Disease modeling and pharmacological rescue of autosomal dominant retinitis pigmentosa associated with RHO copy number variation.

Retinitis pigmentosa (RP), a heterogenous group of inherited retinal disorder, causes slow progressive vision loss with no effective treatments available. Mutations in the rhodopsin gene (RHO) account for ~25% cases of autosomal dominant RP (adRP). In this study, we describe the disease characteristics of the first-ever reported mono-allelic copy number variation (CNV) in RHO as a novel cause of adRP. We (a) show advanced retinal degeneration in a male patient (68 years of age) harboring four transcriptionally active intact copies of rhodopsin, (b) recapitulated the clinical phenotypes using retinal organoids, and (c) assessed the utilization of a small molecule, Photoregulin3 (PR3), as a clinically viable strategy to target and modify disease progression in RP patients associated with RHO-CNV. Patient retinal organoids showed photoreceptors dysgenesis, with rod photoreceptors displaying stunted outer segments with occasional elongated cilia-like projections (microscopy); increased RHO mRNA expression (quantitative real-time PCR [qRT-PCR] and bulk RNA sequencing); and elevated levels and mislocalization of rhodopsin protein (RHO) within the cell body of rod photoreceptors (western blotting and immunohistochemistry) over the extended (300 days) culture time period when compared against control organoids. Lastly, we utilized PR3 to target NR2E3, an upstream regulator of RHO, to alter RHO expression and observed a partial rescue of RHO protein localization from the cell body to the inner/outer segments of rod photoreceptors in patient organoids. These results provide a proof-of-principle for personalized medicine and suggest that RHO expression requires precise control. Taken together, this study supports the clinical data indicating that RHO-CNV associated adRPdevelops as a result of protein overexpression, thereby overloading the photoreceptor post-translational modification machinery.

CT Perfusion Derived rCBV < 42% Lesion Volume Is Independently Associated with Followup FLAIR Infarct Volume in Anterior Circulation Large Vessel Occlusion.

Pretreatment CT Perfusion (CTP) parameter rCBV < 42% lesion volume has recently been shown to predict 90-day mRS. In this study, we aim to assess the relationship between rCBV < 42% and a radiographic follow-up infarct volume delineated on FLAIR images. In this retrospective evaluation of our prospectively collected database, we included acute stroke patients triaged by multimodal CT imaging, including CT angiography and perfusion imaging, with confirmed anterior circulation large vessel occlusion between 9 January 2017 and 10 January 2023. Follow-up FLAIR imaging was used to determine the final infarct volume. Student t, Mann-Whitney-U, and Chi-Square tests were used to assess differences. Spearman's rank correlation and linear regression analysis were used to assess associations between rCBV < 42% and follow-up infarct volume on FLAIR. In total, 158 patients (median age: 68 years, 52.5% female) met our inclusion criteria. rCBV < 42% (ρ = 0.56, p < 0.001) significantly correlated with follow-up-FLAIR infarct volume. On multivariable linear regression analysis, rCBV < 42% lesion volume (beta = 0.60, p < 0.001), ASPECTS (beta = -0.214, p < 0.01), mTICI (beta = -0.277, p < 0.001), and diabetes (beta = 0.16, p < 0.05) were independently associated with follow-up infarct volume. The rCBV < 42% lesion volume is independently associated with FLAIR follow-up infarct volume.

The Impact of the Pandemic on the Quality of Colorectal and Anal Cancer Care, and 2-Year Clinical Outcomes.

We undertook a retrospective study to compare the quality of care delivered to a cohort of newly diagnosed adults with colon, rectal or anal cancer during the early phase of COVID-19 (02/20-12/20) relative to the same period in the year prior (the comparator cohort), and examine the impact of the pandemic on 2-year disease progression and all-cause mortality. We observed poorer performance on a number of quality measures, such as approximately three times as many patients in the COVID-19 cohort experienced 30-day post-surgical readmission (10.5% vs. 3.6%; SD:0.27). Despite these differences, we observed no statistically significant adjusted associations between COVID-19 and time to either all-cause mortality (HR: 0.88, 95% CI: 0.61-1.27, p = 0.50) or disease progression (HR: 1.16, 95% CI: 0.82-1.64, p = 0.41). However, there was a substantial reduction in new patient consults during the early phase of COVID-19 (12.2% decrease), which appeared to disproportionally impact patients who traditionally experience sociodemographic disparities in access to care, given that the COVID-19 cohort skewed younger and there were fewer patients from neighborhoods with the highest Housing and Dwelling, ands Age and Labour Force marginalization quintiles. Future work is needed to understand the more downstream effects of COVID-19 related changes on cancer care to inform planning for future disruptions in care.

Inhibition of Neuron Restrictive Silencing Factor (REST/NRSF) Chromatin Binding Attenuates Epileptogenesis.

The mechanisms by which brain insults lead to subsequent epilepsy remain unclear. Insults including trauma, stroke, infections and long seizures (status epilepticus; SE) increase the nuclear expression and chromatin binding of the neuronal restrictive silencing factor / RE-1 silencing transcription factor (NRSF/REST). REST/NRSF orchestrates major disruption of the expression of key neuronal genes, including ion channels and neurotransmitter receptors, potentially contributing to epileptogenesis. Accordingly, transient interference with REST/NRSF chromatin binding after an epilepsy-provoking SE suppressed spontaneous seizures for the 12- day duration of a prior study. However, whether the onset of epileptogenesis was suppressed or only delayed has remained unresolved. The current experiments determined if transient interference with REST/NRSF chromatin binding prevented epileptogenesis enduringly, or, alternatively, slowed epilepsy onset.Epileptogenesis was elicited in adult male rats via systemic kainic acid-induced SE (KA-SE). We then determined if decoy, NRSF-binding-motif oligodeoxynucleotides (NRSE-ODNs), given twice following KA-SE (a) prevented REST/NRSF binding to chromatin, using chromatin immunoprecipitation; (b) prevented the onset of spontaneous seizures, measured with chronic digital video-EEG.Blocking NRSF function transiently after KA-SE significantly lengthened the latent period to a first spontaneous seizure. Whereas this intervention did not influence the duration and severity of spontaneous seizures, total seizure number and seizure burden were lower in the NRSE- ODN compared with scrambled-ODN cohorts.Transient interference with REST/NRSF function after KA-SE delays and moderately attenuates insult-related hippocampal epilepsy, but does not abolish it. Thus, the anticonvulsant and antiepileptogenic actions of NRSF are but one of the multifactorial mechanisms generating epilepsy in the adult brain.Significance Statement The mechanisms by which brain insults can lead to subsequent epilepsy remain unclear. Insults may influence neuronal functions by enduringly changing their gene expression programs, often via changes in master regulators such as transcription factors (TFs). The TF REST/NRSF is activated by insults, alters gene expression selectively, and thus promotes aberrant neuronal function and connectivity. Previously, blocking REST/NRSF function transiently in developing brain prevented cognitive problems that accompany SE-induced epilepsy. Here, blocking REST/NRSF DNA binding transiently following SE in adult rats delayed and attenuated epileptogenesis, but did not abolish it.

Biologic Augmentation of Isolated Meniscal Repair.

PURPOSE OF REVIEW: The limited blood supply and intrinsic healing capacity of the meniscus contributes to suboptimal tissue regeneration following injury and surgical repair. Biologic augmentation techniques have been utilized in combination with isolated meniscal repair to improve tissue regeneration. Several innovative strategies such as Platelet-Rich Plasma (PRP), fibrin clots, mesenchymal stem cells (MSCs), bone marrow stimulation, meniscal scaffolds, and meniscal wrapping, are being explored to enhance repair outcomes. This article provides a comprehensive review of recent findings and conclusions regarding biologic augmentation techniques. RECENT FINDINGS: Studies on PRP reveal mixed outcomes, with some suggesting benefits in reducing failure rates of isolated meniscal repair, while others question its efficacy. Fibrin clots and PRF (Platelet-rich fibrin), although promising, show inconsistent results and lack sufficient evidence for definitive conclusions. MSCs demonstrate potential in preclinical studies, but clinical trials have been limited and inconclusive. Bone marrow stimulation appears effective in certain contexts, but its broader applicability remains uncertain. Meniscal scaffolds, including CMI (Collagen Meniscal Implants) and Actifit (polyurethane scaffolds), show encouraging short- and mid-term outcomes but have not consistently surpassed traditional methods in the long term. Meniscal wrapping is infrequently studied but demonstrates positive short-term results with certain applications. The review reveals a diverse range of outcomes for biologic augmentation in meniscal repair. While certain techniques show promise, particularly in specific scenarios, the overall efficacy of these methods has yet to reach a consensus. The review underscores the necessity for standardized, high-quality research to establish the definitive effectiveness of these biologic augmentation methods.

Derivation and external validation of a simple risk score for predicting severe acute kidney injury after intravenous cisplatin: cohort study.

OBJECTIVE: To develop and externally validate a prediction model for severe cisplatin associated acute kidney injury (CP-AKI). DESIGN: Multicenter cohort study. SETTING: Six geographically diverse major academic cancer centers across the US. PARTICIPANTS: Adults (≥18 years) receiving their first dose of intravenous cisplatin, 2006-22. MAIN OUTCOME MEASURES: The primary outcome was CP-AKI, defined as a twofold or greater increase in serum creatinine or kidney replacement therapy within 14 days of a first dose of intravenous cisplatin. Independent predictors of CP-AKI were identified using a multivariable logistic regression model, which was developed in a derivation cohort and tested in an external validation cohort. For the primary model, continuous variables were examined using restricted cubic splines. A simple risk model was also generated by converting the odds ratios from the primary model into risk points. Finally, a multivariable Cox model was used to examine the association between severity of CP-AKI and 90 day survival. RESULTS: A total of 24 717 adults were included, with 11 766 in the derivation cohort (median age 59 (interquartile range (IQR) 50-67)) and 12 951 in the validation cohort (median age 60 (IQR 50-67)). The incidence of CP-AKI was 5.2% (608/11 766) in the derivation cohort and 3.3% (421/12 951) in the validation cohort. Each of the following factors were independently associated with CP-AKI in the derivation cohort: age, hypertension, diabetes mellitus, serum creatinine level, hemoglobin level, white blood cell count, platelet count, serum albumin level, serum magnesium level, and cisplatin dose. A simple risk score consisting of nine covariates was shown to predict a higher risk of CP-AKI in a monotonic fashion in both the derivation cohort and the validation cohort. Compared with patients in the lowest risk category, those in the highest risk category showed a 24.00-fold (95% confidence interval (CI) 13.49-fold to 42.78-fold) higher odds of CP-AKI in the derivation cohort and a 17.87-fold (10.56-fold to 29.60-fold) higher odds in the validation cohort. The primary model had a C statistic of 0.75 and showed better discrimination for CP-AKI than previously published models, the C statistics for which ranged from 0.60 to 0.68 (DeLong P<0.001 for each comparison). Greater severity of CP-AKI was monotonically associated with shorter 90 day survival (adjusted hazard ratio 4.63 (95% CI 3.56 to 6.02) for stage 3 CP-AKI versus no CP-AKI). CONCLUSION: This study found that a simple risk score based on readily available variables from patients receiving intravenous cisplatin could predict the risk of severe CP-AKI, the occurrence of which is strongly associated with death.

The Relative Cerebral Blood Volume (rCBV) < 42% Is Independently Associated with Collateral Status in Anterior Circulation Large Vessel Occlusion.

Background: The pretreatment CT perfusion (CTP) marker the relative cerebral blood volume (rCBV) < 42% lesion volume has recently been shown to predict 90-day functional outcomes; however, studies assessing correlations of the rCBV < 42% lesion volume with other outcomes remain sparse. Here, we aim to assess the relationship between the rCBV < 42% lesion volume and the reference standard digital subtraction angiography (DSA)-derived American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology (ASITN) collateral score, hereby referred as the DSA CS. Methods: In this retrospective evaluation of our prospectively collected database, we included acute stroke patients triaged by multimodal CT imaging, including CT angiography and perfusion imaging, with confirmed anterior circulation large vessel occlusion between 1 September 2017 and 1 October 2023. Group differences were assessed using the Student's t test, Mann-Whitney U test and Chi-Square test. Spearman's rank correlation and logistic regression analyses were used to assess associations between rCBV < 42% and DSA CS. Results: In total, 222 patients (median age: 69 years, 56.3% female) met our inclusion criteria. In the multivariable logistic regression analysis, taking into account age, sex, race, hypertension, hyperlipidemia, diabetes, atrial fibrillation, prior stroke or transient ischemic attack, the admission National Institute of Health stroke scale, the premorbid modified Rankin score, the Alberta stroke program early CT score (ASPECTS), and segment occlusion, the rCBV < 42% lesion volume (adjusted OR: 0.98, p < 0.05) was independently associated with the DSA CS. Conclusion: The rCBV < 42% lesion volume is independently associated with the DSA CS.

Effect of a Telehealth Navigator Program on Video Visit Scheduling and Completion in Primary Care.

INTRODUCTION: Patients and clinicians face challenges in participating in video telehealth visits. Patient navigation has been effective in other settings in enhancing patients' engagement with clinical programs. Our objective was to assess whether implementing a telehealth navigator program to support patients and clinicians affected video visit scheduling, video usage, and non-attendance. METHODS: This was a quasi-experimental quality improvement project using difference-in-differences. We included data from 17 adult primary care sites at a large, urban public healthcare system from October 1, 2021 to October 31, 2022. Six sites received telehealth navigators and 11 sites were used as comparators. Navigators contacted patients (by phone) with upcoming video visits to assess and address potential barriers to successful video visit completion. They also provided on-site support to patients and clinicians regarding telehealth visits and usage of an electronic patient portal. The primary outcomes were difference-in-differences for the proportion of telehealth visits scheduled and, separately, completed as video visits and non-attendance for visits scheduled as video visits. RESULTS: There were 65 488 and 71 504 scheduled telehealth appointments at intervention and non-intervention sites, respectively. The adjusted difference-in-differences for the proportion of telehealth visits scheduled as video was -9.1% [95% confidence interval -26.1%, 8.0%], the proportion of telehealth visits completed as video visits 1.3% [-4.9%, 7.4%], and non-attendance for visits scheduled as video visits -3.7% [-6.0%, -1.4%]. CONCLUSIONS: Sites with telehealth navigators had comparatively lower video visit non-attendance but did not have comparatively different video visit scheduling or completion rates. Despite this, navigators' on-the-ground presence can help identify opportunities for improvements in care design.

Mast cells help organize the Peyer's patch niche for induction of IgA responses.

Peyer's patches (PPs) are lymphoid structures situated adjacent to the intestinal epithelium that support B cell responses that give rise to many intestinal IgA-secreting cells. Induction of isotype switching to IgA in PPs requires interactions between B cells and TGFß-activating conventional dendritic cells type 2 (cDC2s) in the subepithelial dome (SED). However, the mechanisms promoting cDC2 positioning in the SED are unclear. Here, we found that PP cDC2s express GPR35, a receptor that promotes cell migration in response to various metabolites, including 5-hydroxyindoleacetic acid (5-HIAA). In mice lacking GPR35, fewer cDC2s were found in the SED, and frequencies of IgA+ germinal center (GC) B cells were reduced. IgA plasma cells were reduced in both the PPs and lamina propria. These phenotypes were also observed in chimeric mice that lacked GPR35 selectively in cDCs. GPR35 deficiency led to reduced coating of commensal bacteria with IgA and reduced IgA responses to cholera toxin. Mast cells were present in the SED, and mast cell-deficient mice had reduced PP cDC2s and IgA+ cells. Ablation of tryptophan hydroxylase 1 (Tph1) in mast cells to prevent their production of 5-HIAA similarly led to reduced PP cDC2s and IgA responses. Thus, mast cell-guided positioning of GPR35+ cDC2s in the PP SED supports induction of intestinal IgA responses.

A Case of Postpartum Obsessive-Compulsive Disorder in a First-Time Father.

Obsessive-Compulsive Disorder (OCD) is a well-recognized psychiatric condition characterized by distressing obsessions and compulsions. While the perinatal period is a known trigger for OCD in women, less attention has been given to its occurrence in men, particularly new fathers. This case report examines the unique presentation of postpartum-onset OCD (ppOCD) in a first-time father. A 33-year-old father presented eight months after the birth of his first child with distressing intrusive thoughts related to harming his eight-month-old daughter. These thoughts were ego-dystonic, causing significant distress, and led to a rapid deterioration in his mental health. Intrusive thoughts included a desire to leave his daughter in a busy street and place her in a hot oven. The patient became severely depressed, experienced significant weight loss, and was unable to perform daily activities of living. He repeatedly denied any intent to act on these thoughts. Following a visit to the ED, the patient was admitted to a psychiatric facility and started on escitalopram and aripiprazole. Approximately one month post-discharge, the patient reported significant symptom improvement, and after two months, his symptoms were well-controlled. He was successfully tapered off aripiprazole due to remission of symptoms and adverse effects. This case report highlights the need for greater awareness and screening of ppOCD in both men and women during the perinatal period. Utilizing existing screening tools and well-established pharmacological treatments for OCD can significantly improve the recognition and management of this distressing disorder in fathers, ultimately improving their quality of life and that of their families. Further research is needed to better understand the prevalence and specific management of male ppOCD.

Metabolic Quadrivalency in RSeT Human Embryonic Stem Cells.

One of the most important properties of human embryonic stem cells (hESCs) is related to their pluripotent states. In our recent study, we identified a previously unrecognized pluripotent state induced by RSeT medium. This state makes primed hESCs resistant to conversion to naïve pluripotent state. In this study, we have further characterized the metabolic features in these RSeT hESCs, including metabolic gene expression, metabolomic analysis, and various functional assays. The commonly reported metabolic modes include glycolysis or both glycolysis and oxidative phosphorylation (i.e., metabolic bivalency) in pluripotent stem cells. However, besides the presence of metabolic bivalency, RSeT hESCs exhibited a unique metabolome with additional fatty acid oxidation and imbalanced nucleotide metabolism. This metabolic quadrivalency is linked to hESC growth independent of oxygen tension and restricted capacity for naïve reprogramming in these cells. Thus, this study provides new insights into pluripotent state transitions and metabolic stress-associated hPSC growth in vitro.

Patient Experiences With Telehealth During Versus After a System-Wide Telehealth Mandate During the COVID-19 Pandemic.

This study examines whether patients' telehealth experiences differed during a health system mandate for telehealth encounters due to the COVID-19 pandemic versus after the mandate was relaxed. Patient experience surveys from telehealth visits across 17 adult (age 18+) primary care sites at a large, urban public health system were analyzed during two periods: when a mandate was active (March 1, 2020-June 30, 2020) and when the mandate was relaxed and any appointment modality was available (July 1, 2020-November 30, 2021). Primary outcomes were odds ratios (ORs) comparing top-box percentages of survey responses at multiple levels: individual questions, four domains, and all questions together as a composite. Key findings: Patients had higher odds of selecting top-box answers in the elective telehealth period for the Care Provider (1.09 [95% confidence interval 1.03, 1.16]) and General Assessment (1.13 [1.02, 1.24]) domains and the survey composite (1.08 [1.04, 1.13]), but there was no difference for individual questions.Women reported more positive experiences during the elective telehealth period in the Access (1.22 [1.01, 1.47]), Care Provider (1.32 [1.17, 1.50]), and Telemedicine Technology (1.24 [1.04, 1.50]) domains.Our findings suggest that patients had better telehealth experiences when mandates were relaxed.

Neuraxial Anesthesia and Analgesia During Cardiothoracic Surgery: A Narrative Review.

PURPOSE OF REVIEW: The purpose of this review is to synthesize and examine the literature on the use of neuraxial anesthesia and analgesia during cardiothoracic surgery. As cardiothoracic procedures often require systemic anticoagulation, neuraxial techniques are quite often underutilized due to the theoretical risk of epidural hematoma. In this review, we seek to examine the literature to review the indications and contraindications and to explore if neuraxial anesthesia and analgesia has a role in cardiothoracic surgery. RECENT FINDINGS: Neuraxial techniques have multiple advantages during cardiothoracic surgery including coronary vasodilation, decreased sympathetic surge, and a decreased cortisol level leading to overall reduction in stress response. Multiple studies have shown an improvement in pain scores, reduction in pulmonary complications, faster extubation times, with minimal complications when neuraxial techniques are utilized in cardiothoracic surgeries. Given the numerous advantages and minimal complications of neuraxial techniques in cardiothoracic surgeries, we hope its utilization continues to increase. Moving forward, we hope additional studies continue to reaffirm the benefits of neuraxial anesthesia and analgesia for cardiothoracic surgeries to improve its utilization.

CT perfusion based rCBF <38% volume is independently and negatively associated with digital subtraction angiography collateral score in anterior circulation large vessel occlusions.

BACKGROUND: Collateral status (CS) is an important biomarker of functional outcomes in patients with acute ischemic stroke secondary to large vessel occlusion (AIS-LVO). Pretreatment CT perfusion (CTP) parameters serve as reliable surrogates of collateral status (CS). In this study, we aim to assess the relationship between the relative cerebral blood flow less than 38% (rCBF <38%), with the reference standard American Society of Interventional and Therapeutic Neuroradiology (ASITN) collateral score (CS) on DSA. METHODS: In this prospectively collected, retrospectively reviewed analysis, inclusion criteria were as follows: (a) CT angiography (CTA) confirmed anterior circulation large vessel occlusion from 9/1/2017 to 10/01/2023; (b) diagnostic CT perfusion; and (c) underwent mechanical thrombectomy with documented ASITN CS. The ratios of the CTP-derived CBF values were calculated by dividing the values of the ischemic lesion by the corresponding values of the contralateral normal region (which were defined as rCBF). Spearman's rank correlation and logistic regression analysis were performed to determine the relationship of rCBF <38% lesion volume with DSA ASITN CS. p ≤ .05 was considered significant. RESULTS: In total, 223 patients [mean age: 67.77 ± 15.76 years, 56.1% (n = 125) female] met our inclusion criteria. Significant negative correlation was noted between rCBF <38% volume and DSA CS (ρ = -0.37, p < .001). On multivariate logistic regression analysis, rCBF <38% volume was found to be independently associated with worse ASITN CS (unadjusted OR: 3.03, 95% CI: 1.60-5.69, p < .001, and adjusted OR: 2.73, 95% CI: 1.34-5.50, p < .01). CONCLUSION: Greater volume of tissue with rCBF <38% is independently associated with better DSA CS. rCBF <38% is a useful adjunct tool in collateralization-based prognostication. Future studies are needed to expand our understanding of the role of rCBF <38% within the decision-making in patients with AIS-LVO.

Quite a Pickle: A 10-Year Increase in Pickleball-Related Hand Injuries.

BACKGROUND: Pickleball popularity has significantly increased in the United States. Wrist, hand, and finger injuries are commonly seen among pickleball players and are on the rise. METHODS: The National Electronic Injury Surveillance System database was queried from 2013 to 2022 tennis- and pickleball-related injuries in the United States. Data were filtered to include wrist, hand, and finger injuries only. RESULTS: There were a total of 12 021 estimated pickleball injuries between 2013 and 2022, most commonly in white women greater than 55 years old. The most common mechanism of injury (90.5%) was a fall. The number of injuries increased by 765.6% between 2013 and 2022. The growth in the number of pickleball-related injuries was found to be statistically significant (P < .05), whereas the growth for tennis-related injuries was found to be not statistically different from 0. There was a statistical difference between the growth of the number of pickleball injuries per year and the number of tennis injuries. The wrist was the most common location of injury (70.0%) compared with the hand (10.5%) and fingers (19.5%). The most common injury diagnosis was fracture (60.3%). Overall, the most common injury was wrist fracture (50.0%). CONCLUSIONS: Hand surgeons should be aware of the increasing prevalence of pickleball-related injuries as an alternative mechanism of injury, particularly among the elderly.

Comparing Rates of Undiagnosed Hypertension and Diabetes in Patients With and Without Substance Use Disorders.

BACKGROUND: Individuals with substance use disorders (SUDs) have increased risk for developing chronic conditions, though few studies assess rates of diagnosis of these conditions among patients with SUDs. OBJECTIVE: To compare rates of undiagnosed hypertension and diabetes among patients with and without an SUD. DESIGN: Cross-sectional analysis using electronic health record (EHR) data from 58 primary care clinics at a large, urban, healthcare system in New York. PARTICIPANTS: Patients who had at least two primary care visits from 2019-2022 were included in our patient sample. Patients without an ICD-10 hypertension diagnosis or prescribed hypertension medications and with at least two blood pressure (BP) readings ≥ 140/90 mm were labeled 'undiagnosed hypertension,' and patients without a diabetes diagnosis or prescribed diabetes medications and with A1C/hemoglobin ≥ 6.5% were labeled 'undiagnosed diabetes.' MAIN MEASURES: We calculated the mean number of patients with and without an ICD-10 SUD diagnosis who were diagnosed and undiagnosed for each condition. We used multivariate logistic regression to assess the association between being undiagnosed for each condition, and having an SUD diagnosis, patient demographic characteristics, clinical characteristics (body mass index, Elixhauser comorbidity count, diagnosed HIV and psychosis), the percentage of visits without a BP screening, and the total number of visits during the time period. KEY RESULTS: The percentage of patients with undiagnosed hypertension (2.74%) and diabetes (22.98%) was higher amongst patients with SUD than patients without SUD. In multivariate models, controlling for other factors, patients with SUD had significantly higher odds of having undiagnosed hypertension (OR: 1.81; 95% CI: 1.48, 2.20) and undiagnosed diabetes (OR: 1.93; 1.72, 2.16). Being younger, female, and having an HIV diagnosis was also associated with significantly higher odds for being undiagnosed. CONCLUSIONS: We found significant disparities in rates of undiagnosed chronic diseases among patients with SUDs, compared with patients without SUDs.

Role of the Exposome in Neurodegenerative Disease: Recent Insights and Future Directions.

Neurodegenerative diseases are increasing in prevalence and place a significant burden on society. The causes are multifactorial and complex, and increasing evidence suggests a dynamic interplay between genes and the environment, emphasizing the importance of identifying and understanding the role of lifelong exposures, known as the exposome, on the nervous system. This review provides an overview of recent advances toward defining neurodegenerative disease exposomes, focusing on Parkinson's disease, amyotrophic lateral sclerosis, and Alzheimer's disease. We present the current state of the field based on emerging data, elaborate on key themes and potential mechanisms, and conclude with limitations and future directions. ANN NEUROL 2024;95:635-652.

Linking gene expression to clinical outcomes in pediatric Crohn's disease using machine learning.

Pediatric Crohn's disease (CD) is characterized by a severe disease course with frequent complications. We sought to apply machine learning-based models to predict risk of developing future complications in pediatric CD using ileal and colonic gene expression. Gene expression data was generated from 101 formalin-fixed, paraffin-embedded (FFPE) ileal and colonic biopsies obtained from treatment-naïve CD patients and controls. Clinical outcomes including development of strictures or fistulas and progression to surgery were analyzed using differential expression and modeled using machine learning. Differential expression analysis revealed downregulation of pathways related to inflammation and extra-cellular matrix production in patients with strictures. Machine learning-based models were able to incorporate colonic gene expression and clinical characteristics to predict outcomes with high accuracy. Models showed an area under the receiver operating characteristic curve (AUROC) of 0.84 for strictures, 0.83 for remission, and 0.75 for surgery. Genes with potential prognostic importance for strictures (REG1A, MMP3, and DUOX2) were not identified in single gene differential analysis but were found to have strong contributions to predictive models. Our findings in FFPE tissue support the importance of colonic gene expression and the potential for machine learning-based models in predicting outcomes for pediatric CD.

Aberrant miR-29 is a predictive feature of severe phenotypes in pediatric Crohn's disease.

Crohn's disease (CD) is a chronic inflammatory gut disorder. Molecular mechanisms underlying the clinical heterogeneity of CD remain poorly understood. MicroRNAs (miRNAs) are important regulators of gut physiology, and several have been implicated in the pathogenesis of adult CD. However, there is a dearth of large-scale miRNA studies for pediatric CD. We hypothesized that specific miRNAs uniquely mark pediatric CD. We performed small RNA-Seq of patient-matched colon and ileum biopsies from treatment-naive pediatric patients with CD (n = 169) and a control cohort (n = 108). Comprehensive miRNA analysis revealed 58 miRNAs altered in pediatric CD. Notably, multinomial logistic regression analysis revealed that index levels of ileal miR-29 are strongly predictive of severe inflammation and stricturing. Transcriptomic analyses of transgenic mice overexpressing miR-29 show a significant reduction of the tight junction protein gene Pmp22 and classic Paneth cell markers. The dramatic loss of Paneth cells was confirmed by histologic assays. Moreover, we found that pediatric patients with CD with elevated miR-29 exhibit significantly lower Paneth cell counts, increased inflammation scores, and reduced levels of PMP22. These findings strongly indicate that miR-29 upregulation is a distinguishing feature of pediatric CD, highly predictive of severe phenotypes, and associated with inflammation and Paneth cell loss.