Effectiveness of intravenous methylprednisolone pulse in patients with severe microscopic polyangiitis and granulomatosis with polyangiitis.

OBJECTIVES: To evaluate the effectiveness and safety of two different intravenous methylprednisolone (IVMP) pulse doses in patients with severe microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA). METHODS: We emulated a target trial using observational data from the nationwide registry in Japan. Patients with severe glomerulonephritis or diffuse alveolar haemorrhage were selected and pseudo-randomised into three groups using propensity score-based overlap weighting as follows: non-IVMP, IVMP 0.5 g/day, and IVMP 1.0 g/day. The primary outcome was all-cause death, and the secondary outcomes were composite all-cause death and kidney failure, severe relapse, and serious infection from 2 to 48 weeks after treatment initiation. To estimate the treatment effects, the Cox proportional hazard model and Fine-Gray subdistribution hazard model were used. RESULTS: In this emulated target trial, of 201 eligible patients (MPA, 175; GPA, 26), 6 (2.8%) died, 4 (2.0%) had kidney failure, 11 (5.3%) had severe relapse, and 40 (19.8%) had severe infections. Hazard ratios (HR) for IVMP 0.5 g/day and IVMP 1.0 g/day pulse groups compared with non-IVMP pulse were as follows: all-cause death = 0.46 (95% confidence interval [95%CI]: 0.07-2.81) and 0.07 (95%CI: 0.01-0.41); all-cause death/kidney failure = 1.18 (95%CI: 0.26-5.31) and 0.59 (95%CI: 0.08-4.52); subdistribution HRs for severe relapse = 1.26 (95%CI: 0.12-13.70) and 3.36 (95%CI: 0.49-23.29); and serious infection = 1.88 (95%CI: 0.76-4.65) and 0.94 (95%CI: 0.28-3.13). CONCLUSIONS: IVMP 1.0 g/day pulse may improve 48-week mortality in patients with severe MPA/GPA.

Robust inference methods for meta-analysis involving influential outlying studies.

Meta-analysis is an essential tool to comprehensively synthesize and quantitatively evaluate results of multiple clinical studies in evidence-based medicine. In many meta-analyses, the characteristics of some studies might markedly differ from those of the others, and these outlying studies can generate biases and potentially yield misleading results. In this article, we provide effective robust statistical inference methods using generalized likelihoods based on the density power divergence. The robust inference methods are designed to adjust the influences of outliers through the use of modified estimating equations based on a robust criterion, even when multiple and serious influential outliers are present. We provide the robust estimators, statistical tests, and confidence intervals via the generalized likelihoods for the fixed-effect and random-effects models of meta-analysis. We also assess the contribution rates of individual studies to the robust overall estimators that indicate how the influences of outlying studies are adjusted. Through simulations and applications to two recently published systematic reviews, we demonstrate that the overall conclusions and interpretations of meta-analyses can be markedly changed if the robust inference methods are applied and that only the conventional inference methods might produce misleading evidence. These methods would be recommended to be used at least as a sensitivity analysis method in the practice of meta-analysis. We have also developed an R package, robustmeta, that implements the robust inference methods.

Variance Estimation for Logistic Regression in Case-cohort Studies.

BACKGROUND: The logistic regression analysis proposed by Schouten et al (Stat Med. 1993;12:1733-1745) has been a standard method in current statistical analysis of case-cohort studies, and it enables effective estimation of risk ratios from selected subsamples, with adjustment of potential confounding factors. Schouten et al (1993) also proposed the standard error estimate of the risk ratio estimator can be calculated using the robust variance estimator, and this method has been widely adopted. METHODS AND RESULTS: The robust variance estimator does not account for the duplications of case and subcohort samples and generally has certain bias (ie, inaccurate confidence intervals and P-values are possibly obtained). To address the invalid statistical inference problem, we provide an alternative bootstrap-based valid variance estimator. Through simulation studies, the bootstrap method consistently provided more precise confidence intervals compared with those provided using the robust variance method, while retaining adequate coverage probabilities. CONCLUSION: The robust variance estimator has certain bias, and inadequate conclusions might be deduced from the resultant statistical analyses. The proposed bootstrap variance estimator can provide more accurate and precise interval estimates. The bootstrap method would be an alternative effective approach in practice to provide accurate evidence.

Anti-vascular endothelial growth factor biosimilars for neovascular age-related macular degeneration.

RATIONALE: Neovascular age-related macular degeneration (AMD) is a progressive eye disease characterized by choroidal neovascularization (CNV) and is a leading cause of vision loss and disability worldwide. Although intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy is an effective treatment option that helps to prevent vision loss or to improve visual acuity in people with neovascular AMD, treatment imposes a significant financial burden on patients and healthcare systems. A biosimilar is a biological product that has been developed to be nearly identical to a previously approved biological product. The use of biosimilars may help reduce costs and so may increase patient access to effective biologic medicines with similar levels of safety to the drugs on which they are based. OBJECTIVES: To assess the benefits and harms of anti-VEGF biosimilar agents compared with their corresponding anti-VEGF agents (i.e. the reference products) that have obtained regulatory approval for intravitreal injections in people with neovascular AMD. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, two other databases, and two trials registries together with reference checking and contact with study authors to identify studies that are included in the review. The latest search date was 2 June 2023. ELIGIBILITY CRITERIA: We included randomized controlled trials (RCTs) that compared approved anti-VEGF biosimilars with their reference products for treating the eyes of adult participants (≥ 50 years) who had an active primary or recurrent choroidal neovascularization lesion secondary to neovascular AMD. OUTCOMES: Our outcomes were: best-corrected visual acuity (BCVA), central subfield thickness (CST), vision-related quality of life, serious ocular and non-ocular adverse events (AE), treatment-emergent adverse events (TEAEs), anti-drug antibodies (ADAs), and serum concentrations of biosimilars and reference drugs. RISK OF BIAS: We assessed the risk of bias (RoB) for seven outcomes reported in a summary of findings table by using the Cochrane RoB 2 tool. SYNTHESIS METHODS: We synthesized results for each outcome using meta-analysis, where possible, by calculating risk ratios (RR) and mean differences (MD) with 95% confidence intervals (CI) for dichotomous outcomes and continuous outcomes, respectively. Where this was not possible due to the nature of the data, we summarized the results narratively. We used GRADE to assess the certainty of evidence for prespecified outcomes. INCLUDED STUDIES: We included nine parallel-group multi-center RCTs that enrolled a total of 3814 participants (3814 participating eyes), with sample sizes that ranged from 160 to 705 participants per study. The mean age of the participants in these studies ranged from 67 to 76 years, and the proportion of women ranged from 26.5% to 58.7%. Ranibizumab (Lucentis) was the reference product in seven studies, and aflibercept (Eyelea) was the reference product in two others. All the included studies had been supported by industry. The follow-up periods ranged from 12 to 52 weeks (median 48 weeks). Five studies (56%) were conducted in multi-country settings across Europe, North America and Asia, two studies in India, and one each in Japan and the Republic of Korea. We judged all the included studies to have met high methodological standards. SYNTHESIS OF RESULTS: With regard to efficacy, our meta-analyses demonstrated that anti-VEGF biosimilars for neovascular AMD resulted in little to no difference compared with the reference products for BCVA change at 8 to 12 weeks (MD -0.55 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, 95% CI -1.17 to 0.07; 8 studies, 3603 participants; high-certainty evidence) and the proportion of participants who lost fewer than 15 letters in BCVA at 24 to 48 weeks (RR 0.99, 95% CI 0.98 to 1.01; 7 studies, 2658 participants; moderate-certainty evidence). Almost all participants (96.6% in the biosimilar group and 97.0% in the reference product group) lost fewer than 15 letters in BCVA. The evidence from two studies suggested that there was no evidence of difference between biosimilars and reference products in vision-related quality of life measured by the 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ-25) summary scores at 24 to 48 weeks (MD 0.82, 95% CI -0.70 to 2.35; 2 studies, 894 participants; moderate-certainty evidence). With regard to the safety profile, meta-analyses also revealed little to no difference between anti-VEGF biosimilars and the reference products for the proportion of participants who experienced serious ocular AEs (RR 1.24, 95% CI 0.68 to 2.26; 7 studies, 3292 participants; moderate-certainty evidence), and for TEAEs leading to investigational product discontinuation or death (RR 0.96, 95% CI 0.63 to 1.46; 8 studies, 3497 participants; moderate-certainty evidence). Overall, 1.4% of participants in the biosimilar group and 1.2% in the reference product group experienced serious ocular adverse events. The most frequently documented serious ocular AEs were retinal hemorrhage and endophthalmitis. Although the evidence is of low certainty due to imprecision, meta-analysis suggested that anti-VEGF biosimilars led to no difference compared with the reference products for cumulative incidence of ADAs (RR 0.84, 95% CI 0.58 to 1.22; 8 studies, 3066 participants; low-certainty evidence) or mean maximum serum concentrations (MD 0.42 ng/mL, 95% CI -0.22 to 1.05; subgroup of 3 studies, 100 participants; low-certainty evidence). We judged the overall risk of bias to be low for all studies. AUTHORS' CONCLUSIONS: In our review, low to high certainty evidence suggests that there is little to no difference, to date, between the anti-VEGF biosimilars approved for treating neovascular AMD and their reference products in terms of benefits and harms. While anti-VEGF biosimilars may be a viable alternative to reference products, current evidence for their use is based on a limited number of studies - particularly for comparison with aflibercept - with sparse long-term safety data, and infrequent assessment of quality of life outcomes. Our effect estimates and conclusions may be modified once findings have been reported from studies that are currently ongoing, and studies of biosimilar agents that are currently in development. FUNDING: Cochrane Eyes and Vision US Project is supported by grant UG1EY020522, National Eye Institute, National Institutes of Health. Takeshi Hasegawa and Hisashi Noma were supported by Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (Grant numbers: 22H03554, 19K03092, 24K06239). REGISTRATION: Protocol available via doi.org/10.1002/14651858.CD015804.

Efficacy of carbapenems and alternative antimicrobials for treating complicated urinary tract infections caused by third-generation cephalosporin-resistant gram-negative bacteria: A systematic review and meta-analysis of randomised controlled trials.

BACKGROUND: Specific data concerning the efficacy of alternative antibiotics for carbapenems against complicated urinary tract infections (cUTIs) attributed to antimicrobial-resistant (AMR) uropathogens are lacking. OBJECTIVES: This study aimed to assess the efficacy of carbapenems and non-carbapenem antibiotics in the clinical outcomes of cUTIs caused by AMR uropathogens. METHODS: In this systematic review and meta-analysis, databases, including MEDLINE/PubMed, the Cochrane Library, Embase and ClinicalTrials.gov, were searched. The study eligibility criteria were research articles conducted as randomised controlled trials that evaluated the composite outcomes of cUTIs. Participants were adult patients with cUTIs caused by gram-negative uropathogens resistant to third-generation cephalosporins. The intervention involved a non-carbapenem class of antimicrobial agents with in vitro activities against gram-negative uropathogens resistant to third-generation cephalosporins. Two independent researchers assessed the risk-of-bias using the second version of the Cochrane risk-of-bias tool for randomised trials. The treatment effects on each outcome were estimated as a risk ratio (RR) with a 95 % confidence interval (CI) using the random-effects model. Heterogeneity was assessed using the Cochrane Q-test and I2 statistics. RESULTS: Through database searches, 955 articles were retrieved. After screening the titles and abstracts, 52 articles were screened in full text. Finally, 12 studies met the inclusion criteria. No significant differences in efficacy were observed between alternative antibiotics and carbapenems (composite outcome, RR, 0.96; 95 % CI, 0.63-1.49; I2 = 21 %; low certainty of evidence). CONCLUSIONS: Alternative antibiotics had clinical efficacy similar to that of carbapenems for treating patients with cUTI caused by gram-negative uropathogens resistant to third-generation cephalosporins.

Comparison of perioperative outcomes and complications between intracorporeal, extracorporeal, and hybrid ileal conduit urinary diversion during robot-assisted radical cystectomy: a comparative propensity score-matched analysis from nationwide multi-institutional study in Japan.

BACKGROUND: To investigate the impact of different urinary diversion (UD) techniques on the peri- and postoperative complications of robot-assisted radical cystectomy (RARC) with ileal conduit. METHODS: We retrospectively analyzed 373 patients undergoing RARC with ileal conduit at 11 institutions in Japan between April 2018 and December 2021. Propensity score weighting was performed to adjust for confounding factors such as age, sex, body mass index, performance status, American Society of Anesthesiologists score, previous abdominal surgery, neoadjuvant chemotherapy, and preoperative high T stage (≥ cT3) and high N stage (≥ cN1). Perioperative complications were then compared among three groups: extracorporeal, intracorporeal, and hybrid urinary diversion (ECUD, ICUD, and HUD, respectively). RESULTS: A total of 150, 68, and 155 patients received ECUD, HUD, and ICUD, respectively. Bowel reconstruction time and UD time were significantly shorter in the ECUD group (p < 0.001), and console time was significantly longer and blood loss was significantly higher in the ICUD group (p < 0.001). For postoperative complications (Clavien-Dindo Classification grade ≥ 3), surgical site infection (p = 0.004), pelvic abscess (p = 0.013), anastomotic urine leak (p = 0.007), and pelvic organ prolapse (p = 0.011) significantly occurred in the ECUD group. For all grades, ileus was more common in the HUD group, whereas anastomotic stricture was more common in the ECUD group compared with the other groups (p < 0.05). CONCLUSIONS: Severe complications did not increase after HUD and ICUD compared with ECUD; however, console time tended to be longer and blood loss was slightly higher during RARC.

Optimizing smartphone psychotherapy for depressive symptoms in patients with cancer: Multiphase optimization strategy using a decentralized multicenter randomized clinical trial (J-SUPPORT 2001 Study).

AIM: Patients with cancer experience various forms of psychological distress, including depressive symptoms, which can impact quality of life, elevate morbidity risk, and increase medical costs. Psychotherapy and pharmacotherapy are effective for reducing depressive symptoms among patients with cancer, but most patients prefer psychotherapy. This study aimed to develop an efficient and effective smartphone psychotherapy component to address depressive symptom. METHODS: This was a decentralized, parallel-group, multicenter, open, individually randomized, fully factorial trial. Patients aged ≥20 years with cancer were randomized by the presence/absence of three cognitive-behavioral therapy (CBT) skills (behavioral activation [BA], assertiveness training [AT], and problem-solving [PS]) on a smartphone app. All participants received psychoeducation (PE). The primary outcome was change in the patient health questionnaire-9 (PHQ-9) total score between baseline and week 8. Secondary outcomes included anxiety. RESULTS: In total, 359 participants were randomized. Primary outcome data at week 8 were obtained for 355 participants (99%). The week 8 PHQ-9 total score was significantly reduced from baseline for all participants by -1.41 points (95% confidence interval [CI] -1.89, -0.92), but between-group differences in change scores were not significant (BA: -0.04, 95% CI -0.75, 0.67; AT: -0.16, 95% CI -0.87, 0.55; PS: -0.19, 95% CI -0.90, 0.52). CONCLUSION: As the presence of any of the three intervention components did not contribute to a significant additive reduction of depressive symptoms, we cannot make evidence-based recommendations regarding the use of specific smartphone psychotherapy.

Three types of university students with subthreshold depression characterized by distinctive cognitive behavioral skills.

Subthreshold depression impairs young people's quality of life and places them at greater risk of developing major depression. Cognitive behavioral therapy (CBT) is an evidence-based approach for addressing such depressive states. This study identified subtypes of university students with subthreshold depression and revealed discrete profiles of five CBT skills: self-monitoring, cognitive restructuring, behavioral activation, assertive communication, and problem solving. Using data from the Healthy Campus Trial (registration number: UMINCTR-000031307), a hierarchical clustering analysis categorized 1,080 students into three clusters: Reflective Low-skilled, Non-reflective High-skilled, and Non-reflective Low-skilled students. Non-reflective Low-skilled students were significantly more depressed than other students (p < .001). The severity of depression seemed to be related to the combination of self-monitoring skills and other CBT skills. Considering the high prevalence of poor self-monitoring skills in persons with autism, the most severe depression was observed in the significant association between Non-reflective Low-skilled students and autistic traits (p = .008). These findings suggest that subthreshold depression can be categorized into three subtypes based on CBT skill profiles. The assessment of autistic traits is also suggested when we provide CBT interventions for Non-reflective Low-skilled students.

Association between hypogammaglobulinaemia and severe infections during induction therapy in ANCA-associated vasculitis: from J-CANVAS study.

OBJECTIVES: To investigate the association between decreased serum IgG levels caused by remission-induction immunosuppressive therapy of antineutrophil cytoplasmic antibody-associated vasculitis (AAV) and the development of severe infections. METHODS: We conducted a retrospective cohort study of patients with new-onset or severe relapsing AAV enrolled in the J-CANVAS registry, which was established at 24 referral sites in Japan. The minimum serum IgG levels up to 24 weeks and the incidence of severe infection up to 48 weeks after treatment initiation were evaluated. After multiple imputations for all explanatory variables, we performed the multivariate analysis using a Fine-Gray model to assess the association between low IgG (the minimum IgG levels <500 mg/dl) and severe infections. In addition, the association was expressed as a restricted cubic spline (RCS) and analysed by treatment subgroups. RESULTS: Of 657 included patients (microscopic polyangiitis, 392; granulomatosis with polyangiitis, 139; eosinophilic granulomatosis with polyangiitis, 126), 111 (16.9%) developed severe infections. The minimum serum IgG levels were measured in 510 patients, of whom 77 (15.1%) had low IgG. After multiple imputations, the confounder-adjusted hazard ratio of low IgG for the incidence of severe infections was 1.75 (95% confidence interval: 1.03-3.00). The RCS revealed a U-shaped association between serum IgG levels and the incidence of severe infection with serum IgG 946 mg/dl as the lowest point. Subgroup analysis showed no obvious heterogeneity between treatment regimens. CONCLUSION: Regardless of treatment regimens, low IgG after remission-induction treatment was associated with the development of severe infections up to 48 weeks after treatment initiation.

Which psychotherapy is most effective and acceptable in the treatment of adults with a (sub)clinical borderline personality disorder? A systematic review and network meta-analysis.

A broad range of psychotherapies have been proposed and evaluated in the treatment of borderline personality disorder (BPD), but the question which specific type of psychotherapy is most effective remains unanswered. In this study, two network meta-analyses (NMAs) were conducted investigating the comparative effectiveness of psychotherapies on (1) BPD severity and (2) suicidal behaviour (combined rate). Study drop-out was included as a secondary outcome. Six databases were searched until 21 January 2022, including RCTs on the efficacy of any psychotherapy in adults (⩾18 years) with a diagnosis of (sub)clinical BPD. Data were extracted using a predefined table format. PROSPERO ID:CRD42020175411. In our study, a total of 43 studies (N = 3273) were included. We found significant differences between several active comparisons in the treatment of (sub)clinical BPD, however, these findings were based on very few trials and should therefore be interpreted with caution. Some therapies were more efficacious compared to GT or TAU. Furthermore, some treatments more than halved the risk of attempted suicide and committed suicide (combined rate), reporting RRs around 0.5 or lower, however, these RRs were not statistically significantly better compared to other therapies or to TAU. Study drop-out significantly differed between some treatments. In conclusion, no single treatment seems to be the best choice to treat people with BPD compared to other treatments. Nevertheless, psychotherapies for BPD are perceived as first-line treatments, and should therefore be investigated further on their long-term effectiveness, preferably in head-to-head trials. DBT was the best connected treatment, providing solid evidence of its effectiveness.

A comparison of bias-adjusted generalized estimating equations for sparse binary data in small-sample longitudinal studies.

Using a generalized estimating equation (GEE) can lead to a bias in regression coefficients for a small sample or sparse data. The bias-corrected GEE (BCGEE) and penalized GEE (PGEE) were proposed to resolve the small-sample bias. Moreover, the standard sandwich covariance estimator leads to a bias of standard error for small samples; several modified covariance estimators have been proposed to address this issue. We review the modified GEEs and modified covariance estimators, and evaluate their performance in sparse binary data from small-sample longitudinal studies. The simulation results showed that GEE and BCGEE often failed to achieve convergence, whereas the convergence proportion for PGEE was quite high. The bias for the regression coefficients was generally in the ascending order of PGEE < $$ < $$ BCGEE < $$ < $$ GEE. However, PGEE and BCGEE did not sufficiently remove the bias involving 20-30 subjects with unequal exposure levels with a 5% response rate. The coverage probability (CP) of the confidence interval for BCGEE was relatively poor compared with GEE and PGEE. The CP with the sandwich covariance estimator deteriorated regardless of the GEE methods under the small sample size and low response rate, whereas the CP with the modified covariance estimators-such as Morel's method-was relatively acceptable. PGEE will be the reasonable way for analyzing sparse binary data in small-sample studies. Instead of using the standard sandwich covariance estimator, one should always apply the modified covariance estimators for analyzing these data.

Diagnostic accuracy of point-of-care ultrasound for shock: a systematic review and meta-analysis.

BACKGROUND: Circulatory failure is classified into four types of shock (obstructive, cardiogenic, distributive, and hypovolemic) that must be distinguished as each requires a different treatment. Point-of-care ultrasound (POCUS) is widely used in clinical practice for acute conditions, and several diagnostic protocols using POCUS for shock have been developed. This study aimed to evaluate the diagnostic accuracy of POCUS in identifying the etiology of shock. METHODS: We conducted a systematic literature search of MEDLINE, Cochrane Central Register of Controlled Trials, Embase, Web of Science, Clinicaltrial.gov, European Union Clinical Trials Register, WHO International Clinical Trials Registry Platform, and University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) until June 15, 2022. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and assessed study quality using the Quality Assessment of Diagnostic Accuracy Studies 2 tool. Meta-analysis was conducted to pool the diagnostic accuracy of POCUS for each type of shock. The study protocol was prospectively registered in UMIN-CTR (UMIN 000048025). RESULTS: Of the 1553 studies identified, 36 studies were full-text reviewed, and 12 studies with 1132 patients were included in the meta-analysis. Pooled sensitivity and specificity were 0.82 [95% confidence interval (CI) 0.68-0.91] and 0.98 [95% CI 0.92-0.99] for obstructive shock, 0.78 [95% CI 0.56-0.91] and 0.96 [95% CI 0.92-0.98] for cardiogenic shock, 0.90 [95% CI 0.84-0.94] and 0.92 [95% CI 0.88-0.95] for hypovolemic shock, and 0.79 [95% CI 0.71-0.85] and 0.96 [95% CI 0.91-0.98] for distributive shock, respectively. The area under the receiver operating characteristic curve for each type of shock was approximately 0.95. The positive likelihood ratios for each type of shock were all greater than 10, especially 40 [95% CI 11-105] for obstructive shock. The negative likelihood ratio for each type of shock was approximately 0.2. CONCLUSIONS: The identification of the etiology for each type of shock using POCUS was characterized by high sensitivity and positive likelihood ratios, especially for obstructive shock.

Identifying risk factors for adverse events of pyridoxal phosphate in infantile epileptic spasms syndrome.

INTRODUCTION: Infantile epileptic spasms syndrome (IESS) is characterized by epileptic spasms, regardless of hypsarrhythmia on electroencephalogram or neurodevelopmental delay. In Japan, pyridoxal 5'-phosphate (PLP) is often used as the first-line treatment for IESS because it is effective in a certain number of patients. Although several studies have reported serious adverse events following PLP treatment, no study has investigated the risk factors for such occurrences. OBJECTIVE: To investigate adverse events associated with PLP therapy for the treatment of IESS and to identify the associated risk factors. MATERIALS AND METHODS: We retrospectively evaluated adverse events in 59 patients with IESS at Tottori University Hospital between January 1995 and September 2022. We subsequently collected and analyzed their clinical data and analyzed the risk factors associated with each adverse event. The cutoff values and relative risk (RR) were analyzed for items with significant associations with adverse events. RESULTS: Twenty-seven (51.9%) participants experienced adverse events, including vomiting in 16 participants (59.3%), elevated liver enzyme levels in 15 participants (55.6%), and rhabdomyolysis in two participants (3.4%). No significant differences were observed between the non-adverse events group and the overall adverse events group, as well as between the non-adverse events group and the vomiting group, in terms of the factors examined. However, when comparing the non-adverse events group with the group with elevated liver enzyme levels, age at PLP treatment showed a negative correlation, whereas PLP dose showed a positive correlation with elevated liver enzyme levels. The cutoff dose was 40 mg/kg/day (73.3% sensitivity and 60.7% specificity), and the cutoff age was 9 months (100% sensitivity and 40.0% specificity). RRs of doses ≥40 mg/kg/day and age <9 months were 2.6 and 3.6, respectively. CONCLUSIONS: Adverse events of PLP therapy, including vomiting, elevated liver enzymes, and rhabdomyolysis, were observed in approximately half of the participants. Age under 9 months and a dose ≥40 mg/kg/day were identified as risk factors for elevation of liver enzymes on PLP treatment in infants with IESS, with rhabdomyolysis can occur in the younger or higher dose cases.

Risk Ratio and Risk Difference Estimation in Case-cohort Studies.

BACKGROUND: In case-cohort studies with binary outcomes, ordinary logistic regression analyses have been widely used because of their computational simplicity. However, the resultant odds ratio estimates cannot be interpreted as relative risk measures unless the event rate is low. The risk ratio and risk difference are more favorable outcome measures that are directly interpreted as effect measures without the rare disease assumption. METHODS: We provide pseudo-Poisson and pseudo-normal linear regression methods for estimating risk ratios and risk differences in analyses of case-cohort studies. These multivariate regression models are fitted by weighting the inverses of sampling probabilities. Also, the precisions of the risk ratio and risk difference estimators can be improved using auxiliary variable information, specifically by adapting the calibrated or estimated weights, which are readily measured on all samples from the whole cohort. Finally, we provide computational code in R (R Foundation for Statistical Computing, Vienna, Austria) that can easily perform these methods. RESULTS: Through numerical analyses of artificially simulated data and the National Wilms Tumor Study data, accurate risk ratio and risk difference estimates were obtained using the pseudo-Poisson and pseudo-normal linear regression methods. Also, using the auxiliary variable information from the whole cohort, precisions of these estimators were markedly improved. CONCLUSION: The ordinary logistic regression analyses may provide uninterpretable effect measure estimates, and the risk ratio and risk difference estimation methods are effective alternative approaches for case-cohort studies. These methods are especially recommended under situations in which the event rate is not low.

Evaluation of the Characteristics of Ovarian Endometriomas in Patients with Endometriosis: Efficacy of a Low-Dose Estrogen/Progestogen Combination.

OBJECTIVES: Approximately 17-44% of women diagnosed with endometriosis have ovarian endometriomas (cysts). Although ovarian endometriomas may adversely affect quality of life and work performance, the associations among patient characteristics, cyst size, and pain in women with endometriosis have not yet been reported. Thus, the objective of this study was to assess the association among age, cyst size, and pain in women with ovarian endometriomas. DESIGN: This was a retrospective secondary analysis of pooled data from six randomized clinical trials on the use of low-dose estrogen/progestogen drugs for endometriosis. PARTICIPANTS/MATERIALS, SETTING, AND METHODS: Data on 491 patients enrolled in four randomized and two nonrandomized trials between 2003 and 2017 were pooled. None of the participants had undergone surgical treatment before trial participation. We examined differences in dysmenorrhea score, menstrual pain score, analgesic score, and pelvic pain, as measured using a visual analog scale (VAS), by age and endometrioma size. RESULTS: The mean dysmenorrhea, menstrual pain, and analgesic scores were 4.2, 2.2, and 2.0, respectively. The mean VAS for pelvic pain was 55, which decreased significantly with an increase in age. Age was not associated with endometrioma size, including volume and maximum diameter, or dysmenorrhea score. Additionally, endometrioma volume and maximum diameter were not associated with menstrual pain, analgesic score, or pelvic pain. LIMITATIONS: The details of past treatment history were not available; therefore, these could not be considered in the analysis. Additionally, the assessment of pain is heavily influenced by psychological factors, making it difficult to assess the true extent of pain. CONCLUSIONS: Endometrioma size was not associated with dysmenorrhea or pelvic pain measured using the VAS.

The effects of psychological treatments of depression in children and adolescents on response, reliable change, and deterioration: a systematic review and meta-analysis.

Meta-analyses show that psychotherapies are effective in the treatment of depression in children and adolescents. However, these effects are usually reported in terms of effect sizes. For patients and clinicians, it is important to know whether patients achieve a clinically significant improvement or deterioration. We conducted such a meta-analysis to examine response, clinically significant change, clinically significant deterioration and recovery as outcomes. We searched four bibliographic databases and included 40 randomised trials comparing psychotherapy for youth depression against control conditions. We used a validated method to estimate outcome rates, based on means, standard deviation and N at baseline and post-test. We also calculated numbers-need-to- treat (NNT). The overall response rate in psychotherapies at 2 (±1) months after baseline was 39% (95% CI: 34-45) and 24% (95% CI: 0.19-28) in control conditions (NNT: 6.2). The difference between therapy and control was still significant at 6-12 months after baseline (NNT=7.8). Clinically significant improvement was found in 54% of youth in therapy, compared with 32% in control groups (NNT=5.3); clinically significant deterioration was 6% in therapy, 13% in controls (NNT=5.1); recovery was 58% in therapy, 36% in controls (NNT=3.3). Smaller effects were found in studies with low risk of bias. Psychotherapies for depression in youth are effective compared to control conditions, but more than 60% of youth receiving therapy do not respond. More effective treatments and treatment strategies are clearly needed. Trial registration https://osf.io/84xka.

A unified method for improved inference in random effects meta-analysis.

Random effects meta-analyses have been widely applied in evidence synthesis for various types of medical studies. However, standard inference methods (e.g. restricted maximum likelihood estimation) usually underestimate statistical errors and possibly provide highly overconfident results under realistic situations; for instance, coverage probabilities of confidence intervals can be substantially below the nominal level. The main reason is that these inference methods rely on large sample approximations even though the number of synthesized studies is usually small or moderate in practice. In this article, we solve this problem using a unified inference method based on Monte Carlo conditioning for broad application to random effects meta-analysis. The developed method provides improved confidence intervals with coverage probabilities that are closer to the nominal level than standard methods. As specific applications, we provide new inference procedures for three types of meta-analysis: conventional univariate meta-analysis for pairwise treatment comparisons, meta-analysis of diagnostic test accuracy, and multiple treatment comparisons via network meta-analysis. We also illustrate the practical effectiveness of these methods via real data applications and simulation studies.

Meta-analysis Using Flexible Random-effects Distribution Models.

BACKGROUND: In meta-analysis, the normal distribution assumption has been adopted in most systematic reviews of random-effects distribution models due to its computational and conceptual simplicity. However, this restrictive model assumption is possibly unsuitable and might have serious influences in practices. METHODS: We provide two examples of real-world evidence that clearly show that the normal distribution assumption is explicitly unsuitable. We propose new random-effects meta-analysis methods using five flexible random-effects distribution models that can flexibly regulate skewness, kurtosis and tailweight: skew normal distribution, skew t-distribution, asymmetric Subbotin distribution, Jones-Faddy distribution, and sinh-arcsinh distribution. We also developed a statistical package, flexmeta, that can easily perform these methods. RESULTS: Using the flexible random-effects distribution models, the results of the two meta-analyses were markedly altered, potentially influencing the overall conclusions of these systematic reviews. CONCLUSION: The restrictive normal distribution assumption in the random-effects model can yield misleading conclusions. The proposed flexible methods can provide more precise conclusions in systematic reviews.

Walking speed is associated with postoperative pain catastrophizing in patients with lumbar spinal stenosis: a prospective observational study.

BACKGROUND: The purpose of this study was to investigate whether walking speed is associated with postoperative pain catastrophizing in patients with lumbar spinal stenosis. METHODS: In this prospective observational study, consecutive patients with clinically and radiologically defined lumbar spinal stenosis underwent surgical treatment (decompression, or posterolateral or transforaminal lumbar interbody fusion) at Tottori University Hospital, between October 2015 and April 2018. The pain catastrophizing scale, walking speed, leg and back pain (numerical rating scale), and Japanese Orthopaedic Association score were evaluated preoperatively and at 3, 6, and 12 months postoperatively. Correlations between the pain catastrophizing scale and each variable were analyzed at each evaluation time point. The effect of walking speed on the pain catastrophizing scale was analyzed using mixed-effect models for repeated measurements. RESULTS: Ninety-four patients were included at baseline, and 83, 88, and 82 patients were analyzed at 3, 6, and 12 months postoperatively, respectively. The pain catastrophizing scale was significantly correlated with walking speed, leg pain, back pain, and the Japanese Orthopaedic Association score at all evaluation time points. The pain catastrophizing scale was associated with walking speed at all evaluation time points. CONCLUSIONS: Our results suggest that changes in postoperative pain catastrophizing after lumbar spine surgery are associated with walking speed. Thus, walking speed is a necessary assessment for the management of pain catastrophizing and associated pain and disability in patients after lumbar spine surgery.

Efficient testing and effect size estimation for set-based genetic association inference via semiparametric multilevel mixture modeling.

In genetic association studies, rare variants with extremely low allele frequencies play a crucial role in complex traits. Therefore, set-based testing methods that jointly assess the effects of groups of single nucleotide polymorphisms (SNPs) were developed to increase the powers of the association tests. However, these powers are still insufficient, and precise estimations of the effect sizes of individual SNPs are largely impossible. In this article, we provide an efficient set-based statistical inference framework that addresses both of these important issues simultaneously using an empirical Bayes method with semiparametric multilevel mixture modeling. We propose to utilize the hierarchical model that incorporates variations in set-specific effects and to apply the optimal discovery procedure (ODP) that achieves the largest overall power in multiple significance testing. In addition, we provide an optimal "set-based" estimator of the empirical distribution of effect sizes. The efficiency of the proposed methods is demonstrated through application to a genome-wide association study of coronary artery disease and through simulation studies. The results demonstrated numerous rare variants with large effect sizes for coronary artery disease, and the number of significant sets detected by the ODP was much greater than those identified by existing methods.