Search

Background & aimsWhile abstinence-promoting behavioral and pharmacotherapies are part of the therapeutic foundation for alcohol use disorder (AUD) and alcohol-associated liver disease (ALD), these therapies, along with alcohol screening and education, are often underutilized. Our aim was to examine provider attitudes and practices for alcohol screening, treatment and education in patients with liver disease.MethodsWe conducted a survey of primarily (89%) hepatology and gastroenterology providers within (80%) and outside the United States (20%). Surveys were sent to 921 providers with 408 complete responses (44%), of whom 343 (80%) work in a tertiary liver transplant center.ResultsWhile alcohol screening rates in liver disease patients was nearly universal, less than half of providers reported practicing with integrated addiction providers, using alcohol biomarkers and screening tools. Safe alcohol use by liver disease patients was felt to exist by 40% of providers. While 60% of providers reported referring AUD patients for behavioral therapy, 71% never prescribed AUD pharmacotherapy due to low comfort (84%). Most providers (77%) reported low addiction education and 90% desired more during GI/hepatology fellowship training. Amongst prescribers, baclofen was preferred, but with gaps in pharmacotherapy knowledge. Overall, there was low adherence to the 2019 AASLD practice guidance for ALD, although higher in hepatologists and experienced providers.ConclusionsWhile our survey of hepatology and gastroenterology providers demonstrated higher rates of alcohol screening and referrals for behavioral therapy, we found low rates of prescribing AUD pharmacotherapy due to knowledge gaps from insufficient education. Further studies are needed to assess interventions to improve provider alignment with best practices for treating patients with AUD and ALD.

Arginine synthesis deficiency due to the suppressed expression of ASS1 (argininosuccinate synthetase 1) represents one of the most frequently occurring metabolic defects of tumor cells. Arginine-deprivation therapy has gained increasing attention in recent years. One challenge of ADI-PEG20 (pegylated ADI) therapy is the development of drug resistance caused by restoration of ASS1 expression and other factors. The goal of this work is to identify novel factors conferring therapy resistance. Methods: Multiple, independently derived ADI-resistant clones including derivatives of breast (MDA-MB-231 and BT-549) and prostate (PC3, CWR22Rv1, and DU145) cancer cells were developed. RNA-seq and RT-PCR were used to identify genes upregulated in the resistant clones. Unbiased genome-wide CRISPR/Cas9 knockout screening was used to identify genes whose absence confers sensitivity to these cells. shRNA and CRISPR/Cas9 knockout as well as overexpression approaches were used to validate the functions of the resistant genes both in vitro and in xenograft models. The signal pathways were verified by western blotting and cytokine release. Results: Based on unbiased CRISPR/Cas9 knockout screening and RNA-seq analyses of independently derived ADI-resistant (ADIR) clones, aberrant activation of the TREM1/CCL2 axis in addition to ASS1 expression was consistently identified as the resistant factors. Unlike ADIR, MDA-MB-231 overexpressing ASS1 cells achieved only moderate ADI resistance both in vitro and in vivo, and overexpression of ASS1 alone does not activate the TREM1/CCL2 axis. These data suggested that upregulation of TREM1 is an independent factor in the development of strong resistance, which is accompanied by activation of the AKT/mTOR/STAT3/CCL2 pathway and contributes to cell survival and overcoming the tumor suppressive effects of ASS1 overexpression. Importantly, knockdown of TREM1 or CCL2 significantly sensitized ADIR toward ADI. Similar results were obtained in BT-549 breast cancer cell line as well as castration-resistant prostate cancer cells. The present study sheds light on the detailed mechanisms of resistance to arginine-deprivation therapy and uncovers novel targets to overcome resistance. Conclusion: We uncovered TREM1/CCL2 activation, in addition to restored ASS1 expression, as a key pathway involved in full ADI-resistance in breast and prostate cancer models.

This work demonstrates a RISC-V vector microprocessor implemented in 28 nm FDSOI with fully integrated simultaneous-switching switched-capacitor DC-DC (SC DC-DC) converters and adaptive clocking that generates four on-chip voltages between 0.45 and 1 V using only 1.0 V core and 1.8 V IO voltage inputs. The converters achieve high efficiency at the system level by switching simultaneously to avoid charge-sharing losses and by using an adaptive clock to maximize performance for the resulting voltage ripple. Details about the implementation of the DC-DC switches, DC-DC controller, and adaptive clock are provided, and the sources of conversion loss are analyzed based on measured results. This system pushes the capabilities of dynamic voltage scaling by enabling fast transitions (20 ns), simple packaging (no off-chip passives), low area overhead (16%), high conversion efficiency (80%-86%), and high energy efficiency (26.2 DP GFLOPS/W) for mobile devices.

Background: Metabolic dysfunction‐associated steatotic liver disease (MASLD) and alcohol consumption have both increased in recent years, and there is debate as to whether nonheavy alcohol use is safe in MASLD. We analyzed the association between different nonheavy alcohol use patterns and at‐risk liver fibrosis among individuals with MASLD. Methods: We conducted a cross‐sectional study of 1072 eligible National Health and Nutrition Examination Survey participants with MASLD who reported nonheavy alcohol consumption. We used vibration‐controlled transient elastography to define the primary outcome of at‐risk liver fibrosis as >8.2 kPa (stage F2‐F4). Multivariable logistic regression models were used to determine the association of different alcohol consumption patterns (average drinks/day, drinking days/week, weekly alcohol intake, type of alcoholic beverage) and at‐risk hepatic fibrosis, controlling for demographic/socioeconomic, lifestyle/dietary, and metabolic risk factors. Results: Exclusive liquor or cocktail drinkers had a 5.02‐fold odds of at‐risk fibrosis (95% CI: 1.15–21.95) compared with non‐drinkers when controlling for potential confounders. While consuming an average of 2 drinks/day, ≥3 drinking days/week, or 1–3 drinks/week appeared to have a lower association with at‐risk fibrosis when controlling for demographic/socioeconomic risk factors, the association was not present after controlling for lifestyle/dietary and metabolic risk factors. Conclusions: There is an association between exclusive liquor/cocktail consumption and at‐risk liver fibrosis in patients with MASLD who report nonheavy alcohol consumption. In a nationally representative sample of US adults with metabolic dysfunction‐associated steatotic liver disease (MASLD), exclusive liquor or cocktail consumption is associated with a 5.02‐fold increased risk of liver fibrosis among nonheavy alcohol users. Nonheavy alcohol use overall was not associated with F2 or greater liver fibrosis after adjusting for confounders. Our findings highlight the need to investigate subcategories of drinking behavior that may lead to liver fibrosis even among those without heavy drinking. [ABSTRACT FROM AUTHOR]

Increased alcohol consumption during the coronavirus disease 2019 pandemic is projected to impact alcohol-related liver disease (ALD) morbidity and mortality. Inter-hospital escalation-of-care referral requests to our tertiary-care hepatology unit were analyzed from January 2020 through December 2022. Most requests to our center were for ALD with an increase in requests from intermediate care units, suggestive of higher acuity illness. [ABSTRACT FROM AUTHOR]

Summary: Background: Clostridioides difficile infections (CDIs) are common among patients with inflammatory bowel disease (IBD) and can mimic and exacerbate IBD flares, thus warranting appropriate testing during flares. Aims: To examine recent trends in rates of CDI and associated risk factors in hospitalized IBD patients, which may better inform targeted interventions to mitigate the risk of infection. Methods: This is a retrospective analysis using the Nationwide Readmissions Database from 2010 to 2020 of hospitalized individuals with Crohn's disease (CD) or ulcerative colitis (UC). Longitudinal changes in rates of CDI were evaluated using International Classification of Diseases codes. Multivariable logistic regression evaluated the association between patient‐ and hospital‐related factors and CDI. Results: There were 2,521,935 individuals with IBD who were hospitalized at least once during the study period. Rates of CDI in IBD‐related hospitalizations increased from 2010 to 2015 (CD: 1.64%–3.32%, p < 0.001; UC: 4.15%–5.81%, p < 0.001), followed by a steady decline from 2016 to 2020 (CD: 3.15%–2.27%, p < 0.001; UC: 5.04%–4.27%, p < 0.001). In multivariable models, CDI was associated with the Charlson–Deyo comorbidity index, public insurance, and hospital size. CDI was associated with increased mortality. Conclusions: Rates of CDI among hospitalized patients with IBD had initially increased, but have declined since 2015. Increased comorbidity, large hospital size, public insurance, and urban teaching hospitals were associated with higher rates of CDI. CDI was associated with increased mortality in hospitalized patients with IBD. Continued vigilance, infection control, and treatment of CDI can help continue the trend of declining infection rates. [ABSTRACT FROM AUTHOR]