Miracle-dz/UniFAR-FTUs huggingface dataset:
Testing Computer Models Predicting Human Responses to a High-Salt Diet: Implications for Understanding Mechanisms of Salt-Sensitive Hypertension

Recently, mathematical models of human integrative physiology, derived from Guyton’s classic 1972 model of the circulation, have been used to investigate potential mechanistic abnormalities mediating salt sensitivity and salt-induced hypertension. We performed validation testing of 2 of the most evolved derivatives of Guyton’s 1972 model, Quantitative Cardiovascular Physiology-2005 and HumMod-3.0. 4, to determine whether the models accurately predict sodium balance and hemodynamic responses of normal subjects to increases in salt intake within the real-life range of salt intake in humans. Neither model, nor the 1972 Guyton model, accurately predicts the usual changes in sodium balance, cardiac output, and systemic vascular resistance that normally occur in response to clinically realistic increases in salt intake. Furthermore, although both contemporary models are extensions of the 1972 Guyton model, testing revealed major inconsistencies between model predictions with respect to sodium balance and hemodynamic responses of normal subjects to short-term and long-term salt loading. These results demonstrate significant limitations with the hypotheses inherent in the Guyton models regarding the usual regulation of sodium balance, cardiac output, and vascular resistance in response to increased salt intake in normal salt-resistant humans. Accurate understanding of the normal responses to salt loading is a prerequisite for accurately establishing abnormal responses to salt loading. Accordingly, the present results raise concerns about the interpretation of studies of salt sensitivity with the various Guyton models. These findings indicate a need for continuing development of alternative models that incorporate mechanistic concepts of blood pressure regulation fundamentally different from those in the 1972 Guyton model and its contemporary derivatives.
Long-term cardiovascular safety of psychostimulants in children with attention deficit hyperactivity disorder

Abstract Objective: Side effects are a concern during psychostimulant treatment. Unfortunately, many previous studies only investigated short-term effects of psychostimulants in laboratory settings which lack clinical daily routines. Methods: We examined 1042 patient records of patients with attention deficit hyperactivity disorder (ADHD) who were referred to a pediatric-psychiatry practice over 12 years. Data analysis was based on 466 children with ADHD who were newly treated with psychostimulants and who were not in treatment for elevated blood pressure. We analysed blood pressure percentiles, heart rate and BMI percentiles. Results: There was a decrease in systolic and diastolic blood pressure percentiles. Heart rate was not affected. BMI slightly declined in girls. Conclusions: In general psychostimulants were safe. To further elucidate negative effects of psychostimulants, long-term controlled and randomized studies in naturalistic settings are of interest.
CRLF2 expression associates with ICN1 stabilization in T‐cell acute lymphoblastic leukemia

T‐cell acute lymphoblastic leukemia (T‐ALL) is an aggressive hematopoietic malignancy with few molecular alterations showing a consensual prognostic value. CRLF2 overexpression was recently identified in high‐risk T‐ALL patients. For these cases, no genomic abnormality was found to be associated with CRLF2 overexpression. IKZF1 has been recently shown to be a direct transcriptional regulator of CRLF2 expression. Moreover, it is known that NOTCH1 antagonizes IKZF1 in T‐ALL. In light of these pieces of evidence, we reasoned that IKZF1 binding perturbation and CRLF2 upregulation could be associated in T‐ALL. We evaluated two independent series of pediatric T‐ALL cases (PHOP, n = 57 and TARGET, n = 264) for the presence of common T‐ALL molecular abnormalities, such as NOTCH1/FBXW7 mutations. We also assessed CRLF2 and IKZF1 gene expression. CRLF2 overexpression was observed in 14% (PHOP) and 16% (TARGET) of T‐ALL patients. No correlation was found between mRNA expression of CRLF2 and IKZF1 in both cohorts. Interestingly, we show that patients with mutations affecting NOTCH1‐PEST domain and/or FBXW7 had higher CRLF2 expression (P = .04). In summary, we demonstrate for the first time that only mutations resulting in ICN1 (intracellular domain of NOTCH1) stabilization are associated with CRLF2 overexpression.
Progress in the HIV epidemic: Identifying goals and measuring success

Substantial progress has been made towards the goal of ending the HIV/AIDS epidemic due to advancements in both prevention and treatment of HIV. However, major challenges still remain. We describe basic principles of epidemic control in the context of HIV and identify a number of attainable goals in terms of control and elimination of HIV in specific populations and risk groups, given currently available HIV prevention and treatment methods. Currently available HIV prevention methods make it a feasible goal to eliminate HIV transmission attributable to mother-to-child transmission and blood transfusions. Reductions in transmission attributable to sexual behavior and injection drug use are feasible, but elimination of these modes of transmission will require further advancements in behavioral and biomedical HIV prevention. With regard to HIV-related mortality, we argue that elimination of death due to HIV-related causes is a feasible goal. HIV-related deaths should be treated as sentinel events triggering epidemiological investigation into the breakdowns in the HIV care continuum that led to them. We briefly discuss additional considerations that will affect the success of HIV prevention programs.
EEG-based age-prediction models as stable and heritable indicators of brain maturational level in children and adolescents

The human brain shows remarkable development of functional brain activity from childhood to adolescence. Here, we investigated whether electroencephalogram (EEG) recordings are suitable for predicting the age of children and adolescents. Moreover, we investigated whether over-or underestimation of age was stable over longer time periods, as stable prediction error can be interpreted as reflecting individual brain maturational level. Finally, we established whether the age-prediction error was genetically determined. Three minutes eyes-closed resting state EEG data from the longitudinal EEG studies of Netherlands Twin Register (n=836) and Washington University in St. Louis (n = 702) were used at ages 5, 7, 12, 14, 16 and 18. Longitudinal data were available within childhood and adolescence. We calculated power in 1 Hz wide bins (1 to 24 Hz). Random Forest regression and Relevance Vector Machine with 6-fold cross-validation were applied. The best mean absolute prediction error was obtained with Random Forest (1.22 years). Classification of childhood vs. adolescence reached over 94% accuracy. Prediction errors were moderately to highly stable over periods of 1.5 to 2.1 years (0.53 < r < 0.74) and signifcantly affected by genetic factors (heritability between 42% and 79%). Our results show that age prediction from low-cost EEG recordings is comparable in accuracy to those obtained with MRI. Children and adolescents showed stable over- or underestimation of their age, which means that some participants have stable brain activity patterns that reflect those of an older or younger age, and could therefore reflect individual brain maturational level. This prediction error is heritable, suggesting that genes underlie maturational level of functional brain activity. We propose that age prediction based on EEG recordings can be used for tracking neurodevelopment in typically developing children, in preterm children, and in children with neurodevelopmental disorders.
Effectiveness of an mHealth-Based Electronic Decision Support System for Integrated Management of Chronic Conditions in Primary Care: The mWellcare Cluster-Randomized Controlled Trial

Background: The burden of noncommunicable diseases and their risk factors has rapidly increased worldwide, including in India. Innovative management strategies with electronic decision support and task sharing have been assessed for hypertension, diabetes mellitus, and depression individually, but an integrated package for multiple chronic condition management in primary care has not been evaluated. Methods: In a prospective, multicenter, open-label, cluster-randomized controlled trial involving 40 community health centers, using hypertension and diabetes mellitus as entry points, we evaluated the effectiveness of mWellcare, an mHealth system consisting of electronic health record storage and an electronic decision support for the integrated management of 5 chronic conditions (hypertension, diabetes mellitus, current tobacco and alcohol use, and depression) versus enhanced usual care among patients with hypertension and diabetes mellitus in India. At trial end (12-month follow-up), using intention-to-treat analysis, we examined the mean difference between arms in change in systolic blood pressure and glycated hemoglobin as primary outcomes and fasting blood glucose, total cholesterol, predicted 10-year risk of cardiovascular disease, depression score, and proportions reporting tobacco and alcohol use as secondary outcomes. Mixed-effects regression models were used to account for clustering and other confounding variables. Results: Among 3698 enrolled participants across 40 clusters (mean age, 55.1 years; SD, 11 years; 55.2% men), 3324 completed the trial. There was no evidence of difference between the 2 arms for systolic blood pressure (&Dgr;=−0.98; 95% CI, −4.64 to 2.67) and glycated hemoglobin (&Dgr;=0.11; 95% CI, −0.24 to 0.45) even after adjustment of several key variables (adjusted differences for systolic blood pressure: – 0.31 [95% CI, −3.91 to 3.29]; for glycated hemoglobin: 0.08 [95% CI, −0.27 to 0.44]). The mean within-group changes in systolic blood pressure in mWellcare and enhanced usual care were −13.65 mm Hg versus −12.66 mm Hg, respectively, and for glycated hemoglobin were −0.48% and −0.58%, respectively. Similarly, there were no differences in the changes between the 2 groups for tobacco and alcohol use or other secondary outcomes. Conclusions: We did not find an incremental benefit of mWellcare over enhanced usual care in the management of the chronic conditions studied. Clinical Trial Registration: URL: https://www.clinicaltrials. gov. Unique identifier: NCT02480062.
Importance of GFAP isoform‐specific analyses in astrocytoma

Gliomas are a heterogenous group of malignant primary brain tumors that arise from glia cells or their progenitors and rely on accurate diagnosis for prognosis and treatment strategies. Although recent developments in the molecular biology of glioma have improved diagnosis, classical histological methods and biomarkers are still being used. The glial fibrillary acidic protein (GFAP) is a classical marker of astrocytoma, both in clinical and experimental settings. GFAP is used to determine glial differentiation, which is associated with a less malignant tumor. However, since GFAP is not only expressed by mature astrocytes but also by radial glia during development and neural stem cells in the adult brain, we hypothesized that GFAP expression in astrocytoma might not be a direct indication of glial differentiation and a less malignant phenotype. Therefore, we here review all existing literature from 1972 up to 2018 on GFAP expression in astrocytoma patient material to revisit GFAP as a marker of lower grade, more differentiated astrocytoma. We conclude that GFAP is heterogeneously expressed in astrocytoma, which most likely masks a consistent correlation of GFAP expression to astrocytoma malignancy grade. The GFAP positive cell population contains cells with differences in morphology, function, and differentiation state showing that GFAP is not merely a marker of less malignant and more differentiated astrocytoma. We suggest that discriminating between the GFAP isoforms GFAPδ and GFAPα will improve the accuracy of assessing the differentiation state of astrocytoma in clinical and experimental settings and will benefit glioma classification.
Unconfirmed death as a predictor of psychological morbidity in family members of disappeared persons

Abstract Background The 2004 tsunami, the civil conflict until 2009 and the youth insurrection in the late 1980s in Sri Lanka resulted in many persons being classified as ‘missing’ as they disappeared and were unaccounted for. Our aim was to compare the prevalence of major depressive disorder (MDD) and prolonged grief disorder (PGD) in families of disappeared individuals, who eventually received the mortal remains and those who did not. Method An ethically approved cross sectional study was conducted in a purposively selected sample after informed consent. Information on the circumstances of the family member going missing was gathered. Culturally adapted versions of the General Health Questionnaire and the Beck Depression Scale were administered. Those who screened positive were assessed by a psychiatrist on Diagnostic and Statistical Manual of Mental Disorders-5 criteria to arrive at a diagnosis. Results Of 391 cases of disappearances studied, MDD (17.5% v. 6%) and PGD (22% v. 7%) were significantly higher in those who did not eventually receive the mortal remains of the disappeared person. Among those who did not receive the mortal remains, being unsure whether the disappeared person was dead or alive was highly predictive of MDD and PGD. Mothers and wives, older family members and those with a family history of mental illness were more vulnerable. Conclusions Family members of missing individuals unsure whether their loved one was alive or dead have higher psychological morbidity in the form of MDD and PGD.
Secrecy versus disclosure of mental illness among adolescents: I. The perspective of adolescents with mental illness

Abstract Background: Many adolescents with mental illness (MI) struggle with the decision whether to disclose their condition. They may decide to keep their MI secret, whether due to fear of public stigma or due to self-stigma and shame. Secrecy may protect against discrimination, but has often negative long-term consequences such as social isolation. Aim: To explore personal views of adolescents with MI on secrecy and disclosure of their MI. Method: Six focus groups consisting of 39 adolescents with MI were recorded, transcribed, and analyzed by qualitative content analysis to identify major themes deductively and inductively. Results: Participants described MI as a stigmatized condition and stressed both the benefits and risks of secrecy. Disadvantages included fear of stigma and loss of friendships, benefits included emotional support and relief. Adolescents underlined the importance of individual disclosure decisions (DDs). The majority preferred selective disclosure. Additionally, the role of other adolescents with and without MI was emphasized. Conclusions: DDs are individual and depend on social factors since stigma and fear of discrimination remain significant concerns for adolescents with MI. Implications for future interventions to support adolescents with MI are discussed.
Antiaging effects of bioactive molecules isolated from plants and fungi

Aging is influenced by many lifestyle choices that are under human control, including nutrition and exercise. The most effective known antiaging intervention consists of calorie restriction (CR), which increases lifespan in yeasts, worms, fruit flies, mice, and nonhuman primates. CR also improves healthspan by preventing the development of various aging‐related diseases such as cancer, cardiovascular disease, diabetes, and neurodegeneration. Many compounds isolated from plants and fungi prolong lifespan and prevent age‐related diseases in model organisms. These plant and fungal compounds modulate the same cellular and physiological pathways as CR, including those involving insulin and insulin‐like growth factor‐1, mammalian target of rapamycin, and sirtuins. Modulation of these aging‐related pathways results in the activation of various cellular processes such as autophagy, DNA repair, and neutralization of reactive oxygen species. Together, these cellular processes are believed to delay aging and prevent chronic diseases by improving bodily functions and stress resistance. We review here the mechanisms of action of plant and fungal molecules possessing antiaging properties and discuss the possibilities and challenges associated with the development of antiaging compounds isolated from natural products.
Assessment of Different Dimensions of Shame Proneness: Validation of the SHAME

A large body of research revealed that shame is associated with adaptive and maladaptive correlates. The aim of this work was to validate a new dimensional instrument (SHAME), which was developed to disentangle adaptive and maladaptive dimensions of shame proneness. Confirmatory factor analyses supported the three-factorial structure (bodily, cognitive, and existential shame) in American (n = 502) and German (n = 496) community samples, using invariance testing. Bifactor model analyses exhibited distinct associations of adaptive (bodily and cognitive shame) and maladaptive (existential shame) dimensions of shame with psychopathology and social functioning. Network analyses highlighted the role of existential shame in psychopathology, especially for a clinical sample of patients with Borderline Personality Disorder (n = 92). By placing shame pronenesss into a network of similar and dissimilar constructs, the current findings serve as a foundation for drawing conclusions about the adaptive and maladaptive nature of shame.
A randomized clinical trial for the assessment of the efficacy and safety of guluronic acid (G2013) in patients with rheumatoid arthritis

Abstract Objective: To evaluate the safety, efficacy and tolerability of guluronic acid (G2013) in order to treat the rheumatoid arthritis patients who had inadequate response to conventional drugs. Methods: A randomized, 12-week clinical trial with two treatment arms: guluronic acid (G2013) and conventional treatment was performed. The diagnosed RA patients according to the ACR/European League against Rheumatism 2010 classification criteria, with an active disease at baseline that had inadequate response to conventional therapy were considered for the study. G2013 was administered orally twice a day with capsules of 500 mg during a period of 12 weeks and the patients were followed up for the safety and efficacy. Results: Our data showed that, the mean changes in the G2013 and control groups were −7.54 and −2.5 for tender joint count; −7.59 and −3.59 for swollen joint count; −30 and −0.9 for physician global assessment; −23.18 and −1.81 for patient global assessment; −14.45 and −1.45 for erythrocyte sedimentation rate, respectively. Improvements seen with G2013 were significantly greater than those with conventional drugs. In total, in 15.3% of G2013-treated patients and 69.2% of conventional-treated patients adverse events (AEs) occurred in this study. Conclusion: These data from routine rheumatology clinical practice highlight the effectivenessof G2013 in combination with conventional therapy with more desirable safety profile compared to the conventional-treated patients. Therefore, G2013 therapy could be an appropriate choice in order to manage the RA disease. (Clinical trial identifier: IRCT2016092813739N5).
One problem, too many solutions: How costly is honest signalling of need?

The “cost of begging” is a prominent prediction of costly signalling theory, suggesting that offspring begging has to be costly in order to be honest. More specifically, it predicts that there is a single cost function for the offspring (depending on e.g. offspring quality) that maintains honesty and it must be proportional to parent’s fitness loss. Here we show another interpretation of the cost. We demonstrate that cost, proportional to the fitness gain of the offspring, also results in honest signalling. Since the loss of the parent does not necessarily coincide with the gain of the offspring, it is provable that any linear combination of the two cost functions (one proportional to parent’s loss, one to offspring’s gain) also leads to honest signalling. Our results, applied for a specific model, support the previous general conclusion that signalling games have different cost functions for different equilibria. Consequently, costly signalling theory cannot predict a unique equilibrium cost in signalling games especially in case of parent-offspring conflicts. As an important consequence, any measured equilibrium cost in real cases has to be compared both to the parent’s fitness loss and to the offspring’s fitness gain in order to provide meaningfully interpretation.
Statin treatment and the risk of depression

The effect of statin treatment on the risk of developing depression remains unclear. Therefore, we aimed to assess the association between statin treatment and depression in a nationwide register-based cohort study with up to 20 years of follow up. We identified all statin users among all individuals born in Denmark between 1920 and 1983. One non-user was matched to each statin user based on age, sex and a propensity score taking several potential confounders into account. Using Cox regression we investigated the association between statin use and: I) redemption of prescriptions for antidepressants, II) redemption of prescriptions for any other drug, III) depression diagnosed at psychiatric hospitals, IV) cardiovascular mortality and V) all-cause mortality. A total of 193,977 statin users and 193,977 non-users were followed for 2,621,282 person-years. Statin use was associated with I) increased risk of antidepressant use (hazard rate ratio (HRR)=1.33; 95% confidence interval (95%-CI)=1.31-1.36), II) increased risk of any other prescription drug use (HRR=1.33; 95%-CI=1.31-1.35), III) increased risk of receiving a depression diagnosis (HRR=1.22, 95%-CI=1.12-1.32) - but not after adjusting for antidepressant use (HRR=1.07, 95%-CI=0.99- 1.15), IV) reduced cardiovascular mortality (HRR=0.92, 95%-CI=0.87-0.97) and V) reduced all-cause mortality (HRR=0.90, 95%-CI=0.88-0.92). These results suggest that the association between statin treatment and antidepressant use was unspecific (equivalent association between statins and other drugs) and that the association between statin use and depression diagnoses was mediated by antidepressant use. Thus, statin users and non-users appear to be equally likely to develop depression, but the depression is more often detected/treated among statin users.