Socioeconomic deprivation is associated with worse patient and graft survival following adult liver transplantation.

BACKGROUND: The impact of social determinants of health (SDOH) on adult liver transplant recipient outcomes is not clear at a national level. Further understanding of the impact of SDOH on patient outcomes can inform effective equitable healthcare delivery. METHODS: Unadjusted and multivariable models were used to analyze the Scientific Registry of Transplant Recipients to evaluate the association between the Social Deprivation Index (SDI) based on liver transplant recipient's residential location and patient and graft survival. We included adult recipients between 1/1/2008-12/1/2021. RESULTS: Patient and graft survival were lower in adults living in areas with deprivation scores above the median. Five-year patient and graft survival were 78.7% and 76.5% respectively in the cohort above median SDI compared to 80.5% and 78.3% below median SDI. Compared to the recipients in low deprivation residential areas, recipients residing in highest deprivation (SDI quintile=5) cohort had 6% higher adjusted risk of mortality (Adjusted Hazard Ratio [AHR]=1.06,95%C.I. 1.01-1.13) and 6% higher risk of graft failure (AHR=1.06,95% C.I. 1.001-1.11). The increased risks for recipients residing in more vulnerable residential areas were higher (AHR=1.11,95% CI 1.03-1.20 for both death and graft loss) following the first-year post-transplantation. Importantly, overall risk for graft loss associated with SDI was not linear but instead accelerated above the median level of deprivation. DISCUSSION: In the United States, SDOH, as reflected by residential distress, significantly impact 5-year patient and graft survival. The overall effect of residential deprivation are modest, but importantly, results illustrate they are more strongly associated with longer-term follow up and accelerate at higher deprivation levels. Further research is needed to evaluate effective interventions and policies to attenuate disparities in outcomes among recipients in highly disadvantaged areas.

Seladelpar efficacy and safety at 3 months in patients with primary biliary cholangitis: ENHANCE, a phase 3, randomized, placebo-controlled study.

BACKGROUND AND AIMS: ENHANCE was a phase 3 study that evaluated efficacy and safety of seladelpar, a selective peroxisome proliferator-activated receptor-δ (PPAR) agonist, versus placebo in patients with primary biliary cholangitis with inadequate response or intolerance to ursodeoxycholic acid (UDCA). APPROACH AND RESULTS: Patients were randomized 1:1:1 to oral seladelpar 5 mg (n=89), 10 mg (n=89), placebo (n=87) daily (with UDCA, as appropriate). Primary end point was a composite biochemical response [alkaline phosphatase (ALP) < 1.67×upper limit of normal (ULN), ≥15% ALP decrease from baseline, and total bilirubin ≤ ULN] at month 12. Key secondary end points were ALP normalization at month 12 and change in pruritus numerical rating scale (NRS) at month 6 in patients with baseline score ≥4. Aminotransferases were assessed. ENHANCE was terminated early following an erroneous safety signal in a concurrent, NASH trial. While blinded, primary and secondary efficacy end points were amended to month 3. Significantly more patients receiving seladelpar met the primary end point (seladelpar 5 mg: 57.1%, 10 mg: 78.2%) versus placebo (12.5%) ( p < 0.0001). ALP normalization occurred in 5.4% ( p =0.08) and 27.3% ( p < 0.0001) of patients receiving 5 and 10 mg seladelpar, respectively, versus 0% receiving placebo. Seladelpar 10 mg significantly reduced mean pruritus NRS versus placebo [10 mg: -3.14 ( p =0.02); placebo: -1.55]. Alanine aminotransferase decreased significantly with seladelpar versus placebo [5 mg: 23.4% ( p =0.0008); 10 mg: 16.7% ( p =0.03); placebo: 4%]. There were no serious treatment-related adverse events. CONCLUSIONS: Patients with primary biliary cholangitis (PBC) with inadequate response or intolerance to UDCA who were treated with seladelpar 10 mg had significant improvements in liver biochemistry and pruritus. Seladelpar appeared safe and well tolerated.

Short-Term Cannabidiol with Δ-9-Tetrahydrocannabinol in Parkinson's Disease: A Randomized Trial.

BACKGROUND: Cannabis use is frequent in Parkinson's disease (PD), despite inadequate evidence of benefits and risks. OBJECTIVE: The aim is to study short-term efficacy and tolerability of relatively high cannabidiol (CBD)/low Δ-9-tetrahydrocannabinol (THC) to provide preliminary data for a longer trial. METHODS: Persons with PD with ≥20 on motor Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) who had negative cannabis testing took cannabis extract (National Institute of Drug Abuse) oral sesame oil solution for 2 weeks, increasing to final dose of 2.5 mg/kg/day. Primary outcome was change in motor MDS-UPDRS from baseline to final dose. RESULTS: Participants were randomized to CBD/THC (n = 31) or placebo (n = 30). Mean final dose (CBD/THC group) was 191.8 ± 48.9 mg CBD and 6.4 ± 1.6 mg THC daily. Motor MDS-UPDRS was reduced by 4.57 (95% CI, -8.11 to -1.03; P = 0.013) in CBD/THC group, and 2.77 (-4.92 to -0.61; P = 0.014) in placebo; the difference between groups was non-significant: -1.80 (-5.88 to 2.27; P = 0.379). Several assessments had a strong placebo response. Sleep, cognition, and activities of daily living showed a treatment effect, favoring placebo. Overall adverse events were mild and reported more in CBD/THC than placebo group. On 2.5 mg/kg/day CBD plasma level was 54.0 ± 33.8 ng/mL; THC 1.06 ± 0.91 ng/mL. CONCLUSIONS: The brief duration and strong placebo response limits interpretation of effects, but there was no benefit, perhaps worsened cognition and sleep, and there was many mild adverse events. Longer duration high quality trials that monitor cannabinoid concentrations are essential and would require improved availability of research cannabinoid products in the United States. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Structural violence and the uncertainty of viral undetectability for African, Caribbean and Black people living with HIV in Canada: an institutional ethnography.

Biomedical advances in healthcare and antiretroviral treatment or therapy (ART) have transformed HIV/AIDS from a death sentence to a manageable chronic disease. Studies demonstrate that people living with HIV who adhere to antiretroviral therapy can achieve viral suppression or undetectability, which is fundamental for optimizing health outcomes, decreasing HIV-related mortality and morbidity, and preventing HIV transmission. African, Caribbean, and Black (ACB) communities in Canada remain structurally disadvantaged and bear a disproportionate burden of HIV despite biomedical advancements in HIV treatment and prevention. This institutional ethnography orients to the concept of 'structural violence' to illuminate how inequities shape the daily experiences of ACB people living with HIV across the HIV care cascade. We conducted textual analysis and in-depth interviews with ACB people living with HIV (n = 20) and health professionals including healthcare providers, social workers, frontline workers, and health policy actors (n = 15). Study findings produce a cumulative understanding that biomedical HIV discourses and practices ignore structural violence embedded in Canada's social fabric, including legislation, policies and institutional practices that produce inequities and shape the social world of Black communities. Findings show that inequities in structural and social determinants of health such as food insecurity, financial and housing instability, homelessness, precarious immigration status, stigma, racial discrimination, anti-Black racism, criminalization of HIV non-disclosure, health systems barriers and privacy concerns intersect to constrain engagement and retention in HIV healthcare and ART adherence, contributing to the uncertainty of achieving and maintaining undetectability and violating their right to health. Biomedical discourses and practices, and inequities reduce Black people to a stigmatized, pathologized, and impoverished detectable viral underclass. Black people perceived as nonadherent to ART and maintain detectable viral loads are considered "bad" patients while privileged individuals who achieve undetectability are considered "good" patients. An effective response to ending HIV/AIDS requires implementing policies and institutional practices that address inequities in structural and social determinants of health among ACB people.

A Randomized, Dose-Finding, Proof-of-Concept Study of Berberine Ursodeoxycholate in Patients With Primary Sclerosing Cholangitis.

INTRODUCTION: Primary sclerosing cholangitis (PSC) is a fibroinflammatory disease of the bile ducts leading to cirrhosis and hepatic decompensation. There are no approved pharmaceutical therapies for PSC. Berberine ursodeoxycholate (HTD1801) is an ionic salt of berberine and ursodeoxycholic acid with pleiotropic mechanisms of action. METHODS: An 18-week proof-of-concept study was conducted to assess the safety and efficacy of HTD1801 in PSC. This study had three 6-week periods: (i) a placebo-controlled period, (ii) a treatment extension period, and (iii) a randomized treatment withdrawal period. The primary end point was change from baseline in alkaline phosphatase (ALP) at week 6. RESULTS: Fifty-five patients were randomized and treated; 35 (64%) had inflammatory bowel disease and 22 (40%) had previously received ursodeoxycholic acid. Patients were initially randomized to placebo (n = 16), HTD1801 500 mg BID (n = 15), or HTD1801 1000 mg BID (n = 24). At baseline, mean (range) ALP values were 414 U/L (138-1,048), 397 U/L (237-773), and 335 U/L (122-882) for the placebo, HTD1801 500 mg BID, and HTD1801 1,000 mg BID groups, respectively. At week 6, a significant decrease in ALP was observed with HTD1801 (least square mean; HTD1801 500 mg BID = -53 U/L, P = 0.016; HTD1801 1000 mg BID = -37 U/L, P = 0.019) compared with placebo (98 U/L). ALP reductions were sustained through week 18 in those who remained on therapy, whereas ALP increased in those who crossed over to placebo during period 3. HTD1801 was generally well tolerated; 4 patients experienced serious adverse events, none attributed to HTD1801. DISCUSSION: HTD1801 is associated with significant improvement in ALP and warrants further study as a treatment for PSC.

Legislatively Excluded, Medically Uninsured and Structurally Violated: The Social Organization of HIV Healthcare for African, Caribbean and Black Immigrants with Precarious Immigration Status in Toronto, Canada.

African, Caribbean and Black immigrants face persistent legislative barriers to accessing healthcare services in Canada. This Institutional Ethnography examines how structural violence and exclusionary legislative frameworks restrict the right to HIV healthcare access for many Black immigrants. We conducted semi-structured interviews with Black immigrants living with HIV (n = 20) and healthcare workers in Toronto, Canada (n = 15), and analyzed relevant policy texts. Findings revealed that exclusionary immigration and healthcare legislation shaping and regulating immigrants' right to health restricted access to public resources, including health insurance and HIV healthcare and related services, subjecting Black immigrants with precarious status to structural violence. Healthcare providers and administrative staff worked as healthcare gatekeepers. These barriers undermine public health efforts of advancing health equity and ending HIV "while leaving no one behind." We urge continued policy reforms in Canada's immigration and healthcare systems regarding HIV care access for Canada's precarious status immigrants.

Cannabinoid Use Among Liver Transplant Recipients.

The effect of cannabinoids on liver transplant outcomes is an area of active research. We aimed to investigate marijuana (MJ) and cannabidiol (CBD) use among liver transplant recipients at the University of Colorado Hospital (UCH), specifically prevalence, habits, and predictors of use. Liver transplant recipients followed at UCH with valid email addresses were sent an informed consent postcard and survey invitation. This exploratory survey was conducted using REDCap. IBM SPSS Statistics software was used for statistical analysis. Of 1227 recipients who were sent surveys, 538 people responded. On average, respondents were 59 years old, with 63.7% male and 81.7% White. Hepatitis C virus (HCV; 30.4%) and alcohol use (17.7%) were the most common etiologies of liver disease. Among respondents, 23.8% reported current MJ use. Methods of use included smoking (72.4%), ingestion (55.3%), and vaporization (31.7%). Top reasons for MJ use were recreation (56.5%), anxiety (54.8%), and pain (53.2%). Among respondents, 21.0% currently used CBD, usually in the form of creams or lotions (58.9%) and to relieve pain (84.9%) and anxiety (31.1%). In multivariable analysis, age (odds ratio [OR], 0.941; 95% confidence interval [CI], 0.923-0.959; P < 0.001), diabetes mellitus (OR, 0.357; 95% CI, 0.171-0.746; P = 0.01), HCV cirrhosis (OR, 3.949; 95% CI, 2.281-6.835; P < 0.001), alcohol-related cirrhosis (OR, 2.101; 95% CI, 1.202-3.671; P = 0.01), and current tobacco use (OR, 2.918; 95% CI, 1.065-7.990; P = 0.04) were significant predictors of MJ use. Our study shows that cannabinoid use after liver transplant is common. MJ use is associated with decreasing age, alcohol-related and HCV cirrhosis, and tobacco use. Anxiety, pain, and recreation were top reasons for its use. Transplant teams should address reasons why their patients use MJ and CBD and develop programs to mitigate anxiety and pain after transplant. Further studies are needed to examine effects of cannabinoids on liver transplant outcomes.

Long-Term Obeticholic Acid Therapy Improves Histological Endpoints in Patients With Primary Biliary Cholangitis.

BACKGROUND & AIMS: Primary biliary cholangitis (PBC) is an autoimmune disease characterized by bile duct destruction that can progress to cirrhosis. A liver biopsy substudy was conducted in the PBC obeticholic acid (OCA) International Study of Efficacy (POISE) to determine the long-term effects of OCA on liver damage and fibrosis in patients with PBC. POISE is a phase 3, double-blind, placebo-controlled, randomized trial with a 5-year open-label extension that evaluated 5 to 10 mg OCA daily in patients who were intolerant or unresponsive to ursodeoxycholic acid. METHODS: Liver biopsy specimens were collected from 17 patients at time of enrollment in the double-blind phase and after 3 years of OCA treatment. Histologic evaluations were performed by 2 pathologists in a blinded, randomized fashion to determine the effects of OCA on fibrosis and other histologic parameters. Collagen morphometry assessments were performed by automated second harmonic generation and 2-photon excitation microscopy to observe quantitative measures of fibrosis. RESULTS: From the time of enrollment until 3 years of treatment, most patients had improvements or stabilization in fibrosis (71%), bile duct loss (76%), ductopenia (82%), ductular reaction (82%), interface hepatitis (100%), and lobular hepatitis (94%). Over the 3-year period, we found significant reductions in collagen area ratio (median, -2.1; first quartile, -4.6, third quartile, -0.3; P = .013), collagen fiber density (median, -0.8; first quartile, -2.5; third quartile, 0; P = .021), collagen reticulation index (median, -0.1; first quartile, -0.3; third quartile, 0; P = .008), and fibrosis composite score (median, -1.0; first quartile, -2.5; third quartile, -0.5; P = .002). CONCLUSIONS: A subanalysis of data from the POISE study showed that long-term OCA treatment in patients with PBC is associated with improvements or stabilization of disease features, including ductular injury, fibrosis, and collagen morphometry features (ClinicalTrials.gov no: NCT01473524 and EudraCT no: 2011-004728-36).

Analyzing the impact of trade and investment agreements on pharmaceutical policy: provisions, pathways and potential impacts.

BACKGROUND: Trade and investment agreements negotiated after the World Trade Organization's Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS) have included increasingly elevated protection of intellectual property rights along with an expanding array of rules impacting many aspects of pharmaceutical policy. Despite the large body of literature on intellectual property and access to affordable medicines, the ways in which other provisions in trade agreements can affect pharmaceutical policy and, in turn, access to medicines have been little studied. There is a need for an analytical framework covering the full range of provisions, pathways, and potential impacts, on which to base future health and human rights impact assessment and research. A framework exploring the ways in which trade and investment agreements may affect pharmaceutical policy was developed, based on an analysis of four recently negotiated regional trade agreements. First a set of core pharmaceutical policy objectives based on international consensus was identified. A systematic comparative analysis of the publicly available legal texts of the four agreements was undertaken, and the potential impacts of the provisions in these agreements on the core pharmaceutical policy objectives were traced through an analysis of possible pathways. RESULTS: An analytical framework is presented, linking ten types of provisions in the four trade agreements to potential impacts on four core pharmaceutical policy objectives (access and affordability; safety, efficacy, and quality; rational use of medicines; and local production capacity and health security) via various pathways. CONCLUSIONS: The analytical framework highlights provisions in trade and investment agreements that need to be examined, pathways that should be explored, and potential impacts that should be taken into consideration with respect to pharmaceutical policy. This may serve as a useful checklist or template for health and human rights impact assessments and research on the implications of trade agreements for pharmaceuticals.

Pro: Steroids Can Be Withdrawn After Transplant in Recipients With Autoimmune Hepatitis.

Corticosteroids have been a mainstay of immunosuppression following liver transplantation. However, evolution in the field of transplant immunology has produced steroid-free options, resulting in most transplant centers weaning steroids after transplant within days to months-an evidence-based management decision. Patients with autoimmune hepatitis (AIH), however, receive corticosteroids prior to transplant. This raises the question of whether these patients should also be weaned from corticosteroids. In this review, we discuss the benefits of avoiding steroid use in this population of patients-an approach that not only avoids the adverse effects of corticosteroids but does so without risking graft failure from recurrent AIH or from acute cellular rejection.

The right to health of non-nationals and displaced persons in the sustainable development goals era: challenges for equity in universal health care.

INTRODUCTION: Under the Millennium Development Goals (MDGs), United Nations (UN) Member States reported progress on the targets toward their general citizenry. This focus repeatedly excluded marginalized ethnic and linguistic minorities, including people of refugee backgrounds and other vulnerable non-nationals that resided within a States' borders. The Sustainable Development Goals (SDGs) aim to be truly transformative by being made operational in all countries, and applied to all, nationals and non-nationals alike. Global migration and its diffuse impact has intensified due to escalating conflicts and the growing violence in war-torn Syria, as well as in many countries in Africa and in Central America. This massive migration and the thousands of refugees crossing borders in search for safety led to the creation of two-tiered, ad hoc, refugee health care systems that have added to the sidelining of non-nationals in MDG-reporting frameworks. CONCLUSION: We have identified four ways to promote the protection of vulnerable non-nationals' health and well being in States' application of the post-2015 SDG framework: In setting their own post-2015 indicators the UN Member States should explicitly identify vulnerable migrants, refugees, displaced persons and other marginalized groups in the content of such indicators. Our second recommendation is that statisticians from different agencies, including the World Health Organization's Gender, Equity and Human Rights programme should be actively involved in the formulation of SDG indicators at both the global and country level. In addition, communities, civil society and health justice advocates should also vigorously engage in country's formulation of post-2015 indicators. Finally, we advocate that the inclusion of non-nationals be anchored in the international human right to health, which in turn requires appropriate financing allocations as well as robust monitoring and evaluation processes that can hold technocratic decision-makers accountable for progress.