Vohenstrauss, Germany

Role of Bilirubin Molecular Species in Hepatic Encephalopathy and Acute-on-chronic Liver Failure

Liver cirrhosis is a pathological diagnosis characterized by diffuse fibrosis, severe alteration of intrahepatic arterial and venous flow, portal hypertension, and, ultimately, liver failure. The prevalence of liver cirrhosis in the Mexican population depends on various factors, including gender, ethnic groups, and geographic regions, in addition to the nature, frequency, and time of acquisition of the main risk factors for cirrhosis, such as the hepatitis B virus, hepatitis C virus (HCV) in addition to non-alcoholic steatohepatitis, non-alcoholic fatty liver or alcoholic liver disease. Liver cirrhosis has been classified as decompensated or compensated. Decompensated liver cirrhosis occurs when there is gradual progression over months causing liver and extrahepatic organ failure. On the other hand, if it appears suddenly, in a short-term deterioration for days or several weeks after the defined triggering disease, it is known as Acute-on-chronic liver failure (ACLF). ACLF is a syndrome characterized by acute and severe liver abnormalities as a result of different types of lesions present in patients with underlying chronic liver disease or cirrhosis, but unlike decompensated cirrhosis, it has a high short-term mortality. It is important to determine the prognosis of patients with ACLF, in a short period of time, in order to act appropriately and reduce the use of temporary liver support or liver transplantation, an important variable that is included in various scores that assess liver function in different scenarios such as the Child-Pugh score and Model for End-stage Liver Disease (MELD) systems. Among liver cirrhosis complications, there is the Hepatic encephalopathy (HE) involves a wide range of neurocognitive and psychiatric abnormalities that can range from subclinical neurological deficits and disturbances in attention to coma. Diagnosis of hepatic encephalopathy can be made using the West Haven (WH) criteria, which are clinical criteria that evaluate the degree of neurological deterioration and divide hepatic encephalopathy into 5 grades (from grade 0 to grade 4), with grades 3 and 4 having a worse prognosis. In addition to these criteria, it can be diagnose based on psychometric tests such as the Portosystemic- Encephalopathy- Syndrome test (PSE) and psychophysiological tests, such as the Critical flicker frequency (CFF). Despite the existence of this evidence and the WH criteria, there is no quantitative parameter that can be used to diagnose the hepatic encephalopathy. In addition, although the quantification of ammonia levels is carried out in multiple centers as part of the protocol for diagnosing HE, there are numerous studies showing that ammonia levels cannot be used to diagnose or rule out the presence of HE.

Phase 1 Trial of SYNC-T - Immunotherapy for Patients With Advanced/Metastatic Solid Tumors

Prolonged Release Pirfenidone for Advanced Residual Liver Fibrosis (MINERVA).

Design: Observational clinical study, in an open population, of 12 months duration. Sixty patients with chronic Viral C hepatitis, who have been treated with direct-acting antivirals, with a sustained viral response and who still have advanced fibrosis (F3-F4). Aim: to know if the epigenetic factors induced by PR-PFD have a regulatory role to understand the progression variants in liver fibrosis in a group of patients with viral hepatitis C, with a history of sustained viral response and advanced residual liver fibrosis. To assess the safety and efficacy of two daily doses of pirfenidone (KitosCell® LP), in patients with compensated liver cirrhosis. Dosage: 1200 mg / day of Pirfenidone (KitosCell® LP) Variables to Analyze: Reduction of fibrosis and evaluation of epigenetic changes in the expression of various genes: PPARγ, PPARδ, PPARα, TGFβ1, Col1A1 and PDGFα. Additionally, changes in the expression levels of miR-122, miR192, miR-200a / b, miR-34a, miR-16, miR-21 and miR-181b will be evaluated, as well as changes in the transcriptome in ccfRNA. Ethical considerations: The study will be conducted in accordance with the Declaration of Helsinki and the E6 Good Clinical Practice Standards International Conference on Harmonization (ICH). Statistical Data Analysis: Descriptive statistics will be used and according to analytical statistical requirements that include parametric or non-parametric tests. The value of p <0.05 will be considered as significant.

REgistry of Pulmonary Arterial Hypertension Associated With CONNECTIVE Tissue Diseases (RECONNECTIVE)

Connective tissue diseases represents an important risk factor for pulmonary hypertension, either due to vasculopathy or chronic pulmonary thromboembolism. These chronic conditions are characterized by being disabling, progressive and fatal in a short time and are caused by multiple mechanisms that results in remodeling of the pulmonary microvasculature and right heart failure. In recent years, due to international registries, we have acquired a better understanding of high-risk subpopulations, their poor prognostic factors, and the results of specific combination therapies. In Mexico, the National Institute of Medical Sciences and Nutrition Salvador Zubirán (INCMNSZ) is a referral center for connective tissue diseases and pathologies of the pulmonary circulation. The RECONNECTIVE registry is a five years follow-up cohort that offers the possibility to obtain data regarding to the clinical characteristics and hemodynamic assesment of pulmonary circulation. The main objective is to evaluate the clinical course of the PAH in this subgroup of patients and their specific therapy for PAH.

A Study to Assess Effectiveness and Safety of Deucravacitinib Compared With Placebo in Participants With Active Systemic Lupus Erythematosus (SLE)

TrEatment Approach in the Multimodal Era Registry

Exercise and Cerebral Hemodynamics in MAFLD.

Hepatic steatosis associated with metabolic dysfunction, abbreviated as MAFLD (Metabolic Associated Fatty Liver Disease) is currently the most common liver disease and has become one of the main etiologies of chronic liver disease and hepatocellular carcinoma (HCC) in the western world, it is estimated that in a few years it will be the leading cause of liver cirrhosis1. MAFLD encompasses a broad spectrum of liver injury of varying severity ranging from simple steatosis to steatohepatitis (NASH). In principle, simple steatosis is the accumulation of lipids in more than 5% of hepatocytes, but it can progress in approximately 10-20% of subjects with simple steatosis to steatohepatitis which is defined as steatosis accompanied by cell ballooning, lobular inflammation, and fibrosis, and if this persists without treatment, up to 10-25% may progress to liver cirrhosis and/or hepatocellular carcinoma .2,3 Epidemiology MAFLD is a common disease worldwide and presents a significant burden on health systems. It is present in 6-25% of the world population. In Latin America, the prevalence ranges between 17% to 33%, while in Mexico the prevalence is 14-30% in the general population.4 MAFLD is more common in patients in their fifth decade of life, and there are groups at higher risk, such as subjects with Type 2 Diabetes Mellitus (DM2) and patients with dyslipidemia, where the frequency of the disease increases to 62% and 83% respectively.5 Due to the increasing trend of obesity, the incidence rate of NAFLD is expected to increase significantly in the coming decades; in fact, only 3-20% of patients with this pathology are not obese, so it is concluded that obesity is the most common clinical phenotype associated with MAFLD.4,5 MAFLD-associated complications Obesity has been linked not only to simple steatosis but also to advanced disease, i.e., NASH. As a consequence, in addition to increasing all-cause mortality, obesity appears to increase liver-specific mortality in patients with MAFLD, and due to the lack of approved pharmacological interventions to counteract the disease, targeting obesity is considered an option. essential for its management.6 In NAFLD, as in other metabolic disorders, there is low-grade inflammation that is mainly determined by the expansion of visceral adipose tissue, which produces proinflammatory cytokines (IL-1B, IL-6, and TNF-a) that cause both inflammation at the hepatic level through the portal route, as well as systemic inflammation with repercussions in different organs and tissues, including muscle, heart, and brain.7 These characteristics in combination with the release of pro-coagulant, pro-oxidant, and pro-fibrogenic factors represent a risk factor for endothelial dysfunction and vascular damage. Additionally, MAFLD is associated with an increase in components of the renin-angiotensin system, particularly angiotensin II, which may contribute to vascular damage by increasing oxidative stress and accelerating atherosclerosis7,8 The mechanisms described suggest that in MAFLD, vascular alterations and endothelial dysfunction, in addition to the known manifestations of cardiovascular risk, lead to incipient alterations in cerebral blood flow (microvascular) that contribute to cognitive deterioration and increase the risk of ischemic stroke. In fact, MAFLD is associated with ischemic stroke even after adjustment for other cardiovascular risk factors such as obesity, dyslipidemia, and type 2 DM.9,10 Pharmacological and non-pharmacological treatment in MAFLD There is no registered effective pharmacological treatment for MAFLD, but guidelines support the use of vitamin E in MAFLD subjects without type 2 diabetes, or pioglitazone in NASH patients, and four drugs (obeticholic acid, elafibranor, selonsertib, and cenicriviroc) have entered phase III of development.11 Due to the above, lifestyle modification to achieve weight reduction represents the first-line treatment for MAFLD and resolves hepatic steatosis and hepatic fibrosis.12 Loss of at least 7% of body weight is associated with improvement in steatosis, but greater weight loss (>10%) is needed to reverse the histopathologic features of NASH, including fibrosis. In obese subjects a reduction of 1 kg/week is suggested and in morbid obesity 1.5-2.5 kg/week; Weight loss greater than these amounts is associated with adverse effects, such as an increased inflammatory state in these patients, and increased mobilization of intrahepatic fat, which is associated with worsening hepatic steatosis.12 Although nutritional management is the cornerstone of MAFLD treatment, physical activity should always be part of comprehensive management. Exercise intervention studies in MAFLD have shown that both aerobic and resistance exercise significantly decrease intrahepatic lipid content. In addition, there is evidence that exercise has a role in improving endothelial dysfunction in patients with MAFLD, which could have implications for the prevention of cardiovascular diseases. These benefits appear to be independent of exercise intensity and dose.13 The exact mechanisms by which exercise decreases intrahepatic lipid content are not fully understood. Some studies reported that the improvement is related to weight loss, while others reported an independent benefit.14 Several pathways could be involved in this improvement, such as decreasing insulin resistance, modifying de novo free fatty acid synthesis, and improving mitochondrial function. On the other hand, high-intensity interval training has recently been recognized as an exercise modality that demonstrated an improvement in liver stiffness (-16.8%), these benefits appear to be independent of weight loss.15 It is important to understand that the optimal exercise prescription will vary widely among patients, depending on their physical ability, personal preferences, and even their environment. Background Arterial stiffness and endothelial dysfunction present in metabolic associated fatty liver disease (MAFLD) confer increased cardiovascular risk, which represents the leading cause of mortality in this group of patients. Mechanisms involved in the cardiovascular complications of MAFLD have recently been found to also affect cerebral blood flow altering cerebral hemodynamics in MAFLD subjects. These alerations can be detected through transcranial Doppler, which measures the medial cerebral artery blood flow and estimates the pulsatile index (IP) and resistance (IR), markers of cerebrovascular vasoconstriction These alterations are detected by transcranial Doppler, which measures the blood flow velocity of the middle cerebral artery and estimates the pulsatility index (PI) and resistance index(RI), which are markers of cerebrovascular vasoconstriction; and the respiratory retention index (RRI), which indicates cerebrovascular autoregulation. These abnormalities are related to vascular disease in MAFLD, which plays an essential role in ischemic stroke and cognitive impairment, which explains why MAFLD patients had lower scores on cognitive function tests. Nonetheless, there are no studies evaluating the effect of lifestyle interventions (specifically exercise) on cerebral hemodynamics in patients with MAFLD, however, it has been shown that in other pathologies that share pathophysiological similarities with NAFLD there are beneficial changes in this outcome. An example of the above is chronic heart failure and liver cirrhosis, where physical exercise attenuates the inflammatory cascade (decrease in IL6, IL8, IL12, TNFa), and decreases the activation of the renin-angiotensin system with a direct effect on endothelial function improvement. A previous report showed that a 12-week physical training program acts on this mechanism and has a beneficial effect on cerebral hemodynamics evaluated by transcranial Doppler in patients with liver cirrhosis, which leads to an improvement in neuropsychometric tests. Therefore, improvement in the previously described pathways through a 16-week physical training program in MAFLD patients could potentially improve alterations in cerebral blood flow, cognitive function, endothelial function, body composition, and the degree of liver steatosis and fibrosis. This outcome has never been assessed in MAFLD patients undergoing exercise. In addition, although there are studies that demonstrate the impact of diet and exercise, most have evaluated these interventions individually, which represents a limitation when implementing them as a multidisciplinary intervention. Therefore a 16-week physical training program will decrease the pulsatility index and resistance index (cerebral hemodynamics parameters) in patients with metabolic-associated fatty liver compared to the control group without a physical training program. AIM To evaluate the effect of a 16-week physical training program on cerebral hemodynamics in patients with fatty liver disease associated with metabolic dysfunction. Specific objectives 1. To evaluate the effect of a 16-week physical training program compared to a control group on cerebral hemodynamics assessed by transcranial Doppler in patients with MAFLD. 2. To evaluate the effect of a physical training program for 16 weeks compared to a control group on the neuropsychometric function of patients with fatty liver disease associated with metabolic dysfunction. Secondary Objectives 1. To assess the effect of a physical training program for 16 weeks compared to a control group on endothelial function assessed by pulse rate testing in patients with MAFLD. 2. To evaluate the effect of a physical training program for 16 weeks compared to a control group on liver enzymes and the degree of liver steatosis and fibrosis evaluated by transient elastography in fatty liver disease associated with metabolic dysfunction. 3. To assess the effect of a physical training program for 16 weeks compared to a control group on the body composition of patients with MAFLD. Methodology Population and place of study Outpatients with MAFLD from the gastroenterology service of the Salvador Zubirán National Institute of Medical Sciences and Nutrition. Location Department of Gastroenterology, Department of Neurology and Metabolic Diseases Research Unit (UIEM), Salvador Zubirán National Institute of Medical Sciences and Nutrition. Sample size and sampling type n= 18 per group (2)= 36 (.20) = 36 (21 per group) It is necessary to include 21 patients in each group considering a 20% loss if it is desired to obtain an 80% chance of detecting a difference in the pulsatility/resistance index of the middle cerebral artery or more between the two treatment groups. Assignment of arms At baseline, patients will be randomized into two groups, using the block sequence of three. The groups are: - Control: Nutritional treatment with caloric restriction and mental exercise. - Intervention: Nutritional treatment with caloric restriction, mental exercise, and physical training program.

Gedatolisib Plus Fulvestrant With or Without Palbociclib vs Standard-of-Care for the Treatment of Patients With Advanced or Metastatic HR+/HER2- Breast Cancer

This is a Phase 3, open-label, randomized clinical trial evaluating the efficacy and safety of gedatolisib plus fulvestrant with or without palbociclib for the treatment of patients with advanced (inoperable) or metastatic Hormone Receptor Positive, Human Epidermal Growth Factor Receptor 2 Negative (HR+/HER2-) following progression on or after CDK4/6 and aromatase inhibitor therapy. Gedatolisib is an intravenously administered pan-PI3K/mTOR inhibitor. Palbociclib is a CDK4/6 inhibitor. Fulvestrant is a selective estrogen receptor degrader (SERD). Subjects will be assessed for PIK3CA status and then randomized to treatment arms according to their confirmed PIK3CA mutation status.

A Study to Investigate the Efficacy and Safety of Efgartigimod PH20 SC in Adult Participants With Active Idiopathic Inflammatory Myopathy.