Development and Validation of a Scoring System to Predict Response to Obeticholic Acid in Primary Biliary Cholangitis.

BACKGROUND & AIMS: Obeticholic acid (OCA) is the only licensed second-line therapy for primary biliary cholangitis (PBC). With novel therapeutics in advanced development, clinical tools are needed to tailor the treatment algorithm. We aimed to derive and externally validate the OCA response score (ORS) for predicting the response probability of individuals with PBC to OCA. METHODS: We used data from the Italian RECAPITULATE (N = 441) and the IBER-PBC (N = 244) OCA real-world prospective cohorts to derive/validate a score including widely available variables obtained either pre-treatment (ORS) or also after 6 months of treatment (ORS+). Multivariable Cox regressions with backward selection were applied to obtain parsimonious predictive models. The predicted outcomes were biochemical response according to POISE (alkaline phosphatase [ALP]/upper limit of normal [ULN]<1.67 with a reduction of at least 15%, and normal bilirubin), or ALP/ULN<1.67, or Normal range criteria (NR: normal ALP, alanine aminotransferase [ALT], and bilirubin) up to 24 months. RESULTS: Depending on the response criteria, ORS included age, pruritus, cirrhosis, ALP/ULN, ALT/ULN, GGT/ULN, and bilirubin. ORS+ also included ALP/ULN and bilirubin after 6 months of OCA therapy. Internally validated c-statistics for ORS were 0.75, 0.78, and 0.72 for POISE, ALP/ULN<1.67, and NR response, which raised to 0.83, 0.88, and 0.81 with ORS+, respectively. The respective performances in validation were 0.70, 0.72, and 0.71 for ORS and 0.80, 0.84, and 0.78 for ORS+. Results were consistent across groups with mild/severe disease. CONCLUSIONS: We developed and externally validated a scoring system capable to predict OCA response according to different criteria. This tool will enhance a stratified second-line therapy model to streamline standard care and trial delivery in PBC.

Portal hypertension hemorrhage secondary to a stomal varicose vein in a patient with two consecutive thrombosis of a transjugular intrahepatic portosystemic shunt (TIPS).

Less than 5% of patients with liver cirrhosis (LC) with portal hypertension (PH) develop atypical shunt (in regions other than the esophagus or the stomach). Within this group are varices associated with a stoma, for example the ones associated with an uretero-ileostomy which are infrequent. They are a diagnostic and therapeutic challenge, as they can cause hemorrhages due to PH. We present a clinical case about stoma varicose bleeding as the latest guidelines for the management of PH do not mention them or their treatment due to their low incidence.

[Epithelial basement membrane corneal dystrophy: A case report]. / Distrofia de membrana basal epitelial corneal: a propósito de un caso.

Epithelial basement membrane corneal dystrophy is a rare entity, characterized by recurrent corneal erosions secondary to a disorder in the attachment of the corneal epithelium to the basement membrane. To date, mainly the ophthalmological aspect of cases has been reported, with little emphasis on the pathology of this lesion. Here we aim to describe the microscopy and discuss the clinical and therapeutic aspects of a case.

Protein Susceptibility to Peroxidation by 4-Hydroxynonenal in Hereditary Hemochromatosis.

Iron overload caused by hereditary hemochromatosis (HH) increases free reactive oxygen species that, in turn, induce lipid peroxidation. Its 4-hydroxynonenal (HNE) by-product is a well-established marker of lipid peroxidation since it reacts with accessible proteins with deleterious consequences. Indeed, elevated levels of HNE are often detected in a wide variety of human diseases related to oxidative stress. Here, we evaluated HNE-modified proteins in the membrane of erythrocytes from HH patients and in organs of Hfe-/- male and female mice, a mouse model of HH. For this purpose, we used one- and two-dimensional gel electrophoresis, immunoblotting and MALDI-TOF/TOF analysis. We identified cytoskeletal membrane proteins and membrane receptors of erythrocytes bound to HNE exclusively in HH patients. Furthermore, kidney and brain of Hfe-/- mice contained more HNE-adducted protein than healthy controls. Our results identified main HNE-modified proteins suggesting that HH favours preferred protein targets for oxidation by HNE.

Does delaying surgery for "healthy" hip fracture patients have increased complications and mortality?

INTRODUCTION: Surgical delay is one of the risk factors for mortality and morbidity in patients with HF. One of the causes of delay is due to admission on Thursday-Friday, weekends, holidays or previous periods. The final objective of this study is to analyze administrative-organizational delay in complication and mortality rates. MATERIAL AND METHODS: A total of 607 cases of surgically operated hip fractures were analyzed. Two groups were established, one of them operated on in < 48 h (ND group) and the other surgically delayed for administrative organizational reasons (AA group). Demographic variables related to treatment and fracture were analyzed in both groups, as well as the rates of surgical wound complications, general complications and mortality rate in the first 30 days, in the first year and more than one year after surgery. RESULTS: We observed a surgical wound seroma and staining rate of 15.7% in the AA group and 9.6% in the ND group; and a surgical wound surface infection rate of 1.9% in the AA group and 0.8% in the ND group (p = 0.275). General complications occurred in 34.4% (AA group) and 29% (ND group). The 30-day mortality rate was 4.8% in the AA group and 1.9% in the ND group (p = 0.081). CONCLUSION: We found no statistically significant differences in patients delayed for administrative reasons in terms of mortality and surgical wound and general complication rates. Although the proportion of surgical wound complications and 30-day mortality was higher in the AA group versus the ND group.

Endoscopic resolution of intestinal obstruction secondary to colonic gallstone ileus and radicular stenosis of the sigma.

A 93-year-old woman with a history of endometrial adenocarcinoma treated with surgery and pelvic radiotherapy that led to radicular stenosis in the sigma and acute biliary pancreatitis, without subsequent cholecystectomy. She attended the emergency department for abdominal pain, vomiting and abdominal distension, with metallic noises. An abdominal CT scan showed a gallbladder with cholelithiasis, in wide contact with the colonic framework and dilation of the colonic loops with hydro-aerial levels with a partially calcified image embedded in the known sigmoid stenosis, compatible with intestinal obstruction. Given the high surgical risk, colonoscopy was performed, which identified an impassable punctate stricture with a fibrous appearance. Pneumatic dilatation and subsequent removal of gallstones with biopsy forceps was performed, with an adequate evolution. While gallstone ileus is a rare condition that accounts for 5% of episodes of intestinal obstruction, its location in the colon is even rarer. It is usually managed surgically, with a significant impact on morbidity. This case is of interest because of the infrequent occurrence of obstruction secondary to these two concomitant causes and the possible usefulness of endoscopic treatment in patients at high surgical risk.

SARS-CoV-2 vaccine, a new autoimmune hepatitis trigger?

SARS-CoV2 infection and vaccination against this virus have been related to the development of autoimmune diseases. We report a case of autoimmune hepatitis (AIH) after SARS-COV2 vaccine. Male, 76 years old, with a history of hepatic cirrhosis secondary to primary biliary cholangitis (PBC), compensated, treated with ursodeoxycholic acid and obeticholic acid. The patient received the third dose of the SARS-CoV2 vaccine (BioNTech/Pfizer) in December 2021. In subsequent analytical control, the patient presented altered liver test, with elevation of ALT and AST. Ultrasound was performed, without alterations, and viral causes were ruled out. IgG elevation and positive antinuclear antibodies were observed. A liver biopsy was performed, with findings of intense interface and lobular hepatitis and areas of centrilobular necrosis. The inflammation was predominantly lymphoplasmacytic. The patient was diagnosed with AIH and initiated therapy with steroids and azathioprine, currently with an adequate response. AIH is an immune-mediated disease of uncertain etiology. Cases of AIH with SARS-CoV2 vaccination as a possible trigger have recently been published, with characteristics similar to ours. Some of them had a history of autoimmune pathology, such as this case (PBC). Therefore, it is suggested that vaccination can induce the development of autoimmune pathology in patients at risk. Our reported case reinforces the hypothesis of an association between AIH and the SARS-CoV2 vaccine.

Ustekinumab for corticodependent immune-mediated colitis by pembrolizumab, an alternative for patients with concomitant liver injury.

Pembrolizumab, a programmed cell death receptor (PD-1) inhibitor, have improved the prognosis in several types of cancer. Despite the important clinical benefits, checkpoint inhibition have been associated with inflammatory and immune-related side effects (irAE).

Regional Cortical Thickness Predicts Top Cognitive Performance in the Elderly.

While aging is typically associated with cognitive decline, some individuals are able to diverge from the characteristic downward slope and maintain very high levels of cognitive performance. Prior studies have found that cortical thickness in the cingulate cortex, a region involved in information processing, memory, and attention, distinguish those with exceptional cognitive abilities when compared to their cognitively more typical elderly peers. Others major areas outside of the cingulate, such as the prefrontal cortex and insula, are also key in successful aging well into late age, suggesting that structural properties across a wide range of areas may better explain differences in cognitive abilities. Here, we aim to assess the role of regional cortical thickness, both in the cingulate and the whole brain, in modeling Top Cognitive Performance (TCP), measured by performance in the top 50th percentile of memory and executive function. Using data from National Alzheimer's Coordinating Center and The 90 + Study, we examined healthy subjects aged 70-100 years old. We found that, while thickness in cingulate regions can model TCP status with some degree of accuracy, a whole-brain, network-level approach out-performed the localist, cingulate models. These findings suggests a need for more network-style approaches and furthers our understanding of neurobiological factors contributing to preserved cognition.

[Interactions between herbals medicines and drugs in chronic patients with complexity in primary care.] / Interacciones entre plantas medicinales y medicamentos en pacientes crónicos complejos en atención primaria.

OBJECTIVE: Taking medicinal herbs (MH) is frequent in patients and can cause interactions with others medications. Consumption of MH could be high in chronic patients with complexity (CPC) and produce interactions with drugs and knowledge about these drugs in primary health care (PC) professionals about these interactions is low. The aim was to measure the prevalence of potencial interactions between HM and drugs in CPC and evaluate the degree of knowledge of PC professionals. METHODS: Descriptive observational study in a population of CPC assigned to two PC teams. We investigated MH consumption through interviews and review potential drug interactions. We evaluated the degree of professionals knowledge through a survey designed for the study. A descriptive analysis was carried out. The Student-t test for paired data was used to compare the means.The statistical significance was established at p<0.05. RESULTS: The survey was distributed among 179 patients, mean age 76.9 years old (DE 9.7), 54.6% women. 62.57% (112) take MH. We detected 88 potentially relevant interactions in 51 patients (45.54%). Of the 219 professionals interviewed 51.1% consider that their knowledge about MH were low and 64,4% thought that was important to know the mH consumption of their patients. CONCLUSIONS: We detected a high prevalence of MH consumption in CPC and interactions between herbs medicinal and drugs. Lack of knowledge of PC health professionals is important. It's necessary to record this consumption in the medical history and improve the knowledge of professionals about MH to detect possible interactions, reduce the associated risk and improve the quality of care.

OBJETIVO: El consumo de plantas medicinales (PM) es frecuente en pacientes y puede causar interacciones con otros medicamentos. El consumo de PM puede ser alto en pacientes crónicos complejos (PCC) y producir interacciones con su medicación y el conocimiento sobre estos fármacos en profesionales sanitarios de Atención Primaria (AP) es bajo. El objetivo del estudio fue medir prevalencia de interacciones potenciales entre PM y medicamentos en PCC y evaluar grado de conocimiento de los profesionales de AP. METODOS: Estudio observacional descriptivo en una población de PCC asignados a dos equipos de AP. Se evaluaron el consumo de PM mediante entrevistas y se revisaron las interacciones potenciales con su medicación. Se evaluó el grado de conocimiento de los profesionales mediante una encuesta diseñada para el estudio. Se realizó un análisis descriptivo, La comparación de medias se realizó con la prueba t de Student. La significación estadística se estableció en p<0,05. RESULTADOS: La encuesta se distribuyó entre 179 pacientes, con una edad media de 76,9 años (DE 9,7), 54,6% mujeres. El 62,57% (112) consumieron PM. Detectamos 88 interacciones potencialmente relevantes en 51 pacientes (45,54%). De los 219 profesionales entrevistados el 51,1% consideraron que sus conocimientos sobre PM eran bajos y 64,4% pensaron que era importante conocer el consumo de PM de sus pacientes. CONCLUSIONES: Detectamos una alta prevalencia del consumo de PM en PCC y de interacciones entre PM y medicamentos. La falta de conocimientos de los profesionales sanitarios es importante. Es necesario registrar en la historia clínica este consumo y mejorar el conocimiento de los profesionales de AP sobre PM para detectar posibles interacciones, disminuir el riesgo asociado y mejorar la calidad asistencial.

Obeticholic Acid and Fibrates in Primary Biliary Cholangitis: Comparative Effects in a Multicentric Observational Study.

INTRODUCTION: Obeticholic acid (OCA) and fibrates therapy results in biochemical improvement in placebo-controlled trials in patients with primary biliary cholangitis and insufficient response to ursodeoxycholic acid. There is scarce information outside of clinical trials. Therefore, we have assessed the effectiveness and adverse events of these treatments. METHODS: Data from patients included in the ColHai registry treated with OCA, fibrates, or both were recorded during a year, as well as adverse events and treatment discontinuation. RESULTS: Eighty-six patients were treated with OCA, 250 with fibrates (81% bezafibrate; 19% fenofibrate), and 15 with OCA plus fibrates. OCA group had baseline significantly higher alkaline phosphatase (ALP) (P = 0.01) and lower platelets (P = 0.03) than fibrates. Both treatments significantly decreased ALP, gamma-glutamyl transferase (GGT), and transaminases and improved Globe score. Albumin and immunoglobulin type M improved in the fibrates group. ALP decrease was higher under fibrates, whereas alanine aminotransferase decline was higher under OCA. Although baseline transaminases and GGT were higher in patients with OCA plus fibrates, significant ALP, GGT, alanine aminotransferase, and Globe score improvement were observed during triple therapy. Adverse events were reported in 14.7% of patients (21.3% OCA; 17.6% fenofibrate; 10.7% bezafibrate), mainly pruritus (10.1% with OCA). Discontinuation was more frequent in fenofibrate treatment mainly because of intolerance or adverse events. DISCUSSION: Second-line therapy with OCA or fibrates improves hepatic biochemistry and the GLOBE score in primary biliary cholangitis patients with suboptimal response to ursodeoxycholic acid. Simultaneous treatment with OCA and fibrates improved ALP as well.

SARS-CoV-2 en aguas residuales y superficiales: ¿cómo lidiar con el problema? / Sars-cov-2 in wastewater and surface water: how to deal with the problem?

Introducción: hoy la humanidad sufre uno de los peores episodios debido a la pandemia causada por el SARS-CoV-2. Su alta infectividad, rápida propagación y persistencia en ciertas superficies dificultan el combate de este virus. Su presencia en aguas residuales y posible transmisión fecal-oral podría ser una nueva amenaza para la salud pública. Objetivo: alertar a la comunidad científica internacional y a los gobiernos sobre la presencia de SARS-CoV-2 en las aguas residuales y sobre qué hacer para evitar su propagación por este medio. Métodos: se realizó una revisión de artículos referenciados en SCOPUS y Web of Science desde el año 2019 relacionados con la presencia del virus en aguas residuales y superficiales. Resultados y discusión: es necesario establecer sistemas de monitoreo, utilizar métodos analíticos sensibles y rápidos para la detección del virus en las aguas residuales y superficiales. Asimismo, implantar protocolos de inactivación del virus en las unidades de salud y en las plantas de tratamiento de aguas. Se recomiendan procesos con oxidantes químicos, radiación ultravioleta, fotocatálisis, foto-Fenton, ozono o filtración por membrana. Además, se debe alertar a la población sobre la importancia del lavado y de la desinfección de productos agrícolas, así como del cuidado en su manejo por parte de los trabajadores agrícolas

Introduction: Today, humanity suffers one of the worst episodes due to a pandemic caused by the SARS-CoV-2. Its high infectivity and rapid spread combined with its persistence on certain surfaces difficult to fight this virus. Its presence in wastewater and possible fecal-oral transmission could be a new public health threat. Objective: To alert the international scientific community and governments about the presence of SARS-CoV-2 in wastewater, and what to do to prevent its spread by this means. Methods: A review of articles referenced in SCOPUS and Web of Science since 2019 related to the presence of the virus in wastewater and surface water was performed. Results and discussion: It is necessary to establish monitoring systems with the use of sensitive and rapid analytical methods for the on-site detection of viruses in wastewaters and surface waters. It should be established virus inactivation protocols at the health units, and water treatment plants, where are recommended processes with chemical oxidants, ultraviolet radiation, photocatalysis, photo-Fenton, ozone, or membrane filtration. It is necessary to alert the population about the importance of washing and disinfecting agricultural products, mainly vegetables and fruits, as well as the care in its handling by agricultural workers

Comparative study of biorefinery processes for the valorization of fast-growing Paulownia wood.

In this work, valorization of Paulownia wood (PW) was proposed following several process configurations for biofuels and value-added compounds production. Firstly, autohydrolysis and ethanol-organosolv strategies were assessed separately for the fractionation of PW to enhance the enzymatic digestibility of cellulose. A third strategy focused on a sequential process (autohydrolysis and organosolv) was explored. Two temperatures were selected for the first stage of the combined process. High concentration of oligosaccharides (26.29 g/L) and high concentration of degradation products (17.21 g/L) were obtained at 210 and 230 °C, respectively. The solids obtained from both pretreatments were subjected to organosolv delignification (200 °C, 3 h and 50% ethanol) achieving delignification of 58 and 30% for the autohydrolyzed biomass at 210 °C and 230 °C, respectively. The combined process resulted in susceptible biomass able to produce 64 g/L of ethanol. Therefore, the strategies explored in this work open the possibility to build a refinery around Paulownia wood.

Kynurenic Acid Levels are Increased in the CSF of Alzheimer's Disease Patients.

Kynurenic acid (KYNA) is a product of the tryptophan (TRP) metabolism via the kynurenine pathway (KP). This pathway is activated in neurodegenerative disorders, such as Alzheimer´s disease (AD). KYNA is primarily produced by astrocytes and is considered neuroprotective. Thus, altered KYNA levels may suggest an inflammatory response. Very recently, significant increases in KYNA levels were reported in cerebrospinal fluid (CSF) from AD patients compared with normal controls. In this study, we assessed the accuracy of KYNA in CSF for the classification of patients with AD, cognitively healthy controls, and patients with a variety of other neurodegenerative diseases, including frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), and progressive supranuclear palsy (PSP). Averaged KYNA concentration in CSF was higher in patients with AD when compared with healthy subjects and with all the other differentially diagnosed groups. There were no significant differences in KYNA levels in CSF between any other neurodegenerative groups and controls. These results suggest a specific increase in KYNA concentration in CSF from AD patients not seen in other neurodegenerative diseases.

Computer-Assisted Definition of the Inflammatory Infiltrates in Patients With Different Categories of Banff Kidney Allograft Rejection.

Currently, the diagnosis of kidney allograft rejection relies on individual histological assessments made by expert pathologists according to the Banff classification. In this study, we applied new Computer-Assisted System Technology (newCAST™) by Visiopharm® with the aim of identifying and quantifying the immune cells in inflammatory infiltrates. We searched for distinctive cellular profiles that could be assigned to each rejection category of the Banff schema: antibody-mediated rejection (active and chronic active), borderline, T cell-mediated rejection (TCMR), and mixed rejection. This study was performed with 49 biopsy samples, 42 from patients with rejection and 7 from patients with clinical signs of dysfunction but an absence of histological findings of rejection. Plasma cells, B and T lymphocytes, natural killer cells, and macrophages, with a special focus on the M1 and M2 subsets, were studied. A major difference among the Banff rejection groups was in the total amount of cells/mm2 tissue. Principal component analysis identified some distinctive associations. The borderline category grouped with CD4+ lymphocytes and M1 macrophages, and active antibody-mediated rejection (aAMR) clustered with natural killer cells. Despite these findings, the search for characteristic profiles linked to the rejection types proved to be a very difficult task since the cellular composition varied significantly among individuals within the same diagnostic category. The results of this study will be analyzed from the perspective of reconciling the classic way of diagnosing rejection and the immune situation "in situ" at the time of diagnosis.

Presentation and Outcomes of Pregnancy in Patients With Autoimmune Hepatitis.

Autoimmune hepatitis (AIH) frequently affects women of childbearing age in whom the desire to have a family raises the question regarding the potential risks for the fetus and the mother. The information on AIH in pregnant patients is scarce.1 The aims of this study were (1) to identify the risk factors associated with flares in pregnant patients diagnosed with AIH, (2) to determine the course of AIH in patients with pregnancy-related flares, and (3) to describe the outcome of AIH diagnosed in the postpartum period.

Healing of autoimmune hepatitis associated with hepatitis C virus infection treated with direct-acting antivirals.

The use of direct-acting antivirals (DAA) for the hepatitis C virus (HCV) has yielded a significant improvement in the treatment of autoimmune hepatitis (AIH) associated with HCV infection. Interferon was the cornerstone of HCV therapy before the introduction of these agents into the clinical practice. Herein, we report the case of an HCV-infected patient who developed an interferon-induced AIH and since then, has received immunosuppressive therapy. Administration of DAA resulted in a sustained virologic response (SVR) and clinical AIH remission which allowed a discontinuation of immunosuppressive treatment.