Multi-ancestry GWAS analysis identifies two novel loci associated with diabetic eye disease and highlights APOL1 as a high risk locus in patients with diabetic macular edema.

Diabetic retinopathy (DR) is a common complication of diabetes. Approximately 20% of DR patients have diabetic macular edema (DME) characterized by fluid leakage into the retina. There is a genetic component to DR and DME risk, but few replicable loci. Because not all DR cases have DME, we focused on DME to increase power, and conducted a multi-ancestry GWAS to assess DME risk in a total of 1,502 DME patients and 5,603 non-DME controls in discovery and replication datasets. Two loci reached GWAS significance (p<5x10-8). The strongest association was rs2239785, (K150E) in APOL1. The second finding was rs10402468, which co-localized to PLVAP and ANKLE1 in vascular / endothelium tissues. We conducted multiple sensitivity analyses to establish that the associations were specific to DME status and did not reflect diabetes status or other diabetic complications. Here we report two novel loci for risk of DME which replicated in multiple clinical trial and biobank derived datasets. One of these loci, containing the gene APOL1, is a risk factor in African American DME and DKD patients, indicating that this locus plays a broader role in diabetic complications for multiple ancestries. Trial Registration: NCT00473330, NCT00473382, NCT03622580, NCT03622593, NCT04108156.

The road to pandemic recovery: Tracking COVID-19's impact on cirrhosis care and outcomes among 111,558 Veterans.

BACKGROUND AIMS: This study aimed to evaluate quarterly trends in process and health outcomes among Veterans with cirrhosis and assess the factors associated with cirrhosis outcomes before and during the COVID-19 pandemic. APPROACH RESULTS: US Veterans with cirrhosis were identified using the Veterans Health Administration Corporate Data Warehouse. Quarterly measures were evaluated from September 30, 2018, through March 31, 2022, including twice yearly screening for hepatocellular carcinoma (HCC-6), new HCC, surveillance for or treatment of esophageal varices, variceal bleeding, all-cause hospitalization, and mortality. Joinpoint analyses were used to assess the changes in trends over time. Logistic regression models were used to identify the demographic and medical factors associated with each outcome over time. Among 111,558 Veterans with cirrhosis with a mean Model for End-stage Liver Disease-Sodium of 11±5, rates of HCC-6 sharply declined from a prepandemic peak of 41%, to a nadir of 28%, and rebounded to 36% by March 2022. All-cause mortality did not significantly change over the pandemic, but new HCC diagnosis, EVST, variceal bleeding, and all-cause hospitalization significantly declined over follow-up. Quarterly HCC diagnosis declined from 0.49% to 0.38%, EVST from 50% to 41%, variceal bleeding from 0.15% to 0.11%, and hospitalization from 9% to 5%. Rurality became newly, significantly associated with nonscreening over the pandemic (aOR for HCC-6=0.80, 95% CI 0.74 to 0.86; aOR for EVST=0.95, 95% CI 0.90 to 0.997). CONCLUSIONS: The pandemic continues to impact cirrhosis care. Identifying populations at the highest risk of care disruptions may help to address ongoing areas of need.

The impact of macro- and micro-steatosis on the outcomes of patients who undergo liver transplant: Analysis of the UNOS-STAR database.

BACKGROUND AND AIMS: The presence of steatosis in a donor liver and its relation to post-transplantation outcomes are not well defined. This study evaluates the effect of the presence and severity of micro- and macro-steatosis of a donor graft on post-transplantation outcomes. METHODS: The UNOS-STAR registry (2005-2019) was used to select patients who received a liver transplant graft with hepatic steatosis. The study cohort was stratified by the presence of macro- or micro-vesicular steatosis, and further stratified by histologic grade of steatosis. The primary endpoints of all-cause mortality and graft failure were compared using sequential Cox regression analysis. Analysis of specific causes of mortality was further performed. RESULTS: There were 9184 with no macro-steatosis (control), 150 with grade 3 macro-steatosis, 822 with grade 2 macro-steatosis and 12 585 with grade 1 macro-steatosis. There were 10 320 without micro-steatosis (control), 478 with grade 3 micro-steatosis, 1539 with grade 2 micro-steatosis and 10 404 with grade 1 micro-steatosis. There was no significant difference in all-cause mortality or graft failure among recipients who received a donor organ with any evidence of macro- or micro-steatosis, compared to those receiving non-steatotic grafts. There was increased mortality due to cardiac arrest among recipients of a grade 2 macro-steatosis donor organ. CONCLUSION: This study shows no significant difference in all-cause mortality or graft failure among recipients who received a donor liver with any degree of micro- or macro-steatosis. Further analysis identified increased mortality due to specific aetiologies among recipients receiving donor organs with varying grades of macro- and micro-steatosis.

Impact of the COVID-19 pandemic on pediatric faculty: a report from nine academic institutions.

BACKGROUND: The COVID-19 pandemic affected home and work routines, which may exacerbate existing academic professional disparities. Objectives were to describe the impact of the pandemic on pediatric faculty's work productivity, identify groups at risk for widening inequities, and explore mitigation strategies. METHODS: A cross-sectional study of faculty members was conducted at nine U.S. pediatric departments. Responses were analyzed by demographics, academic rank, and change in home caregiving responsibility. RESULTS: Of 5791 pediatric faculty members eligible, 1504 (26%) completed the survey. The majority were female (64%), over 40 years old (60%), and assistant professors (47%). Only 7% faculty identified as underrepresented in medicine. Overall 41% reported an increase in caregiving during the pandemic. When comparing clinical, administrative, research, and teaching activities, faculty reported worse 1-year outlook for research activities. Faculty with increased caregiving responsibilities were more likely to report concerns over delayed promotion and less likely to have a favorable outlook regarding clinical and research efforts. Participants identified preferred strategies to mitigate challenges. CONCLUSIONS: The COVID-19 pandemic negatively impacted pediatric faculty productivity with the greatest effects on those with increased caregiving responsibilities. COVID-19 was particularly disruptive to research outlook. Mitigation strategies are needed to minimize the long-term impacts on academic pediatric careers. IMPACT: The COVID-19 pandemic most negatively impacted work productivity of academic pediatric faculty with caregiving responsibilities. COVID-19 was particularly disruptive to short-term (1-year) research outlook among pediatric faculty. Faculty identified mitigation strategies to minimize the long-term impacts of the pandemic on academic pediatric career pathways.

Informal Family Care Partner Well-Being Is Diminished in End-Stage Liver Disease.

BACKGROUND: Chronic liver disease is a significant global neglected public health problem. End-stage liver disease is associated with substantial symptom complexity, disability, and care needs that require assistance from informal family care partners. Research on these care partners' caregiver burden or strain, symptoms, and quality of life is sparse and has not focused on these variables as co-occurring or in the context of the quality of the relationship care partners have with the patients. OBJECTIVES: The purpose of this study was to provide a collective presentation of patterns and determinants of well-being as measured by caregiver strain, depression, sleep, and quality of life in a cohort of informal family care partners for adult outpatients with end-stage liver disease. METHODS: Care partners (aged >18 years) were recruited from two liver clinics within two tertiary healthcare systems and invited to complete a cross-sectional survey. They completed the Multidimensional Caregiver Strain Index, Patient Health Questionnaire, Pittsburgh Sleep Quality Index, Short Form Health Survey, and Mutuality Scale. Descriptive statistics and latent class mixture modeling were used to analyze these data. RESULTS: The sample was predominantly female and White. The well-being of care partners was diminished. Three distinct classes of well-being were identified: mildly diminished (53.2%), moderately diminished (39.0%), and severely diminished (7.8%). Those at a greater risk of worse well-being were younger and spouses and had poorer relationship quality with the patients. DISCUSSION: To improve the well-being of care partners in moderately and severely diminished classes, assessing and addressing caregiver strain and co-occurring symptoms is essential. Addressing the strain and symptoms has the potential to maintain or optimize care partners' ability to provide care to patients. Future researchers should include longitudinal and dyadic studies to examine how patients' disease progression and symptoms may affect family care partners' well-being and vice versa.

The Effect of Aromatherapy on Anxiety and Pain in Patients Undergoing Oculoplastic Surgery.

PURPOSE: To determine the effect of aromatherapy on postoperative anxiety and pain in patients undergoing oculoplastic surgery. METHODS: A randomized controlled study of 60 patients who underwent monitored anesthesia care sedation for oculoplastic procedures from August 2018 to November 2020. Patients were randomized to an aromatherapy (n = 32) or placebo (n = 28) condition. Anxiety was measured with State-Trait Anxiety Inventory and visual analog scale for anxiety. Pain was measured with a visual analog scale for pain. RESULTS: Compared with control patients, aromatherapy patients had significantly lower postoperative State-Trait Anxiety Inventory state anxiety (24.1 vs. 29.1; p = 0.05) and visual analog scale pain scores (1.9 vs. 3.2; p = 0.05). Aromatherapy patients also had shorter stays in the postanesthesia care unit than control patients (57.7 vs. 79.4 minutes; p = 0.03). CONCLUSIONS: Patients who received aromatherapy reported lower postoperative anxiety and pain. Aromatherapy may be a useful adjuvant analgesic and/or anxiolytic for patients undergoing oculoplastic procedures with monitored anesthesia care sedation.

Aging Effects on Optic Nerve Neurodegeneration.

Common risk factors for many ocular pathologies involve non-pathologic, age-related damage to the optic nerve. Understanding the mechanisms of age-related changes can facilitate targeted treatments for ocular pathologies that arise at any point in life. In this review, we examine these age-related, neurodegenerative changes in the optic nerve, contextualize these changes from the anatomic to the molecular level, and appreciate their relationship with ocular pathophysiology. From simple structural and mechanical changes at the optic nerve head (ONH), to epigenetic and biochemical alterations of tissue and the environment, multiple age-dependent mechanisms drive extracellular matrix (ECM) remodeling, retinal ganglion cell (RGC) loss, and lowered regenerative ability of respective axons. In conjunction, aging decreases the ability of myelin to preserve maximal conductivity, even with "successfully" regenerated axons. Glial cells, however, regeneratively overcompensate and result in a microenvironment that promotes RGC axonal death. Better elucidating optic nerve neurodegeneration remains of interest, specifically investigating human ECM, RGCs, axons, oligodendrocytes, and astrocytes; clarifying the exact processes of aged ocular connective tissue alterations and their ultrastructural impacts; and developing novel technologies and pharmacotherapies that target known genetic, biochemical, matrisome, and neuroinflammatory markers. Management models should account for age-related changes when addressing glaucoma, diabetic retinopathy, and other blinding diseases.

Cumulative Erythemal Ultraviolet Radiation and Risk of Cancer in 3 Large US Prospective Cohorts.

Ultraviolet radiation (UVR) exposure is the major risk factor for melanoma. However, epidemiologic studies on UVR and noncutaneous cancers have reported inconsistent results, with some suggesting an inverse relationship potentially mediated by vitamin D. To address this, we examined 3 US prospective cohorts, the Health Professionals Follow-up Study (HPFS) (1986) and Nurses' Health Study (NHS) I and II (1976 and 1989), for associations between cumulative erythemal UVR and incident cancer risk, excluding nonmelanoma skin cancer. We used a validated spatiotemporal model to calculate erythemal UVR. Participants (47,714 men; 212,449 women) were stratified into quintiles by cumulative average erythemal UVR, using the first quintile as referent, for Cox proportional hazards regression analysis. In the multivariable-adjusted meta-analysis of all cohorts, compared with the lowest quintile, risk of any cancer was slightly increased across all other quintiles (highest quintile hazard ratio (HR) = 1.04, 95% confidence interval (CI): 1.01, 1.07; P for heterogeneity = 0.41). All UVR quintiles were associated with similarly increased risk of any cancer excluding melanoma. As expected, erythemal UVR was positively associated with risk of melanoma (highest quintile HR = 1.17, 95% CI: 1.04, 1.31; P for heterogeneity = 0.83). These findings suggest that elevated UVR is associated with increased risk of both melanoma and noncutaneous cancers.

Symptom Classes in Decompensated Liver Disease.

BACKGROUND & AIMS: Patients with decompensated liver disease have been categorized by disease severity. This analysis sought to classify patients with end-stage liver disease based on symptoms rather than disease state and to identify distinct severity classes of physical and psychological symptoms. METHODS: Patients with a model for end-stage liver disease-sodium score of 15 or higher were recruited from liver clinics in 2 health care organizations. They completed the Condensed Memorial Symptom Assessment Scale, Revised Ways of Coping Checklist, Patient Health Questionnaire, Life Orientation Test-Revised, and the Short-Form Health Survey. Cross-sectional data were analyzed using latent class mixture modeling. RESULTS: The sample (N = 191; age, 56.6 ± 11.1 y; 33.5% ETOH; 28.3% nonalcoholic fatty liver disease; 13.1% autoimmune/primary biliary cholangitis/primary sclerosing cholangitis) was predominantly male (64.2%), Child-Turcotte-Pugh class C (49.5%), with an average model for end-stage liver disease-sodium score of 18.7 ± 4.9. Three distinct classes of symptoms were identified, as follows: mild (26.7%), moderate (41.4%), or severe (31.9%) symptoms. Symptom classes were independent of disease severity and demographic characteristics, except age. All Condensed Memorial Symptom Assessment Scale symptoms and Patient Health Questionnaire scores were significantly different across the 3 classes (P < .05). The symptom classes also differed significantly in physical and mental quality of life, optimism, and avoidance coping behaviors (all P < .001). CONCLUSIONS: Patient-reported symptom severity occurred independent of disease severity, contrary to common assumptions. Focusing on the moderate and severe symptom classes as well as patient history of end-stage liver disease complications may enhance providers' ability to improve symptom management for this population.

Optical phased array neural probes for beam-steering in brain tissue.

Implantable silicon neural probes with integrated nanophotonic waveguides can deliver patterned dynamic illumination into brain tissue at depth. Here, we introduce neural probes with integrated optical phased arrays and demonstrate optical beam steering in vitro. Beam formation in brain tissue is simulated and characterized. The probes are used for optogenetic stimulation and calcium imaging.

Comparison of cold snare and hot snare polypectomy for the resection of sporadic nonampullary duodenal adenomas.

BACKGROUND AND AIMS: Nonampullary duodenal adenomas can undergo malignant transformation, making endoscopic resection, often by hot snare (HSP) or cold snare polypectomy (CSP), necessary. Although CSP has been shown to be safer for removal of colon polyps, data comparing these techniques for the resection of duodenal adenomas are limited. Our aim was to compare the safety and efficacy of CSP and HSP for the removal of nonampullary duodenal adenomas. METHODS: We performed a retrospective cohort study of patients referred to 2 academic medical centers with a histologically confirmed sporadic, nonampullary duodenal adenoma who underwent endoscopic snare polypectomy between January 1, 2007 and March 1, 2021. Patients with underlying polyposis syndromes were excluded. Outcomes included postprocedural adverse events and polyp recurrence. RESULTS: Of 110 total patients, 69 underwent HSP and 41 underwent CSP. Intraprocedural bleeding was similar between both groups, but 7 patients in the HSP group experienced delayed adverse events versus none in the CSP group (P = .04). Fifty-four patients had complete polyp resection and subsequent surveillance endoscopies. Multivariate analysis showed polyp size to be associated with recurrence (per mm; odds ratio, 1.11; 95% confidence interval, 1.04-1.20; P < .01). Endoscopic resection technique (HSP vs CSP) was not a predictor of recurrence (P = .18). CONCLUSIONS: HSP led to more delayed adverse events compared with CSP, whereas no significant differences on outcomes were noted, suggesting that CSP is equally effective and potentially safer for the removal of duodenal adenomas.

Increased relative proportions of advanced melanoma among veterans: A comparative analysis with the Surveillance, Epidemiology, and End Results registry.

BACKGROUND: The Surveillance, Epidemiology, and End Results (SEER) program reflects a third of the population of the United States. However, SEER may not be generalizable to the veteran population. Because veterans comprise a high-risk population, this discrepancy may limit our understanding of the epidemiology of melanoma in such high-risk populations. OBJECTIVES: To assess differences in demographics, tumor characteristics, and melanoma-specific survival (MSS) in veterans compared to the general population. METHODS: Data were collected from the Veterans Affairs Cancer Registry (VACR) and SEER (18 registries) from 2009 to 2017. RESULTS: We identified 15,334 veterans and 166,265 SEER patients with melanoma. Veterans were more likely to present with regional or distant disease (17.5% vs 13.0% in SEER). In VACR relative to SEER, the 5-year MSS was lower across all ages, except those diagnosed at ≥80 years. From 2009 to 2017, MSS by stage was lower across all stages in VACR. However, for stage IV melanomas diagnosed in 2015 to 2017 compared to 2011-2014, 2-year MSS increased from 37.8% to 51.5% in VACR versus 36.4% to 44.8% in SEER. LIMITATIONS: Unique veteran demographics and missing data inherent to VACR. CONCLUSION: Compared to SEER, veterans with melanoma were diagnosed at later stages; however, both exhibited recent improvement in stage IV MSS.

Identifying Brigham and Women's Hospital stage T2a cutaneous squamous cell carcinomas at risk of poor outcomes.

BACKGROUND: Although most of the poor outcomes with cutaneous squamous cell carcinoma (CSCC) occur in high-stage tumors, 26% of nodal metastases and 8% of disease-specific deaths develop in Brigham and Women's Hospital (BWH) T2a tumors. OBJECTIVE: To determine risk factors associated with poor outcomes (nodal metastasis, distant metastases, and disease-specific deaths) in BWH T2a CSCC. METHODS: A 17-year retrospective multi-institutional cohort study of primary CSCC BWH T2a tumors. A predictive model based on tumor characteristics was developed to identify those at higher risk of poor outcomes. RESULTS: Presence of 1 major criterion (primary tumor diameter ≥40 mm, invasion depth beyond subcutaneous fat, poor differentiation, or large-caliber perineural invasion) and ≥ 1 minor criterion (invasion depth in subcutaneous fat, moderate differentiation, small-caliber perineural invasion, or lymphovascular invasion) was most predictive of developing poor outcomes (area under the curve, 0.53; C-statistic, 0.60). This model has a sensitivity of 7.7%, specificity of 97.4%, and a positive and negative predictive value of 33.3% and 86.1%, respectively. The 5-year cumulative incidence of poor outcomes in these tumors is 8.0% (95% CI, 5.1-13.7) compared to 2.8% (95% CI, 1.9-4.1) in other T2a tumors (sub-hazard ratio, 3.0; 95% CI, 1.5-5.8). LIMITATIONS: Multi-institutional cohort study was not externally validated. CONCLUSIONS: BWH T2a-high CSCCs have an 8% chance of developing poor outcomes.

Higher metastasis and death rates in cutaneous squamous cell carcinomas with lymphovascular invasion.

BACKGROUND: Lymphovascular invasion (LVI) is an aggressive histologic finding but is excluded from current staging systems due to its lack of demonstrated independent prognostic significance. OBJECTIVE: To evaluate the impact of LVI on cutaneous squamous cell carcinoma tumor outcomes. METHODS: In total, 10,707 cutaneous squamous cell carcinoma tumors from a 20-year, retrospective, multicenter cohort were stratified by the presence (LVI+) or absence (LVI-) of LVI. Outcomes (local recurrence, in-transit metastasis, nodal metastasis, disease-specific death) were compared based on low (Brigham and Women's Hospital [BWH] stage T1/T2a) and high (BWH T2b/T3) tumor stages. RESULTS: Of the 10,707 tumors, 78 had LVI. The analysis of low-stage BWH tumors showed the LVI+ group had a significantly higher 5-year cumulative incidence of local recurrence (LVI+: 12.3%; LVI-: 1.1%; P < .01), metastasis (LVI+: 4.2%; LVI-: 0.4%; P < .01), and disease-specific death (LVI+: 16.2%; LVI-: 0.4%; P < .01). The analysis of BWH high-stage tumors showed the LVI+ group maintained a higher 5-year cumulative incidence of metastasis (LVI+: 28.5%; LVI-: 16.8%; P = .06) and disease-specific death (LVI+: 25.3%; LVI-: 13.9%; P = .03), however, there was no difference in local recurrence (LVI+: 16.3%; LVI-: 15.8%; P = .11). LIMITATIONS: Retrospective study design. CONCLUSION: LVI+ cutaneous squamous cell carcinomas have higher rates of metastasis and death at 5 years. Future staging systems should consider incorporating LVI.

Symptom Frequency and Distress Underestimated in Decompensated Cirrhosis.

BACKGROUND: Studies assessing multiple symptoms and the distress of these symptoms in decompensated cirrhosis are lacking. AIMS: The aims of this study were to assess symptom prevalence and distress among patients with decompensated cirrhosis and to describe medical management of the most prevalent symptoms. METHODS: Patients were recruited from hepatology clinics within two health-care systems. Eligibility criteria included a model for end-stage liver disease (MELD-Na) score ≥15. Patients completed the Condensed Memorial Symptom Assessment Scale and Patient Health Questionnaire. Comparative statistics were used to analyze the cross-sectional survey data. RESULTS: Of the sample (n = 146), most patients were Child-Turcotte-Pugh (CTP) class B (49.7%) and C (46.2%). Mean age was 56.5 years, 65.1% were male, and 88.4% were white. Average MELD-Na score was 19.1 ± 4.5. The most prevalent symptoms were lack of energy and feeling drowsy while the most distressing were lack of energy and difficulty sleeping. Only 24 patients (16.4%) were treated for their difficulty sleeping with sleep medication. Importantly, those prescribed sleep medications had similar distress (3.9 ± 1.2 vs. 3.5 ± 1.2, p = 0.229) compared with patients not prescribed sleep medications. Opioids were prescribed to 57 (39.0%) patients; antidepressants to 34 (23.3%). Forty patients (27.4%) who reported moderate or greater depression were not prescribed an antidepressant. CONCLUSIONS: The study highlights the multiple symptoms and distress experienced by patients with decompensated cirrhosis, and the need for improved medical management by health-care providers through enhanced awareness and attention to these complex symptoms. Future research should focus on improvements in symptom management.

Participant Characteristics and Attendance Patterns for a Multispecialty Veterans Affairs ECHO Program 2012-2018.

Introduction: The Veteran Integrated Service Network (VISN) 20 Veterans Affairs-Extension for Community Healthcare Outcomes (VA-ECHO) program connects specialty and primary care providers (PCPs) across large geographic areas, utilizing video-teleconferencing with the intention of increasing access to care among underserved and isolated populations. No previously published work describes participation patterns of a multispecialty ECHO program. We describe the development of VISN 20 VA-ECHO program to inform the design and evaluation of ECHO programs. Methods: The participant cohort included VA-affiliated licensed health care professionals, including trainees, who attended at least one VISN 20 VA-ECHO session between April 2012 and December 2018. Participant characteristics reported include gender, clinical location, clinical specialty, discipline, and rurality. Results: Over the 6-year time frame, VISN 20 VA-ECHO offered 945 sessions in 14 clinical specialties and recorded 17,893 hours of attendance. The cohort included 1,346 participants, 74.3% of whom were female, 85.2% employed in medical centers, and 40.7% affiliated with primary care. Most participants (62.3%) attended one specialty exclusively; among all participants, 40% attended five or more sessions. Discussion: Although VA-ECHO was implemented to develop single specialty expertise among PCPs, our participant cohort represented a more diverse audience from a range of disciplines and specialties. Our experience may be valuable to other teams implementing ECHO programs. Conclusions: Through adaptability and strategies that actively promoted inclusion of a diverse audience, VISN 20 VA-ECHO expanded to include multiple clinical specialties and successfully engaged an audience across a large geographic area and beyond PCPs.

ER Unfolded Protein Response in Liver In Vivo Is Characterized by Reduced, Not Increased, De Novo Lipogenesis and Cholesterol Synthesis Rates with Uptake of Fatty Acids from Adipose Tissue: Integrated Gene Expression, Translation Rates and Metabolic Fluxes.

The unfolded protein response in the endoplasmic reticulum (UPRER) is involved in a number of metabolic diseases. Here, we characterize UPRER-induced metabolic changes in mouse livers in vivo through metabolic labeling and mass spectrometric analysis of lipid and proteome-wide fluxes. We induced UPRER by tunicamycin administration and measured synthesis rates of proteins, fatty acids and cholesterol, as well as RNA-seq. Contrary to reports in isolated cells, hepatic de novo lipogenesis and cholesterogenesis were markedly reduced, as were mRNA levels and synthesis rates of lipogenic proteins. H&E staining showed enrichment with lipid droplets while electron microscopy revealed ER morphological changes. Interestingly, the pre-labeling of adipose tissue prior to UPRER induction resulted in the redistribution of labeled fatty acids from adipose tissue to the liver, with replacement by unlabeled glycerol in the liver acylglycerides, indicating that the liver uptake was of free fatty acids, not whole glycerolipids. The redistribution of adipose fatty acids to the liver was not explicable by altered plasma insulin, increased fatty acid levels (lipolysis) or by reduced food intake. Synthesis of most liver proteins was suppressed under UPRER conditions, with the exception of BiP, other chaperones, protein disulfide isomerases, and proteins of ribosomal biogenesis. Protein synthesis rates generally, but not always, paralleled changes in mRNA. In summary, this combined approach, linking static changes with fluxes, revealed an integrated reduction of lipid and cholesterol synthesis pathways, from gene expression to translation and metabolic flux rates, under UPRER conditions. The reduced lipogenesis does not parallel human fatty liver disease. This approach provides powerful tools to characterize metabolic processes underlying hepatic UPRER in vivo.

Physical and Mental Quality of Life in Patients With End-Stage Liver Disease and Their Informal Caregivers.

BACKGROUND & AIMS: Management of end-stage liver disease (ESLD) has implications for not only patients' quality of life (QOL), but also their caregivers'. We aimed to identify characteristics of patients with ESLD and their caregivers that are associated with QOL. METHODS: We obtained cross-sectional baseline data from patients and their caregivers (132 dyads; 62% were married or partners), recruited from outpatient hepatology clinics within 2 healthcare centers. Patients were included if their model for end-stage liver disease score was 15 or more; caregivers were identified by the patient as the primary informal caregiver. QOL was measured by the SF-36 and relationship quality using the mutuality scale. We measured uncertainty using the uncertainty in illness scales for patients and caregivers. Multilevel modeling was used to analyze the data. RESULTS: Refractory ascites was associated with worse physical QOL for patients (unstandardized beta [B], -9.19; standard error [SE], 2.28) and caregivers (B, -5.41; SE, 2.33); history of hepatic encephalopathy was associated with worse patient physical QOL (B, -3.86; SE, 1.65). High levels of uncertainty were associated with worse physical and mental QOL for both members of the dyads; relationship quality was significantly associated with patient mental QOL (B, 2.73; SE, 1.19). CONCLUSIONS: Clinicians and researchers should consider the effects of ESLD on caregivers as well as their patients to optimize the QOL for both.

Transient elastography versus liver biopsy: discordance in evaluations for fibrosis and steatosis from a pathology standpoint.

Vibration-controlled transient elastography (VCTE) is a non-invasive method of evaluating liver fibrosis and steatosis. It can easily be performed in the outpatient setting and has been suggested as an alternative to liver biopsy. However, VCTE and biopsy discrepancies commonly occur. Patient characteristics, procedure performance, and liver features can impact the reliability of VCTE results. We identified 82 patients who received VCTE and biopsy within one month to assess how frequently major discrepancies occur and to determine the role of the liver biopsy in this workup. In our study, 35.4% of patients had a major fibrosis discrepancy, which was defined as advanced fibrosis or cirrhosis by VCTE and no to minimal fibrosis on biopsy. This was significantly associated with increased BMI, and liver features including steatohepatitis, inflammation, congestion, and cholestasis were important contributors to discrepancies. All patients with advanced fibrosis or cirrhosis on liver biopsy were appropriately detected by VCTE (n = 28). Detection of steatosis was less sensitive as 19% (n = 4 of 21) of patients with moderate to severe steatosis on biopsy were missed by VCTE. Liver biopsy has been traditionally performed for diagnosis, but with the emergence of non-invasive tools to evaluate for liver fibrosis and steatosis, biopsies are now additionally being performed to confirm findings from noninvasive procedures. Although VCTE is a highly sensitive tool for liver fibrosis, it is not as specific, and therefore, the liver biopsy remains the gold standard for accurate fibrosis assessment.

Plasma microRNA Interindividual Variability in Healthy Individuals, Pregnant Women, and an Individual with a Stably Altered Neuroendocrine Phenotype.

BACKGROUND: Extracellular RNAs (exRNAs) in biofluids are amenable to quantitative analysis and proposed as noninvasive biomarkers for monitoring organ function. Cell-lineage-specific microRNAs (miRNAs) are present in plasma as soluble ribonucleoproteins or enclosed in exRNA carriers and transported through the vasculature. However, more extensive studies of healthy individuals are needed to gain insights into the variability of plasma miRNA abundance and composition. METHODS: The exRNA composition of platelet-depleted plasma collected twice from 236 healthy individuals was characterized by small RNA sequencing. Plasma of pregnant women featuring dramatically increased placental miRNAs and samples from subject P12 with noticeably increased epithelial- and neuroendocrine-origin miRNAs were included for comparison. The miRNA content of 10 000g and 100 000g pellet fractions of plasma generated by ultracentrifugation was also determined. Data analysis methods included Pearson correlation, differential gene expression, and unsupervised clustering. RESULTS: The abundance changes for more variable miRNAs in plasma of normal individuals correlated between coexpressed cell-lineage-specific miRNAs of the liver, neuroendocrine organs, epithelial cells, and muscle. ExRNA of pellet fractions contained <2% of total plasma miRNA with modest enrichment of lineage-specific and variable miRNAs compared to supernatant. The abundance fold changes of miRNAs observed in pregnancy and P12 compared to normal exceeded interquartile variability of healthy individuals. The neuroendocrine miRNA signature of P12 persisted for more than 4 years and was absent in other individuals. CONCLUSIONS: This study defines the framework and effect size for screening of extensive plasma collections for miRNA phenotypes and biomarker discovery.