Drug exposure as a predictor in diabetic retinopathy risk prediction models; a systematic review and meta-analysis.

PURPOSE: To conduct a systematic review to assess drug exposure handling in diabetic retinopathy (DR) risk prediction models, a network-meta-analysis to identify drugs associated with DR and a meta-analysis to determine which drugs contributed to enhanced model performance. DESIGN: Systematic review and meta-analysis. METHODS: We included studies presenting DR models incorporating drug exposure as a predictor. We searched EMBASE, MEDLINE and SCOPUS from inception to December 2023. We evaluated the quality of studies using the Prediction model Risk of Bias Assessment Tool and certainty using GRADE. We conducted network meta-analysis and meta-analysis to estimate the odds ratio (OR) and pooled C-statistic, respectively, and 95% confidence intervals (CI) (PROSPERO: CRD42022349764). RESULTS: Of 5,653 records identified, we included 28 studies of 678,837 type 1 or 2 diabetes participants, of which 38,579 (5.7%) had DR. A total of 19, 3 and 7 studies were at high, unclear, and low risk of bias, respectively. Drugs included in models as predictors were: insulin (n=24), antihypertensives (n=5), oral antidiabetics (n=12), lipid-lowering drugs (n=7), antiplatelets (n=2). Drug exposure was modelled primarily as a categorical variable (n=23 studies). Two studies handled drug exposure as time-varying covariates, and one as a time-dependent covariate. Insulin was associated with an increased risk of DR (OR= 2.50; 95%-CI: 1.61-3.86). Models that included insulin (n=9) had a higher pooled C-statistic (C-statistic=0.84, CI: 0.80-0.88), compared to models (n=9) that incorporated a combination of drugs alongside insulin (C-statistic= 0.79, CI:0.74-0.84), as well as models (n=3) not including insulin (C-statistic =0.70, CI: 0.64-0.75). Limitations include the high risk of bias and significant heterogeneity in reviewed studies. CONCLUSION: This is the first review assessing drug exposure handling in DR prediction models. Drug exposure was primarily modelled as a categorical variable, with insulin associated with improved model performance. However, due to suboptimal drug handling, associations between other drugs and model performance may have been overlooked. This review proposes the following for future DR prediction models: 1) evaluation of drug exposure as a variable, 2) use of time-varying methodologies, and 3) consideration of drug regimen details. Improving drug exposure handling could potentially unveil novel variables capable of significantly enhancing the predictive capability of prediction models.

Rising Unscheduled Healthcare Utilisation of Children and Young People: How Does the Rise Vary Across Deprivation Quintiles in UK Nations?

This retrospective population-based analysis assessed variations in urgent healthcare use by children and young people (CYP) across UK nations (England, Scotland and Wales) between 2007 and 2017. The study focused on urgent hospital admissions, short stay urgent admissions (SSUA) and Emergency Department (ED) attendances among CYP aged <25 years, stratified by age groups and Index of Multiple Deprivation (IMD) quintile groups. A linear mixed model was used to assess trends in healthcare activity over time and across deprivation quintiles. Urgent admissions, SSUA and ED attendances increased across all deprivation quintiles in all studied nations. Increasing deprivation was consistently associated with higher urgent healthcare utilisation. In England, the rise in urgent admissions and SSUA for CYP was slower for CYP from the quintile of greatest deprivation compared those from the least deprived quintile (respective mean differences 0.69/1000/y [95% CI 0.53, 0.85] and 0.25/1000/y [0.07, 0.42]), leading to a narrowing in health inequality. Conversely, in Scotland, urgent admissions and SSUA increased more rapidly for CYP from all deprivation quintiles, widening health inequality. Understanding the differences we describe here could inform changes to NHS pathways of care across the UK which slow the rise in urgent healthcare use for CYP.

Effect of the dual sodium-glucose co-transporter-1 and -2 inhibitor sotagliflozin on renal outcomes in type 1 diabetes and type 2 diabetes: A systematic review and meta-analysis of randomized controlled trials.

AIM: To investigate the renal safety profile of sotagliflozin, a novel sodium-glucose co-transporter-1 and -2 inhibitor, in patients with type 1 diabetes and type 2 diabetes, with or without renal impairment, as well as its efficacy in decreasing the risk of further renal events, with an emphasis on those with previous renal impairment. METHODS: Embase, Medline, CENTRAL and Scopus were searched from their inception until 24 April 2023 for randomized controlled trials that reported estimated glomerular filtration rate (eGFR), urinary albumin excretion or composite renal events (CRE). The Cochrane risk of bias 2 tool was used. Mean difference, relative risk (RR) and 95% confidence intervals were estimated (PROSPERO: CRD42023425583). RESULTS: Fourteen studies were included in this review (n = 17 574 participants; intervention n = 9312, control n = 8262). The median follow-up was 24.5 (Q1 = 15.25, Q3 = 28) months. Four studies recruited participants with renal impairment; baseline eGFR ranged from 23.8 to 50.5 mL/min/1.73m2 . The change in eGFR for studies (n = 6) with a follow-up of 52 weeks or longer was -1.23 (-1.45, -1.01) mL/min/1.73m2 . Sotagliflozin did not significantly alter urinary albumin excretion. No change was observed in the risk of CRE (n = 6 studies; RR = 0.82 [0.61, 1.12]), including in participants with renal impairment. High risk of bias was a limitation of this review. CONCLUSIONS: Sotagliflozin did not adversely affect renal function or change the risk of key renal outcomes, including for participants with pre-existing renal impairment. Therefore, sotagliflozin was safe; however, further research is needed to determine its efficacy in reducing the risk of diabetic kidney disease.

Enfortumab vedotin and pembrolizumab as monotherapies and combination treatment in locally advanced or metastatic urothelial carcinoma: A narrative review.

Background: Bladder cancer is the 10th most common cancer globally. The majority of bladder cancers are urothelial carcinomas (UCs), which, if locally advanced or metastatic, carry poor long-term prognosis. Cancer cells can evade the immune system by expressing the programmed cell death ligand 1 protein (PD-L1). Programmed cell death ligand 1 protein binds to programmed cell death protein 1 (PD-1) on T cells, inhibiting their antitumor action. Bladder tumor cells also overexpress nectin-4, a cell adhesion polypeptide that contributes to metastasis, worsening prognosis. Current platinum-based chemotherapy treatments are suboptimal. This review aimed to assess novel treatments for locally advanced or metastatic UC that specifically target PD-L1 or nectin-4, namely, the PD-1 inhibitor pembrolizumab and the anti-nectin-4 antibody-drug conjugate enfortumab vedotin (EV). Materials and methods: Relevant English-language peer-reviewed articles and conference abstracts from the last 5 years were identified through MEDLINE and EMBASE database searches. A narrative review was performed, with key results outlined below. Results: Pembrolizumab was demonstrated to be superior to chemotherapy as a second-line treatment for platinum-unresponsive participants in the KEYNOTE-045 trial, resulting in its Food and Drug Administration (FDA) approval. Enfortumab vedotin therapy resulted in superior outcomes compared with chemotherapy in the EV-301 trial, resulting in FDA approval for its use for patients with locally advanced or metastatic UC who had previously undergone treatment with platinum-based chemotherapy and PD-1/PD-L1 inhibitors. Positive preliminary results for pembrolizumab and EV combination therapy have led to FDA approval in patients with locally advanced or metastatic UC who are not eligible for platinum chemotherapy. Conclusions: Pembrolizumab and EV represent novel treatment options for patients with locally advanced or metastatic UC with documented superior outcomes and tolerability as compared with standard chemotherapy.

Transitional Care in Anorectal Malformation and Hirschsprung's Disease: A Systematic Review of Challenges and Solutions.

BACKGROUND: The literature on transitional care in anorectal malformation (ARM) and Hirschsprung's disease (HD) is diverse and heterogeneous. There is a lack of standards and guidelines specific to transitional care in these conditions. We aim to establish and systematically categorize challenges and solutions related to colorectal transition care. METHODS: Systematic review of qualitative studies from MEDLINE, EMBASE, PubMed and Scopus databases (2008-2022) was conducted to identify the challenges and solutions of healthcare transition specific to ARM and HD. Thematic analyses are reported with reference to patient, healthcare provider and healthcare system. RESULTS: Sixteen studies from 234 unique articles were included. Fourteen themes related to challenges and solutions, each, are identified. Most challenges identified are patient related. The key challenges pertain to: (1) patient's lack of understanding of their disorder, resulting in over-reliance on the pediatric surgical team and reluctance towards transitioning to adult services; (2) a lack of education and awareness among adult colorectal surgeons in caring for pediatric colorectal conditions and inadequate communication between pediatric and adult teams; and (3) a lack of structured transition program and joint-clinic to meet the needs of the transitioning patients. The key solutions are: (1) fostering young adult patient's autonomy and independence; (2) conducting joint pediatric-adult transition clinics; and (3) ensuring a structured and coordinated transition program is available using a standardized guideline. CONCLUSION: A comprehensive framework related to barriers and solutions for pediatric colorectal transition is established to help benchmark care quality of transitional care services. LEVEL OF EVIDENCE: IV. TYPE OF STUDY: Systematic review without meta-analysis.

Melatonin and Related Compounds: Antioxidant and Anti-Inflammatory Actions.

Melatonin, an indoleamine derived from tryptophan and produced in the pineal gland and other tissues [...].