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Abstract Background Blood biomarkers predictive of the progression of idiopathic pulmonary fibrosis (IPF) would be of value for research and clinical practice. We used data from the IPF-PRO Registry to investigate whether the addition of “omics” data to risk prediction models based on demographic and clinical characteristics improved prediction of the progression of IPF. Methods The IPF-PRO Registry enrolled patients with IPF at 46 sites across the US. Patients were followed prospectively. Median follow-up was 27.2 months. Prediction models for disease progression included omics data (proteins and microRNAs [miRNAs]), demographic factors and clinical factors, all assessed at enrollment. Data on proteins and miRNAs were included in the models either as raw values or based on clusters in various combinations. Least absolute shrinkage and selection operator (Lasso) Cox regression was applied for time-to-event composite outcomes and logistic regression with L1 penalty was applied for binary outcomes assessed at 1 year. Model performance was assessed using Harrell’s C-index (for time-to-event outcomes) or area under the curve (for binary outcomes). Results Data were analyzed from 231 patients. The models based on demographic and clinical factors, with or without omics data, were the top-performing models for prediction of all the time-to-event outcomes. Relative changes in average C-index after incorporating omics data into models based on demographic and clinical factors ranged from 1.7 to 3.2%. Of the blood biomarkers, surfactant protein-D, serine protease inhibitor A7 and matrix metalloproteinase-9 (MMP-9) were among the top predictors of the outcomes. For the binary outcomes, models based on demographics alone and models based on demographics plus omics data had similar performances. Of the blood biomarkers, CC motif chemokine 11, vascular cell adhesion protein-1, adiponectin, carcinoembryonic antigen and MMP-9 were the most important predictors of the binary outcomes. Conclusions We identified circulating protein and miRNA biomarkers associated with the progression of IPF. However, the integration of omics data into prediction models that included demographic and clinical factors did not materially improve the performance of the models. Trial registration ClinicalTrials.gov; No: NCT01915511; registered August 5, 2013; URL: www.clinicaltrials.gov .

The relevance of biomaterials to successfully restore the function of lost tissues to improve human health is increasing. There is a need to develop new biocompatible, low-cost biomaterial with better strength that can perform the intended purpose. Porcine tunica vaginalis, - a readily available abattoir bio-waste from slaughterhouses and being an expansion of the peritoneum into the scrotum, can be considered a candidate scaffold. A study was carried out to examine the in-vitro characteristics of variably decellularised porcine tunica vaginalis. The native or non-decellularised tissue was maintained as a control group (PTV). The varied protocols for decellularisation included (a) Trypsin-EDTA-Triton-X-100 treated tunica vaginalis (DTV1) (b) Sodium deoxycholate (SDC) and DNase treated porcine tunica vaginalis (DTV2) and (c) a combined protocol (DTV3) for decellularising porcine tunica vaginalis. The efficiency of decellularisation was evaluated by histological examination, DNA quantification, and 4, 6- diamidino-2-phenylindole (DAPI) nuclear staining. The biomechanical properties of the materials were examined by analyzing tensile strength, maximum load at the break, and Young’s modulus. Further, the surface and other structural characteristics were analyzed using scanning electron microscopy and special staining techniques. The concentration of DNA, nuclear staining, and surface characters was in an acceptable range after decellularization for all three scaffolds. All decellularisation protocols reduced DNA concentration significantly compared to the non-decellularised control and retained collagen and other extracellular matrices (ECM) components. However, the DTV3 scaffold revealed minimal nuclear remnants, acceptable DNA concentration as well as good surface topography. Comparison of biomechanical characters of the decellularised scaffolds with non-decellularised tissue evidenced better tensile strength and Young’s modulus for DTV3. This work highlights the influence of different decellularisation protocols on the final scaffolds which could pave the way for developing a novel scaffold that can address various clinical problems in the medical field.

The development of induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) has been a critical in vitro advance in the study of patient-specific physiology, pathophysiology, and pharmacology. We designed a new deep learning multitask network approach intended to address the low throughput, high variability, and immature phenotype of the iPSC-CM platform. The rationale for combining translation and classification tasks is because the most likely application of the deep learning technology we describe here is to translate iPSC-CMs following application of a perturbation. The deep learning network was trained using simulated action potential (AP) data and applied to classify cells into the drug-free and drugged categories and to predict the impact of electrophysiological perturbation across the continuum of aging from the immature iPSC-CMs to the adult ventricular myocytes. The phase of the AP extremely sensitive to perturbation due to a steep rise of the membrane resistance was found to contain the key information required for successful network multitasking. We also demonstrated successful translation of both experimental and simulated iPSC-CM AP data validating our network by prediction of experimental drug-induced effects on adult cardiomyocyte APs by the latter.

In the last decade, there has been tremendous progress in identifying genetic anomalies linked to clinical disease. New experimental platforms have connected genetic variants to mechanisms underlying disruption of cellular and organ behavior and the emergence of proarrhythmic cardiac phenotypes. The development of induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) signifies an important advance in the study of genetic disease in a patient-specific context. However, considerable limitations of iPSC-CM technologies have not been addressed: 1) phenotypic variability in apparently identical genotype perturbations, 2) low-throughput electrophysiological measurements, and 3) an immature phenotype which may impact translation to adult cardiac response. We have developed a computational approach intended to address these problems. We applied our recent iPSC-CM computational model to predict the proarrhythmic risk of 40 KCNQ1 genetic variants. An IKs computational model was fit to experimental data for each mutation, and the impact of each mutation was simulated in a population of iPSC-CM models. Using a test set of 15 KCNQ1 mutations with known clinical long QT phenotypes, we developed a method to stratify the effects of KCNQ1 mutations based on proarrhythmic markers. We utilized this method to predict the severity of the remaining 25 KCNQ1 mutations with unknown clinical significance. Tremendous phenotypic variability was observed in the iPSC-CM model population following mutant perturbations. A key novelty is our reporting of the impact of individual KCNQ1 mutant models on adult ventricular cardiomyocyte electrophysiology, allowing for prediction of mutant impact across the continuum of aging. This serves as a first step toward translating predicted response in the iPSC-CM model to predicted response of the adult ventricular myocyte given the same genetic mutation. As a whole, this study presents a new computational framework that serves as a high throughput method to evaluate risk of genetic mutations based-on proarrhythmic behavior in phenotypically variable populations.

Key pointsInduced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) capture patient-specific genotype-phenotype relationships, as well as cell-to-cell variability of cardiac electrical activity Computational modelling and simulation provide a high throughput approach to reconcile multiple datasets describing physiological variability, and also identify vulnerable parameter regimes We have developed a whole-cell model of iPSC-CMs, composed of single exponential voltage-dependent gating variable rate constants, parameterized to fit experimental iPSC-CM outputs We have utilized experimental data across multiple laboratories to model experimental variability and investigate subcellular phenotypic mechanisms in iPSC-CMs This framework links molecular mechanisms to cellular-level outputs by revealing unique subsets of model parameters linked to known iPSC-CM phenotypes ABSTRACT: There is a profound need to develop a strategy for predicting patient-to-patient vulnerability in the emergence of cardiac arrhythmia. A promising in vitro method to address patient-specific proclivity to cardiac disease utilizes induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). A major strength of this approach is that iPSC-CMs contain donor genetic information and therefore capture patient-specific genotype-phenotype relationships. A cited detriment of iPSC-CMs is the cell-to-cell variability observed in electrical activity. We postulated, however, that cell-to-cell variability may constitute a strength when appropriately utilized in a computational framework to build cell populations that can be employed to identify phenotypic mechanisms and pinpoint key sensitive parameters. Thus, we have exploited variation in experimental data across multiple laboratories to develop a computational framework for investigating subcellular phenotypic mechanisms. We have developed a whole-cell model of iPSC-CMs composed of simple model components comprising ion channel models with single exponential voltage-dependent gating variable rate constants, parameterized to fit experimental iPSC-CM data for all major ionic currents. By optimizing ionic current model parameters to multiple experimental datasets, we incorporate experimentally-observed variability in the ionic currents. The resulting population of cellular models predicts robust inter-subject variability in iPSC-CMs. This approach links molecular mechanisms to known cellular-level iPSC-CM phenotypes, as shown by comparing immature and mature subpopulations of models to analyse the contributing factors underlying each phenotype. In the future, the presented models can be readily expanded to include genetic mutations and pharmacological interventions for studying the mechanisms of rare events, such as arrhythmia triggers.

BACKGROUND Fibrocytes are BM-derived circulating cells that traffic to the injured lungs and contribute to fibrogenesis. The mTOR inhibitor, sirolimus, inhibits fibrocyte CXCR4 expression, reducing fibrocyte traffic and attenuating lung fibrosis in animal models. We sought to test the hypothesis that short-term treatment with sirolimus reduces the concentration of CXCR4+ circulating fibrocytes in patients with idiopathic pulmonary fibrosis (IPF).METHODS We conducted a short-term randomized double-blind placebo-controlled crossover pilot trial to assess the safety and tolerability of sirolimus in IPF. Participants were randomly assigned to sirolimus or placebo for approximately 6 weeks, and after a 4-week washout, they were assigned to the alternate treatment. Toxicity, lung function, and the concentration of circulating fibrocytes were measured before and after each treatment.RESULTS In the 28 study participants, sirolimus resulted in a statistically significant 35% decline in the concentration of total fibrocytes, 34% decline in CXCR4+ fibrocytes, and 42% decline in fibrocytes expressing α-smooth muscle actin, but no significant change in these populations occurred on placebo. Respiratory adverse events occurred more frequently during treatment with placebo than sirolimus; the incidence of adverse events and drug tolerability did not otherwise differ during therapy with drug and placebo. Lung function was unaffected by either treatment, with the exception of a small decline in gas transfer during treatment with placebo.CONCLUSION As compared with placebo, short-term treatment with sirolimus resulted in reduction of circulating fibrocyte concentrations in participants with IPF, with an acceptable safety profile.TRIAL REGISTRATION ClinicalTrials.gov, accession no. NCT01462006.FUNDING NIH R01HL098329 and American Heart Association 18TPA34170486.

Introduction: The term 'hepatitis' describes an inflammation of the liver. A viral infection commonly causes it, but there are other possible causes of hepatitis. These include hepatitis caused by drugs, alcohol, toxins and other pharmaceuticals, as well as hepatitis caused by autoimmune conditions. The World Health Organisation suggested that by the close of the 20th century, all nations should include the Hepatitis B vaccine (HBV) in their regular infant and childhood immunisation regimens. Objective: To evaluate the knowledge, attitude and practice of Hepatitis B vaccination among students attending medical, dental, nursing and physiotherapy courses. Materials and Methods: Students studying medicine, dentistry, nursing and physiotherapy at a tertiary health care facility in Kerala's Kozhikode district are participating in this cross-sectional survey. A structured, open-ended questionnaire that the self-administered knowledge, attitude and practice (KAP) used to gather information regarding HBV infection and vaccination was employed to assess the KAP. For the assessment of knowledge, attitude and practice, appropriate scoring was carried out. Utilising SPSS Software version 20.0, the data was analysed. Results: Out of the total 335 students who responded, 256 (76.4%) students were vaccinated, 232 (69.3%) showed poor knowledge towards Hepatitis B vaccination, 6 (16.7%) were not vaccinated and the remaining 23 (6.9%) are not sure about vaccination status. About 38.8% of students have good practice and show a significant association between knowledge, attitude and practice of Hepatitis B vaccination among students. Conclusion: This study shows an association between knowledge, attitude and practice of Hepatitis B vaccination among students, implying that a better understanding of the disease has a positive effect on the practices exercised by an individual. [ABSTRACT FROM AUTHOR]

Background & Aims: The gallbladder and biliary tract are structures that are in close proximity to the adjacent organs and can exhibit a variety of anomalies and anatomic variations. However, the literature on morphological variations of the gallbladder and their prevalence are limited. This study aims to identify various anatomical variations in gallbladder shape and position that should be considered for clinical implications, investigative procedures, radiological studies, surgical interventions, embryological explanations, and comparative anatomy. Aim of this study is to study the morphology of gallbladder in cadavers. Materials & Methods: This study was done on 100 cadaveric liver and gallbladder specimens available in the Department of Anatomy, Sri Devaraj Urs Medical College, Kolar, India. Parameters such as maximum transverse diameter and maximum length were measured with help of metallic tape. Each specimen was studied for morphological variations. The observations were tabulated and analysed statistically. Results: Gallbaladder samples had length ranging between 3.3 and 12 cm, transverse diameter between 2.0 and 5.0 cm. The commonest shape observed in this study was pear shaped in 84% of cases. The length of gallbladder below the inferior border of liver varied between 0.4 and 2.5 cm. Conclusion: The anatomic variations of the gallbladder and biliary tract are critical during their surgical procedures. The present study describes the different anatomic variations of human gallbladder and its clinical importance. This study will greatly assist surgeons in understanding the possible morphology of the gallbladder.