Miracle-dz/UniFAR-FTUs huggingface dataset:
Macrophage-derived granulin drives resistance to immune checkpoint inhibition in metastatic pancreatic cancer

The ability of disseminated cancer cells to evade the immune response is a critical step for efficient metastatic progression. Protection against an immune attack is often provided by the tumour microenvironment that suppresses and/or excludes cytotoxic CD8+ T cells. Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive metastatic disease with unmet needs, yet the immuno-protective role of the metastatic tumour microenvironment in pancreatic cancer is not completely understood. In this study we find that macrophage-derived granulin contributes to cytotoxic CD8+ T cell exclusion in metastatic livers. Mechanistically, we find that granulin expression by macrophages is induced in response to colony stimulating factor-1. Genetic depletion of granulin reduces the formation a fibrotic stroma, thereby allowing T cell entry at the metastatic site. While metastatic PDAC tumours are largely resistant to anti-PD-1 therapy, blockade of PD-1 in granulin depleted tumours restored the anti-tumour immune defence and dramatically decreased metastatic tumour burden. These findings suggest that targeting granulin may serve as a potential therapeutic strategy to restore CD8+ T cell infiltration in metastatic PDAC, thereby converting PDAC metastatic tumours, which are refractory to immune checkpoint inhibitors, into tumours that respond to immune checkpoint inhibition therapies.
Cerebrospinal Fluid Neurochemical Phenotypes in Vascular Dementias: Original Data and Mini-Review

Background/Aims: The study evaluated the patterns of cerebrospinal fluid (CSF), amyloid-β (Aβ) peptides, total tau and phospho-tau among Alzheimer’s disease (AD) and vascular dementias (VAD). Methods: Aβ-SDS-PAGE immunoblot and commercially available ELISAs were applied to the CSF analysis of 52 patients with probable (n = 21) and possible (n = 16) VAD, AD with cerebrovascular disease (n = 15), 30 patients with probable AD and 30 nondemented disease controls. Results: AD and AD with cerebrovascular disease displayed a similar neurochemical phenotype in contrast to nondemented disease controls and probable VAD with regard to tau, p-tau, Aβ1–40ox and Aβ1–42%. Possible VAD displayed AD-like changes only for Aβ1–40ox and Aβ1–42%. Conclusion: CSF neurochemical phenotypes sufficiently discriminate probable AD and VAD from each other, but their diagnostic value is limited in case of no clear-cut clinical appearance, such as possible VAD. Conversely, CSF Aβ peptides and p-tau levels may help estimate the involvement of AD-like pathophysiological pathways in VAD subgroups.
CD8+ T cells provide an immunologic signature of tuberculosis in young children.

RATIONALE The immunologic events surrounding primary Mycobacterium tuberculosis infection and development of tuberculosis remain controversial. Young children who develop tuberculosis do so quickly after first exposure, thus permitting study of immune response to primary infection and disease. We hypothesized that M. tuberculosis-specific CD8(+) T cells are generated in response to high bacillary loads occurring during tuberculosis. OBJECTIVES To determine if M. tuberculosis-specific T cells are generated among healthy children exposed to M. tuberculosis and children with tuberculosis. METHODS Enzyme-linked immunosorbent spot assays were used to measure IFN-γ production in response to M. tuberculosis-specific proteins ESAT-6/CFP-10 by peripheral blood mononuclear cells and CD8(+) T cells isolated from Ugandan children hospitalized with tuberculosis (n = 96) or healthy tuberculosis contacts (n = 62). MEASUREMENTS AND MAIN RESULTS The proportion of positive CD8(+) T-cell assays and magnitude of CD8(+) T-cell responses were significantly greater among young (<5 yr) tuberculosis cases compared with young contacts (P = 0.02, Fisher exact test, P = 0.01, Wilcoxon rank-sum, respectively). M. tuberculosis-specific T-cell responses measured in peripheral blood mononuclear cells were equivalent between groups. CONCLUSIONS Among young children, M. tuberculosis-specific CD8(+) T cells develop in response to high bacillary loads, as occurs during tuberculosis, and are unlikely to be found after M. tuberculosis exposure. T-cell responses measured in peripheral blood mononuclear cells are generated after M. tuberculosis exposure alone, and thus cannot distinguish exposure from disease. In young children, IFN-γ-producing M. tuberculosis-specific CD8(+) T cells provide an immunologic signature of primary M. tuberculosis infection resulting in disease.
Vision-related quality of life in patients with ocular chemical burns.

PURPOSE To assess vision-related quality of life in patients with ocular chemical burns by the application of the 25-item National Eye Institute Visual Function Questionnaire (NEI VFQ-25). METHODS Eighty-seven patients with ocular chemical burns were enrolled in the study from January 1 through May 31, 2010. Apart from the collection of sociodemographic and clinical data, NEI VFQ-25 with an additional appendix question, being translated to Chinese, was administered to all subjects. Main outcome measures were comparison of the NEI VFQ-25 subscale item scores among subgroups and multivariate analysis of the NEI VFQ-25 subscale scores. RESULTS Fifty-five subjects were bilaterally burned and the rest were unilaterally injured. The mean age of enrolled subjects was 39.4 ± 11.6 years, with the majority being male (98.9%) and worker (77.0%); the mean composite score of all subjects was 40.4 ± 23.8. The composite score and majority subscale scores of binocularly injured patients were significantly lower than those of monocularly injured patients. Further comparisons among groups divided by either clinical severity classification or best-corrected visual acuity (BCVA) produced similar results. The BCVA of both the better-seeing eye and the worse-seeing eye strongly correlated with the NEI VFQ-25 composite score (ρ = 0.664 and 0.498, both P = 0.000). Multivariate regression analysis revealed that the VFQ-25 composite score correlated significantly with the following independent variables: BCVA of the better-seeing eye and the worse-seeing eye, the injury classification of the less severely injured eye, and correct and immediate irrigation after injury as well. CONCLUSIONS Ocular chemical burns have a significant and extensive impact on patients' visual function outcomes and vision-related quality of life.
Short Adolescents Born Small for Gestational Age : Gonadal and thyroid function, bone mineral density, quality of life and adult height: The effects of growth hormone and additional postponement of puberty

textabstractFrom 1991, our research group and others have been investigating children with short stature who were born small for gestational age (SGA), both before and during treatment with biosynthetic growth hormone (GH). In 2005, GH treatment was licensed for short SGA children in the Netherlands. Many questions though remained unanswered, especially about the efficacy of GH treatment when started at an older age, just before or during puberty. This doctoral thesis describes studies evaluating short adolescents born SGA who were treated with GH, and additionally with postponement of puberty by gonadotropin-releasing hormone analogue (GnRHa).
Rubella in South Africa : an impending Greek tragedy?

Background . The incidence of congenital rubella syndrome (CRS) is unknown in South Africa. There is evidence that it may be significant and largely undetected, particularly in the upper socio-economic group. This may be due to incomplete routine administration of MMR vaccine in infancy and a build-up of susceptible females reaching the childbearing age group who could be exposed to the extensive reservoir of virus in the unimmunised public sector of the population. Objective . To assess the extent of the immunity gap to rubella by testing for protective IgG antibodies and the incidence of rubella infection by testing for IgM antibodies in sera. The data obtained would also be used to model the extent of CRS. Design . Residual laboratory serum specimens from public and private laboratories were serologically tested for rubella IgG antibodies to investigate the immunity gap in the population and IgM antibodies in sera collected from the measles rashlike illness surveillance programme. Modelling exercises calculated the force of infection and the predicted incidence of CRS in South Africa. Results . The serological immunity gap was significantly greater in the private sector specimens compared with the public sector – 10.7% versus 5.4%, respectively. In most years rubella caused much more rash-like illness than measles, with a significant number (5.1 - 9.6%) of rubella-positive IgM specimens occurring in women of childbearing age. Conclusion . Modelling of the data suggests that the extent of CRS may be grossly underestimated in South Africa. Approximately 654 cases are calculated to occur every year. It is suggested that selective immunisation of girls before puberty should be instituted together with a routine rubella immunisation programme of infants to forestall a possible future outbreak of CRS, as occurred in Greece in 1993.
Fatores associados ao tempo de espera e ao acesso ao transplante renal em Belo Horizonte, Minas Gerais, Brasil

The objective of this study was to analyze factors associated with access to kidney transplants from living and cadaver donors in Belo Horizonte, Minas Gerais State, Brazil. The authors conducted a non-concurrent cohort study of patients on the waiting list for kidney transplants from 2000 to 2004 and followed until transplantation, death, exclusion, or continued presence on the line at the end of the study on December 31, 2005. The Cox model was used for competing risks. Of the 835 patients, 22.7% were transplanted. Lower risk of transplantation from living donors and cadavers was observed in patients with more time on dialysis and blood type O. Lower risk of transplantation from living donors was observed in residents in a high health risk area and in recipients with diabetes. The greatest disparity in access was observed in transplants from living donors, since there were no significant socio-demographic differences in transplants from cadaver donors. One can infer that the organ allocation system contributed to mitigating socio-demographic inequalities, and that clinical issues were more relevant in access to transplants from cadaver donors.
The smart therapist: A look to the future of smartphones and mHealth technologies in psychotherapy.

mHealth refers to the use of mobile technologies in the provision of health care and is an expanding field within psychotherapy research. Mobile technologies have the capacity to greatly enhance patient access, uptake, and engagement in psychological treatment. The purpose of the present article is to define mHealth within clinical psychology, provide a review and discussion of the functionality of mHealth devices, current trends within the field of psychological mHealth, the challenges faced by researchers and clinicians in this field, and examine directions for future research. The main areas of research identified included the use of SMS technologies, ecological momentary assessment, online and software application-based interventions and the recent integration of sensor and data mining technologies. Much of the research to date is lacking in methodological rigor, and reliance on standard research designs often used in other areas of psychological research may constrain development of interventions. Research indicates that consumers want to engage in mHealth interventions, although only a limited number of empirically supported options currently exist. Future research incorporating innovative trial designs is required to meet consumer demand and provide users with evidence-based treatment options.
Acute systemic erythropoietin therapy to reduce delayed ischemic deficits following aneurysmal subarachnoid hemorrhage: a Phase II randomized, double-blind, placebo-controlled trial. Clinical article.

OBJECT Delayed ischemic deficits (DIDs), a major source of disability following aneurysmal subarachnoid hemorrhage (aSAH), are usually associated with severe cerebral vasospasm and impaired autoregulation. Systemic erythropoietin (EPO) therapy has been demonstrated to have neuroprotective properties acting via EPO receptors on cerebrovascular endothelia and ischemic neurons. In this trial, the authors explored the potential neuroprotective effects of acute EPO therapy following aSAH. METHODS Within 72 hours of aSAH, 80 patients (age range 24-82 years) were randomized to receive intravenous EPO (30,000 U) or placebo every 48 hours for a total of 90,000 U. Primary end points were the incidence, duration, and severity of vasospasm and impaired autoregulation on transcranial Doppler ultrasonography. Secondary end points were incidence of DIDs and outcome at discharge and at 6 months. RESULTS Randomization characteristics were balanced except for age, with the EPO group being older (mean age 59.6 vs 53.3 years, p=0.034). No differences were demonstrated in the incidence of vasospasm and adverse events; however, patients receiving EPO had a decreased incidence of severe vasospasm from 27.5 to 7.5% (p=0.037), reduced DIDs with new cerebral infarcts from 40.0 to 7.5% (p=0.001), a shortened duration of impaired autoregulation (ipsilateral side, p<0.001), and more favorable outcome at discharge (favorable Glasgow Outcome Scale score, p=0.039). Among the 71 survivors, the EPO group had fewer deficits measured with National Institutes of Health Stroke Scale (median Score 2 vs 6, p=0.008). CONCLUSIONS This preliminary study showed that EPO seemed to reduce delayed cerebral ischemia following aSAH via decreasing severity of vasospasm and shortening impaired autoregulation.
2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.

Paul K. Whelton, MB, MD, MSc, FAHA, Chair, Writing Committee, Robert M. Carey, MD, FAHA, Vice Chair, Writing Committee, Wilbert S. Aronow, MD, FACC, FAHA, Writing Committee Member, Donald E. Casey, Jr., MD, MPH, MBA, FAHA, Writing Committee Member, Karen J. Collins, MBA, Writing Committee Member, Cheryl Dennison Himmelfarb, RN, ANP, PhD, FAHA, Writing Committee Member, Sondra M. DePalma, MHS, PA-C, CLS, AACC, Writing Committee Member, Samuel Gidding, MD, FACC, FAHA, Writing Committee Member, Kenneth A. Jamerson, MD, Writing Committee Member, Daniel W. Jones, MD, FAHA, Writing Committee Member, Eric J. MacLaughlin, PharmD, Writing Committee Member, Paul Muntner, PhD, FAHA, Writing Committee Member, Bruce Ovbiagele, MD, MSc, MAS, MBA, FAHA, Writing Committee Member, Sidney C. Smith, Jr., MD, MACC, FAHA, Writing Committee Member, Crystal C. Spencer, JD, Writing Committee Member, Randall S. Stafford, MD, PhD, Writing Committee Member, Sandra J. Taler, MD, FAHA, Writing Committee Member, Randal J. Thomas, MD, MS, FACC, FAHA, Writing Committee Member, Kim A. Williams, Sr., MD, MACC, FAHA, Writing Committee Member, Jeff D. Williamson, MD, MHS, Writing Committee Member, Jackson T. Wright, Jr., MD, PhD, FAHA, Writing Committee Member
Platelet hem-immunoreceptor tyrosine-based activation motif receptors: at least one required.

Platelet interaction with the vessel wall in thrombosis and hemostasis is mediated through a complex interplay of distinct activation and signaling events, involving cell adhesion receptors for matrix proteins (von Willebrand Factor, collagen) and G-protein receptors for soluble agonists (thrombin, ADP, thromboxane A2). 1 Adding to this complexity, it has become apparent in recent years that hemostasis and thrombosis as patho(physiological) processes are not identical, raising the hope that new antithrombotic therapeutic targets can be identified that are not associated with increased risk of bleeding.2 Two receptors, with promise, as potential antithrombotic therapeutic targets are members of the (hem)ITAM receptor family on platelets, glycoprotein VI (GPVI)/FcRγ-chain, the primary platelet collagen receptor,1–3 and C-type lectin-like receptor 2 (CLEC-2), which potentially plays a role in platelet aggregate and thrombus formation under arterial flow and is a receptor for the lymphatic endothelial cell protein, podoplanin.4–6 GPVI/FcRγ-chain and CLEC-2 are the only (hem)ITAM receptors present on mouse platelets. Human platelets have a third member of this family, the Fc receptor, FcγRIIa. 7 GPVI/FcRγ-chain and CLEC-2 receptors signal through Src-family kinase tyrosine phosphorylation of the receptor cytoplasmic tail and a similar, but not identical, …
The Hallucinations of Widowhood

227 widows and 66 widowers were interviewed to determine the extent to which they had hallucinatory experiences of their dead spouse. The people interviewed formed 80·7% of all widowed people resident within a defined area, in mid-Wales, and 94·2% of those suitable, through the absence of incapacitating illness, for interview. Almost half the people interviewed had hallucinations or illusions of the dead spouse. The proportion of men and women who had these experiences was similar. The hallucinations often lasted many years but were most common during the first 10 years of widowhood. Social isolation did not affect the incidence of hallucination, nor was it related to the incidence of known depressive illness. There was no variation within cultural groups and there was no variation with place of residence, whether this was within town, country, or village, or within England and Wales. Young people were less likely to be hallucinated than those widowed after the age of 40. The incidence of hallucination increased with length of marriage and was particularly associated with a happy marriage and parenthood. Members of the “professional and managerial” group were particularly likely to be hallucinated, while widows of “non-manual and sales workers” were the ones least likely to be hallucinated. The incidence was greater with hysteroid than obsessoid people. It was unusual for the hallucinations to have been disclosed, even to close friends or relatives. These hallucinations are considered to be normal and helpful accompaniments of widowhood.
Implications of bicuspid aortic valves for transcatheter aortic valve implantation.

Bicuspid aortic valve (BAV) occurs in 0.5% to 2% of the general population, with strong male predilection.1 Valvular complications include aortic stenosis, aortic regurgitation (AR), and infective endocarditis. Vascular complications comprise aortic dilatation, aneurysm formation, and aortic dissection. Coarctation of the aorta and left coronary artery dominance are also associated with BAV.1 BAV consists of 2 cusps, usually of unequal size.2 The larger cusp may contain 1 or 2 raphes—fibrous ridges extending from the malformed commissure to the free edge of the 2 conjoint cusps.2 An anatomic classification distinguishes BAV types principally by the number of raphes (Figure). 2 Because a raphe can be missed on echocardiography, Schaefer et al3 proposed 3 types based instead on the pattern of leaflet fusion. Clinical presentation of BAV is variable. Some patients present with severe disease in infancy, whereas others present with asymptomatic disease in old age.1 In a recent series of 642 asymptomatic adults with BAV referred to a tertiary center, 25% had a primary cardiac event at mean follow-up of 9 years.4 Aortic valve or ascending aorta intervention comprised most (22%) events.4 In another series of 212 asymptomatic adults with BAV recruited from the community, primary cardiac outcomes occurred in 42% at 20-year follow-up.5 Overall survival rates were similar to the general population.5 Figure. Anatomic classification of bicuspid aortic valves (BAV) based on a study of 304 surgical specimens.2 Prominent black lines denote the raphe (s). Type 0=no raphe, type 1=1 raphe, and type 2=2 raphes. Each type is subcategorized according to the spatial position of the cusps (type 0) or raphes (types 1 and 2). Percentages represent the approximate prevalence of each BAV type observed in the Sievers study.2 ap indicates anterior-posterior; L, left coronary sinus; lat, lateral; …
A Unifying Concept of Uveal Pigment Cell Distribution and Dissemination Based on an Animal Model: Insights into Ocular Melanogenesis

Pigmented cells are derived from neural crest cells, which migrate along the peripheral nerve sheets into their specific final region. During their migration, cells progressively acquire pigment-producing capabilities, maturation, and the shape of melanocytes. These insights, along with specific clinical characteristics of melanocytic nevi, have led to new concepts of cutaneous, periocular, and iris nevogenesis. To further elucidate the specific ocular embryogenic melanoblast distribution and dissemination - that could explain the distinct distribution of uveal melanocytic neoplasms - we investigated the ocular pigmentation of dogs affected by a specific mutation called Merle, which results in either pigment- (wild type) or non-pigment- (mutated type) producing cells. Based on our observations, we propose a unifying concept of uveal pigment cell distribution and dissemination, which postulates melanoblast migration and maturation following the trigeminal V1 branch and, later, their entrance into the eye along the ciliary nerves and their finest iris branches. Our concept provides an explanation not only for the specific distribution of ocular melanocytic lesions, including uveal and iris nevi, but also for the different locations depending on the metastatic potential of the ocular melanoma. Though speculative, the higher metastatic potential of posterior uveal melanomas compared to iris melanomas may be related to a less differentiated stage in the maturation of migrating melanocytes in the posterior segment compared to the anterior segment of the eye. However, there is a need of further studies focusing on cell differentiation markers of melanocytes at different locations in the eye.
Expression of PSCA, PIWIL1, and TBX2 in Endometrial Adenocarcinoma

Background: Endometrial cancer is the 4th most common gynecological cancer. The expression of prostate stem cell antigen (PSCA), piwi-like 1 (PIWIL1), and T-box 2 (TBX2) in endometrial cancer remains to be elucidated. Material and Methods: The expression of PSCA, PIWIL1, and TBX2 was examined using the streptavidin-peroxidase method in 64 endometrial endometrioid adenocarcinoma (EAC) and paired normal endometrium (NE) samples from the Shaanxi Province in China. Results: Positive expression rates of PSCA, PIWIL1, and TBX2 were 75% (48/64), 25% (16/64), and 56% (36/64), respectively in EACs, but 5% (3/64), 6% (4/64), and 2% (1/64), respectively in NEs. The difference was statistically significant (p < 0.05). PSCA was positively correlated with TBX2 (p = 0.003) but not PIWIL1 (p = 0.188). PIWIL1 was positively correlated with TBX2 (p = 0.003). PSCA was positively correlated with age, tumor grade, and lymph node metastasis (p < 0.05). TBX2 had an association with lymph node metastasis (p = 0.014). PIWIL1 was not associated with clinicopathological features (p > 0.05). Conclusions: We report the first analysis of PSCA, PIWIL1, and TBX2 expression in EAC. Our findings suggest that PSCA and TBX2 might be candidate targets for cancer therapy, and have helped us further understand the carcinogenesis of endometrial cancer.