Complete alcohol abstinence increases the risk of NAFLD but not severity. A population analysis with transient elastography.

BACKGROUND & AIMS: As the global prevalence of non-alcoholic fatty liver disease (NAFLD) continues to rise, ubiquity of alcohol use has also prompted discussion regarding the potential interactions between the two. This study aims to examine the effects of modest alcohol consumption on the prevalence and complications of NAFLD in a multi-ethnic population. METHODS: This study analyses the 2017-2018 cycles of NHANES that examined liver fibrosis and steatosis with vibration controlled transient elastography. A coarsened exact matching was conducted to reduce confounding. Logistic regression was done with a multivariate model to assess the relationship between alcohol consumption (modest drinkers and non-drinkers) and risk of NAFLD and its complications. RESULTS: 2,067 individuals were found to have NAFLD and 284 NAFLD patients had a total history of alcohol abstinence. After coarsened exact matching, the prevalence of NAFLD was 49% (CI: 0.41 - 0.58) in non-drinkers and 33% (CI: 0.26 - 0.41) in modest drinkers. Non-drinkers had twice the odds of NAFLD compared to modest drinkers (OR: 1.99, CI: 1.22 - 3.22, p<.01) after adjustment for confounders. There were no significant differences in the odds of significant fibrosis, advance fibrosis, cirrhosis, cardiovascular disease and stroke between non-drinkers and modest drinkers. The odds of malignancy in non-drinkers were almost significantly less than modest drinkers (OR: 0.28, CI:0.08 - 1.02, p=.053). CONCLUSION: Interestingly, modest alcohol consumption is associated with decreased odds of NAFLD. Further investigations are required to examine the relationship between alcohol consumption and NAFLD and subsequently the potential impact on NAFLD management.

Metabolic Associated Fatty Liver Disease Increases the Risk of Systemic Complications and Mortality. A Meta-Analysis and Systematic Review of 12 620 736 Individuals.

OBJECTIVE: The recent introduction of the term metabolic associated fatty liver disease (MAFLD) sought to reclassify nonalcoholic fatty liver disease (NAFLD). MAFLD is thought to improve the encapsulation of metabolic dysregulation. However, recent evidence has found significant differences between MAFLD and NAFLD, and prevailing knowledge has largely arisen from studies on NAFLD. Hence, we conducted a meta-analysis and systematic review of the outcomes associated with MAFLD. METHODS: MEDLINE and Embase databases were searched for articles relating to outcomes in MAFLD. Analysis was conducted in random effects with hazard ratios (HRs) to account for longitudinal risk assessment of mortality and systemic complications. RESULTS: A total of 554 articles were identified, of which 17 articles were included. MAFLD resulted in an increase in the overall mortality (HR, 1.24; confidence interval [CI], 1.13-1.34), cancer-related mortality (HR, 1.27; CI, 1.01-1.54), and cardiovascular disease mortality (HR, 1.28, 1.03-1.53; P = .04) compared with non-MAFLD. MAFLD also increases the risk of cardiovascular events (HR, 1.49; CI, 1.34-1.64; P < .01), stroke (HR, 1.55; CI, 1.37-1.73; P < .01), and chronic kidney disease (HR, 1.53; CI, 1.38-1.68). The presence of MAFLD was also associated with an increased risk of heart failure, obstructive sleep apnea, and malignancy. CONCLUSION: MAFLD can significantly elevate the risk of systemic diseases and mortality. The care of MAFLD thus requires interdisciplinary collaboration, and future clinical trials conducted on MAFLD should aim to reduce the incidence of end-organ damage aside from improving liver histology.

Flow and Mixing Behavior in a New Bottom Blown Copper Smelting Furnace.

A mathematical model was developed to describe gas-liquid flow and mixing behavior in a new bottom blown oxygen copper smelting furnace, and the model validation was carried out through a water model experiment. The effects of different nozzle locations, nozzle numbers, and gas flow rates on the gas-liquid flow, gas total volume, and mixing efficiency were investigated. The results show that the gas-liquid two-phase flow and mixing time predicted by the present model agree well with the experimental data. When the nozzles are located near the center of the bath bottom, the gas total volume is larger, but the mixing efficiency is very low. With the increase of nozzle arrangement angle, the mixing time decreased. However, the excessive angle arrangement of nozzles exceeding 21° was found to be detrimental to the bubble residence time and mixing efficiency. With the increase in nozzle numbers from nine to 13, the gas total volume in the furnace increases, and the mixing efficiency does not change greatly. When the number of nozzles is further increased to 18, the mixing efficiency begins to decrease significantly. As the gas flow rate increases from 4.7 m3/h to 14.1 m3/h, the gas total volume in the furnace increases, and the mixing time is rapidly reduced from 314.5 s to 251.5 s. When the gas flow rate exceeds 18.8 m3/h, the gas total volume and mixing efficiency change little.

Synthesis of a reactive oxygen species responsive heterobifunctional thioketal linker.

A new heterobifunctional reactive oxygen species (ROS) responsive thioketal linker and its synthesis are described. This linker allows for developing new ROS-responsive agents with two distinct functionalities using universal bioconjugation methods. The reaction kinetics of the thioketal cleavage in the presence of ROS is also described.

Cannabinoid CB2 receptor as a new phototherapy target for the inhibition of tumor growth.

The success of targeted cancer therapy largely relies upon the selection of target and the development of efficient therapeutic agents that specifically bind to the target. In the current study, we chose a cannabinoid CB2 receptor (CB2R) as a new target and used a CB2R-targeted photosensitizer, IR700DX-mbc94, for phototherapy treatment. IR700DX-mbc94 was prepared by conjugating a photosensitizer, IR700DX, to mbc94, whose binding specificity to CB2R has been previously demonstrated. We found that phototherapy treatment using IR700DX-mbc94 greatly inhibited the growth of CB2R positive tumors but not CB2R negative tumors. In addition, phototherapy treatment with nontargeted IR700DX did not show significant therapeutic effect. Similarly, treatment with IR700DX-mbc94 without light irradiation or light irradiation without the photosensitizer showed no tumor-inhibitory effect. Taken together, IR700DX-mbc94 is a promising phototherapy agent with high target-specificity. Moreover, CB2R appears to have great potential as a phototherapeutic target for cancer treatment.

A Systematic Review of the Reliability and Validity of the Patient Activation Measure Tool.

Patient activation, broadly defined as the ability of individuals to manage their health and navigate the healthcare system effectively, is crucial for achieving positive health outcomes. The Patient Activation Measure (PAM), a popularly used tool, was developed to assess this vital component of health care. This review is the first to systematically examine the validity of the PAM, as well as study its reliability, factor structure, and validity across various populations. Following the PRISMA and COSMIN guidelines, a search was conducted in MEDLINE, EMBASE, and Cochrane Library, from inception to 1 October 2023, using combinations of keywords related to patient activation and the PAM. The inclusion criteria were original quantitative or mixed methods studies focusing on PAM-13 or its translated versions and containing data on psychometric properties. Out of 3007 abstracts retrieved, 39 studies were included in the final review. The PAM has been extensively studied across diverse populations and geographical regions, including the United States, Europe, Asia, and Australia. Most studies looked at populations with chronic conditions. Only two studies applied the PAM to community-dwelling individuals and found support for its use. Studies predominantly showed a high internal consistency (Cronbach's alpha > 0.80) for the PAM. Most studies supported a unidimensional construct of patient activation, although cultural differences influenced the factor structure in some cases. Construct validity was established through correlations with health behaviors and outcomes. Despite its strengths, there is a need for further research, particularly in exploring content validity and differential item functioning. Expanding the PAM's application to more diverse demographic groups and community-dwelling individuals could enhance our understanding of patient activation and its impact on health outcomes.

The effects of anti-TNF-α biologics on insulin resistance and insulin sensitivity in patients with rheumatoid arthritis: An update systematic review and meta-analysis.

BACKGROUND AND AIM: Increasing evidence demonstrates a link between the chronic inflammatory state in patients with rheumatoid arthritis (RA) and the development of insulin resistance. It is thought that anti-TNF-α biologic therapy may improve insulin sensitivity and ameliorate insulin resistance by the downregulation of inflammatory cytokines, however, pre-clinical and clinical studies have yielded conflicting results. A meta-analysis on this topic is necessary to summarize current evidence and generate hypotheses for future research. METHODS: Literature search was performed in four databases, namely PubMed, EMBASE, Scopus, and The Cochrane Library, from inception till April 9, 2023, querying studies reporting peripheral insulin resistance with and without anti-TNF-α use in patients with RA. Peripheral insulin resistance or sensitivity was quantified by the Homeostasis Model Assessment of Insulin Resistance (HOMA) index or the Quantitative Insulin Sensitivity Check Index (QUICKI) respectively. The difference in insulin resistance or sensitivity between the treatment and control group was calculated using standardized mean difference (SMD) for the purposes of the meta-analysis. RESULTS: Twelve articles were reviewed, with 10 longitudinal studies with a total of 297 patients included in the meta-analysis. The pooled standardized mean difference (SMD) from baseline HOMA was -0.82 (95% CI: -1.38 to -0.25) suggesting significant beneficial effects of anti-TNF-α therapy on insulin resistance. CONCLUSION: Current evidence supports the significant clinical efficacy of anti-TNF-α biologics in alleviating insulin resistance and improving insulin sensitivity in patients with active RA.

Determining the Electron Scattering from Interfacial Coulomb Scatterers in Two-Dimensional Transistors.

Two-dimensional (2D) transistors are promising for potential applications in next-generation semiconductor chips. Owing to the atomically thin thickness of 2D materials, the carrier scattering from interfacial Coulomb scatterers greatly suppresses the carrier mobility and hampers transistor performance. However, a feasible method to quantitatively determine relevant Coulomb scattering parameters from interfacial long-range scatterers is largely lacking. Here, we demonstrate a method to determine the Coulomb scattering strength and the density of Coulomb scattering centers in InSe transistors by comprehensively analyzing the low-frequency noise and transport characteristics. Moreover, the relative contributions from long-range and short-range scattering in the InSe transistors can be distinguished. This method is employed to make InSe transistors consisting of various interfaces a model system, revealing the profound effects of different scattering sources on transport characteristics and low-frequency noise. Quantitatively accessing the scattering parameters of 2D transistors provides valuable insight into engineering the interfaces of a wide spectrum of ultrathin-body transistors for high-performance electronics.

Comparative policy analysis of national rare disease funding policies in Australia, Singapore, South Korea, the United Kingdom and the United States: a scoping review.

BACKGROUND: Rare diseases pose immense challenges for healthcare systems due to their low prevalence, associated disabilities, and attendant treatment costs. Advancements in gene therapy, such as treatments for Spinal Muscular Atrophy (SMA), have introduced novel therapeutic options, but the high costs, exemplified by Zolgensma® at US$2.1 million, present significant financial barriers. This scoping review aimed to compare the funding approaches for rare disease treatments across high-performing health systems in Australia, Singapore, South Korea, the United Kingdom (UK), and the United States (US), aiming to identify best practices and areas for future research. METHODS: In accordance with the PRISMA-ScR guidelines and the methodological framework by Arksey and O'Malley and ensuing recommendations, a comprehensive search of electronic databases (Medline, EMBASE, and Cochrane) and grey literature from health department websites and leading national organizations dedicated to rare diseases in these countries was conducted. Countries selected for comparison were high-income countries with advanced economies and high-performing health systems: Australia, Singapore, South Korea, the UK, and the US. The inclusion criteria focused on studies detailing drug approval processes, reimbursement decisions and funding mechanisms, and published from 2010 to 2024. RESULTS: Based on a thorough review of 18 published papers and grey literature, various strategies are employed by countries to balance budgetary constraints and access to rare disease treatments. Australia utilizes the Life Saving Drugs Program and risk-sharing agreements. Singapore depends on the Rare Disease Fund, which matches public donations. South Korea's National Health Insurance Service covers specific orphan drugs through risk-sharing agreements. The UK relies on the National Institute for Health and Care Excellence (NICE) to evaluate treatments for cost-effectiveness, supported by the Innovative Medicines Fund. In the US, a combination of federal and state programs, private insurance and non-profit support is used. CONCLUSION: Outcome-based risk-sharing agreements present a practical solution for managing the financial strain of costly treatments. These agreements tie payment to actual treatment efficacy, thereby distributing financial risk and promoting ongoing data collection. Countries should consider adopting and expanding these agreements to balance immediate expenses with long-term benefits, ultimately ensuring equitable access to crucial treatments for patients afflicted by rare diseases.

In vivo type 2 cannabinoid receptor-targeted tumor optical imaging using a near infrared fluorescent probe.

The type 2 cannabinoid receptor (CB2R) plays a vital role in carcinogenesis and progression and is emerging as a therapeutic target for cancers. However, the exact role of CB2R in cancer progression and therapy remains unclear. This has driven the increasing efforts to study CB2R and cancers using molecular imaging tools. In addition, many types of cancers overexpress CB2R, and the expression levels of CB2R appear to be associated with tumor aggressiveness. Such upregulation of the receptor in cancer cells provides opportunities for CB2R-targeted imaging with high contrast and for therapy with low side effects. In the present study, we report the first in vivo tumor-targeted optical imaging using a novel CB2R-targeted near-infrared probe. In vitro cell fluorescent imaging and a competitive binding assay indicated specific binding of NIR760-mbc94 to CB2R in CB2-mid delayed brain tumor (DBT) cells. NIR760-mbc94 also preferentially labeled CB2-mid DBT tumors in vivo, with a 3.7-fold tumor-to-normal contrast enhancement at 72 h postinjection, whereas the fluorescence signal from the tumors of the mice treated with NIR760 free dye was nearly at the background level at the same time point. SR144528, a CB2R competitor, significantly inhibited tumor uptake of NIR760-mbc94, indicating that NIR760-mbc94 binds to CB2R specifically. In summary, NIR760-mbc94 specifically binds to CB2R in vitro and in vivo and appears to be a promising molecular tool that may have great potential for use in diagnostic imaging of CB2R-positive cancers and therapeutic monitoring as well as in elucidating the role of CB2R in cancer progression and therapy.

Quantum-interference transport through surface layers of indium-doped ZnO nanowires.

We have fabricated indium-doped ZnO (IZO) nanowires (NWs) and carried out four-probe electrical-transport measurements on two individual NWs with geometric diameters of ≈70 and ≈90 nm in a wide temperature T interval of 1-70 K. The NWs reveal overall charge conduction behavior characteristic of disordered metals. In addition to the T dependence of resistance R, we have measured the magnetoresistance (MR) in magnetic fields applied either perpendicular or parallel to the NW axis. Our R(T) and MR data in different T intervals are consistent with the theoretical predictions of the one- (1D), two- (2D) or three-dimensional (3D) weak-localization (WL) and the electron-electron interaction (EEI) effects. In particular, a few dimensionality crossovers in the two effects are observed. These crossover phenomena are consistent with the model of a 'core-shell-like structure' in individual IZO NWs, where an outer shell of thickness t (~15-17 nm) is responsible for the quantum-interference transport. In the WL effect, as the electron dephasing length Lφ gradually decreases with increasing T from the lowest measurement temperatures, a 1D-to-2D dimensionality crossover takes place around a characteristic temperature where Lφ approximately equals d, an effective NW diameter which is slightly smaller than the geometric diameter. As T further increases, a 2D-to-3D dimensionality crossover occurs around another characteristic temperature where Lφ approximately equals t (

Tuning interfacial two-component superconductivity in CoSi2/TiSi2 heterojunctions via TiSi2 diffusivity.

We report the observation of enhanced interfacial two-component superconductivity possessing a dominant triplet component in nonmagnetic CoSi2/TiSi2 superconductor/normal-metal planar heterojunctions. This is accomplished through the detection of odd-frequency spin-triplet even-parity Cooper pairs in the diffusive normal-metal component of T-shaped proximity junctions. We show that by modifying the diffusivity of the normal-metal part, the transition temperature enhancement can be tuned by a factor of up to 2.3 while the upper critical field increases by up to a factor of 20. Our data suggest that the C49 phase of TiSi2, which is stabilized in confined geometries, underlies this enhancement. These findings are addressed via a Ginzburg-Landau model and the quasi-classical theory. We also relate our findings to the enigmatic 3-K phase reported in Sr2 RuO4.

Safety and tolerability of obeticholic acid in chronic liver disease: a pooled analysis of 1878 individuals.

BACKGROUND AND AIMS: Obeticholic acid (OCA) is a farnesoid X receptor agonist used in primary biliary cholangitis (PBC) treatment. Recent studies have expanded OCA use for NASH treatment and results from phase 3 clinical trial have shown beneficial reduction of ≥1 stage of fibrosis with no NASH worsening. However, safety concerns still preside, thus we systematically examine the safety profile of OCA in chronic liver disease. MATERIALS AND METHODS: A search was conducted in Medline and Embase databases for OCA randomized controlled trials in chronic liver disease. Binary events were pooled with Paule-Mandel random effects model and proportional events were examined in a generalized linear mixed model with Clopper-Pearson intervals. RESULTS: A total of 8 studies and 1878 patients were analyzed. There was a 75% [risk ratio (RR): 1.75, 95% CI: 1.43-2.15, p < 0.01] increased pruritis risk. OCA increased constipation incidence (RR: 1.88, 95% CI: 1.45-2.43, p < 0.01), decreased diarrhea (RR: 0.62, 95% CI: 0.50-0.77, p < 0.01), and increased development of hyperlipidemia (RR: 2.69, 95% CI: 1.85-3.92, p < 0.01) relative to placebo. Sensitivity analysis in NASH-only studies found a dose-dependent effect with pruritis which increases to RR: 3.07 (95% CI: 1.74-5.41) at 25 mg. However, up to 9.98% (95% CI: 5.01%-18.89%) of NAFLD patients with placebo similarly experience pruritis events. Overall, 16.55% (95% CI: 6.47%-36.24%) of patients with NAFLD on OCA experienced pruritis. There was no significant increase in cardiovascular events. CONCLUSIONS: OCA may represent the first pharmacological treatment approved for NASH. However, pruritis, constipation, diarrhea, and hyperlipidemia were major events with evident dose-dependent effect that affect tolerability in NASH. Future long-term studies for longitudinal safety events are required.

Global prevalence of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in the overweight and obese population: a systematic review and meta-analysis.

BACKGROUND: The global burden of non-alcoholic fatty liver disease (NAFLD) parallels the increase in obesity rates across the world. Although overweight and obesity status are thought to be an effective indicator for NAFLD screening, the exact prevalence of NAFLD in this population remains unknown. We aimed to report the prevalence of NAFLD, non-alcoholic fatty liver (NAFL), and non-alcoholic steatohepatitis (NASH) in the overweight and obese population. METHODS: In this systematic review and meta-analysis, we searched Medline and Embase from database inception until March 6, 2022, using search terms including but not limited to "non-alcoholic fatty liver disease", "overweight", "obesity", and "prevalence". Cross-sectional and longitudinal observational studies published after Jan 1, 2000, written in or translated into English were eligible for inclusion; paediatric studies were excluded. Articles were included if the number of NAFLD, NAFL, or NASH events in an overweight and obese population could be extracted. Summary data were extracted from published reports. The primary outcomes were the prevalence of NAFLD, NAFL, and NASH in an overweight and obese population and the prevalence of fibrosis in individuals who were overweight or obese and who had NAFLD. A meta-analysis of proportions was done with the generalised linear mixed model. This study is registered with PROSPERO (CRD42022344526). FINDINGS: The search identified 7389 articles. 151 studies met the inclusion criteria and were included in the meta-analysis. In the pooled analysis comprising 101 028 individuals, the prevalence of NAFLD in the overweight population was 69·99% (95% CI 65·40-74·21 I2=99·10%), the prevalence of NAFL was 42·49% (32·55-53·08, I2=96·40%), and the prevalence of NASH was 33·50% (28·38-39·04, I2=95·60%). Similar prevalence estimates were reported in the obese population for NAFLD (75·27% [95% CI 70·90-79·18]; I2=98·50%), NAFL (43·05% [32·78-53·97]; I2=96·30%) and NASH (33·67% [28·45-39·31]; I2=95·60%). The prevalence of NAFLD in the overweight population was the highest in the region of the Americas (75·34% [95% CI: 67·31-81·93]; I2=99·00%). Clinically significant fibrosis (stages F2-4) was present in 20·27% (95% CI 11·32-33·62; I2= 93·00%) of overweight individuals with NAFLD and in 21·60% (11·47-36·92; I2=95·00%) of obese patients with NAFLD while 6·65% (4·35-10·01; I2=58·00%) of overweight individuals with NAFLD and 6·85% (3·85-11·90; I2=90·00%) of obese individuals with NAFLD had advanced fibrosis (stages F3-4). INTERPRETATION: This study summarises the estimated global prevalence of NAFLD, NAFL, and NASH in overweight and obese individuals; these findings are important for improving the understanding of the global NAFLD burden and supporting disease management in the at-risk overweight and obese population. FUNDING: None.

Higher risk of adverse cardiovascular outcomes in females with type 2 diabetes Mellitus: an Umbrella review of systematic reviews.

BACKGROUND: Previous studies have shown that females with type 2 diabetes mellitus (T2DM) may have excess mortality risk compared to their male counterparts. An important next step to address the high global burden of T2DM and cardiovascular disease (CVD) is an umbrella review to summarize data on sex differences in cardiovascular outcomes for patients with T2DM and assess the strength of the evidence observed. METHODS AND RESULTS: Medline and Embase were searched from inception till 7 August 2022 for systematic reviews and meta-analyses studying the effects of sex on cardiovascular outcomes in T2DM patients. Results from reviews were synthesized with a narrative synthesis, with a tabular presentation of findings and forest plots for reviews that performed a meta-analysis. 27 review articles evaluating sex differences in cardiovascular outcomes were included. Females with T2DM had a higher risk of developing coronary heart disease (CHD; RRR: 1.52, 95%CI: 1.32-1.76, P < 0.001), acute coronary syndrome (ACS; RRR: 1.38, 95%CI: 1.25-1.52, P < 0.001), heart failure (RRR: 1.09, 95%CI: 1.05-1.13, P < 0.001) than males. Females had a higher risk of all-cause mortality (RRR: 1.13, 95%CI: 1.07-1.19, P < 0.001), cardiac mortality (RRR: 1.49, 95%CI: 1.11-2.00, P = 0.009) and CHD mortality (RRR: 1.44, 95%CI: 1.20-1.73, P < 0.001) as compared to males. CONCLUSIONS: This umbrella review demonstrates that females with T2DM have a higher risk of cardiovascular outcomes than their male counterparts. Future research should address the basis of this heterogeneity and epidemiological factors for better quality of evidence, and identify actionable interventions that will narrow these sex disparities.

This umbrella review highlights the sex differences in adverse cardiovascular events in patients with type 2 diabetes mellitus (T2DM), with females at a higher risk than males. This is contributed by both biological and healthcare disparities and underscores the need for equitable care and personalized medical therapy.Females with T2DM have a higher risk of coronary heart disease, acute coronary syndrome, heart failure, and cardiac mortality compared to males.Clinicians need to be aware of the substantial heterogeneity across the current T2DM studies, and future meta-analysis and large-scale studies examining sex differences in outcomes should attempt to address the heterogeneity and epidemiological factors for a better quality of evidence.

Impact of Pretransplant Diabetes on Outcomes After Liver Transplantation: An Updated Meta-analysis With Systematic Review.

BACKGROUND: Preliver transplant diabetes mellitus (pre-LT DM) is a common comorbidity in LT recipients associated with poorer post-transplant survival. However, its relationship with other important outcomes, including cardiovascular and renal outcomes, remains unclear. This meta-analysis aims to provide an updated analysis of the impact of pre-LT DM on key post-LT outcomes. METHODS: A search was conducted in Medline and Embase databases for articles comparing the post-transplant outcomes between patients with and without pre-LT DM. Pairwise analysis using random effects with hazard ratios (HRs) was used to assess the longitudinal post-LT impacts of pre-LT DM. In the absence of HR, pooled odds ratios analysis was conducted for secondary outcomes. RESULTS: Forty-two studies involving 77,615 LT recipients were included in this analysis. The pooled prevalence of pre-LT DM amongst LT recipients was 24.79%. Pre-LT DM was associated with significantly lower overall survival (HR, 0.65; 95% confidence interval, 0.52-0.81; P<0.01) and significantly increased cardiovascular disease-related mortality (HR, 1.78; 95% confidence interval, 1.11-2.85; P=0.03). Meta-regression of other patient characteristics identified Asian ethnicity and hypertension to be significant predictors of worse overall survival, whereas African-American ethnicity was associated with significantly improved overall survival in patients with pre-LT DM. Further analysis of secondary outcomes revealed pre-LT DM to be a significant predictor of post-LT cardiovascular events and end-stage renal disease. CONCLUSIONS: The present study illustrates the impact of pre-LT DM on post-LT survival, and cardiovascular and renal outcomes and provides a sound basis for revision of preoperative management of pre-LT DM.

Survival Trends in Sorafenib for Advanced Hepatocellular Carcinoma: A Reconstructed Individual Patient Data Meta-Analysis of Randomized Trials.

Background: Emerging data suggest that outcomes for advanced hepatocellular carcinoma (HCC) treated with sorafenib may have improved over time. We aimed to provide robust, time-to-event estimates of survival outcomes for sorafenib in advanced HCC. Summary: In this systematic review and individual patient data meta-analysis of randomized-controlled trials (RCTs), we searched MEDLINE and Embase from inception till September 2022 for RCTs that provided data for overall survival (OS) and progression-free survival (PFS) for sorafenib monotherapy as first-line systemic therapy for advanced HCC. We performed a pooled analysis using reconstructed individual participant data from published Kaplan-Meier curves to obtain robust estimates for OS and PFS. Of 1,599 articles identified, 29 studies (5,525 patients) met the inclusion criteria. Overall, the median OS was 10.4 (95% CI: 9.6-11.4) months. Median OS increased over time, from 9.8 (95% CI: 8.8-10.7) months in studies before 2015 to 13.4 (95% CI: 11.03-15.24) months in studies from 2015 onwards (p < 0.001). OS did not differ by trial phase, geographical region, or study design. The overall median PFS was 4.4 (95% CI: 3.9-4.8) months, but PFS did not improve over time. Sensitivity analysis of studies from 2015 and onwards to account for the introduction of direct-acting antivirals determined that hepatitis C virus was associated with reduced mortality (p < 0.001). There was minimal heterogeneity in the estimates for OS (all I2 ≤ 33). Key Messages: Survival outcomes for sorafenib in advanced HCC have improved over time. These data have important implications for clinical trial design.

Clinical Course, Immunogenicity, and Efficacy of BNT162b2 mRNA Vaccination Against SARS-CoV-2 Infection in Liver Transplant Recipients.

Background: Immunocompromised individuals have been excluded from landmark studies of messenger RNA vaccinations for severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2). In such patients, the response to vaccination may be blunted and may wane more quickly compared with immunocompetent patients. We studied the factors associated with decreased antibody response to SARS-CoV-2 vaccination and risk factors for subsequent breakthrough infections in liver transplant (LT) patients undergoing coronavirus disease 2019 vaccination with at least 2 doses of messenger RNA vaccine from April 28, 2021, to April 28, 2022. Methods: All LT recipients received at least 2 doses of the BNT162b2 (Pfizer BioNTech) vaccine 21 d apart. We measured the antibody response against the SARS-CoV-2 spike protein using the Roche Elecsys immunoassay to the receptor-binding domain of the SARS-CoV-2 spike protein, and the presence of neutralizing antibodies was measured by the surrogate virus neutralization test (cPass) before first and second doses of vaccination and also between 2 and 3 mo after the second dose of vaccination. Results: Ninety-three LT recipients who received 2 doses of BNT162b2 were included in the analysis. The mean time from LT was 110 ± 154 mo. After 2-dose vaccination, 38.7% of LT recipients (36/93) were vaccine nonresponders on the cPass assay compared with 20.4% (19/93) on the Roche S assay. On multivariable analysis, increased age and increased tacrolimus trough were found to be associated with poor neutralizing antibody response (P = 0.038 and 0.022, respectively). The use of antimetabolite therapy in conjunction with tacrolimus approached statistical significance (odds ratio 0.21; 95% confidence interval, 0.180-3.72; P = 0.062). Breakthrough infection occurred in 18 of 88 LT recipients (20.4%). Female gender was independently associated with breakthrough infections (P < 0.001). Conclusions: Among LT recipients, older age and higher tacrolimus trough levels were associated with poorer immune response to 2-dose SARS-CoV-2 vaccination. Further studies are needed to assess variables associated with breakthrough infections and, hence, who should be prioritized for booster vaccination.