Longitudinal outcomes of obeticholic acid therapy in ursodiol-nonresponsive primary biliary cholangitis: Stratifying the impact of add-on fibrates in real-world practice.

BACKGROUND: Suboptimal response to ursodeoxycholic acid occurs in 40% of primary biliary cholangitis (PBC) patients, affecting survival. Achieving a deep response (normalisation of alkaline phosphatase [ALP] and bilirubin ≤0.6 upper limit of normal) improves survival. Yet, the long-term effectiveness of second-line treatments remains uncertain. AIMS: To evaluate the long-term effectiveness of obeticholic acid (OCA) ± fibrates. Focusing on biochemical response (ALP ≤1.67 times the upper limit of normal, with a decrease of at least 15% from baseline and normal bilirubin levels), normalisation of ALP, deep response and biochemical remission (deep response plus aminotransferase normalisation). METHODS: We conducted a longitudinal, observational, multicentre study involving ursodeoxyccholic acid non-responsive PBC patients (Paris-II criteria) from Spain and Portugal who received OCA ± fibrates. RESULTS: Of 255 patients, median follow-up was 35.1 months (IQR: 20.2-53). The biochemical response in the whole cohort was 47.2%, 61.4% and 68.6% at 12, 24 and 36 months. GLOBE-PBC and 5-year UK-PBC scores improved (p < 0.001). Triple therapy (ursodeoxycholic acid plus OCA plus fibrates) had significantly higher response rates than dual therapy (p = 0.001), including ALP normalisation, deep response and biochemical remission (p < 0.001). In multivariate analysis, triple therapy remained independently associated with biochemical response (p = 0.024), alkaline phosphatase normalisation, deep response and biochemical remission (p < 0.001). Adverse effects occurred in 41.2% of cases, leading to 18.8% discontinuing OCA. Out of 55 patients with cirrhosis, 12 developed decompensation. All with baseline portal hypertension. CONCLUSION: Triple therapy was superior in achieving therapeutic goals in UDCA-nonresponsive PBC. Decompensation was linked to pre-existing portal hypertension.

The effect of hepatitis C-associated premature deaths on labour productivity losses in Spain: a ten-year analysis.

Hepatitis C virus (HCV) infection causes a substantial economic burden, not only in terms of healthcare costs, but also in labour productivity losses. The main objective of this study is to provide objective and comparable information about the trend in labour productivity losses caused by premature HCV-associated deaths in Spain in recent years (2009-2018). We used nationwide data from several official sources to create a simulation model based on the human capital approach and to estimate the flows in labour productivity losses due to deaths identified in the period considered. Based on a pessimistic scenario, the annual number of deaths due to HCV infections decreased by 19.7% between 2009 and 2018. The years of potential labour productive life lost (YPLPLL) decreased by 38.1%. That reduction led to a decrease in annual labour productivity losses from €236 million in 2009 to €156 million in 2018 (-33.8%). The aggregate HCV-related labour productivity losses between 2009 and 2018 ranged from €1742 million (optimistic scenario) to €1949 million (pessimistic scenario), with an intermediate estimation of €1846 million (moderately optimistic scenario). These results show a substantial reduction in annual deaths, working-age deaths, YPLPLL, and labour productivity losses associated with HCV infection over this period.

Hepatitis C Virus positivity prediction from serum samples using NIRS and L1-penalized classification.

AIMS: The hepatitis C virus (HCV) has developed a strategy to coexist with its host resulting in varying degrees of tissue and cell damage, which generate different pathological phenotypes, such as varying degrees of fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). However, there is no integrated information that can predict the evolutionary course of the infection. We propose to combine Near-infrared spectroscopy (NIRS) and machine learning techniques to provide a predictive model. In this work, we propose to discriminate HCV positivity in biobank patient serum samples. METHODS: 126 serum samples from 38 HCV patients in different stages of the disease were obtained from the Biobank of Hospital Universitario Fundación Alcorcon. NIRS spectrum was captured by a FT-NIRS Spectrum 100 (Perkin Elmer) device in reflectance mode. For each patient, the HCV positivity was identified (PCR) and labeled as detectable =1 and undetectable =0. We propose an L1-penalized logistic regression model to classify each spectrum as positive (1) or negative (0) for HCV presence (x). The regularization parameter is selected using 5- fold cross-validation. The penalized model will induce sparsity in the solution so that only a few relevant wavelengths will be different from zero. RESULTS: L1-penalized logistic regression model provided 167 wavelengths different from zero. The accuracy on an independent test set was 0.78. CONCLUSIONS: We present a straightforward promising approach to detect HCV positivity from patient serum samples combining NIRS and machine learning techniques. This result is encouraging to predict HCV progression, among other applications. Clinical relevance- We presented a simple while promising approach to use machine learning and NIRS to analyze viral presence on sample serums.

miR-146a rs2431697 identifies myeloproliferative neoplasm patients with higher secondary myelofibrosis progression risk.

Myelofibrosis (MF) occurs as part of the natural history of polycythemia vera (PV) and essential thrombocythemia (ET), and remarkably shortens survival. Although JAK2V617F and CALR allele burden are the main transformation risk factors, inflammation plays a critical role by driving clonal expansion toward end-stage disease. NF-κB is a key mediator of inflammation-induced carcinogenesis. Here, we explored the involvement of miR-146a, a brake in NF-κB signaling, in MPN susceptibility and progression. rs2910164 and rs2431697, that affect miR-146a expression, were analyzed in 967 MPN (320 PV/333 ET/314 MF) patients and 600 controls. We found that rs2431697 TT genotype was associated with MF, particularly with post-PV/ET MF (HR = 1.5; p < 0.05). Among 232 PV/ET patients (follow-up time=8.5 years), 18 (7.8%) progressed to MF, being MF-free-survival shorter for rs2431697 TT than CC + CT patients (p = 0.01). Multivariate analysis identified TT genotype as independent predictor of MF progression. In addition, TT (vs. CC + CT) patients showed increased plasma inflammatory cytokines. Finally, miR-146a-/- mice showed significantly higher Stat3 activity with aging, parallel to the development of the MF-like phenotype. In conclusion, we demonstrated that rs2431697 TT genotype is an early predictor of MF progression independent of the JAK2V617F allele burden. Low levels of miR-146a contribute to the MF phenotype by increasing Stat3 signaling.

Main Contributory Factors on Asthma Control and Health-Related Quality of Life in Elderly Asthmatics.

OBJECTIVE: To assess the main factors involved in asthma control and health-related quality of life in elderly asthmatic patients. METHODS: We performed a retrospective case-control study nested in a historical cohort that compared patients who had partly controlled or uncontrolled asthma (Asthma Control Test [ACT] score ≤19) (cases) with patients who had well-controlled asthma (ACT ≥20) (controls). Clinical data were collected from medical records. Outcomes included ACT score and health-related quality of life (Asthma-Specific Quality of Life Questionnaire [AQLQ]). Pulmonary function was determined by spirometry. RESULTS: We evaluated 209 asthma patients (151 women) aged ≥65 years. Mean age was 73.55 years. Most patients had persistent moderate (47.60%) or severe (47.12%) asthma. A total ACT score ≤19 was obtained in 64 (30.62%) patients. Lack of adherence to treatment and presence of severe exacerbations were risk factors for partly controlled/uncontrolled asthma (OR, 8.33 and 5.29, respectively). In addition, for each additional unit score in the AQLQ, the risk of poor control increased by 1.51. The factors influencing the AQLQ score were asthma control (ACT) and presence of comorbidities such as depression, gastroesophageal reflux disease, and osteoporosis. CONCLUSIONS: Despite receiving antiasthma therapy, almost one-third of elderly patients had uncontrolled asthma, possibly as a result of poor adherence, exacerbations, and reduced health-related quality of life. Nonrespiratory comorbid conditions in older patients do not seem to be associated with worse control of asthma symptoms, although their effect on health-related quality of life could indirectly affect asthma control.

Transforming Growth Factor Beta 1 and Vascular Risk in Alcoholics.

INTRODUCTION: Transforming growth factor beta-1 (TGF-ß1) is a pleiotropic cytokine. Its relationship with atherosclerosis is debatable, protective or deleterious effects have been described. Alcoholics are at increased vascular risk. Although TGF-ß1 is increased in alcoholics, its role on vascular risk factors has not been analyzed. This is the objective of this study. PATIENTS AND METHODS: 79 heavy alcoholics and 34 controls were included. Calcium deposition in the aortic arch was assessed in the plain thorax X-ray film. Ankle-brachial index was recorded in 48 patients. All the patients underwent complete laboratory evaluation, including serum levels of TGF-ß1, tumor necrosis factor (TNF)-α, interleukin (IL)-4, IL-6, and interferon-γ (IFN-γ).We analyzed the relationships between TGF-ß1 and vascular risk factors by both univariate (parametric or non parametric tests), or multivariate analysis to discern on which variables TGF-ß1 levels depend. RESULTS: Serum TGF-ß1 levels were higher among patients (t = 2.73; P = 0.008), but no differences exist among cirrhotics (17246 ± 11,021 pg/mL) and non-cirrhotics (21,340 ± 12,442 pg/mL). TGF-ß1 showed significant correlations with total cholesterol (r = 0.28; P = 0.017) and HDL- cholesterol (r = 0.25; P = 0.042), and inverse correlations with body mass index (BMI; ρ = -0.37; P = 0.004), IL-4 (ρ = -0.31; P = 0.009), INF-γ (ρ = -0.28; P = 0.001), and IL-6 (ρ = -0.38; P = 0.001). By multivariate analysis, only BMI, IL-6 and HDL-cholesterol showed independent relationships with TGF-ß1. No relationships were observed with ankle-brachial index or calcium in the aortic arch, hypertension, diabetes, left ventricular hypertrophy or atrial fibrillation. CONCLUSION: TGF-ß1 levels are increased in alcoholics, but are unrelated to vessel wall calcification or arterial stiffness.

A western route of prehistoric human migration from Africa into the Iberian Peninsula.

Being at the western fringe of Europe, Iberia had a peculiar prehistory and a complex pattern of Neolithization. A few studies, all based on modern populations, reported the presence of DNA of likely African origin in this region, generally concluding it was the result of recent gene flow, probably during the Islamic period. Here, we provide evidence of much older gene flow from Africa to Iberia by sequencing whole genomes from four human remains from northern Portugal and southern Spain dated around 4000 years BP (from the Middle Neolithic to the Bronze Age). We found one of them to carry an unequivocal sub-Saharan mitogenome of most probably West or West-Central African origin, to our knowledge never reported before in prehistoric remains outside Africa. Our analyses of ancient nuclear genomes show small but significant levels of sub-Saharan African affinity in several ancient Iberian samples, which indicates that what we detected was not an occasional individual phenomenon, but an admixture event recognizable at the population level. We interpret this result as evidence of an early migration process from Africa into the Iberian Peninsula through a western route, possibly across the Strait of Gibraltar.

Effectiveness and safety of sofosbuvir-based regimens plus an NS5A inhibitor for patients with HCV genotype 3 infection and cirrhosis. Results of a multicenter real-life cohort.

Patients with HCV genotype 3 (GT3) infection and cirrhosis are currently the most difficult to cure. We report our experience with sofosbuvir+daclatasvir (SOF+DCV) or sofosbuvir/ledipasvir (SOF/LDV), with or without ribavirin (RBV) in clinical practice in this population. This was a multicenter observational study including cirrhotic patients infected by HCV GT3, treated with sofosbuvir plus an NS5A inhibitor (May 2014-October 2015). In total, 208 patients were included: 98 (47%) treatment-experienced, 42 (20%) decompensated and 55 (27%) MELD score >10. In 131 (63%), treatment was SOF+DCV and in 77 (37%), SOF/LDV. Overall, 86% received RBV. RBV addition and extension to 24 weeks was higher in the SOF/LDV group (95% vs 80%, P=.002 and 83% vs 72%, P=.044, respectively). A higher percentage of decompensated patients were treated with DCV than LDV (25% vs 12%, P=.013). Overall, SVR12 was 93.8% (195/208): 94% with SOF+DCV and 93.5% with SOF/LDV. SVR12 was achieved in 90.5% of decompensated patients. Eleven treatment failures: 10 relapses and one breakthrough. RBV addition did not improve SVR (RR: 1.08; P=.919). The single factor associated with failure to achieve SVR was platelet count <75×10E9/mL (RR: 3.50, P=.019). In patients with MELD <10, type of NS5A inhibitor did not impact on SVR12 (94% vs 97%; adjusted RR: 0.49). Thirteen patients (6.3%) had serious adverse events, including three deaths (1.4%) and one therapy discontinuation (0.5%), higher in decompensated patients (16.7% vs 3.6%, P<.006). In patients with GT3 infection and cirrhosis, SVR12 rates were high with both SOF+DCV and SOF/LDV, with few serious adverse events.

Therapy with ombitasvir/paritaprevir/ritonavir plus dasabuvir is effective and safe for the treatment of genotypes 1 and 4 hepatitis C virus (HCV) infection in patients with severe renal impairment: A multicentre experience.

Limited data are available on direct-acting antivirals for treating hepatitis C virus (HCV) infection in patients with severe renal impairment. The aim of this study was to evaluate the effectiveness and safety of ombitasvir/paritaprevir/ritonavir (OBV/PTV/r) ± dasabuvir (DSV) ± ribavirin (RBV) in patients with stage 4 or 5 chronic kidney disease (CKD) and HCV genotype 1 or 4 infection in real clinical practice, and to investigate pharmacological interactions. This retrospective study included patients treated with OBV/PTV/r+DSV±RBV or OBV/PTV/r+RBV with CKD stage 4 (eGFR: 15-29 mL/min/1.73m2 ) or 5 (eGFR<15 mL/min/1.73m2 or requiring dialysis) and HCV infection by genotypes 1 and 4 between April 2015 and October 2015 in nine Spanish centres. Sustained virological response at 12 weeks (SVR12) was assessed, and clinical and laboratory data, fibrosis stage, adverse events and pharmacological interactions were reported. Forty-six patients were included: 10 (21.7%) had CKD stage 4 and 36 (78.2%) CKD stage 5. Seventeen (36.9%) had cirrhosis. SVR12 rate in the intention-to-treat population was 95.7%. Twenty-one (45.6%) received RBV, which was discontinued in two (9.5%) patients. Anaemia (haemoglobin <10 g/dl) occurred in 12 patients (57.1%) with RBV vs 10 (40.0%) without RBV (P=.246). Renal function remained stable during antiviral therapy. Nine patients (19.5%) experienced serious adverse events unrelated to antiviral therapy. Concomitant medication was discontinued or modified in 41.3% of patients. In conclusion, the effectiveness of OBV/PTV/r±DSV±RBV in patients with CKD 4-5 was similar to that observed in those with normal renal function and was not associated with severe adverse events.

Effectiveness and safety of ombitasvir, paritaprevir, ritonavir ± dasabuvir ± ribavirin: An early access programme for Spanish patients with genotype 1/4 chronic hepatitis C virus infection.

Over the last 5 years, therapies for hepatitis C virus (HCV) infection have improved significantly, achieving sustained virologic response (SVR) rates of up to 100% in clinical trials in patients with HCV genotype 1. We investigated the effectiveness and safety of ombitasvir/paritaprevir/ritonavir±dasabuvir in an early access programme. This was a retrospective, multicentre, national study that included 291 treatment-naïve and treatment-experienced patients with genotype 1 or 4 HCV infection. Most patients (65.3%) were male, and the mean age was 57.5 years. The mean baseline viral load was 6.1 log, 69.8% had HCV 1b genotype, 72.9% had cirrhosis and 34.7% were treatment-naïve. SVR at 12 weeks posttreatment was 96.2%. Four patients had virological failure (1.4%), one leading to discontinuation. There were no statistical differences in virological response according to genotype or liver fibrosis. Thirty patients experienced serious adverse events (SAEs) (10.3%), leading to discontinuation in six cases. Hepatic decompensation was observed in five patients. Four patients died during treatment or follow-up, three of them directly related to liver failure. Multivariate analyses showed a decreased probability of achieving SVR associated with baseline albumin, bilirubin and Child-Pugh score B, and a greater probability of developing SAEs related to age and albumin. This combined therapy was highly effective in clinical practice with an acceptable safety profile and low rates of treatment discontinuation.

miR-203 and miR-221 regulate SOCS1 and SOCS3 in essential thrombocythemia.

The biological basis of essential thrombocythemia (ET) patients lacking known mutations is still unknown. MicroRNAs (miRNA) regulate hematopoietic differentiation and are deregulated in several hematopoietic malignancies. However, miRNA expression in ET patients has been poorly explored. We performed miRNA profiling in platelets from 19 ET patients and 10 healthy controls. Hierarchical cluster analysis showed two well-separated clusters between patients and controls, indicating that ET platelets had a characteristic 70-miRNA signature (P<0.0001), 68 of which were downregulated. According to the mutational status, three differentially expressed miRNAs, miR-15a (P=0.045), miR-150 (P=0.001) and miR-519a (P=0.036), were identified. A 40-miRNA signature was identified characterizing JAK2V617F-positive ET patients. Eight genes, whose interaction with the miRNAs could activate the JAK/STAT pathway were identified. An inverse correlation was observed between miRNAs expression and their target genes for SOCS1 and miR-221, SOCS3 and miR-221, SOCS3 and miR-203, and PTPN11 and miR-23a. All three miRNAs were upregulated in JAK2V617F-negative ET patients. SOCS1 and SOCS3 were validated as targets of miR-221 and miR-203, respectively. In summary, our study shows that platelets from JAK2V617F-negative ET patients harbor a specific miRNA signature that can participate in the modulation of the JAK/STAT pathway through regulation of key genes as SOCS1 and SOCS3.

Multidisciplinary Approach in Hepatocellular Carcinoma in a Level II Hospital: The First Decade of Hospital Universitario Fundacion Alcorcon.

BACKGROUND/AIMS: Mean survival in hepatocellular carcinoma remains low. Many efforts have been done during the last years through screening, diagnosis and treatment to improve the results. The aim of this work is to present the experience of our hospital multidisciplinary group during the first decade of this century. METHODOLOGY: The patients with hepatocellullar carcinoma presented at the multidisciplinary meeting from 1999 to 2009 were prospectively studied. According to the tumor and functional status they were treated through the current available guidelines by transplant, partial hepatectomy, local/regional procedures, systemic or symptomatic treatment. RESULTS: One hundred and forty two patients were studied. Median tumor size was 3 cm. A single tumor was diagnosed in 64.8% of the patients. Eighteen patients had liver resection (6 transplantation and 12 with partial resection), 53 tumors were not treated due to advanced stage or liver dysfunction, and in the remaining patients radiofrequency, ethanol or embolization treatments were used, single or combined. CONCLUSIONS: a multidisciplinary approach of hepatocellular carcinoma in a second level hospital with trained professionals permits a diagnosis in early tumoral and functional stages in the majority of patients, and a variety of possible treatments with adequate survival outcomes.

[The influence of sleep and emotional states on childhood body mass index]. / La influencia del sueño y los estados emocionales sobre el índice de masa corporal infantil.

INTRODUCTION: By using path analysis, the aim of this study iso show how anxiety, low self-esteem and a decrease in hours of sleep interact to lead to an increase in overweight in children. METHOD: A random sample of 291 schoolchildren was included. A cross-sectional design was used, measuring their body mass index (BMI) and applying the State-Trait Anxiety inventory for Children and the Children' Depression Inventory. RESULTS: The mean sleep time was 9 hours and 50 minutes. There was an inverse relationship between hours of sleep and BMI. Similarly, anxiety and low self-esteem were predictors of the number of hours of sleep. CONCLUSIONS: These data allow it to be concluded that, on one hand, the population studied sleeps less than the 10 or 11 hours recommended for their age. On the other hand, it has been demonstrated how certain emotional states can encourage increased BMI in children, but this relationship is associated with reduced sleep.