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.

Tratamiento de la depresión comórbida después de un síndrome coronario agudo: metaanálisis de ensayos controlados aleatorizados / Treatment of comorbid depression after acute coronary syndrome: meta-analysis of randomized controlled trials

La depresión postsíndrome coronario agudo (post-SCA) aumenta el riesgo cardíaco; sin embargo, la eficacia de las terapias antidepresivas para su tratamiento no está suficientemente demostrada. Nuestro objetivo es metaanalizar ensayos controlados con muestras homogéneas que permitan explicar la inconsistencia de los resultados obtenidos hasta el momento. Tras revisar 1525 artículos, dos revisores independientes identificaron 7 estudios que cumplían criterios muy restrictivos para asegurar la homogeneidad de las muestras. Los resultados indicaron que los pacientes tratados con intervenciones de eficacia demostrada para la depresión reducen sus niveles de trastorno depresivo significativamente más que los sujetos sin este tratamiento, y que existen diferencias significativas en el número de pacientes que reducen los síntomas depresivos de forma clínicamente relevante. Además, se observaron menos eventos cardiovasculares adversos durante el tratamiento, aunque esta diferencia fue mínimamente significativa y no se mantuvo tras el seguimiento. Estos resultados sugieren que la inconsistencia de los datos actualmente disponibles podría deberse a dificultades metodológicas que evidencian la necesidad de nuevas investigaciones que aclaren el efecto del tratamiento de la depresión sobre el pronóstico post-SCA.(AU)

Depression post-acute coronary syndrome (ACS) increases the cardiac risk;however, the efficacy of antidepressant therapies for its treatment has not beensufficiently demonstrated. Our aim is to meta-analyze controlled trials withhomogeneous samples that allow us to explain the inconsistency of the resultsobtained so far. After reviewing 1525 articles, two independent reviewersidentified 7 studies that met very restrictive criteria to ensure homogeneity of thesamples. The results indicated that patients treated with interventions of provenefficacy for the depression, reduce their levels of depressive disorder significantlymore than subjects without this treatment and that there are significantdifferences in the number of patients who reduce depressive symptoms in clinically relevant way. In addition, fewer adverse cardiovascular events wereobserved during treatment, although this difference was minimally significant andwas not maintained after the follow-up. These results suggest that theinconsistency of the currently available data could be due to methodologicaldifficulties evidencing the need for further research to clarify the effect ofdepression treatment on post-ACS prognosis.K EY WORDS : coronary heart disease, acute coronary syndrome, depressiontreatment, meta-analysis.(AU)

Long-term surveillance of the feline leukemia virus in the endangered Iberian lynx (Lynx pardinus) in Andalusia, Spain (2008-2021).

Feline leukemia virus (FeLV) infection is considered one of the most serious disease threats for the endangered Iberian lynx (Lynx pardinus) Over 14 years (2008-2021), we investigated FeLV infection using point-of-care antigen test and quantitative real-time TaqMan qPCR for provirus detection in blood and tissues in lynxes from Andalusia (Southern Spain). A total of 776 samples from 586 individuals were included in this study. The overall prevalence for FeLV antigen in blood/serum samples was 1.4% (5/360) (95% CI: 0.2-2.6), FeLV proviral DNA prevalence in blood samples was 6.2% (31/503) (95% CI: 4.1-8.6), and FeLV proviral DNA in tissues samples was 10.2% (34/333) (95% CI: 7-13.5). From a subset of 129 longitudinally sampled individuals, 9.3% (12/129) PCR-converted during the study period. Our results suggest that FeLV infection in the Andalusian population is enzootic, with circulation of the virus at low levels in almost all the sampling years. Moreover, since only one viremic individual succumbed to the infection, this study suggests that lynxes may therefore control the infection decreasing the possibility of developing a more aggressive outcome. Although our results indicate that the FeLV infection in the Iberian lynx from Andalusia tends to stay within the regressive stage, continuous FeLV surveillance is paramount to predict potential outbreaks and ensure the survival of this population.

Predictive factors for decompensating events in patients with cirrhosis with primary biliary cholangitis under different lines of therapy.

BACKGROUND AND AIMS: The landscape in primary biliary cholangitis (PBC) has changed with the advent of second-line treatments. However, the use of obeticholic acid (OCA) and fibrates in PBC-related cirrhosis is challenging. We assessed the impact of receiving a second-line therapy as a risk factor for decompensated cirrhosis in a real-world population with cirrhosis and PBC, and identify the predictive factors for decompensated cirrhosis in these patients. APPROACH AND RESULTS: Multicenter study enrolling 388 patients with PBC-cirrhosis from the Spanish ColHai registry. Biopsy (20%), ultrasound (59%), or transient elastography (21%) defined cirrhosis, and the presence of varices and splenomegaly defined clinically significant portal hypertension (CSPH). Paris-II and PBC OCA international study of efficacy criteria determined the response to ursodeoxycholic acid (UDCA), fibrates (n=93), and OCA (n=104). The incidence of decompensated cirrhosis decreased for UDCA versus OCA or fibrates in the real-world population, but they were similar considering the propensity score-matched cohort (UDCA 3.77 vs. second-line therapy 4.5 100 persons-year, respectively), as patients on second-line therapy exhibited advanced liver disease. Consequently, GGT, albumin, platelets, clinically significant portal hypertension, and UDCA response were associated with a decompensating event. OCA response (achieved in 52% of patients) was associated with bilirubin (OR 0.21 [95% CI: 0.06-0.73]) and AST (OR 0.97 [95% CI: 0.95-0.99]), while fibrate response (achieved in 55% of patients) with AST [OR 0.96 (95% CI: 0.95-0.98]). In patients treated with OCA, drug response (sHR 0.23 [95% CI: 0.08-0.64]), diabetes (sHR 5.62 [95% CI: 2.02-15.68]), albumin (sHR 0.34 [95% CI: 0.13-0.89]), and platelets (sHR 0.99 [95% CI: 0.98-1.00]) were related to decompensation. In patients treated with fibrate, drug response (sHR 0.36 (95% CI: 0.14-0.95]), albumin (sHR 0.36 (95% CI: 0.16-0.81]), and clinically significant portal hypertension (sHR 3.70 (95% CI: 1.17-11.70]) were associated with decompensated cirrhosis. CONCLUSIONS: Advanced PBC, rather than OCA and fibrates, was found to be associated with decompensating events. Therefore, biochemical and clinical variables should be considered when making decisions about the management of these drugs. Moreover, a positive response to OCA and fibrates reduced the risk of decompensation.

A randomized controlled pilot study of a cognitive-behavioral video game intervention for the promotion of active aging.

Background: Due to the accessibility barriers of in-person programs for active aging, the development of programs that use innovative technologies is needed. Video games can be an engaging tool for disseminating active aging interventions. Objective: The objective of this pilot study was to analyze the feasibility of a cognitive-behavioral intervention to promote active aging administered through a video game. Methods: Fifty-five participants (63.6% women, mean age = 53.0 years) were randomly assigned to a cognitive-behavioral intervention to promote active aging administered through an interactive multimedia online video game with a complementary app (CBI-V; n = 29) or to a control group that received nonspecific online information (CG; n = 26). Results: Only 3.6% of the participants dropped out of the study (6.9% in CBI-V and 0.0% in CG; without significant differences between groups). The mean number of modules completed was 7.6 (SD = 0.9) out of 8 in the CBI-V and 7.9 (SD = 0.5) in the control group (CG), without significant between-group differences. In the CBI-V, the mean total time dedicated to the game was 516.8 min (SD = 94.3), including 143.2 min (SD = 31.6) of cognitive training tasks, and the mean of completed tasks was 206.2 (SD = 33.7) out of 259. Participants were highly engaged (M = 39.9, SD = 8.6) and satisfied (M = 25.8, SD = 4.5) with the intervention. After the intervention, the CBI-V group significantly improved on SF-36 dimensions of General Health (p = .0386), Vitality (p = .0283), Social Functioning (p = .0130), and Physical Summary Index (p = .0370) compared to the CG, with medium effect sizes (d = 0.56-0.75). Conclusions: The results demonstrate the feasibility of the video game intervention to promote active aging and encourage conducting a large-scale randomized controlled trial.

A randomized, double-blind study on the efficacy of oral domperidone versus placebo for reducing SARS-CoV-2 viral load in mild-to-moderate COVID-19 patients in primary health care.

INTRODUCTION: The clinical effect of domperidone against COVID-19 has been investigated in a double-blind phase III clinical trial (EudraCT number 2021-001228-17). Domperidone has shown in vitro antiviral activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and potential immudolatory properties through the stimulation of prolactin secretion. PATIENTS AND METHODS: The efficacy of oral domperidone plus standard of care (SOC; n = 87) versus placebo plus SOC (n = 86) was evaluated in a 28-day randomized double-blind multicentre study in primary health care centres. A total of 173 outpatients with mild-to-moderate COVID-19 were included. Three daily doses of 10 mg (30 mg/day) of domperidone or placebo were administered for 7 days. Reduction of viral load on day 4 was the primary efficay endpoint. It was estimated in saliva samples by reverse transcription-quantitative polymerase chain reaction (RT-qPCR), as the cycle thresholds detected ORF1ab, N Protein and S Protein genes. RESULTS: A significant reduction in the viral load was observed (p < 0.001) from baseline to days 4, 7 and 14 of the three genes studied with non-significant differences between domperidone and placebo groups. Twenty-three patients (13.3%) experienced adverse events, 14 patients in the domperidone group (16.1%) and 9 patients in the placebo group (10.5%). No patients needed to be hospitalized. CONCLUSION: Results do not prove the use of domperidone as antiviral in patients with COVID-19.

A 28-day double-blind clinical trial was performed to investigate the antiviral effect of domperidone, 30 mg/day for 7 days (n = 87) versus placebo (n = 86) in outpatients with mild-to-moderate COVID-19.The primary efficacy endpoint was the reduction of viral load on day 4 as compared with baseline, estimated as the cycle thresholds to detect ORF1ab, N Protein and S Protein genes by RT-qPCR in saliva samples.The study findings do not prove the use of domperidone as antiviral in patients with COVID-19.

Tenofovir Disoproxil Fumarate Reduces the Severity of COVID-19 in Patients with Chronic Hepatitis B.

BACKGROUND AND AIMS: HIV-positive patients on tenofovir hydroxyl fumarate (TDF)/emtricitabine have a lower risk of COVID-19 and hospitalization than those given other treatments. Our aim was to analyze the severity of COVID-19 in patients with chronic hepatitis B (CHB) on TDF or entecavir (ETV). METHODS: Spanish hospital databases (n = 28) including information regarding adult CHB patients on TDF or ETV for the period February 1st to November 30th 2020 were searched for COVID-19, defined as a positive SARS-CoV-2 polymerase chain reaction, and for severe COVID-19. RESULTS: Of 4736 patients, 117 had COVID-19 (2.5%), 67 on TDF and 50 on ETV. Compared to patients on TDF, those on ETV showed (p < 0.05) greater rates of obesity, diabetes, ischemic cardiopathy, and hypertension. COVID-19 incidence was similar in both groups (2.3 vs. 2.6%). Compared to TDF, patients on ETV more often (p < 0.01) had severe COVID-19 (36 vs. 6%), required intensive care unit (ICU) (10% vs. 0) or ventilatory support (20 vs. 3%), were hospitalized for longer (10.8 ± 19 vs. 3.1 ± 7 days) or died (10 vs. 1.5%, p = 0.08). In an IPTW propensity score analysis adjusted for age, sex, obesity, comorbidities, and fibrosis stage, TDF was associated with a sixfold reduction in severe COVID-19 risk (adjusted-IPTW-OR 0.17, 95%CI 0.04-0.67, p = 0.01). CONCLUSION: Compared to ETV, TDF seems to play a protective role in CHB patients with SARS-CoV-2 whereby the risk of severe COVID-19 is lowered.

Sleep Disturbance, Psychological Distress and Perceived Burden in Female Family Caregivers of Dependent Patients with Dementia: A Case-Control Study.

This case-control study analyzed the sleep disturbance, psychological distress and perceived burden in female family caregivers of dependent people with dementia (n = 74) compared with female family caregivers of dependent people without dementia (n = 74) and with age-matched non-caregiver control females (n = 74). Participants completed the Pittsburgh Sleep Quality Index (PSQI), the 12-item General Health Questionnaire (GHQ-12), the Caregiver Burden Inventory (CBI) and an ad hoc questionnaire to collect sociodemographic data. There were significant differences between the groups in PSQI total (F = 24.93; p < 0.001), psychological distress (F = 26.71; p < 0.001) and in all sleep domains assessed: subjective sleep quality (F = 16.19; p < 0.001), sleep latency (F = 9.5; p< 0.001), sleep duration (F = 18.57; p < 0.001), habitual sleep efficiency (F = 19.77; p < 0.001), sleep disturbances (F = 9.22; p < 0.001), use of sleep medications (F = 4.24; p< 0.01) and daytime dysfunction (F = 5.57; p < 0.01). In all measures, the female family caregivers of dependent people with dementia showed the significantly higher mean scores. Regarding the two groups of female caregivers, statistically significant differences were found in daily hours of care (t = −2.45; p < 0.05) and perceived burden (t = −3.65; p < 0.001), as well as in the following dimensions of caregiver burden: time-dependence burden (t = −5.09; p < 0.001), developmental burden (t = −2.42; p < 0.05) and physical burden (t = −2.89; p < 0.01). These findings suggest that female family caregivers of dependent patients with dementia should be subject to psychopathological screening and preventive cognitive-behavioral interventions in clinical practice in primary health care.

Prevalence and Associated Factors with Poor Sleep Quality in Non-Professional Caregivers.

This study aimed to determine the prevalence and associated factors of poor sleep quality in non-professional caregivers. With this purpose, cross-sectional data were collected from 201 dependent people's family caregivers using the Pittsburgh Sleep Quality Index (PSQI), the Caregiver Burden Inventory (CBI), the General Health Questionnaire (GHQ-12), and an ad hoc questionnaire to obtain sociodemographic data. A total of 153 family caregivers were categorized as poor sleepers (PSQI > 5), resulting in a prevalence of poor sleep quality of 76.1% (95% CI = 70.5-82.5). Poor sleepers were more likely to care for persons with mental disorders (χ2 = 7.31; p < 0.01) and scored significantly higher on perceived burden (z = -4.44; p < 0.001), psychological distress (z = -6.24; p < 0.001), and in all the PSQI subscales (p < 0.001), compared with good sleepers (PSQI ≤ 5). By contrast, no differences were found between poor and good sleepers in age, gender, years providing care, and daily hours of care. Multiple linear regression analysis showed that the factors of caregiver burden (ß = 0.15; p < 0.05) and psychological distress (ß = 0.53; p < 0.001) were significantly associated with sleep quality in dependent people's family caregivers. Cognitive-behavioral strategies to improve sleep quality in the primary health care of family caregivers are suggested.

Levels of Physical Activity and Their Relationship With Motivational Determinants, Self-Regulation, and Other Health-Related Parameters in University Students.

Motivational processes and emotional self-regulation are relevant factors for predicting the practice of physical exercise and for certain health-related parameters. The aim of the present work, developed along two different phases, was, on the one hand, to determine the prevalence of physical inactivity and, on the other hand, to carry out a comparative analysis between physically active and inactive university students in relation to their motivational determinants, emotional self-regulation, physical condition, health-related quality of life and other health parameters. The results obtained showed a prevalence of physical inactivity of 12.78%. Physically inactive participants showed significantly lower scores in intrinsic motivation, emotion regulation, and in some dimensions of health-related quality of life, as well as significantly high levels of body fat mass. Lastly, logistic regression analysis identified low scores in Emotional Clarity (p= .009) and Identified Regulation (p = .011), and high scores in Amotivation (p = .006) as reliable predictors of a physically inactive lifestyle. These results are useful for the design and implementation of programs aimed at promoting health and physical activity, with special attention on physically inactive youth populations.

Factorial Structure and Psychometric Properties of the Spanish Version of the Pittsburgh Sleep Quality Index in Non-Professional Caregivers.

Although sleep issues are among the symptoms commonly experienced by the non-professional caregiver population, and the Pittsburgh Sleep Quality Index (PSQI) is the most widely used instrument for the assessment of sleep quality, this has not been validated specifically for this population. The objective of this study was to analyze the factorial structure and psychometric properties of the Spanish version of the PSQI in a sample of Spanish non-professional caregivers. Trained clinical psychologists assessed sleep quality using the PSQI, as well as caregiver burden and psychological distress in 201 non-professional caregivers (87.1% female, Mage = 56.2 years). The internal consistency of the PSQI was 0.75. The two-factor model (Sleep quality and Disturbances) had an acceptable fit to the data, was found to be superior to the one-factor model, and more parsimonious than the three-factor model. There was a significant correlation between the PSQI and caregiver burden, as well as between the PSQI and psychological distress (p < 0.001 in all cases). A total score ≥ 9 allowed the identification of caregivers with possible anxiety and depression disorders (sensitivity 70.5%, specificity 71.9%). The results show that the PSQI is a reliable and valid instrument for the assessment of sleep quality in caregivers.

Late presentation of chronic HBV and HCV patients seeking first time specialist care in Spain: a 2-year registry review.

Chronic viral hepatitis infection affects an estimated 325 million people globally. People who initiate treatment after significant disease progression face increased risk of severe liver complications and death. Data are scarce on the characteristics and risk factors of people who present late to care in Spain and globally. Data were collected from January 2018 to December 2019 to report late presentation (LP) to specialist care at 11 large university hospitals in Spain to assess related risk factors using a multivariable logistic regression model. 2290 (CHB = 505, CHC = 1785) patients were analysed, with 581 (25.2%) presenting late. Hepatitis C patients more frequently reported LP compared to hepatitis B patients (28.1% vs 15.0%; p < 0.001). Older age (p < 0.001), being male (p < 0.001), being Spanish-born (p < 0.001), and having an unknown origin of referral (p = 0.08) were associated with a higher likelihood of LP. Advanced liver disease was identified in 533 (23%) patients and late-stage liver disease in 124 (5.4%). LP, including with irreversible liver damage, to viral hepatitis specialist care is frequent in Spain, despite being a country with unrestricted treatment access. Initiatives to reduce LP should specifically target men, older individuals, foreign-born populations for CHB, and Spanish nationals for CHC.

Prediction of liver stiffness by serum indexes in HCV-infected patients with or without HIV coinfection.

ABSTRACT: Identification of advanced fibrosis/cirrhosis in hepatitis C virus (HCV)-infected patients should be a mainstay before starting treatment; however, the limited access of many centres to transient elastography (TE) is often a barrier for early assessments. We aimed to investigate the diagnostic accuracy of serum indexes for predicting liver stiffness.Retrospective analysis of HCV patients (with or without HIV coinfection) routinely assessed in 7 centres in Spain. The diagnostic accuracy of aspartate aminotransferase-to-platelet ratio index (APRI), fibrosis-4 (FIB-4), and their combinations was evaluated using a recent TE examination as a reference test (liver stiffness ≥ 9.5 kPa and ≥12.5 kPa for advanced fibrosis and cirrhosis, respectively). In addition to area under the receiving operating characteristic curves, sensitivity, specificity, and negative predictive value (NPV) and positive predictive value were estimated.The analysis included 1391 patients: 346 (25%) HIV-positive, 732 (53%) people who inject drugs, and 178 (13%) incarcerated. Advanced fibrosis and cirrhosis were found in 557 (40%) and 351 (25%) patients, respectively. APRI < 0.5 (n = 595; 43%) had an NPV of 95% for excluding cirrhosis. Combined FIB-4 < 1.45 with APRI < 0.5 (n = 467; 34%) had an NPV of 87% for excluding advanced fibrosis. Combined APRI > 2 and FIB-4 > 3.25 (n = 134; 10%) had a positive predictive value of 89% for advanced fibrosis. Globally, this approach would avoid the need for TE in 53% of patients. HIV coinfection did not influence diagnostic accuracy.Inexpensive and simple serum indexes confidently allowed identifying the absence of cirrhosis and the presence of advanced fibrosis in 53% of a heterogeneous series of real-world HCV patients with or without HIV infection.

Neuroactive venom compounds obtained from Phlogiellus bundokalbo as potential leads for neurodegenerative diseases: insights on their acetylcholinesterase and beta-secretase inhibitory activities in vitro.

BACKGROUND: Spider venom is a rich cocktail of neuroactive compounds designed to prey capture and defense against predators that act on neuronal membrane proteins, in particular, acetylcholinesterases (AChE) that regulate synaptic transmission through acetylcholine (ACh) hydrolysis - an excitatory neurotransmitter - and beta-secretases (BACE) that primarily cleave amyloid precursor proteins (APP), which are, in turn, relevant in the structural integrity of neurons. The present study provides preliminary evidence on the therapeutic potential of Phlogiellus bundokalbo venom against neurodegenerative diseases. METHODS: Spider venom was extracted by electrostimulation and fractionated by reverse-phase high-performance liquid chromatography (RP-HPLC) and characterized by matrix-assisted laser desorption ionization-time flight mass spectrometry (MALDI-TOF-MS). Neuroactivity of the whole venom was observed by a neurobehavioral response from Terebrio molitor larvae in vivo and fractions were screened for their inhibitory activities against AChE and BACE in vitro. RESULTS: The whole venom from P. bundokalbo demonstrated neuroactivity by inducing excitatory movements from T. molitor for 15 min. Sixteen fractions collected produced diverse mass fragments from MALDI-TOF-MS ranging from 900-4500 Da. Eleven of sixteen fractions demonstrated AChE inhibitory activities with 14.34% (± 2.60e-4) to 62.05% (± 6.40e-5) compared with donepezil which has 86.34% (± 3.90e-5) inhibition (p > 0.05), while none of the fractions were observed to exhibit BACE inhibition. Furthermore, three potent fractions against AChE, F1, F3, and F16 displayed competitive and uncompetitive inhibitions compared to donepezil as the positive control. CONCLUSION: The venom of P. bundokalbo contains compounds that demonstrate neuroactivity and anti-AChE activities in vitro, which could comprise possible therapeutic leads for the development of cholinergic compounds against neurological diseases.

Effectiveness and safety of obeticholic acid in a Southern European multicentre cohort of patients with primary biliary cholangitis and suboptimal response to ursodeoxycholic acid.

BACKGROUND: Obeticholic acid (OCA) was recently approved as the only on-label alternative for patients with primary biliary cholangitis (PBC) with intolerance or suboptimal response to ursodeoxycholic acid (UDCA). However, few data are available outside clinical trials. AIM: To assess the effectiveness and safety of OCA in a real-world cohort of patients with non-effective UDCA therapy. METHODS: Open-label, prospective, real-world, multicentre study, enrolling consecutive patients who did not meet Paris II criteria, from 18 institutions in Spain and Portugal. Effectiveness was assessed by the changes in GLOBE and UK-PBC scores from baseline. POISE and Paris II criteria were evaluated after 12 months of OCA . Liver fibrosis was evaluated by FIB-4 and AST to platelet ratio index (APRI). RESULTS: One hundred and twenty patients were eligible, median time since PBC diagnosis 9.3 (4.0-13.8) years, 21.7% had cirrhosis, and 26.7% received had previous or concomitant treatment with fibrates. Seventy-eight patients completed at least 1 year of OCA. The Globe-PBC score decreased to 0.17 (95% CI 0.05 to 0.28; P = 0.005) and the UK-PBC score decreased to 0.81 (95% CI -0.19 to 1.80; P = 0.11). There was a significant decrease in alkaline phosphatase of 81.3 U/L (95% CI 42.5 to 120; P < 0.001), ALT 22.1 U/L (95% CI 10.4 to 33.8; P < 0.001) and bilirubin 0.12 mg/dL (95% CI 0 to 0.24; P = 0.044). FIB-4 and APRI remained stable. According to the POISE criteria, 29.5% (23 out of 78) achieved response. The adverse events rate was 35%; 11.67% discontinued (8.3% due to pruritus). CONCLUSIONS: This study supports data from phase III trials with significant improvement of PBC-Globe continuous prognostic marker score among OCA-treated patients with good tolerability.

Flexible endoscopy assisted by Ligasure™ for treatment of Zenker's diverticulum: an effective and safe procedure.

BACKGROUND: Flexible endoscopy allows use of the vessel-tissue sealer Ligasure™ (Covidien, Massachusetts, USA) to perform diverticulotomy. Few studies have used this endoscopic approach in the uncommon disorder Zenker's diverticulum. The aim of the present study was to evaluate the effectiveness and safety of flexible endoscopy treatment assisted by Ligasure™. METHODS: The single-center prospective and descriptive study included patients treated by flexible endoscopy using Ligasure™ for resection of Zenker's diverticulum. Consecutive patients were included from March 2009 to April 2018. Patients were censored until the end of follow-up or death. Complications, symptoms before treatment, type of sedation, and number of interventions needed to resolve Zenker's diverticulum were analyzed. Bleeding complications were considered when a case required a second endoscopy. RESULTS: A total of 46 symptomatic patients with Zenker's diverticulum were included in the final analysis (41.3% women, median age of 73.7 ± 11 years). The median follow-up period was 37.21 ± 28 months. Of all cases, 58.7% were considered small (< 3 cm). Solid or semi-solid food-related dysphagia was present in 55.6% of patients previously to the procedure. The technique was successful in a single procedure in 78.3% of cases. However, the success rate increased to 89.1% with a second procedure, and we had a complication rate of 4.3% with this technique. Most patients (79.66%) were managed as out-patients or with short (< 24 h) admission. CONCLUSION: In this large case series, treatment of Zenker's diverticulum based on flexible endoscopy assisted by Ligasure™ was a safe and effective procedure with a high success rate in a few endoscopy sessions and low complication rate.

Neuroactive venom compounds obtained from Phlogiellus bundokalbo as potential leads for neurodegenerative diseases: insights on their acetylcholinesterase and beta-secretase inhibitory activities in vitro

Spider venom is a rich cocktail of neuroactive compounds designed to prey capture and defense against predators that act on neuronal membrane proteins, in particular, acetylcholinesterases (AChE) that regulate synaptic transmission through acetylcholine (ACh) hydrolysis - an excitatory neurotransmitter - and beta-secretases (BACE) that primarily cleave amyloid precursor proteins (APP), which are, in turn, relevant in the structural integrity of neurons. The present study provides preliminary evidence on the therapeutic potential of Phlogiellus bundokalbo venom against neurodegenerative diseases. Methods Spider venom was extracted by electrostimulation and fractionated by reverse-phase high-performance liquid chromatography (RP-HPLC) and characterized by matrix-assisted laser desorption ionization-time flight mass spectrometry (MALDI-TOF-MS). Neuroactivity of the whole venom was observed by a neurobehavioral response from Terebrio molitor larvae in vivo and fractions were screened for their inhibitory activities against AChE and BACE in vitro. Results The whole venom from P. bundokalbo demonstrated neuroactivity by inducing excitatory movements from T. molitor for 15 min. Sixteen fractions collected produced diverse mass fragments from MALDI-TOF-MS ranging from 900-4500 Da. Eleven of sixteen fractions demonstrated AChE inhibitory activities with 14.34% (± 2.60e-4) to 62.05% (± 6.40e-5) compared with donepezil which has 86.34% (± 3.90e-5) inhibition (p > 0.05), while none of the fractions were observed to exhibit BACE inhibition. Furthermore, three potent fractions against AChE, F1, F3, and F16 displayed competitive and uncompetitive inhibitions compared to donepezil as the positive control. Conclusion The venom of P. bundokalbo contains compounds that demonstrate neuroactivity and anti-AChE activities in vitro, which could comprise possible therapeutic leads for the development of cholinergic compounds against neurological diseases.(AU)

Phlogiellus bundokalbo spider venom: Its neuroactive, phospholipase a2 and cytotoxic components against human breast adenocarcinoma (MCF-7)

@#Spider venoms and toxins are valuable sources of lead compounds for drug development due to their essential role in cellular and physiological processes targeting various receptors. Here, we present the protein profile of the venom of Phlogiellus bundokalbo, an endemic Philippine tarantula, to screen and characterize its cytotoxicity against MCF-7 cells, secretory phospholipase a2 (sPLA2), and neurotoxicity to evaluate its potential anticancer properties. Spider venom was extracted via electrical stimulation. Venom components were fractionated by reversed-phase high-performance liquid chromatography and characterized through liquid chromatography-mass spectrometry (LC-MS) and SDS-PAGE analysis before assay. The resulting five venom fractions were amphiphilic peptides showing cytotoxicity against MCF-7 cells in a concentrationdependent manner (IC50 ranging from 52.25μg/ml to 110.20μg/ml) after 24-hour incubation. Cells appeared detached, rounded, and shrunk with cytoplasmic condensation upon overnight incubation with venom fractions. The sPLA2 was observed in all the venom fractions tested for cytotoxicity. Venom fractions revealed a predominant mass of ~3-5 kDa with LC-MS analysis. Results showed distinct similar mass as μ- theraphotoxin-Phlo1a, an Australian tarantula, Phlogiellus sp. toxin with inhibitor cystine knot motif. The venom fractions exhibit excitatory neurotoxins that might activate presynaptic voltage-gated ion channels, such as an agonist or gating modifier toxins that slow down the channel inactivation similar to spider toxins. In conclusion, the spider venom of P. bundokalbo exhibits cytotoxic, phospholipase A2, and neuroactive properties suggesting that its venom components, upon further purification and structure-function analysis, can be potential tools in the development of targeted breast chemotherapeutics.

The Venom of Philippine Tarantula (Theraphosidae) Contains Peptides with Pro-Oxidative and Nitrosative-Dependent Cytotoxic Activities against Breast Cancer Cells (MCF-7) In Vitro.

BACKGROUND: Breast cancer is a multifactorial disease that affects women worldwide. Its progression is likely to be executed by oxidative stress wherein elevated levels of reactive oxygen and nitrogen species drive several breast cancer pathologies. Spider venom contains various pharmacological peptides which exhibit selective activity to abnormal expression of ion channels on cancer cell surface which can confer potent anti-cancer activities against this disease. METHODS: Venom was extracted from a Philippine tarantula by electrostimulation and fractionated by reverse phase-high performance liquid chromatography (RP-HPLC). Venom fractions were collected and used for in vitro analyses such as cellular toxicity, morphological assessment, and oxidative stress levels. RESULTS: The fractionation of crude spider venom generated several peaks which were predominantly detected spectrophotometrically and colorimetrically as peptides. Treatment of MCF-7 cell line of selected spider venom peptides induced production of several endogenous radicals such as hydroxyl radicals (•OH), nitric oxide radicals (•NO), superoxide anion radicals (•O2-) and lipid peroxides via malondialdehyde (MDA) reaction, which is comparable with the scavenging effects afforded by 400 µg/mL vitamin E and L-cysteine (p<0.05). Concomitantly, the free radicals produced decrease the mitochondrial membrane potential and metabolic activity as detected by rhodamine 123 and tetrazolium dye respectively (p>0.05). This is manifested by cytotoxicity in MCF-7 cells as seen by increase in membrane blebbing, cellular detachment, caspase activity and nuclear fragmentation. CONCLUSION: These data suggest that the Philippine tarantula venom contains peptide constituents exhibiting pro-oxidative and nitrosative-dependent cytotoxic activities against MCF-7 cells and can indicate mechanistic insights to further explore its potential application as prooxidants in cancer therapy.
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