Serologic extracellular matrix remodeling markers are related to fibrosis stage and prognosis in a phase 2b trial of simtuzumab in patients with primary sclerosing cholangitis.

BACKGROUND: Novel noninvasive predictors of disease severity and prognosis in primary sclerosing cholangitis (PSC) are needed. This study evaluated the ability of extracellular matrix remodeling markers to diagnose fibrosis stage and predict PSC-related fibrosis progression and clinical events. METHODS: Liver histology and serum markers of collagen formation (propeptide of type III collagen [Pro-C3], propeptide of type IV collagen, propeptide of type V collagen), collagen degradation (type III collagen matrix metalloproteinase degradation product and type IV collagen matrix metalloproteinase degradation product), and fibrosis (enhanced liver fibrosis [ELF] score and its components [metalloproteinase-1, type III procollagen, hyaluronic acid]) were assessed in samples from baseline to week 96 in patients with PSC enrolled in a study evaluating simtuzumab (NCT01672853). Diagnostic performance for advanced fibrosis (Ishak stages 3-6) and cirrhosis (Ishak stages 5-6) was evaluated by logistic regression and AUROC. Prognostic performance for PSC-related clinical events and fibrosis progression was assessed by AUROC and Wilcoxon rank-sum test. RESULTS: Among 234 patients, 51% had advanced fibrosis and 11% had cirrhosis at baseline. Baseline Pro-C3 and ELF score and its components provided moderate diagnostic ability for discrimination of advanced fibrosis (AUROC 0.73-0.78) and cirrhosis (AUROC 0.73-0.81). Baseline Pro-C3, ELF score, and type III procollagen provided a moderate prognosis for PSC-related clinical events (AUROC 0.70-0.71). Among patients without cirrhosis at baseline, median changes in Pro-C3 and ELF score to week 96 were higher in those with than without progression to cirrhosis (both p < 0.001). CONCLUSIONS: Pro-C3 correlated with fibrosis stage, and Pro-C3 and ELF score provided discrimination of advanced fibrosis and cirrhosis and predicted PSC-related events and fibrosis progression. The results support the clinical utility of Pro-C3 and ELF score for staging and as prognostic markers in PSC.

Inadequate Dietary Education and Poor Adherence to a High Protein, Low Sodium Diet in Cirrhosis: Mixed Methods Approach.

BACKGROUND: Malnutrition in cirrhosis is associated with poor outcomes, leading to guidelines for a high protein, low sodium diet; however, there is no guidance regarding the implementation of diet education in clinical practice. METHODS: A mixed methods study enrolled 21 patients with cirrhosis and their caregivers. Semi-structured interviews on barriers and facilitators of dietary education and adherence were conducted. Demographic and clinical data were obtained, along with quantitative measures of dietary adherence, including 24-h food recall and spot urine sodium. Combined deductive and inductive coding was used to identify qualitative themes, along with a quantitative assessment of interviews. Quantitative data was reported using descriptive statistics with frequencies, mean and confidence intervals. RESULTS: Participants were mostly male (16/21) with a mean age 57.8 years (SE 2.8) and MELD-Na 9 (SE 1.2). 4 themes emerged: 1. More than 50% of participants and caregivers endorsed no or inadequate diet education 2. They reported mostly negative experiences with dietary adherence with largest impact on social life 3. Facilitators of adherence included the presence of household support and fear of complications of cirrhosis 4. Overwhelmingly desired non-generic handouts and information. Dietary adherence was poor with only one participant meeting protein and sodium requirements based on food recall. Four participants who adhered to < 2000 mg sodium had inadequate daily caloric intake. CONCLUSIONS: Dietary education is inadequate, and adherence to dietary recommendations is poor in patients with cirrhosis. Future studies should use these barriers and facilitators for intervention development.

Psychological processes and alcohol reduction in patients with chronic hepatitis C: Results from the HepART trial.

BACKGROUND: There is a lack of randomized controlled trials of behavioral interventions and process-level research related to alcohol reduction among patients with chronic liver disease (e.g., hepatitis C viral (HCV) infection). We conducted a process-level, secondary analysis of the Hepatitis C-Alcohol Reduction Treatment (HepART) trial to investigate the association between change in psychological processes posited by the Integrated Behavioral Model (IBM) and change in World Health Organization (WHO) drinking risk levels. METHODS: Patients with HCV who consume alcohol were recruited from hepatology clinics and received provider-delivered SBIRT (Screening, Brief Intervention, Referral to Treatment) or SBIRT+ 6 months of co-located alcohol counseling. Treatment arms were combined for this analysis because no between-group differences were found. At baseline and 6 months, the timeline followback method was used to determine alcohol risk levels according to the 2000 WHO risk categories (based on average grams of alcohol per day). Changes in alcohol consumption and WHO risk levels were quantified and regressed on change in individual psychological processes (e.g., readiness, self-efficacy, motives, attitudes, and strategies) from baseline to 6 months. RESULTS: At the baseline assessment, 162 participants were classified as abstinent (5%), low (47%), moderate (16%), high (19%), or very high (13%) WHO risk levels. At 6 months, 38% remained at the same risk level and 48% decreased by at least one level. In univariate analyses, changes in 7 of 12 psychological processes were associated with change in risk levels. Adjusted multivariate analyses demonstrated that change in four processes were significantly associated with change in risk levels, including SOCRATES Taking Steps, Ambivalence, and Recognition scores and alcohol reduction strategies. CONCLUSIONS: These findings demonstrate significant reductions in quantitative indices of alcohol consumption following opportunistic alcohol interventions in patients with HCV. However, results provided mixed support for associations between change in IBM psychological processes and alcohol consumption.

Parental leave, childcare policies, and workplace bias for hepatology professionals: A national survey.

BACKGROUND: The presence of workplace bias around child-rearing and inadequate parental leave may negatively impact childbearing decisions and sex equity in hepatology. This study aimed to understand the influence of parental leave and child-rearing on career advancement in hepatology. METHODS: A cross-sectional survey of physician members of the American Association for the Study of Liver Diseases (AASLD) was distributed through email listserv in January 2021. The 33-item survey included demographic questions, questions about bias, altering training, career plans, family planning, parental leave, and work accommodations. RESULTS: Among 199 US physician respondents, 65.3% were women, and 83.4% (n = 166) were attendings. Sex and racial differences were reported in several domains, including paid leave, perceptions of bias, and child-rearing. Most women (79.3%) took fewer than the recommended 12 paid weeks of parental leave for their first child (average paid leave 7.5 wk for women and 1.7 for men). A majority (75.2%) of women reported workplace discrimination, including 83.3% of Black and 62.5% of Hispanic women. Twenty percent of women were asked about their/their partners' pregnancy intentions or child-rearing plans during interviews for training. Women were more likely to alter career plans due to child-rearing (30.0% vs. 15.9%, p = 0.030). Women were also more likely to delay having children than men (69.5% vs.35.9%). CONCLUSIONS: Women reported sex and maternity bias in the workplace and during training interviews, which was more frequently experienced by Black and Hispanic women. As two-thirds of women had children during training, it is a particularly influential time to reevaluate programmatic support to address long-term gender disparities in career advancement.

Characterization of social determinants of health of a liver transplant referral population.

Disparities exist in referral and access to the liver transplant (LT) waitlist, and social determinants of health (SDOH) are increasingly recognized as important factors driving health inequities, including in LT. The SDOH of potential transplant candidates is therefore important to characterize when designing targeted interventions to promote equity in access to LT. Yet, it is uncertain how a transplant center should approach this issue, characterize SDOH, identify disparities, and use these data to inform interventions. We performed a retrospective study of referrals for first-time, single-organ LT to our center from 2016 to 2020. Addresses were geoprocessed and mapped to the corresponding county, census tract, and census block group to assess their geospatial distribution, identify potential disparities in referrals, and characterize their communities across multiple domains of SDOH to identify potential barriers to evaluation and selection. We identified variability in referral patterns and areas with disproportionately low referrals, including counties in the highest quartile of liver disease mortality (9%) and neighborhoods in the highest quintile of socioeconomic deprivation (17%) and quartile of poverty (21%). Black individuals were also under-represented compared with expected state demographics (12% vs. 18%). Among the referral population, several potential barriers to evaluation and selection for LT were identified, including poverty, educational attainment, access to healthy food, and access to technology. This approach to the characterization of a transplant center's referral population by geographic location and associated SDOH demonstrates a model for identifying disparities in a referral population and potential barriers to evaluation that can be used to inform targeted interventions for disparities in LT access.

Rates of employment after liver transplant: A nationwide cohort study.

BACKGROUND: Employment outcomes after liver transplant (LT) over the past decade have not been described. METHODS: LT recipients ages 18-65 from 2010-2018 were identified in Organ Procurement and Transplantation Network data. Employment within two years post-transplant was assessed. RESULTS: Of 35,340 LT recipients, 34.2% were employed post-LT, including 70.4% who were working pre-transplant, compared to only 18.2% not working preLT. Younger age, male sex, educational attainment, and functional status were associated with returning to employment. CONCLUSION: Returning to employment is an important goal for many LT candidates and recipients, and these findings can be used to guide their expectations.

Access to technology to support telehealth in areas without specialty care for liver disease.

BACKGROUND AND AIMS: Telehealth may be a successful strategy to increase access to specialty care for liver disease, but whether the areas with low access to care and a high burden of liver-related mortality have the necessary technology access to support a video-based telehealth strategy to expand access to care is unknown. APPROACH AND RESULTS: Access to liver disease specialty care was defined at the county level as <160.9 km (100 miles) from a liver transplant (LT) center or presence of local gastroenterology (GI). Liver-related mortality rates were compared by access to care, and access to technology was compared by degree of access to care and burden of liver-related mortality. Counties with low access to liver disease specialty care had higher rates of mortality from liver disease, and this was highest in areas both >160.9 km from an LT center and without local GI. These counties were more rural, had higher poverty, and had decreased access to devices and internet at broadband speeds. Technology access was lowest in areas with low access to care and the highest burden of liver-related mortality. CONCLUSIONS: Areas with poor access to liver disease specialty care have a greater burden of liver-related mortality, and many of their residents lack access to technology. Therefore, a telehealth strategy based solely on patient device ownership and internet access will exclude a large proportion of individuals in the areas of highest need. Further work should be done at the local and state levels to design optimal strategies to reach their populations of need.

Performance of the Pooled Cohort Equations in non-alcoholic fatty liver disease: The Multi-Ethnic Study of Atherosclerosis.

BACKGROUND AND AIMS: Non-alcoholic fatty liver disease (NAFLD) is associated with a high risk of cardiovascular disease. Whether risk scores developed in the general population accurately assess cardiovascular risk in the NAFLD population is unknown. This study aimed to evaluate the performance of the Pooled Cohort Equations (PCE) in NAFLD. METHODS: Individuals in the Multi-Ethnic Study of Atherosclerosis with baseline non-contrast cardiac computed tomography scans with sufficient data to determine the presence of hepatic steatosis were identified and assessed for the development of incident 10-year atherosclerotic cardiovascular disease. The discrimination and calibration of the PCE were evaluated, and the observed and expected events by risk category (<5%, 5-<7.5%, 7.5-<20%, ≥20%) were determined. Risk reclassification with the addition of NAFLD to the PCE was assessed. RESULTS: Of 4014 participants included, 698 (17.4%) with NAFLD were identified, including 247 (35.3%) with moderate-to-severe steatosis. Discrimination of the PCE was suboptimal in NAFLD (c-statistic 0.69), particularly moderate-to-severe steatosis (0.65), and calibration was overall poor. While risk was overestimated in non-NAFLD, it was underestimated in NAFLD in lower/intermediate risk categories, predominantly in women (5-<7.5% observed/expected ratio = 1.67). The addition of NAFLD to the PCE improved risk classification in women. CONCLUSIONS: The PCE overall performed suboptimally in cardiovascular risk assessment in NAFLD, particularly in women and individuals with moderate-to-severe steatosis in clinically relevant risk categories. Primary prevention may need to be considered at a lower risk threshold in these groups, and further work is needed to improve risk stratification in this growing high-risk population.

Evaluation of an Abnormal Liver Panel After Liver Transplantation.

Abnormal liver tests are common after liver transplantation. The differential diagnosis depends on the clinical context, particularly the time course, pattern and degree of elevation, and donor and recipient factors. The perioperative period has distinct causes compared with months and years after transplant, including ischemia-reperfusion injury, vascular thrombosis, and primary graft nonfunction. Etiologies seen beyond the perioperative period include biliary complications, rejection, infection, recurrent disease, and non-transplant-specific causes. The evaluation begins with a liver ultrasound with Doppler as well as appropriate laboratory testing and culminates in a liver biopsy if the imaging and laboratory testing is unrevealing.

Safety and Sustained Efficacy of the Farnesoid X Receptor (FXR) Agonist Cilofexor Over a 96-Week Open-label Extension in Patients With PSC.

BACKGROUND & AIMS: Primary sclerosing cholangitis (PSC) is a major unmet medical need in clinical hepatology. Cilofexor is a nonsteroidal farnesoid X receptor agonist being evaluated for the treatment of PSC. Here, we describe the safety and preliminary efficacy of cilofexor in a 96-week, open-label extension (OLE) of a phase II trial. METHODS: Noncirrhotic subjects with large-duct PSC who completed the 12-week, blinded phase of a phase II study (NCT02943460) were eligible, after a 4-week washout period, for a 96-week OLE with cilofexor 100 mg daily. Safety, liver biochemistry, and serum markers of fibrosis, cellular injury, and pharmacodynamic effects of cilofexor (fibroblast growth factor 19, C4, and bile acids [BAs]) were evaluated. RESULTS: Among 52 subjects enrolled in the phase II study, 47 (90%) continued in the OLE phase (median age, 44 years; 60% male patients, 60% with inflammatory bowel disease, and 45% on ursodeoxycholic acid [UDCA]). At OLE baseline (BL), the median serum alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) were 368 U/L (interquartile range [IQR], 277-468 U/L) and 417 U/L (IQR, 196-801 U/L), respectively. Of the 47 subjects enrolled, 15 (32%) discontinued treatment prematurely (pruritus [n = 5], other adverse events [n = 5], subject decision/investigator discretion [n = 5]). At week 96, reductions in liver biochemistry parameters occurred, including serum ALP (median, -8.3% [IQR, -25.9% to 11.0%]; P = .066), GGT (-29.8% [IQR, -42.3% to -13.9%]; P < .001), alanine aminotransaminase (ALT) (-29.8% [IQR, -43.7% to -6.6%]; P = .002), and aspartate aminotransaminase (AST) (-16.7% [IQR, -35.3% to 1.0%]; P = .010), and rebounded after 4 weeks of untreated follow-up. ALP response (≥20% reduction from BL to week 96) was similar in the presence or absence of UDCA therapy (29% vs 39%; P = .71). At week 96, cilofexor treatment was associated with a significant reduction in serum 7α-hydroxy-4-cholesten-3-one (C4) (-29.8% [IQR, -64.3% to -8.5%]; P = .001). In subjects with detectable serum BAs at BL (n = 40), BAs decreased -23.9% (IQR, -44.4% to -0.6%; P = .006) at week 48 (n = 28) and -25.7% (IQR, -35.9% to 53.7%; P = .91) at week 96 (n = 26). Serum cytokeratin 18 (CK18) M30 and M65 were reduced throughout the OLE; significant reductions were observed at week 72 (CK18 M30, -17.3% [IQR, -39.3% to 8.8%]; P = .018; CK18 M65, -43.5% [IQR, -54.9% to 15.3%]; P = .096). At week 96, a small, but statistically significant absolute increase of 0.15 units in Enhanced Liver Fibrosis score was observed compared with BL (median, 9.34 vs 9.53; P = .028). CONCLUSIONS: In this 96-week OLE of a phase II study of PSC, cilofexor was safe and improved liver biochemistry and biomarkers of cholestasis and cellular injury. CLINICALTRIALS: gov identifier: NCT02943460.

Recent updates in preemptive transjugular intrahepatic portosystemic shunt for acute variceal bleeding.

Content available: Author Interview and Audio Recording.

Patient-Predicted Outcomes Are Associated with Quality of Life in Patients with Primary Sclerosing Cholangitis.

BACKGROUND: Primary sclerosing cholangitis (PSC) is a chronic, progressive liver disease, and many patients ultimately require liver transplantation (LT). PSC also confers an increased risk of malignancies, including cholangiocarcinoma (CCA) and colorectal cancer. AIMS: This study aimed to evaluate patient-perceived outcomes and the extent to which these impact health-related quality of life (HRQoL). METHODS: Patients with PSC completed a risk perception questionnaire, the Short Form-36 (SF-36), and the Chronic Liver Disease Questionnaire. Multivariable models were used to determine factors associated with patient-perceived risks of malignancy, LT, and life expectancy, as well as their relationship with HRQoL scores. RESULTS: A total of 95 patients completed the risk perception questionnaire, and 73 returned the remaining instruments. The estimated risks varied widely. Half overestimated their one-year or lifetime CCA risk, while some predicted zero chance. Predicted LT risk was the only outcome concordant with disease severity. Pruritus was associated with higher predicted one-year risks and lower life expectancy. Lifetime CCA and LT risks were associated with the SF-36 physical component score, while perceived life expectancy was strongly associated with mental health domains, including the SF-36 mental component score. CONCLUSIONS: Predicted prognosis varies widely among patients with PSC and is influenced more by symptoms than objective disease severity. The psychological burden of shorter perceived life expectancy impacts mental HRQoL more than the risks of malignancy or LT. These findings highlight an opportunity for improved patient communication regarding these outcomes, as well as the importance of discussing them, as they may impact HRQoL.

Racial disparities in transjugular intrahepatic portosystemic shunt procedure outcomes.

OBJECTIVE: The transjugular intrahepatic portosystemic shunt (TIPS) procedure is an important intervention for management of complications of portal hypertension. The objective of this study was to identify predictors of mortality from the TIPS procedure with a focus on race and ethnicity. DESIGN: TIPS procedures from 2012 to 2014 in the National Inpatient Sample were identified. Weighting was applied to generate nationally representative results. In-hospital mortality was the primary outcome of interest. χ2 and Student's t-tests were performed for categorical and continuous variables, respectively. Predictors of mortality following TIPS were assessed by survey-weighted logistic regression. RESULTS: 17 175 (95% CI 16 254 to 18 096) TIPS cases were identified. Approximately 71% were non-Hispanic (NH) white, 6% were NH black, 16% were Hispanic and 7% were other. NH black patients undergoing TIPS had an in-hospital mortality rate of 20.1%, nearly double the in-hospital mortality of any other racial or ethnic group. NH black patients also had significantly longer median postprocedure and total lengths of stay (p=0.03 and p<0.001, respectively). The interaction of race by clinical indication was a significant predictor of in-hospital mortality (p<0.001). NH black patients had increased mortality compared with other racial/ethnic groups when presenting with bleeding oesophageal varices (OR 3.85, 95% CI 2.14 to 6.95). CONCLUSION: This cohort study presents important findings in end-stage liver disease care, with clear racial disparities in in-hospital outcomes following the TIPS procedure. Specifically, black patients had significantly higher in-hospital mortality and longer lengths of stay. Further research is needed to understand how we can better care for black patients with liver disease.

Racial and Socioeconomic Disparities in Utilization of Telehealth in Patients with Liver Disease During COVID-19.

BACKGROUND AND AIMS: The coronavirus disease 2019 (COVID-19) pandemic resulted in a rapid expansion of telehealth services in hepatology. However, known racial and socioeconomic disparities in internet access potentially translate into barriers for the use of telehealth, particularly video technology. The specific aim of this study was to determine if disparities in race or socioeconomic status exist among patients utilizing telehealth visits during COVID-19. METHODS: We performed a retrospective cohort study of all adult patients evaluated in hepatology clinics at Duke University Health System. Visit attempts from a pre-COVID baseline period (January 1, 2020 through February 29, 2020; n = 3328) were compared to COVID period (April 1, 2020 through May 30, 2020; n = 3771). RESULTS: On multinomial regression modeling, increasing age was associated with higher odds of a phone or incomplete visit (canceled, no-show, or rescheduled after May 30,2020), and non-Hispanic Black race was associated with nearly twice the odds of completing a phone visit instead of video visit, compared to non-Hispanic White patients. Compared to private insurance, Medicaid and Medicare were associated with increased odds of completing a telephone visit, and Medicaid was associated with increased odds of incomplete visits. Being single or previously married (separated, divorced, widowed) was associated with increased odds of completing a phone compared to video visit compared to being married. CONCLUSIONS: Though liver telehealth has expanded during the COVID-19 pandemic, disparities in overall use and suboptimal use (phone versus video) remain for vulnerable populations including those that are older, non-Hispanic Black, or have Medicare/Medicaid health insurance.

Cirrhosis regression is associated with improved clinical outcomes in patients with nonalcoholic steatohepatitis.

BACKGROUND AND AIMS: Surrogate endpoints that predict complications are necessary for assessment and approval of NASH therapies. We assessed associations between histologic and noninvasive tests (NITs) of fibrosis with liver-related complications in patients with NASH cirrhosis. APPROACH AND RESULTS: Patients with compensated cirrhosis due to NASH were enrolled in two placebo-controlled trials of simtuzumab and selonsertib. Liver fibrosis at baseline and week 48 (W48) was staged by NASH Clinical Research Network (CRN) and Ishak classifications and a machine learning (ML) approach, hepatic collagen and alpha-smooth muscle actin (α-SMA) expression were quantified by morphometry, liver stiffness (LS) was measured by transient elastography, and serum NITs (enhanced liver fibrosis [ELF], NAFLD fibrosis score [NFS], and Fibrosis-4 index [FIB-4]) were calculated. Cox regression determined associations between these parameters at baseline and their changes over time with adjudicated liver-related clinical events. Among 1,135 patients, 709 (62%) had Ishak stage 6 fibrosis, and median ELF and LS were 10.66 and 21.1 kPa, respectively. During a median follow-up of 16.6 months, 71 (6.3%) had a liver-related event; associated baseline factors included Ishak stage 6 fibrosis, and higher hepatic collagen, α-SMA expression, ML-based fibrosis parameters, LS, ELF, NFS, and FIB-4. Cirrhosis regression observed in 16% (176/1,135) between BL and W48 was associated with a lower risk of events versus nonregression (1.1% [2/176] vs. 7.2% [69/957]; HR, 0.16; 95% CI, 0.04, 0.65 [p = 0.0104]). Conversely, after adjustment for baseline values, increases in hepatic collagen, α-SMA, ML-based fibrosis parameters, NFS, and LS were associated with an increased risk of events. CONCLUSIONS: In patients with compensated cirrhosis due to NASH, regression of fibrosis is associated with a reduction in liver-related complications. These data support the utility of histologic fibrosis regression and NITs as clinical trial endpoints for NASH cirrhosis.

MELD-Na Accurately Predicts 6-Month Mortality in Patients With Decompensated Cirrhosis: Potential Trigger for Hospice Referral.

GOAL: The goal of this study was to determine the accuracy of Model of End-stage Liver Disease-Sodium (MELD-Na) in predicting 6-month mortality for patients listed for liver transplantation on the United Network of Organ Sharing (UNOS) waitlist. BACKGROUND: End-stage liver disease patients underutilize hospice services despite significant morbidity and mortality associated with advanced liver disease. A well-known barrier to hospice referral is clinician uncertainty in identifying patients with an expected survival of <6 months, a requirement for a referral. METHODS: Retrospective cross-sectional analysis was performed from UNOS data spanning February 27, 2002, to September 30, 2019. Inclusion criteria of patients aged 18 years and above, diagnosis of cirrhosis, liver transplant eligible, and listed in the UNOS database. Exclusion criteria included fulminant hepatic failure, prior history of liver transplantation, diagnosis of hepatocellular carcinoma, receipt of liver transplant in <180 days, or removal from waiting list <180 days for a reason other than death. MEASUREMENT: Mortality by 180 days. RESULTS: Of the 93,157 patients that met inclusion criteria, MELD-Na was calculated for all patients with sodium, total bilirubin, international normalized ratio, and creatinine available (N=79,611). The c -statistic with 95% confidence interval for MELD-Na for the predicted 6-month mortality was 0.83 (0.827-0.835). Mean MELD-Na of 28.2 was associated with ≤50% 6-month survival. CONCLUSION: MELD-Na is an objective, quick measure that can aid providers in identifying patients with increased 6-month mortality in time-constrained settings, and a score of 28 can trigger the discussion for hospice as a means of improving value-based health care.

Autologous platelet-rich plasma effects on Staphylococcus aureus-induced chondrocyte death in an in vitro bovine septic arthritis model.

OBJECTIVE: To investigate the chondroprotective effects of autologous platelet-rich plasma (PRP), ampicillin-sulbactam (AmpS), or PRP combined with AmpS (PRP+AmpS) in an in vitro chondrocyte explant model of bovine Staphylococcus aureus-induced septic arthritis. SAMPLE: Autologous PRP and cartilage explants obtained from 6 healthy, adult, nonlactating Jersey-crossbred cows. PROCEDURES: Autologous PRP was prepared prior to euthanasia using an optimized double centrifugation protocol. Cartilage explants collected from grossly normal stifle joints were incubated in synovial fluid (SF) alone, S aureus-inoculated SF (SA), or SA supplemented with PRP (25% culture medium volume), AmpS (2 mg/mL), or both PRP (25% culture medium volume) and AmpS (2 mg/mL; PRP+AmpS) for 24 hours. The metabolic activity, percentage of dead cells, and glycosaminoglycan content of cartilage explants were measured with a resazurin-based assay, live-dead cell staining, and dimethylmethylene blue assay, respectively. Treatment effects were assessed relative to the findings for cartilage explants incubated in SF alone. RESULTS: Application of PRP, AmpS, and PRP+AmpS treatments significantly reduced S aureus-induced chondrocyte death (ie, increased metabolic activity and cell viability staining) in cartilage explants, compared with untreated controls. There were no significant differences in chondrocyte death among explants treated with PRP, AmpS, or PRP+AmpS. CLINICAL RELEVANCE: In this in vitro explant model of S aureus-induced septic arthritis, PRP, AmpS, and PRP+AmpS treatments mitigated chondrocyte death. Additional work to confirm the efficacy of PRP with bacteria commonly associated with clinical septic arthritis in cattle as well as in vivo evaluation is warranted.

A retrospective longitudinal study and comprehensive review of adult patients with glycogen storage disease type III.

INTRODUCTION: A deficiency of glycogen debrancher enzyme in patients with glycogen storage disease type III (GSD III) manifests with hepatic, cardiac, and muscle involvement in the most common subtype (type a), or with only hepatic involvement in patients with GSD IIIb. OBJECTIVE AND METHODS: To describe longitudinal biochemical, radiological, muscle strength and ambulation, liver histopathological findings, and clinical outcomes in adults (≥18 years) with glycogen storage disease type III, by a retrospective review of medical records. RESULTS: Twenty-one adults with GSD IIIa (14 F & 7 M) and four with GSD IIIb (1 F & 3 M) were included in this natural history study. At the most recent visit, the median (range) age and follow-up time were 36 (19-68) and 16 years (0-41), respectively. For the entire cohort: 40% had documented hypoglycemic episodes in adulthood; hepatomegaly and cirrhosis were the most common radiological findings; and 28% developed decompensated liver disease and portal hypertension, the latter being more prevalent in older patients. In the GSD IIIa group, muscle weakness was a major feature, noted in 89% of the GSD IIIa cohort, a third of whom depended on a wheelchair or an assistive walking device. Older individuals tended to show more severe muscle weakness and mobility limitations, compared with younger adults. Asymptomatic left ventricular hypertrophy (LVH) was the most common cardiac manifestation, present in 43%. Symptomatic cardiomyopathy and reduced ejection fraction was evident in 10%. Finally, a urinary biomarker of glycogen storage (Glc4) was significantly associated with AST, ALT and CK. CONCLUSION: GSD III is a multisystem disorder in which a multidisciplinary approach with regular clinical, biochemical, radiological and functional (physical therapy assessment) follow-up is required. Despite dietary modification, hepatic and myopathic disease progression is evident in adults, with muscle weakness as the major cause of morbidity. Consequently, definitive therapies that address the underlying cause of the disease to correct both liver and muscle are needed.