton Depression Rating Scale (HDRS). Symptom specificity was evaluated with correlates of overall depression severity. Disease specificity was evaluated in two independent samples comprising 2108 healthy controls, and in 260 clinical controls with bipolar disorder. Results showed that MDD patients with more severe insomnia had a smaller cortical surface area, mostly driven by the right insula, left inferior frontal gyrus pars triangularis, left frontal pole, right superior parietal cortex, right medial orbitofrontal cortex, and right supramarginal gyrus. Associations were specific for insomnia severity, and were not found for overall depression severity. Associations were also specific to MDD; healthy controls and clinical controls showed differential insomnia severity association profiles. The findings indicate that MDD patients with more severe insomnia show smaller surfaces in several frontoparietal cortical areas. While explained variance remains small, symptom-specific associations could bring us closer to clues on underlying biological phenomena of MDD.

Background Although caregivers of patients with eating disorders usually experience a heavy caregiving burden, the effects of social support on caregivers of patients with eating disorders are unknown. This study aimed to investigate how social support for mothers who are caregivers of patients with an eating disorder improves the mothers’ mental status and, consequently, the symptoms and status of the patients. Methods Fifty-seven pairs of participants were recruited from four family self-help groups and one university hospital in Japan. Recruitment was conducted from July 2017 to August 2018. Mothers were evaluated for social support using the Japanese version of the Social Provisions Scale-10 item (SPS-10), self-efficacy using the General Self-Efficacy Scale, loneliness using the University of California, Los Angeles Loneliness Scale, listening attitude using the Active Listening Attitude Scale, family functioning using the Family Assessment Device, depression symptoms using the Beck Depression Inventory (Second Edition), and psychological distress using the Kessler Psychological Distress Scale. Patients were evaluated for self-esteem using the Rosenberg Self-Esteem Scale, assertion using the Youth Assertion Scale, and their symptoms using the Eating Disorder Inventory. We divided the mothers and patients into two groups based on the mean score of the SPS-10 of mothers and compared the status of mothers and patients between the high- and low-scoring groups. Results High social support for mothers of patients with eating disorders was significantly associated with lower scores for loneliness and depression of these mothers. We found no significant differences in any patient scores based on mothers’ level of social support. Conclusions For patients with eating disorders, social support for a caregiver cannot be expected to improve their symptoms, but it may help prevent caregiver depression and loneliness.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a common and progressive disease characterised by chronic cough, airflow limitation and recurrent exacerbations. Since COPD exacerbations are linked to rising mortality and reduced quality of life, the condition poses a substantial burden on individuals, society and the healthcare system. Effective management of COPD exacerbations that includes treatment of related conditions in people with COPD is thus recognised as a relevant clinical question and an important research topic. Gastroesophageal reflux disease (GERD) is a known comorbidity of COPD, and pulmonary microaspiration of gastric acid is thought to be a possible cause of COPD exacerbations. Therefore, reducing gastric acid secretion may lead to a reduction in COPD exacerbations. Proton pump inhibitors (PPIs) are one of the most commonly prescribed medications and are recommended as first‐line therapy for people with GERD because of their inhibitory effects on gastric acid secretion. Treatment with PPIs may present a viable treatment option for people with COPD. OBJECTIVES: To evaluate the efficacy and safety of PPI administration for people with COPD, focusing on COPD‐specific outcomes. SEARCH METHODS: We searched the Cochrane Airways Register of Trials and conventional clinical trial registers from inception to 22 May 2020. We also screened bibliographies of relevant studies. SELECTION CRITERIA: Parallel‐group and cluster‐randomised controlled trials (RCTs) that compared oral PPIs versus placebo, usual care or low‐dose PPIs in adults with COPD were eligible for inclusion. We excluded cross‐over RCTs, as well as studies with a duration of less than two months. DATA COLLECTION AND ANALYSIS: Two independent review authors screened search results, selected studies for inclusion, extracted study characteristics and outcome data, and assessed risk of bias according to standard Cochrane methodology. We resolved discrepancies by involving a third review author. Primary outcomes of interest were COPD exacerbations, pneumonia and other serious adverse events. Secondary outcomes were quality of life, lung function test indices, acute respiratory infections and disease‐specific adverse events. We extracted data on these outcome measures and entered into them into Review Manager software for analysis. MAIN RESULTS: The search identified 99 records, and we included one multicentre RCT that randomised 103 adults with COPD. The 12‐month RCT compared an oral PPI (lansoprazole) and usual care versus usual care alone. It was conducted at one tertiary care hospital and three secondary care hospitals in Japan. This study recruited participants with a mean age of 75 years, and excluded people with symptoms or history of GERD. No placebo was used in the usual care arm. Among the primary and secondary outcomes of this review, the study only reported data on COPD exacerbations and acute respiratory infections (the common cold). As we only included one study, we could not conduct a meta‐analysis. The included study reported that 12 of the 50 people on lansoprazole had at least one exacerbation over a year, compared to 26 out of 50 on usual care (risk ratio 0.46, 95% CI 0.26 to 0.81). The frequency of COPD exacerbations per person in a year was also lower in the PPI plus usual care group than in the usual care alone group（0.34 ± 0.72 vs 1.18 ± 1.40; P < 0.001). The number of people with at least one cold over the year was similar in both groups: 26 people on lansoprazole and 27 people in the usual care group. We judged the evidence to be of low to very low certainty, according to GRADE criteria. The study reported no data on pneumonia and other serious adverse events, quality of life, lung function test indices or disease‐specific adverse events. The risk of bias was largely low or unclear for the majority of domains, though the performance bias was a high risk, as the study was not blinded. AUTHORS' CONCLUSIONS: Evidence identified by this review is insufficient to determine whether treatment with PPIs is a potential option for COPD. The sample size of the included trial is small, and the evidence is low to very low‐certainty. The efficacy and safety profile of PPIs for people with COPD remains uncertain. Future large‐scale, high‐quality studies are warranted, which investigate major clinical outcomes such as COPD exacerbation rate, serious adverse events and quality of life.

Background Overactive bladder (OAB) symptoms affect daily life by decreasing health-related quality of life (HRQol). However, there remain no very effective treatment for OAB. Pharmacotherapy is one of the best treatments, but it is not always efficient and may incur adverse events. Although behavioral therapy is another effective treatment, there are very few structured treatment manuals on how to prescribe behavioral therapy to treat OAB for whom. Cognitive behavioral therapy (CBT) is a psychotherapy consisting of structured sessions to solve problems with the collaborative empiricism between therapists and patients. OAB symptoms are supposed to worsen with cognitive distortion, and CBT is expected to be effective in treating OAB by modifying such cognitive processes. In this trial, we will evaluate the efficacy of CBT for OAB. Methods A randomized, controlled, open-label, multicenter parallel-group superiority trial will be conducted. Participants with moderate to severe OAB symptoms with or without pharmacotherapy will be recruited and will be randomly allocated 1:1 to two different groups by minimization (age, baseline OAB severity, treatment status, types of intervention, and treating institutions). The intervention group will be prescribed an individual CBT program covering six techniques in 4 sessions (30 min each), with or without pharmacotherapy. The primary outcome is the change scores in an OAB-questionnaire (OAB-q) from baseline to the end of the trial (week 13). Secondary outcomes will include other patient reported outcome measures and the frequency volume chart. All analyses will be conducted on an intention-to-treat principle. Discussion This trial will determine the efficacy of CBT to treat OAB using a rigorous methodology. The effectiveness of CBT with a structured manual may not only lead to a new treatment option for patients suffering from OAB symptoms, but may also reduce the social burden by OAB. Trial registration UMIN-CTR Clinical Trial, CTR-UMIN000038513. Registered on November 7, 2019.

This is the protocol for a review and there is no abstract. The objectives are as follows: (1) Primary objective: to examine effectiveness of psychotherapy in comparison with non-treatment, waiting-list control or treatment as usual in the treatment of depression in children and adolescents (2) Secondary objective: to examine adverse effects of psychotherapy in comparison with non-treatment, waiting-list control or treatment as usual in the treatment of depression in children and adolescents (3) To examine cost-effectiveness of structured psychotherapy in comparison with non-treatment, waiting-list control or treatment as usual in the treatment of depression in children and adolescents

Intensive cytotoxic chemotherapy for people with cancer can cause severe and prolonged cytopenia, especially neutropenia, a critical condition that is potentially life-threatening. When manifested by fever and neutropenia, it is called febrile neutropenia (FN). Invasive fungal disease (IFD) is one of the serious aetiologies of chemotherapy-induced FN. In pre-emptive therapy, physicians only initiate antifungal therapy when an invasive fungal infection is detected by a diagnostic test. Compared to empirical antifungal therapy, pre-emptive therapy may reduce the use of antifungal agents and associated adverse effects, but may increase mortality. The benefits and harms associated with the two treatment strategies have yet to be determined. OBJECTIVES: To assess the relative efficacy, safety, and impact on antifungal agent use of pre-emptive versus empirical antifungal therapy in people with cancer who have febrile neutropenia.We searched CENTRAL, MEDLINE Ovid, Embase Ovid, and ClinicalTrials.gov to October 2021.We included randomised controlled trials (RCTs) that compared pre-emptive antifungal therapy with empirical antifungal therapy for people with cancer.We identified 2257 records from the databases and handsearching. After removing duplicates, screening titles and abstracts, and reviewing full-text reports, we included seven studies in the review. We evaluated the effects on all-cause mortality, mortality ascribed to fungal infection, proportion of antifungal agent use (other than prophylactic use), duration of antifungal use (days), invasive fungal infection detection, and adverse effects for the comparison of pre-emptive versus empirical antifungal therapy. We presented the overall certainty of the evidence for each outcome according to the GRADE approach.This review includes 1480 participants from seven randomised controlled trials. Included studies only enroled participants at high risk of FN (e.g. people with haematological malignancy); none of them included participants at low risk (e.g. people with solid tumours). Low-certainty evidence suggests there may be little to no difference between pre-emptive and empirical antifungal treatment for all-cause mortality (risk ratio (RR) 0.97, 95% confidence interval (CI) 0.72 to 1.30; absolute effect, reduced by 3/1000); and for mortality ascribed to fungal infection (RR 0.92, 95% CI 0.45 to 1.89; absolute effect, reduced by 2/1000). Pre-emptive therapy may decrease the proportion of antifungal agent used more than empirical therapy (other than prophylactic use; RR 0.71, 95% CI 0.47 to 1.05; absolute effect, reduced by 125/1000; very low-certainty evidence). Pre-emptive therapy may reduce the duration of antifungal use more than empirical treatment (mean difference (MD) -3.52 days, 95% CI -6.99 to -0.06, very low-certainty evidence). Pre-emptive therapy may increase invasive fungal infection detection compared to empirical treatment (RR 1.70, 95% CI 0.71 to 4.05; absolute effect, increased by 43/1000; very low-certainty evidence). Although we were unable to pool adverse events in a meta-analysis, there seemed to be no apparent difference in the frequency or severity of adverse events between groups. Due to the nature of the intervention, none of the seven RCTs could blind participants and personnel related to performance bias. We identified considerable clinical and statistical heterogeneity, which reduced the certainty of the evidence for each outcome. However, the two mortality outcomes had less statistical heterogeneity than other outcomes.For people with cancer who are at high-risk of febrile neutropenia, pre-emptive antifungal therapy may reduce the duration and rate of use of antifungal agents compared to empirical therapy, without increasing over-all and IFD-related mortality; but the evidence regarding invasive fungal infection detection and adverse events was inconsistent and uncertain.

Background Whether the ramped or sniffing laryngoscopy position is better for tracheal intubation is unclear. This study aimed to determine the efficacy and safety of tracheal intubation in the ramped versus sniffing position. Methods We conducted a systematic review and meta-analysis of randomized clinical trials to compare the ramped position with the sniffing position for tracheal intubation. We searched the databases of Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Excerpta Medica Database (Embase), ClinicalTrials.gov , and World Health Organization Clinical Trials Registry Platform up to December 2018. We included randomized-controlled trials, trials of participants who required tracheal intubation in any setting, and that compared tracheal intubation in the ramped and the sniffing positions. Two authors independently screened the trials, extracted the data, and assessed the risk of bias. We conducted the meta-analysis using the random-effects model to calculate the pooled risk ratio with 95% confidence interval. Results Of the 2631 titles/abstracts screened, three studies (representing 513 patients) were included in the meta-analysis. The pooled risk ratio with 95% confidence interval (CI) of the sniffing versus the ramped position was as follows: a first successful attempt, 0.97 (95% CI, 0.86–1.09; I2 = 55%); laryngoscopy attempts ≤2, 1.08 (95% CI, 0.88–1.31; I2 = 93%); and good glottic view with Cormack–Lehane grade ≤ 2, 0.86 (95% CI, 0.69–1.07; I2 = 86%). Conclusions This systematic review and meta-analysis indicated no favorable aspects of the ramped position as compared to the sniffing position. Thus, further research is warranted to identify which is better in tracheal intubation. Trial registration: PROSPERO identifier, CRD42019116819.

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To assess the effects of interventions to increase outdoor time on myopia incidence and progression in children.

Objectives Drug-resistant overactive bladder (OAB) represents an unmet medical need in that treatment options are limited. We developed a treatment model based on cognitive behavioral therapy and evaluated its feasibility and acceptability for drug-resistant OAB in women. Methods This was an open-label, single-arm, multicenter pilot study. We defined drug-resistant OAB as OAB with moderate to severe symptoms despite pharmacotherapy for more than 12 weeks. A face-to-face intervention was prescribed as six sessions (30 minutes each) over 6 to 12 weeks according to a treatment manual. The effects were assessed by self-reported questionnaires and frequency voiding charts (FVC) at baseline, during intervention, immediately after intervention, and at follow-up. Results Ten patients participated in this study. Median age was 72 years, median OAB Symptom Score was nine points, and median duration of prior treatment for OAB was 5.5 years at baseline. Two participants dropped out of the study. Among the remaining patients, the scores of the OAB Questionnaire subscales improved (effect size: 0.75-1.73), and the mean urinary frequency in the FVC also improved from baseline (9.0 times, SD: 2.1) to follow-up (6.2 times, SD: 1.2). All participants were satisfied with the intervention. There were no adverse events during this study. Conclusions The new treatment based on cognitive behavioral therapy was well tolerated and feasible in women with drug-resistant OAB. Further randomized research is needed to rigorously evaluate the efficacy of the treatment.

We examined the dose–response relationship between long sleep duration and health outcomes including mortality and the incidence of diabetes mellitus, hypertension, cardiovascular diseases, stroke, coronary heart diseases, obesity, depression and dyslipidemia. We collected data from 5, 134, 036 participants from 137 prospective cohort studies. For the independent variable, we categorized participants at baseline as having long sleep duration or normal sleep duration. Risk ratios (RRs) for mortality and incident health conditions during follow-up were calculated through meta-analyses of adjusted data from individual studies. Meta-regression analyses were performed to investigate the association between each outcome and specific thresholds of long sleep. Long sleep was significantly associated with mortality (RR, 1.39; 95% CI, 1.31–1.47), incident diabetes mellitus (1.26, 1.11–1.43), cardiovascular disease (1.25, 1.14–1.37), stroke (1.46, 1.26–1.69), coronary heart disease (1.24, 1.13–1.37), and obesity (1.08, 1.02–1.15). Long sleep was not significantly related to incident hypertension (1.01, 0.95–1.07). Insufficient data were available for depression and dyslipidemia. Meta-regression analyses found statistically significant linear associations between longer sleep duration and increased mortality and incident cardiovascular disease. Future studies should address whether the relationship between long sleep and health outcomes is causal and modifiable.

Background Exon skipping has been considered a promising therapeutic approach for Duchenne muscular dystrophy (DMD). Eteplirsen received conditional approval in the United States in 2016. To date, no systematic reviews or meta-analyses of randomized controlled trials (RCTs) of exon skipping drugs have been published to determine the pooled estimates for the effect of exon skipping in treating DMD. Methods A systematic review and meta-analysis of double-blind RCTs comparing exon-skipping drugs with placebo in DMD was performed. Trials were identified by searching published and unpublished studies from electronically available databases and clinical trial registries through October 2017. The primary outcomes were changes in the 6-min walk test (6MWT) distance, North Star Ambulatory Assessment (NSAA) scores, and adverse events. Random-effects meta-analysis and assessment of risk of bias were performed. This systematic review was registered at PROSPERO (CRD42016037504). Results Five studies involving 322 participants were included, investigating eteplirsen in one and drisapersen in four studies. There were no changes in 6MWT distance (mean difference [MD] − 9.16, 95% confidence interval [CI] − 21.94 to 3.62) or NSAA scores (MD 1.20, 95% CI − 2.35 to 4.75) after 24 weeks of treatment in the exon-skipping group compared with placebo. Subgroup analysis for a 6 mg/kg weekly injection of drisapersen showed significant changes in the 6MWT, favoring drisapersen after 24 weeks (MD − 20.24; 95% CI − 39.59 to − 0.89). However, drisapersen resulted in a significant increase in injection site reactions (risk ratio [RR] 3.67, 95% CI 1.96 to 6.89, p

Objective The dose–response of short sleep duration in mortality has been studied, in addition to the incidences of notable health complications and diseases such as diabetes mellitus, hypertension, cardiovascular diseases, stroke, coronary heart diseases, obesity, depression, and dyslipidemia. Methods We collected data from prospective cohort studies with follow-ups of one year or more on associations between short sleep duration and the outcomes. For the independent variable, we divided participants at baseline into short sleepers and normal sleepers. The primary outcomes were defined as mortality and an incident of each health outcome in the long-term follow-up. Risk ratios (RRs) for each outcome were calculated through meta-analyses of adjusted data from individual studies. Sub-group and meta-regression analyses were performed to investigate the association between each outcome and the duration of short sleep. Results Data from a cumulative total of 5,172,710 participants were collected from 153 studies. Short sleep was significantly associated with the mortality outcome (RR, 1.12; 95% CI, 1.08–1.16). Similar significant results were observed in diabetes mellitus (1.37, 1.22–1.53), hypertension (1.17, 1.09–1.26), cardiovascular diseases (1.16, 1.10–1.23), coronary heart diseases (1.26, 1.15–1.38), and obesity (1.38, 1.25–1.53). There was no sufficient usable evidence for meta-analyses in depression and dyslipidemia. Meta-regression analyses found a linear association between a statistically significant increase in mortality and sleep duration at less than six hours. No dose–response was identified in the other outcomes. Conclusions Based on our findings, future studies should examine the effectiveness of psychosocial interventions to improve sleep on reducing these health outcomes in general community settings.

A woman in her seventies who was started on warfarin after heart valve replacement began outpatient adjuvant chemotherapy with tegafur‐uracil/leucovorin for rectal cancer. The patient performed weekly INR self‐measurements at a health insurance pharmacy between outpatient visits. Results recorded in her personal medicine notebook were shared between her physician, a hospital pharmacist, and a pharmacy pharmacist. When INR values were outside the therapeutic target range, doses were altered according to the physician's instruction. Our approach enables the fine adjustment of warfarin doses according to changes in INR and contributes to the maintenance of the therapeutic target range and safe and appropriate outpatient chemotherapy.

Background Multi-systemic symptoms of varying severity in myotonic dystrophy type 1 (DM1) may pose difficulties in caregiving. However, the factors which affect their care burden are yet to be sufficiently understood. Objective We investigated care burden and its correlates among caregivers of patients with DM1. Methods General demographic information was obtained from patients with DM1, as well as Barthel index (ADL), body mass index, and genetic information. Patients completed SF-36v2 (health-related quality of life), CES-D (depressive symptoms), and ESS (daytime sleepiness) questionnaires. Caregivers reported their perception of patient's status through these questionnaires, and completed Zarit Caregiver Burden Interview (ZBI). Correlation analysis of these variables were performed, and regression analysis was utilized to assess the relationship between caregiver burden and other variables. Results Forty-three patient-caregiver dyads participated. Mean ZBI score was 20.7±17.4, and 32.6% reported a significant care burden. ZBI correlated with caregiver-reported CES-D, but not with patient-reported CES-D. Both patient-reported and caregiver-reported physical QoL of patients correlated with patient ADL. Multiple regression analysis revealed that the combination of caregiver-reported CES-D, caregiver-reported mental QoL, and genetic characteristics predicted caregiver burden. Conclusions Caregiver burden was felt although patients were relatively well-functioning. Patients' and caregivers' assessment of patients' physical condition were similar. However, they did not agree on the evaluation of the patients' psychological state. Cognitive characteristic of the patients and the caregivers' perception of the patients' state may have affected the results. Future DM1 care strategies need to work on improvement of patient-caregiver communication and provide support for the caregiver's psychological health.

Peripheral intravenous cannulation is one of the most fundamental and common procedures in medicine. Securing a peripheral line is occasionally difficult with the landmark method. Ultrasound guidance has become a standard procedure for central venous cannulation, but its efficacy in achieving peripheral venous cannulation is unclear.To evaluate the effectiveness and safety of ultrasound guidance compared to the landmark method for peripheral intravenous cannulation in adults. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was 29 November 2021.We included randomised controlled trials (RCTs) and quasi-RCTs (RCTs in which participants are systematically allocated based on data such as date of birth or recruitment) comparing the effects of ultrasound guidance to the landmark method for peripheral intravenous cannulation in adults.We used standard Cochrane methods. Our primary outcomes were first-pass success of cannulation, overall success of cannulation, and pain. Our secondary outcomes were procedure time for first-pass cannulation, procedure time for overall cannulation, number of attempts, patient satisfaction, and overall complications. We used GRADE to assess the certainty of the evidence. Placing a peripheral intravenous line in individuals can be classed as 'difficult', 'moderate', or 'easy'. We use the terms 'difficult participants', 'moderate/moderately difficult participants' and 'easy participants' as shorthand to characterise the difficulty level in placing a peripheral line using the landmark method. We used the original studies' definitions of difficulty levels of peripheral intravenous cannulation with the landmark method. We analysed the results in these subgroups: 'difficult participants', 'moderate participants', and 'easy participants'. We did this because we expected the effect of ultrasound-guided peripheral venous cannulation to be largest in participants classed as 'difficult' and smaller in participants classed as 'moderate' and 'easy'. MAIN RESULTS: We included 14 RCTs and two quasi-RCTs involving 2267 participants undergoing peripheral intravenous cannulation. Participants were classed as 'difficult' in 12 studies (880 participants), 'moderate' in one study (401 participants), and 'easy' in one study (596 participants). Two studies (390 participants) did not restrict by landmark method difficulty level. The overall risk of bias assessments ranged from low to high. We judged studies to be at high risk of bias mainly because of concerns about blinding for subjective outcomes. In difficult participants, ultrasound guidance increased the first-pass success of cannulation (risk ratio (RR) 1.50, 95% confidence interval (95% CI) 1.15 to 1.95; 10 studies, 815 participants; low-certainty evidence), and the overall success of cannulation (RR 1.40, 95% CI 1.10 to 1.77; 10 studies, 670 participants; very low-certainty evidence). There was no clear difference in pain (mean difference (MD) -0.20, 95% CI -1.13 to 0.72; 4 studies, 323 participants; very low-certainty evidence; numerical rating scale (NRS) 0 to 10 where 10 is maximum pain). Ultrasound guidance increased the procedure time for first-pass cannulation (MD 119.9 seconds, 95% CI 88.6 to 151.1; 2 studies, 219 participants; low-certainty evidence), and patient satisfaction (standardised mean difference (SMD) 0.49, 95% CI 0.07 to 0.92; 5 studies, 333 participants; very low-certainty evidence; NRS 0 to 10 where 10 is maximum satisfaction). Ultrasound guidance decreased the number of cannulation attempts (MD -0.33, 95% CI -0.64 to -0.02; 9 studies, 568 participants; very low-certainty evidence). Ultrasound guidance showed no clear difference in the procedure time for overall cannulation (MD -24.9 seconds, 95% CI -323.1 to 273.3; 8 studies, 413 participants; very low-certainty evidence) and overall complications (RR 0.64, 95% CI 0.37 to 1.10; 5 studies, 431 participants; low-certainty evidence). In moderate participants, ultrasound guidance increased the first-pass success of cannulation (RR 1.14, 95% CI 1.02 to 1.27; 1 study, 401 participants; moderate-certainty evidence). No studies assessed the overall success of cannulation. There was no clear difference in pain (MD 0.10, 95% CI -0.47 to 0.67; 1 study, 401 participants; low-certainty evidence; NRS 0 to 10 where 10 is maximum pain). Ultrasound guidance increased the procedure time for first-pass cannulation (MD 95.2 seconds, 95% CI 72.8 to 117.6; 1 study, 401 participants; high-certainty evidence). Ultrasound guidance showed no clear difference in overall complications (RR 0.83, 95% CI 0.38 to 1.82; 1 study, 401 participants; moderate-certainty evidence). No studies assessed the procedure time for overall cannulation, number of cannulation attempts, or patient satisfaction. In easy participants, ultrasound guidance decreased the first-pass success of cannulation (RR 0.89, 95% CI 0.85 to 0.94; 1 study, 596 participants; high-certainty evidence). No studies assessed the overall success of cannulation. Ultrasound guidance increased pain (MD 0.60, 95% CI 0.17 to 1.03; 1 study, 596 participants; moderate-certainty evidence; NRS 0 to 10 where 10 is maximum pain). Ultrasound guidance increased the procedure time for first-pass cannulation (MD 94.8 seconds, 95% CI 81.2 to 108.5; 1 study, 596 participants; high-certainty evidence). Ultrasound guidance showed no clear difference in overall complications (RR 2.48, 95% CI 0.90 to 6.87; 1 study, 596 participants; moderate-certainty evidence). No studies assessed the procedure time for overall cannulation, number of cannulation attempts, or patient satisfaction. AUTHORS' CONCLUSIONS: There is very low- and low-certainty evidence that, compared to the landmark method, ultrasound guidance may benefit difficult participants for increased first-pass and overall success of cannulation, with no difference detected in pain. There is moderate- and low-certainty evidence that, compared to the landmark method, ultrasound guidance may benefit moderately difficult participants due to a small increased first-pass success of cannulation with no difference detected in pain. There is moderate- and high-certainty evidence that, compared to the landmark method, ultrasound guidance does not benefit easy participants: ultrasound guidance decreased the first-pass success of cannulation with no difference detected in overall success of cannulation and increased pain.

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: This review aims to assess the effects of pharmacological interventions for osteoporosis in patients with CKD stages 3‐5D.

Background Crohn's disease (CD) is a chronic inflammatory disease of the gastrointestinal tract, and immune response modulation is the main treatment strategy to induce remission in active CD. Certolizumab pegol (CZP) is a tumor necrosis factor-alfa (TNF-α) inhibitor which regulates impaired immune response. Objectives The primary objectives were to evaluate the efficacy and safety of CZP for the induction of remission in CD. Search methods We searched MEDLINE, Embase, CENTRAL, the Cochrane IBD group specialized register, trials registers and other sources from inception to 28 January 2019. Moreover, we contacted the pharmaceutical company that manufactures CZP. Selection criteria We included randomized controlled trials comparing CZP with placebo or no treatment in active CD patients. Data collection and analysis We used standard Cochrane methodological procedures. The main outcomes selected for GRADE analysis were clinical remission at week 8 (Crohn's Disease Activity Index [CDAI] ≤150), clinical response at week 8 (CDAI reduction ≥ 100 or clinical remission), and serious adverse events. The Mantel-Haenszel random-effects method was applied for the statistical analyses. For dichotomous outcomes, we calculated the risk ratio (RR) and corresponding 95% confidence interval (95% CI). Main results Four studies involving 1485 participants with moderate to severe CD met the inclusion criteria and were used in the meta-analyses. All studies included active CD patients with CDAI ranging from 220 to 450. Most patients were adults over 18 years of age. One study was identified as high risk of bias due to a non-identical placebo while the other studies were judged to be at low risk of bias.CZP (100 mg to 400 mg every 2 to 4 weeks) was shown to be superior to placebo for achieving clinical remission at week 8 (RR 1.36, 95% CI 1.11 to 1.66; moderate certainty evidence). The raw numbers of participants achieving clinical remission at week 8 were 26.9% (225/835) and 19.8% (129/650) in the CZP and the placebo groups, respectively.CZP was shown to be superior to placebo for achieving clinical response at week 8 (RR 1.29, 95% CI 1.09 to 1.53; moderate certainty evidence). In raw numbers, clinical response at week 8 was achieved in 40.2% (336/835) and 30.9% (201/650) of participants in the CZP and the placebo groups, respectively.In raw numbers, serious adverse events were observed in 8.7% (73/835) and 6.2% (40/650) of participants in the CZP and the placebo groups, respectively (RR 1.35, 95% CI 0.93 to 1.97; moderate certainty evidence). Serious adverse events included worsening Crohn's disease, infections, and malignancy. Authors' conclusions Moderate certainty evidence suggests that CZP is effective for induction of clinical remission and clinical response in participants with active CD patients. It is uncertain whether the risk of serious adverse events differs between CZP and placebo as the 95% CI includes the possibility of a small decrease or doubling of events. Future studies are needed to evaluate the long-term efficacy and safety of CZP in CD patients.

BACKGROUND: Anxiety frequently coexists with depression and adding benzodiazepines to antidepressant treatment is common practice to treat people with major depression. However, more evidence is needed to determine whether this combined treatment is more effective and not any more harmful than antidepressants alone. It has been suggested that benzodiazepines may lose their efficacy with long‐term administration and their chronic use carries risks of dependence. This is the 2019 updated version of a Cochrane Review first published in 2001, and previously updated in 2005. This update follows a new protocol to conform with the most recent Cochrane methodology guidelines, with the inclusion of 'Summary of findings' tables and GRADE evaluations for quality of evidence. OBJECTIVES: To assess the effects of combining antidepressants with benzodiazepines compared with antidepressants alone for major depression in adults. SEARCH METHODS: We searched the Cochrane Common Mental Disorders Group's Controlled Trials Register (CCMDCTR), the Cochrane Central Register of Controlled Trials, MEDLINE, Embase and PsycINFO to May 2019. We searched the World Health Organization (WHO) trials portal and ClinicalTrials.gov to identify any additional unpublished or ongoing studies. SELECTION CRITERIA: All randomised controlled trials that compared combined antidepressant plus benzodiazepine treatment with antidepressants alone for adults with major depression. We excluded studies administering psychosocial therapies targeted at depression and anxiety disorders concurrently. Antidepressants had to be prescribed, on average, at or above the minimum effective dose as presented by Hansen 2009 or according to the North American or European regulations. The combination therapy had to last at least four weeks. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed risk of bias in the included studies, according to the criteria of the Cochrane Handbook for Systematic Reviews of Interventions. We entered data into Review Manager 5. We used intention‐to‐treat data. We combined continuous outcome variables of depressive and anxiety severity using standardised mean differences (SMD) with 95% confidence intervals (CIs). For dichotomous efficacy outcomes, we calculated the risk ratio (RR) with 95% CI. Regarding the primary outcome of acceptability, only overall dropout rates were available for all studies. MAIN RESULTS: We identified 10 studies published between 1978 to 2002 involving 731 participants. Six studies used tricyclic antidepressants (TCAs), two studies used selective serotonin reuptake inhibitors (SSRIs), one study used another heterocyclic antidepressant and one study used TCA or heterocyclic antidepressant. Combined therapy of benzodiazepines plus antidepressants was more effective than antidepressants alone for depressive severity in the early phase (four weeks) (SMD –0.25, 95% CI –0.46 to –0.03; 10 studies, 598 participants; moderate‐quality evidence), but there was no difference between treatments in the acute phase (five to 12 weeks) (SMD –0.18, 95% CI –0.40 to 0.03; 7 studies, 347 participants; low‐quality evidence) or in the continuous phase (more than 12 weeks) (SMD –0.21, 95% CI –0.76 to 0.35; 1 study, 50 participants; low‐quality evidence). For acceptability of treatment, there was no difference in the dropouts due to any reason between combined therapy and antidepressants alone (RR 0.76, 95% CI 0.54 to 1.07; 10 studies, 731 participants; moderate‐quality evidence). For response in depression, combined therapy was more effective than antidepressants alone in the early phase (RR 1.34, 95% CI 1.13 to 1.58; 10 studies, 731 participants), but there was no evidence of a difference in the acute phase (RR 1.12, 95% CI 0.93 to 1.35; 7 studies, 383 participants) or in the continuous phase (RR 0.97, 95% CI 0.73 to 1.29; 1 study, 52 participants). For remission in depression, combined therapy was more effective than antidepressants alone in the early phase (RR 1.39, 95% CI 1.03 to 1.90, 10 studies, 731 participants), but there was no evidence of a difference in the acute phase (RR 1.27, 95% CI 0.99 to 1.63; 7 studies, 383 participants) or in the continuous phase (RR 1.31, 95% CI 0.80 to 2.16; 1 study, 52 participants). There was no evidence of a difference between combined therapy and antidepressants alone for anxiety severity in the early phase (SMD –0.76, 95% CI –1.67 to 0.14; 3 studies, 129 participants) or in the acute phase (SMD –0.48, 95% CI –1.06 to 0.10; 3 studies, 129 participants). No studies measured severity of insomnia. In terms of adverse effects, the dropout rates due to adverse events were lower for combined therapy than for antidepressants alone (RR 0.54, 95% CI 0.32 to 0.90; 10 studies, 731 participants; moderate‐quality evidence). However, participants in the combined therapy group reported at least one adverse effect more often than participants who received antidepressants alone (RR 1.12, 95% CI 1.01 to 1.23; 7 studies, 510 participants; moderate‐quality evidence). Most domains of risk of bias in the majority of the included studies were unclear. Random sequence generation, allocation concealment, blinding and selective outcome reporting were problematic due to insufficient details reported in most of the included studies and lack of availability of the study protocols. The greatest limitation in the quality of evidence was issues with attrition. AUTHORS' CONCLUSIONS: Combined antidepressant plus benzodiazepine therapy was more effective than antidepressants alone in improving depression severity, response in depression and remission in depression in the early phase. However, these effects were not maintained in the acute or the continuous phase. Combined therapy resulted in fewer dropouts due to adverse events than antidepressants alone, but combined therapy was associated with a greater proportion of participants reporting at least one adverse effect. The moderate quality evidence of benefits of adding a benzodiazepine to an antidepressant in the early phase must be balanced judiciously against possible harms and consideration given to other alternative treatment strategies when antidepressant monotherapy may be considered inadequate. We need long‐term, pragmatic randomised controlled trials to compare combination therapy against the monotherapy of antidepressant in major depression.

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To investigate the effects of fenofibrate on the prevention and progression of diabetic retinopathy.

Makiko Endo,1 Kaori Odaira,2 Ryohei Ono,3 Go Kurauchi,4 Atsushi Koseki,5 Momoko Goto,3 Yumi Sato,4 Seiko Kon,6 Norio Watanabe,7 Norio Sugawara,8 Hiroto Takada,6 En Kimura9 1Clinical Research Unit, National Center Hospital, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8551, Japan; 2Regional Medical Liaison Office, National Hospital Organization, Aomori Hospital, Namioka, Aomori 038-1331, Japan; 3Section for Development and Disability Training, National Hospital Organization, Aomori Hospital, Namioka, Aomori 038-1331, Japan; 4Department of Rehabilitation, National Hospital Organization, Aomori Hospital, Namioka, Aomori 038-1331, Japan; 5Section for Development and Disability Training, National Hospital Organization, Hanamaki Hospital, Hanamaki, Iwate 025-0033, Japan; 6Department of Neurology, National Hospital Organization, Aomori Hospital, Namioka, Aomori 038-1331, Japan; 7School of Public Health, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan; 8Department of Clinical Epidemiology, Translational Medical Center, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8551, Japan; 9Department of Clinical Research Support, Translational Medical Center, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8551, Japan Purpose: Myotonic dystrophy type 1 (DM1) is a common form of muscular dystrophy that presents with a variety of symptoms that can affect patients’ quality of life (QoL). Despite the importance of clarifying patients’ subjective experience in both physical and psychosocial aspects for improved symptom management, there is lack of evidence concerning QoL of patients with DM1 in Japan.Patients and methods: A cross-sectional study was performed with 51 DM1 patients who completed questionnaires that measured health-related QoL (HRQoL), depression, and daytime sleepiness. Activities of daily living, body mass index (BMI), and genetic information were also collected, together with general demographic information. Correlation analyses using these variables were performed. Furthermore, regression analysis was utilized to assess the relationship that HRQoL, depression, and daytime sleepiness scores have with other variables.Results: Physical component summary (PCS) score was affected by the disease more than the mental component summary (MCS) score among study participants. Moderate correlation was observed between PCS and depression, PCS and Barthel index, and depression and daytime sleepiness. Regression analysis revealed that age, sex, cytosine–thymine–guanine repeats, and BMI did not predict the aforementioned dependent variables.Conclusion: DM1 symptoms influenced physical component scores more than mental component scores, although the state of physical wellness seemed to affect patients’ mood. Explaining the QoL of these patients only using biologic and genetic characteristics was not sufficient. We conclude that social and psychological aspects of these patients’ lives and the nature of adjustments made by patients due to DM1 to require further examination in order to improve the standard of care. Keywords: depression, excessive daytime sleepiness, chronic illness, psychosocial perspective&nbsp

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To assess the clinical effectiveness and safety of gabapentinoids in preventing chronic post‐thoracotomy pain after lung surgery in adults. The primary objective is to evaluate the effectiveness of perioperative systemic drugs for the prevention of chronic pain after lung surgery by examining the prevalence of patients reporting pain three months or longer postoperatively.

IntroductionDrug misuse is associated with significant global morbidity, mortality, economic costs and social costs. Many primary care facilities have integrated drug misuse screening and brief intervention (BI) into their usual care delivery. However, the efficacy of BI for drug misuse in primary care has not been substantiated through meta-analysis. The aim of this systematic review and meta-analysis is to determine the efficacy of BI for drug misuse in primary care settings.Methods and analysisWe will include all randomised controlled trials comparing primary care-delivered BI for drug misuse with no intervention or minimal screening/assessment and usual care. Primary outcomes are (1) drug use frequency scores and (2) severity scores at intermediate follow-up (4–8 months). We will retrieve all studies through searches in CENTRAL, Embase, MEDLINE and PsycINFO until 31 May 2020. The reference list will be supplemented with searches in trial registries (eg, www.clinicaltrials.gov) and through relevant existing study reference lists identified in the literature. We will conduct a random-effect pairwise meta-analysis for primary and secondary outcomes. We will assess statistical heterogeneity though visual inspection of a forest plot and calculate I2 statistics. We will assess risk of bias using the Cochrane Risk of Bias Tool V.2 and evaluate the certainty of evidence through the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Sensitivity analyses will account for studies with control group variations and studies with a high risk of bias. If heterogeneity is present, subgroup analyses will consider patient variables of age, sex/gender, race/ethnicity, per cent insured, baseline severity and primary drug misused.Ethics and disseminationThis study will use published aggregate data and will not require ethical approval. Findings will be disseminated in a peer-reviewed journal.

Summary Long-term benzodiazepine (BZD) use is not recommended in the treatment of chronic insomnia, and psychosocial interventions, particularly cognitive behavioral therapy for insomnia (CBT-I), are a potential treatment option for discontinuing BZDs. This systematic review and meta-analysis aimed to clarify whether psychosocial interventions are effective for discontinuing BZD hypnotics in patients with chronic insomnia. A literature search of major electronic databases was conducted up to July 2018. Two researchers independently selected relevant publications, extracted data, and evaluated methodological quality according to the Cochrane criteria. Eight randomized-controlled trials, all of which evaluated CBT-I, were included in this review, and meta-analyses were performed. The results indicated that short-term (≤3 mo) CBT-I plus gradual tapering was more effective than gradual tapering alone for discontinuing BZDs hypnotics (risk ratio: 1.68, 95% confidence interval [CI]: 1.19–2.39, p = 0.003) and for improving insomnia symptoms (g: −0.69, 95% CI: −1.09 – −0.28, p = 0.0009). However, the long-term (12 mo) efficacy of CBT-I for discontinuing BZDs was not significant (risk ratio: 1.67, 95% CI: 0.91–3.07, p = 0.10). Thus, CBT-I is effective for discontinuing BZD hypnotics for ≤3 mo. Further studies are needed to clarify the long-term efficacy of psychosocial interventions for discontinuing BZD hypnotics.