A global survey on the use of the international classification of diseases codes for metabolic dysfunction-associated fatty liver disease.

BACKGROUND: With the implementation of the 11th edition of the International Classification of Diseases (ICD-11) and the publication of the metabolic dysfunction-associated fatty liver disease (MAFLD) nomenclature in 2020, it is important to establish consensus for the coding of MAFLD in ICD-11. This will inform subsequent revisions of ICD-11. METHODS: Using the Qualtrics XM and WJX platforms, questionnaires were sent online to MAFLD-ICD-11 coding collaborators, authors of papers, and relevant association members. RESULTS: A total of 890 international experts in various fields from 61 countries responded to the survey. We also achieved full coverage of provincial-level administrative regions in China. 77.1% of respondents agreed that MAFLD should be represented in ICD-11 by updating NAFLD, with no significant regional differences (77.3% in Asia and 76.6% in non-Asia, p = 0.819). Over 80% of respondents agreed or somewhat agreed with the need to assign specific codes for progressive stages of MAFLD (i.e. steatohepatitis) (92.2%), MAFLD combined with comorbidities (84.1%), or MAFLD subtypes (i.e., lean, overweight/obese, and diabetic) (86.1%). CONCLUSIONS: This global survey by a collaborative panel of clinical, coding, health management and policy experts, indicates agreement that MAFLD should be coded in ICD-11. The data serves as a foundation for corresponding adjustments in the ICD-11 revision.

Rifaximin plus lactulose versus lactulose alone for reducing the risk of HE recurrence.

BACKGROUND: The aim was to examine rifaximin plus lactulose efficacy in patients with cirrhosis at a risk of developing overt HE who were stratified by important baseline characteristics such as comorbid ascites or diabetes. METHODS: Pooled post hoc subgroup analysis of adults receiving rifaximin 550 mg twice daily plus lactulose or lactulose alone for 6 months in a phase 3 randomized, double-blind trial and a phase 4 open-label trial was conducted. RESULTS AND CONCLUSION: Rifaximin plus lactulose was more efficacious than lactulose alone for reducing the risk of overt HE recurrence and HE-related hospitalization in adults grouped by select baseline disease characteristics.

A novel method for the establishment of autologous skin cell suspensions: characterisation of cellular sub-populations, epidermal stem cell content and wound response-enhancing biological properties.

Introduction: Autologous cell suspension (ACS)-based therapy represents a highly promising approach for burns and chronic wounds. However, existing technologies have not achieved the desired clinical success due to several limitations. To overcome practical and cost-associated obstacles of existing ACS methods, we have established a novel methodology for rapid, enzymatic disaggregation of human skin cells and their isolation using a procedure that requires no specialist laboratory instrumentation and is performed at room temperature. Methods: Cells were isolated using enzymatic disaggregation of split-thickness human skin followed by several filtration steps for isolation of cell populations, and cell viability was determined. Individual population recovery was confirmed in appropriate culture medium types, and the presence of epidermal stem cells (EpSCs) within keratinocyte sub-populations was defined by flow cytometry via detection of CD49 and CD71. Positive mediators of wound healing secreted by ACS-derived cultures established on a collagen-based wound-bed mimic were detected by proteome arrays and quantified by ELISA, and the role of such mediators was determined by cell proliferation assays. The effect of ACS-derived conditioned-medium on myofibroblasts was investigated using an in-vitro model of myofibroblast differentiation via detection of α-SMA using immunoblotting and immunofluorescence microscopy. Results: Our methodology permitted efficient recovery of keratinocytes, fibroblasts and melanocytes, which remained viable upon long-term culture. ACS-derivatives comprised sub-populations with the CD49-high/CD71-low expression profile known to demarcate EpSCs. Via secretion of mitogenic factors and wound healing-enhancing mediators, the ACS secretome accelerated keratinocyte proliferation and markedly curtailed cytodifferentiation of myofibroblasts, the latter being key mediators of fibrosis and scarring. Discussion: The systematic characterisation of the cell types within our ACS isolates provided evidence for their superior cell viability and the presence of EpSCs that are critical drivers of wound healing. We defined the biological properties of ACS-derived keratinocytes, which include ability to secrete positive mediators of wound healing as well as suppression of myofibroblast cytodifferentiation. Thus, our study provides several lines of evidence that the established ACS isolates comprise highly-viable cell populations which can physically support wound healing and possess biological properties that have the potential to enhance not only the speed but also the quality of wound healing.

Pharmacologic Management of Hepatic Encephalopathy.

Hepatic encephalopathy is a common cause of morbidity and mortality among patients with decompensated liver cirrhosis. In this article, we review the history, mechanism, and evidence for first-line pharmacologic therapies for hepatic encephalopathy including nonabsorbable disaccharides, antibiotics, and electrolyte management. We also review newer, second-line therapies including polyethylene glycol, albumin, branched-chain amino acids, probiotics and fecal microbiota transplant, zinc, and l-ornithine-l-aspartate.

Hepatocellular Carcinoma Incidence and Mortality in the USA by Sex, Age, and Race: A Nationwide Analysis of Two Decades.

Background and Aims: While the incidence rates of hepatocellular carcinoma (HCC) are increasing, there are limited comprehensive data on demographic-specific incidence and mortality trends in the USA. We aimed to evaluate recent trends in HCC incidence and mortality among different demographic groups in the USA. Methods: Age-adjusted HCC incidence rates were calculated from the Centers for Disease Control's United States Cancer Statistics database, which combines incidence data on newly diagnosed cancer cases and covers approximately 98% of the population in the USA. Additionally, age-adjusted HCC mortality rates were obtained from the Centers for Disease Control's National Center for Health Statistics database, which offers comprehensive coverage spanning nearly 100% of deaths attributed to HCC in the USA. Rates were stratified by sex, age (older [≥55 years] and younger [<55 years] adults), race and ethnicity (Non-Hispanic White, Non-Hispanic Black, Hispanic, Non-Hispanic Asian/Pacific Islander, and Non-Hispanic American Indian/Alaska Native), and tumor stage at diagnosis (early and late). Annual and average annual percentage change (AAPC) were calculated using joinpoint regression. A sex-specific pairwise comparison was conducted. Results: Between 2001 and 2020, there were 467,346 patients diagnosed with HCC (26.0% women), with increasing incidence in both sexes without significant difference (p=0.65). In younger adults (78,169 patients), the incidence decreased in men but not in women (AAPC difference=-2.39, p=0.002). This was seen in various racial and ethnic groups, mostly driven by early-stage tumors (AAPC difference=-2.65, p=0.02). There were 329,973 deaths attributed to HCC between 2000 and 2020 (28.4% women). In younger adults (43,093 deaths), mortality decreased in men at a greater rate than in women (AAPC difference=1.61, p=0.007). This was seen in various racial and ethnic groups, most notably in non-Hispanic American Indian/Alaska Natives (AAPC difference=-4.51, p=0.01). Conclusions: Nationwide USA data, covering nearly all HCC cases, show an increasing incidence and mortality over the last two decades. In younger adults, there was a decreasing incidence in men but not in women, due to early-stage tumors. Mortality improved in younger men at a greater rate than in women, especially in Non-Hispanic American Indian/Alaska Natives. Future studies are warranted to identify the risk factors associated with the occurrence and outcomes of HCC in demographic-specific populations, especially younger women.

Serum Ammonia Levels Do Not Correlate With Overt Hepatic Encephalopathy Severity in Hospitalized Patients With Cirrhosis.

Although ammonia is involved in the pathophysiology of hepatic encephalopathy (HE), the use of ammonia levels in clinical practice is problematic.1-3 For example, in a study of 551 patients with overt HE (OHE) receiving lactulose who had ammonia levels tested, only 60% had an increased ammonia level (defined as >72 µmol/L).2 Overall, there was no correlation observed between lactulose dose and whether ammonia levels were obtained (ie, presence/absence of increased ammonia level did not guide therapy), or between time to OHE resolution and ammonia levels.2 Additionally, there is substantial interlaboratory variability in sample handling and processing, which may affect ammonia measurements.4.

Chronic Liver Disease and Cirrhosis Mortality Rates Are Disproportionately Increasing in Younger Women in the United States Between 2000-2020.

BACKGROUND & AIMS: Previous studies show that mortality from chronic liver disease (CLD) and cirrhosis is increasing in the United States. However, there are limited data on sex-specific mortality trends by age, race, and geographical location. The aim of this study was to conduct a comprehensive time-trend analysis of liver disease-related mortality rates in the National Center of Health Statistics (NCHS) database. METHODS: CLD and cirrhosis mortality rates between 20002020 (age-adjusted to the 2000 standard U.S. population) were collected from the NCHS database and categorized by sex and age into older adults (≥55 years) and younger adults (<55 years), race (Non-Hispanic-White, Non-Hispanic-Black, Hispanic, Non-Hispanic-American-Indian/Alaska-Native, and Non-Hispanic-Asian/Pacific-Islander), U.S. state, and cirrhosis etiology. Time trends, annual percentage change (APC), and average APC (AAPC) were estimated using Joinpoint Regression using Monte Carlo permutation analysis. We used tests for parallelism and identicalness for sex-specific pairwise comparisons of mortality trends (two-sided P value cutoff = .05). RESULTS: Between 20002020, there were 716,651 deaths attributed to CLD and cirrhosis in the U.S. (35.68% women). In the overall population and in older adults, CLD and cirrhosis-related mortality rates were increasing similarly in men and women. However, in younger adults (246,149 deaths, 32.72% women), the rate of increase was greater in women compared with men (AAPC = 3.04 vs 1.08, AAPC-difference = 1.96; P < .001), with non-identical non-parallel data (P values < .001). The disparity was driven by Non-Hispanic-White (AAPC = 4.51 vs 1.79, AAPC-difference = 2.71; P < .001) and Hispanic (AAPC = 1.89 vs -0.65, AAPC-difference = 2.54; P = .001) individuals. The disparity varied between U.S. states and was seen in 16 states, mostly in West Virginia (AAPC = 4.96 vs 0.88, AAPC-difference = 4.08; P < .001) and Pennsylvania (AAPC = 2.81 vs -1.02, AAPC-difference = 3.84; P < .001). Etiology-specific analysis did not show significant sex disparity in younger adults. CONCLUSIONS: Mortality rates due to CLD and cirrhosis in the U.S. are increasing disproportionately in younger women. This finding was driven by higher rates in Non-Hispanic White and Hispanic individuals, with variation between U.S. states. Future studies are warranted to identify the reasons for these trends with the ultimate goal of improving outcomes.

Trends of Hepatocellular Carcinoma (HCC) Inpatients Mortality and Financial Burden From 2011 to 2017: A Nationwide Analysis.

INTRODUCTION: Liver cancer, including Hepatocellular carcinoma (HCC) is the seventh most common tumor worldwide. Previously, the financial burden of HCC in the United States between 2002 and 2011 was noted to be continuously increasing. This study aims to evaluate temporal trends of hospitalizations due to HCC. METHOD: This is a retrospective analysis utilizing the National Inpatient Sample (NIS) database. All subjects admitted between 2011 and 2017 with a diagnosis of HCC were identified. The primary trend characteristics were in-hospital mortality, hospital charges, and length of stay. RESULTS: An increase in hospitalization from 67,779 (0.18%) admissions in 2011 to 84,580 (0.23%) admissions in 2017( P <0.05) was noted. Most patients were 45 to 64 years old (median 50%), predominantly men (median 68%) ( P <0.05). The primary health care payer was Medicare (Median 49%) and Medicaid (Median 18%) ( P <0.05). The most common geographical location was the south (Median 36%) ( P <0.05). Most patients were admitted to large hospitals (Median 62%) in urban areas ( P <0.05). The median inpatient mortality was estimated to be 9% in 2017 ( P <0.05), which has decreased from 10%( P <0.05) in 2011. The total charges per admission have increased steadily from $58,406 in 2011 to $78,791 in 2017 ( P <0.05). The median length of stay has increased from 5.79 (SD 6.93) in 2011 to 6.07 (SD 8.3) in 2017( P <0.05). The most common mortality risk factor was sepsis, Acute renal failure, and GI hemorrhage. CONCLUSION: HCC-related admissions continue to be on the rise. HCC mortality has decreased across the years with earlier diagnoses and advances in therapy. However, we observed a significant increase in financial burden on health care with increasing in-hospital costs, a finding that needs to be verified in prospective trials.

Classification and Epidemiologic Aspects of Acute-on-Chronic Liver Failure.

The three most common definitions of acute-on-chronic liver failure (ACLF) are derived from data from North America, Europe, and the Asian-Pacific Region. All three definitions identify patients with underlying liver disease who are at increased risk for mortality who develop a syndrome often characterized by associated organ failures. The epidemiology of ACLF differs throughout various regions globally and is driven by the cause of the underlying chronic liver disease and the triggers of ACLF.

Identification of volatile compounds from fruits aroma and citrus essential oils and their effect on oviposition of Ceratitis capitata (Diptera: Tephritidae).

Ceratitis capitata (Wiedemann), also known as the Mediterranean fruit fly, is one of the most serious pests for several fresh fruit commodities causing extensive fruit losses worldwide. The response of C. capitata adults to fruit and nonfruit volatiles has been extensively studied. However, the linkage between fruit volatiles and the female ovipositional choice has not been fully elucidated. The present study focused on identifying the volatile organic compounds emitted by detached intact fresh fruits (oranges, lemons, bergamots, and apples) and citrus essential oils and evaluate their effect on Mediterranean fruit fly oviposition. There were more than 130 and 45 volatiles compounds detected in fruits odors and citrus essential oils, respectively. The volatile profile of fruits was dominated either from terpenes and terpenoids or from esters of butanoic, hexanoic, and octanoic acids while limonene was by far the most abundant compound in all citrus essential oils. Oviposition of C. capitata was strongly affected by volatiles emanated from both intact fruit and the citrus essential oils. Regarding the volatiles of the intact fruits, the odor of sweet orange elicited strong oviposition responses to females, while bergamot had the least stimulatory effect on oviposition. Bergamot oil also elicited the least oviposition stimulation compared to sweet orange and lemon essential oils. Our discussion elaborates on the role of fruit volatiles on host finding behavior and fruit susceptibility to C. capitata infestation and includes possible practical implication of the above findings.

Mast cells participate in smooth muscle cell reprogramming and atherosclerotic plaque calcification.

BACKGROUND: Calcification, a key feature of advanced human atherosclerosis, is positively associated with vascular disease burden and adverse events. We showed that macrocalcification can be a stabilizing factor for carotid plaque molecular biology, due to inverse association with immune processes. Mast cells (MCs) are important contributors to plaque instability, but their relationship with macrocalcification is unexplored. With a hypothesis that MC activation negatively associates with carotid plaque macrocalcification, we aimed to investigate the link between MCs and carotid plaque vulnerability, and study MC role in plaque calcification via smooth muscle cells (SMCs). METHODS: Pre-operative computed tomography angiographies of patients (n = 40) undergoing surgery for carotid stenosis were used to characterize plaque morphology. Plaque microarrays (n = 40 and n = 126) were used for bioinformatic deconvolution of immune cell populations. Tissue microarrays (n = 103) were used to histologically validate the contribution of activated and resting MCs in plaques. RESULTS: Activated MCs and their typical markers were negatively correlated with macrocalcification. The ratio of activated vs. resting MCs was increased in low-calcified plaques from symptomatic patients. There was no modulating effect of medication on MC ratios. In vitro experiments showed that SMC calcification attenuated MC activation, while both active and resting MCs stimulated SMC calcification and induced dedifferentiation towards a pro-inflammatory-, osteochondrocyte-like phenotype, without modulating their migro-proliferative function. CONCLUSIONS: Integrative analyses from human plaques showed that MC activation is inversely associated with macrocalcification and positively with parameters of plaque vulnerability. Mechanistically, MCs induce SMC osteogenic reprograming, while matrix calcification in turn attenuates MC activation, offering new therapeutic avenues for exploration.

Emerging Pharmacotherapies in Alcohol-Associated Hepatitis.

The incidence of alcoholic-associated hepatitis (AH) is increasing. The treatment options for severe AH (sAH) are scarce and limited to corticosteroid therapy which showed limited mortality benefit in short-term use only. Therefore, there is a dire need for developing safe and effective therapies for patients with sAH and to improve their high mortality rates.This review article focuses on the current novel therapeutics targeting various mechanisms in the pathogenesis of alcohol-related hepatitis. Anti-inflammatory agents such as IL-1 inhibitor, Pan-caspase inhibitor, Apoptosis signal-regulating kinase-1, and CCL2 inhibitors are under investigation. Other group of agents include gut-liver axis modulators, hepatic regeneration, antioxidants, and Epigenic modulators. We describe the ongoing clinical trials of some of the new agents for alcohol-related hepatitis. Conclusion: A combination of therapies was investigated, possibly providing a synergistic effect of drugs with different mechanisms. Multiple clinical trials of novel therapies in AH remain ongoing. Their result could potentially make a difference in the clinical course of the disease. DUR-928 and granulocyte colony-stimulating factor had promising results and further trials are ongoing to evaluate their efficacy in the large patient sample.

Early treatment with terlipressin in patients with hepatorenal syndrome yields improved clinical outcomes in North American studies.

Hepatorenal syndrome type 1 (HRS-1) is a serious complication of advanced cirrhosis and a potentially reversible form of acute kidney injury that is associated with rapidly deteriorating kidney function. Liver transplantation remains the only curative treatment for decompensated cirrhosis. However, terlipressin, a vasopressin analog, successfully reverses HRS-1, and may improve patient survival while awaiting liver transplantation. Patients with higher baseline serum creatinine have a reduced response to treatment with terlipressin. These post hoc analyses examined pooled data from 352 patients with HRS-1 treated with terlipressin in 3 North American-centric, Phase III, placebo-controlled clinical studies (i.e. OT-0401, REVERSE, and CONFIRM)-across 3 serum creatinine subgroups (i.e. <3, ≥3-<5, and ≥5 mg/dL)-to further delineate their correlation with HRS reversal, renal replacement therapy-free survival, and overall survival. Serum creatinine was significantly associated with HRS reversal in univariate and multivariate logistic regression analyses (P<0.001). The incidence of HRS reversal inversely correlated with serum creatinine subgroup (<3 mg/dL, 49.2%; ≥3-<5 mg/dL, 28.0%; ≥5 mg/dL, 9.1%). At Day 30 follow-up, renal replacement therapy-free survival was significantly higher for patients with HRS-1 in the lower serum creatinine subgroups than in the higher subgroup (<5 vs. >5 mg/dL; p=0.01). Terlipressin-treated patients with HRS-1, with a lower baseline serum creatinine level, had a higher overall survival (p<0.001) and higher transplant-free survival at Day 90 (p=0.04). Patients with HRS-1 and lower serum creatinine levels who were treated with terlipressin had higher HRS reversal and survival outcomes, highlighting the significant need to identify and treat patients with HRS-1 early when they often have lower serum creatinine levels, and likely a greater response to terlipressin.

Dosing of Rifaximin Soluble Solid Dispersion Tablets in Adults With Cirrhosis: 2 Randomized, Placebo-controlled Trials.

BACKGROUND & AIMS: Cirrhosis-related complications are a major burden. Rifaximin soluble solid dispersion (SSD) tablets (immediate-release [IR]; sustained extended-release [SER]) were designed to increase rifaximin water solubility. These analyses evaluate dosing for prevention of cirrhosis complication-related hospitalizations/mortality and overt hepatic encephalopathy (OHE) treatment. METHODS: Two phase II, randomized, double-blind, placebo-controlled trials were conducted. Trial 1: outpatients with early decompensated cirrhosis randomized to placebo or rifaximin SSD once-nightly: IR 40 or 80 mg, SER 40 or 80 mg, or IR 80 mg plus SER 80 mg, for 24 weeks. Trial 2: inpatients with OHE randomized to lactulose plus placebo or rifaximin SSD: IR 40 mg once or twice daily or SER 80 mg once or twice daily for ≤14 days. Primary efficacy endpoint: time to cirrhosis complication-related hospitalization/all-cause mortality (Trial 1) or time to OHE resolution (Trial 2). RESULTS: In Trial 1 (n = 516), no significant difference in time to cirrhosis complication-related hospitalization/all-cause mortality vs placebo. In a post hoc analysis, time to all-cause hospitalization/all-cause mortality was improved with IR 40 mg vs placebo (15.4% [12/78] vs 27.7% [26/94]; P = .03). A Trial 2 prespecified interim analysis (n = 71) showed lactulose plus rifaximin SSD IR 40 mg bid significantly reduced median time to OHE resolution (21.1 hours) vs lactulose plus placebo (62.7 hours; P = .02). Trial 2 was subsequently terminated. CONCLUSION: Rifaximin SSD IR 40 mg may reduce hospitalizations in patients with cirrhosis and shorten duration of OHE during hospitalization-considered a negative finding, yet also hypothesis-generating. (ClinicalTrials.govNCT01904409; NCT03515044).

In silico model of atherosclerosis with individual patient calibration to enable precision medicine for cardiovascular disease.

OBJECTIVE: Guidance for preventing myocardial infarction and ischemic stroke by tailoring treatment for individual patients with atherosclerosis is an unmet need. Such development may be possible with computational modeling. Given the multifactorial biology of atherosclerosis, modeling must be based on complete biological networks that capture protein-protein interactions estimated to drive disease progression. Here, we aimed to develop a clinically relevant scale model of atherosclerosis, calibrate it with individual patient data, and use it to simulate optimized pharmacotherapy for individual patients. APPROACH AND RESULTS: The study used a uniquely constituted plaque proteomic dataset to create a comprehensive systems biology disease model for simulating individualized responses to pharmacotherapy. Plaque tissue was collected from 18 patients with 6735 proteins at two locations per patient. 113 pathways were identified and included in the systems biology model of endothelial cells, vascular smooth muscle cells, macrophages, lymphocytes, and the integrated intima, altogether spanning 4411 proteins, demonstrating a range of 39-96% plaque instability. After calibrating the systems biology models for individual patients, we simulated intensive lipid-lowering, anti-inflammatory, and anti-diabetic drugs. We also simulated a combination therapy. Drug response was evaluated as the degree of change in plaque stability, where an improvement was defined as a reduction of plaque instability. In patients with initially unstable lesions, simulated responses varied from high (20%, on combination therapy) to marginal improvement, whereas patients with initially stable plaques showed generally less improvement. CONCLUSION: In this pilot study, proteomics-based system biology modeling was shown to simulate drug response based on atherosclerotic plaque instability with a power of 90%, providing a potential strategy for improved personalized management of patients with cardiovascular disease.

Improving Outcomes in Hepatorenal Syndrome-Acute Kidney Injury With Early Diagnoses and Implementation of Approved Treatment Regimens.

Decompensated cirrhosis, defined by the overt manifestations of liver failure and portal hypertension (eg, ascites, hepatic encephalopathy, variceal bleeding), is the inflection point associated with increased morbidity and mortality in chronic liver disease. Acute kidney injury in the setting of cirrhosis (hepatorenal syndrome-acute kidney injury [HRS-AKI]) is a severe and often fatal complication. The goals of treatment of HRS-AKI are to reverse renal failure and prolong survival in these critically ill patients or perhaps to allow the transplant team to complete the pretransplant evaluation and bridge the patient to transplant. Historically, in the United States, standard-of-care treatments for HRS-AKI were chosen by default despite lack of data, off-label use, and suboptimal results. Terlipressin represents the first drug in the United States indicated for the treatment of HRS-AKI. This review provides an up-to-date overview of HRS-AKI, discusses terlipressin and how to incorporate this new treatment into patient care and streamline society guidelines on HRS diagnosis and treatment in a practical way for clinical use, and concludes with a sample order set that highlights the recommendations discussed throughout the supplement.

TRAF3/p38-JNK Signalling Crosstalk with Intracellular-TRAIL/Caspase-10-Induced Apoptosis Accelerates ROS-Driven Cancer Cell-Specific Death by CD40.

The capacity to induce tumour-cell specific apoptosis represents the most unique feature of the TNF receptor (TNFR) family member CD40. Recent studies on the signalling events triggered by its membrane-presented ligand CD40L (mCD40L) in normal and malignant epithelial cells have started to unravel an exquisite context and cell type specificity for the functional effects of CD40. Here, we demonstrate that, in comparison to other carcinomas, mCD40L triggered strikingly more rapid apoptosis in colorectal carcinoma (CRC) cells, underpinned by its ability to entrain two concurrently operating signalling axes. CD40 ligation initially activates TNFR-associated factor 3 (TRAF3) and subsequently NADPH oxidase (NOX)/Apoptosis signal-regulating kinase 1 (ASK1)-signalling and induction of reactive oxygen species (ROS) to mediate p38/JNK- and ROS-dependent cell death. At that point, p38/JNK signalling directly activates the mitochondrial pathway, and triggers rapid induction of intracellular TNF-related apoptosis-inducing ligand (TRAIL) that signals from internal compartments to initiate extrinsic caspase-10-asscociated apoptosis, leading to truncated Bid (tBid)-activated mitochondrial signalling. p38 and JNK are essential both for direct mitochondrial apoptosis induction and the TRAIL/caspase-10/tBid pathway, but their involvement follows functional hierarchy and temporally controlled interplay, as p38 function is required for JNK phosphorylation. By engaging both intrinsic and extrinsic pathways to activate apoptosis via two signals simultaneously, CD40 can accelerate CRC cell death. Our findings further unravel the multi-faceted properties of the CD40/mCD40L dyad, highlighted by the novel TNFR crosstalk that accelerates tumour cell-specific death, and may have implications for the use of CD40 as a therapeutic target.

Hypoglycemia Is Associated With Worse Outcomes in Patients With Cholangitis Despite Undergoing Endoscopic Retrograde Cholangiopancreatography.

Background Hypoglycemia has been associated with poorer outcomes in hospitalized patients undergoing surgical interventions. In cholangitis, endoscopic retrograde cholangiopancreatography (ERCP) is often a critical adjunct to surgery, capable of diagnosing and treating various biliary and pancreatic pathologies. While technically less invasive than surgery, the effect of hypoglycemia on clinical outcomes of patients with cholangitis undergoing ERCP has not been elucidated. Methodology Data were extracted from the National Inpatient Sample (NIS) database from 2016 to 2019. Using the International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) codes, patients diagnosed with cholangitis and underwent ERCP were identified. Baseline demographic data, comorbidities, in-hospital mortality, hospital charges, and hospital length of stay (LOS) were extracted and compared based on the presence or absence of hypoglycemia. Statistical analysis was done using t-test and chi-square analyses. A multivariate analysis for the mortality odds ratio (OR) was calculated to adjust for possible confounders. Results A total of 256,540 patients with cholangitis who underwent ERCP were identified, and 2,810 of them had hypoglycemia during their hospitalization. The mean age of the hypoglycemia group was 64.41 years. Most patients were females (54%) and whites (57%). More patients in the hypoglycemia group had a history of alcoholism and congestive heart failure (CHF). Hypoglycemia was associated with higher odds of in-hospital mortality (OR = 6.71, confidence interval (CI) = 5.49-8.2; p < 0.0001). In addition to hypoglycemia, age >65 years, non-white race, and CHF were independently associated with higher mortality. Moreover, patients with hypoglycemia had higher total hospital charges ($87,147 vs. $133,400; p < 0.0001) and a significant increase in the LOS (9.7 vs. 6.7 days; p < 0.0001). Conclusions Previous studies in the surgical literature have linked hypoglycemia to increased incidence of atrial fibrillation, usage of mechanical ventilation, and application of circulatory support. Hypoglycemia may also affect the metabolism of the heart, leading to myocardial ischemia and malignant arrhythmias. However, it is unclear if hypoglycemia represents a proxy for the severity of patient illness as septic shock and renal insufficiency are common etiologies that may strongly impact mortality. Therefore, careful glycemic control during hospitalization should be practiced as hypoglycemia serves as a poor prognostic indicator that should not be overlooked.