Screening patients in general practice for advanced chronic liver disease using an innovative IT solution: The Liver Toolkit.

BACKGROUND: Identifying patients with undiagnosed advanced chronic liver disease (ACLD) is a public health challenge. Patients with advanced fibrosis or compensated cirrhosis have much better outcomes than those with decompensated disease and may be eligible for interventions to prevent disease progression. METHODS: A cloud-based software solution ("the Liver Toolkit") was developed to access primary care practice software to identify patients at risk of ACLD. Clinical history and laboratory results were extracted to calculate aspartate aminotransferase-to-platelet ratio index and fibrosis 4 scores. Patients identified were recalled for assessment, including Liver Stiffness Measurement (LSM) via transient elastography. Those with an existing diagnosis of cirrhosis were excluded. RESULTS: Existing laboratory results of more than 32,000 adults across nine general practices were assessed to identify 703 patients at increased risk of ACLD (2.2% of the cohort). One hundred seventy-nine patients (26%) were successfully recalled, and 23/179 (13%) were identified to have ACLD (LSM ≥10.0 kPa) (10% found at indeterminate risk [LSM 8.0-9.9 kPa] and 77% low risk of fibrosis [LSM <8.0 kPa]). In most cases, the diagnosis of liver disease was new, with the most common etiology being metabolic dysfunction-associated steatotic liver disease (n=20, 83%). Aspartate aminotransferase-to-platelet ratio index ≥1.0 and fibrosis 4 ≥3.25 had a positive predictive value for detecting ACLD of 19% and 24%, respectively. Patients who did not attend recall had markers of more severe disease with a higher median aspartate aminotransferase-to-platelet ratio index score (0.57 vs. 0.46, p=0.041). CONCLUSIONS: This novel information technology system successfully screened a large primary care cohort using existing laboratory results to identify patients at increased risk ACLD. More than 1 in 5 patients recalled were found to have liver disease requiring specialist follow-up.

Challenges and Opportunities for the Clinical Translation of Spatial Transcriptomics Technologies.

Background: The first spatially resolved transcriptomics platforms, GeoMx (Nanostring) and Visium (10x Genomics) were launched in 2019 and were recognized as the method of the year by Nature Methods in 2020. The subsequent refinement and expansion of these and other technologies to increase -plex, work with formalin-fixed paraffin-embedded tissue, and analyze protein in addition to gene expression have only added to their significance and impact on the biomedical sciences. In this perspective, we focus on two platforms for spatial transcriptomics, GeoMx and Visium, and how these platforms have been used to provide novel insight into kidney disease. The choice of platform will depend largely on experimental questions and design. The application of these technologies to clinically sourced biopsies presents the opportunity to identify specific tissue biomarkers that help define disease etiology and more precisely target therapeutic interventions in the future. Summary: In this review, we provide a description of the existing and emerging technologies that can be used to capture spatially resolved gene and protein expression data from tissue. These technologies have provided new insight into the spatial heterogeneity of diseases, how reactions to disease are distributed within a tissue, which cells are affected, and molecular pathways that predict disease and response to therapy. Key Message: The upcoming years will see intense use of spatial transcriptomics technologies to better define the pathophysiology of kidney diseases and develop novel diagnostic tests to guide personalized treatments for patients.

Drug-induced liver injury from selective androgen receptor modulators, anabolic-androgenic steroids and bodybuilding supplements in Australia.

BACKGROUND: Reports of DILI due to herbal and dietary supplements have been increasing over time. AIMS: To characterise clinical, laboratory and histopathological phenotypes and outcomes of drug-induced liver injury (DILI) due to anabolic-androgenic steroids (AAS), selective androgen receptor modulators (SARMs), and bodybuilding supplements (BBS) in Australia. METHODS: Retrospective case series. Patients presented to nine Australian tertiary hospitals, 2017-2023. DILI was defined biochemically and patients were included if their treating physician attributed DILI to preceding use of AAS, SARMs or BBS. Primary endpoint was time to normalisation of liver biochemistry. Secondary endpoints were hospitalisation for investigation or management of DILI, death attributable to liver injury, and liver transplantation. RESULTS: Twenty-three cases of DILI were identified, involving 40 drugs: 18 AAS, 14 SARMs and eight BBS. Patients were predominantly male (22/23), with median age 30 years (IQR 26-42). Most were symptomatic (21/23). Median latency of onset was 58 days (IQR 28-112 days) from drug commencement. Most patients (17/23) were admitted to hospital. Based on updated Roussel Uclaf Causality Assessment Method, DILI was possible in 17/23, probable in 2/23 and unlikely in 4/23. Median time to normalisation of liver biochemistry was 175 days (IQR 70-292 days) from presentation. Three (3/23) were treated with corticosteroids, 14/23 were treated for itch, and one (1/23) underwent liver transplantation. There were no deaths. CONCLUSIONS: The prognosis of DILI from AAS, SARMs and BBS is good although liver transplantation may rarely be required. A detailed drug history is important in uncovering DILI due to these supplements.

Evaluation and Measurement Properties of a Patient-Reported Experience Measure for Home Dialysis.

BACKGROUND: No previously validated patient-reported experience measures exist for use among patients undergoing home dialysis. We tested the Home Dialysis Care Experience survey, a newly developed 26-item experience measure, among patients from 30 dialysis facilities in the United States. METHODS: Using mail and telephone survey modalities, we approached 1372 patients treated with peritoneal dialysis or home hemodialysis for participation. Using the results from completed surveys, we evaluated item calibration by assessing item floor and ceiling effects. We tested three sets of composite scores and used factor analysis to assess model fit for each. We evaluated associations of composite scores with global ratings and separately with patient and dialysis facility characteristics. Finally, we measured test-retest reliability in patients who completed the survey at two separate time points. RESULTS: Overall, 495 eligible patients completed at least one survey (response rate 36%). Of these, 49 completed the survey in Spanish and 61 completed a second survey within 30 days. We did not detect significant floor or ceiling effects, except for one item that demonstrated >90% responses at the top response option. Analyses supported one 12-item composite scale with high internal consistency reliability: Quality of Home Dialysis Care and Operations (Cronbach alpha=0.85). This scale strongly correlated with overall staff rating ( r =0.73) and overall center rating ( r =0.70). Patient demographic and dialysis facility characteristics were not consistently associated with composite scale scores or overall staff or center ratings. Intraclass correlation coefficients in the test-retest population were 0.74 for the Quality scale, 0.88 for overall staff rating, and 0.90 for overall center rating. CONCLUSIONS: The Home Dialysis Care Experience survey is a 26-item measure that includes one composite scale and two global rating scores and is an informative tool to evaluate patient experience of care for home dialysis.

Poor correlation of 2D shear wave elastography and transient elastography in Fontan-associated liver disease: A head-to-head comparison.

Background and Aims: Fontan-associated liver disease (FALD) is a long-term complication of the Fontan procedure. Guidelines recommend elastography, but the utility of transient elastography (TE) and two-dimensional shear wave elastography (2D SWE) is unknown. We aimed to evaluate the relationship between TE and 2D SWE in FALD. Methods: This prospective cohort study included 25 patients managed in a specialist clinic between January 2018 and August 2021. Trained clinicians performed 2D SWE (GE Logiq-E9) and TE (FibroScan 503 Touch) on the same day under the same conditions. Laboratory, echocardiography, and imaging data were collected. The atrioventricular systolic-to-diastolic duration (AVV S/D ratio) was calculated as a measure of cardiac diastolic function. Results: We analyzed 40 paired measurements. Median age was 22 years. Median liver stiffness measurement (LSM) was 15.4 kPa (12.1-19.6) by TE and 8.0 kPa (7.0-10.3) (P = 0.001) by 2D SWE. There was weak correlation between the modalities (r = 0.41, P = 0.004). There was no correlation between time since Fontan and LSM by TE (r = 0.15, P = 0.19) or 2D SWE (r = 0.19, P = 0.13). There was no difference in LSM irrespective of whether sonographic cirrhosis was present or absent by TE (17.4 kPa [15.9-23.6] vs. 14.9 kPa [12.0-19.4], respectively, P = 0.6) or 2D SWE (9.0 kPa [2.8-10.5] vs. 8.0 kPa [6.7-10.1], P = 0.46). There was no correlation between AVV S/D ratio and LSM by TE (r = 0.16, P = 0.18) or 2D SWE (r = 0.02, P = 0.45). Conclusions: In FALD, TE and 2D SWE are poorly correlated. LSM by either modality was not associated with known risk factors for liver fibrosis or Fontan function. Based on these data, the role of elastography in FALD is uncertain.

Combining biomimetic collagen/hyaluronan hydrogels with discogenic growth factors promotes mesenchymal stroma cell differentiation into Nucleus Pulposus like cells.

Based on stem cell injection into degenerated Nucleus Pulposus (NP), novel treatments for intervertebral disc (IVD) regeneration were disappointing because of cell leakage or inappropriate cell differentiation. In this study, we hypothesized that mesenchymal stromal cells encapsulated within injectable hydrogels possessing adequate physico-chemical properties would differentiate into NP like cells. Composite hydrogels consisting of type I collagen and tyramine-substituted hyaluronic acid (THA) were prepared to mimic the NP physico-chemical properties. Human bone marrow derived mesenchymal stromal cells (BM-MSCs) were encapsulated within hydrogels and cultivated in proliferation medium (supplemented with 10% fetal bovine serum) or differentiation medium (supplemented with GDF5 and TGFß1) over 28 days. Unlike pure collagen, collagen/THA composite hydrogels were stable over 28 days in culture. In proliferation medium, the cell viability within pure collagen hydrogels was high, whereas that in composite and pure THA hydrogels was lower due to the weaker cell adhesion. Nonetheless, BM-MSCs proliferated in all hydrogels. In composite hydrogels, cells exhibited a rounded morphology similar to NP cells. The differentiation medium did not impact the hydrogel stability and cell morphology but negatively impacted the cell viability in pure collagen hydrogels. A high THA content within hydrogels promoted the gene expression of NP markers such as collagen II, aggrecan, SOX9 and cytokeratin 18 at day 28. The differentiation medium potentialized this effect with an earlier and higher expression of these NP markers. Taken together, these results show that the physico-chemical properties of collagen/THA composite hydrogels and GDF5/TGFß1 act in synergy to promote the differentiation of BM-MSCs into NP like cells.

Associations of Biomarkers of Tubular Injury and Inflammation with Biopsy Features in Type 1 Diabetes.

BACKGROUND: Whether biomarkers of tubular injury and inflammation indicate subclinical structural kidney pathology early in type 1 diabetes remains unknown. METHODS: We investigated associations of biomarkers of tubular injury and inflammation with kidney structural features in 244 adults with type 1 diabetes from the Renin-Angiotensin System Study, a randomized, placebo-controlled trial testing effects of enalapril or losartan on changes in glomerular, tubulointerstitial, and vascular parameters from baseline to 5-year kidney biopsies. Biosamples at biopsy were assessed for kidney injury molecule 1 (KIM-1), soluble TNF receptor 1 (sTNFR1), arginine-to-citrulline ratio in plasma, and uromodulin and epidermal growth factor (EGF) in urine. We examined cross-sectional correlations between biomarkers and biopsy features and baseline biomarker associations with 5-year changes in biopsy features. RESULTS: Participants' mean age was 30 years (SD 10) and diabetes duration 11 years (SD 5); 53% were women. The mean GFR measured by iohexol disappearance was 128 ml/min per 1.73 m 2 (SD 19) and median urinary albumin excretion was 5 µ g/min (interquartile range, 3-8). KIM-1 was associated with most biopsy features: higher mesangial fractional volume (0.5% [95% confidence interval (CI), 0.1 to 0.9] greater per SD KIM-1), glomerular basement membrane (GBM) width (14.2 nm [95% CI, 6.5 to 22.0] thicker), cortical interstitial fractional volume (1.1% [95% CI, 0.6 to 1.6] greater), fractional volume of cortical atrophic tubules (0.6% [95% CI, 0.2 to 0.9] greater), and arteriolar hyalinosis index (0.03 [95% CI, 0.1 to 0.05] higher). sTNFR1 was associated with higher mesangial fractional volume (0.9% [95% CI, 0.5 to 1.3] greater) and GBM width (12.5 nm [95% CI, 4.5 to 20.5] thicker) and lower GBM surface density (0.003 µ m 2 / µ m 3 [95% CI, 0.005 to 0.001] lesser). EGF and arginine-to-citrulline ratio correlated with severity of glomerular and tubulointerstitial features. Baseline sTNFR1, uromodulin, and EGF concentrations were associated with 5-year glomerular and tubulointerstitial feature progression. CONCLUSIONS: Biomarkers of tubular injury and inflammation were associated with kidney structural parameters in early type 1 diabetes and may be indicators of kidney disease risk. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Renin Angiotensin System Study (RASS/B-RASS), NCT00143949.

Neuron Navigator 1 (Nav1) regulates the response to cocaine in mice.

Genetic variation accounts for much of the risk for developing a substance use disorder, but the underlying genetic factors and their genetic effector mechanisms are mostly unknown. Inbred mouse strains exhibit substantial and heritable differences in the extent of voluntary cocaine self-administration. Computational genetic analysis of cocaine self-administration data obtained from twenty-one inbred strains identified Nav1, a member of the neuron navigator family that regulates dendrite formation and axonal guidance, as a candidate gene. To test this genetic hypothesis, we generated and characterized Nav1 knockout mice. Consistent with the genetic prediction, Nav1 knockout mice exhibited increased voluntary cocaine intake and had increased motivation for cocaine consumption. Immunohistochemistry, electrophysiology, and transcriptomic studies were performed as a starting point for investigating the mechanism for the Nav1 knockout effect. Nav1 knockout mice had a reduced inhibitory synapse density in their cortex, increased excitatory synaptic transmission in their cortex and hippocampus, and increased excitatory neurons in a deep cortical layer. Collectively, our results indicate that Nav1 regulates the response to cocaine, and we identified Nav1 knockout induced changes in the excitatory and inhibitory synaptic balance in the cortex and hippocampus that could contribute to this effect.

Alcohol-Associated Liver Disease: Evolving Concepts and Treatments.

Alcohol is a prominent cause of liver disease worldwide with higher prevalence in developed nations. The spectrum of alcohol-associated liver disease (ALD) encompasses a diverse range of clinical entities, from asymptomatic isolated steatosis to decompensated cirrhosis, and in some cases, acute or chronic liver failure. Consequently, it is important for healthcare practitioners to maintain awareness and systematically screen for ALD. The optimal evaluation and management of ALD necessitates a collaborative approach, incorporating a multidisciplinary team and accounting for concurrent medical conditions. A repertoire of therapeutic interventions exists to support patients in achieving alcohol cessation and sustaining remission, with complete abstinence being the ultimate objective. This review explores the existing therapeutic options for ALD acknowledging geographical discrepancies in accessibility. Recent innovations, including the inclusion of alcohol consumption biomarkers into clinical protocols and the expansion of liver transplantation eligibility to encompass severe alcohol-associated hepatitis, are explored.

Developmental Diet Alters the Fecundity-Longevity Relationship and Age-Related Gene Expression in Drosophila melanogaster.

The standard evolutionary theory of aging predicts a negative relationship (trade-off) between fecundity and longevity. However, in principle, the fecundity-longevity relationship can become positive in populations in which individuals have unequal resources. Positive fecundity-longevity relationships also occur in queens of eusocial insects such as ants and bees. Developmental diet is likely to be central to determining trade-offs as it affects key fitness traits, but its exact role remains uncertain. For example, in Drosophila melanogaster, changes in adult diet can affect fecundity, longevity, and gene expression throughout life, but it is unknown how changes in developmental (larval) diet affect fecundity-longevity relationships and gene expression in adults. Using D. melanogaster, we tested the hypothesis that varying developmental diets alters the directionality of fecundity-longevity relationships in adults, and characterized associated gene expression changes. We reared larvae on low (20%), medium (100%), and high (120%) yeast diets, and transferred adult females to a common diet. We measured fecundity and longevity of individual adult females and profiled gene expression changes with age. Adult females raised on different larval diets exhibited fecundity-longevity relationships that varied from significantly positive to significantly negative, despite minimal differences in mean lifetime fertility or longevity. Treatments also differed in age-related gene expression, including for aging-related genes. Hence, the sign of fecundity-longevity relationships in adult insects can be altered and even reversed by changes in larval diet quality. By extension, larval diet differences may represent a key mechanistic factor underpinning positive fecundity-longevity relationships observed in species such as eusocial insects.

Vessels that encapsulate tumour clusters vascular pattern in hepatocellular carcinoma.

Vessels that encapsulate tumour clusters (VETC) is a distinct histologic vascular pattern associated with a novel mechanism of metastasis. First described in human cancers in 2004, its prevalence and prognostic significance in hepatocellular carcinoma (HCC) has only been appreciated in the past decade with a rapidly increasing body of literature. A robust biomarker of aggressive disease, the VETC pattern is easy to recognise but relies on histologic examination of tumour tissue for its diagnosis. Radiological recognition of the VETC pattern is an area of active research and is becoming increasingly accurate. As a prognostic marker, VETC has consistently proven to be an independent predictor of disease recurrence and overall survival in patients with HCC undergoing resection and liver transplantation. It can also guide treatment by predicting response to other therapies such as transarterial chemoembolisation and sorafenib. Without prospective randomised-controlled trials or routine evaluation of VETC in clinical practice, there are currently no firm treatment recommendations for VETC-positive tumours, although some perspectives are provided in this review based on the latest knowledge of their pathogenesis - a complex interplay between tumour angiogenesis and the immune microenvironment. Nevertheless, VETC has great potential as a future biomarker that could take us one step closer to precision medicine for HCC.

Costs of reproduction are present but latent in eusocial bumblebee queens.

BACKGROUND: The standard evolutionary theory of ageing proposes that ageing occurs because of a trade-off between reproduction and longevity. Eusocial insect queens exhibit positive fecundity-longevity associations and so have been suggested to be counter-examples through not expressing costs of reproduction and through remodelling conserved genetic and endocrine networks regulating ageing and reproduction. If so, eusocial evolution from solitary ancestors with negative fecundity-longevity associations must have involved a stage at which costs of reproduction were suppressed and fecundity and longevity became positively associated. Using the bumblebee (Bombus terrestris), we experimentally tested whether queens in annual eusocial insects at an intermediate level of eusocial complexity experience costs of reproduction, and, using mRNA-seq, the extent to which they exhibit a remodelling of relevant genetic and endocrine networks. Specifically, we tested whether costs of reproduction are present but latent, or whether a remodelling of relevant genetic and endocrine networks has already occurred allowing queens to reproduce without costs. RESULTS: We experimentally increased queens' costs of reproduction by removing their eggs, which caused queens to increase their egg-laying rate. Treatment queens had significantly reduced longevity relative to control queens whose egg-laying rate was not increased. Reduced longevity in treatment queens was not caused by increased worker-to-queen aggression or by increased overall activity in queens. In addition, treatment and control queens differed in age-related gene expression based on mRNA-seq in both their overall expression profiles and the expression of ageing-related genes. Remarkably, these differences appeared to occur principally with respect to relative age, not chronological age. CONCLUSIONS: This study represents the first simultaneously phenotypic and transcriptomic experimental test for a longevity cost of reproduction in eusocial insect queens. The results support the occurrence of costs of reproduction in annual eusocial insects of intermediate social complexity and suggest that reproductive costs are present but latent in queens of such species, i.e. that these queens exhibit condition-dependent positive fecundity-longevity associations. They also raise the possibility that a partial remodelling of genetic and endocrine networks underpinning ageing may have occurred in intermediately eusocial species such that, in unmanipulated conditions, age-related gene expression depends more on chronological than relative age.

Alcohol and its associated liver carcinogenesis.

Alcohol consumption is a major cause of cirrhosis and hepatocellular carcinoma (HCC). The prevalence of alcohol-associated hepatocellular carcinoma (aHCC) varies worldwide but is highest in Eastern Europe. Alcohol is the second fastest-growing cause of age-standardized liver cancer mortality with tumors more often diagnosed outside surveillance protocols and at a more advanced stage. Risk factors for aHCC include greater amounts of alcohol consumption, sex, and certain genetic polymorphisms. Smoking, concomitant liver disease, obesity, and diabetes act synergistically in increasing the risk of HCC in alcohol-associated liver disease. Alcohol-related hepatocarcinogenesis results from the complex interactions of several mechanistic pathways. Although not completely understood, underlying mechanisms include acetaldehyde-related hepatotoxicity, oxidative stress, activation of the innate immune system, and alterations of the host microbiome.

Integrated Analysis of Blood and Urine Biomarkers to Identify Acute Kidney Injury Subphenotypes and Associations With Long-term Outcomes.

RATIONALE & OBJECTIVE: Acute kidney injury (AKI) is a heterogeneous clinical syndrome with varying causes, pathophysiology, and outcomes. We incorporated plasma and urine biomarker measurements to identify AKI subgroups (subphenotypes) more tightly linked to underlying pathophysiology and long-term clinical outcomes. STUDY DESIGN: Multicenter cohort study. SETTING & PARTICIPANTS: 769 hospitalized adults with AKI matched with 769 without AKI, enrolled from December 2009 to February 2015 in the ASSESS-AKI Study. PREDICTORS: 29 clinical, plasma, and urinary biomarker parameters used to identify AKI subphenotypes. OUTCOME: Composite of major adverse kidney events (MAKE) with a median follow-up period of 4.7 years. ANALYTICAL APPROACH: Latent class analysis (LCA) and k-means clustering were applied to 29 clinical, plasma, and urinary biomarker parameters. Associations between AKI subphenotypes and MAKE were analyzed using Kaplan-Meier curves and Cox proportional hazard models. RESULTS: Among 769 AKI patients both LCA and k-means identified 2 distinct AKI subphenotypes (classes 1 and 2). The long-term risk for MAKE was higher with class 2 (adjusted HR, 1.41 [95% CI, 1.08-1.84]; P=0.01) compared with class 1, adjusting for demographics, hospital level factors, and KDIGO stage of AKI. The higher risk of MAKE among class 2 was explained by a higher risk of long-term chronic kidney disease progression and dialysis. The top variables that were different between classes 1 and 2 included plasma and urinary biomarkers of inflammation and epithelial cell injury; serum creatinine ranked 20th out of the 29 variables for differentiating classes. LIMITATIONS: A replication cohort with simultaneously collected blood and urine sampling in hospitalized adults with AKI and long-term outcomes was unavailable. CONCLUSIONS: We identify 2 molecularly distinct AKI subphenotypes with differing risk of long-term outcomes, independent of the current criteria to risk stratify AKI. Future identification of AKI subphenotypes may facilitate linking therapies to underlying pathophysiology to prevent long-term sequalae after AKI. PLAIN-LANGUAGE SUMMARY: Acute kidney injury (AKI) occurs commonly in hospitalized patients and is associated with high morbidity and mortality. The AKI definition lumps many different types of AKI together, but subgroups of AKI may be more tightly linked to the underlying biology and clinical outcomes. We used 29 different clinical, blood, and urinary biomarkers and applied 2 different statistical algorithms to identify AKI subtypes and their association with long-term outcomes. Both clustering algorithms identified 2 AKI subtypes with different risk of chronic kidney disease, independent of the serum creatinine concentrations (the current gold standard to determine severity of AKI). Identification of AKI subtypes may facilitate linking therapies to underlying biology to prevent long-term consequences after AKI.

Randomized crossover clinical trial of coenzyme Q10 and nicotinamide riboside in chronic kidney disease.

BackgroundCurrent studies suggest mitochondrial dysfunction is a major contributor to impaired physical performance and exercise intolerance in chronic kidney disease (CKD). We conducted a clinical trial of coenzyme Q10 (CoQ10) and nicotinamide riboside (NR) to determine their impact on exercise tolerance and metabolic profile in patients with CKD.MethodsWe conducted a randomized, placebo-controlled, double-blind, crossover trial comparing CoQ10, NR, and placebo in 25 patients with an estimated glomerular filtration rate (eGFR) of less than 60mL/min/1.73 m2. Participants received NR (1,000 mg/day), CoQ10 (1,200 mg/day), or placebo for 6 weeks each. The primary outcomes were aerobic capacity measured by peak rate of oxygen consumption (VO2 peak) and work efficiency measured using graded cycle ergometry testing. We performed semitargeted plasma metabolomics and lipidomics.ResultsParticipant mean age was 61.0 ± 11.6 years and mean eGFR was 36.9 ± 9.2 mL/min/1.73 m2. Compared with placebo, we found no differences in VO2 peak (P = 0.30, 0.17), total work (P = 0.47, 0.77), and total work efficiency (P = 0.46, 0.55) after NR or CoQ10 supplementation. NR decreased submaximal VO2 at 30 W (P = 0.03) and VO2 at 60 W (P = 0.07) compared with placebo. No changes in eGFR were observed after NR or CoQ10 treatment (P = 0.14, 0.88). CoQ10 increased free fatty acids and decreased complex medium- and long-chain triglycerides. NR supplementation significantly altered TCA cycle intermediates and glutamate that were involved in reactions that exclusively use NAD+ and NADP+ as cofactors. NR decreased a broad range of lipid groups including triglycerides and ceramides.ConclusionsSix weeks of treatment with NR or CoQ10 improved markers of systemic mitochondrial metabolism and lipid profiles but did not improve VO2 peak or total work efficiency.Trial registrationClinicalTrials.gov NCT03579693.FundingNational Institutes of Diabetes and Digestive and Kidney Diseases (grants R01 DK101509, R03 DK114502, R01 DK125794, and R01 DK101509).

Value Placed on Comfort vs Life Prolongation Among Patients Treated With Maintenance Dialysis.

Importance: Patients receiving maintenance dialysis experience intensive patterns of end-of-life care that might not be consistent with their values. Objective: To evaluate the association of patients' health care values with engagement in advance care planning and end-of-life care. Design, Setting, and Participants: Survey study of patients who received maintenance dialysis between 2015 and 2018 at dialysis centers in the greater metropolitan areas of Seattle, Washington, and Nashville, Tennessee, with longitudinal follow-up of decedents. Logistic regression models were used to estimate probabilities. Data analysis was conducted between May and October 2022. Exposures: A survey question about the value that the participant would place on longevity-focused vs comfort-focused care if they were to become seriously ill. Main Outcomes and Measures: Self-reported engagement in advance care planning and care received near the end of life through 2020 using linked kidney registry data and Medicare claims. Results: Of 933 patients (mean [SD] age, 62.6 [14.0] years; 525 male patients [56.3%]; 254 [27.2%] identified as Black) who responded to the question about values and could be linked to registry data (65.2% response rate [933 of 1431 eligible patients]), 452 (48.4%) indicated that they would value comfort-focused care, 179 (19.2%) that they would value longevity-focused care, and 302 (32.4%) that they were unsure about the intensity of care they would value. Many had not completed an advance directive (estimated probability, 47.5% [95% CI, 42.9%-52.1%] of those who would value comfort-focused care vs 28.1% [95% CI, 24.0%-32.3%] of those who would value longevity-focused care or were unsure; P < .001), had not discussed hospice (estimated probability, 28.6% [95% CI, 24.6%-32.9%] comfort focused vs 18.2% [95% CI, 14.7%-21.7%] longevity focused or unsure; P < .001), or had not discussed stopping dialysis (estimated probability, 33.3% [95% CI, 29.0%-37.7%] comfort focused vs 21.9% [95% CI, 18.2%-25.8%] longevity focused or unsure; P < .001). Most respondents wanted to receive cardiopulmonary resuscitation (estimated probability, 78.0% [95% CI, 74.2%-81.7%] comfort focused vs 93.9% [95% CI, 91.4%-96.1%] longevity focused or unsure; P < .001) and mechanical ventilation (estimated probability, 52.0% [95% CI, 47.4%-56.6%] comfort focused vs 77.9% [95% CI, 74.0%-81.7%] longevity focused or unsure; P < .001). Among decedents, the percentages of participants who received an intensive procedure during the final month of life (estimated probability, 23.5% [95% CI, 16.5%-31.0%] comfort focused vs 26.1% [95% CI, 18.0%-34.5%] longevity focused or unsure; P = .64), discontinued dialysis (estimated probability, 38.3% [95% CI, 32.0%-44.8%] comfort focused vs 30.2% [95% CI, 23.0%-37.8%] longevity focused or unsure; P = .09), and enrolled in hospice (estimated probability, 32.2% [95% CI, 25.7%-38.7%] comfort focused vs 23.3% [95% CI, 16.4%-30.5%] longevity focused or unsure; P = .07) were not statistically different. Conclusions and Relevance: This survey study found that there appeared to be a disconnect between patients' expressed values, which were largely comfort focused, and their engagement in advance care planning and end-of-life care, which reflected a focus on longevity. These findings suggest important opportunities to improve the quality of care for patients receiving dialysis.

A Patient Decision Aid About Conservative Kidney Management in Advanced Kidney Disease: A Randomized Pilot Trial.

RATIONALE & OBJECTIVE: Available decision aids for patients about treatment of advanced chronic kidney disease (CKD) often lack information on conservative kidney management (CKM). We assessed the feasibility and acceptability of a decision aid on CKM among patients with advanced CKD and their family members. STUDY DESIGN: Randomized pilot trial. SETTING & PARTICIPANTS: Patients aged≥75 years with stage 4 or 5 CKD and their family members at 4 medical centers in the greater Seattle area between August 2020 and December 2021. INTERVENTIONS: Usual care with or without a decision aid on CKM. OUTCOME: Acceptability was assessed by attrition rates between the initial study visit (T1) and the 3-month follow-up evaluation (T3). The primary outcome and measure of feasibility was the proportion of participants who discussed CKM with a health care provider between T1 and T3. RESULTS: We randomized 92 patients of whom 86 (55.8% male; age 82±6 years; 82.6% White) completed T1-42 in the usual care arm and 44 in the usual care plus decision aid arm-and 56 family members of whom 53 (18.9% male; age 71±11 years; 86.8% White) completed T1-20 in usual care arm and 33 in the usual care plus decisions aid arm. The attrition rates were 21% versus 21% (P=1.0) for patients, and 10% versus 18% (P=0.46) for family members in the usual care versus usual care plus decisions aid arms. Receipt of the decision aid significantly increased discussion of CKM with a health care provider for patients (26.4% vs 3.0%, P=0.007) and family members (26.9% vs 0, P=0.02). LIMITATIONS: Possible limited generalizability because participants were a relatively homogenous group. The decision aid focuses on CKM and may be less applicable to those with limited knowledge of kidney replacement therapies. CONCLUSIONS: A CKM decision aid was feasible and acceptable, and increased discussion of this treatment option with health care providers. This aid may serve as a useful adjunct to the currently available educational tools on treatments for advanced CKD. FUNDING: Grant from a not-for-profit entity (National Palliative Care Research Center). TRIAL REGISTRATION: Registered at ClinicalTrials.gov with study number NCT04919941.