Illicit drug use during pregnancy is a concern worldwide, with many international studies describing attempted strategies to mitigate this problem. Drug misuse during pregnancy is associated with significant maternal as well as perinatal complications, which include a high incidence of stillbirths, fetal distress, neonatal abstinence syndrome (NAS) and increased neonatal mortality. Unfortunately, the identification of a drug-exposed mother or neonate is challenging. Maternal disclosure of drug use is often inaccurate, principally due to psychosocial factors including behavioral denial or the fear of the consequences resulting from such admissions. Likewise, many infants who have been exposed to drugs in utero may appear normal at birth and initially show no overt manifestations of drug effects. Thus, the identification of the drug-exposed infant requires a high index of clinical suspicion. Conversely, analytical testing is an objective means of determining drug exposure when it may be necessary to document proof of the infant's exposure to illicit drugs. The review will discuss the different matrices that are most commonly used for testing (e.g., maternal urine, neonatal urine, meconium, and umbilical cord), the strengths and limitations for each matrix, which drugs and metabolites are appropriate for testing, the various testing methods, and the advantages and disadvantages of each method.

Cystic fibrosis is a monogenic lung disease caused by dysfunction of the cystic fibrosis transmembrane conductance regulator anion channel, resulting in significant morbidity and mortality. The progress in elucidating the role of CFTR using established animal and cell-based models led to the recent discovery of effective modulators for most individuals with CF. However, a subset of individuals with CF do not respond to these modulators and there is an urgent need to develop novel therapeutic strategies. In this study, we generate a panel of airway epithelial cells using induced pluripotent stem cells from individuals with common or rare CFTR variants representative of three distinct classes of CFTR dysfunction. To measure CFTR function we adapt two established in vitro assays for use in induced pluripotent stem cell-derived airway cells. In both a 3-D spheroid assay using forskolin-induced swelling as well as planar cultures composed of polarized mucociliary airway epithelial cells, we detect genotype-specific differences in CFTR baseline function and response to CFTR modulators. These results demonstrate the potential of the human induced pluripotent stem cell platform as a research tool to study CF and in particular accelerate therapeutic development for CF caused by rare variants.

Objective Electronic consultations (e-consults) are clinician-to-clinician communications that may obviate face-to-face specialist visits. E-consult programs have spread within the US and internationally despite limited data on outcomes. We conducted a systematic review of the recent peer-reviewed literature on the effect of e-consults on access, cost, quality, and patient and clinician experience and identified the gaps in existing research on these outcomes. Materials and Methods We searched 4 databases for empirical studies published between 1/1/2015 and 2/28/2019 that reported on one or more outcomes of interest. Two investigators reviewed titles and abstracts. One investigator abstracted information from each relevant article, and another confirmed the abstraction. We applied the GRADE criteria for the strength of evidence for each outcome. Results We found only modest empirical evidence for effectiveness of e-consults on important outcomes. Most studies are observational and within a single health care system, and comprehensive assessments are lacking. For those outcomes that have been reported, findings are generally positive, with mixed results for clinician experience. These findings reassure but also raise concern for publication bias. Conclusion Despite stakeholder enthusiasm and encouraging results in the literature to date, more rigorous study designs applied across all outcomes are needed. Policy makers need to know what benefits may be expected in what contexts, so they can define appropriate measures of success and determine how to achieve them.

A 44-year-old man presented with fatigue, unintentional weight loss, and a 2-year history of hip and chest-wall pain. He had earlier presented with acute right clavicle pain after he pushed himself up on the arms of chair in order to stand. A radiograph of the shoulder showed a fracture in the distal third of the clavicle at the site of a lytic lesion.

OBJECTIVE:Medium chain triglycerides (MCT) have unique metabolic properties which may improve insulin sensitivity (Si) and beta cell function but data in humans are limited. We conducted a 6-week clinical trial of MCT oil supplementation. METHODS:22 subjects without diabetes (8 males, 14 females, mean ± standard error age 39±2.9 years, baseline BMI 27.0±1.4 kg/m2) were counseled to maintain their body weight and physical activity (PA) during the trial. Dietary intake, PA data, body composition, and resting energy expenditure (REE) were obtained through dietary recall, international PA questionnaire, dual x-ray absorptiometry, and indirect calorimetry, respectively. MCT prescriptions were given based on REE and PA to replace part of dietary fat with 30 grams of MCT per 2000 kcal daily. Insulin-modified frequently sampled intravenous glucose tolerance tests were performed before and after MCT to measure changes in Si, acute insulin response (AIR), disposition index (DI), and glucose effectiveness (Sg). RESULTS:MCT were well tolerated and weight remained stable (mean change 0.3 kg, p = 0.39). Fasting REE, respiratory quotient, and body composition were stable during the intervention. There were no significant changes in mean fasting glucose, insulin, insulin resistance, fasting total ketones, Si, AIR, DI, Sg, leptin, fructosamine, and proinsulin. The mean change in Si was 0.5 10-4 min-1 per mU/L (95% CI: -1.4, 2.4), corresponding to a 12% increase from baseline, and the range was -4.7 to 12.9 10-4 min-1 per mU/L. Mean total adiponectin decreased significantly from 22925 ng/mL at baseline to 17598 ng/mL at final visit (p = 0.02). The baseline clinical and laboratory parameters were not significantly associated with the change in Si. DISCUSSION:There were a wide range of changes in the minimal model parameters of glucose and insulin metabolism in subjects following 6 weeks of MCT as an isocaloric substitution for part of usual dietary fat intake. Since this was a single-arm non-randomized study without a control group, it cannot be certain whether these changes were due to MCT so further randomized controlled trials are warranted.

BACKGROUND:Cardiac troponin I (cTnI) 99th percentile cutoffs, used in the diagnosis of acute myocardial infarction, are not standardized across cTnI assays. We compared 3 point-of-care (POC) and 1 central laboratory contemporary cTnI assays against the Abbott high-sensitivity (hs) cTnI to evaluate the analytical concordance and the feasibility of using a single cutoff value for all assays.METHODS:Fresh blood samples collected from 102 inpatients in the coronary care unit were measured on central laboratory instruments (Beckman Coulter DxI AccuTnI+3 TnI, Abbott Architect hs-TnI) and cTnI POC analyzers (Alere Triage Troponin I, Radiometer AQT90, Abbott i-STAT). Agreement and correlation between the contemporary cTnI assays and hs-cTnI assay were assessed using regression analysis. Proportional bias was assessed using Bland-Altman plots. Concordance between the contemporary cTnI and hs-cTnI assays was determined by diagnostic contingency tables at specific cutoffs.RESULTS:Most POC cTnI assays had excellent correlation with the Abbott hs-cTnI method (r 2 = 0.955-0.970) except for Alere Triage (r 2 = 0.617), while proportional bias is evident between all cTnI assays. Overall concordance between POC contemporary cTnI assays and hs-cTnI assay was 80% to 90% at their respective 99th percentile cutoffs. The concordance increased to 90% to 95% when a fixed cutoff of 0.03 to 0.05 ng/mL was used across the assays.CONCLUSIONS:This study demonstrates poor analytical concordance between cTnI assays at the 99th percentile and supports the notion of a single clinical decision limit for cTnI and consequently standardization of diagnostic protocols despite the analytical differences among these assays.

Alveolar epithelial type II cells (AEC2s) are the facultative progenitors of lung alveoli and serve as the surfactant-producing cells of air-breathing organisms. Although primary human AEC2s are difficult to maintain stably in cell cultures, recent advances have facilitated the derivation of AEC2-like cells from human pluripotent stem cells (hPSCs) in vitro. Here, we provide a detailed protocol for the directed differentiation of hPSCs into self-renewing AEC2-like cells that can be maintained for up to 1 year in culture as epithelial-only spheres without the need for supporting mesenchymal feeder cells. The month-long protocol requires recapitulation of the sequence of milestones associated with in vivo development of the distal lung, beginning with differentiation of cells into anterior foregut endoderm, which is followed by their lineage specification into NKX2-1(+) lung progenitors and then distal/alveolar differentiation to produce progeny that express transcripts and possess functional properties associated with AEC2s.

Hyperinsulinemia is strongly associated with type 2 diabetes. Racial and ethnic minority populations are disproportionately affected by diabetes and obesity-related complications. This mini-review provides an overview of the genetic and environmental factors associated with hyperinsulinemia with a focus on racial and ethnic differences and its metabolic consequences. The data used in this narrative review were collected through research in PubMed and reference review of relevant retrieved articles. Insulin secretion and clearance are regulated processes that influence the development and progression of hyperinsulinemia. Environmental, genetic, and dietary factors are associated with hyperinsulinemia. Certain pharmacotherapies for obesity and bariatric surgery are effective at mitigating hyperinsulinemia and are associated with improved metabolic health. Hyperinsulinemia is associated with many environmental and genetic factors that interact with a wide network of hormones. Recent studies have advanced our understanding of the factors affecting insulin secretion and clearance. Further basic and translational work on hyperinsulinemia may allow for earlier and more personalized treatments for obesity and metabolic diseases.

ObjectiveWeight‐management medications (WMM) are recommended for the treatment of obesity. This study examined characteristics associated with initial receipt of WMM among eligible veterans in the first year following enrollment in the Veterans Health Administration (VHA) MOVE! behavioral weight‐management program.MethodsWe conducted a retrospective cohort study of VHA patients with obesity or overweight and obesity‐related comorbidities who enrolled in MOVE! from October 2013 to September 2016 (N = 153,939). Multivariable logistic regression models estimated predictors of having a filled prescription for WMM and for orlistat.ResultsA total of 1.1% of these veterans received WMM. The most common WMM included orlistat (70.4%), phentermine/topiramate (11.2%), and bupropion/naltrexone (9.7%). Female sex, higher BMI, obstructive sleep apnea, osteoarthritis, depression, lower back pain, and alcohol abuse were associated with greater odds of use of WMM, whereas age over 65 years, Hispanic ethnicity, and required co‐payments were associated with lower odds. Among patients receiving WMM, older age, black race, female sex, higher BMI, cardiovascular disease, lower back pain, and congestive heart failure were associated with use of orlistat versus any other WMM.ConclusionsOf patients engaged in MOVE! in the VHA, 1.1% received WMM. WMM are underutilized among veterans. Additional research is needed to understand barriers to incorporating WMM into comprehensive obesity treatment plans.

Weight‐management medications (WMM) are recommended for the treatment of obesity. This study examined characteristics associated with initial receipt of WMM among eligible veterans in the first year following enrollment in the Veterans Health Administration (VHA) MOVE! behavioral weight‐management program.

Goals: To determine whether diabetic patients with hepatitis C virus (HCV) treated with direct-acting antiviral agents have improved diabetes, accounting for change in both hemoglobin A1c (HbA1c) and diabetes medications, and whether any improvement was sustained. Background: HCV infection is associated with an increased risk of diabetes, with improvement in glycemic control after eradication. There remains uncertainty about the durability and magnitude of this effect. Study: HbA1c and diabetes medications were recorded at 6-month intervals for 1.5 years pretreatment and posttreatment for 122 patients. Subjects were classified as having improved diabetes if there was a decrease in HbA1c≥0.5% with no increase in diabetes medications or a decrease in diabetes medications with a stable HbA1c. Results: HbA1c at the nearest time point before treatment was 8.4%±1.9%, compared with 7.8%±1.7% after treatment, a mean difference of 0.6% [95% CI (0.2, 0.9), P <0.01]. A linear mixed effects model incorporating each subject’s repeated measurements over time also demonstrated a reduction after treatment of 0.5% [95% CI, (0.3, 0.8), P <0.001]. Accounting for both HbA1c and diabetes medications, 42 of 122 (34%) had an improvement in diabetes after HCV treatment, and 20 of 28 (71%) of these subjects sustained improvement at 1.5 years follow-up. Prescription of insulin was associated with improved diabetes. Conclusions: Treatment of HCV with direct-acting antiviral agents was associated with improved diabetes in a significant portion of patients with an average reduction in HbA1c of clinically significant magnitude. Among responders, this effect was sustained over 1.5 years of follow-up.

Objective: Electronic consultations (e-consults) are clinician-to-clinician communications that may obviate faceto-face specialist visits. E-consult programs have spread within the US and internationally despite limited data on outcomes. We conducted a systematic review of the recent peer-reviewed literature on the effect of e-consults on access, cost, quality, and patient and clinician experience and identified the gaps in existing research on these outcomes. Materials and Methods: We searched 4 databases for empirical studies published between 1/1/2015 and 2/28/ 2019 that reported on one or more outcomes of interest. Two investigators reviewed titles and abstracts. One investigator abstracted information from each relevant article, and another confirmed the abstraction. We applied the GRADE criteria for the strength of evidence for each outcome. Results: We found only modest empirical evidence for effectiveness of e-consults on important outcomes. Most studies are observational and within a single health care system, and comprehensive assessments are lacking. For those outcomes that have been reported, findings are generally positive, with mixed results for clinician experience. These findings reassure but also raise concern for publication bias. Conclusion: Despite stakeholder enthusiasm and encouraging results in the literature to date, more rigorous study designs applied across all outcomes are needed. Policy makers need to know what benefits may be expected in what contexts, so they can define appropriate measures of success and determine how to achieve them. Published by Oxford University Press on behalf of the American Medical Informatics Association 2019. This work is written by US Government employees and is in the public domain in the US. 1 Journal of the American Medical Informatics Association, 0(0), 2019, 1–9 doi: 10.1093/jamia/ocz185 Review ow naded rom http/academ ic.p.com jam ia/advance-astract/doi/10.1093/jam ia/ocz5/5588944 by U niersity of C orado sstem s user on 30 O cber 2019

Objective: Overweight and obesity affect over 4 million veterans receiving health care in the Veterans Administration (VA). In VA, WMM are available to any Veteran who is engaged in behavioral weight management and meets BMI criteria. In 2010, weight management medications (WMM) were found to be underused in VA, but since then new WMM have been approved and guidelines have recommended them for long-term obesity treatment. We examined the frequency of WMM use and patient characteristics associated with WMM use and with the selection of orlistat versus other WMM for veterans with overweight or obesity enrolled in the VA MOVE! behavioral weight management program. Methods: Retrospective cohort study of VA patients participating in MOVE! between October 2014 – October 2016 with body mass index (BMI)≥30kg/m2 or BMI>27kg/m2 with obesity-related comorbidities. Data from the electronic health record were accessed. Logistic regression models estimated predictors of filling a prescription for any WMM within VA and for orlistat versus other WMM. Results: Of the 153,892 eligible veterans enrolled in MOVE!, 1,888 (1.2%) received a WMM. The most common prescriptions were for orlistat (61.0%), bupropion/naltrexone (13.8%), and phentermine/topiramate (11.7%). The percent of patients receiving WMMs ranged from 0.5% among patients with overweight to 2.9% among patients with alcohol abuse. Factors associated with WMM were female sex (adjusted odds ratio (aOR) = 1.8, 95% CI: 1.6 – 2.0), higher BMI (class I obesity aOR=1.6, 95%CI: 1.3 – 2.0, class II obesity aOR=2.9, 95% CI: 2.3 – 3.6, class III obesity aOR=4.5, 95%CI: 3.6 – 5.6 compared to overweight), alcohol abuse (aOR=2.3, 95% CI: 1.8 – 2.9), substance abuse (aOR=1.6, 95% CI: 1.4 – 1.9), diabetes (aOR=1.2, 95% CI: 1.1-1.3), obstructive sleep apnea (aOR=1.3, 95% CI: 1.2 – 1.4), depression (aOR=1.2, 95% CI: 1.1 – 1.3), low back pain (aOR=1.2, 95% CI: 1.1 – 1.3). Factors associated with lower odds of WMM receipt included age over 65 years (aOR=0.7, 95% CI: 0.6 – 0.8) and required copayments (aOR=0.8, 95% CI: 0.7 – 0.8). Factors associated with receiving orlistat vs. other WMMs were increasing age (age ≥ 65 aOR=2.6, 95%CI: 1.6 – 4.1), Black/non-Hispanic race (aOR=1.5, 95% CI: 1.2 – 1.9), female sex (aOR=1.8, 95% CI: 1.4 – 2.3), hypertension (aOR=1.4, 95% CI: 1.1-1.7) and low back pain (aOR=1.6, 95% CI: 1.3-1.9). Factors associated with lower aOR for orlistat vs. other WMM were diabetes (aOR=0.7, 95% CI: 0.5-0.8), alcohol abuse (aOR=0.5, 95% CI: 0.3-0.9), and substance abuse (aOR=0.4, 95%CI: 0.3-0.6). Conclusion: There is a substantial opportunity to increase the use of WMM for weight management in eligible veterans engaged in MOVE!. Patient characteristics affect whether veterans receive WMM, and which WMM is used. Additional research is needed to understand provider and patient decision-making regarding WMM and address barriers to incorporating WMM into obesity treatment.

Background: Serum protein electrophoresis (SPE) and immunofixation electrophoresis (IFE) are used in the diagnosis and monitoring of plasma cell dyscrasias. IFE is considered the most sensitive method for the detection of monoclonal proteins (M-proteins), but it is not quantitative. The goal of this study was to establish the analytical sensitivity and diagnostic performance of SPE on the Sebia Hydrasys using HYDRAGEL 30 PROTEIN(E) beta 1-beta 2. Methodology: Patient sera with a previously identified M-protein (IgG, IgA or IgM) were serially diluted with a normal serum pool and electrophoresed on the Sebia Hydrasys using HYDRAGEL 30 PROTEIN( E) beta 1-beta 2. The SPE gels were individually interpreted by five independent observers and IFE was performed on selected samples. Limit of detection was determined as the lowest concentration of M-protein band visible on the gel. SPE diagnostic performance was evaluated against the "gold standard" IFE according CLSI EP12-A2 guidelines. Results: Detection limit was comparable among all M-proteins migrating in the gamma region, IgG-kappa( 0.18 +/- 0.08 g/L; n=6), IgG-kappa (0.36 +/- 0.25 g/ L; n = 8), IgA-kappa (0.40 +/- 0.13 g/ L; n= 7), IgA-kappa (0.37 +/- 0.23 g/ L; n = 4), IgM-kappa (0.47 +/- 0.20 g/ L; n = 13) and IgM-kappa (0.29 +/- 0.24 g/L; n= 6). Percentage agreement with IFE for IgG and IgA in the gamma region ranged from 65% to 100%, whereas IgM migrating in the gamma region and immunoglobulins co-migrating with alpha or beta globulins, showed poor (0-38%) agreement. Conclusions: This study evaluates the analytical sensitivity and diagnostic performance of SPE on the Sebia Hydrasys using HYDRAGEL 30 PROTEIN(E) beta 1-beta 2. There was acceptable agreement between SPE and IFE for IgG-kappa/lambda and IgA-kappa/lambda migrating in the gamma region, suggesting that repeating IFE for samples with these isotypes, when the previous IFE and second SPE are both negative, may not be necessary.

OBJECTIVE:Weight recidivism following Roux-en-Y gastric bypass (RYGB) is common and is associated with recurrence of comorbidities. Studies with long-term follow-up of recidivism quantified by weight regain (WR) are lacking. A retrospective review of all RYGB at our center from 2004 to 2015 was performed to examine the effects of race and type 2 diabetes on WR following RYGB. METHODS:Multivariable linear mixed models were used for the effects of time and race on weight, WR relative to nadir weight (WR/nadir), and WR relative to maximal weight loss, and Cox regressions were used for low, moderate, and high WR/nadir. RESULTS:A total of 1,395 participants were identified. The sample was limited to African American (AA), Caucasian American (CA), and Hispanic American (HA) participants. The effects of time (P < 0.0001), race (P < 0.0001), and race × time interaction (P = 0.0008) on weight trajectory were significant. AA had significantly more WR than CA (P < 0.01). AA and HA had a higher hazard ratio for having low, moderate, and rapid WR/nadir. CONCLUSIONS:Racial disparities after RYGB include WR and particularly affect AA. Understanding the etiologic factors that contribute to these disparities is important to optimize the long-term clinical outcomes of bariatric surgery.