Miracle-dz/UniFAR-FTUs huggingface dataset:
A human population-based organotypic in vitro model for cardiotoxicity screening

Assessing inter-individual variability in responses to xenobiotics remains a substantial challenge, both in drug development with respect to pharmaceuticals and in public health with respect to environmental chemicals. Although approaches exist to characterize pharmacokinetic variability, there are no methods to routinely address pharmacodynamic variability. In this study, we aimed to demonstrate the feasibility of characterizing inter-individual variability in a human in vitro model. Specifically, we hypothesized that genetic variability across a population of iPSC-derived cardiomyocytes translates into reproducible variability in both baseline phenotypes and drug responses. We measured baseline and drug-related effects in iPSC-derived cardiomyocytes from 27 healthy donors on kinetic Ca2+ flux and high-content live cell imaging. Cells were treated in concentration-response with cardiotoxic drugs: isoproterenol (β-adrenergic receptor agonist/positive inotrope), propranolol (β-adrenergic receptor antagonist/negative inotrope), and cisapride (hERG channel inhibitor/QT prolongation). Cells from four of the 27 donors were further evaluated in terms of baseline and treatment-related gene expression. Reproducibility of phenotypic responses was evaluated across batches and time. iPSC-derived cardiomyocytes exhibited reproducible donor-specific differences in baseline function and drug-induced effects. We demonstrate the feasibility of using a panel of population-based organotypic cells from healthy donors as an animal replacement experimental model. This model can be used to rapidly screen drugs and chemicals for inter-individual variability in cardiotoxicity. This approach demonstrates the feasibility of quantifying inter-individual variability in xenobiotic responses and can be expanded to other cell types for which in vitro populations can be derived from iPSCs.
Integrity testing of a smooth surface resin sealant around orthodontic brackets using a new Fluorescence-aided Identification Technique (FIT).

OBJECTIVE: To investigate the integrity of a fluorescing resin-based sealant placed around orthodontic brackets using the Fluorescence-aided Identification Technique (FIT). MATERIALS AND METHODS: Standard brackets were bonded to the buccal surfaces of 17 extracted sound permanent premolar crowns sealed with ProSeal®. Specimens were thermocycled (20,000 cycles, 5-55°C), and toothbrushing was simulated using an electric toothbrush and artificial aqueous toothpaste slurry. Changes in the sealed area were measured after one, two, three, and four alternating thermocycling-brushing cycles simulating 2 years of wear. Digital images were captured applying FIT (405 nm) using a digital camera-equipped stereomicroscope. ImageJ was used to measure sealant integrity and loss. RESULTS: There was a time-dependent decrease in sealed areas by between 21% and 100% (mean 54%). The sealant lost its integrity immediately after the first cycle, and unfilled areas were observed in all samples. CONCLUSIONS: The analyzed sealant lost its integrity over time. Using the proposed FIT, sealed surfaces were easily verified and quantified.
IL-7 Enables Antibody Responses to Bacterial Polysaccharides by Promoting B Cell Receptor Diversity

Polysaccharide vaccines such as the Vi polysaccharide (ViPS) of Salmonella enterica serovar Typhi induce efficient Ab responses in adults but not in young children. The reasons for this difference are not understood. IL-7 dependency in B cell development increases progressively with age. IL-7Rα–mediated signals are required for the expression of many VH gene segments that are distal to DH–JH in the IgH locus and for the complete diversification of the BCR repertoire. Therefore, we hypothesized that B cells generated in the absence of IL-7 do not recognize a wide range of Ags because of a restricted BCR repertoire. Compared with adult wildtype mice, young wildtype mice and IL-7–deficient adult mice generated a significantly reduced Ab response to ViPS. Additionally, ViPS-binding B cells in adult wildtype mice predominantly used distal VH gene segments. Transgenic expression of either IL-7 or a BCR encoded by a distal VH gene segment permitted young mice to respond efficiently to bacterial polysaccharides. These results indicate that restricted VH gene usage early in life results in a paucity of Ag-specific B cell precursors, thus limiting antipolysaccharide responses.
Periodontal status of liver transplant candidates and healthy controls.

BACKGROUND This study aimed to compare the periodontal status of liver transplant candidates (LTCs) with healthy controls. METHODS Fifty liver transplant candidates (LTC group) and fifty patients without liver disease (control group) underwent a complete periodontal examination. The groups were matched according to sex, age, and smoking status. A structured questionnaire was applied to record demographic data, systemic health, and information related to liver disease. Full-mouth complete periodontal examination of six sites per tooth was performed: gingival recession (GR), probing depth (PD), attachment loss (AL), bleeding on probing (BOP), and visible plaque index (VPI). The groups were compared in regard to periodontal clinical variables. RESULTS Patients with cirrhosis had greater prevalence of periodontitis than healthy controls (P < 0.001). In addition, they had greater mean percentage of sites with AL ≥3 mm (P = 0.008) and AL ≥5 mm (P = 0.023), greater mean AL (P = 0.003), greater mean gingival recession (P < 0.001), and more missing teeth than in the control group (P = 0.02). CONCLUSION Liver transplant candidates presented greater prevalence, extent, and severity of periodontitis than matched control patients.
Multicenter Study of Intense Pulsed Light Therapy for Patients With Refractory Meibomian Gland Dysfunction

Purpose: To evaluate the efficacy of intense pulsed light (IPL) therapy combined with meibomian gland expression (MGX) for refractory meibomian gland dysfunction (MGD) in a prospective study conducted at 3 sites in Japan. Methods: Patients with refractory obstructive MGD were enrolled and underwent 4 to 8 IPL-MGX treatment sessions at 3-week intervals. Clinical assessment included the Standard Patient Evaluation of Eye Dryness questionnaire; noninvasive breakup time of the tear film and interferometric fringe pattern as determined by tear interferometry; lid margin abnormalities, fluorescein breakup time of the tear film, corneal and conjunctival fluorescein staining (CFS), and meibum grade as evaluated with a slit-lamp microscope; meibomian gland morphology (meiboscore); and tear production as measured by the Schirmer test without anesthesia. Results: Sixty-two eyes of 31 patients (17 women, 14 men; mean age ± SD, 47.6 ± 16.8 years) were enrolled. The Standard Patient Evaluation of Eye Dryness score (P < 0.001), noninvasive breakup time (P < 0.001), and interferometric fringe pattern (P < 0.001) were significantly improved after therapy, with 74% of eyes showing a change in the interferometric fringe pattern from 1 characteristic of lipid deficiency to the normal condition. Meibum grade, lid margin abnormality scores, fluorescein breakup time, and CFS were also significantly improved (P < 0.001, P < 0.001, P < 0.001, and P = 0.002, respectively) after treatment, whereas the meiboscore and Schirmer test value remained unchanged. Conclusions: IPL-MGX ameliorated symptoms and improved the condition of the tear film in patients with refractory MGD and is therefore a promising treatment option for this disorder.
Treatment with Lobeglitazone Attenuates Hepatic Steatosis in Diet-Induced Obese Mice

Nonalcoholic fatty liver disease (NAFLD) is strongly associated with insulin resistance. The peroxisome proliferator-activated receptor (PPAR) activators, thiazolidinediones, (TZDs), are insulin sensitizers used as a treatment for NAFLD. However, TZDs are a controversial treatment for NAFLD because of conflicting results regarding hepatic steatosis and fibrosis. To evaluate a possible effective drug for treatment of NAFLD, we investigated the effects of a newly developed TZD, lobeglitazone, with an emphasis on hepatic lipid metabolism. Lobeglitazone treatment for 4 weeks in high fat diet- (HFD-) induced obese mice (HL group) improved insulin resistance and glucose intolerance compared to HFD-induced obese mice (HU group). The gene levels related to hepatic gluconeogenesis also decreased after treatment by lobeglitazone. The livers of mice in the HL group showed histologically reduced lipid accumulation, with lowered total plasma cholesterol and triglyceride levels. In addition, the HL group significantly decreased the hepatic expression of genes associated with lipid synthesis, cholesterol biosynthesis, and lipid droplet development and increased the hepatic expression of genes associated with fatty acid β-oxidation, thus suggesting that lobeglitazone decreased hepatic steatosis and reversed hepatic lipid dysregulation. Livers with steatohepatitis contained increased levels of PPARγ and phosphorylated PPARγ at serine 273, leading to downregulation of expression of genes associated with insulin sensitivity. Notably, the treatment of lobeglitazone increased the protein levels of PPARα and diminished levels of PPARγ phosphorylated at serine 273, which were increased by a HFD, suggesting that induction of PPARα and posttranslational modification of PPARγ in livers by lobeglitazone might be an underlying mechanism of the improvement seen in NAFLD. Taken together, our data showed that lobeglitazone might be an effective treatment for NAFLD.
Alternative assessment of knee joint muscle balance of soccer players through total work-based hamstring: quadriceps ratios

Abstract Isokinetic hamstring-to-quadriceps (H:Q) ratios are frequently used to assess knee muscle strength imbalances and risk of injuries/re-injuries. The use of peak torque (PT) or total work (TW) to estimate joint stability may lead to different results because of the differences between these two neuromuscular variables. Thus, the current study aimed to compare the conventional and functional H:Q ratios calculated by PT and TW. Ninety-three male professional soccer players from Brazilian first division teams performed isokinetic concentric and eccentric contractions of the quadriceps and the hamstrings at 60°/s. Muscle strength balance was calculated using the conventional torque ratio (CTR) and conventional work ratio (CWR), functional torque ratio (FTR) and functional work ratio (FWR) were highly and moderately correlated between them (r = 0.83 and r = 0.73, respectively). The Wilcoxon statistical test revealed significant differences between CTR and CWR, as well as FTR and FWR (p < 0.05). T-test demonstrated significant differences in mean CTR–CWR and FTR–FWR, whereas Bland–Altman plots showed non-consistent bias. In addition, the chi-square test demonstrated significant differences between players below the conventional reference values and functional reference values (p < 0.001). In conclusion, TW ratios seem to provide distinct and additional information regarding the H:Q strength balance in professional soccer players. Moreover, taking into account that TW captures torque information throughout the entire range of motion, it is possible that TW ratios represent a more comprehensive assessment of muscle strength imbalance.
The Impact of a Shared Decision-Making Training Program on Dementia Care Planning in Long-Term Care.

BACKGROUND Shared decision-making (SDM) can be a way for staff to adopt international recommendations advocating the involvement of nursing home residents and their family members in care planning and the development of personalized care plans. OBJECTIVE The main aim was to analyze the effects of training nursing home staff in the implementation of SDM on agreement of residents' 'life-and-care plans' with the recommendations (primary outcome) and on family caregivers' quality of life and sense of competence, and staff's job satisfaction (secondary outcomes). METHODS In the intervention condition, staff attended a training program on the use of SDM with residents and family caregivers in the care planning process. In the control condition, care planning as usual took place. For the primary outcome, in-depth qualitative and quantitative analyses of the care plans were performed. Multivariate Permutation Tests were applied to assess the impact on secondary outcomes. RESULTS Forty-nine residents and family caregivers and 34 professionals were involved. Overall, many of the care plans developed during the intervention showed a high level of agreement with the care planning recommendations. Both Italian and Dutch care plans showed improvement in the number of clear problem statements (p < 0.001). In Italy, significant improvements (p < 0.05) were also found regarding specific care objectives, documentation of objectives met, and of residents and families' involvement. No impact was found on secondary outcomes. CONCLUSION The involvement of residents and family caregivers in care planning contributed to an improvement of the residents' care plans, but it did not have an effect on family caregivers and staff outcomes.
Therapeutic Alliance, Cultural Competence and Minority Status in Premature Termination of Psychotherapy

Premature termination is a pervasive barrier to effective implementation of outpatient psychotherapy that frequently results in poorer outcomes for clients as well as poor resource allocation for clients, therapists, and society. Despite its high prevalence and cost, premature termination remains poorly understood, especially from the clients’ perspective. The current study addressed some gaps in the literature using a national online survey design that permitted investigation of a broad range of potential predictors of premature termination. Participants were 278 respondents from Amazon.com’s Mechanical Turk who completed an online survey about their treatment history, their most recent outpatient therapy experience and therapist, termination status, reasons for terminating prematurely (if applicable), treatment satisfaction, and demographics. Results indicated that being a woman, identifying as a sexual minority, and having a therapist low in perceived multicultural competence were associated with increased risk of premature termination. However, the best predictors of premature termination were a weak therapeutic alliance and symptoms of depression. These results support previous research that shows both client and therapist variables contribute to premature termination. Potential interventions that can be implemented by providers or agencies to reduce premature termination are discussed, along with limitations of the study and recommendations for future research.
Guideline for the treatment of chronic lymphocytic leukaemia

Anna H. Schuh, Nilima Parry-Jones, Niamh Appleby, Adrian Bloor, Claire E. Dearden, Christopher Fegan, George Follows, Christopher P. Fox, Sunil Iyengar, Ben Kennedy, Helen McCarthy, Helen M. Parry, Piers Patten, Andrew R. Pettitt, Ingo Ringshausen, Renata Walewska and Peter Hillmen NIHR BRC Oxford Molecular Diagnostic Centre, Oxford University Hospitals NHS Trust and Department of Oncology, University of Oxford, John Radcliffe Hospital, Oxford, Department of Haematology, Aneurin Bevan University Health Board, Abergavenny, Haematology, Christie Hospital, Manchester, Haematology, Royal Marsden Hospital NHS Trust, London, Cardiff & Vale University Health Board, Cardiff, Haematology, Addenbrooke’s Hospital, Cambridge, Clinical Haematology, Nottingham University Hospitals NHS Trust, Nottingham, Haematology, Royal Marsden NHS Trust, Sutton, Department of Haematology, University Hospital Leicester, Leicester, Haematology, Bournemouth and Christchurch Hospitals, Bournemouth, NIHR-ACL Haematology, University of Birmingham, Birmingham, Kings College Hospital, London, UK, Clatterbridge Cancer Centre NHS Foundation Trust, Liverpool, University of Cambridge, Cambridge, and Haematology, Leeds Teaching Hospital NHS Trust, Leeds, UK
Conversational agents in healthcare: a systematic review

Abstract Objective Our objective was to review the characteristics, current applications, and evaluation measures of conversational agents with unconstrained natural language input capabilities used for health-related purposes. Methods We searched PubMed, Embase, CINAHL, PsycInfo, and ACM Digital using a predefined search strategy. Studies were included if they focused on consumers or healthcare professionals; involved a conversational agent using any unconstrained natural language input; and reported evaluation measures resulting from user interaction with the system. Studies were screened by independent reviewers and Cohen’s kappa measured inter-coder agreement. Results The database search retrieved 1513 citations; 17 articles (14 different conversational agents) met the inclusion criteria. Dialogue management strategies were mostly finite-state and frame-based (6 and 7 conversational agents, respectively); agent-based strategies were present in one type of system. Two studies were randomized controlled trials (RCTs), 1 was cross-sectional, and the remaining were quasi-experimental. Half of the conversational agents supported consumers with health tasks such as self-care. The only RCT evaluating the efficacy of a conversational agent found a significant effect in reducing depression symptoms (effect size d = 0.44, p = .04). Patient safety was rarely evaluated in the included studies. Conclusions The use of conversational agents with unconstrained natural language input capabilities for health-related purposes is an emerging field of research, where the few published studies were mainly quasi-experimental, and rarely evaluated efficacy or safety. Future studies would benefit from more robust experimental designs and standardized reporting. Protocol Registration The protocol for this systematic review is registered at PROSPERO with the number CRD42017065917.
The impact of exercise and nutrition on the regulation of skeletal muscle mass

The maintenance of skeletal muscle mass and strength throughout life is a key determinant of human health and well‐being. There is a gradual loss of both skeletal muscle mass and strength with ageing (a process termed sarcopenia) that increases the risk of functional dependence, morbidity and mortality. Understanding the factors that regulate the size of human muscle mass, particularly during the later years of life, has therefore become an area of intense scientific inquiry. The amount of muscle mass is determined by coordinated changes in muscle protein synthesis (MPS) and muscle protein breakdown (MPB). In this review, we assess both classical and contemporary work that has examined how resistance exercise and nutrition impact on MPS and MPB. Special consideration is given to the role of different sources of dietary protein (food vs. supplements) and non‐protein nutrients such as omega‐3 fatty acids in regulating MPS. We also critically evaluate recent studies that have employed novel ‘omic’ technologies such as dynamic protein profiling to probe for changes in rates of MPS and MPB at the individual protein level following exercise. Finally, we provide suggestions for future research that we hope will yield important information for the development of exercise and nutritional strategies to counteract muscle loss in a variety of clinical settings.
Time-evolving dynamics in brain networks forecast responses to health messaging

Neuroimaging measures have been used to forecast complex behaviors, including how individuals change decisions about their health in response to persuasive communications, but have rarely incorporated metrics of brain network dynamics. How do functional dynamics within and between brain networks relate to the processes of persuasion and behavior change? To address this question, we scanned 45 adult smokers by using functional magnetic resonance imaging while they viewed anti-smoking images. Participants reported their smoking behavior and intentions to quit smoking before the scan and 1 month later. We focused on regions within four atlas-defined networks and examined whether they formed consistent network communities during this task (measured as allegiance). Smokers who showed reduced allegiance among regions within the default mode and fronto-parietal networks also demonstrated larger increases in their intentions to quit smoking 1 month later. We further examined dynamics of the ventromedial prefrontal cortex (vmPFC), as activation in this region has been frequently related to behavior change. The degree to which vmPFC changed its community assignment over time (measured as flexibility) was positively associated with smoking reduction. These data highlight the value in considering brain network dynamics for understanding message effectiveness and social processes more broadly. Author Summary How do functional dynamics within and between brain networks relate to the processes of persuasion and behavior change? In this report, we assess brain network dynamics by using fMRI while smokers view antismoking messages, and relate these metrics to smoking behavior and intentions to quit smoking 1 month following the scan. Smokers who showed reduced allegiance (less consistent network communities) among regions within the default mode and fronto-parietal networks also demonstrated larger increases in their intentions to quit smoking. Furthermore, the degree to which the ventromedial prefrontal cortex flexibly changed its community assignment over time was positively associated with later smoking reduction. These data show that metrics of functional network dynamics can provide new information about individual differences in responsiveness to anti-smoking messaging.
Fatal correlation between YAP1 expression and glioma aggressiveness: clinical and molecular evidence

During the last decade, large‐scale genomic analyses have clarified the somatic alterations in gliomas, providing new molecular classification based on IDH1/2 mutations and 1p19q codeletion with more accurate patient prognostication. The Hippo pathway downstream effectors, YAP1 and TAZ, have recently emerged as major determinants of malignancy by inducing proliferation, chemoresistance, and metastasis in solid tumors. In this study, we investigated the expression of YAP1 in 117 clinical samples of glioma described according to the WHO 2016 classification. We showed for the first time that YAP1 was tightly associated with glioma molecular subtypes and patient outcome. We validated our results in an independent cohort from the TCGA database. More interestingly, we found that YAP1 may have prognostic significance for predicting patient survival, especially in low‐grade gliomas. Using patient‐derived glioblastoma stem cell cultures, we demonstrated that YAP1 was activated and that it controlled cell proliferation. Transcriptome analysis revealed lower expression of YAP1 in the proneural GBM subtype. Furthermore, we found that overexpression of YAP1 was sufficient to inhibit the OLIG2 proneural marker, suggesting its involvement in maintenance of the GBM phenotype. Taken together, our results showed that YAP1 could be a relevant prognostic biomarker and a potential therapeutic target in glioma. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.