Digital Spatial Profiling Identifies Distinct Molecular Signatures of Vascular Lesions in Pulmonary Arterial Hypertension.

Rationale: Idiopathic pulmonary arterial hypertension (IPAH) is characterized by extensive pulmonary vascular remodeling caused by plexiform and obliterative lesions, media hypertrophy, inflammatory cell infiltration, and alterations of the adventitia. Objective: We sought to test the hypothesis that microscopic IPAH vascular lesions express unique molecular profiles, which collectively are different from control pulmonary arteries. Methods: We used digital spatial transcriptomics to profile the genomewide differential transcriptomic signature of key pathological lesions (plexiform, obliterative, intima+media hypertrophy, and adventitia) in IPAH lungs (n = 11) and compared these data with the intima+media hypertrophy and adventitia of control pulmonary artery (n = 5). Measurements and Main Results: We detected 8,273 transcripts in the IPAH lesions and control lung pulmonary arteries. Plexiform lesions and IPAH adventitia exhibited the greatest number of differentially expressed genes when compared with intima+media hypertrophy and obliterative lesions. Plexiform lesions in IPAH showed enrichment for 1) genes associated with transforming growth factor ß signaling and 2) mutated genes affecting the extracellular matrix and endothelial-mesenchymal transformation. Plexiform lesions and IPAH adventitia showed upregulation of genes involved in immune and IFN signaling, coagulation, and complement pathways. Cellular deconvolution indicated variability in the number of vascular and inflammatory cells between IPAH lesions, which underlies the differential transcript profiling. Conclusions: IPAH lesions express unique molecular transcript profiles enriched for pathways involving pathogenetic pathways, including genetic disease drivers, innate and acquired immunity, hypoxia sensing, and angiogenesis signaling. These data provide a rich molecular-structural framework in IPAH vascular lesions that inform novel biomarkers and therapeutic targets in this highly morbid disease.

Paternal Alcohol Consumption and Childhood Malnutrition: A Community-based Participatory Case-control Study among Adivasis in Rural South India.

BACKGROUND: Childhood malnutrition in India remains among the highest in the world. Adult alcohol consumption and severe malnutrition have increased among indigenous people in South India. However, the association between them is poorly understood. OBJECTIVES: We aimed to evaluate this association, which could help design better intervention strategies. METHODS: This case-control observational study was conducted in the Nilgiri district in South India. Cases included children aged 1-5 years with moderate malnutrition. Controls were defined as children in the same age group with normal weight-for-age. A questionnaire was used to collect data on demographics, socioeconomic status (SES), and parental education. The WHO Alcohol Use Disorders Identification Test (AUDIT) questionnaire was used to estimate parental alcohol use. Health-care workers collected data from within the community. RESULTS: The baseline demographics of the children in the control (n = 250) and case groups (n = 177) were similar. Paternal age and AUDIT scores were not different in the two groups. SES was lower in the malnourished group, while maternal education among cases was significantly lower. Maternal and paternal education were associated with childhood malnutrition (odds ratio [OR]: 0.728 [95% confidence interval (CI): 0.583-0.903] and OR: 0.753 [95% CI: 0.589-0.957], respectively). After adjustment for covariates, paternal alcohol use was associated with a higher risk of malnutrition (OR: 1.56 [95% CI: 1.00-2.47]), which SES partly mediated. CONCLUSION: Paternal alcohol consumption is associated with childhood malnutrition, partially mediated by lower SES. Furthermore, lower SES appeared to be strongly associated with paternal alcohol consumption.

Inner Ear Breaches from Vestibular Schwannoma Surgery: Revisiting the Incidence of Otologic Injury from Retrosigmoid and Middle Cranial Fossa Approaches.

OBJECTIVE: To assess the rate of iatrogenic injury to the inner ear in vestibular schwannoma resections. STUDY DESIGN: Retrospective case review. SETTING: Multiple academic tertiary care hospitals. PATIENTS: Patients who underwent retrosigmoid or middle cranial fossa approaches for vestibular schwannoma resection between 1993 and 2015. INTERVENTION: Diagnostic with therapeutic implications. MAIN OUTCOME MEASURE: Drilling breach of the inner ear as confirmed by operative note or postoperative computed tomography (CT). RESULTS: 21.5% of patients undergoing either retrosigmoid or middle fossa approaches to the internal auditory canal were identified with a breach of the vestibulocochlear system. Because of the lack of postoperative CT imaging in this cohort, this is likely an underestimation of the true incidence of inner ear breaches. Of all postoperative CT scans reviewed, 51.8% had an inner ear breach. As there may be bias in patients undergoing postoperative CT, a middle figure based on sensitivity analyses estimates the incidence of inner ear breaches from lateral skull base surgery to be 34.7%. CONCLUSIONS: A high percentage of vestibular schwannoma surgeries via retrosigmoid and middle cranial fossa approaches result in drilling breaches of the inner ear. This study reinforces the value of preoperative image analysis for determining risk of inner ear breaches during vestibular schwannoma surgery and the importance of acquiring CT studies postoperatively to evaluate the integrity of the inner ear.