Yirui Hu

Background: Truncating variants in the Titin gene (TTNtvs) are common in individuals with idiopathic dilated cardiomyopathy (DCM). However, a comprehensive genomics-first evaluation of the impact of TTNtvs in different clinical contexts, and the evaluation of modifiers such as genetic ancestry, has not been performed. Methods: We reviewed whole exome sequence data for >71 000 individuals (61 040 from the Geisinger MyCode Community Health Initiative (2007 to present) and 10 273 from the PennMedicine BioBank (2013 to present) to identify anyone with TTNtvs. We further selected individuals with TTNtvs in exons highly expressed in the heart (proportion spliced in [PSI] >0.9). Using linked electronic health records, we evaluated associations of TTNtvs with diagnoses and quantitative echocardiographic measures, including subanalyses for individuals with and without DCM diagnoses. We also reviewed data from the Jackson Heart Study to validate specific analyses for individuals of African ancestry. Results: Identified with a TTNtv in a highly expressed exon (hiPSI) were 1.2% individuals in PennMedicine BioBank and 0.6% at Geisinger. The presence of a hiPSI TTNtv was associated with increased odds of DCM in individuals of European ancestry (odds ratio [95% CI]: 18.7 [9.1–39.4] {PennMedicine BioBank} and 10.8 [7.0–16.0] {Geisinger}). hiPSI TTNtvs were not associated with DCM in individuals of African ancestry, despite a high DCM prevalence (odds ratio, 1.8 [0.2–13.7]; P =0.57). Among 244 individuals of European ancestry with DCM in PennMedicine BioBank, hiPSI TTNtv carriers had lower left ventricular ejection fraction (β=–12%, P =3×10 –7 ), and increased left ventricular diameter (β=0.65 cm, P =9×10 –3 ). In the Geisinger cohort, hiPSI TTNtv carriers without a cardiomyopathy diagnosis had more atrial fibrillation (odds ratio, 2.4 [1.6–3.6]) and heart failure (odds ratio, 3.8 [2.4–6.0]), and lower left ventricular ejection fraction (β=–3.4%, P =1×10 –7 ). Conclusions: Individuals of European ancestry with hiPSI TTNtv have an abnormal cardiac phenotype characterized by lower left ventricular ejection fraction, irrespective of the clinical manifestation of cardiomyopathy. Associations with arrhythmias, including atrial fibrillation, were observed even when controlling for cardiomyopathy diagnosis. In contrast, no association between hiPSI TTNtvs and DCM was discerned among individuals of African ancestry. Given these findings, clinical identification of hiPSI TTNtv carriers may alter clinical management strategies.

Gastric outlet obstruction (GOO) is characterized by epigastric pain and postprandial vomiting secondary to mechanical obstruction. Management of GOO is usually focused on alleviating the symptoms of obstruction and can be achieved by surgical gastrojejunostomy or enteral stenting. Recent studies have shown success with EUS-guided gastroenterostomy (EUS-GE) in the management of GOO but data is limited. We, therefore, conducted a meta-analysis to evaluate the safety and efficacy of EUS-GE in the management of GOO. A comprehensive literature review was conducted by searching the Embase and PubMed databases from inception to January 2019 to identify all studies that evaluate the efficacy and safety of EUS-GE in GOO. Our primary outcome was to evaluate technical success and clinical success. Secondary outcomes were to evaluate the need for reintervention and adverse events of the procedure. Twelve studies including 285 patients were included in the meta-analysis. Technical success was achieved in 266 patients with a pooled technical success of 92% (95% confidence interval [CI]: 88%–95%). Clinical success was achieved in 90% of the patients (95% CI: 85%–94%). Recurrence of symptoms or unplanned reintervention was needed in 9% of the patients (95% CI: 6%–13%) and adverse events were reported in 12% of the patients (95% CI: 8%–16%). The heterogeneity tests among studies were nonsignificant with I2 = 0. EUS-GE is a safe and efficacious treatment modality for the management of benign and malignant GOO. Larger prospective studies are needed to further evaluate its utility in GOO.

BACKGROUND: To estimate a pooled association between hearing impairment and risk of mild cognitive impairment and dementia. METHODS: PubMed, Embase, and Web of Science were searched for prospective cohort studies that examined the association between hearing impairment and risk of mild cognitive impairment and/or dementia. Random-effects models were fitted to estimate the summary risk ratios (RRs) and 95% confidence interval (CIs), which represents the pooled association between hearing impairment with risk of mild cognitive impairment and dementia, compared to subjects free of hearing impairment. RESULTS: Four studies on hearing impairment with mild cognitive impairment and 7 studies on hearing impairment with dementia were included in the meta-analysis. A total of 15,521 subjects were studied with follow-up periods between 2 and 16.8 years. Hearing impairment was associated with a greater risk of mild cognitive impairment (RR = 1.30, 95% CI: 1.12, 1.51) and dementia (RR = 2.39, 95% CI: 1.58, 3.61). CONCLUSIONS: The meta-analysis showed that hearing impairment is associated with a higher risk of mild cognitive impairment and dementia among older adults.

Importance: Exome sequencing is a first-tier diagnostic test for individuals with neurodevelopmental disorders, including intellectual disability/developmental delay and autism spectrum disorder; however, this recommendation does not include cerebral palsy. Objective: To evaluate if the diagnostic yield of exome or genome sequencing in cerebral palsy is similar to that of other neurodevelopmental disorders. Data Sources: The study team searched PubMed for studies published between 2013 and 2022 using cerebral palsy and genetic testing terms. Data were analyzed during March 2022. Study Selection: Studies performing exome or genome sequencing in at least 10 participants with cerebral palsy were included. Studies with fewer than 10 individuals and studies reporting variants detected by other genetic tests were excluded. Consensus review was performed. The initial search identified 148 studies, of which 13 met inclusion criteria. Data Extraction and Synthesis: Data were extracted by 2 investigators and pooled using a random-effects meta-analysis. Incidence rates with corresponding 95% CIs and prediction intervals were calculated. Publication bias was evaluated by the Egger test. Variability between included studies was assessed via heterogeneity tests using the I2 statistic. Main Outcomes and Measures: The primary outcome was the pooled diagnostic yield (rate of pathogenic/likely pathogenic variants) across studies. Subgroup analyses were performed based on population age and on the use of exclusion criteria for patient selection. Results: Thirteen studies were included consisting of 2612 individuals with cerebral palsy. The overall diagnostic yield was 31.1% (95% CI, 24.2%-38.6%; I2 = 91%). The yield was higher in pediatric populations (34.8%; 95% CI, 28.3%-41.5%) than adult populations (26.9%; 95% CI, 1.2%-68.8%) and higher among studies that used exclusion criteria for patient selection (42.1%; 95% CI, 36.0%-48.2%) than those that did not (20.7%; 95% CI, 12.3%-30.5%). Conclusions and Relevance: In this systematic review and meta-analysis, the genetic diagnostic yield in cerebral palsy was similar to that of other neurodevelopmental disorders for which exome sequencing is recommended as standard of care. Data from this meta-analysis provide evidence to support the inclusion of cerebral palsy in the current recommendation of exome sequencing in the diagnostic evaluation of individuals with neurodevelopmental disorders.