Diminishing Use of Liver Biopsy among Liver Transplant Recipients for Hepatitis C.

Background and Aims: Hepatitis C virus (HCV) cirrhosis is the leading indication for liver transplantation in the United States and recurrent HCV following liver transplantation is a major cause of allograft loss and mortality. Liver biopsies are commonly used to identify recurrent HCV and determine the need for antiviral therapy. The introduction of direct-acting antiviral agents (DAAs) has changed the management of recurrent HCV infection. This study aimed to describe the role of liver biopsies in liver transplant recipients with HCV after the introduction of DAAs. Methods: A retrospective analysis was performed looking at the rate of liver biopsies post-liver transplantation for HCV. The analysis included 475 adult liver transplants for hepatitis C performed at the University of California, Los Angeles from January 1, 2006 to October 1, 2015. Patients were divided into two eras, pre- and post-introduction of DAAs on December 1, 2013. Results: In the era before the introduction of DAAs, the percentage of patients biopsied was significantly higher compared to the era after the introduction of DAAs (56.1% vs. 26.9%, p < 0.001). Conclusions: The introduction of DAAs has changed the management of liver biopsy following liver transplantation and the management of recurrent HCV. Given that DAAs are well tolerated and have high efficacy, liver biopsies are no longer routinely used to justify the use antiviral therapy following liver transplantation

A Nationwide Analysis of Community‐Level Floodplain Development Outcomes and Key Influences

Development patterns and climate change are contributing to increasing flood risk across the United States. Limiting development in floodplains mitigates risk by reducing the assets and population exposed to flooding. Here, we develop two indexes measuring floodplain development for 18,548 communities across the continental United States. We combine land use, impervious surface, and housing data with regulatory flood maps to determine what proportion of new development has taken place in the floodplain. Nationwide from 2001 to 2019, 2.1 million acres of floodplain land were developed, and 844,000 residential properties were built in the floodplain. However, contrary to conventional perceptions of rampant floodplain development, just 26% of communities nationwide have developed in floodplains more than would be expected given the hazard they face. The indexes and the analyses they enable can help guide targeted interventions to improve flood risk management, to explore underlying drivers of flood exposure, and to inform how local‐to‐federal policy choices can be leveraged to limit hazardous development. Plain Language Summary Development in areas prone to flooding increases flood risk by increasing the exposure of people and infrastructure. Reducing or limiting development in hazardous areas can be a critical way for communities to manage flood risk. In this study, we use national flood hazard, impervious surface, and housing data sets to create two indexes measuring the extent of floodplain development across the United States from 2001 to 2019. Surprisingly, we find that despite seemingly large aggregate numbers, most communities have actually limited hazardous development when we account for how much of their developable land is in the floodplain. We show that floodplain development outcomes vary across key influences, including geography, wealth, and flood risk management efforts. Our indexes enable comparisons across community contexts, potentially unlocking important lessons for effective floodplain management. Proactive, climate‐smart land use planning will be key to ensuring resilient growth for communities moving forward. Key Points Substantial development took place in floodplains across the US from 2001 to 2019 but less than expected given the extent of flood hazards Floodplain development outcomes vary across a number of key factors, including geography, socioeconomics, and flood risk management Nationwide indexes capturing local outcomes enable evaluation of floodplain management policies and drivers of floodplain developmen

Proteomic analysis of HIV-1 Nef cellular binding partners reveals a role for exocyst complex proteins in mediating enhancement of intercellular nanotube formation

<p>Abstract</p> <p>Background</p> <p>HIV-1 Nef protein contributes to pathogenesis via multiple functions that include enhancement of viral replication and infectivity, alteration of intracellular trafficking, and modulation of cellular signaling pathways. Nef stimulates formation of tunneling nanotubes and virological synapses, and is transferred to bystander cells via these intercellular contacts and secreted microvesicles. Nef associates with and activates Pak2, a kinase that regulates T-cell signaling and actin cytoskeleton dynamics, but how Nef promotes nanotube formation is unknown.</p> <p>Results</p> <p>To identify Nef binding partners involved in Pak2-association dependent Nef functions, we employed tandem mass spectrometry analysis of Nef immunocomplexes from Jurkat cells expressing wild-type Nef or Nef mutants defective for the ability to associate with Pak2 (F85L, F89H, H191F and A72P, A75P in NL4-3). We report that wild-type, but not mutant Nef, was associated with 5 components of the exocyst complex (EXOC1, EXOC2, EXOC3, EXOC4, and EXOC6), an octameric complex that tethers vesicles at the plasma membrane, regulates polarized exocytosis, and recruits membranes and proteins required for nanotube formation. Additionally, Pak2 kinase was associated exclusively with wild-type Nef. Association of EXOC1, EXOC2, EXOC3, and EXOC4 with wild-type, but not mutant Nef, was verified by co-immunoprecipitation assays in Jurkat cells. Furthermore, shRNA-mediated depletion of EXOC2 in Jurkat cells abrogated Nef-mediated enhancement of nanotube formation. Using bioinformatic tools, we visualized protein interaction networks that reveal functional linkages between Nef, the exocyst complex, and the cellular endocytic and exocytic trafficking machinery.</p> <p>Conclusions</p> <p>Exocyst complex proteins are likely a key effector of Nef-mediated enhancement of nanotube formation, and possibly microvesicle secretion. Linkages revealed between Nef and the exocyst complex suggest a new paradigm of exocyst involvement in polarized targeting for intercellular transfer of viral proteins and viruses.</p

Describing Characteristics of adults With and Without Congenital Heart Defects Hospitalized With Covid-19

BACKGROUND: We sought to describe patient characteristics in adults with and without congenital heart defects (CHDs) during hospitalization for COVID-19. METHODS: We analyzed data collected by Optum®, a nationally representative database of electronic medical records, for 369 adults with CHDs and 41,578 without CHDs hospitalized for COVID-19 between January 1, 2020, and December 10, 2020. We used Poisson regression to describe and compare epidemiologic characteristics, heart-related conditions, and severe outcomes between these two groups. RESULTS: The distributions of many epidemiologic characteristics were similar between the two groups, but patients with CHDs were significantly more likely to be current or former smokers compared to patients without CHDs (risk ratio [RR]: 1.5, 95% confidence interval [CI]: 1.2, 1.8). Patients with CHDs were also significantly more likely to have heart failure, stroke, acute arrhythmia, myocardial injury, acute pulmonary hypertension, venous thromboembolism, and obesity documented at the time of the COVID-19 hospitalization (RR range: 1.5-4.7) but not respiratory failure. Patients with CHDs (7 days) had a significantly longer median length of stay than those without CHDs (5 days; p \u3c .001) and were significantly more likely to have an intensive care unit (ICU) admission (RR: 1.6, 95 CI: 1.2-1.9). CONCLUSIONS: Our description of patients among a large population improves our understanding of the clinical course of COVID-19 among adults with CHDs. Adults with CHD appear to be at greater risk for more severe CHD, including greater risk of ICU admission and longer length of hospital stays

Evaluating the Proportion of Isolated Cases Among a Spectrum of Birth Defects in a Population-Based Registry

INTRODUCTION: Because the etiology and outcomes of birth defects may differ by the presence vs. absence of co-occurring anomalies, epidemiologic studies often attempt to classify cases into isolated versus non-isolated groupings. This report describes a computer algorithm for such classification and presents results using data from the Texas Birth Defects Registry (TBDR). METHODS: Each of the 1,041 birth defects coded by the TBDR was classified as chromosomal, syndromic, minor, or needs review by a group of three clinical geneticists. A SAS program applied those classifications to each birth defect in a case (child/fetus), and then hierarchically combined them to obtain one summary classification for each case, adding isolated and multiple defect categories. The program was applied to 136,121 cases delivered in 2012-2017. RESULTS: Of total cases, 49% were classified by the platform as isolated (having only one major birth defect). This varied widely by birth defect; of those examined, the highest proportion classified as isolated was found in pyloric stenosis (87.6%), whereas several cardiovascular malformations had low proportions, including tricuspid valve atresia/stenosis (2.3%). DISCUSSION: This is one of the first and largest attempts to identify the proportion of isolated cases across a broad spectrum of birth defects, which can inform future epidemiologic and genomic studies of these phenotypes. Our approach is designed for easy modification for use with any birth defects coding system and category definitions, allowing scalability for different studies or birth defects registries, which often do not have resources for individual clinical review of all case records

Factors Associated With Nonsyndromic Anotia and Microtia, Texas, 1999–2014

BACKGROUND: Few risk factors have been identified for nonsyndromic anotia/microtia (A/M). METHODS: We obtained data on cases and a reference population of all livebirths in Texas for 1999-2014 from the Texas Birth Defects Registry (TBDR) and Texas vital records. We estimated prevalence ratios (PRs) and 95% confidence intervals (CIs) for A/M (any, isolated, nonisolated, unilateral, and bilateral) using Poisson regression. We evaluated trends in prevalence rates using Joinpoint regression. RESULTS: We identified 1,322 cases, of whom 982 (74.3%) had isolated and 1,175 (88.9%) had unilateral A/M. Prevalence was increased among males (PR: 1.3, 95% CI: 1.2-1.4), offspring of women with less than high school education (PR: 1.3, 95% CI: 1.1-1.5), diabetes (PR: 2.0, 95% CI: 1.6-2.4), or age 30-39 versus 20-29 years (PR: 1.2, 95% CI: 1.0-1.3). The prevalence was decreased among offspring of non-Hispanic Black versus White women (PR: 0.6, 95% CI: 0.4-0.8) but increased among offspring of Hispanic women (PR: 2.9, 95% CI: 2.5-3.4) and non-Hispanic women of other races (PR: 1.7, 95% CI: 1.3-2.3). We observed similar results among cases with isolated and unilateral A/M. Sex disparities were not evident for nonisolated or bilateral phenotypes, nor did birth prevalence differ between offspring of non-Hispanic Black and non-Hispanic White women. Maternal diabetes was more strongly associated with nonisolated (PR: 4.5, 95% CI: 3.2-6.4) and bilateral A/M (PR: 5.0, 95% CI: 3.3-7.7). Crude prevalence rates increased throughout the study period (annual percent change: 1.82). CONCLUSION: We identified differences in the prevalence of nonsyndromic A/M by maternal race/ethnicity, education, and age, which may be indicators of unidentified social/environmental risk factors

Prevalence and Clustering of Congenital Heart Defects among Boys With Hypospadias

IMPORTANCE: Hypospadias is a common birth defect of the male urinary tract that may be isolated or may co-occur with other structural malformations, including congenital heart defects (CHDs). The risk for co-occurring CHDs among boys with hypospadias remains unknown, which limits screening and genetic testing strategies. OBJECTIVE: to characterize the risk of major CHDs among boys born with hypospadias. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study used data from population-based birth defect surveillance programs on all male infants born in 11 US states from January 1, 1995, to December 31, 2014. Statistical analysis was performed from September 2, 2020, to March 25, 2022. EXPOSURE: Hypospadias. MAIN OUTCOMES AND MEASURES: Demographic and diagnostic data were obtained from 2 active state-based birth defect surveillance programs for primary analyses, the Texas Birth Defects Registry and the Arkansas Reproductive Health Monitoring System, with validation among 9 additional states in the National Birth Defects Prevention Network (NBDPN). Birth defect diagnoses were identified using the British Pediatric Association coding for hypospadias (exposure) and major CHDs (primary outcomes). Maternal covariates and birth year were also abstracted from the vital records. Poisson regression was used to estimate adjusted prevalence ratios and 95% CIs for major CHDs within Texas and Arkansas and combined using inverse variance-weighted meta-analysis. Findings were validated using the NBDPN. RESULTS: Among 3.7 million pregnancies in Texas and Arkansas, 1485 boys had hypospadias and a co-occurring CHD. Boys with hypospadias were 5.8 times (95% CI, 5.5-6.1) more likely to have a co-occurring CHD compared with boys without hypospadias. Associations were observed for every specific CHD analyzed among boys with hypospadias, occurred outside of chromosomal anomalies, and were validated in the NBDPN. An estimated 7.024% (95% CI, 7.020%-7.028%) of boys with hypospadias in Texas and 5.503% (95% CI, 5.495%-5.511%) of boys with hypospadias in Arkansas have a co-occurring CHD. In addition, hypospadias severity and maternal race and ethnicity were independently associated with the likelihood for hypospadias to co-occur with a CHD; boys in Texas with third-degree (ie, more severe) hypospadias were 2.7 times (95% CI, 2.2-3.4) more likely than boys with first-degree hypospadias to have a co-occurring CHD, with consistent estimates in Arkansas (odds ratio, 2.7; 95% CI, 1.4-5.3), and boys with hypospadias born to Hispanic mothers in Texas were 1.5 times (95% CI, 1.3-1.8) more likely to have a co-occurring CHD than boys with hypospadias born to non-Hispanic White mothers. CONCLUSIONS AND RELEVANCE: In this cohort study, boys with hypospadias had a higher prevalence of CHDs than boys without hypospadias. These findings support the need for consideration of additional CHD screening programs for boys born with hypospadias

High Clinical Exome Sequencing Diagnostic Rates and Novel Phenotypic Expansions for Nonisolated Microphthalmia, Anophthalmia, and Coloboma

PURPOSE: A molecular diagnosis is only made in a subset of individuals with nonisolated microphthalmia, anophthalmia, and coloboma (MAC). This may be due to underutilization of clinical (whole) exome sequencing (cES) and an incomplete understanding of the genes that cause MAC. The purpose of this study is to determine the efficacy of cES in cases of nonisolated MAC and to identify new MAC phenotypic expansions. METHODS: We determined the efficacy of cES in 189 individuals with nonisolated MAC. We then used cES data, a validated machine learning algorithm, and previously published expression data, case reports, and animal models to determine which candidate genes were most likely to contribute to the development of MAC. RESULTS: We found the efficacy of cES in nonisolated MAC to be between 32.3% (61/189) and 48.1% (91/189). Most genes affected in our cohort were not among genes currently screened in clinically available ophthalmologic gene panels. A subset of the genes implicated in our cohort had not been clearly associated with MAC. Our analyses revealed sufficient evidence to support low-penetrance MAC phenotypic expansions involving nine of these human disease genes. CONCLUSIONS: We conclude that cES is an effective means of identifying a molecular diagnosis in individuals with nonisolated MAC and may identify putatively damaging variants that would be missed if only a clinically available ophthalmologic gene panel was obtained. Our data also suggest that deleterious variants in BRCA2, BRIP1, KAT6A, KAT6B, NSF, RAC1, SMARCA4, SMC1A, and TUBA1A can contribute to the development of MAC

A case–control study of maternal bathing habits and risk for birth defects in offspring

Abstract Background Nearly all women shower or take baths during early pregnancy; however, bathing habits (i.e., shower and bath length and frequency) may be related to the risk of maternal hyperthermia and exposure to water disinfection byproducts, both of which are suspected to increase risk for multiple types of birth defects. Thus, we assessed the relationships between bathing habits during pregnancy and the risk for several nonsyndromic birth defects in offspring. Methods Data for cases with one of 13 types of birth defects and controls from the National Birth Defects Prevention Study delivered during 2000–2007 were evaluated. Logistic regression analyses were conducted separately for each type of birth defect. Results There were few associations between shower frequency or bath frequency or length and risk for birth defects in offspring. The risk for gastroschisis in offspring was increased among women who reported showers lasting ≥15 compared to &lt;15 minutes (adjusted odds ratio: 1.43, 95% confidence interval: 1.18-1.72). In addition, we observed modest increases in the risk for spina bifida, cleft lip with or without cleft palate, and limb reduction defects in offspring of women who showered ≥15 compared to &lt;15 minutes. The results of comparisons among more specific categories of shower length (i.e., &lt;15 minutes versus 15–19, 20–29, and ≥ 30 minutes) were similar. Conclusions Our findings suggest that shower length may be associated with gastroschisis, but the modest associations with other birth defects were not supported by analyses of bath length or bath or shower frequency. Given that showering for ≥15 minutes during pregnancy is very common, further evaluation of the relationship between maternal showering habits and birth defects in offspring is worthwhile. </jats:sec

Patterns of Co-occurring Birth Defects in Children with Anotia and Microtia

Many infants with anotia or microtia (A/M) have co-occurring birth defects, although few receive syndromic diagnoses in the perinatal period. Evaluation of co-occurring birth defects in children with A/M could identify patterns indicative of undiagnosed/unrecognized syndromes. We obtained information on co-occurring birth defects among infants with A/M for delivery years 1999-2014 from the Texas Birth Defects Registry. We calculated observed-to-expected ratios (OER) to identify birth defect combinations that occurred more often than expected by chance. We excluded children diagnosed with genetic or chromosomal syndromes from analyses. Birth defects and syndromes/associations diagnosed ≤1 year of age were considered. We identified 1310 infants with non-syndromic A/M, of whom 38% (N = 492) were diagnosed with co-occurring major defects. Top combinations included: hydrocephalus, ventricular septal defect, and spinal anomalies (OER 58.4); microphthalmia and anomalies of the aorta (OER 55.4); and cleft lip with or without cleft palate and rib or sternum anomalies (OER 32.8). Some combinations observed in our study may represent undiagnosed/atypical presentations of known A/M associations or syndromes, or novel syndromes yet to be described in the literature. Careful evaluation of infants with multiple birth defects including A/M is warranted to identify individuals with potential genetic or chromosomal syndromes