Early intervention is associated with improved outcomes for young children with developmental delays, yet many with mild delays are ineligible for services under the Individuals with Disabilities Education Act (IDEA). The Early Discovery (ED) Program addressed this gap by providing short-term, targeted intervention for children ages 0-5 who did not qualify for publicly funded services. This study evaluated program outcomes across intervention types. During 2024-2025, 342 families completed the ED Program, receiving one of the following: speech-language (68%), general developmental (12%), occupational (14%), or behavioral (6%) intervention across 8-20 sessions. Eligibility required Miami-Dade residency and ineligibility for IDEA-funded services. Standardized pre- and post-intervention assessments were analyzed using descriptive statistics, correlations, and group comparisons. Most households reported incomes <$70,000 (71%), with many experiencing additional risk factors including prematurity (15%), public or no insurance (47%), limited English proficiency (21%), and single-caregiver households (30%). Overall, 85% of children met criteria for improvement. Improvement rates varied by child ethnicity. No statistically significant differences were observed by child age, race, gender, prematurity, insurance status, caregiver demographics, household characteristics, or intervention type. Sensitivity analyses largely confirmed the primary findings, with ethnicity no longer significant and younger age emerging as a significant predictor of improvement. Findings suggest short-term, targeted intervention may support developmental progress among young children with mild delays who would otherwise remain unserved. Community-based programs such as ED may play a critical role in advancing developmental equity by reaching children with developmental and socioeconomic risk factors prior to school entry.
Cognitive reserve (CR) reflects variability in cognitive adaptability that modifies the impact of Alzheimer's disease (AD) pathology on cognition. However, blood-based biomarkers of CR have not been established in prodromal AD. We operationalized CR as memory reserve, defined by the attenuation of the cerebrospinal fluid (CSF) phosphorylated tau threonine 181 (pTau181)-memory association and aimed to identify blood DNA methylation (DNAm) loci involved in memory reserve. We studied 92 amyloid-positive participants with mild cognitive impairment (MCI) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) with blood DNAm, CSF pTau181, and memory (PHC_MEM) measured at the same visit. Memory was residualized after adjustment for age, sex, APOE 𝜀4 allele count, and estimated immune cell-type proportions. For each CpG, linear models tested DNAm, pTau181, and DNAm×pTau181 interaction; inflation was corrected using the bacon method. In addition, we also identified differentially methylated regions (DMRs). Moreover, we constructed a methylation reserve score (MRS) from loci identified in this cohort at baseline and tested its associations with longitudinal memory using linear mixed-effects models in 88 participants with follow-up information. After removing low-variability CpGs, we identified six CpGs with suggestive DNAm×pTau181 interaction (p value < 1 × 10-5, none passed a 5% false discovery rate) and 11 DMRs passing multiple-comparisons correction. The suggestive CpGs and significant DMRs mapped to genes implicating synaptic function, vascular/blood-brain barrier integrity, and immune regulation, with minimal marginal associations with pTau181 or memory, consistent with a moderation model rather than mediation. In this cohort, higher baseline MRS was associated with attenuation of the pTau181-memory association and with slower subsequent memory decline, independent of age, sex, education, APOE ε4, and baseline pTau181. Blood DNAm that moderates the pTau181-memory association may reflect epigenetic correlates of memory reserve (i.e., differential susceptibility to tau-related memory impairment), rather than reflecting variations in pTau181 levels. These DNAm patterns can be summarized as a MRS that, in this cohort, was associated with longitudinal memory trajectories in MCI. Further validation in independent cohorts is warranted.
The rising prevalence of illicit drug use among Romanian youth underscores the need for effective prevention service delivery systems, particularly in European contexts characterized by high social transition, severe resource constraints, and limited prevention service infrastructure. This study explored international expert and local Romanian stakeholder perspectives regarding factors contributing to the contextual adaptation and potential implementation of the Communities That Care (CTC) prevention system in Romania. Through qualitative interviews with experts in CTC (n = 15) and validation of findings with Romanian community stakeholders (n = 9), this study examined potential challenges in implementing CTC in Romania, such as lack of evidence-based interventions, resource scarcity, cultural differences, and resistance to change. Key factors identified by CTC experts as needed for successful implementation include community improved readiness, continuous adaptation, favorable facilitator and champion characteristics, and community engagement. Romanian stakeholder perspectives further suggested that rural communities may offer particularly favorable conditions for CTC implementation. Stakeholders emphasized the need for partnerships that reflect the needs of local groups and for attention to Romanian values (e.g., including strong family ties, religious traditions, and respect for authority), which should be considered alongside broader societal experiences (e.g., migration, funding limitations, and long-standing institutional distrust). By situating Romania within a broader European context, these findings provide valuable insights for stakeholders seeking to adapt and implement CTC in countries new to the prevention science movement and highlight the relevance of the Romanian case for the Balkan region and similar European settings.
Mild traumatic brain injury (mTBI) is often considered low risk, yet growing evidence suggests that outcomes may differ by sex, and when explored, also by gender. We examined sex-associated differences in structural injury, acute-care complications, and neuropsychiatric diagnoses for patients with mTBI. This retrospective cohort study used the TriNetX Global Health Research Network to identify adults (≥18 years) diagnosed with mTBI (Glasgow Coma Scale 13-15) between 2010 and 2022. Patients were identified using ICD-10 codes (S06, S09, R40.2411-R40.2413), with exclusion of moderate and severe TBI. Outcomes were assessed at 1 month, 6 months, 1 year, and 2 years. Propensity score matching (1:1) was performed to balance demographic and clinical characteristics. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated using logistic regression. Among 26,829 patients with mTBI, 9,999 (37.3%) were female and 16,830 (62.7%) were male. After matching, 9,649 patients remained in each cohort. Female patients had significantly lower odds of intracranial lesions, including epidural hematoma (OR 0.59, 95% CI 0.46-0.76) and subdural hematoma (OR 0.79, 95% CI 0.73-0.87), as well as lower odds of mortality, intensive care unit admission, neurosurgical intervention, and systemic complications across follow-up. In contrast, females demonstrated higher odds of anxiety (OR range 1.86-1.95) and depression (OR range 1.63-1.81) at all time points. In this large cohort, women with mTBI exhibited lower structural and acute-care burden but higher long-term neuropsychiatric sequelae. These findings highlight the importance of sex- and gender-informed approaches to acute risk stratification and longitudinal mental health follow-up after mTBI.
Autoimmune diseases are associated with increased atherosclerotic cardiovascular disease (ASCVD) risk driven by chronic systemic inflammation and prothrombotic mechanisms. Lipoprotein(a) [Lp(a)] is a causal ASCVD risk factor with proinflammatory and antifibrinolytic properties; however, its role in autoimmune diseases and the impact of immunomodulatory therapies remain unclear. To evaluate the consistency of Lp(a) elevation across autoimmune diseases and whether anti-inflammatory or immunomodulatory therapies modify circulating Lp(a) levels. A Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020-guided systematic review registered in International Prospective Register of Systematic Reviews (PROSPERO)(CRD420251121143) was conducted. MEDLINE and Cochrane were searched for English-language studies (1990-2025) assessing Lp(a) in adults with autoimmune diseases, including systemic lupus erythematosus, rheumatoid arthritis, antiphospholipid syndrome, psoriasis, Behçet's disease, and Takayasu arteritis. Two reviewers independently screened studies and assessed quality using the Newcastle-Ottawa Scale. Findings were synthesized descriptively. Of 313 records, 13 studies met the inclusion criteria. Elevated Lp(a) was frequently observed, with variable outcome associations. In systemic lupus erythematosus, higher Lp(a) correlated with renal involvement and inflammatory activity, whereas cardiovascular associations were inconsistent. In rheumatoid arthritis, tumor necrosis factor inhibitor therapy did not significantly modify Lp(a). In psoriasis, Mendelian randomization supported a causal association between psoriasis and elevated Lp(a). In Takayasu arteritis and Behçet's disease, elevated Lp(a) was linked to vascular involvement. A population-based cohort demonstrated additive cardiovascular risk among individuals with autoimmune disease and elevated Lp(a). Lp(a) elevation is common across autoimmune diseases and may contribute to excess ASCVD risk. Evidence for modification with immunomodulatory therapy is limited. Prospective studies are needed.
Background and Objectives: There are known associations between bipolar disorder and obesity, but it has not been well characterized in older adults with bipolar disorder (OABD). This study aims to examine body mass index (BMI) and its clinical correlations in OABD. Materials and Methods: A secondary analysis was conducted using data from the Global Aging and Geriatric Experiments in Bipolar Disorder (GAGE-BD) project, an international harmonized dataset of OABD cohorts. To examine the relationship between BMI and clinical characteristics (e.g., sex, psychiatric history, symptom severity, medication use, comorbidities), multivariable linear regression and multinomial logistic regression models with random effect for study cohort were used, with BMI as a continuous and as an ordinal (underweight vs. healthy weight vs. overweight vs. obese) dependent variable, respectively. Results: Of 1,226 OABD participants with BMI data, 405 (33.0%) were classified as overweight (BMI 25-29.99) and 462 (37.7%) as obese (BMI > 30). In linear regression models, higher BMI was associated with younger age, higher number of somatic comorbidities, and anticonvulsant use, while lower BMI was associated with lithium use. In logistic regression models, obesity was associated with cardiovascular comorbidity, musculoskeletal comorbidity and endocrine comorbidity. Conclusions: A high proportion of individuals with OABD are overweight or obese. Several demographic and clinical correlations of higher BMI were found, including younger age, higher number of medical comorbidities and anticonvulsant use. Clinicians should monitor and manage weight changes and associated comorbidities, and promote lifestyle and health interventions to minimize the risk of negative health outcomes associated with high BMI.
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BackgroundAlzheimer's disease (AD) is marked by amyloid-β and tau accumulation, processes increasingly linked to impaired protein clearance and neuroinflammation. The choroid plexus (CP), which regulates cerebrospinal fluid (CSF) production and immune signaling, may contribute to these mechanisms. This review aimed to evaluate alterations in CP volume (CPV) in AD and their clinical significance.MethodsPubMed, Embase, Scopus, and Web of Science were searched up to March 2025. Eligible MRI-based studies comparing CPV between AD patients and healthy controls (HCs), as well as investigations examining associations of CPV with demographic, cognitive, structural, and pathological variables, were included. Random-effects models estimated pooled effect sizes, while narrative synthesis explored associations with clinical and pathological features.ResultsSixteen studies (2004 AD; 883 HCs) met inclusion criteria. Pooled findings demonstrated significantly larger CPV in AD relative to HCs (SMD = 1.05, 95% CI: 0.67 to 1.43; p < 0.01). Narrative review indicated consistent links between CP enlargement and worse cognition, hippocampal and cortical atrophy, ventricular expansion, and increased amyloid and tau deposition. CP changes were also associated with impaired glymphatic clearance and systemic inflammation. Notably, enlargement was observed in mild cognitive impairment, suggesting early involvement in the disease course.ConclusionsCP enlargement may represent a neuroimaging feature of AD, reflecting the interplay between impaired clearance mechanisms and neuroinflammatory processes. Given its visibility on routine MRI, CPV may hold considerable potential as an imaging marker for disease stratification and longitudinal monitoring of AD.
Sturge-Weber syndrome (SWS) is a rare congenital neurocutaneous disorder presenting unique anesthetic challenges due to extensive vascular malformations. Key considerations include difficult airway management due to extensive facial and oral angiomas, seizure control, and maintaining stable intracranial and intraocular pressures. This case report discusses the perioperative management of a 57-year-old female with SWS undergoing dental surgery under general anesthesia and synthesizes the current literature on anesthetic considerations and management. Preoperative examination revealed a facial port-wine stain covering more than 75% of the face, extensive oral angiomas, macroglossia, and severe lip hypertrophy, raising concerns for difficult airway management and risk of hemorrhage. A rapid sequence induction was performed following upright preoxygenation, and video laryngoscopy provided a grade I view of the glottis. Endotracheal intubation was accomplished atraumatically, and the case proceeded uneventfully. The patient was extubated but experienced mild desaturation in the post-anesthesia care unit, prompting overnight observation before discharge at baseline oxygenation. This case highlights the importance of anticipating and planning for difficult airway management, maintaining vigilance for perioperative seizure control, and implementing strategies to minimize elevations in intracranial and intraocular pressures.
College students' well-being is a critical determinant of academic success, and for Native American students, cultural strengths, resilience, and community support are key in fostering persistence in higher education. Alongside these assets, health behaviors are key contributors to psychological well-being (PWB) and academic performance. This study examined how modifiable health behaviors, such as physical activity (PA) and sleep duration, relate to PWB and academic performance among Native American college students. A secondary data analysis was conducted using a nationally representative sample of Native Americans (N = 1914) from the Spring 2023 American College Health Association-National College Health Assessment (ACHA-NCHA) survey. Independent variables include meeting PA guidelines (≥150 min moderate or ≥75 min vigorous/week) and sleep duration (categorized as poor or good). The Diener Flourishing Scale measured PWB. Academic performance was measured based on self-reported cumulative grade averages. Biological sex and PA were significantly associated, χ2 = 40.60, p < 0.001, with a higher proportion of males meeting PA guidelines. Students with good sleep reported higher PWB than others, F(1, 1817) = 62.08, p < 0.001. Similarly, students who met PA guidelines reported higher PWB, F(1, 1817) = 35.71, p < 0.001. Poor sleep was associated with lower odds of higher academic performance (B = -0.33, p < 0.001). Contrarily, PA was not significant (p = 0.350). PWB was positively associated with academic performance (B = 0.031, p < 0.001). Sleep and PWB are key factors associated with both PWB and academic performance, while PA is associated with PWB. These findings highlight the importance of relevant interventions that promote these factors to support overall well-being, academic success, and retention among Native American college students.
The adult congenital heart disease population is on the rise, and coronary artery angiography may be required for evaluation of epicardial coronary arteries in these patients. A patient with complex congenital heart disease, including the Taussig-Bing anomaly, repaired with the Rastelli operation, developed iatrogenic right coronary artery dissection during selective angiography. This was successfully managed in a challenging procedure involving extensive stenting of the right coronary artery with a good outcome.
Pain is a hallmark of inflammation and tissue injury, particularly following major surgical procedures. Despite its prevalence and clinical impact, pathological pain, defined as persistent pain that impairs function, remains a major unmet medical need. Human birth tissue, including the amniotic membrane and umbilical cord, has long been recognized for its regenerative properties and its ability to support wound healing. Recent studies have identified heavy chain 1 (HC)-hyaluronic acid (HA)/pentraxin 3 (HC-HA/PTX3) as a key matrix component within these tissues. This complex exhibits anti-inflammatory and anti-scarring activities and helps maintain stem cell quiescence. Emerging evidence, including our own findings, indicates that human birth tissue-derived products may also modulate pain responses in certain settings, such as post-surgical pain, potentially through mechanisms involving neuronal inhibition and regenerative healing. We summarize the molecular and cellular mechanisms by which human birth tissue-derived products and HC-HA/PTX3 may exert anti-inflammatory and analgesic effects. We then highlight preclinical and clinical studies evaluating their potential roles in wound healing and pathological pain. Finally, we discuss translational opportunities, current challenges, and future directions for advancing these biologics within the emerging field of regenerative pain medicine. This review outlines a framework for potential regenerative pain management using birth tissue-derived products, which may serve as a foundation for developing new therapies for certain pathological pain conditions.
Emphysematous pyelonephritis is a life-threatening necrotizing infection of the renal parenchyma characterized by gas formation and systemic toxicity. Although advances in imaging and minimally invasive techniques have altered treatment patterns, reported mortality rates and optimal management strategies remain variable across institutions. This systematic review and meta-analysis were conducted in accordance with the PRISMA guidelines to evaluate contemporary mortality and compare outcomes between non-nephrectomy management and nephrectomy. Peer-reviewed studies published between 2010 and 2025 reporting mortality in adult patients were identified through structured database searches. Quantitative synthesis was performed using R software. Mortality proportions were pooled using random-effects modeling, and ORs were calculated to compare management approaches. In total, 26 studies met the inclusion criteria for qualitative synthesis, and 11 studies comprising 523 patients were eligible for meta-analysis. The pooled mortality was 7.6% (95% CI, 5.4-10.5) under the fixed-effects model and 7.7% (95% CI, 4.4-13.3) under the random-effects model, with moderate between-study heterogeneity. Comparative analysis demonstrated significantly lower odds of mortality in patients managed without nephrectomy. These findings indicate that contemporary mortality is lower than previously reported and support a selective, stepwise management approach.
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To assess the combination of high dose interleukin 2 (HD IL2) and nivolumab in patients with checkpoint inhibitor-refractory melanoma or renal cell carcinoma (RCC), we performed a single-arm, Simon two-stage phase II trial for patients with unresectable stage III or IV melanoma or any histology RCC. The primary endpoint was overall response rate (ORR); secondary endpoints were adverse events and progression-free survival (PFS), defined as time to radiographic or clinical progression, whichever occurred first. Five patients enrolled, three with melanoma and two with RCC. Median age at registration was 47 (35-77) years. Two patients (40%) had treated or asymptomatic brain metastases, and one (20%) had liver metastases. Median prior lines of systemic therapy per patient were 3 (2-5). Patients completed a median of 1 (0.5-3) treatment cycle, involving two admissions for HD IL2 administration and two doses of nivolumab. ORR was 20%. Median PFS was 1.4 (0.8-45.0) months. Time to next therapy for each living patient was 2.5 and 45.6 months for local modalities, and 2.0, 2.3, and 45.9 months for systemic therapies. Adverse events reflected the known toxicity of HD IL2. One treatment-related death occurred, leading to trial termination. The combination of HD IL2 and nivolumab resulted in a durable response in one of five patients with PD-1-refractory advanced melanoma or RCC. Use of HD IL2 remains limited by its toxicity; augmented IL2 formulations and administration strategies are needed. ClinicalTrials.gov ID: NCT03889782 (Registered 6/16/2019; https://clinicaltrials.gov/study/NCT03889782).
Killer whales (Orcinus orca) exhibit substantial genetic and ecological variation across their global distribution. Differentiation between neighboring or sympatric populations is thought to be driven by foraging specialization and social organization, which can lead to reproductive isolation and facilitate the emergence of distinct ecotypes or morphotypes. Here, we use whole-genome resequencing and compound-specific stable isotope analysis of amino acids to investigate links between genetic and ecological differentiation in two genetically distinct killer whale populations in the northwest Atlantic, specifically in the eastern Canadian Arctic and Greenland (ECAG1 and ECAG2). Essential amino acid stable carbon isotope ratios (δ13C) suggest that the populations maintain largely distinct distributions or habitat use patterns. Amino acid-specific stable nitrogen isotope ratios (δ15N) indicate ECAG1 has a higher trophic level diet than ECAG2. Previously undetected genetic substructure within the ECAG1 population revealed finer-scale genetic differentiation between individuals sampled in the eastern Canadian Arctic and those sampled in more temperate northwest Atlantic waters. However, small sample sizes prevented exploration of isotopic differentiation among them. Within ECAG1, considerable interannual variation in δ13C and δ15N amino acid values of seven individuals sampled across different years suggests some degree of ecological plasticity. Concurrent genetic and ecological differentiation suggests that northwest Atlantic killer whales have diverged ecologically, possibly in allopatry, and are now reproductively isolated under secondary contact, comparable to population-level differences observed in other regions. However, their degree of ecological plasticity and secondary contact within expanding Arctic ranges raises questions about whether current levels of divergence will be maintained or eroded with ongoing Arctic warming.
Drug-induced kidney injury remains a major clinical challenge associated with diverse therapeutic agents and is an important cause of acute kidney injury, chronic renal dysfunction, and treatment-related morbidity. Growing evidence indicates that nephrotoxicity caused by anticancer, immunosuppressive, and anti-infective drugs is strongly driven by oxidative stress and redox homeostasis disruption. Excessive production of reactive oxygen species (ROS) in renal tubular cells overwhelms endogenous antioxidant defenses and triggers mitochondrial dysfunction, inflammatory signaling, and activation of stress-responsive pathways that culminate in tubular injury and renal functional decline. These processes promote apoptosis, necrosis, microvascular injury, and a reduction in the glomerular filtration rate, while dysregulation of redox-sensitive pathways involved in cell survival and repair further heightens renal vulnerability. This review summarizes current mechanistic insights into oxidative stress-mediated pathways of drug-induced nephrotoxicity, with emphasis on their translational relevance. In addition, it discusses emerging biomarkers for early detection and highlights recent advances in antioxidant-based and redox-modulating strategies that may help prevent renal injury and preserve kidney function.