Schlemm's canal is a critical ocular drainage structure that maintains intraocular pressure with important consequences for glaucoma. Despite this, Schlemm's canal has been relatively understudied with the molecular process that mediate its function, maintain its health, or that are compromised in glaucoma needing much deeper characterization. This study is important as it provides the most comprehensive molecular characterization of Schlemm's canal cells to date providing a wealth of molecular details. In addition to highlighting important biological pathways, this information will guide studies to develop new treatments against glaucoma.

This study aimed to assess perioperative bleeding complications and in-hospital mortality in patients requiring emergency general surgery presenting with a history of antiplatelet (AP) versus direct oral anticoagulant (DOAC) versus warfarin use. A prospective observational study across 21 centers between 2019 and 2022 was conducted. Inclusion criteria were age 18 years or older, and DOAC, warfarin, or AP use within 24 hours of an emergency general surgery procedure. Outcomes included perioperative bleeding and in-hospital mortality. The study was conducted using analysis of variance, χ 2 , and multivariable regression models. Of the 413 patients, 221 (53.5%) reported AP use, 152 (36.8%) DOAC use, and 40 (9.7%) warfarin use. The most common indications for surgery were obstruction (23% [AP], 45% [DOAC], and 28% [warfarin]), intestinal ischemia (13%, 17%, and 23%), and diverticulitis/peptic ulcers (7%, 7%, and 15%). Compared with DOAC use, warfarin use was associated with significantly higher perioperative bleeding complication (odds ratio [OR], 4.4 [95% confidence interval (CI), 2.0-9.9]). There was no significant difference in perioperative bleeding complication between DOAC and AP use (OR, 0.7 [95% CI, 0.4-1.1]). Compared with DOAC use, there was no significant difference in mortality between warfarin use (OR, 0.7 [95% CI, 0.2-2.5]) or AP use (OR, 0.5 [95% CI, 0.2-1.2]). After adjusting for confounders, warfarin use (OR, 6.3 [95% CI, 2.8-13.9]), medical history, and operative indication were associated with an increase in perioperative bleeding complications. However, warfarin was not independently associated with risk of mortality (OR, 1.3 [95% CI, 0.39-4.7]), whereas intraoperative vasopressor use (OR, 4.7 [95% CI, 1.7-12.8]), medical history, and postoperative bleeding (OR, 5.5 [95% CI, 2.4-12.8]) were. Despite ongoing concerns about the increase in DOAC use and lack of readily available reversal agents, this study suggests that warfarin, rather than DOACs, is associated with higher perioperative bleeding complications. However, that risk does not result in an increase in mortality, suggesting that perioperative decisions should be dictated by patient disease and comorbidities rather than type of AP or anticoagulant use. Prognostic and Epidemiological; Level III.

Protein molecular interactions and post-translational modifications (PTMs), such as phosphorylation, can be co-dependent and reciprocally co-regulate each other. Although this interplay is central for many biological processes, a systematic method to simultaneously study assembly-states and PTMs from the same sample is critically missing. Here, we introduce SEC-MX (Size Exclusion Chromatography fractions MultipleXed), a global quantitative method combining Size Exclusion Chromatography and PTM-enrichment for simultaneous characterization of PTMs and assembly-states. SEC-MX enhances throughput, allows phosphopeptide enrichment, and facilitates quantitative differential comparisons between biological conditions. Applying SEC-MX to HEK293 and HCT116 cells, we generated a proof-of-concept dataset mapping thousands of phosphopeptides and their assembly-states. Our analysis revealed intricate relationships between phosphorylation events and assembly-states and generated testable hypotheses for follow-up studies. Overall, we establish SEC-MX as a valuable tool for exploring protein functions and regulation beyond abundance changes.

The efficiency and validity of the Patient-Reported Outcomes Measurement Information System (PROMIS) surveys were determined for pediatric orthopaedic trauma patients with posttraumatic stress disorder (PTSD) symptoms in a clinic setting. Prospective cohort study. Single-institution, Level I trauma center. All consecutive children aged 8-18 years undergoing procedures or surgery for orthopaedic trauma. The convergent, divergent, and discriminant validity of the PROMIS Anger and Anxiety computerized adaptive tests (CATs) were evaluated and compared with the previously validated Child PTSD Symptom Scale (CPSS). The efficiency in time to completion of the outcome measures was compared between the CPSS and PROMIS surveys. Cutoffs for increased likelihood of PTSD were established for the PROMIS questionnaires. A total of 233 subjects were included in this study (mean age 13.1 years with SD 2.8 years, 71% male). The majority (51%) of injuries were related to sports, and most (60%) involved the upper extremity. Of those included, 41 patients had high levels of PTSD symptoms on the CPSS (18%; 95% CI, 13.1-23.2%). The CPSS took 182 (interquartile range [IQR] 141-228) seconds versus 52 (IQR 36-84) and 52 (IQR 36-70) seconds for PROMIS Anger and Anxiety CATs, respectively. Convergent validity showed patient scores on both PROMIS instruments significantly correlated with CPSS scores (Anger: P < 0.001, r = 0.51; Anxiety: P < 0.001, r = 0.41). Neither PROMIS score correlated with University of California Los Angeles Activity Score (Anger: r = -0.26; Anxiety: r = -0.22), a functional outcome measure, demonstrating divergent validity. Both PROMIS instruments sufficiently discriminated across PTSD risk groups (Anger P < 0.001; Anxiety P < 0.001). A score of at least 53 on PROMIS Anger or at least 48 on PROMIS Anxiety indicated an increased likelihood of PTSD risk. PROMIS Anger and Anxiety CATs are efficient and valid for evaluating posttraumatic stress in children following orthopaedic trauma procedures. Diagnostic Level I. See Instructions for Authors for a complete description of levels of evidence.

High-grade gliomas (HGG) are deadly diseases for both adult and pediatric patients. Recently, it has been shown that neuronal activity promotes the progression of multiple subgroups of HGG. However, epigenetic mechanisms that govern this process remain elusive. Here we report that the chromatin remodeler chromodomain helicase DNA-binding protein 2 (CHD2) regulates neuron-glioma interactions in diffuse midline glioma (DMG) characterized by onco-histone H3.1K27M. Depletion of CHD2 in H3.1K27M DMG cells compromises cell viability and neuron-to-glioma synaptic connections in vitro, neuron-induced proliferation of H3.1K27M DMG cells in vitro and in vivo, activity-dependent calcium transients in vivo, and extends the survival of H3.1K27M DMG-bearing mice. Mechanistically, CHD2 coordinates with the transcription factor FOSL1 to control the expression of axon-guidance and synaptic genes in H3.1K27M DMG cells. Together, our study reveals a mechanism whereby CHD2 controls the intrinsic gene program of the H3.1K27M DMG subtype, which in turn regulates the tumor growth-promoting interactions of glioma cells with neurons. Significance: Neurons drive the proliferation and invasion of glioma cells. Here we show that chromatin remodeler chromodomain helicase DNA-binding protein 2 controls the epigenome and expression of axon-guidance and synaptic genes, thereby promoting neuron-induced proliferation of H3.1K27M diffuse midline glioma and the pathogenesis of this deadly disease.

In this study, we examine how impairments in vision, hearing, touch, and olfaction relate to depression in older adults, considering both individual and multisensory impairments (MSIs). Analysis of cross-sectional data from a longitudinal investigation involving black and white older adults aged 70 to 79 at enrollment. We studied 1640 black and white participants in the Health ABC study using complete sensory evaluation data from years 3 to 5. Our MSI assessment utilized data obtained for visual acuity, hearing perception, olfactory performance, and tactile function. We performed multivariable logistic regression analyses to examine the associations between the presence of individual and MSIs and depression which was defined as the presence of antidepressants prescribed for depression, or a Center for Epidemiological Studies Depression Scale score of greater than 10. We observed a possible dose-response relationship between the number of sensory impairments and depression. In adjusted models, when compared to no impairments, vision (odds ratio [OR] = 1.45, 95% confidence interval [CI]: 1.09-1.93) and hearing impairments (OR = 1.49, 95% CI: 1.11-1.99) were significantly associated with depression, whereas olfaction (OR = 1.11, 95% CI: 0.83-1.47) and tactile impairments (OR = 1.28, 95% CI: 0.96-1.70) were not. Participants with 3 sensory impairments had a higher rate of depression (OR = 2.05, 95% CI: 1.22-3.54) compared to those without impairments, and this risk increased further for those with 4 sensory impairments (OR = 2.95, 95% CI: 1.48-5.88). The findings suggest that individuals with MSI represent a high-risk population for depression, warranting close monitoring to screen for depression. The study emphasizes the importance of considering multiple sensory impairments in the context of mental health and supports the early identification and monitoring of depression in this population.

To investigate the posterior and equatorial scleral thickness in patients with autosomal dominant Best disease, a condition that has chronic subretinal fluid. Retrospective study involving patients with Best disease and age-matched controls. Participants were evaluated with contact B-scan ultrasonography and enhanced depth imaging optical coherence tomography to evaluate scleral thickness in the posterior pole and equator. Univariate analysis and generalized estimating equations were used. Of 9 patients with genetically proven Best disease and 23 age-matched controls, there was no significant difference in the age or the gender proportion between groups. Subfoveal choroidal thickness and axial length were not significantly different between groups. Both posterior scleral (OD; 1.38mm vs. 0.89mm, P<.001 and OS; 1.39mm vs. 0.83mm, P<.001) and equatorial scleral (OD; 0.61mm vs. 0.42mm, P=.003, and OS; 0.55mm vs. 0.41mm, P=.017) thicknesses were much greater in cases as compared with controls. Multivariate analysis showed male sex and having Best disease were each significant predictors of posterior scleral thickness and Best disease was the sole significant predictor for equatorial scleral thickness. BEST1 gene may have a developmental role leading to having a thicker sclera, influencing disease manifestation, and contributing to the accumulation of subretinal fluid in Best disease.

AbstractBackgroundThe primary purpose of this study was to assess the interreader reliability of a grading system for UIP based on the quantification of normal lung. This grading system considers each of the following lung regions: right upper and middle lobes, right lower lobe, left upper lobe, and left lower lobe. Each is assigned a grade based on the following: 0: 0% normal lung; 1: 1–49% normal lung; 2: 50–74% normal lung; 3: 75–89% normal lung; 4: 90–99% normal lung; 5: 100% normal lung. The secondary purpose was to compare the grades rendered by non-cardiothoracic subspecialty trained radiologists to grades established by cardiothoracic radiologists, which were considered the gold standard.MethodsChest CT images of patients were obtained by searching the radiology record system for the terms “usual interstitial pneumonia” and “UIP”. Each case was confirmed by radiologist review; pathology was not assessed given the small fraction of cases that underwent biopsy due to the high risk of complications in patients with fibrotic lung disease. Two cardiothoracic radiologists evaluated each CT and reached a consensus grade. Two different radiologists who were not subspecialty trained in cardiothoracic radiology independently graded each case. Spearman correlation analysis was performed to compare the two reader's grades as well as each reader's grade independently to the gold standard score.ResultsOur analysis demonstrated a strongly positive statistically significant interreader correlation coefficient (RS) = 0.7062, P &lt; 0.001. Our analysis of each reader compared to the gold standard demonstrated an Rs = 0.77559, P &lt; 0.001 and an RS = 0.69958, P &lt; 0.001 for readers 1 and 2, respectively, both representing statistically significant strongly positive correlations.ConclusionsThese results demonstrate strong interreader reproducibility and show that radiologists without subspecialty training in cardiothoracic radiology render grades that correlate strongly with those given by cardiothoracic radiologists. These findings support the use of this grading system for UIP both to monitor clinical progression and as a surrogate endpoint for antifibrotic drug trials.

Psychiatric disorders after liver transplantation (LT) are associated with worse patient and graft outcomes, which may be amplified by inadequate treatment. We aimed to characterize the burden of psychiatric disorders, treatment patterns, and associated financial burden among liver transplantation recipients (LTRs). IQVIA PharMetrics (R) Plus for Academics-a large health plan claims database representative of the commercially insured US population-was used to identify psychiatric diagnoses among adult LTRs and assess treatment. Multivariable logistic regression analysis identified factors associated with post-LT psychiatric diagnoses and receipt of pharmacotherapy. Patient financial liability was estimated using adjudicated medical/pharmacy claims for LTRs with and without psychiatric diagnoses. Post-LT psychiatric diagnoses were identified in 395 (29.5%) of 1338 LTRs, of which 106 (26.8%) were incident cases. Treatment varied, with 67.3% receiving pharmacotherapy, 32.1% psychotherapy, 21.0% combination therapy, and 21.5% no treatment. Among 340 LTRs on psychotropic medications before transplant, 24% did not continue them post-LT. Post-LT psychiatric diagnoses were independently associated with female sex, alcohol-associated liver disease (ALD), prolonged LT hospitalization (>2 wk), and pre-LT psychiatric diagnosis. Incident psychiatric diagnoses were associated with female sex, ALD, and prolonged LT hospitalization. Patients with a post-LT psychiatric diagnosis had higher rates of hospitalization (89.6% vs. 81.5%, p <0.001) and financial liability (median $5.5K vs. $4.6K USD, p =0.006). Having a psychiatric diagnosis post-LT was independently associated with experiencing high financial liability >$5K. Over 1 in 4 LTRs had a psychiatric diagnosis in a large national cohort, yet nearly a quarter received no treatment. LTRs with psychiatric diagnoses experienced increased health care utilization and higher financial liability. Sociodemographic and clinical risk factors could inform high-risk subgroups who may benefit from screening and mitigation strategies.