Miracle-dz/UniFAR-FTUs huggingface dataset:
Pharmacological Profile of AZD8871 (LAS191351), a Novel Inhaled Dual M3 Receptor Antagonist/β2-Adrenoceptor Agonist Molecule with Long-Lasting Effects and Favorable Safety Profile

AZD8871 is a novel muscarinic antagonist and β2-adrenoceptor agonist in development for chronic obstructive pulmonary disease. This study describes the pharmacological profile of AZD8871 in in vitro and in vivo assays. AZD8871 is potent at the human M3 receptor (pIC50 in binding assays: 9.5) and shows kinetic selectivity for the M3 (half-life: 4.97 hours) over the M2 receptor (half-life: 0.46 hour). It is selective for the β2-adrenoceptor over the β1 and β3 subtypes (3- and 6-fold, respectively) and shows dual antimuscarinic and β2-adrenoceptor functional activity in isolated guinea pig tissue (pIC50 in electrically stimulated trachea: 8.6; pEC50 in spontaneous tone isolated trachea: 8.8, respectively), which are sustained over time. AZD8871 exhibits a higher muscarinic component than batefenterol in human bronchi, with a shift in potency under propranolol blockade of 2- and 6-fold, respectively, together with a persisting relaxation (5.3% recovery at 8 hours). Nebulized AZD8871 prevents acetylcholine-induced bronchoconstriction in both guinea pig and dog with minimal effects on salivation and heart rate at doses with bronchoprotective activity. Moreover, AZD8871 shows long-lasting effects in dog, with a bronchoprotective half-life longer than 24 hours. In conclusion, these studies demonstrate that AZD8871 is a dual-acting molecule with a high muscarinic component and a long residence time at the M3 receptor; moreover, its preclinical profile in animal models suggests a once-daily dosing in humans and a favorable safety profile. Thus, AZD8871 has the potential to be a next generation of inhaled bronchodilators in respiratory diseases.
The Relation of Pain to the Eysenck Personality Inventory, Cornell Medical Index and Whiteley Index of Hypochondriasis

Pain in organic disease has anatomical, physiological and psychological components which are inseparably linked, but there does not appear to be a strict relationship between the nature and apparent severity of noxious stimulation and the point at which different individuals experience pain. Moreover, in any group of patients at the same stage of an illness known to be associated with pain, some complain whereas others do not. Many factors are known to influence pain and complaint behaviour. The elderly experience less pain than younger patients with similar disorders (Exton-Smith, 1961). Pain thresholds tend to be lower in women than men, and racial differences are significant when considering both thresholds and complaint behaviour (Merskey and Spear, 1967). Pain may not be immediately associated with wounding in the physical and emotional struggles of battle, and the later intensity of suffering has been shown to be related to the significance of the wound to the patient (Beecher, 1956). There is an increase in pain in the presence of anxiety (Kennard, 1952; Masson, 1966) and Cole (1965) reported that factors associated with persistent pain include a disagreeable environment, a long history of pain, anxiety, depression, poor general health, resentment and lack of confidence in the doctor. Complaint behaviour is regarded by some as a learned response developed in childhood (Schilder, 1935; Russell, 1962; Sarbin, 1962; Simpson and others 1965). Bond and Pilowsky (1966) have demonstrated that in a clinical setting differences in complaint behaviour between the sexes depend in part upon the attitudes of nursing staff towards pain.
Possible Serological Markers to Predict Mortality in Acute Exacerbation of Idiopathic Pulmonary Fibrosis

Background and objectives: Idiopathic pulmonary fibrosis (IPF) has a particularly poor prognosis, and most IPF-related deaths are due to acute exacerbation (AE) of this condition. Few reports about biomarkers to predict prognosis of AE-IPF have been published since the release of the new AE-IPF criteria in 2016. The present study investigated relationships between serological markers and in-hospital mortality after the onset of AE-IPF. Methods: Demographic, serological, and imaging data from patients hospitalized at the Maebashi Red Cross Hospital (Gunma, Japan) between 1 January 2013, and 31 December 2017, were retrospectively reviewed. Subjects fulfilling the diagnostic criteria for AE-IPF were divided into those who survived or died; statistical analysis of risk factors was performed using data from these two groups. Results: Diagnostic criteria for AE-IPF were fulfilled by 84 patients (59 males (70.2%)), with a median age of 78 years (range, 56–95 years). IPF was diagnosed before hospitalization in 50 (59.5%) patients and 38 (45.2%) died in hospital. Among the serological markers at hospitalization in the deceased group, C-reactive protein (CRP) was significantly higher than in the survivor group (p = 0.002), while total serum protein (p = 0.031), albumin (p = 0.047) and total cholesterol (p = 0.039) were significantly lower. Cox hazard analysis of factors predicting mortality, corrected for age, sex and BMI, revealed the following: CRP (hazard ratio (HR) 1.080 (95% confidence interval (CI) 1.022–1.141); p = 0.006), LDH (HR 1.003 (95% CI 1.000–1.006); p = 0.037), and total cholesterol (HR 0.985 (95% CI 0.972–0.997); p = 0.018). Conclusions: Our data suggest that CRP, LDH, and total cholesterol may be biomarkers predicting mortality in patients with AE-IPF. However, only prospective controlled studies can confirm or not our observation as a generalizable one.
Associates of health status in patients with systemic lupus erythematosus.

OBJECTIVE To determine the health status of patients with systemic lupus erythematosus (SLE) and to identify the associations of this domain. METHODS One hundred ninety-five consecutively attending patients with SLE were studied at 2 centers. Health status was measured by 8 composite scales of the Medical Outcomes Study Short Form 36 (SF-36). The mean scores for each subscale of the SF-36 for patients with SLE were compared to those of a healthy population. The effect of patients' age, sex, ethnic origin, marital status, education level, disease duration, disease activity (assessed by the Systemic Lupus Activity Measure), end organ damage (assessed by the Systemic Lupus International Coordinating Clinics/American College of Rheumatology Damage Index), social support (using the Interpersonal Support Evaluation List), and patients' satisfaction with medical care (using the Patient Satisfaction Questionnaire) on each SF-36 subscale was determined. Student's unpaired t test and multiple regression analysis were applied for statistical analysis. RESULTS Patients with SLE had significantly lower scores in each subscale of the SF-36 compared to a control population. Higher disease activity was associated with worse physical function, role-physical, bodily pain, general health, vitality, and social function. Greater social support was associated with higher scores in physical function, bodily pain, general health, vitality, social function, role-emotional, and mental health. Increasing total end organ damage determined worse physical function and general health. Higher patient general satisfaction with care was associated with better general health. CONCLUSION The health status of patients with SLE may be improved by increasing patients' social support and satisfaction with health care, as well as controlling SLE disease activity and preventing organ damage.
A New Confidence Interval for the Mean of a Bounded Random Variable

We present a new method for constructing a confidence interval for the mean of a bounded random variable from samples of the random variable. We conjecture that the confidence interval has guaranteed coverage, i.e., that it contains the mean with high probability for all distributions on a bounded interval, for all samples sizes, and for all confidence levels. This new method provides confidence intervals that are competitive with those produced using Student's t-statistic, but does not rely on normality assumptions. In particular, its only requirement is that the distribution be bounded on a known finite interval.
The accuracy of trans rectal ultrasonography (TRUS) in early-stage rectal cancer or benign adenomas

Abstract Background: Screening for colorectal cancer in Denmark has resulted in more patients being diagnosed with benign adenomas and early-stage rectal cancer. In general, TRUS is accepted as a good modality for evaluating the above mentioned before deciding on surgery. Objective: To investigate the accuracy of TRUS in a clinical setting at the Region Hospital in Herning, Denmark. Study design: Retrospective cohort study from January 2016 to June 2018. Methods: Quantitative method. The cohort (117 patients) was recruited by searching for specific procedure codes. Data were collected by going through the electronic patient files. Results: TRUS predicted T0, T1, T2 and T3 with an accuracy of 91%, 35%, 43% and 20% respectively and an overall accuracy of 68%. A weighted Cohens kappa value of 0.30 (p .05). TRUS differentiated between T0/T1 with a sensitivity of 70%, specificity of 85% and an accuracy of 85% and kappa value of 0.44 (p .05). Conclusion: TRUS can with great precision establish whether the tumor is benign so correct local treatment can be instituted.
Nifedipine vs. Enalapril in Treatment of Hypertensive Patients with Glucose Intolerance

To compare the metabolic effects of nifedipine and enalapril. we studied 21 obese patients (BMI of 31.6 ± 1.1) with mild-to-moderate hypertension and glucose intolerance. None of the patients were receiving insulin or hypoglycemic agents. After a washout period of 15 days, blood pressure was recorded and fasting blood glucose, insulin, and lipid concentrations were determined. At random, 11 patients were started on nifedipine and 10 patients on enalapril. At the 90th day of treatment, clinical and laboratory tests were again performed. Both of the drugs reduced blood pressure values comparably. No significant variation of metabolic parameters was found after 90 days of treatment in the enalapril group. In the nifedipine group, the fasting insulin level was decreased and the glocuse/insulin ratio was significantly increased, suggesting an improvement in insulin sensitivity: moreover, total plasma cholesterol was significantly reduced. Enalapril and nifedipine seem to be effective and safe drugs in the treatment of hypertensive subjects with obesity and glucose intolerance. Nifedipine can ameliorate insulin resistance and the lipid state.
Human skin fibroblasts express m2, m4, and m5 subtypes of muscarinic acetylcholine receptors

Previous studies have demonstrated that muscarinic acetylcholine receptors (mAChRs) are expressed by human skin fibroblasts (HSF). We have identified the molecular subtypes of these receptors by reverse transcription‐polymerase chain reaction (RT‐PCR), using m1‐m5 subtype‐specific primers. These experiments showed that only mRNAs for m2, m4, and m5 mAChR subtypes are present in HSF. The RT‐PCR products were characterized by restriction analysis and Southern blotting. Northern blot analysis showed the presence of m2 and m4 mAChR RNA. Rabbit antibodies were raised using a synthetic peptide as immunogen corresponding to the C‐terminus of the m2 protein and were used to visualize fibroblast mAChRs. Cell membranes of HSF in cell culture and specimens of normal human skin had a unique staining pattern specific for anti‐m2 antibody, as well as for antibodies against m4 and m5. In Western blots of fibroblast proteins, the antibodies visualized the m2 receptor at 65 kDa, m4 at 70 kDa, and m5 at 95 kDa. The function of fibroblast mAChRs was examined by measuring muscarinic effects on intracellular free Ca2+ concentration ([Ca2+]i). Muscarine increased transiently [Ca2+]i in cultured HSF. This effect could be abolished by the muscarinic antagonist atropine. Thus, the results of this study showed that HSF express m2, m4, and m5 mAChR subtypes, and that fibroblast mAChRs are coupled to the regulation of [Ca2+]i. J. Cell. Biochem. 74:264–277, 1999. © 1999 Wiley‐Liss, Inc.
NHERF1 is Required for Localization of PMCA2 and Suppression of Early Involution in the Female Lactating Mammary Gland.

Prior studies have demonstrated that the calcium pump, PMCA2, mediates calcium transport into milk and prevents mammary epithelial cell death during lactation. PMCA2 also regulates cell proliferation and cell death in breast cancer cells, in part, by maintaining the receptor tyrosine kinase, ErbB2/HER2, within specialized plasma membrane domains. Furthermore, the regulation of PMCA2 membrane localization and activity in breast cancer cells requires its interaction with the PDZ-domain-containing scaffolding molecule, NHERF1. In this study, we asked whether NHERF1 also interacts with PMCA2 in normal mammary epithelial cells during lactation. Our results demonstrate that NHERF1 expression is upregulated during lactation and that it interacts with PMCA2 at the apical membrane of secretory luminal epithelial cells. Like PMCA2, NHERF1 expression is rapidly reduced by milk stasis after weaning. Examining lactating NHERF1KO mice showed that NHERF1 contributes to the proper apical location of PMCA2, for proper apical-basal polarity in luminal epithelial cells and that it participates in the suppression of STAT3 activation and the prevention of premature mammary gland involution. In addition, we found that PMCA2 also interacts with the closely related scaffolding molecule, NHERF2, at the apical membrane, which likely maintains PMCA2 at the plasma membrane of mammary epithelial cells in lactating NHERF1KO mice. Based on these data, we conclude that, during lactation, NHERF1 is required for the proper expression and apical localization of PMCA2, which, in turn, contributes to preventing the premature activation of Stat3 and the lysosome-mediated cell death pathway that usually occur only early mammary involution.
Regenerative bone potential after sinus floor elevation using various bone graft materials: a systematic review.

OBJECTIVES The purpose of the present study was to review and evaluate the effectiveness of bone substitute materials used for maxillary sinus floor elevation and to propose the most effective bone graft material by assessing newly formed bone, remaining graft particles, and soft tissue ratio. METHOD AND MATERIALS The search protocol used the electronic MEDLINE (PubMed) database for articles published between 1 January 2008 and 1 January 2019. The search was limited to English language only and included clinical studies on humans. Outcomes were the percentage of newly formed bone, remaining graft particles, and soft tissue. RESULTS Eighteen studies fulfilled the inclusion criteria. Autologous bone and mineralized cancellous bone allograft showed the best results regarding the percentage of newly formed bone (41.74% and 35.41%, respectively). The worst bone formation was observed when Bio-Oss material was used alone (8.25%) and in combination with recombinant human bone morphogenetic protein-7 (rhBMP-7) (6.55%). During estimation of bone regeneration results when anorganic bovine bone (ABB) substitute was used alone and in combination with platelet-rich plasma (PRP), histomorphometric analysis revealed a higher amount of newly formed bone in sites treated with PRP + ABB (31%) compared to ABB alone (21.3%). CONCLUSIONS The present systemic review demonstrated that autologous bone has the best regenerative potential for sinus floor elevation. Combining autologous bone with bone substitutes leads to more matured newly formed bone and better bone graft osseointegration. PRP/plasma rich in growth factors (PRGF) combined together with bone graft materials enhances bone formation and vascularization. It might also reduce inflammation and decrease the risk of complications.
Acute intraventricular migration of a transcatheter aortic prosthesis

We describe a low-risk patient who underwent transcatheter aortic valve implantation after refusing conventional surgery. During the procedure, prosthesis migration into the left ventricle prompted emergency surgical aortic valve replacement. Transcatheter aortic valve implantation is currently indicated in high-risk patients with aortic stenosis; its role in intermediate-risk subjects remains controversial, while in low-risk patients, surgery is still the procedure of choice. Because of such severe unpredictable procedure-related complications, the management of low-risk patients refusing surgery may be difficult. Whether the heart team should also consider potential ethical and economic aspects remains to be defined.
Which principal components are most sensitive to distributional changes

PCA is often used in anomaly detection and statistical process control tasks. For bivariate data, we prove that the minor projection (the least varying projection) of the PCA-rotated data is the most sensitive to distributional changes, where sensitivity is defined by the Hellinger distance between distributions before and after a change. In particular, this is almost always the case if only one parameter of the bivariate normal distribution changes, i.e., the change is sparse. Simulations indicate that the minor projections are the most sensitive for a large range of changes and pre-change settings in higher dimensions as well. This motivates using the minor projections for detecting sparse distributional changes in high-dimensional data.
Eyes in the Sky: Assessing the Feasibility of Low-Cost, Ready-to-Use Unmanned Aerial Vehicles to Monitor Primate Populations Directly

Primates face many climate and land use change threats, making long-term population monitoring critical to prioritizing conservation efforts. Ground-based line transects are typically conducted to estimate and monitor primate populations. However, transects may be costly and logistically challenging. We sought to test whether low-cost (<5,000 USD), ready-to-use unmanned aerial vehicles (UAVs) could effectively monitor primate populations in north-eastern Madagascar. Critically Endangered [A3cd] golden-crowned sifakas (Propithecus tattersalli) are medium-sized, white lemurs whose creamy colour contrasts against defoliated tree canopies, making them an ideal study species for aerial counts. Quad-copter UAV flights over sifaka groups did not elicit antipredator responses. Photographs demonstrated the ability of UAVs to capture viable imagery of sifakas from approximately 20 m above ground level. Unfortunately, crashes resulting from an inability to programme automated flights over hilly forests cut this pilot study short, highlighting several challenges that remain to implementing UAVs in remote field studies. This study demonstrates that while UAVs offer considerable promise in the future of primate research and conservation, high start-up costs and remote field conditions provide challenging obstacles to first time users hoping to use this exciting new technology. Furthermore, we strongly recommend that thermal cameras be used for direct primate counts with UAVs.
Modelling baryonic feedback for survey cosmology

Observational cosmology in the next decade will rely on probes of the distribution of matter in the redshift range between $0<z<3$ to elucidate the nature of dark matter and dark energy. In this redshift range, galaxy formation is known to have a significant impact on observables such as two-point correlations of galaxy shapes and positions, altering their amplitude and scale dependence beyond the expected statistical uncertainty of upcoming experiments at separations under 10 Mpc. Successful extraction of information in such a regime thus requires, at the very least, unbiased models for the impact of galaxy formation on the matter distribution, and can benefit from complementary observational priors. This work reviews the current state of the art in the modelling of baryons for cosmology, from numerical methods to approximate analytical prescriptions, and makes recommendations for studies in the next decade, including a discussion of potential probe combinations that can help constrain the role of baryons in cosmological studies. We focus, in particular, on the modelling of the matter power spectrum, $P(k,z)$, as a function of scale and redshift, and of the observables derived from this quantity. This work is the result of a workshop held at the University of Oxford in November of 2018.
Determinants of Managerial Preventive Actions in Relation to Common Mental Disorders at Work: A Cross-Sectional Study Among Swedish Managers.

OBJECTIVE Manager characteristics (personal, work-, and competence-related) were investigated as determinants of Managerial Preventive Actions (MPAs) in relation to Common Mental Disorders (CMDs) among employees. METHODS A web survey (n = 2921) among Swedish managers measured diverse managerial characteristics and two types of MPAs: reviewing assignments and work situation (MPA-review); talking about CMDs at the work place (MPA-talk). RESULTS MPA-review was reported by 50% and MPA-talk by 57% of managers. Characteristics that related to more MPAs were: female gender, workplace offering lectures on CMDs, workplace offering stress counselling, being responsible for the work environment, management training on CMDs, and > 10 years of managerial experience (MPA-talk only). CONCLUSIONS Managers who are female, have had training on CMDs and work for organisations paying attention to CMD prevention, initiate MPAs more often.
Gauged sigma models and magnetic Skyrmions

We define a gauged non-linear sigma model for a 2-sphere valued field and a SU(2)SU(2) connection on an arbitrary Riemann surface whose energy functional reduces to that for critically coupled magnetic skyrmions in the plane, with arbitrary Dzyaloshinskii-Moriya interaction, for a suitably chosen gauge field. We use the interplay of unitary and holomorphic structures to derive a general solution of the first order Bogomol’nyi equation of the model for any given connection. We illustrate this formula with examples, and also point out applications to the study of impurities.
A Gene Signature Predicting Natural Killer Cell Infiltration and Improved Survival in Melanoma Patients

Innate immunity can provide new targets for immunotherapy. Singscore, a gene-set scoring method, revealed that NK cell infiltration correlated with improved patient survival rates. Stromal and tumor elements, as well as cytokines involved in NK function were investigated. Natural killer (NK) cell activity is essential for initiating antitumor responses and may be linked to immunotherapy success. NK cells and other innate immune components could be exploitable for cancer treatment, which drives the need for tools and methods that identify therapeutic avenues. Here, we extend our gene-set scoring method singscore to investigate NK cell infiltration by applying RNA-seq analysis to samples from bulk tumors. Computational methods have been developed for the deconvolution of immune cell types within solid tumors. We have taken the NK cell gene signatures from several such tools, then curated the gene list using a comparative analysis of tumors and immune cell types. Using a gene-set scoring method to investigate RNA-seq data from The Cancer Genome Atlas (TCGA), we show that patients with metastatic cutaneous melanoma have an improved survival rate if their tumor shows evidence of NK cell infiltration. Furthermore, these survival effects are enhanced in tumors that show higher expression of genes that encode NK cell stimuli such as the cytokine IL15. Using this signature, we then examine transcriptomic data to identify tumor and stromal components that may influence the penetrance of NK cells into solid tumors. Our results provide evidence that NK cells play a role in the regulation of human tumors and highlight potential survival effects associated with increased NK cell activity. Our computational analysis identifies putative gene targets that may be of therapeutic value for boosting NK cell antitumor immunity.