Faculty Bibliography

The Yazidi community endured an unprecedented genocide by the Islamic State (ISIS) in August 2014, resulting in mass killings, kinocide, abductions, ongoing disappearances, and sexual enslavement. The intense trauma led to high prevalence rates of posttraumatic stress disorder (PTSD), depression, anxiety, and profound sleep disturbances. This comprehensive article integrates epidemiological data, neurobiological mechanisms, and clinical case reports to elucidate sleep disorders among Yazidi survivors. We detail the historical context, transgenerational trauma, specific sleep-related pathologies (insomnia, nightmares, parasomnias, and disrupted circadian rhythms), neurobiological underpinnings, cultural factors, and evidence-based interventions (e.g., Narrative Exposure Therapy (NET); Cognitive Behavioral Therapy for Insomnia (CBT-I)). Furthermore, we discuss the establishment and role of the Institute for Psychotherapy and Psychotraumatology (IPP) at the University of Duhok, outline barriers to care, and propose future research directions and policy recommendations.

Renal papillary necrosis (RPN) is an uncommon but important cause of hematuria in patients with sickle cell trait. We report a 28-year-old female with sickle cell trait and beta thalassemia who developed recurrent, transfusion-dependent gross hematuria. Despite extensive imaging, endoscopic evaluation, and conservative management, bleeding persisted. Ureteroscopy demonstrated findings consistent with RPN. The patient required intensive multidisciplinary care and 21 units of packed red blood cells. Hematuria ultimately resolved following treatment with oral epsilon-aminocaproic acid. This case highlights the potential severity of RPN in sickle cell trait and supports consideration of antifibrinolytics as salvage therapy in refractory cases.

Repetitive head impacts sustained during American football have been associated with neuropathological changes such as white matter shear injuries. However, the impact of specific factors, such as age of first exposure and cumulative head impact burden, on white matter integrity remains unclear. This study investigated in vivo white matter microstructural changes using diffusion tensor imaging and tract-based spatial statistics in 165 male former American football players (mean age 57.3 years, range 45-74) and 52 unexposed asymptomatic male controls (mean age 59.4 years, range 45-74) in the DIAGNOSE CTE Research Project. Compared to controls, former football players exhibited significantly higher fractional anisotropy (FA) in 1.97% of the white matter skeleton (1552 voxels; Cohen's d = 0.587) and higher tissue-corrected FA (FAt) in 1.48% of the white matter skeleton (1004 voxels; Cohen's d = 0.616). No significant differences were observed for mean diffusivity, axial diffusivity, radial diffusivity, or free water between football players and controls. Among football players, there were no significant differences in the white matter microstructure between players diagnosed with traumatic encephalopathy syndrome and those without the diagnosis. Lower FA was significantly associated with older age (P < 0.00001) and an earlier age of first exposure to tackle football (P < 0.01), while lower FAt was associated with greater cumulative head impact burden, specifically higher linear acceleration (P < 0.04) and rotational force (P < 0.02). This study highlights the influential role of exposure factors on white matter microstructure in former American football players, as well as the utility of diffusion tensor imaging to aid in characterizing the long-term effects of repetitive head impacts in contact sport athletes.

INTRODUCTION/BACKGROUND:Immune checkpoint inhibitors (ICI) have transformed the treatment landscape for triple-negative breast cancer (TNBC), but their efficacy in older adults remains unclear. The objective of this systematic review is to evaluate the efficacy of ICI in patients with TNBC aged ≥65 years. MATERIALS AND METHODS/METHODS:We conducted a systematic review of randomized controlled trials (RCTs) between January 2013 and September 2023 using searches of Medline, Embase, the Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform. RESULTS:Eighteen full-text articles representing 11 unique RCTs were identified. Only four RCTs reported efficacy outcomes for patients ≥65 years: KEYNOTE 355, KEYNOTE 522, IMpassion130, and IMpassion131. Across these trials, 602 of 3215 patients (18.7%) were 65 and older. The overall risk of bias was low to intermediate, but heterogeneity in trial design and endpoints precluded meta-analysis. Pembrolizumab, the only FDA-approved ICI in TNBC, showed a nonsignificant trend toward improved pathological complete response and event-free survival among older adults with early-stage TNBC (KEYNOTE-522). In the metastatic setting, pembrolizumab may improve overall survival in older patients with PD-L1 combined positive score ≥ 10 (KEYNOTE-355). All studies enrolled few older patients, and none prespecified age-stratified analyses. DISCUSSION/CONCLUSIONS:These findings highlight a major evidence gap and underscore the need for further research evaluating ICI outcomes in older adults with TNBC.

PURPOSE/OBJECTIVE:SET is a member of the inhibitor of histone acetyltransferases (INHAT) complex, involved in transcriptional silencing and gene regulation. Pathogenic variants in SET are postulated to cause neurodevelopmental disorder (NDD) phenotypes, but as only few individuals are described, detailed clinical information is scarce. Hence, currently counseling on phenotype and prognosis of this condition remains challenging. METHODS:Here we describe the clinical phenotype and mutational spectrum of 23 unreported individuals harboring (likely) pathogenic variants in SET. RESULTS:Phenotypes include global developmental delay with often pronounced hypotonia, delayed motor development and speech and language delay, ultimately evolving into (mild) intellectual disability. Comorbidities include behavioral concerns, sleeping disturbance and variable unspecific ocular problems. Next generation computer-assisted phenotyping using GestaltMatcher showed limited overlapping facial features between affected individuals and differences compared to disorders caused by related chromatin modifying genes. In addition, we generated a DNA methylation signature, able to distinguish individuals carrying pathogenic variants in SET from individuals with other NDDs and healthy controls. We used this DNA methylation signature to assess pathogenicity of two variants of uncertain significance in SET found in two additional individuals. CONCLUSION/CONCLUSIONS:Together, this expands the knowledge on the SET-related disorder and provides novel approaches for its diagnosis.

Advanced gastrointestinal cancers remain a major global health challenge, with rising incidence especially among younger populations. Systemic chemotherapy continues to be the mainstay of care for most patients, but balancing treatment benefit with tolerability is an ongoing concern. Many patients, especially older adults and those with significant medical comorbidities, may struggle with standard dosing due to side effects, yet they are often underrepresented in clinical trials. As a result, real-world practice often relies on adjusting drug doses and schedules to reduce toxicity without compromising outcomes. Personalizing systemic therapy based on patient factors like age, fitness, and individual response can help improve tolerability and maintain quality of life. Emerging evidence supports the use of modified dosing and frequency, but prospective data remain limited. In this review, we discuss current approaches to optimizing systemic therapy for advanced gastrointestinal cancers and the need for practical, patient-centered care pathways.

Alexander von Humboldt's early nineteenth-century explorations of the Andes established foundational methods in biogeography and environmental science, emphasizing measurement, spatial integration, and the interdependence of natural systems. Nearly two centuries later, southern Ecuador became the site of a landmark discovery in endocrine genetics: a population with growth hormone receptor deficiency (Laron syndrome) characterized by severe insulin-like growth factor-1 (IGF-1) deficiency. This article examines the historical and scientific continuity of observation in the Ecuadorian Andes, linking Humboldt's integrative natural philosophy with modern approaches to human molecular physiology. While no direct historical connection exists between Humboldt's writings and the later identification of this endocrine condition, the shared geographic setting underscores the enduring scientific value of place-based investigation.

OBJECTIVE:Although efforts have been made to standardize fluid balance calculations in the ICU, there is a limited understanding of how different calculation methods relate to one another across an ICU admission. We quantified the agreement between the cumulative fluid balance calculated from fluid intake and output (CFBf) and cumulative fluid balance calculated from serial weights (CFBw) in critically ill children during the first week of ICU admission. DESIGN/METHODS:Retrospective, multicenter, federated observational study. SETTING/METHODS:Four pediatric medical-SICUs (PICU) and two pediatric cardiac ICUs (PCICU) from four tertiary care centers. PATIENTS/METHODS:Analysis included 8,895 pediatric patients (younger than 19 yr) representing 12,388 ICU encounters from 2023 to 2024. INTERVENTIONS/METHODS:None. MEASUREMENTS AND MAIN RESULTS/RESULTS:A patient's anchor weight was the weight closest to ICU admission. CFBf and CFBw were calculated at the time of new weight measurements. We assessed agreement between CFBf and CFBw using Bland-Altman analyses, stratified by ICU day and patient subgroups (neonates, early anchor weights [weight on ICU day 0], and encounters with unmeasured urine occurrences). Across all units and subgroups, CFBf exceeded CFBw (mean difference: all patients = 4.7 %CFB, early anchor weight = 4.7 %CFB, neonates = 5.9 %CFB). The mean difference increased significantly over time (days 0-3: 2.7% vs. days 4-7: 8.1%, p < 0.05), with greater divergence in neonates and those with early anchor weights. CONCLUSIONS:CFBf consistently exceeded CFBw across all subgroups, with a greater divergence on ICU days 4-7. Clinicians should understand these differences, prioritizing early and frequent patient weights throughout ICU admission. Future studies should assess each method's association with patient outcomes to identify the most clinically informative CFB method.

BACKGROUND:Preterm infants encounter DEHP through medical devices and equipment. While hyperoxia is known to promote cardiac remodeling and dysfunction, the impact of early phthalate exposure is understudied. We hypothesized that independent and combined DEHP and hyperoxia exposure would impair neonatal cardiovascular development. METHODS:Newborn rats were exposed from birth to day 14 to one of four conditions: control (21% oxygen), hyperoxia (60% oxygen), DEHP (25 mg/m3), and DEHP + hyperoxia (25 mg/m3 DEHP and 60% oxygen). Cardiac tissue and serum were analyzed by histology, RT-qPCR and ELISA for markers of contractility, angiogenesis, and inflammation: myosin heavy chain 6 (Myh6), vascular endothelial growth factor (VEGF), interleukin-4 (IL-4), interleukin-10 (IL-10), and fractalkine (CX3CL1). RESULTS:Histology found increased cell size, cytoplasm per nucleus, and nuclear area in all exposures. DEHP exposure and hyperoxia exposure reduced Myh6 and VEGF gene expression. Serum VEGF was higher in the DEHP + hyperoxia group compared to hyperoxia alone. IL-10 was decreased in all exposed groups. IL-4 was reduced in the DEHP + hyperoxia group. CXC3L1 was increased in the DEHP + hyperoxia group compared to hyperoxia alone. CONCLUSION(S)/CONCLUSIONS:Independent and concurrent DEHP and hyperoxia exposure during early neonatal development significantly disrupted markers of cardiac morphology, contractility, angiogenesis, and inflammation. IMPACT/CONCLUSIONS:Key Message: Postnatal exposure to DEHP adversely impacts neonatal rat cardiovascular development. Adds to Existing Literature: This is the first study to examine concurrent long-term hyperoxia and DEHP exposure on cardiovascular development in an animal model relevant to preterm infants. Identifies a modifiable contributor, DEHP, to adverse cardiovascular development. Identifies various cardiovascular components affected by DEHP and hyperoxia, including structural, angiogenic, contractile, and inflammatory aspects. Leads to a new approach to investigate the impact of environmental toxins and the origin of cardiovascular disease in the newborn period.