Development and Clinical Validation of a Pangenotypic PCR-Based Assay for the Detection and Quantification of Hepatitis E Virus (Orthohepevirus A Genus).

The objective of this study was to design a pangenotypic PCR-based assay for the detection and quantification of hepatitis E virus (HEV) RNA from across the entire spectrum of described genotypes belonging to the Orthohepevirus A genus. The optimal conditions and the performance of the assay were determined by testing the WHO standard strain (6219/10) and the WHO HEV panel (8578/13). Similarly, performance comparisons were made with two commercial assays (Real Star HEV RT-PCR 2.0 and ampliCube HEV 2.0 Quant) to detect HEV RNA at concentrations below 1,000 IU/ml with viral strains from the WHO and to test samples from 54 patients with acute hepatitis. The assay presented in this study was able to detect the entire spectrum of described genotypes belonging to the Orthohepevirus A genus, demonstrating better performance than both commercial kits. This procedure may represent a significant improvement in the molecular diagnosis of HEV infection.

Classification Accuracy of Hepatitis C Virus Infection Outcome: Data Mining Approach.

BACKGROUND: The dataset from genes used to predict hepatitis C virus outcome was evaluated in a previous study using a conventional statistical methodology. OBJECTIVE: The aim of this study was to reanalyze this same dataset using the data mining approach in order to find models that improve the classification accuracy of the genes studied. METHODS: We built predictive models using different subsets of factors, selected according to their importance in predicting patient classification. We then evaluated each independent model and also a combination of them, leading to a better predictive model. RESULTS: Our data mining approach identified genetic patterns that escaped detection using conventional statistics. More specifically, the partial decision trees and ensemble models increased the classification accuracy of hepatitis C virus outcome compared with conventional methods. CONCLUSIONS: Data mining can be used more extensively in biomedicine, facilitating knowledge building and management of human diseases.

Metalloproteinases 1 and 3 as Potential Biomarkers in Breast Cancer Development.

Breast cancer continues to be one of the main causes of morbidity and mortality globally and was the leading cause of cancer death in women in Spain in 2020. Early diagnosis is one of the most effective methods to lower the incidence and mortality rates of breast cancer. The human metalloproteinases (MMP) mainly function as proteolytic enzymes degrading the extracellular matrix and plays important roles in most steps of breast tumorigenesis. This retrospective cohort study shows the immunohistochemical expression levels of MMP-1, MMP-2, MMP-3, and MMP-9 in 154 women with breast cancer and 42 women without tumor disease. The samples of breast tissue are assessed using several tissue matrices (TMA). The percentages of staining (≤50%->50%) and intensity levels of staining (weak, moderate, or intense) are considered. The immunohistochemical expression of the MMP-1-intensity (p = 0.043) and MMP-3 percentage (p = 0.018) and intensity, (p = 0.025) present statistically significant associations with the variable group (control-case); therefore, expression in the tumor tissue samples of these MMPs may be related to the development of breast cancer. The relationships between these MMPs and some clinicopathological factors in breast cancer are also evaluated but no correlation is found. These results suggest the use of MMP-1 and MMP-3 as potential biomarkers of breast cancer diagnosis.

Hepatitis E virus in Spanish donors and the necessity for screening.

Hepatitis E virus (HEV) represents a major health problem worldwide. As the course of HEV cases is often subclinical, asymptomatic infections could represent an important source of viral spread and infection via routes such as blood donations. Before universal screening for HEV in blood donations can be implemented, studies evaluating the incidence of infection are needed to establish the potential risk of viral transmission. This is a prospective longitudinal study that included blood donors recruited at the Hospital de Ciudad Real Transfusion Service between October 2017 and January 2018. Pools of eight donations were tested for HEV viremia by PCR. Positive pools were individually evaluated following the same procedure. Positive samples were tested for anti-HEV IgG and IgM. Recipients of blood transfusions obtained from HEV-positive donors were retrospectively evaluated. The prevalence of HEV was calculated. A total of 11 313 healthy donors were analysed during the study period. Four blood donations from four different donors were HEV RNA-reactive. The prevalence of HEV infection was 0.035% (95% CI: 0.01%-0.09%), which meant a ratio of one positive donation per 2828 donations. All donors were negative for anti-HEV IgM at the time of the donation. Five patients received transfusions from HEV-positive blood donations, none of them showed an increase in alanine aminotransferase levels after transfusion. In conclusion, our study found a high prevalence of HEV infection in blood donors from south-central Spain. In view of the prevalence, Spanish blood banks should carefully consider including screening for HEV.

Optimisation in the multidisciplinary approach to patients with hepatitis C in the era of direct-acting antivirals. / Optimización en el abordaje multidisciplinar del paciente con hepatitis C en la era de los antivirales de acción directa.

The advents of current direct-acting antiviral treatments has revolutionised the therapeutic approach to hepatitis C, increasing cure rates to above 90% and substantially simplifying treatment, which translates into benefits for patients, clinicians and the health system. These new drugs allow cure to be achieved, irrespective of the patient's characteristics, with tolerability similar to that of placebo and few drug reactions with concomitant medication. This in turn improves patients' quality of life and wellbeing. Moreover, these drugs allow multidisciplinary optimisation of the approach to patients with hepatitis C, thus reducing both short- and long-term costs. All these factors facilitate treatment universality, with treatments that are less influenced by specific factors and that allow better results to be obtained in a larger number of patients. Elimination of hepatitis C is now a real possibility. Supplement information: This article is part of a supplement entitled "The value of simplicity in hepatitis C treatment", which is sponsored by Gilead. © 2019 Elsevier España, S.L.U. All rights reserved.

Prevalence of hepatitis E virus infection in wild boars from Spain: a possible seasonal pattern?

BACKGROUND: It has been shown that wildlife can serve as natural reservoirs of hepatitis E virus (HEV). The wild boar (Sus scrofa) is probably the main natural reservoir of HEV and could therefore represent an important route of transmission in Europe, especially in regions where game meat is widely consumed. We evaluated the prevalence of HEV infection in wild boar in the south of Spain, with the aim of identifying associated risk factors. A cross-sectional study that included hunted wild boar was carried out during the 2015/2016 hunting season (October 15 to February 15) in Andalusia (southern Spain). The outcome variable was HEV infection, defined as amplification of HEV RNA in serum by RT-PCR. RESULTS: A total of 142 animals, selected from 12 hunting areas, were included and formed the study population. Thirty-three wild boars (23.2%; 95% CI: 16.8%-30.7%) were positive for HEV infection. Prevalence peaked in October and November, then gradually declined until the end of December. After multivariate analysis, only hunting date was independently associated with HEV infection across sex and age. CONCLUSIONS: Our study found a relatively high prevalence of HEV infection in wild boar in the south of Spain, suggesting that prevalence may depend on the season when the animal is hunted. In consequence, the potential risk of zoonotic transmission could fluctuate.

Hepatitis E Virus (HEV) Infection in Anti-HEV Immunoglobulin G-Carrying Patients After Successful Hepatitis C Virus Treatment: Reactivation or Reinfection?

Although hepatitis E virus (HEV) is regarded as a self-limiting infection and anti-HEV antibodies seem to protect against reinfection, its pathogenesis is not well established. We describe 2 cases of acute symptomatic HEV infection after hepatitis C therapy in patients carrying anti-HEV immunoglobulin G antibodies, raising 2 major questions: reactivation or reinfection?

Low risk of liver decompensation among human immunodeficiency virus/hepatitis C virus-coinfected patients with mild fibrosis in the short term.

UNLABELLED: Liver fibrosis is used to make decisions about the timing of therapy against hepatitis C virus (HCV) in routine clinical practice, which should be based on the short-term likelihood of liver decompensations. Thus, we aimed at evaluating the risk of decompensations and death among human immunodeficiency virus (HIV)/HCV-coinfected individuals according to their baseline fibrosis classified by either liver biopsy or liver stiffness measurement (LSM). Patients coinfected with HIV/HCV, naive or without sustained virological response to HCV therapy, were included in this cohort. Fibrosis was classified by biopsy in 683 patients and by LSM in 1046 individuals. Reference categories were fibrosis stage 0 and LSM <6 kPa. For patients with biopsy, the adjusted subhazard ratio for decompensations and 95% confidence interval (95% CI) by fibrosis stage were as follows: stage 1, 2.3 (0.27-20.3), P = 0.443; stage 2, 2.8 (0.33-24), P = 0.345; stage 3, 4.91 (0.60-41), P = 0.137; stage 4, 9.89 (1.25-79.5), P = 0.030. For patients with LSM, the adjusted subhazard ratio and 95% CI by LSM category were as follows: 6-9.4 kPa, 1.89 (0.18-20.3), P = 0.599; 9.5-14.5 kPa, 6.59 (0.73-59.2), P = 0.092; ≥14.6 kPa, 59.5 (8.3-427), P < 0.0001. Regarding the risk of death, the adjusted hazard ratio and 95% CI for death by fibrosis stage were as follows: stage 1, 1.3 (0.4-4.11), P = 0.677; stage 2, 2.68 (0.86-8.36), P = 0.090; stage 3, 2.58 (0.82-8.15), P = 0.106; stage 4, 4.35 (1.43-13.3), P = 0.010. For patients with LSM, the adjusted hazard ratio and 95% CI for death by LSM were as follows: 6-9.4 kPa, 1.7 (0.63-4.79), P = 0.288; 9.5-14.5 kPa, 3.38 (1.2-9.5), P = 0.021; ≥14.6 kPa, 12.7 (4.9-33.6), P < 0.0001. CONCLUSION: Patients coinfected with HIV/HCV without advanced fibrosis are at very low risk of decompensations in the short term; deferral of HCV therapy for a few years and monitoring fibrosis progression is a safe option until cheaper, more effective, and more convenient HCV treatment becomes widely available.

Progression of liver stiffness predicts clinical events in HIV/HCV-coinfected patients with compensated cirrhosis.

BACKGROUND: Our objective was to assess the predictive value of the changes of liver stiffness (LS) for clinical outcome in HIV/HCV-coinfected patients with compensated liver cirrhosis and a LS value < 40 kPa. METHODS: Prospective cohort of 275 HIV/HCV-coinfected patients with cirrhosis, no previous liver decompensation (LD) and LS < 40 kPa. The time from diagnosis to LD and/or hepatocellular carcinoma (HCC) and the predictors of this outcome were evaluated. Significant progression of LS was defined as an increase ≥ 30 % over the baseline value at any time during the follow-up. RESULTS: After a median (Q1-Q3) follow-up of 32 (20-48) months, 19 (6.9 %, 95 % CI: 3.8 %-9.9 %) patients developed a first LD and/or HCC. At the end of the follow-up, 247 (90 %) patients had undergone a further LS examination. Of them, 77 (31 %) patients had a significant progression of LS. The mean (SD) survival time free of LD and/or HCC was 67 (3) and 77 (1) months in patients with or without significant progression of LS (p = 0.01). Significant progression of LS was an independent predictor of LD and/or HCC (Adjusted Hazard Ratio 4.63; 95 % confidence interval: 1.34-16.02; p = 0.015). CONCLUSIONS: Significant progression of LS is associated with a higher risk of clinical events in HIV/HCV-coinfected patients with compensated cirrhosis and LS < 40 kPa.

Rationale and Design of a Randomized Controlled Trial Evaluating Whole Muscle Exercise Training Effects in Outpatients with Pulmonary Arterial Hypertension (WHOLEi+12).

BACKGROUND AND AIMS: Physical exercise is an important component in the management of pulmonary artery hypertension (PAH). The aim of this randomized controlled trial (RCT) is to determine the effects of an 8-week intervention combining muscle resistance, aerobic and inspiratory pressure load exercises in PAH outpatients. METHODS: The RCT will be conducted from September 2015 to September 2016 following the recommendations of the Consolidated Standards of Reported Trials (CONSORT), with a total sample size of n ≥ 48 (≥24 participants/group). We will determine the effects of the intervention on: (i) skeletal-muscle power and mass (primary end points); and (ii) NT-proBNP, cardiopulmonary exercise testing variables (VO2peak, ventilatory equivalent for CO2 at the anaerobic threshold (VE/VCO2 at the AT), end-tidal pressure of CO2 at the anaerobic threshold (PETCO2 at the AT), 6-min walking distance (6MWD), maximal inspiratory pressure (PImax), health-related quality of life (HRQoL), objectively-assessed spontaneous levels of physical activity, and safety (secondary end points). CONCLUSIONS AND PERSPECTIVES: This trial will provide insight into biological mechanisms of the disease and indicate the potential benefits of exercise in PAH outpatients, particularly on muscle power.

Efficient control of coulomb enhanced second harmonic generation from excitonic transitions in quantum dot ensembles.

In this work, the second harmonic generation from excitonic transitions in semiconductor quantum dots is computationally studied. By integrating a density matrix treatment with a partial configuration interaction approach, we obtain the second order susceptibility as a function of externally applied electric and magnetic fields for highly confined neutral and charged excitons. Our results show an enhancement in the nonlinear response with respect to analogous optical processes based on intraband transitions, and predict their efficient tunability by taking advantage of the interplay between Coulomb effects and field-driven wave function manipulation.

High prevalence of antibodies against hepatitis E virus in HIV-infected patients with unexplained liver disease.

OBJECTIVE: To look for evidence of hepatitis E virus (HEV) exposure in HIV-infected patients with unexplained elevations of liver stiffness (LS). METHODS: Case-control study conducted in 31 HIV-infected patients with unexplained elevations of LS and in 31 HIV-controls with normal LS, matched by age, sex and CD4 cell-counts. Serum HEV antibodies were tested by two ELISA procedures and by Immunoblot. We defined exposure to HEV as the detection of serum HEV antibodies by at least one of the two ELISA assays, provided that it was confirmed by Immunoblot. A real-time PCR RNA assay was conducted in all plasma samples to identify subjects with active HEV infection. RESULTS: Exposure to HEV was demonstrated, according to the criteria used in this study, in 9 (29%) of the cases, whereas it was shown in 5 (16%) of the controls (p=.3). Serum HEV RNA was detected in none of the controls and in only in one case. This patient had a documented chronic hepatitis E with progression to cirrhosis. CONCLUSIONS: HEV antibodies are frequently found in HIV-infected patients with unexplained liver disease.

A 24-week treatment strategy with pegylated interferon/ribavirin in HIV/hepatitis C virus genotype 3-coinfected patients who achieved a rapid virologic response results in a high sustained virologic response rate.

We designed a study to evaluate the efficacy of a 24-week treatment strategy in HIV/hepatitis C virus (HCV) genotype 3-coinfected patients achieving rapid virologic response for a first HCV treatment with pegylated interferon plus ribavirin (peg-IFN/RBV). Our results suggest that a shorter course of peg-IFN/RBV therapy may be sufficient in this population.

[Positioning of lopinavir/ritonavir in antiretroviral treatment schemes]. / Posicionamiento de lopinavir/ritonavir en los esquemas de la terapia antirretroviral.

Lopinavir/ritonavir (LPV/r) was approved for use in the treatment of human immunodeficiency virus (HIV) infection in 2001 and is the protease inhibitor that has been most widely studied in clinical trials. Despite the time interval since its approval, all the evidence accumulated in the last 14 years indicates that LPV/r continues to occupy an important position among antiretroviral drugs. Firstly, LPV/r plus 2 nucleoside/nucleotide analogs is still considered a good option for initial antiretroviral therapy (ART). Secondly, numerous studies have evaluated the efficacy and safety of new initial ART strategies based on LPV/r in dual therapy. The results obtained suggest that LPV/r plus lamivudine (3TC) or raltegravir can be as effective in initial ART as standard triple therapy and justify their consideration as alternative regimens in this scenario. Thirdly, LPV/r is a pioneer drug, as well as being the agent with the largest amount of evidence from clinical trials on simplification to monotherapy (LPV/r) or dual therapy (LPV/r + 3TC). Lastly, LPV/r is highly useful is special situations. It has a low risk of liver toxicity in patients with chronic liver disease, its use is preferred in the treatment of patients with HIV-2, and it is safe and effective in preventing vertical HIV transmission.

A Retrospective Study on tDCS Treatment in Patients with Drug-Resistant Chronic Pain.

Background. Transcranial direct current stimulation (tDCS) of the primary motor cortex (M1) has an analgesic effect superior to a placebo in chronic pain. Some years ago, tDCS was implemented at the Hospital Nacional of Paraplegics (Toledo, Spain) to treat patients with pharmacological resistance to chronic pain. Objective. The main objectives of this study with tDCS were (1) to confirm the safety of one-year treatment; (2) to estimate the number of patients after one year in treatment; (3) to describe the effects of tDCS on the pain intensity during one-year treatment; and (4) to identify factors related to treatment success. Methods. This was a retrospective study conducted at the National Hospital for Paraplegics with 155 patients with pharmacologically resistant chronic pain. Anodal tDCS was applied over the M1 for 20 min at 1.5 mA for 10 treatment sessions from Monday to Friday (Induction phase), followed by 2-3 sessions per month (Maintenance phase). Pain intensity was assessed using a Visual Analogue Scale (VAS). Results. Anodal tDCS on M1 confirmed the reduction in the pain intensity. Moreover, 58% of outpatients completed one year of treatment. Only the VAS values obtained during the baseline influenced the response to treatment. Patients with a very high VAS at the baseline were more likely to not respond adequately to tDCS treatment. Conclusions. Anodal tDCS over M1 is an adequate therapy (safe and efficient) to treat drug-resistant chronic pain. Moreover, pain intensity at the start of treatment could be a predictor of patients' continuity with tDCS for at least one year.

Effectiveness and safety of bictegravir/emtricitabine/tenofovir alafenamide in HIV late presenters.

OBJECTIVES: The efficacy of BIC/FTC/TAF in HIV late presenters initiating antiretroviral therapy (ART) has not been sufficiently evaluated. METHODS: The aim of this study was to assess the effectiveness and tolerability of BIC/FTC/TAF compared to other first-line antiretroviral regimens in treatment-naïve adult individuals from the CoRIS Cohort starting ART with CD4 counts <200 cells/mm3 and/or AIDS-defining conditions between January 1st 2019 and November 30th 2020. Logistic regression models were used to estimate odds ratios (ORs) of association between initial regimen and achievement of viral suppression (VS) (primary objective), defined as HIV RNA <50 cop/mL, and immunological recovery (IR) (secondary objective), defined as CD4 count >200 cells/mm3, at weeks 24 and 48 after initiation of ART. RESULTS: We evaluated 314 individuals (84.7% men, median age 40 years). Of them, 158 initiated with BIC/FTC/TAF. At inclusion, 117 had an AIDS-defining condition. In multivariable analyses, individuals with AIDS-defining conditions initiating ART with BIC/FTC/TAF achieved higher rates of VS at 24 weeks than other regimens (aOR: 0.2; 95% CI: 0.06-0.64) and, at 48 weeks, than DTG/ABC/3TC (aOR: 0.06; 95% CI: 0.01-0.76) and DTG + TDF/3TC (aOR: 0.2; 95% CI: 0.47-0.9). No other differences in VS or IR were observed. At 24 and 48 weeks after ART initiation, treatment discontinuations were lower with BIC/FTC/TAF than with other regimens (3.2% and 7.6% vs. 24.4% and 37.8%, respectively; P < 0.005). CONCLUSION: Our results suggest that BIC/FTC/TAF could be a preferred regimen as initial therapy in HIV late presenters because of its high effectiveness and good tolerability.

Breast Cancer in a Filipino Male: A Case Report and Brief Literature Review.

This is a case report of a 76-year-old Filipino male who presented with a six-year history of a steadily growing left breast mass. The mass was eventually diagnosed to be Invasive Ductal Carcinoma, Anatomic and Prognostic Stage IIIB (T4b cN0 M0), Grade 3, Luminal A. Subsequently, the patient underwent neoadjuvant chemotherapy of doxorubicin/cyclophosphamide and paclitaxel, followed by modified radical mastectomy with axillary lymph node dissection, concluded by post-mastectomy radiation therapy. The patient had complete clinical response to this trimodality therapy. The rarity of this case is juxtaposed and integrated with the present literature on male breast cancer.

Fatigue insights from walking tests in spinal cord injury and multiple sclerosis individuals.

In the last decade, fatigue in clinical populations has been re-conceptualized, including dimensions such as perceived fatigue (trait and state fatigue) and fatigability. The aim of this study was to evaluate different expressions of fatigue in Spinal Cord Injury (SCI) and Multiple Sclerosis (MS) participants compared to able-bodied controls, during activities of daily living, especially during gait. A total of 67 participants were included in this study (23 with SCI, 23 with MS, and 21 able-bodied controls). All participants performed two functional tests (6-Minute Walk Test and 10-Meter Walk Test) and they completed the Fatigue Severity Scale (FSS). The rate of trait fatigue was different between groups, with MS participants showing the highest rate. Moreover, scores on functional tests and state fatigue were different between groups after the tests. Our results indicate that trait fatigue and state fatigue in individuals with SCI and MS are different with respect to able-bodied population. Both SCI and MS groups experienced more trait fatigue than control group in daily life. In addition, walking tasks produced similar levels of state fatigue between healthy people and patients with MS/SCI. However, these tests induced longer-lasting levels of state fatigue in the patients.

Value of exercise right heart catheterization in the differential diagnosis of chronic thromboembolic pulmonary disease.

INTRODUCTION AND OBJECTIVES: Chronic thromboembolic disease refers to the presence of chronic thrombotic pulmonary vascular thrombosis without pulmonary hypertension (PH) at rest but with exercise limitation after pulmonary embolism (PE). Our aim was to evaluate the hemodynamic response to exercise in these patients and its correlation with the values reached in cardiopulmonary exercise testing. METHODS: We included symptomatic patients with persistent pulmonary thrombosis after PE. We excluded patients with left heart disease or significant PH (mean pulmonary arterial pressure [mPAP] >25mmHg, pulmonary vascular resistance >3 WU, and pulmonary capillary wedge pressure [PCWP] >15mmHg). Cardiopulmonary exercise testing and exercise right heart catheterization were performed. Exercise-induced precapillary PH was defined as mPAP/CO slope >3 and PCWP/CO slope <2mmHg/l/min. The hemodynamic response and the values obtained in cardiopulmonary exercise testing were compared between patients with and without exercise-induced precapillary PH. RESULTS: We studied 36 patients; 4 were excluded due to incomplete hemodynamic data. Out of the 32 patients analyzed; 3 developed a pathological increase in PCWP. Among the remaining 29 patients (mean age, 49.4±13.7 years, 34.5% women), 13 showed exercise-induced PH. Resting mPAP was higher in those who developed exercise-induced PH (23.3±5.4 vs 19.0±3.8mmHg; P=.012), although CO was similar in the 2 groups. Patients with exercise-induced PH exhibited data of ventilatory inefficiency with reduced values of end-tidal CO2 pressure at the anaerobic threshold (32.8±3.0 vs 36.2±3.3mmHg; P=.021) and a higher Ve/VCO2 slope (34.2±4.8 vs 30.7±5.0; P=.049). CONCLUSIONS: Exercise limitation and ventilatory inefficiency could be attributable to exercise-induced precapillary PH in a subgroup of patients with persistent pulmonary thrombosis and dyspnea.