Miracle-dz/UniFAR-FTUs huggingface dataset:
Rifampicin effect on intracellular and plasma pharmacokinetics of tenofovir alafenamide.

OBJECTIVES Tenofovir alafenamide produces lower plasma tenofovir and higher intracellular tenofovir diphosphate (DP) concentrations than tenofovir disoproxil fumarate but it is likely a victim of interactions with rifampicin. We aimed to investigate the pharmacokinetics of tenofovir alafenamide/emtricitabine with rifampicin. PATIENTS AND METHODS Healthy volunteers received tenofovir alafenamide/emtricitabine at 25/200 mg once daily, followed by tenofovir alafenamide/emtricitabine + rifampicin daily followed by tenofovir disoproxil fumarate. Plasma tenofovir alafenamide, tenofovir, emtricitabine and intracellular tenofovir-DP and emtricitabine triphosphate pharmacokinetics and genetic polymorphisms were assessed. RESULTS Tenofovir alafenamide exposure decreased when tenofovir alafenamide/emtricitabine + rifampicin was used compared with tenofovir alafenamide/emtricitabine [geometric mean ratio (GMR) (90% CI): 0.45 (0.33-0.60)]. Plasma tenofovir and intracellular tenofovir-DP concentrations decreased with rifampicin [GMR (90% CI): 0.46 (0.40-0.52) and 0.64 (0.54-0.75), respectively]. GMR (90% CI) of intracellular tenofovir-DP AUC0-24 for tenofovir alafenamide/emtricitabine + rifampicin versus tenofovir disoproxil fumarate was 4.21 (2.98-5.95). Rifampicin did not affect emtricitabine pharmacokinetics. CYP3A4*22 rs35599367 was associated with higher plasma tenofovir alafenamide AUC0-24 at day 56. CONCLUSIONS Following tenofovir alafenamide/emtricitabine administration with rifampicin, intracellular tenofovir-DP concentrations were still 4.21-fold higher than those achieved by tenofovir disoproxil fumarate, supporting further study during HIV/TB co-infection.
SS18-SSX–Dependent YAP/TAZ Signaling in Synovial Sarcoma

Purpose: Synovial sarcoma is a soft tissue malignancy characterized by a reciprocal t(X;18) translocation. The chimeric SS18-SSX fusion protein acts as a transcriptional dysregulator representing the major driver of the disease; however, the signaling pathways activated by SS18-SSX remain to be elucidated to define innovative therapeutic strategies. Experimental Design: Immunohistochemical evaluation of the Hippo signaling pathway effectors YAP/TAZ was performed in a large cohort of synovial sarcoma tissue specimens. SS18-SSX dependency and biological function of the YAP/TAZ Hippo signaling cascade were analyzed in five synovial sarcoma cell lines and a mesenchymal stem cell model in vitro. YAP/TAZ-TEAD–mediated transcriptional activity was modulated by RNAi-mediated knockdown and the small-molecule inhibitor verteporfin. The effects of verteporfin were finally tested in vivo in synovial sarcoma cell line-based avian chorioallantoic membrane and murine xenograft models as well as a patient-derived xenograft. Results: A significant subset of synovial sarcoma showed nuclear positivity for YAP/TAZ and their transcriptional targets FOXM1 and PLK1. In synovial sarcoma cells, RNAi-mediated knockdown of SS18-SSX led to significant reduction of YAP/TAZ-TEAD transcriptional activity. Conversely, SS18-SSX overexpression in SCP-1 cells induced aberrant YAP/TAZ-dependent signals, mechanistically mediated by an IGF-II/IGF-IR signaling loop leading to dysregulation of the Hippo effectors LATS1 and MOB1. Modulation of YAP/TAZ-TEAD–mediated transcriptional activity by RNAi or verteporfin treatment resulted in significant growth inhibitory effects in vitro and in vivo. Conclusions: Our preclinical study identifies an elementary role of SS18-SSX–driven YAP/TAZ signals, highlights the complex network of oncogenic signaling pathways in synovial sarcoma pathogenesis, and provides evidence for innovative therapeutic approaches.
Mental Contrasting With Implementation Intentions Reduces Drinking When Drinking Is Hazardous: An Online Self-Regulation Intervention

Introduction. Drinking alcohol has detrimental health consequences, and effective interventions to reduce hazardous drinking are needed. The self-regulation intervention of Mental Contrasting with Implementation Intentions (MCII) promotes behavior change across a variety of health behaviors. In this study, we tested if online delivery of MCII reduced hazardous drinking in people who were worried about their drinking. Method. Participants (N = 200, female = 107) were recruited online. They were randomized to learn MCII or solve simple math problems (control). Results. Immediately after the intervention, participants in the MCII condition (vs. control) reported an increased commitment to reduce drinking. After 1 month, they reported having taken action measured by the Readiness to Change drinking scale. When drinking was hazardous (Alcohol Use Disorders Identification Test ≥ 8, n = 85), participants in the MCII condition indicated a decreased number of drinking days, exp(β) = 0.47, CI (confidence interval) [−1.322, −. 207], p = . 02, and drinks per week, exp(β) = 0.57, CI [0.94, 5.514], p = . 007, compared with the control condition. Discussion. These findings demonstrate that a brief, self-guided online intervention (Mdn = 28 minutes) can reduce drinking in people who worry about their drinking. Our findings show a higher impact in people at risk for hazardous drinking. Conclusion. MCII is scalable as an online intervention. Future studies should test the cost-effectiveness of the intervention in real-world settings.
Columnar clusters in the human motion complex reflect consciously perceived motion axis

Significance Existing knowledge of how cortical responses link to conscious content in humans is either inferred from animal models or from human studies limited by lower spatial resolution. While previous studies could relate distinct categorical percepts (faces vs. places) to signal differences across brain areas, measuring responses at submillimeter resolution allowed us to link subcategory conscious percepts (vertical vs. horizontal motion) to amplitude changes of separate populations within the same brain area. Furthermore, preferences for horizontal and vertical motion were organized into columnar clusters. We pave the way for future studies investigating if columnar clusters represent subcategorical distinctions in conscious content different from motion or in high-level perceptual and cognitive phenomena. The specific contents of human consciousness rely on the activity of specialized neurons in cerebral cortex. We hypothesized that the conscious experience of a specific visual motion axis is reflected in response amplitudes of direction-selective clusters in the human motion complex. Using submillimeter fMRI at ultrahigh field (7 T) we identified fine-grained clusters that were tuned to either horizontal or vertical motion presented in an unambiguous motion display. We then recorded their responses while human observers reported the perceived axis of motion for an ambiguous apparent motion display. Although retinal stimulation remained constant, subjects reported recurring changes between horizontal and vertical motion percepts every 7 to 13 s. We found that these perceptual states were dissociatively reflected in the response amplitudes of the identified horizontal and vertical clusters. We also found that responses to unambiguous motion were organized in a columnar fashion such that motion preferences were stable in the direction of cortical depth and changed when moving along the cortical surface. We suggest that activity in these specialized clusters is involved in tracking the distinct conscious experience of a particular motion axis.
Detection of Anti-Cardiolipin and Anti-β2glycoprotein I Antibodies Differs between Platforms without Influence on Association with Clinical Symptoms

Abstract Background The anti-phospholipid syndrome (APS) is characterized by thrombosis and/or pregnancy morbidity with persistent presence of anti-phospholipid antibodies (aPL). Laboratory criteria include aPL detection by coagulation tests for lupus anticoagulant (LAC) or solid phase assays measuring anti-β2 glycoprotein I (aβ2GPI) or anti-cardiolipin (aCL) immunoglobulin (Ig) G/IgM antibodies. External quality control programs illustrate that commercially available aPL assays produce variable results. Objective We aimed to investigate the agreement and diagnostic accuracy of solid phase assays. Materials and Methods In this multi-centre study, 1,168 patient samples were tested on one site for aCL and aβ2GPI IgG/IgM antibodies by four solid phase test systems. Samples included APS patients, controls and monoclonal antibodies (MoAB) against different epitopes of β2GPI. LAC was determined by the local centre. Results aCL IgM assays resulted in the most discrepancies (60%), while aCL IgG and aβ2GPI IgM assays resulted in lower discrepancies (36%), suggesting better agreement. Discrepant samples displayed lower median aPL titers. Dependent on the solid phase test system, odds ratios (ORs) for thrombosis and pregnancy morbidity ranged from 1.98 to 2.56 and 3.42 to 4.78, respectively. Three platforms showed lower sensitivity for MoAB directed against the glycine (Gly) 40-arginine (Arg) 43 epitope of domain I of β2GPI. Conclusion Poor agreement was observed between different commercially available aCL and aβ2GPI IgG/IgM assays, hampering uniformity in the identification of aPL-positive patients. Clinical association was globally concordant between solid phase test systems considering results of the four aPL together. An assay sensitive in detecting the MoAB against Gly40-Arg43 of domain I of β2GPI reached the highest OR for thrombosis.
Extracellular fluid volume expansion, arterial stiffness and uncontrolled hypertension in patients with chronic kidney disease.

BACKGROUND Hypertension is prevalent in patients with chronic kidney disease (CKD) and is related to extracellular fluid volume (ECFV) expansion. Arterial stiffening is another implication of CKD that can be caused by ECFV expansion. In this study, we hypothesized that CKD patients with uncontrolled hypertension are more likely to be fluid volume expanded than normotensive patients, which in turn is associated with increased arterial stiffness. METHODS Adult hypertensive patients with mild-severe CKD (n = 82) were recruited. ECFV was assessed using multifrequency bioimpedance and arterial stiffness by applanation tonometry and oscillometry. RESULTS Patients with uncontrolled hypertension had fluid volume expansion compared with controls (1.0 ± 1.5 versus 0.0 ± 1.6 L, P < 0.001), and had a higher augmentation index (AIx) and pulse wave velocity. Fluid volume expansion was more prevalent in patients with uncontrolled hypertension (58%) than patients who were at target (27%). Fluid volume expansion was correlated with age, AIx and systolic blood pressure. In a binary logistic regression analysis, AIx, age and fluid volume status were independent predictors of uncontrolled hypertension in both univariate and multivariate models. DISCUSSION In summary, uncontrolled hypertension among hypertensive CKD patients is associated with ECFV expansion. Our data suggest a relationship between ECFV expansion, increased arterial stiffness and uncontrolled hypertension.
Repeated transarterial chemoembolization in the treatment of liver metastases of colorectal cancer: prospective study.

PURPOSE To evaluate local tumor control and survival data after transarterial chemoembolization with different drug combinations in the palliative treatment of liver metastases in patients with colorectal cancer. MATERIALS AND METHODS The study was approved by institutional review board, and informed consent was obtained from all patients included in the study. A total of 463 patients (mean age, 62.5 years; range, 34.7-88.1 years) with unresectable liver metastases of colorectal cancer that did not respond to systemic chemotherapy were repeatedly treated with chemoembolization in 4-week intervals. In total, 2441 chemoembolization procedures were performed (mean, 5.3 sessions per patient). Of 463 patients, 67.4% had multiple (five or more) metastases, 8% had one metastasis, 10.4% had two metastases, and 14.3% had three or four metastases. The local chemotherapy protocol consisted of mitomycin C alone (n = 243), mitomycin C with gemcitabine (n = 153), or mitomycin C with irinotecan (n = 67). Embolization was performed with lipiodol and starch microspheres for vessel occlusion. Tumor response was evaluated with magnetic resonance imaging. The change in tumor size was calculated and the response was evaluated according to the Response Evaluation Criteria in Solid Tumors. Survival rates from first diagnosis and from first chemoembolization session were calculated according to the Kaplan-Meier method. Follow-up imaging was performed until patient death. RESULTS Evaluation of local tumor control resulted in partial response (68 patients [14.7%]), stable disease (223 patients [48.2%]), and progressive disease (172 patients [37.1%]). The 1-year survival rate after chemoembolization was 62%, and the 2-year survival rate was 28%. Median survival from date of diagnosis of liver metastases was 38 months and from the start of chemoembolization treatment was 14 months. There was no statistically significant difference between the three treatment protocols. CONCLUSION Chemoembolization is a minimally invasive therapy option for palliative treatment of liver metastases in patients with colorectal cancer, with similar results among three chemoembolization protocols.
Type 2 Diabetes Self-Management Barriers in Older Adults: An Integrative Review of the Qualitative Literature.

Type 2 diabetes is a prevalent chronic health condition more frequently affecting adults ages 65 and older. Furthermore, these individuals tend to have more type 2 diabetes-associated complications, compared with younger individuals with diabetes, and face unique challenges throughout the self-management process. Despite many studies and reviews about diabetes self-management, few researchers focus specifically on older adults. Of particular importance is the need to understand self-management challenges through the patient's lens. Therefore, the purpose of the current review is to examine and summarize the qualitative literature concerning type 2 diabetes self-management barriers in older adults. Following critical appraisal of literature published from 2007-2018, 10 articles were reviewed and content analysis performed. Four themes emerged: Lack of Knowledge and Understanding, Self-Management Implementation Challenges, Culture and Language Barriers, and Health Care Providers as a Perceived Barrier. The state of the qualitative science, implications for nursing practice, and recommendations for future research are discussed. [Journal of Gerontological Nursing, 45(3), 43-54. ].
The dynamics of preferential host switching: Host phylogeny as a key predictor of parasite distribution *

Parasites often jump to and become established in a new host species. There is much evidence that the probability of such host shifts decreases with increasing phylogenetic distance between donor and recipient hosts, but the consequences of such preferential host switching remain little explored. We develop a computational model to investigate the dynamics of parasite host shifts in the presence of this phylogenetic distance effect. In this model, a clade of parasites evolves on an evolving clade of host species where parasites can cospeciate with their hosts, switch to new hosts, speciate within hosts or become extinct. Our model predicts that host phylogenies are major determinants of parasite distributions across trees. In particular, we predict that trees consisting of few large clades of host species and those with fast species turnover should harbor more parasites than trees with many small clades and those that diversify more slowly. Within trees, large clades are predicted to exhibit a higher fraction of infected species than small clades. We discuss our results in the light of recent cophylogenetic studies in a wide range of host–parasite systems.
Phytoplasmas Associated with Elm Yellows: Molecular Variability and Differentiation from Related Organisms.

Restriction fragment length polymorphism (RFLP) analyses were performed on polymerase chain reaction (PCR) amplimers of phytoplasmal DNA from eight samples obtained from Ulmus spp. (elms) affected by elm yellows (EY) in Italy and the United States, from Catharanthus roseus infected with strain EY1, and from five other plant species infected with phytoplasmas of the EY group sensu lato (group 16SrV). RFLP profiles obtained with restriction enzyme TaqI from ribosomal DNA amplified with primer pair P1/P7 differentiated elm-associated phytoplasmas from strains originally detected in Apocynum cannabinum, Prunus spp. , Rubus fruticosus, Vitis vinifera, and Ziziphus jujuba. RFLP profiles obtained similarly with BfaI differentiated strains from A. cannabinum and V. vinifera from other phytoplasmas of group 16SrV. Elm-associated strains from within the United States had two RFLP patterns in ribosomal DNA based on presence or absence of an RsaI site in the 16S-23S spacer. Elm-associated phytoplasma strains from Italy were distinguished from those of American origin by RFLPs obtained with MseI in the same fragment of non-ribosomal DNA. Strain HD1, which was discovered in A. cannabinum associated with EY-diseased elms in New York State, was unique among the strains studied.
Chronic Pulmonary Aspergillosis in Patients with Underlying Respiratory Disorders in Cuba—A Pilot Study

Chronic pulmonary aspergillosis (CPA) is a fungal infection with high mortality and morbidity rates. This disease is caused by several Aspergillus species and affects patients with an underlying respiratory condition. This pilot study aims to recognize CPA among patients with different respiratory diseases. Twenty-one out of 47 patients were classified as CPA based on the examination of clinical signs and symptoms, radiological findings, mycological culture of respiratory samples and analysis of Aspergillus IgG antibodies. There was a close association between high levels of Aspergillus IgG antibodies and the presence of cavities. Although Aspergillus flavus was the predominant species among clinical isolates, the number of isolates was small to reach conclusions on the prevalence of this species as main cause of CPA in Cuba. From the eleven evaluable patients for the treatment with itraconazole (Lozartil®), nine improved their health status while two did not show any recovery. This drug is included in the therapy schemes for aspergillosis in Cuba.
Computational insights into the interaction mechanisms of estrogen‐related receptor alpha with endogenous ligand cholesterol

Estrogen‐related receptor alpha (ERRα) has attracted increasing concerns. ERRα, orphan nuclear receptor, plays important roles in energy metabolism. Therefore, small molecule agonists of ERRα could be a potential therapeutic strategy in the treatment of metabolic diseases such as diabetes. Recently, Wei et al. identified cholesterol as the endogenous agonist of ERRα. However, the detailed molecular mechanism of cholesterol bound with ERRα remains ambiguous. Thus, in this study molecular docking and molecular dynamics (MD) simulations were performed to characterize how cholesterol affects the behavior of ERRα. Based on the results, we found that a proven residue Phe232 and others including Leu228, Glu235, Arg276, and Phe399 were key residues to ligand binding. A hydrogen‐bonding interaction between cholesterol and Glu235 ensured the orientation of the ligand in the binding pocket, while hydrophobic interactions between cholesterol and the above‐mentioned residues promoted the stability of ERRα‐cholesterol complex. In the presence of the proliferator‐activated receptor γ coactivator 1α (PGC‐1α), the cholesterol‐ERRα interaction became more stable. Interestingly, we observed that cholesterol facilitated the binding of ERRα with its coactivator PGC‐1α via stabilizing the conformation of helix 12 and the interaction surface of ERRα/PGC‐1α. Overall, these findings would be valuable for the future rational design of novel ERRα agonists.
Ozone therapy in 65 patients with fibromyalgia: an effective therapy.

OBJECTIVE Fibromyalgia is a chronic disorder with a very complex symptomatology. Although generalized severe pain is considered to be the cardinal symptom of the disease, many other associated symptoms, especially non-restorative sleep, chronic fatigue, anxiety, and depressive symptoms also play a relevant role in the degree of disability characteristic of the disease. Ozone therapy, which is used to treat a wide range of diseases and seems to be particularly useful in the treatment of many chronic diseases, is thought to act by exerting a mild, transient, and controlled oxidative stress that promotes an up-regulation of the antioxidant system and a modulation of the immune system. According to these mechanisms of action, it was hypothesized that ozone therapy could be useful in fibromyalgia management, where the employed therapies are very often ineffective. PATIENTS AND METHODS Sixty-five patients with fibromyalgia, according to the definition of the American College of Rheumatology (Arthritis Rheum 1990; 33: 160-172), were treated at the MEDE Clinic (Sacile, Pordenone, Italy) from February 2016 to October 2018. Females were 55 and males were 10; age ranged from 30 to 72 years, and the time from fibromyalgia diagnosis ranged from 0.5 to 33 years. Treatment was made by autohemotransfusion in 55 patients and by ozone rectal insufflations in 10 patients, according to SIOOT (Scientific Society of Oxygen Ozone Therapy) protocols, twice a week for one month and then twice a month as maintenance therapy. RESULTS We found a significative improvement (>50% of symptoms) in 45 patients (70%). No patient reported important side effects. In conclusion, at our knowledge, this is the largest study of patients with fibromyalgia treated with ozone therapy reported in the literature and it demonstrates that the ozone therapy is an effective treatment for fibromyalgia patients without significant side effects. CONCLUSIONS At the moment, ozone therapy seems a treatment that, also because without any side effect, is possible to be proposed to patients with fibromyalgia that are not obtaining adequate results from other available treatments and it can be considered as complementary/integrative medicine.
A new cognitive behavior therapy for adolescents with avoidant/restrictive food intake disorder in a day treatment setting: A clinical case series

Abstract Objective Avoidant/restrictive food intake disorder (ARFID) is a new diagnosis in the DSM‐5 Feeding and Eating Disorders section, for which very limited treatment research has been carried out, yet. A new, 4‐week exposure based cognitive behavioral therapy (CBT) day treatment, which integrated the inhibitory learning principles, was developed for adolescents with ARFID, and tested in the current study. Method A nonconcurrent multiple baseline design was used in a clinical case series of eleven 10‐ to 18‐year‐old patients. After baseline, the 4‐week CBT followed. Measurements of DSM‐5 ARFID diagnosis, food neophobia and related measures such as body weight and length, were taken at baseline (t1), at the end of the 4‐week intensive day treatment (t2) and 3 months after treatment (follow‐up, t3). A food selectivity test, a 1‐week food diary, and behavioral measures on food intake were also taken at baseline and at 3‐month follow‐up. Furthermore, continuous measurements of believability of dysfunctional cognitions, anxiety, and food acceptance were taken throughout the 4‐weeks day treatment. Results At follow‐up, 10 out of 11 patients were in remission and had a healthy body weight and an average, age‐adequate nutritional intake. For most patients, food neophobia scores decreased to a nonclinical range. The belief in dysfunctional cognitions and anxiety levels decreased during treatment. Discussion This new exposure‐based CBT for adolescents with ARFID seems promising. These results may be very useful for clinical practice and stimulate further development of effective CBT interventions in the area of ARFID.