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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., (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.)

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.

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.

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., Competing Interests: Disclosure Summary: C.M.A. reports grants from Aspire Bariatrics, the Vela Foundation, Coherence Laboratory, Energesis, NIH, and PCORI; grants and personal fees from GI Dynamics, Takeda, Novo Nordisk, and Gelesis; and personal fees from Orexigen, EnteroMedics, Nutrisystem, Zafgen, Sanofi-Aventis, Scientific Intake, Xeno Biosciences, Rhythm Pharmaceuticals, Eisai, and Bariatrix Nutrition and other fees from Science-Smart LLC, outside the submitted work. The remaining authors have nothing to disclose.Data sharing is not applicable to this article as no data sets were generated or analyzed during the current study.

Objective: 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., Methods: We 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., Results: A 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., Conclusions: Of 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., (© 2019 The Obesity Society.)

Environmental stresses dramatically impact the balance between the production of photosynthetically derived energetic electrons and Calvin-Benson-Bassham cycle (CBBC) activity; an imbalance promotes accumulation of reactive oxygen species and causes cell damage. Hence, photosynthetic organisms have developed several strategies to route electrons toward alternative outlets that allow for storage or harmless dissipation of their energy. In this work, we explore the activities of three essential outlets associated with Chlamydomonas reinhardtii photosynthetic electron transport: ( i ) reduction of O 2 to H 2 O through flavodiiron proteins (FLVs) and ( ii ) plastid terminal oxidases (PTOX) and ( iii ) the synthesis of starch. Real-time measurements of O 2 exchange have demonstrated that FLVs immediately engage during dark-to-light transitions, allowing electron transport when the CBBC is not fully activated. Under these conditions, we quantified maximal FLV activity and its overall capacity to direct photosynthetic electrons toward O 2 reduction. However, when starch synthesis is compromised, a greater proportion of the electrons is directed toward O 2 reduction through both the FLVs and PTOX, suggesting an important role for starch synthesis in priming/regulating CBBC and electron transport. Moreover, partitioning energized electrons between sustainable (starch; energetic electrons are recaptured) and nonsustainable (H 2 O; energetic electrons are not recaptured) outlets is part of the energy management strategy of photosynthetic organisms that allows them to cope with the fluctuating conditions encountered in nature. Finally, unmasking the repertoire and control of such energetic reactions offers new directions for rational redesign and optimization of photosynthesis to satisfy global demands for food and other resources., Competing Interests: The authors declare no conflict of interest., (Copyright © 2019 the Author(s). Published by PNAS.)

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., (© 2018 American Association for Clinical Chemistry.)

Sloths are canopy-dwelling inhabitants of American neotropical rainforests that exhibit suspensory behaviors. These abilities require both strength and muscular endurance to hang for extended periods of time; however, the skeletal muscle mass of sloths is reduced, thus requiring modifications to muscle architecture and leverage for large joint torque. We hypothesize that intrinsic muscle properties are also modified for fatigue resistance and predict a heterogeneous expression of slow/fast myosin heavy chain (MHC) fibers that utilize oxidative metabolic pathways for economic force production. MHC fiber type distribution and energy metabolism in the forelimb muscles of three-toed ( Bradypus variegatus, n = 5) and two-toed ( Choloepus hoffmanni, n = 4) sloths were evaluated using SDS-PAGE, immunohistochemistry, and enzyme activity assays. The results partially support our hypothesis by a primary expression of the slow MHC-1 isoform as well as moderate expression of fast MHC-2A fibers, whereas few hybrid MHC-1/2A fibers were found in both species. MHC-1 fibers were larger in cross-sectional area (CSA) than MHC-2A fibers and comprised the greatest percentage of CSA in each muscle sampled. Enzyme assays showed elevated activity for the anaerobic enzymes creatine kinase and lactate dehydrogenase compared with low activity for aerobic markers citrate synthase and 3-hydroxyacetyl CoA dehydrogenase. These findings suggest that sloth forelimb muscles may rely heavily on rapid ATP resynthesis pathways, and lactate accumulation may be beneficial. The intrinsic properties observed match well with suspensory requirements, and these modifications may have further evolved in unison with low metabolism and slow movement patterns as means to systemically conserve energy. NEW & NOTEWORTHY Myosin heavy chain (MHC) fiber type and fiber metabolic properties were evaluated to understand the ability of sloths to remain suspended for extended periods without muscle fatigue. Broad distributions of large, slow MHC-1 fibers as well as small, fast MHC-2A fibers are expressed in sloth forelimbs, but muscle metabolism is generally not correlated with myosin fiber type or body size. Sloth muscles rely on rapid, anaerobic pathways to resist fatigue and sustain force production.

Purpose of Review: We review the underlying mechanisms and potential benefits of intermittent fasting (IF) from animal models and recent clinical trials., Recent Findings: Numerous variations of IF exist, and study protocols vary greatly in their interpretations of this weight loss trend. Most human IF studies result in minimal weight loss and marginal improvements in metabolic biomarkers, though outcomes vary. Some animal models have found that IF reduces oxidative stress, improves cognition, and delays aging. Additionally, IF has anti-inflammatory effects, promotes autophagy, and benefits the gut microbiome. The benefit-to-harm ratio varies by model, IF protocol, age at initiation, and duration. We provide an integrated perspective on potential benefits of IF as well as key areas for future investigation. In clinical trials, caloric restriction and IF result in similar degrees of weight loss and improvement in insulin sensitivity. Although these data suggest that IF may be a promising weight loss method, IF trials have been of moderate sample size and limited duration. More rigorous research is needed.

Protein sparing therapies were developed to mitigate the harms associated with protein-calorie malnutrition and nitrogen losses induced by either acute illness or hypocaloric diets in patients with obesity. We review the development of protein sparing therapies in illness and obesity with a focus on the pioneering contributions of George Blackburn, MD, PhD. He recognized that protein-calorie malnutrition is a common and serious clinical condition and developed new approaches to its treatment in hospitalized patients. His work with stable isotopes and with animal models provided answers about the physiological nutritional requirements and metabolic changes across a spectrum of conditions with varying degrees of stress and catabolism. This led to improvements in enteral and parenteral nutrition for patients with acute illness. Blackburn also demonstrated that lean body mass can be preserved during weight loss with carefully designed very low calorie treatments which became known as the protein sparing modified fast (PSMF). We review the role of the PSMF as part of the comprehensive management of obesity., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Protein electrophoresis is commonly used as an aid in the diagnosis of monoclonal gammopathies and is performed in many laboratories in Canada and throughout the world. However, unlike many other diagnostic tests, there is limited guidance for standardization and neither guidance nor specific recommendations for clinical reporting of serum (SPE) or urine (UPE) protein electrophoresis and immunotyping available in the literature. Therefore, a Canadian effort was undertaken to recommend standards that cover all aspects of clinical reporting with an ultimate goal towards reporting standardization. The Canadian Society of Clinical Chemists (CSCC) Monoclonal Gammopathy Interest Group (MGIG), which is composed of CSCC members with an interest in protein electrophoresis, has formed a Monoclonal Gammopathy Working Group (MGWG) to take initial steps towards standardization of SPE, UPE and immunotyping. Candidate standardization recommendations were developed, discussed and voted upon by the MGWG. Candidate recommendations that achieved 90% agreement are presented as consensus recommendations. Recommendations that did not achieve 90% consensus remain candidate recommendations and are presented with accompanying MGWG discussion. Eleven consensus recommendations along with candidate recommendations for nomenclature, protein fraction reporting, test utilization, interference handling and interpretive reporting options are presented., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

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) β1-β2., 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) β1-β2. 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-κ (0.18±0.08g/L; n=6), IgG-λ (0.36±0.25g/L; n=8), IgA-κ (0.40±0.13g/L; n=7), IgA-λ (0.37±0.23g/L; n=4), IgM-κ (0.47±0.20g/L; n=13) and IgM-λ (0.29±0.24g/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) β1-β2. There was acceptable agreement between SPE and IFE for IgG-κ/λ and IgA-κ/λ 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., (Copyright © 2017 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Interactions between macrophages and adipocytes influence both metabolism and inflammation. Obesity-induced changes to macrophages and adipocytes lead to chronic inflammation and insulin resistance. This paper reviews the various functions of macrophages in lean and obese adipose tissue and how obesity alters adipose tissue macrophage phenotypes. Metabolic disease and insulin resistance shift the balance between numerous pro- and anti-inflammatory regulators of macrophages and create a feed-forward loop of increasing inflammatory macrophage activation and worsening adipocyte dysfunction. This ultimately leads to adipose tissue fibrosis and diabetes. The molecular mechanisms underlying these processes have therapeutic implications for obesity, metabolic syndrome, and diabetes., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: Lack of physician knowledge about transgender medicine is a barrier to care. An intervention with medical students changed attitudes about providing transgender medical care, but it is unknown whether at the level of postgraduate education an intervention could have a similar effect. We conducted such an intervention with resident-physicians., Methods: An intervention on transgender medicine covering the durability of gender identity and hormonal treatment regimens was added to the curriculum for residents. An anonymous survey assessed the residents' knowledge and willingness to assist with hormonal therapy before and after the lecture., Results: The percent of residents who agreed that they felt sufficiently knowledgeable to assist with hormonal therapy for a female-to-male patient increased significantly, from 5% before to 76% following the lecture (χ(2), 24.7; degrees of freedom, 1; P<.001). The percent of residents who reported that they felt sufficiently knowledgeable to assist with hormonal therapy for a male-to-female patient increased significantly, from 5% before to 71% following the lecture (χ(2), 24.0; degrees of freedom, 1; P<.001). The intervention increased resident knowledge about hormonal therapy for hypogonadal men (χ(2), 11.4; degrees of freedom, 1; P<.001) and women (χ(2), 9.4; degrees of freedom, 1; P = .002). The intervention made more residents agree that gender identity has a biologic basis that remains constant (P<.001) and that hormonal and surgical therapies should be offered (P = .047)., Conclusion: The lecture significantly increased residents' knowledge and willingness to assist with hormonal therapy for transgender patients.

Background: The CALIPER program has established a comprehensive database of age- and sex-stratified pediatric reference intervals for over 85 common biochemical markers, largely using the Abbott ARCHITECT assays. To allow a broader application of the CALIPER database, we examined transference to 36 Beckman Coulter Synchron Unicel DxC800 assays, based on the CLSI C28-A3/EP9-A3 guidelines., Methods: Patient sample comparisons were performed for 36 biochemical assays using 200 serum specimens obtained from pediatric patients on the Abbott ARCHITECT ci8200 and the Beckman Coulter DxC800. For each analyte, R(2) values were calculated to assess the quality of correlation between the platforms. Statistical criteria used to assess transferability included a) regression analysis to create the equation of the line of best fit, b) standardized residual, c) Bland-Altman, and d) quantile-quantile plots. Transferred reference intervals were further verified by analyzing serum samples from 100 healthy children from the CALIPER cohort on the Beckman Coulter system., Results: The reference intervals for most of the assessed analytes were transferable to Beckman Coulter assays (31 out of 36 studied) and the newly calculated reference intervals were verified through analysis of CALIPER reference samples (28 out of 31). Eighteen assays demonstrated excellent correlation (R(2)≥0.95), and 13 assays showed strong correlation (0.77≤R2≤0.94)., Conclusion: The current study allowed successful transference of a large number of biochemical markers from the CALIPER database to assays on the Beckman Coulter DxC800 platform. Transference should facilitate broader application of CALIPER reference intervals at pediatric centers using DxC biochemical assays., (Copyright © 2015 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Protein arginine methylation is one of the epigenetic modifications to proteins that is studied in yeast and is known to be involved in a number of human diseases. All eukaryotes produce Nη-monomethylarginine (ηMMA), asymmetric Nη1, Nη1-dimethylarginine (aDMA), and most produce symmetric Nη1, Nη2-dimethylarginine (sDMA) on proteins, but only yeast produce Nδ-monomethylarginine (δMMA). It has proven difficult to differentiate among all of these methylarginines using mass spectrometry. Accordingly, we demonstrated that the two forms of MMA have indistinguishable primary product ion spectra. However, the secondary product ion spectra of δMMA and ηMMA exhibited distinct patterns of ions. Using incorporation of deuterated methyl-groups in yeast, we determined which secondary product ions were methylated and their structures. Utilizing distinct secondary product ions, a triple quadrupole multiple reaction monitoring cubed (MRM(3)) assay was developed to measure δMMA, ηMMA, sDMA and aDMA derived from hydrolyzed protein. As a proof-of-concept, δMMA and ηMMA were measured using the MRM(3) method in wild type and mutant strains of Saccharomyces cerevisiae and compared to the total MMA measured using an existing assay. The MRM(3) assay represents the only method to directly quantify δMMA and the only method to simultaneously quantify all yeast methylarginines., (Copyright © 2013 Elsevier B.V. All rights reserved.)