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.

Image Quality and Lesion Detection of Multiplanar Reconstruction Images Using Deep Learning: Comparison with Hybrid Iterative Reconstruction.

Background: We assessed and compared the image quality of normal and pathologic structures as well as the image noise in chest computed tomography images using "adaptive statistical iterative reconstruction-V" (ASiR-V) or deep learning reconstruction "TrueFidelity". Methods: Forty consecutive patients with suspected lung disease were evaluated. The 1.25-mm axial images and 2.0-mm coronal multiplanar images were reconstructed under the following three conditions: (i) ASiR-V, lung kernel with 60% of ASiR-V; (ii) TF-M, standard kernel, image filter (Lung) with TrueFidelity at medium strength; and (iii) TF-H, standard kernel, image filter (Lung) with TrueFidelity at high strength. Two radiologists (readers) independently evaluated the image quality of anatomic structures using a scale ranging from 1 (best) to 5 (worst). In addition, readers ranked their image preference. Objective image noise was measured using a circular region of interest in the lung parenchyma. Subjective image quality scores, total scores for normal and abnormal structures, and lesion detection were compared using Wilcoxon's signed-rank test. Objective image quality was compared using Student's paired t-test and Wilcoxon's signed-rank test. The Bonferroni correction was applied to the P value, and significance was assumed only for values of P < 0.016. Results: Both readers rated TF-M and TF-H images significantly better than ASiR-V images in terms of visualization of the centrilobular region in axial images. The preference score of TF-M and TF-H images for reader 1 were better than that of ASiR-V images, and the preference score of TF-H images for reader 2 were significantly better than that of ASiR-V and TF-M images. TF-M images showed significantly lower objective image noise than ASiR-V or TF-H images. Conclusion: TrueFidelity showed better image quality, especially in the centrilobular region, than ASiR-V in subjective and objective evaluations. In addition, the image texture preference for TrueFidelity was better than that for ASiR-V.

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.

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.

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.

Association between phase angle and clinical outcomes in patients with lumbar spinal stenosis from the preoperative to 12-month postoperative period: A prospective observational study.

No reports of longitudinal studies on phase angle (PhA) in lumbar spinal stenosis (LSS) exist, and its association with postoperative clinical outcomes is unclear. We longitudinally investigated PhA in patients with LSS preoperatively to 12 months postoperatively and determined the association between PhA and the Japanese Orthopedic Association (JOA) score. This prospective observational study included patients who underwent consecutive surgical treatments for clinically and radiologically defined LSS. Outcome measures including walking speed, Timed Up and Go test (TUG), JOA score, and PhA based on bioelectrical impedance analysis were measured preoperatively and at 3, 6, and 12 months postoperatively. Correlations between PhA and the JOA score and motor function were analyzed. The effect of PhA on JOA scores was evaluated using mixed-effect models for repeated measurements (MMRM). Eighty-nine patients were included at baseline, and 85, 85, and 78 patients were analyzed at 3, 6, and 12 months postoperatively, respectively. PhA was 3.9 ± 0.8 (p = 0.086), 4.0 ± 0.8 (p = 0.644), and 4.1 ± 0.9 (p = 0.791) at 3, 6, and 12 months postoperatively and 4.2 ± 0.8 at baseline. PhA was significantly correlated with the JOA score (p < 0.01) and walking speed and TUG results (p < 0.01) at all assessment points. In the MMRM, PhA was associated with the JOA score at all assessment points. Changes in postoperative JOA scores after lumbar spine surgery are associated with PhA at each assessment time point. PhA may be a useful postoperative clinical indicator after surgery for LSS.

Associations of vitamin D receptor activators and calcimimetics with falls and effect modifications by physical activity: A prospective cohort study on the Japan Dialysis Outcomes and Practice Patterns Study.

INTRODUCTION: This study aimed to examine the associations of vitamin D receptor activators (VDRA) and calcimimetics use with falls. METHODS: This is a prospective cohort study on hemodialysis patients in the Japan Dialysis Outcomes and Practice Patterns Study. We excluded those who were unable to walk. The associations of VDRA or calcimimetics use with falls and effect modifications by physical activity were analyzed using marginal structural models. RESULTS: In total, 1875 patients were included. VDRA and calcimimetics use was not associated with falls (risk ratio [95% CI]: 1.13 [0.84-1.51] and 1.02 [0.72-1.44]). The risk ratio for falls associated with VDRA use was lower among those with poor physical activity (p for interaction <0.1). CONCLUSIONS: Although vitamin D receptor activators and calcimimetics use was not associated with falls, the lower risk ratio for falls with vitamin D receptor activators use among those with poor physical activity suggests that vitamin D receptor activators use might be beneficial among these patients.

Postural Control Characteristics in Alzheimer's Disease, Dementia With Lewy Bodies, and Vascular Dementia.

BACKGROUND: Dementia often results in postural control impairment, which could signify central nervous system dysfunction. However, no studies have compared postural control characteristics among various types of dementia. This study aimed to compare static postural control in patients with Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and vascular dementia (VaD). METHODS: Cross-sectional relationship between the clinical diagnoses (AD, DLB, VaD, or normal cognition [NC]) of outpatients at a memory clinic and their upright postural control characteristics were examined. In the postural control test, participants were instructed to maintain a static upright standing on a stabilometer for 60 seconds under the eyes-open and eyes-closed conditions. Forty postural control parameters, including distance, position, and velocity in the anterior-posterior and medio-lateral directions, derived from the trajectory of the center of mass sway, were calculated. The characteristics of each type of dementia were compared to those of NC, and the differences among the 3 types of dementia were evaluated using linear regression models. RESULTS: The study included 1 789 participants (1 206 with AD, 111 with DLB, 49 with VaD, and 423 with NC). Patients with AD exhibited distinct postural control characteristics, particularly in some distance and velocity parameters, only in the eyes-closed condition. Those with DLB exhibited features in the mean position in the anterior-posterior direction. In patients with VaD, significant differences were observed in most parameters, except the power spectrum. CONCLUSIONS: Patients with AD, DLB, and VaD display disease-specific postural control characteristics when compared to cognitively normal individuals.

Prognostic Factors for Severe-to-Fatal Post-Endoscopic Retrograde Cholangiopancreatography Pancreatitis: A Multicenter Prospective Cohort Study.

The prognostic factors associated with severe-to-fatal post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) remain unclear despite the extensive number of studies on PEP. In total, 3739 ERCP patients with biliary disease with an intact papilla and indicated for ERCP were prospectively enrolled at 36 centers from April 2017 to March 2018. Those with acute pancreatitis diagnosed before ERCP, altered gastrointestinal anatomy, and an American Society of Anesthesiologists (ASA) physical status > 4 were excluded. Univariate and multivariate logistic regression analyses were performed on patient-related factors, operator-related factors, procedure-related factors, and preventive measures to identify potential prognostic factors for severe-to-fatal PEP. Multivariate analyses revealed pancreatic guidewire-assisted biliary cannulation (OR 13.59, 95% CI 4.21-43.83, p < 0.001), post-ERCP non-steroidal anti-inflammatory drug (NSAID) administration (OR 11.54, 95% CI 3.83-34.81, p < 0.001), and previous pancreatitis (OR 6.94, 95% CI 1.45-33.33, p = 0.015) as significant risk factors for severe-to-fatal PEP. Preventive measures included endoscopic biliary sphincterotomy (EST; OR 0.29, 95% CI, 0.11-0.79, p = 0.015) and prophylactic pancreatic stents (PPSs; OR 0.11, 95% CI, 0.01-0.87, p = 0.036). In biliary ERCP, pancreatic guidewire-assisted biliary cannulation, NSAID administration after ERCP, and previous pancreatitis were risk factors for severe-to-fatal PEP, whereas EST and PPS were significant preventive measures for severe-to-fatal PEP.

Acceptability, Safety, and Feasibility of Transnasal and Peroral Ultrathin Endoscopy Using GAGLESS Mouthpieces: A Prospective Randomized Trial.

BACKGROUND/AIM: Esophagogastroduodenoscopy (EGD) is an effective screening method for early detection of gastric cancer. The GAGLESS mouthpiece has a structure that widens the pharyngeal cavity and suppresses the pharyngeal reflex. This study aimed to investigate the acceptability, safety, and feasibility of transnasal and peroral ultrathin endoscopy using GAGLESS mouthpieces (Clinical Trial Number: UMIN000036922). PATIENTS AND METHODS: This study was a multicenter, prospective, randomized, open-label trial performed using a questionnaire. The study included 101 consecutive patients who visited the participating medical institutions between June 2019 and March 2022 (median age=47 years, range=24-87 years; all male). Patients aged ≥20 years at the time of consent acquisition who were the first to undergo EGD were included in the study. The primary endpoint was the degree of distress during EGD, as determined using a visual analog scale (VAS). RESULTS: The VAS score during endoscopic passage through the pharynx was significantly better in the transnasal endoscopy group than in the oral endoscopy group (2.420 vs. 4.092, p=0.001). There was no significant difference in the VAS scores between the two groups during anesthesia or throughout the examination. Compared with nasal endoscopy, oral endoscopy with a GAGLESS mouthpiece did not reduce the VAS score but did significantly improve gastric visibility. CONCLUSION: For patients in whom there was difficulty in inserting a nasal endoscope, using a GAGLESS mouthpiece rather than a conventional mouthpiece may be more useful in reducing pain.

Efficacy of biological agents combined with oral immunotherapy (OIT) for food allergy: a protocol for a systematic review and meta-analysis.

INTRODUCTION: Food allergy affects a large population throughout the world. Recently, oral immunotherapy (OIT) has been reported as an effective treatment for severe food allergy. Although OIT was successful in numerous trials in desensitisation, adverse events including anaphylaxis during OIT frequently occur. Additionally, some patients fail to be desensitised after OIT and the response to treatment is often not sustained. As a further adjunctive therapy to facilitate OIT, the role of biological agents has been identified. For example, efficacy and safety of omalizumab as an adjuvant therapy of OIT has become apparent through some RCTs and observational studies. Interest towards this topic is growing worldwide, and ongoing trials will provide additional data on the biologics in food allergy.We aim to systematically analyse the efficacy and safety of OIT combined with biological agents for food allergy. METHODS AND ANALYSIS: This paper provides a protocol for a systematic review of the relevant published analytical studies using an aggregate approach following the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols guidelines. Two authors will perform a comprehensive search for studies on MEDLINE/PubMed, EMBASE and the Cochrane Central Register of Controlled Trials (CENTRAL) databases. Subsequently, two independent authors will perform abstract screening, full-text screening and data extraction. A meta-analysis will be conducted as appropriate. ETHICS AND DISSEMINATION: The protocol of this systematic review will be provided in a peer-reviewed journal. As the researchers will not identify the individual patients included in the studies, they do not need to acquire ethics approval. PROSPERO REGISTRATION NUMBER: CRD42022373015.

A chatbot to improve adherence to internet-based cognitive-behavioural therapy among workers with subthreshold depression: a randomised controlled trial.

BACKGROUND: Internet-based cognitive-behavioural therapy (iCBT) is effective for subthreshold depression. However, iCBT has problems with adherence, especially when unaccompanied by human guidance. Knowledge on how to enhance adherence to iCBT without human involvement can contribute to improving the effectiveness of iCBT. OBJECTIVE: This is an implementation study to examine the effect of an automated chatbot to improve the adherence rate of iCBT. METHODS: We developed a chatbot to increase adherence to an existing iCBT programme, and a randomised controlled trial was conducted with two groups: one group using iCBT plus chatbot (iCBT+chatbot group) and one group not using the chatbot (iCBT group). Participants were full-time employees with subthreshold depression working in Japan (n=149, age mean=41.4 (SD=11.1)). The primary endpoint was the completion rate of the iCBT programme at 8 weeks. FINDINGS: We analysed data from 142 participants for the primary outcome. The completion rate of the iCBT+chatbot group was 34.8% (24/69, 95% CI 23.5 to 46.0), that of the iCBT group was 19.2% (14/73, 95% CI 10.2 to 28.2), and the risk ratio was 1.81 (95% CI 1.02 to 3.21). CONCLUSIONS: Combining iCBT with a chatbot increased participants' iCBT completion rate. CLINICAL IMPLICATIONS: Encouraging messages from the chatbot could improve participation in an iCBT programme. Further studies are needed to investigate whether chatbots can improve adherence to the programme in the long term and to assess their impact on depression, anxiety and well-being. TRIAL REGISTRATION NUMBER: UMIN000047621.

Deep learning model for extensive smartphone-based diagnosis and triage of cataracts and multiple corneal diseases.

AIM: To develop an artificial intelligence (AI) algorithm that diagnoses cataracts/corneal diseases from multiple conditions using smartphone images. METHODS: This study included 6442 images that were captured using a slit-lamp microscope (6106 images) and smartphone (336 images). An AI algorithm was developed based on slit-lamp images to differentiate 36 major diseases (cataracts and corneal diseases) into 9 categories. To validate the AI model, smartphone images were used for the testing dataset. We evaluated AI performance that included sensitivity, specificity and receiver operating characteristic (ROC) curve for the diagnosis and triage of the diseases. RESULTS: The AI algorithm achieved an area under the ROC curve of 0.998 (95% CI, 0.992 to 0.999) for normal eyes, 0.986 (95% CI, 0.978 to 0.997) for infectious keratitis, 0.960 (95% CI, 0.925 to 0.994) for immunological keratitis, 0.987 (95% CI, 0.978 to 0.996) for cornea scars, 0.997 (95% CI, 0.992 to 1.000) for ocular surface tumours, 0.993 (95% CI, 0.984 to 1.000) for corneal deposits, 1.000 (95% CI, 1.000 to 1.000) for acute angle-closure glaucoma, 0.992 (95% CI, 0.985 to 0.999) for cataracts and 0.993 (95% CI, 0.985 to 1.000) for bullous keratopathy. The triage of referral suggestion using the smartphone images exhibited high performance, in which the sensitivity and specificity were 1.00 (95% CI, 0.478 to 1.00) and 1.00 (95% CI, 0.976 to 1.000) for 'urgent', 0.867 (95% CI, 0.683 to 0.962) and 1.00 (95% CI, 0.971 to 1.000) for 'semi-urgent', 0.853 (95% CI, 0.689 to 0.950) and 0.983 (95% CI, 0.942 to 0.998) for 'routine' and 1.00 (95% CI, 0.958 to 1.00) and 0.896 (95% CI, 0.797 to 0.957) for 'observation', respectively. CONCLUSIONS: The AI system achieved promising performance in the diagnosis of cataracts and corneal diseases.

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.

Maternal-neonatal events resulting from medications for preventing hypertensive disorders in high-risk pregnant women: A systematic review and network meta-analysis.

BACKGROUND: There have been few studies reporting on maternal and neonatal events in high-risk pregnant women receiving medications for preventing hypertensive disorders of pregnancy (HDP). OBJECTIVE: To identify placental abruption, postpartum hemorrhage, neonatal intraventricular hemorrhage, and neonates with small for gestational age (SGA) or growth restriction resulting from medications for preventing HDP in high-risk pregnant women using a network meta-analysis. SEARCH STRATEGY: All randomized controlled trials comparing the most commonly used medications (antiplatelet agents, anticoagulants, antioxidants, nitric oxide, and calcium) for preventing HDP in high-risk pregnant women were searched from the Cochrane Pregnancy and Childbirth's Specialized Register of Controlled Trials until July 31, 2020, without language restriction. SELECTION CRITERIA: Two of the authors independently selected the eligible trials. DATA COLLECTION AND ANALYSIS: Two authors independently extracted the data and assessed the methodological quality of the included trials. Pairwise and network meta-analyses were used to determine comparative risk ratios and 95% confidence intervals. MAIN RESULTS: The 51 included trials involved 69 669 pregnant women. Compared with placebo/no treatment, antioxidants slightly reduced placental abruption with high-certainty evidence. Antiplatelet agents probably reduced SGA with low-certainty evidence and slightly increased neonatal intraventricular hemorrhage with moderate-certainty evidence. CONCLUSION: Antiplatelet agents probably reduce SGA, but neonatal intraventricular hemorrhage should be monitored. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, CRD42018096276.

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.

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.

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.

Efficacy and safety of drug therapy for the prevention and treatment of chemotherapy-induced peripheral neuropathy: a protocol for a systematic review and network meta-analysis.

INTRODUCTION: Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most common dose-limiting side effects of chemotherapeutic drugs. Numerous clinical trials of various targeted drugs for the prevention or treatment of CIPN have been conducted; however, previous systematic reviews with direct comparisons have failed to demonstrate the efficacy of these drugs in the prevention or treatment of CIPN. In addition, no systematic reviews have indirectly compared CIPN prevention and treatment. This article describes a protocol for evaluating the efficacy and safety of drug therapy for the prevention and treatment of CIPN. The results of the proposed systematic review with network meta-analysis (NMA) will provide new insights into the prevention and treatment of CIPN. METHODS AND ANALYSIS: We will conduct a literature search in MEDLINE, PubMed, Embase, Cochrane Central Register of Controlled Trials and ClinicalTrials.gov to find relevant articles published through January 2023. We will include studies that investigated the efficacy and safety of vitamin B12, goshajinkigan, non-steroidal anti-inflammatory analgesics, opioids, calcium and magnesium, antidepressants and anticonvulsants on CIPN. Two authors will individually screen the retrieved reports and review the full text based on the selection criteria. The primary outcome is the incidence and severity of CIPN. The risk of bias will be assessed using V.2.0 of the Cochrane risk-of-bias tool. We will apply a frequentist random-effects NMA model to pool effect sizes across trials using risk ratios and mean differences with their 95% CIs. Competing interventions will be ranked using the surface under cumulative ranking probabilities. Heterogeneity will be assessed using the heterogeneity variance τ2, Cochran's Q test and I² statistic. ETHICS AND DISSEMINATION: This review does not require ethical approval. The research will be published in a peer-reviewed journal. PROSPERO REGISTRATION NUMBER: CRD42022371829.