Citations

Importance Elevated low-density lipoprotein cholesterol (LDL-C) is a modifiable risk factor for cardiovascular disease, the leading cause of premature death worldwide. Assessing the LDL-C–related burden is critical for guiding prevention and treatment strategies. Objectives To estimate the global, regional, and national burden of ischemic heart disease and ischemic stroke attributable to elevated LDL-C (relative to 35-54 mg/dL) from 1990 to 2023 and to quantify the contributions of population growth, aging, risk-deleted burden, and exposure changes to burden trends. Design, Setting, and Population This comparative risk assessment, part of the Global Burden of Disease Study 2023, estimated population-level LDL-C exposure and associated health loss in 204 countries and territories. Mean LDL-C levels were estimated using spatiotemporal gaussian process regression based on 806 studies across 161 countries. Relative risks were derived from meta-analyses of 38 randomized clinical trials. Population-attributable fractions for deaths and disability-adjusted life-years (DALYs) were estimated by age and sex for adults aged 25 years or older from 1990 to 2023, with 95% uncertainty intervals. Exposure Population-level LDL-C concentrations. Main Outcomes and Measures Population-attributable fractions, counts, and rates (all ages and age standardized per 100 000) of LDL-C–attributable deaths and DALYs from ischemic heart disease and ischemic stroke, with uncertainty intervals. Results In 2023, elevated LDL-C accounted for 3.6 million deaths (95% uncertainty interval, 2.2-5.4 million; 6.0% of global mortality) and 90.7 million DALYs (95% uncertainty interval, 58.9-123.3 million; 3.2% of DALYs). Although global all-ages rates remained stable, age-standardized death and DALY rates decreased by 45.6% and 39.5%, respectively, since 1990. In 2023, age-standardized LDL-C–attributable DALY rates were highest in Eastern Europe and lowest in high-income Asia-Pacific. One-third of the global LDL-C burden occurred in India and China. Population growth and aging drove the increasing burden, with notable regional disparities in LDL-C exposure and risk-deleted DALY rates shifting toward middle-sociodemographic settings. Conclusions and Relevance Despite declining age-standardized rates, the absolute LDL-C burden has increased since 1990 due to demographic changes and has shifted toward middle-sociodemographic countries. Measurement and surveillance gaps persist. Strengthened prevention, diagnosis, and treatment access strategies are essential to mitigate the health burden of LDL-C.

Abstract Objectives To describe and compare anorectal manometry findings in constipated adolescents with and without dyssynergic defecation (DD). Methods We retrospectively reviewed adolescents ≤18 years who underwent anorectal manometry (ARM) and/or balloon expulsion testing (BET) between 2015 and 2022. Patients with prior pelvic floor therapy, inflammatory bowel disease, or colon surgery were excluded. DD was defined by abnormal ARM (paradoxical anal contraction or inadequate anal relaxation ≤20% during simulated evacuation) and/or abnormal BET (>60 s). Manometric parameters were compared between patients with and without DD and between those with abnormal versus normal BET. Diagnostic performance of rectoanal pressure gradient cutoffs were assessed. Results A total of 170 adolescents were included; 69 (40.6%) met criteria for DD. Median age was 17 years (interquartile range [IQR] 16–18), and 80.7% were female. Gastrointestinal symptoms did not differ between groups. Patients with DD demonstrated significantly more negative rectoanal pressure gradients compared with those without DD (median [IQR]: −49.0 mmHg [−73.9 to −31.4] vs. −25.2 mmHg [−40.2 to −9.8]; p < 0.001). Rectal sensory thresholds did not differ significantly between groups. A rectoanal pressure gradient cutoff of −45 mmHg demonstrated the best balance of sensitivity (58%) and specificity (86%) for identifying DD. Depression was more prevalent among adolescents with DD ( p = 0.007). Conclusions Rectoanal pressure gradient is a useful manometric parameter for identifying DD in constipated adolescents, particularly when BET is unavailable. Psychological factors such as depression may be more prevalent in this population.

Abstract Objective Constipation is a common gastrointestinal concern in children, often prompting screening for celiac disease (CeD), particularly in refractory cases. However, limited data exist on the clinical course of constipation in children with CeD following treatment with a gluten‐free diet. Methods We reviewed electronic health records from the Mayo Clinic between 1994 and 2024 for children (<18 years) who presented with constipation and then diagnosed with CeD. Children were classified into groups based on the symptoms at the time of presentation. Constipation outcome was considered resolved by the documentation of improvement on a gluten‐free diet without ongoing laxative use, while unresolved cases required continued laxative therapy. A sub‐analysis was performed for children with encopresis. Results We identified 248 children with CeD, 177 (71%) had biopsy‐confirmed CeD, and 56 (23%) were diagnosed with serology‐only criteria. The mean age at diagnosis was 7.8 years (±4.98), with most being White (99%) and female (68%). Constipation was the main presenting symptom, but most children also exhibited additional symptoms at the time of diagnosis. Over an average of 5.3 years (±2.1) of follow‐up, constipation was resolved in 32% of children, while 68% required ongoing laxatives, in the subgroup of children with encopresis, only 29% had documented resolution. Tissue transglutaminase antibody normalization was slower in children with unresolved constipation. Trends were observed toward a higher prevalence of anxiety, depression (42% vs. 30%) and thyroid disorders (13% vs. 9%) in the unresolved group. We also noticed a trend to a higher likelihood of constipation resolution in children with type 1 diabetes mellitus (14% vs. 4%), but none reached statistical significance. Conclusion Many children with CeD continue to experience persistent unresolved constipation despite adherence to a gluten‐free diet. Comorbidities are associated with a lower rate of constipation resolution.

Abstract Background Risk of bias (RoB) tools are critical in systematic reviews and affect subsequent decision‐making. RoB tools should have adequate interrater reliability and interconsensus agreement. We present an approach of post hoc evaluation of RoB tools using duplicated studies that overlap systematic reviews. Methods Using a back‐citation approach, we identified systematic reviews that used the Risk Of Bias In Nonrandomized Studies‐of Interventions (ROBINS‐I) tool and retrieved all the included primary studies. We selected studies that were appraised by more than one systematic review and calculated observed agreement and unweighted kappa comparing the different systematic reviews' assessments. Results We identified 903 systematic reviews that used the tool with 51,676 cited references, from which we eventually analyzed 171 duplicated studies assessed using ROBINS‐I by different systematic reviewers. The observed agreement on ROBINS‐I domains ranged from 54.9% (missing data domain) to 70.3% (deviations from intended interventions domain), and was 63.0% for overall RoB assessment of the study. Kappa coefficient ranged from 0.131 (measurement of outcome domain) to 0.396 (domains of confounding and deviations from intended interventions), and was 0.404 for overall RoB assessment of the study. Conclusion A post hoc evaluation of RoB tools is feasible by focusing on duplicated studies that overlap systematic review. ROBINS‐I assessments demonstrated considerable variation in interconsensus agreement among various systematic reviewes that assessed the same study and outcome, suggesting the need for more intensive upfront work to calibrate systematic reviewers on how to identify context‐specific information and agree on how to judge it.

AbstractALG1‐CDG is a rare, clinically variable metabolic disease, caused by the defect of adding the first mannose (Man) to N‐acetylglucosamine (GlcNAc2)‐pyrophosphate (PP)‐dolichol to the growing oligosaccharide chain, resulting in impaired N‐glycosylation of proteins. N‐glycosylation has a key role in functionality, stability, and half‐life of most proteins. Therefore, congenital defects of glycosylation typically are multisystem disorders. Here we report a 3‐year‐old patient with severe neurological, cardiovascular, respiratory, musculoskeletal and gastrointestinal symptoms. ALG1‐CDG was suggested based on exome sequencing and Western blot analysis. Despite her severe clinical manifestations and genetic diagnosis, serum transferrin glycoform analysis was normal. Western blot analysis of highly glycosylated proteins in fibroblasts revealed decreased intercellular adhesion molecule 1 (ICAM1), but normal lysosomal associated membrane protein 1 and 2 (LAMP1 and LAMP2) expression levels. Glycoproteomics in fibroblasts showed the presence of the abnormal tetrasacharide. Reviewing the literature, we found 86 reported ALG1‐CDG patients, but only one with normal transferrin analysis. Based on our results we would like to highlight the importance of multiple approaches in diagnosing ALG1‐CDG, as normal serum transferrin glycosylation or other biomarkers with normal expression levels can occur.