HPB ultrasound guidance techniques - Targeting.

Ultrasound is an indispensable tool for intraoperative assessment and treatment of hepatopancreatobiliary pathology. As minimally invasive approaches to HPB surgery continue to expand and the benefits of parenchymal-sparing liver surgery are increasingly appreciated, skillful targeting will play an even bigger role in HPB surgical practice. Techniques for intraoperative targeting of liver lesions for the purposes of biopsy and ablation, particularly in the laparoscopic setting, are the focus of this chapter. Current evidence supports the use of ablation for a variety of liver lesions including hepatocellular carcinoma and metastatic colorectal cancer, particularly for smaller lesions. Successful targeting requires optimization of patient position and port placement. When targeting multiple lesions, thoughtful treatment sequencing is critical to maintaining visualization and optimizing outcomes.

Clinical factors associated with racial differences in the prevalence of occult hypoxemia: a retrospective case-control study.

Background: Recent studies showed that Black patients more often have falsely normal oxygen saturation on pulse oximetry compared to White patients. However, whether the racial differences in occult hypoxemia are mediated by other clinical differences is unknown. Methods: We conducted a retrospective case-control study utilizing two large ICU databases (eICU and MIMIC-IV). We defined occult hypoxemia as oxygen saturation on pulse oximetry within 92-98% despite oxygen saturation on arterial blood gas below 90%. We assessed associations of commonly measured clinical factors with occult hypoxemia using multivariable logistic regression and conducted mediation analysis of the racial effect. Results: Among 24,641 patients, there were 1,855 occult hypoxemia cases and 23,786 controls. In both datasets, Black patients were more likely to have occult hypoxemia (unadjusted odds ratio 1.66 [95%-CI: 1.41-1.95] in eICU and 2.00 [95%-CI: 1.22-3.14] in MIMIC-IV). In multivariable models, higher respiratory rate, PaCO2 and creatinine as well as lower hemoglobin were associated with increased odds of occult hypoxemia. Differences in the commonly measured clinical markers accounted for 9.2% and 44.4% of the racial effect on occult hypoxemia in eICU and MIMIC-IV, respectively. Conclusion: Clinical differences, in addition to skin tone, might mediate some of the racial differences in occult hypoxemia.

A novel application of data-consistent inversion to overcome spurious inference in genome-wide association studies.

The genome-wide association studies (GWAS) typically use linear or logistic regression models to identify associations between phenotypes (traits) and genotypes (genetic variants) of interest. However, the use of regression with the additive assumption has potential limitations. First, the normality assumption of residuals is the one that is rarely seen in practice, and deviation from normality increases the Type-I error rate. Second, building a model based on such an assumption ignores genetic structures, like, dominant, recessive, and protective-risk cases. Ignoring genetic variants may result in spurious conclusions about the associations between a variant and a trait. We propose an assumption-free model built upon data-consistent inversion (DCI), which is a recently developed measure-theoretic framework utilized for uncertainty quantification. This proposed DCI-derived model builds a nonparametric distribution on model inputs that propagates to the distribution of observed data without the required normality assumption of residuals in the regression model. This characteristic enables the proposed DCI-derived model to cover all genetic variants without emphasizing on additivity of the classic-GWAS model. Simulations and a replication GWAS with data from the COPDGene demonstrate the ability of this model to control the Type-I error rate at least as well as the classic-GWAS (additive linear model) approach while having similar or greater power to discover variants in different genetic modes of transmission.

Longitudinal changes in lung function following post-9/11 military deployment in symptomatic veterans.

RATIONALE: Exposure to burn pit smoke, desert and combat dust, and diesel exhaust during military deployment to Southwest Asia and Afghanistan (SWA) can cause deployment-related respiratory diseases (DRRDs) and may confer risk for worsening lung function after return. METHODS: Study subjects were SWA-deployed veterans who underwent occupational lung disease evaluation (n = 219). We assessed differences in lung function by deployment exposures and DRRD diagnoses. We used linear mixed models to assess changes in lung function over time. RESULTS: Most symptomatic veterans reported high intensity deployment exposure to diesel exhaust and burn pit particulates but had normal post-deployment spirometry. The most common DRRDs were deployment-related distal lung disease involving small airways (DDLD, 41%), deployment-related asthma (DRA, 13%), or both DRA/DDLD (24%). Those with both DDLD/DRA had the lowest estimated mean spirometry measurements five years following first deployment. Among those with DDLD alone, spirometry measurements declined annually, adjusting for age, sex, height, weight, family history of lung disease, and smoking. In this group, the forced expiratory volume in the first second/forced vital capacity (FEV1/FVC) ratio declined 0.2% per year. Those with more intense inhalational exposure had more abnormal lung function. We found significantly lower estimated FVC and total lung capacity five years following deployment among active duty participants (n = 173) compared to those in the reserves (n = 26). CONCLUSIONS: More intense inhalational exposures were linked with lower post-deployment lung function. Those with distal lung disease (DDLD) experienced significant longitudinal decline in FEV1/FVC ratio, but other DRRD diagnosis groups did not.

Quantification of Emphysema Progression at CT Using Simultaneous Volume, Noise, and Bias Lung Density Correction.

Background CT attenuation is affected by lung volume, dosage, and scanner bias, leading to inaccurate emphysema progression measurements in multicenter studies. Purpose To develop and validate a method that simultaneously corrects volume, noise, and interscanner bias for lung density change estimation in emphysema progression at CT in a longitudinal multicenter study. Materials and Methods In this secondary analysis of the prospective Genetic Epidemiology of Chronic Obstructive Pulmonary Disease (COPDGene) study, lung function data were obtained from participants who completed baseline and 5-year follow-up visits from January 2008 to August 2017. CT emphysema progression was measured with volume-adjusted lung density (VALD) and compared with the joint volume-noise-bias-adjusted lung density (VNB-ALD). Reproducibility was studied under change of dosage protocol and scanner model with repeated acquisitions. Emphysema progression was visually scored in 102 randomly selected participants. A stratified analysis of clinical characteristics was performed that considered groups based on their combined lung density change measured by VALD and VNB-ALD. Results A total of 4954 COPDGene participants (mean age, 60 years ± 9 [SD]; 2511 male, 2443 female) were analyzed (1329 with repeated reduced-dose acquisition in the follow-up visit). Mean repeatability coefficients were 30 g/L ± 0.46 for VALD and 14 g/L ± 0.34 for VNB-ALD. VALD measurements showed no evidence of differences between nonprogressors and progressors (mean, -5.5 g/L ± 9.5 vs -8.6 g/L ± 9.6; P = .11), while VNB-ALD agreed with visual readings and showed a difference (mean, -0.67 g/L ± 4.8 vs -4.2 g/L ± 5.5; P < .001). Analysis of progression showed that VNB-ALD progressors had a greater decline in forced expiratory volume in 1 second (-42 mL per year vs -32 mL per year; Tukey-adjusted P = .002). Conclusion Simultaneously correcting volume, noise, and interscanner bias for lung density change estimation in emphysema progression at CT improved repeatability analyses and agreed with visual readings. It distinguished between progressors and nonprogressors and was associated with a greater decline in lung function metrics. Clinical trial registration no. NCT00608764 © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Goo in this issue.

Deep Learning Classification of Usual Interstitial Pneumonia Predicts Outcomes.

Rationale: Computed tomography (CT) enables noninvasive diagnosis of usual interstitial pneumonia (UIP), but enhanced image analyses are needed to overcome the limitations of visual assessment. Objectives: Apply multiple instance learning (MIL) to develop an explainable deep learning algorithm for prediction of UIP from CT and validate its performance in independent cohorts. Methods: We trained an MIL algorithm using a pooled dataset (n = 2,143) and tested it in three independent populations: data from a prior publication (n = 127), a single-institution clinical cohort (n = 239), and a national registry of patients with pulmonary fibrosis (n = 979). We tested UIP classification performance using receiver operating characteristic analysis, with histologic UIP as ground truth. Cox proportional hazards and linear mixed-effects models were used to examine associations between MIL predictions and survival or longitudinal FVC. Measurements and Main Results: In two cohorts with biopsy data, MIL improved accuracy for histologic UIP (area under the curve, 0.77 [n = 127] and 0.79 [n = 239]) compared with visual assessment (area under the curve, 0.65 and 0.71). In cohorts with survival data, MIL-UIP classifications were significant for mortality (n = 239, mortality to April 2021: unadjusted hazard ratio, 3.1; 95% confidence interval [CI], 1.96-4.91; P < 0.001; and n = 979, mortality to July 2022: unadjusted hazard ratio, 3.64; 95% CI, 2.66-4.97; P < 0.001). Individuals classified as UIP positive by the algorithm had a significantly greater annual decline in FVC than those classified as UIP negative (-88 ml/yr vs. -45 ml/yr; n = 979; P < 0.01), adjusting for extent of lung fibrosis. Conclusions: Computerized assessment using MIL identifies clinically significant features of UIP on CT. Such a method could improve confidence in radiologic assessment of patients with interstitial lung disease, potentially enabling earlier and more precise diagnosis.

Surgical microwave ablation for the treatment of hepatocellular carcinoma in 791 operations.

INTRODUCTION: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality and often arises in the setting of cirrhosis. The present series reviews outcomes following 791 operations. METHODS: Retrospective review surgical MWA for HCC from March 2007 through December 2022 at a high-volume institution was performed using a prospective database. Primary outcome was overall survival. RESULTS: A total of 791 operations in 623 patients and 1156 HCC tumors were treated with surgical MWA. Median tumor size was 2 cm (range 0.25-10 cm) with an average of 1 tumor ablated per operation (range 1-7 tumors). Nearly 90 % of patients had cirrhosis with a median MELD score of 8 (IQR = 6-11). Mortality within 30 days occurred in 13 patients (1.6 %). Per tumor, the rate of incomplete ablation was 2.25 % and local recurrence was 2.95 %. Previous ablation and tumor size were risk factors for recurrence. One-year overall survival was 82.0 % with a median overall survival of 36.5 months (95 % CI 15.7-93.7) and median disease-free survival of 15.9 months (range 5.7-37.3 months). CONCLUSION: Surgical MWA offers a low-morbidity approach for treatment of HCC, affording low rates of incomplete ablation and local recurrence.

Prospective healthcare-associated links in transmission of nontuberculous mycobacteria among people with cystic fibrosis (pHALT NTM) study: Rationale and study design.

BACKGROUND: Healthcare-associated acquisition and transmission of nontuberculous mycobacteria (NTM) among people with cystic fibrosis (pwCF) has been described, and remains a concern for both patients and providers. This report describes the design of a prospective observational study utilizing the standardized epidemiologic investigation toolkit for healthcare-associated links in transmission of NTM among pwCF. METHODS: This is a parallel multi-site study of pwCF who have infections with respiratory NTM isolates and receive healthcare within a common CF Care Center. Participants have a history of one or more NTM positive airway cultures and have been identified as having NTM infections suggestive of a possible outbreak within a single Center, based on NTM isolate genomic analysis. Participants are enrolled in the study over a 3-year period. Primary endpoints are identification of shared healthcare-associated source(s) among pwCF in a Center, identification of healthcare environmental dust and water biofilm NTM isolates that are genetically highly-related to respiratory isolates, and identification of common home of residence watersheds among pwCF infected with clustered isolates. Secondary endpoints include characterization of healthcare-associated transmission and/or acquisition modes and settings as well as description of incidence and prevalence of healthcare-associated environmental NTM species/subspecies by geographical region. DISCUSSION: We hypothesize that genetically highly-related isolates of NTM among pwCF cared for at the same Center may arise from healthcare sources including patient-to-patient transmission and/or acquisition from health-care environmental dust and/or water biofilms. This study design utilizes a published, standardized, evidence-based epidemiologic toolkit to facilitate confidential, independent healthcare-associated NTM outbreak investigations within CF Care Centers. This study will facilitate real-time, rapid detection and mitigation of healthcare-associated NTM outbreaks to reduce NTM risk, inform infection prevention and control guidelines, and characterize the prevalence and origin of NTM outbreaks from healthcare-associated patient-to-patient transmission and/or environmental acquisition. This study will systematically characterize human disease causing NTM isolates from serial collection of healthcare environmental dust and water biofilms and define the most common healthcare environmental sources harboring NTM biofilms. TRIAL REGISTRATION: ClinicalTrials.gov NCT05686837.

Augmentation Therapy for Severe Alpha-1 Antitrypsin Deficiency Improves Survival and Is Decoupled from Spirometric Decline-A Multinational Registry Analysis.

Rationale: Intravenous plasma-purified alpha-1 antitrypsin (IV-AAT) has been used as therapy for alpha-1 antitrypsin deficiency (AATD) since 1987. Previous trials (RAPID and RAPID-OLE) demonstrated efficacy in preserving computed tomography of lung density but no effect on FEV1. This observational study evaluated 615 people with severe AATD from three countries with socialized health care (Ireland, Switzerland, and Austria), where access to standard medical care was equal but access to IV-AAT was not. Objectives: To assess the real-world longitudinal effects of IV-AAT. Methods: Pulmonary function and mortality data were utilized to perform longitudinal analyses on registry participants with severe AATD. Measurements and Main Results: IV-AAT confers a survival benefit in severe AATD (P < 0.001). We uncovered two distinct AATD phenotypes based on an initial respiratory diagnosis: lung index and non-lung index. Lung indexes demonstrated a more rapid FEV1 decline between the ages of 20 and 50 and subsequently entered a plateau phase of minimal decline from 50 onward. Consequentially, IV-AAT had no effect on FEV1 decline, except in patients with a Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 2 lung index. Conclusions: This real-world study demonstrates a survival advantage from IV-AAT. This improved survival is largely decoupled from FEV1 decline. The observation that patients with severe AATD fall into two major phenotypes has implications for clinical trial design where FEV1 is a primary endpoint. Recruits into trials are typically older lung indexes entering the plateau phase and, therefore, unlikely to show spirometric benefits. IV-AAT attenuates spirometric decline in lung indexes in GOLD stage 2, a spirometric group commonly outside current IV-AAT commencement recommendations.

Exacerbation of Renal, Cardiovascular, and Respiratory Outcomes Associated with Changes in Climate.

Exposure to environmental variables including declining air quality and increasing temperatures can exert detrimental effects on human health including acute exacerbations of chronic diseases. We aim to investigate the association between these exposures and acute health outcomes in a rural community in Colorado. Meteorological and adult emergency department visit data were retrospectively collected (2013-2017); for asthma outcomes, additional data were available (2003-2017). Daily environmental exposure data included PM10, maximum daily temperature (MDT), and mean humidity and precipitation. Total daily counts of emergency department (ED) diagnoses for myocardial infarction, congestive heart failure, urolithiasis, and exacerbation of chronic obstructive pulmonary disease (COPD) and asthma, were calculated during the study period. Time series models using generalized estimating equations were fit for each disease and included all four environmental factors. Between 2013 and 2017, asthma and COPD exacerbation accounted for 30.8% and 25.4% of all ED visits (n=5,113), respectively. We found that for every 5˚C increase in MDT, the rate of urolithiasis visits increased by 13% (95% CI: 2%, 26%) and for every 10µg/m3 increase in 3-day moving average PM10, the rate of urolithiasis visits increased by 7% (95% CI: 1%, 13%). The magnitude of association between 3-day moving average PM10 and rate of urolithiasis visits increased with increasing MDT. The rate of asthma exacerbation significantly increased as 3-day, 7-day, and 21-day moving average PM10 increased. This retrospective study on ED visits is one of the first to investigate the impact of several environmental exposures on adverse health outcomes in a rural community. Research into mitigating the negative impacts of these environmental exposures on health outcomes is needed.

The importance of robotic surgery training in HPB fellowship: a survey of the 2022 AHPBA fellows.

BACKGROUND: The 2022 incoming fellows' expectations for their robotics training, as well as their perceptions of the utility of the surgical robot, are not well defined. METHODS: Cross-sectional survey of 24 AHPBA fellows in 2022, analyzed with descriptive statistics and Spearman's rho. RESULTS: Of 33 current AHPBA fellows, 22 completed the survey (66.7%). Study participants had limited-to-moderate experience with robotics prior to fellowship (mean 2.5 ± SD 1.1; range 1-4). Most participants agreed that robotics influenced their fellowship choice (mean 4.14 ± SD 0.87; range 1-5), would make then more marketable (mean 4.77 ± SD 0.52; range 1-5) and improve job prospects (mean 4.68 ± SD 0.87; range 1-5). Of the study participants, 55% responded that robotics training is "essential" in fellowship, while 64% responded that it is "essential" for their careers. Fellows were only slightly satisfied with overall robotics training within their respective programs (mean 3.44 ± SD 1.17; range 1-5) The majority (73.7%) expect that robotics will comprise <25% of their training. Notably, the majority (75%) have no formal robotics training curriculum. DISCUSSION: This survey identifies potential gaps where robotics training could be improved for future incoming AHPBA fellows.

FEV1/FVC Severity Stages for Chronic Obstructive Pulmonary Disease.

Rationale: The diagnosis of chronic obstructive pulmonary disease (COPD) is based on a low FEV1/FVC ratio, but the severity of COPD is classified using FEV1% predicted (ppFEV1). Objectives: To test a new severity classification scheme for COPD using FEV1/FVC ratio, a more robust measure of airflow obstruction than ppFEV1. Methods: In COPDGene (Genetic Epidemiology of COPD) (N = 10,132), the severity of airflow obstruction was categorized by Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages 1-4 (ppFEV1 of ⩾80%, ⩾50-80%, ⩾30-50%, and <30%). A new severity classification (STaging of Airflow obstruction by Ratio; STAR) was tested in COPDGene-FEV1/FVC ⩾0.60 to <0.70, ⩾0.50 to <0.60, ⩾0.40 to <0.50, and <0.40, respectively, for stages 1-4-and applied to the combined Pittsburgh SCCOR and Emphysema COPD Research Registry for replication (N = 2,017). Measurements and Main Results: The agreements (weighted Bangdiwala B values) between GOLD and the new FEV1/FVC ratio severity stages were 0.89 in COPDGene and 0.88 in the Pittsburgh cohort. In COPDGene and the Pittsburgh cohort, compared with GOLD staging, STAR provided significant discrimination between the absence of airflow obstruction and stage 1 for all-cause mortality, respiratory quality of life, dyspnea, airway wall thickness, exacerbations, and lung function decline. No major differences were noted for emphysema, small airway disease, and 6-minute-walk distance. The STAR classification system identified a greater number of adults with stage 3/4 disease who would be eligible for lung transplantation and lung volume reduction procedure evaluations. Conclusions: The new STAR severity classification scheme provides discrimination for mortality that is similar to the GOLD classification but with a more uniform gradation of disease severity. STAR differentiates patients' symptoms, disease burden, and prognosis better than the existing scheme based on ppFEV1, and is less sensitive to race/ethnicity and other demographic characteristics.

Heterogeneity and Progression of Chronic Obstructive Pulmonary Disease: Emphysema-Predominant and Non-Emphysema-Predominant Disease.

While variation in emphysema severity between patients with chronic obstructive pulmonary disease (COPD) is well-recognized, clinically applicable definitions of the emphysema-predominant disease (EPD) and non-emphysema-predominant disease (NEPD) subtypes have not been established. To study the clinical relevance of the EPD and NEPD subtypes, we tested the association of these subtypes with prospective decline in forced expiratory volume in 1 second (FEV1) and mortality among 3,427 subjects with Global Initiative for Chronic Obstructive Lung Disease (GOLD) spirometric grade 2-4 COPD at baseline in the Genetic Epidemiology of COPD (COPDGene) Study, an ongoing national multicenter study that started in 2007. NEPD was defined as airflow obstruction with less than 5% computed tomography (CT) quantitative densitometric emphysema at -950 Hounsfield units, and EPD was defined as airflow obstruction with 10% or greater CT emphysema. Mixed-effects models for FEV1 demonstrated larger average annual FEV1 loss in EPD subjects than in NEPD subjects (-10.2 mL/year; P < 0.001), and subtype-specific associations with FEV1 decline were identified. Cox proportional hazards models showed higher risk of mortality among EPD patients versus NEPD patients (hazard ratio = 1.46, 95% confidence interval: 1.34, 1.60; P < 0.001). To determine whether the NEPD/EPD dichotomy is captured by previously described COPDGene subtypes, we used logistic regression and receiver operating characteristic (ROC) curve analysis to predict NEPD/EPD membership using these previous subtype definitions. The analysis generally showed excellent discrimination, with areas under the ROC curve greater than 0.9. The NEPD and EPD COPD subtypes capture important aspects of COPD heterogeneity and are associated with different rates of disease progression and mortality.

Quantitative CT Evaluation of Emphysema Progression over 10 Years in the COPDGene Study.

Background Long-term studies of chronic obstructive pulmonary disease (COPD) can evaluate emphysema progression. Adjustment for differences in equipment and scanning protocols of individual CT examinations have not been studied extensively. Purpose To evaluate emphysema progression in current and former smokers in the COPDGene cohort over three imaging points obtained at 5-year intervals accounting for individual CT parameters. Materials and Methods Current and former cigarette smokers enrolled between 2008 and 2011 from the COPDGene study were prospectively followed for 10 years between 2008 and 2020. Extent of emphysema as adjusted lung density (ALD) from quantitative CT was measured at baseline and at 5- and 10-year follow-up. Linear mixed models adjusted for CT technical characteristics were constructed to evaluate emphysema progression. Mean annual changes in ALD over consecutive 5-year study periods were estimated by smoking status and baseline emphysema. Results Of 8431 participants at baseline (mean age, 60 years ± 9 [SD]; 3905 female participants), 4913 were at 5-year follow-up and 1544 participants were at 10-year follow-up. There were 4134 (49%) participants who were current smokers, and 4449 (53%) participants had more than trace emphysema at baseline. Current smokers with more than trace emphysema showed the largest decline in ALD, with mean annual decreases of 1.4 g/L (95% CI: 1.2, 1.5) in the first 5 years and 0.9 g/L (95% CI: 0.7, 1.2) in the second 5 years. Accounting for CT noise, field of view, and scanner model improved model fit for estimation of emphysema progression (P < .001 by likelihood ratio test). Conclusion Evaluation at CT of emphysema progression in the COPDGene study showed that, during the span of 10 years, participants with pre-existing emphysema who continued smoking had the largest decline in ALD. Adjusting for CT equipment and protocol factors improved these longitudinal estimates. Clinical trial registration no. NCT00608764 © RSNA, 2023 Supplemental material is available for this article. See the editorial by Parraga and Kirby in this issue.

Future liver remnant augmentation preceding ex vivo hepatectomy with IVC replacement: a strategy to achieve R0 margins.

PURPOSE: Ex vivo hepatectomy with autotransplantation (EHAT) provides opportunity for R0 resection. As EHAT outcomes after future liver remnant (FLR) augmentation techniques are not well documented, we examine results of EHAT after augmentation for malignant tumors. METHODS: Retrospective analysis of six cases of EHAT was performed. Of these, four occurred after preoperative FLR augmentation between 2018 and 2022. RESULTS: Six patients were offered EHAT of 26 potential candidates. Indications for resection were involvement of hepatic vein outflow and inferior vena cava (IVC) with metastatic colorectal carcinoma (n = 3), cholangiocarcinoma (n = 2), or leiomyosarcoma (n = 1). Five patients were treated with neoadjuvant chemotherapy and four had preoperative liver augmentation. One hundred percent of cases achieved R0 resection. Of the augmented cases, three patients are alive after median follow-up of 28 months. Postoperative mortality due to liver failure was 25% (n = 1). CONCLUSIONS: For select patients with locally advanced tumors involving all hepatic veins and the IVC for whom conventional resection is not an option, EHAT provides opportunity for R0 resection. In addition, in patients with inadequate FLR volume, further operative candidacy with acceptable results can be achieved by combined liver augmentation techniques. To better characterize outcomes in this small subset, a registry is needed.

Molecular Epidemiologic Investigation of Mycobacterium intracellulare Subspecies chimaera Lung Infections at an Adult Cystic Fibrosis Program.

Rationale: Outbreaks of nontuberculous mycobacteria (NTM) among people with cystic fibrosis (pwCF) have been reported at CF centers with conflicting conclusions. The occurrence of NTM at the UVMC (University of Vermont Medical Center) adult CF program was investigated. Objectives: Use the HALT NTM (Healthcare-associated Links in Transmission of NTM) toolkit to investigate the healthcare-associated transmission and/or acquisition of NTM among pwCF having genetically similar NTM isolates. Methods: Whole genome sequencing of NTM isolates from 23 pwCF was conducted to identify genetically similar NTM isolate clusters (30 or fewer single-nucleotide polymorphism differences). The epidemiological investigation, comparison of respiratory and healthcare environmental isolates, and home residence watershed mapping were analyzed. Results: Whole genome sequencing analysis revealed two clusters of NTM isolates (Mycobacterium avium and M. intracellulare ssp. chimaera) among pwCF. The epidemiologic investigation demonstrated opportunities for healthcare-associated transmission within both clusters. Healthcare environmental M. avium isolates revealed no genetic similarity to respiratory isolates. However, M. intracellulare ssp. chimaera respiratory isolates revealed greater genetic similarity to a hospital water biofilm isolate than to each other. Neither cluster had all subjects residing in the same watershed. Conclusions: This study suggests the healthcare-associated transmission of M. avium among pwCF is unlikely at UVMC but supports the healthcare-associated environmental acquisition of M. intracellulare ssp. chimaera. The presence of genetically similar isolates alone is insufficient to confirm healthcare-associated transmission and/or acquisition. The HALT NTM toolkit standardizes outbreak investigation with genetic analysis, epidemiologic investigation, healthcare environmental sampling, and home of residence watershed identification to test the frequency and nature of healthcare-associated NTM transmission among pwCF.

Molecular networks in atopic mothers impact the risk of infant atopy.

BACKGROUND: The prevalence of atopic diseases has increased with atopic dermatitis (AD) as the earliest manifestation. We assessed if molecular risk factors in atopic mothers influence their infants' susceptibility to an atopic disease. METHODS: Pregnant women and their infants with (n = 174, high-risk) or without (n = 126, low-risk) parental atopy were enrolled in a prospective birth cohort. Global differentially methylated regions (DMRs) were determined in atopic (n = 92) and non-atopic (n = 82) mothers. Principal component analysis was used to predict atopy risk in children dependent on maternal atopy. Genome-wide transcriptomic analyses were performed in paired atopic (n = 20) and non-atopic (n = 15) mothers and cord blood. Integrative genomic analyses were conducted to define methylation-gene expression relationships. RESULTS: Atopic dermatitis was more prevalent in high-risk compared to low-risk children by age 2. Differential methylation analyses identified 165 DMRs distinguishing atopic from non-atopic mothers. Inclusion of DMRs in addition to maternal atopy significantly increased the odds ratio to develop AD in children from 2.56 to 4.26. In atopic compared to non-atopic mothers, 139 differentially expressed genes (DEGs) were identified significantly enriched of genes within the interferon signaling pathway. Expression quantitative trait methylation analyses dependent on maternal atopy identified 29 DEGs controlled by 136 trans-acting methylation marks, some located near transcription factors. Differential expression for the same nine genes, including MX1 and IFI6 within the interferon pathway, was identified in atopic and non-atopic mothers and high-risk and low-risk children. CONCLUSION: These data suggest that in utero epigenetic and transcriptomic mechanisms predominantly involving the interferon pathway may impact and predict the development of infant atopy.