Publications by Year: 2026

Data on dementia epidemiology in the Middle East and North Africa (MENA) region is limited. This systematic review and meta-analysis examined dementia prevalence across MENA. Databases were searched up to October 2024. Analyses were stratified by country and sex. Pooled prevalence was estimated using a random-effects model with a 95% confidence interval (CI). Fifty-two studies on the selected countries met inclusion criteria, covering 87,219 individuals with dementia from a total population of 1,045,908. The pooled prevalence was 12.16% (95% CI: 9.61-14.96) for the region and the Israel had the highest prevalence (17.00%), followed by Iran (13.20%), Turkey (11.40%), Saudi Arabia (8.34%), and Egypt (6.86%). Dementia was more common in women than men (13.84% vs. 8.69%). Dementia is prevalent in MENA, with significant variation across countries. The region's aging population highlights the need for ongoing monitoring of dementia trends.

Glioblastoma (GBM) is the most common and deadliest malignancy of the brain. Despite decades of intense research, there has been little change to the overall survival of patients with GBM. Our laboratory recently identified the actin-binding protein advillin (AVIL) as being overexpressed, oncogenic, and necessary for tumorigenesis in GBM. Here, we further examined AVIL expression in GBMs and found that it was enriched across molecular subtypes and states, including GBM stem cells and temozolomide-resistant samples. In contrast, we found that AVIL was scarcely expressed in normal human brain tissue. In addition, Avil knockout in mice had no adverse effects, suggesting that there may be a wide therapeutic window for therapies targeting AVIL. Using high-throughput small-molecule screening, we identified a direct inhibitor of AVIL that bound to the protein and also blocked AVIL binding to its substrate, actin. It induced a transcriptome profile similar to that of AVIL silencing by siRNA and caused down-regulation of FOXM1 and LIN28B, two known downstream targets of AVIL. Moreover, it exhibited selectivity toward tumor cells, sparing astrocytes and neural stem cells in vitro. In vivo, we found that the compound readily crosses the blood-brain barrier and could be delivered orally. We then demonstrated efficacy in five GBM mouse models without evidence of side effects. In summary, we have identified an efficacious first-in-class compound targeting an oncogene in GBM. Further optimization of the molecule may offer an effective therapeutic intervention for GBM.

OBJECTIVE: Undiagnosed diabetes leads to delayed treatment and increased risk of complications, exacerbating global disease burdens. In this study, we estimated the prevalence and absolute numbers of individuals with undiagnosed diabetes globally and across regions and quantified gaps in national diabetes detection efforts.

RESEARCH DESIGN AND METHODS: We systematically compiled estimates of biomarker-based diabetes prevalence and self-reported diabetes diagnosis using 2003-2024 data from all eligible population-based studies and gray literature. We calculated proportions of individuals with undiagnosed diabetes and case numbers among adults aged 20-79 years. For countries without data, we extrapolated estimates using available data within the same geographic region and country income group. Country-level estimates were benchmarked against the World Health Organization 80% diagnosis target.

RESULTS: We identified 193 data sources on undiagnosed diabetes from 109 countries. Across all 215 countries/territories, 42.8% of individuals with diabetes were undiagnosed in 2024, equating to 251.7 million (95% uncertainty interval [UI] 250.4-253.0 million) adults. Proportions undiagnosed ranged from 16.2% in Colombia to 90.4% in Burkina Faso and 29.1% in North America and the Caribbean to 72.6% in Africa. A larger proportion of individuals were undiagnosed in low-income (58.7%) compared with high-income countries (28.9%). Middle-income countries accounted for 206.0 million (95% UI 202.3-209.7 million) adults with undiagnosed diabetes (81.8% of all individuals), including 127.1 million (95% UI 121.2-133.0 million [or 50.5%]) adults in China, India, and Indonesia alone. Less than 5% of all countries attained diabetes diagnosis levels ≥80%.

CONCLUSIONS: Substantial global variability in undiagnosed diabetes indicates opportunities to close existing care gaps, likely requiring context-specific solutions and investments.

Patients with loss-of-function DOCK8 or dominant-negative STAT3 variants have hyper-IgE syndrome, although only DOCK8 deficiency consistently presents with elevated food-specific IgE and symptomatic allergy. We previously found in mice that DOCK8 restricts the differentiation of IL-13+ T follicular helper (Tfh13) cells that drive anaphylactic IgE, although the mechanisms were unclear. Here, we show that DOCK8 promotes STAT3 activity, which inhibits GATA3 in T cells. However, only patients with DOCK8, but not STAT3, deficiency had elevated Tfh13 cells. Cell-specific deletion of either Dock8 (T-Dock8-/-) or Stat3 (T-Stat3-/-) augmented peanut-specific IgE and Tfh13s when oral sensitization was promoted by adjuvants. However, the phenotypes diverged during adjuvant-free oral peanut exposure: only T-Dock8-/- mice developed Tfh13 cells and peanut-specific IgE, accompanied by reduced Foxp3+ Tregs. Treg depletion in T-Stat3-/- mice unmasked Tfh13 induction to oral antigen alone. Thus, DOCK8 and STAT3 cooperate to restrain Tfh13 differentiation to food allergens, and additional Treg impairment in DOCK8 deficiency allows for Tfh13 cell induction and allergy.

BACKGROUND: Many popular botulinum neurotoxin treatments are off-label, yet no review has comprehensively captured their effects. This study provides a systematic review of neurotoxin's off-label aesthetic applications, focusing on muscle targets, aesthetic goals, outcomes, and patient satisfaction.

METHODS: A systematic review of PubMed, MEDLINE, and Web of Science was conducted per Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Eligible studies were published between 2014 and 2024, describing nonwrinkle aesthetic uses of botulinum toxin type A in adults. Data extracted included patient demographics, muscle targets, aesthetic goals, procedural approaches, outcome measures, and patient satisfaction. Proportion meta-analyses were performed using Stata software.

RESULTS: Of 531 search-identified studies, 38 met inclusion criteria, totaling 1903 patients aged 17 to 93 years. Patients were primarily female (94.3%, P < 0.0001), with a mean age of 43.7 years. Most interventions targeted the lower face (70.3%, P < 0.0001). Facial aesthetic goals included eyebrow lift, forehead fat graft retention, nasal flare reduction, nasal tip sculpting, facial slimming, and correction of gummy smile, downturned mouth, chin retrusion, mentalis strain, and lower-face descent. Nonfacial aesthetic goals included neck, arm, and calf contouring and scrotal relaxation. Interventions focused on reducing volume/bulk (n = 21, 61.8%) or reshaping (eg, lifts and smile correction) (n = 16, 47.1%). Overall satisfaction was high (94%; 95% confidence interval, 88%-98%). Studies with quantitative measurements during the first follow-up (n = 23) reported sustained results (75.0%, P < 0.0001), with minimal reported complications.

CONCLUSION: Beyond rhytid reduction, botulinum toxin type A demonstrates versatile aesthetic utility in facial and body contouring, with high patient satisfaction and minimal adverse effects. Standardized protocols and refined evaluation methods are needed to inform decision-making, expand clinical guidance, and optimize outcomes.

BACKGROUND: Deep inferior epigastric perforator (DIEP) flaps are the gold standard in autologous breast reconstruction (ABR) despite being associated with significant abdominal donor-site morbidity. Some surgeons place mesh during abdominal closure to potentially mitigate the risk of postoperative hernias. Nonetheless, existing research on the efficacy of this practice has been limited by small cohort studies. This study aims to evaluate factors that influence mesh placement in DIEP ABR and to assess the short- and long-term effects of mesh placement on postoperative hernia development and donor-site morbidity using a large healthcare database.

METHODS: The TriNetX health database was queried to identify patients who underwent DIEP flap reconstruction with or without abdominal mesh using CPT and HCPCS codes. Cox regression analysis was performed to identify significant covariates influencing both mesh placement and postoperative hernia risk. Patients with BMI of ≥30 kg/m2 were stratified by mesh placement and propensity-score matched 1:1 by demographics and comorbidities. Risk ratios were calculated to determine 5-year hernia rates between the matched cohorts.

RESULTS: Among 12,593 patients who underwent DIEP ABR, 1100 patients (8.7%) had abdominal mesh placed at the time of surgery. Cox regression demonstrated that a BMI of ≥30 kg/m2 and advanced age were significant predictors of postoperative hernias (P < 0.0001). ABR patients were more likely to receive mesh if they had a BMI of ≥30 kg/m2 (P < 0.0001), prior hernia repairs (P < 0.05), tobacco use (P < 0.05), or advanced age (P < 0.01). After propensity-score matching, mesh placement did not significantly reduce 30-day donor-site morbidity or 5-year hernia rates in patients with a BMI of ≥30 kg/m2.

CONCLUSIONS: These findings suggest that surgeons preferentially place mesh in patients they perceive to be at high risk of postoperative complications, particularly those with obesity, history of hernia repairs, tobacco use, and advanced age. Nonetheless, mesh placement during DIEP reconstruction does not provide the anticipated protective effect against postoperative hernias or reduction in donor-site morbidity, even in higher risk patients with a BMI of ≥30 kg/m2. These findings challenge the routine use of mesh during abdominal closure in DIEP flap breast reconstruction and suggest that more targeted approaches to reducing donor-site complications are warranted.

Alzheimer's disease (AD) risk is strongly influenced by genetic variants that converge on pathways regulating endosomal homeostasis. Among these, BIN1 and RIN3 have emerged as susceptibility genes, yet their functional relationship in AD remains largely unknown. Here, we investigated how BIN1 and RIN3 interaction regulates RAB5 activity and endosomal pathology. RIN3 has been shown to bind BIN1, and we previously reported that this interaction modulates amyloid-β (Aβ) precursor protein (APP) trafficking and Aβ generation in vitro. To extend these findings, we used Rin3 constitutive knockout (Rin3-CKO) mice and CRISPR-Cas9-edited human induced pluripotent stem cell-derived neurons carrying either BIN1 knockout or rare familial AD RIN3 missense mutations within the BIN1-binding domain. We found that disruption of BIN1-RIN3 binding, through either genetic deletion or pathogenic RIN3 variants, resulted in RIN3-mediated RAB5 hyperactivation and enlargement of neuronal endosomes, a hallmark of early AD pathology. Transcriptomic profiling further revealed dysregulated expression of AD-related genes. Together, these findings establish BIN1 as a critical regulator of RIN3-driven RAB5 activation and neuronal endosomal homeostasis.

α-Synuclein (αSyn) is a presynaptic protein of unestablished physiological function that plays a central role in Parkinson's disease neuropathology. To date, the reported effects of αSyn expression on the kinetics of axonal synaptic vesicle exocytosis and membrane cycling have been relatively small. In contrast, we report that αSyn is the major modulator of substantia nigra somatodendritic dopamine release, a little-understood form of neurotransmission that is central to sensorimotor and basal ganglia circuitry. This regulation is due to a previously unknown role for αSyn in controlling the activity of the L-type calcium ion channels (LTCC), which are also implicated in Parkinson's pathogenesis. αSyn-deficient neurons further display decreased spike frequency adaptation, hippocampal LTCC-dependent long-term potentiation, and immediate early gene induction, functions that are essential for synaptic adaptation and neuronal plasticity.

OBJECTIVES: Prehospital blood transfusion by emergency medical services (EMS) is associated with improved outcomes in trauma patients, but little is known about the statewide protocols that influence the availability and use of prehospital blood. This study aimed to describe statewide EMS protocols regarding field-initiated prehospital blood and blood product transfusion across the U.S.

METHODS: This was a cross-sectional analysis of publicly available statewide EMS protocols pertaining to field-initiated blood or blood product use during ground transport by advanced life support (ALS) clinicians. We excluded protocols specific to critical care or interfacility transport. We used a standardized data collection tool to compare clinical indications, blood product type, and considerations for pediatrics and biologically female patients who may bear children in the future. Descriptive statistics were used to describe the protocols.

RESULTS: We identified 31 states and the District of Columbia with publicly available statewide EMS protocols. Thirteen (42%) of these protocols allowed for field-initiated prehospital blood transfusion. There was variability regarding recommendations for transfusion indications and the details of administration in the protocols. All protocols allowed for transfusion in traumatic emergencies, and nine (69%) allowed for transfusion in medical emergencies. Three (23%) protocols specifically recommended low titer group O whole blood, and three (23%) protocols allowed transfusion during cardiac arrest. Nine (69%) protocols allowed for transfusion in pediatric patients. Only four (31%) protocols included special considerations for transfusing blood to biologically female patients.

CONCLUSIONS: While most statewide EMS protocols in the US did not include field-initiated blood transfusion, the protocols that do exist vary widely. With the increasing implementation of prehospital blood programs, these findings suggest an opportunity to provide more robust evidence-based guidelines for prehospital blood transfusion to improve patient care and outcomes.

BACKGROUND AND OBJECTIVES: Alzheimer disease (AD) and its related disorders (ADRDs) are characterized by a high frequency of copathologies. We aimed to determine the specificity of plasma pTau217, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) for AD neuropathological change (ADNC) in the presence of common ADRD copathologies.

METHODS: pTau217, GFAP, and NfL were measured using S-PLEX immunoassays from Meso Scale Discovery in banked plasma samples from 2 groups of participants in the Massachusetts Alzheimer's Disease Research Center (MADRC) Longitudinal Cohort study: (1) participants spanning the cognitive spectrum, who underwent brain autopsy, and blood collection within 6 years before death, and (2) participants with normal cognition and no neurologic diagnosis during 5 years of follow-up, but no autopsy data (normal controls [NCs]). Cross-sectional associations between biomarker levels and ADNC, primary neuropathologic diagnosis (NPDx1), and presence of non-AD copathologies were evaluated using linear regression models controlling for age, sex, and time to death.

RESULTS: One hundred eighty-seven participants with brain autopsy (NPDx1: AD n = 85; other n = 102; mean age: 74.3 years, 38.5% female; interval blood collection-death [mean ± SD]: 2.8 ± 1.6 years) and 67 NC without brain autopsy (mean age: 66.5 years, 71.6% female) were included. pTau217, but not GFAP, levels increased stepwise with increasing Thal phases (β = 0.61; 95% CI [0.24-0.97] to β = 0.91 [0.55-1.27]) and Braak stages (β = 0.59; [0.16-1.01] to β = 0.74 [0.33-1.15]). Although 23% of individuals with a non-AD NPDx1 had increased pTau217 levels using a cutoff defined by the contrast between ADNC and NC, the majority (62%) had intermediate/high ADNC copathology and the remaining pTau217+ individuals had borderline increased levels. By contrast, 48% of individuals without ADNC had increased GFAP levels. pTau217 and GFAP were not different in the presence or absence of cerebral amyloid angiopathy, α-synuclein or TDP-43 proteinopathies, or primary tauopathies. NfL was not specifically associated with ADNC.

DISCUSSION: Plasma pTau217, but not GFAP or NfL, levels accurately reflect the presence of ADNC in the brain even in individuals with an NPDx1 of a non-AD dementia. Thus, a positive plasma pTau217 test in an individual with a suspected non-AD dementia should not necessarily be considered a misdiagnosis of the presumed non-AD dementia or as a false positive, but rather as evidence of ADNC copathology.