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ImportanceGlaucoma can develop following cataract removal in children.ObjectiveTo assess the cumulative incidence of glaucoma-related adverse events (defined as glaucoma or glaucoma suspect) and factors associated with risk of these adverse events in the first 5 years after lensectomy prior to 13 years of age.Design, Setting, and ParticipantsThis cohort study used longitudinal registry data collected at enrollment and annually for 5 years from 45 institutional and 16 community sites. Participants were children aged 12 years or younger with at least 1 office visit after lensectomy from June 2012 to July 2015. Data were analyzed from February through December 2022.ExposuresUsual clinical care after lensectomy.Main Outcomes and MeasuresThe main outcomes were cumulative incidence of glaucoma-related adverse events and baseline factors associated with risk of these adverse events.ResultsThe study included 810 children (1049 eyes); 443 eyes of 321 children (55% female; mean [SD] age, 0.89 [1.97] years) were aphakic after lensectomy, and 606 eyes of 489 children (53% male; mean [SD] age, 5.65 [3.32] years) were pseudophakic. The 5-year cumulative incidence of glaucoma-related adverse events was 29% (95% CI, 25%-34%) in 443 eyes with aphakia and 7% (95% CI, 5%-9%) in 606 eyes with pseudophakia; 7% (95% CI, 5%-10%) of aphakic eyes and 3% (95% CI, 2%-5%) of pseudophakic eyes were diagnosed as glaucoma suspect. Among aphakic eyes, a higher risk for glaucoma-related adverse events was associated with 4 of 8 factors, including age less than 3 months (vs ≥3 months: adjusted hazard ratio [aHR], 2.88; 99% CI, 1.57-5.23), abnormal anterior segment (vs normal: aHR, 2.88; 99% CI, 1.56-5.30), intraoperative complications at time of lensectomy (vs none; aHR, 2.25; 99% CI, 1.04-4.87), and bilaterality (vs unilaterality: aHR, 1.88; 99% CI, 1.02-3.48). Neither of the 2 factors evaluated for pseudophakic eyes, laterality and anterior vitrectomy, were associated with risk of glaucoma-related adverse events.Conclusions and RelevanceIn this cohort study, glaucoma-related adverse events were common after cataract surgery in children; age less than 3 months at surgery was associated with elevated risk of the adverse events in aphakic eyes. Children with pseudophakia, who were older at surgery, less frequently developed a glaucoma-related adverse event within 5 years of lensectomy. The findings suggest that ongoing monitoring for the development of glaucoma is needed after lensectomy at any age.

Abstract Although structures of vitrified supramolecular complexes have been determined at near-atomic resolution, elucidating in situ molecular structure in living cells remains a major challenge. Here, we apply a novel but simple liquid-cell technique, developed previously for real-time imaging of the dynamics at a liquid-gas interface, to image wet biological samples. With extra scattering from the liquid phase, the transmission electron micrographs show amplitude contrast comparable to that in negatively stained samples. Single-molecule domains are resolved in the protein complex GroEL imaged in buffer solution at room temperature. Moreover, various stages of virus cell entry, which are transient events with very few structural information to date, are also captured. Morphological details are reconstructed using the technique of individual particle electron tomography. These results demonstrate that this approach can be a valuable yet cost-effective technique complementary to other microscopy techniques for addressing important biological questions at the molecular level.

Abstract Background Mendelian randomization (MR) studies are susceptible to metadata errors (e.g. incorrect specification of the effect allele column) and other analytical issues that can introduce substantial bias into analyses. We developed a quality control (QC) pipeline for the Fatty Acids in Cancer Mendelian Randomization Collaboration (FAMRC) that can be used to identify and correct for such errors. Methods We collated summary association statistics from fatty acid and cancer genome-wide association studies (GWAS) and subjected the collated data to a comprehensive QC pipeline. We identified metadata errors through comparison of study-specific statistics to external reference data sets (the National Human Genome Research Institute-European Bioinformatics Institute GWAS catalogue and 1000 genome super populations) and other analytical issues through comparison of reported to expected genetic effect sizes. Comparisons were based on three sets of genetic variants: (i) GWAS hits for fatty acids, (ii) GWAS hits for cancer and (iii) a 1000 genomes reference set. Results We collated summary data from 6 fatty acid and 54 cancer GWAS. Metadata errors and analytical issues with the potential to introduce substantial bias were identified in seven studies (11.6%). After resolving metadata errors and analytical issues, we created a data set of 219 842 genetic associations with 90 cancer types, generated in analyses of 566 665 cancer cases and 1 622 374 controls. Conclusions In this large MR collaboration, 11.6% of included studies were affected by a substantial metadata error or analytical issue. By increasing the integrity of collated summary data prior to their analysis, our protocol can be used to increase the reliability of downstream MR analyses. Our pipeline is available to other researchers via the CheckSumStats package (https://github.com/MRCIEU/CheckSumStats).

Introduction: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a genetic, progressive microangiopathy caused by mutations in the NOTCH3 gene. Patients often present with migraine and progressive subcortical infarcts resulting in vascular cognitive impairment and death. Currently, there are no disease modifying treatments. Limiting future trials is the lack of an objective construct to classify and monitor severity of disease. The purpose of this study was to gain experience with a novel CADASIL severity grading system. Methods: Neurologists at 5 academic centers retrospectively reviewed charts of those with confirmed CADASIL. Demographic and clinical data were recorded. The CADASIL severity grades were then assigned: 0 (asymptomatic), 1 (migraine alone), 2 (stroke or mild cognitive impairment), 3 (gait impairment or early dementia) and 4 (bedbound) based on available data. Standard descriptive statistical analyses were used. Results: We identified 138 patients; overall mean age of 50.9±13.1 years, 42.8% were men. 15 (10.9%) were grade 0, 50 (36.2%) were grade 1, 41 (44.2%) were grade 2, 12 (8.7%) were grade 3, and none were grade 4. Those with less severe disease tended to be younger, more likely men, had a lower rate of hypertension and diabetes mellitus and were less frequently tobacco users, Table 1. Increasing number of vascular risk factors was associated with higher severity grading. Conclusion: Our study highlights the ability of this severity scale to separate those with CADASIL into an ordinal system. As known in the literature, more advanced phenotypes of CADASIL tend to have more vascular risk factors. Future trials may consider utilizing this ordinal construct to monitor disease progression, response to therapy, or as a screening tool.

Introduction: Embolic stroke of undetermined source (ESUS) is a clinical paradigm that helps to classify and lead investigations into cryptogenic stroke. Diagnostic evaluation of ESUS involves investigating several potential etiologies of stroke. One such etiology includes antiphospholipid syndrome (APLS), a syndrome known to cause hypercoagulability. Clinical characteristics of primary APLS in ESUS have not been described. Methods: This is an IRB approved, retrospective study including patients from 2015-2020 who were seen at Mayo Clinic, were diagnosed with ESUS, and had APLS testing (anti-cardiolipin, beta-2 glycoprotein, or lupus anticoagulant). Baseline characteristics and radiographic features were collected and compared between patients who were and were not diagnosed with APLS, as well as between patients who were and were not APLS antibody positive. Results: Our study included 206 patients. Positive APLS antibody testing was seen in 21 (10%) patients. Of those patients, 8 (4%) received a formal diagnosis of APLS. Compared to controls, patients with positive APLS antibodies as well as those diagnosed with APLS were more likely to have a history of cancer (20 [11%] APLS antibody negative vs 7 [33%] APLS antibody positive p=0.004) (23 [12%] APLS diagnosis negative vs 4 [50%] APLS diagnosis p=0.002). Mean age in primary APLS was greater, 57 years old APLS antibody negative vs 69 years old APLS antibody positive (p<0.001) and 58 years old APLS diagnosis negative vs 75 years old APLS diagnosis (p=0.001) (Table 1). Regressions analyses examining infarct topography and rate of hemorrhagic transformation were non-significant between groups (p>0.1) Conclusion: APLS presenting as ESUS is associated with older age and history of malignancy. We speculate this finding may underscore the need to consider hypercoagulable conditions more broadly in stroke evaluations of older populations. Larger cohorts and longer follow up will be required to validate this observation.

Abstract Background The incidence of inflammatory bowel disease (IBD) has risen among Black individuals and Hispanic or Latino individuals in the USA in recent decades; however, these patients are underrepresented in clinical trials of IBD therapies. We aimed to perform a post hoc analysis of the baseline demographics and clinical characteristics in three phase 3 clinical trials of vedolizumab for ulcerative colitis (UC) to identify differences between racial and ethnic groups. Methods The baseline demographics and clinical characteristics of patients with UC who were enrolled in GEMINI 1, VARSITY, and VISIBLE 1 were pooled and stratified by race and ethnicity, which were self-reported. The inclusion criteria for these trials included adult patients with moderately to severely active UC who had a prior inadequate treatment response, loss of response, or intolerance to conventional therapies or anti-tumour necrosis factor α treatment. Data were analysed using descriptive statistics, with mean or median values calculated for continuous variables, and the number and proportion of patients reported for categorical variables. T-tests and exact tests were used to compare continuous and categorical variables, respectively, between Black and White patients and between Hispanic or Latino patients and those who were not Hispanic or Latino. Results We included 1,358 patients, of whom 1,171 (86.2%) were White, 148 (10.9%) were Asian, 14 (1.0%) were Black, and 25 (1.8%) were of multiple or unspecified racial groups (Table 1). Black patients had significantly higher mean weight (87.9 kg vs 74.8 kg, p &lt; 0.01) and body mass index (30.5 kg/m2 vs 25.2 kg/m2, p &lt; 0.01), but lower albumin (38.5 g/L vs 41.2 g/L, p &lt; 0.05) and haemoglobin levels (115.5 g/L vs 126.1 g/L, p &lt; 0.05) than White patients (Table 1). Ethnicity data were recorded for 465 patients (34.2%). Hispanic or Latino patients were shorter in height (166.6 cm vs 171.0 cm, p &lt; 0.01) and had shorter mean disease duration (4.6 years vs 7.6 years, p &lt; 0.01) than those who were not Hispanic or Latino (Table 2). A non-significant, but numerically greater proportion of Hispanic or Latino patients had pancolitis than those who were not Hispanic or Latino (50.0% vs 35.8%). Conclusion In this post hoc analysis of vedolizumab clinical trials, Black patients and Hispanic or Latino patients with UC had differences in certain demographic and disease characteristics versus White patients and patients who were not Hispanic or Latino, respectively. These differences may have implications for therapy. Thus, inclusion of a more diverse patient population that reflects the demographics of the general population is warranted to adequately ascertain drug efficacy across racial and ethnic groups.

Abstract Background Corticosteroids (CS) may be used for induction of remission in Crohn’s disease (CD); however, side effects, toxicities, and low rates of mucosal healing may limit their long-term use. Safety and efficacy of upadacitinib (UPA), an oral selective Janus kinase inhibitor, were evaluated among patients with CD receiving UPA with CS at baseline in phase 3 clinical trials. Methods In 2 phase 3 studies (U-EXCEL, NCT03345849; U-EXCEED, NCT03345836), patients with moderate-to-severe CD were randomized to 12-week induction with UPA 45 mg once daily (QD) or placebo (PBO). Patients who achieved clinical response to UPA 45 mg were rerandomized in U-ENDURE (NCT03345823) to UPA 30 mg QD, UPA 15 mg QD, or PBO for a 52-week maintenance period. Patients taking CS at baseline or week 0 of maintenance (end of induction) were included. A CS taper began at induction week 4 and continued during maintenance. Endpoints included the proportion of patients who discontinued CS use (CS-free) at week 12 or for ≥ 90 days prior to week 52, and achieved clinical remission by stool frequency/abdominal pain score or by Crohn’s Disease Activity Index (CDAI), enhanced clinical response, decrease of at least 100 points in CDAI from baseline, endoscopic remission, and endoscopic response at week 12 and week 52. CS daily dose (in prednisone equivalent doses) was recorded. Safety was assessed through induction and maintenance. Results Of 1021 patients evaluated, 358 (35.1%) were taking CS at baseline (mean daily prednisone equivalent dose, 23.0 mg). Greater changes from baseline in mean CS daily dose were observed with UPA vs PBO at induction week 12 (−17.3 mg vs −10.7 mg); these changes were sustained at maintenance week 52 (UPA 30 mg, −16.4 mg; UPA 15 mg, −17.4 mg; PBO, −14.7 mg). The proportion of patients who achieved a ≥ 50% reduction in CS daily dose was higher with UPA vs PBO at induction week 12 among patients taking CS at baseline (72.6% vs 48.4%) and at week 52 among patients taking CS at baseline or week 0 of maintenance (UPA 30 mg, 49.2%; UPA 15 mg, 44.4%; PBO, 11.1%). A significantly higher proportion of patients taking UPA vs PBO were CS-free and achieved clinical remission, clinical response, endoscopic response, and endoscopic remission at week 12 (Fig 1A) and week 52 (Fig 1B). Rates of adverse events (AEs), serious AEs, and discontinuation were comparable between groups (Table 1). Serious infections, opportunistic infections, and herpes zoster events were numerically higher with UPA vs PBO (Table 1). Conclusion Patients with CD taking CS were able to taper and discontinue their CS regimen and experience clinical and endoscopic improvements with UPA treatment during the induction and maintenance periods.