Faculty Bibliography

BACKGROUND:Optimal duration and choice of antiplatelet therapy in patients with acute coronary syndrome undergoing percutaneous coronary intervention remain controversial. METHODS AND RESULTS/RESULTS:Digital databases (PubMed, Cochrane, and Embase) were queried to select all randomized controlled trials on a post-percutaneous coronary intervention population with acute coronary syndrome. Dual-antiplatelet therapy (DAPT) with aspirin and clopidogrel for 12 months was compared with 4 major strategies: high-potency, high- to low-potency, low-dose, and short-duration DAPT. A network meta-analysis was performed to compare the safety and efficacy of different antiplatelet strategies. This study was the second updated manuscript under the International Prospective Register of Systematic Review registration (CRD42021286552). Thirty-two randomized controlled trials comprising 103 459 (51 750 experimental, 51 709 control) patients were included. Compared with DAPT with aspirin and clopidogrel for 12 months, high- to low-potency DAPT (risk ratio [RR], 0.69 [95% CI, 0.52-0.92]) and aspirin+prasugrel containing DAPT for 12 months (RR, 0.84 [95% CI, 0.72-0.98]) had a significantly lower, whereas DAPT for 1 month followed by clopidogrel only (RR, 1.59 [95% CI, 1.06-2.39]) had a higher, incidence of major adverse cardiovascular events at 1 year (median follow-up). Prasugrel (RR, 1.35 [95% CI, 1.09-1.66]) and ticagrelor (RR, 1.38 [95% CI, 1.17-1.62]) containing DAPT for 12 months had significantly higher rates, whereas high- to low-potency DAPT (RR, 0.85 [95% CI, 0.63-1.15]) had no significant risk of major bleeding. CONCLUSIONS:Aspirin and ticagrelor for 3 months, followed by aspirin and clopidogrel for the remaining duration, can be considered the optimal strategy for treating post-percutaneous coronary intervention patients with acute coronary syndrome because of a significantly reduced risk of major adverse cardiovascular events without increasing the risk of bleeding.

BACKGROUND:Lipid metabolism has essential roles in skin barrier formation and the regulation of skin inflammation. Lipid homeostasis regulates skin melanogenesis, although the underlying mechanism remains largely unknown. Sterol regulatory element binding protein 1 (SREBP-1) is a key transcription factor essential for cellular lipid metabolism. Loss-of-function variants in SREBF1 are responsible for autosomal-dominant ichthyosis follicularis, alopecia and photophobia syndrome, emphasizing the significance of lipid homeostasis in skin keratinization. OBJECTIVES/OBJECTIVE:To identify the genetic basis of a new entity featuring diffuse skin hyperpigmentation with congenital cataracts, and to unravel the underlying mechanism for the pathogenesis of the SREBF1 variant. METHODS:Whole-exome sequencing was performed to identify underlying genetic variants. Quantitative polymerase chain reaction, Western blot and immunofluorescence staining were used to assess the expression and the subcellular localization of the SREBF1 variant. The transcriptional activity of mutant SREBP-1 was determined by a luciferase reporter assay. A transgenic zebrafish model was constructed. RESULTS:Two unrelated patients presented with generalized skin hyperpigmentation with skin xerosis, congenital cataracts and extracutaneous symptoms. We identified a de novo nonsense variant c.1289C>A (p.Ser430*) in SREBF1 in both patients. The variant encoded a truncated protein that showed preferential nucleus localization, in contrast to wild-type SREBP-1 which - in sterol-sufficient conditions - is mainly localized in the cytoplasm. The luciferase reporter assay revealed that the p.Ser430* mutant exhibited enhanced transcriptional activity. Cultured patient primary melanocytes showed increased melanin synthesis vs. those from healthy controls. At 35 days postfertilization, the p.Ser430* transgenic zebrafish model exhibited more black spots, along with upregulated expression of melanogenic genes. CONCLUSIONS:We demonstrated that a gain-of-function variant of SREBF1 causes a previously undescribed disorder characterized by generalized skin hyperpigmentation and congenital cataracts. Our study reveals the involvement of SREBP-1 in melanogenesis and lens development, and paves the way for the development of novel therapeutic targets for skin dyspigmentation or cataracts.

OBJECTIVE:Data from DNA genotyping via a 96-SNP panel in a study of 25,015 clinical samples were utilized for quality control and tracking of sample identity in a clinical sequencing network. The study aimed to demonstrate the value of both the precise SNP tracking and the utility of the panel for predicting the sex-by-genotype of the participants, to identify possible sample mix-ups. RESULTS:Precise SNP tracking showed no sample swap errors within the clinical testing laboratories. In contrast, when comparing predicted sex-by-genotype to the provided sex on the test requisition, we identified 110 inconsistencies from 25,015 clinical samples (0.44%), that had occurred during sample collection or accessioning. The genetic sex predictions were confirmed using additional SNP sites in the sequencing data or high-density genotyping arrays. It was determined that discrepancies resulted from clerical errors (49.09%), samples from transgender participants (3.64%) and stem cell or bone marrow transplant patients (7.27%) along with undetermined sample mix-ups (40%) for which sample swaps occurred prior to arrival at genome centers, however the exact cause of the events at the sampling sites resulting in the mix-ups were not able to be determined.

This report summarizes the content of a debate sponsored by eGenesis Bio, organized by the International Xenotransplantation Association (IXA), and attended by more than 150 delegates in the context of the IPITA-IXA-CTRMS Joint Congress held in San Diego in October 2023. The debate centered around two important immunological topics relating to xenotransplantation. The first was a debate relating to the statement that "HLA-sensitized patients are at higher risk for rejecting a pig xenograft." Stuart Knechtle provided evidence to support this statement and Massimo Mangiola opposed it. Before the debate, a majority (>80%) of the audience agreed with this statement. After listening to the debate, this percentage was reduced to approximately 60%. The second debated statement was "Recipients of pig xenografts who develop anti-pig antibodies are at higher risk for rejecting a subsequent allograft." This was proposed by A. Joseph Tector and opposed by Léo H. Bühler. Before the debate, once again a majority of the audience (approximately 60%) believed that prior sensitization to a pig xenograft would be detrimental to the survival of a subsequent allograft. However, after listening to the debate, only about 40% believed this statement to be correct. The topics discussed remain complex and answers are not yet conclusive. However, the present evidence suggests that allosensitization may prove detrimental to subsequent xenotransplantation, whilst sensitization to pig antigens may not be detrimental to subsequent allotransplantation.

BACKGROUND/OBJECTIVES/OBJECTIVE:School meals are an important source of nutrition for children and have been found to help mitigate food insecurity. This study evaluated the association between food insecurity and school meal participation and whether parental perceptions about school meals differ by food security status. METHODS:In May 2022, 1110 Californian parents of K-12 students shared their perceptions about school meals, including meal quality, healthiness, stigma, and benefits, as well as their child's participation in school meals, in an online survey. Household food security was determined using the USDA 6-item module. Logistic and Poisson regression models were used for analysis. RESULTS:< 0.05). CONCLUSIONS:Food insecurity is prevalent among California families with school-age children, even in families not eligible for federal FRPMs. Food-insecure households have more negative perceptions of school meals and experience more stigma, though they also report higher breakfast participation. Improving school meal quality and appeal, ensuring parents are familiar with meal quality and healthfulness, and reducing stigma may ease food insecurity while improving children's health.

BACKGROUND/UNASSIGNED:Despite a shortage of potential donors for heart transplant in the United States, most potential donor hearts are discarded. We evaluated predictors of donor heart acceptance in the United States and applied machine learning methods to improve prediction. METHODS/UNASSIGNED:We included a nationwide (2005-2020) cohort of potential heart donors in the United States (n=73 948) from the Scientific Registry of Transplant Recipients and a more recent (2015-2020) rigorously phenotyped cohort of potential donors from DHS (Donor Heart Study; n=4130). We identified predictors of acceptance for heart transplant in both cohorts using multivariate logistic regression, incorporating time-interaction terms to characterize their varying effects over time. We fit models predicting acceptance for transplant in a 50% training subset of DHS using logistic regression, least absolute shrinkage and selection operator, and random forest algorithms and compared their performance in the remaining 50% (test) of the subset. RESULTS/UNASSIGNED:value for time interaction, <0.05 for all). A random forest model (area under the curve, 0.908; accuracy, 0.831) outperformed other prediction algorithms in the test subset and was used as the basis of a novel web-based prediction tool. CONCLUSIONS/UNASSIGNED:Predictors of donor heart acceptance for transplantation have changed significantly over the last 2 decades, likely reflecting evolving evidence regarding their impact on posttransplant outcomes. Real-time prediction of donor heart acceptance, using our web-based tool, may improve efficiency during donor management and heart allocation.

BACKGROUND:The evolution of midline ventral hernia repair has progressed from the open Rives-Stoppa technique to minimally invasive robotic approaches, notably the trans-abdominal retromuscular (TARM) and enhanced-view Totally Extraperitoneal (eTEP) methods. This study compares these two robotic techniques in repairing medium-sized midline ventral hernias. METHODS:A retrospective comparative study of electronic medical records from 2015 to 2021 was conducted on patients undergoing robotic TARM or eTEP at NYU Langone Hospital-Long Island. Data on demographics, comorbid conditions, surgical history, intraoperative details, hernia characteristics, and postoperative outcomes were analyzed. RESULTS:Both eTEP and TARM groups exhibited comparable outcomes regarding operative duration, hernia defect size, and overall complications. However, notable differences were observed in patients' BMI, implanted mesh area, mesh composition, and fixation techniques across the groups. The TARM group required a longer hospital stay (median: 1 day) in contrast to the eTEP group (median: 0 days). Additionally, eTEP patients indicated reduced postoperative pain scores (median: 2) compared to TARM (median: 3), with both differences being statistically significant (p < 0.001). CONCLUSION:The robotic eTEP approach is associated with lower post-operative pain scores, decreased hospital length of stay, and larger areas of mesh implantation as compared to the TARM approach. Other variables are largely comparable between the two techniques. LEVEL OF EVIDENCE:Level III.

BACKGROUND:New York (NY) State implemented a new cystic fibrosis (CF) newborn screen (NBS) algorithm in December 2017 with improvement in positive predictive value and unanticipated increased identification of infants with cystic fibrosis transmembrane conductance regulator (CFTR)-related metabolic syndrome (CRMS). Repeat sweat testing is recommended in infants with CRMS. During the COVID-19 pandemic infants with CRMS were lost to follow up. With this quality improvement (QI) initiative, we aimed to perform repeat sweat testing in 25% of infants lost to follow up. We also describe consensus recommendations for CRMS from the NY CF NBS Consortium. METHODS:Our QI team identified the primary drivers contributing to absent follow up, outreached to families, and created a questionnaire to evaluate parental understanding of CRMS using QI-based strategies. RESULTS:Of 350 infants diagnosed with CRMS during the study period, 179 (51.1%) infants were lost to follow up. A total of 31 (17.3%) were scheduled for repeat sweat tests and followed up at CF Centers. Families reported high satisfaction with the CRMS knowledge questionnaire. CONCLUSIONS:With this QI-based approach, we effectively recaptured infants with CRMS previously lost to follow up during the COVID-19 pandemic. Ongoing concerns about infection risk and lack of understanding on the part of families and pediatricians likely contributed to patients with CRMS lost to follow up. Consensus recommendations for CRMS include annual visits with repeat sweat testing until 2-6 years of age and education for adolescents about clinical and reproductive implications of CRMS.

Acoustic vocoders play a key role in simulating the speech information available to cochlear implant (CI) users. Traditionally, the intelligibility of vocoder CI simulations is assessed through speech recognition experiments with normally-hearing subjects, a process that can be time-consuming, costly, and subject to individual variability. As an alternative approach, we utilized an advanced deep learning speech recognition model to investigate the intelligibility of CI simulations. We evaluated model's performance on vocoder-processed words and sentences with varying vocoder parameters. The number of vocoder bands, frequency range, and envelope dynamic range were adjusted to simulate sound processing settings in CI devices. Additionally, we manipulated the low-cutoff frequency and intensity quantization of vocoder envelopes to simulate psychophysical temporal and intensity resolutions in CI patients. The results were evaluated within the context of the audio analysis performed in the model. Interestingly, the deep learning model, despite not being originally designed to mimic human speech processing, exhibited a human-like response to alterations in vocoder parameters, resembling existing human subject results. This approach offers significant time and cost savings compared to testing human subjects, and eliminates learning and fatigue effects during testing. Our findings demonstrate the potential of speech recognition models in facilitating auditory research.