Miracle-dz/UniFAR-FTUs huggingface dataset:
Survival of malignant mesothelioma and other rare thoracic cancers in Germany and the United States: A population‐based study

Evidence on survival of malignant mesothelioma (MM) and other rare thoracic cancers is limited due to the rarity of these cancer sites. Here, we provide a comprehensive overview of MM incidence and survival after MM and other rare thoracic cancers in Germany and the United States (US). Incidence was estimated from a German National Cancer Database and from the Surveillance, Epidemiology and End Results (SEER) 18 database for 2000–2014. Patients diagnosed in 1997–2013 with malignant epithelial tumors of the trachea (Etra), epithelial tumors of the thymus (Ethy) and MM were extracted from a German cancer survival database and from the SEER 13 database. Period analysis was employed to compute 5‐year relative survival (RS). During 2000–2014, an annual average of 0.9 and 0.6 MM cases per 100,000 person‐years was diagnosed in Germany and the US. Rates decreased in Germany and in the US. Patients with Ethy had highest 5‐year RS with US patients surviving longer (69.1% compared to 63.7%, p = 0.02). Survival after Etra was comparable in both countries (Germany 33.6%, US 34.4%, p = 0.07). Survival in MM patients was poor overall (Germany 11.8%, US 12.1%, p < 0.01). Survival improvements were only observed in MM patients in Germany (10.8% [2002–2007] vs. 13.0% [2008–2013], p < 0.01). The lack of progress in survival for Etra and Ethy patients underlines the need of novel preventive, therapeutic and diagnostic approaches. MM incidence significantly decreased in Germany and in the US. Further monitoring of MM incidence is warranted given that a peak in incidence is expected in 2020–2030 in Western countries.
Kaposi Sarcoma-associated herpesvirus infection and endemic Burkitt's lymphoma.

BACKGROUND Endemic Burkitt's lymphoma (eBL) is associated with Epstein-Barr virus (EBV) and Plasmodium falciparum (Pf) malaria co-infections. However, the role of Kaposi sarcoma-associated herpesvirus (KSHV), also endemic in Africa, has not been evaluated as a co-factor in eBL pathogenesis. METHODS Multiplexed seroprofiles for EBV, malaria and KSHV were generated for 266 eBL patients, 78 non-eBL cancers and 202 healthy children; and KSHV and EBV loads were quantified by digital-droplet PCR. RESULTS KSHV seroprevalence did not differ by study group yet was associated with age. Seropositivity, defined by K8.1/LANA or in combination with 5 other KSHV antigens (ORF59, ORF65, ORF61, ORF38, and K5) was associated with anti-malarial antibody levels to AMA-1 (OR=2.41, p<0.001 and OR=2.07, p<0.001) and MSP-1 (OR=2.41, p=0.0006 and OR=5.78, p<0.001), respectively. KSHV loads did not correlate with antibody levels nor differ across groups, but were significantly lower in children with detectable EBV viremia (p=0.014). CONCLUSIONS Even though KSHV-EBV dual infection does not increase eBL risk, EBV appears to suppress reactivation of KSHV while malaria exposure is associated with KSHV infection and/or reactivation. Both EBV and malaria should, therefore, be considered as potential effect modifiers for KSHV-associated cancers in sub-Saharan Africa.
Blood Metabolite Signature of Metabolic Syndrome Implicates Alterations in Amino Acid Metabolism: Findings from the Baltimore Longitudinal Study of Aging (BLSA) and the Tsuruoka Metabolomics Cohort Study (TMCS)

Rapid lifestyle and dietary changes have contributed to a rise in the global prevalence of metabolic syndrome (MetS), which presents a potential healthcare crisis, owing to its association with an increased burden of multiple cardiovascular and neurological diseases. Prior work has identified the role that genetic, lifestyle, and environmental factors can play in the prevalence of MetS. Metabolomics is an important tool to study alterations in biochemical pathways intrinsic to the pathophysiology of MetS. We undertook a metabolomic study of MetS in serum samples from two ethnically distinct, well-characterized cohorts—the Baltimore Longitudinal Study of Aging (BLSA) from the U.S. and the Tsuruoka Metabolomics Cohort Study (TMCS) from Japan. We used multivariate logistic regression to identify metabolites that were associated with MetS in both cohorts. Among the top 25 most significant (lowest p-value) metabolite associations with MetS in each cohort, we identified 18 metabolites that were shared between TMCS and BLSA, the majority of which were classified as amino acids. These associations implicate multiple biochemical pathways in MetS, including branched-chain amino acid metabolism, glutathione production, aromatic amino acid metabolism, gluconeogenesis, and the tricarboxylic acid cycle. Our results suggest that fundamental alterations in amino acid metabolism may be central features of MetS.
Sarcoma Family Kinase-Dependent Pannexin-1 Activation after Cortical Spreading Depression Is Mediated by NR2A-Containing Receptors

Cortical spreading depression (CSD) is a propagating wave of depolarization followed by depression of cortical activity. CSD triggers neuroinflammation via the pannexin-1 (Panx1) channel opening, which may eventually cause migraine headaches. However, the regulatory mechanism of Panx1 is unknown. This study investigates whether sarcoma family kinases (SFK) are involved in transmitting CSD-induced Panx1 activation, which is mediated by the NR2A-containing N-methyl-D-aspartate receptor. CSD was induced by topical application of K+ to cerebral cortices of rats and mouse brain slices. SFK inhibitor, PP2, or NR2A–receptor antagonist, NVP–AAM077, was perfused into contralateral cerebral ventricles (i.c.v.) of rats prior to CSD induction. Co-immunoprecipitation and Western blot were used for detecting protein interactions, and histofluorescence for addressing Panx1 activation. The results demonstrated that PP2 attenuated CSD-induced Panx1 activation in rat ipsilateral cortices. Cortical susceptibility to CSD was reduced by PP2 in rats and by TAT-Panx308 that disrupts SFK–Panx1 interaction in mouse brain slices. Furthermore, CSD promoted activated SFK coupling with Panx1 in rat ipsilateral cortices. Moreover, inhibition of NR2A by NVP–AAM077 reduced elevation of ipsilateral SFK–Panx1 interaction, Panx1 activation induced by CSD and cortical susceptibility to CSD in rats. These data suggest NR2A-regulated, SFK-dependent Panx1 activity plays an important role in migraine aura pathogenesis.
The quantification of the psychiatric revolution: a quasi-natural experiment of the suicide impact of the Basaglia Law

Abstract Background The Italian 180/1978 reform abolishing asylums is one of the most contested mental health programs ever implemented. It aimed to shift care of mental illness into the community improving outcomes and reducing expenditure. It was a model for successive deinstitutionalization initiatives across Europe and North America. However, there were longstanding concerns that, without expansion of community care, it may have deprived patients with mental illness access to support, placing them at increased risk of suicide. Methods Regression discontinuity models were used to quantify the association between the number of suicides and the introduction of the Basaglia Law, disaggregated by age-group and gender, covering 20 Italian regions during the period 1975–84. Models were adjusted for potential socio-demographic confounding factors, region-specific fixed effects and pre-existing time-trends. Results Italian regions implemented the Basaglia Law to varying degrees over time. We observed that, after adjusting for pre-existing time trends, the implementation was associated with a consistent increase in the number of suicides for all the age-groups [incidence rate ratio, age 15–44: 1.29, 95% confidence interval (CI) 1.18–1.41; age 45–74: 1.45, 95% CI 1.37–1.54] and for both genders (males: 1.47, 95% CI 1.41–1.53; females: 1.36, 95% CI 1.25–1.47). Hospital closure appeared to be an important mediating mechanism. Conclusions The Basaglia Law was associated with a significant increase in the number of suicides, with evidence of an association with closures of facilities, leaving those with mental illness with nowhere to go, as the envisioned community care structures failed to be developed as originally planned.
EBV‐positive diffuse large B‐cell lymphoma, not otherwise specified: 2020 update on diagnosis, risk‐stratification and management

Epstein Barr virus‐positive (EBV+) diffuse large B‐cell lymphoma (DLBCL), not otherwise specified (NOS) is an entity included in the 2016 WHO classification of lymphoid neoplasms. EBV+ DLBCL, NOS, is an aggressive B‐cell lymphoma associated with chronic EBV infection, and a poor prognosis with standard chemotherapeutic approaches.
Associations between the Intake of Different Types of Dairy and Cognitive Performance in Dutch Older Adults: The B-PROOF Study

Various dairy nutrients have been associated with cognitive performance. Several observational studies have explored associations between the intake of total dairy or some dairy subgroups and cognitive performance. However, studies on the potential impact of a broad variety of dairy subclasses are scarce. We examined cross-sectional associations between a wide assortment of dairy products and cognitive performance. A total of 619 Dutch community-dwelling adults aged ≥65 years completed a semi-quantitative Food Frequency Questionnaire. Cognitive performance was assessed with an extensive neuropsychological test battery; the tests were clustered into cognitive domains using z-scores. Linear and logistic regression analyses, adjusted for age, sex, BMI, education, smoking, alcohol consumption, habitual physical activity, total energy intake, and dietary factors, were performed to quantify the associations. The Benjamini–Hochberg method was used to correct for multiple testing. After full adjustment, higher skimmed dairy (β ± SD: 0.05 ± 0.02, p = 0.06), fermented dairy (0.04 ± 0.02, p = 0.09), and buttermilk (0.08 ± 0.03, p = 0.19) consumption were associated with better executive functioning. Logistic regression analyses indicated that a 30 g increase in Dutch cheese intake was associated with a 33% lower probability of poor information processing speed (PR = 0.67, 95% CI 0.47–0.97). No associations were observed between dairy consumption and attention and working memory or episodic memory.
Drug-drug Interactions between and Commonly-used Antiretroviral 2 Treatment: An Individual Participant Data Population Pharmacokinetic Meta-Analysis.

Treating malaria in HIV co-infected individuals should consider potential drug-drug 53 interactions. Artemether-lumefantrine is the most widely recommended treatment for 54 uncomplicated malaria globally. Lumefantrine is metabolized by CYP3A4, an enzyme that 55 commonly-used antiretrovirals often induce or inhibit. A population pharmacokinetic meta- 56 analysis was conducted using individual participant data from ten studies, with 6,100 57 lumefantrine concentrations from 793 non-pregnant adult participants (41% HIV-malaria co- 58 infected, 36% malaria-infected, 20% HIV-infected, and 3% healthy volunteers). 59 Lumefantrine exposure increased 3.4-fold with co-administration of lopinavir/ritonavir-based 60 antiretroviral therapy (ART), while it decreased by 47% with efavirenz-based ART and by 61 59% in the patients with rifampicin-based anti-tuberculosis treatment. Nevirapine- or 62 dolutegravir-based ART and malaria- or HIV-infection were not associated with significant 63 effects. Monte Carlo simulations showed that those on concomitant efavirenz or rifampicin 64 have 49% and 80% probability of day-7 concentrations <200 ng/mL respectively, a threshold 65 associated with an increased risk of treatment failure. The risk of achieving sub-therapeutic 66 concentrations increases with larger body weight. An extended 5-day and 6-day artemether- 67 lumefantrine regimen is predicted to overcome these drug-drug interactions with efavirenz 68 and rifampicin respectively. 69
The characteristics of monosyllable recognition in Mandarin-speaking patients with auditory neuropathy

Abstract Background: A set of Chinese Mandarin monosyllable test lists has been widely used in clinical diagnosis, while the performance of the Mandarin-speaking patients with auditory neuropathy (AN) in the monosyllable tests was still unknown. Objectives: To analyze the characteristics of monosyllable recognition in Mandarin-speaking patients with AN. Materials and methods: Nineteen Mandarin-speaking patients diagnosed with AN were recruited to obtain the performance-intensity (P-I) functions. They were divided into two paired groups according to two conditions: (1) the rising-slope (RS) and the non-rising-slope pattern (NRS) group for the audiogram; or (2) the male and the female group for gender. Results: The performance at 20 and 30 dB SL showed negative correlation with the pure tone-averaged thresholds of 0.5, 1.0, 2.0 and 4.0 kHz (4FA). We found significant differences between the P-I functions of the RS and the NRS group, and surprisingly found that between the male and female as well although there was no difference in 4FA between the paired groups. A notable rollover phenomenon in P-I functions was detected in each group. Conclusions: The monosyllable recognition scores of Mandarin-speaking AN patients showed numerous particular characteristics reflected by P-I functions. Acquiring the complete P-I functions at multiple presentation levels and the rollover index may give us more information about the diagnosis and prognosis.
Circ_PUM1 promotes the development of endometrial cancer by targeting the miR‐136/NOTCH3 pathway

Endometrial cancer is one of the most common gynaecological malignancies and the sixth most common cause of cancer‐related death among women. Here, we define the role and molecular mechanism of circ_0000043 (hereafter referred to as circ_PUM1) in the development and progression of endometrial carcinoma. QRT‐PCR was used to detect the expression of circ_PUM1 in normal endometrial tissue and endometrial carcinoma tissues. Changes in cell function and tumorigenicity in nude mice were examined after circ_PUM1 overexpression or knockdown. Bioinformatic analysis and dual‐luciferase reporter assay were used to predict and analyse the miRNAs that circ_PUM1 binds. Gene expression changes were analysed using Western blot. Circ_PUM1 was expressed at significantly higher levels in endometrial cancer tissues than in normal tissues. Up‐regulation of circ_PUM1 promoted the proliferation, migration and invasion of endometrial carcinoma cells. Opposite results were observed with circ_PUM1 knockdown, and the tumorigenic ability of endometrial cancer cells after circ_PUM1 knockdown was reduced compared to control cells. Circ_PUM1 is capable of binding to miR‐136, and up‐regulating its target gene NOTCH3, which can be reversed by overexpression of miR‐136. Circ_PUM1 can compete with miR‐136, leading to up‐regulation of NOTCH3, and thereby promote the development of endometrial cancer.
The emerging role of dyslipidemia in diabetic microvascular complications.

PURPOSE OF REVIEW To summarize recent advancements in our understanding of the impact of dyslipidemia on microvascular complications in type 2 diabetes (T2D), with an emphasis on peripheral neuropathy and nephropathy. RECENT FINDINGS Mounting evidence suggests that rigorous glycemic control only mitigates certain microvascular complications in T2D patients. Particularly, well regulated blood glucose levels only marginally improve peripheral neuropathy in the T2D setting. Dyslipidemia, an abnormal lipid profile, is emerging as a key factor in peripheral neuropathy. Furthermore, although glycemic control may prevent or slow nephropathy, recent developments demonstrate that dyslipidemia can also affect kidney outcomes in normoglycemic patients. Transcriptomic, epigenomic, and lipidomic investigations, as well as integrative approaches, are shedding light on potential pathomechanisms. These molecular studies are identifying possible targets for therapeutic intervention. Complementing molecular research, lifestyle interventions are on-going to assess whether dietary choices and/or exercise, weight-loss, or surgical interventions, such as bariatric surgery, can ameliorate peripheral neuropathy and nephropathy in T2D patients. SUMMARY Dyslipidemia is an emerging mechanism in microvascular complications in T2D. Elucidating the molecular pathomechanisms may pinpoint potential lipid-centric treatments. Interventional studies of dietary changes, exercise, or weight-loss surgery may also positively impact these highly prevalent and morbid complications.
Cardiorespiratory fitness and mnemonic discrimination across the adult lifespan

With a rising aging population, it is important to develop behavioral tasks that assess and track cognitive decline, and to identify protective factors that promote healthy brain aging. Mnemonic discrimination tasks that rely on pattern separation mechanisms are a promising metric to detect subtle age-related memory impairments. Behavioral performance on these tasks rely on the integrity of the hippocampus and surrounding circuitry, which are brain regions known to be adversely affected in aging and neurodegenerative disorders. Aerobic exercise, which improves cardiorespiratory fitness (CRF), has been shown to counteract aging-related decreases in structural and functional brain integrity and attenuate decline of cognitive performance. Here, we tested the hypothesis that higher CRF attenuates age-related deficits in mnemonic discrimination in both a nonspatial mnemonic discrimination (Mnemonic Similarity Task) and a virtual navigation task (Route Disambiguation Task). Importantly, we included individuals across the lifespan (aged 18–83 yr), including the middle-age range, to determine mnemonic discrimination performance across adulthood. Participants completed two mnemonic discrimination tasks and a treadmill test to assess CRF. Our results demonstrate robust negative age-related effects on mnemonic discrimination performance across both the nonspatial and spatial domains. Critically, higher CRF mitigated age-related attenuation in spatial contextual discrimination task performance, but did not show an attenuation effect on performance for object-based mnemonic discrimination. These results suggest that performance on spatial mnemonic discrimination may be a useful tool to track vulnerability in older individuals at risk for cognitive decline, and that higher CRF may lead to cognitive preservation across the adult lifespan, particularly for spatial disambiguation of similar contexts.
Association Between Peripheral Blood Oxygen Saturation (SpO2)/Fraction of Inspired Oxygen (FiO2) Ratio Time at Risk and Hospital Mortality in Mechanically Ventilated Patients.

INTRODUCTION Acute respiratory failure requiring mechanical ventilation is a leading cause of mortality in the intensive care unit. Although single peripheral blood oxygen saturation/fraction of inspired oxygen (SpO2/FiO2) ratios of hypoxemia have been evaluated to risk-stratify patients with acute respiratory distress syndrome, the utility of longitudinal SpO2/FiO2 ratios is unknown. OBJECTIVE To assess time-based SpO2/FiO2 ratios ≤ 150-SpO2/FiO2 time at risk (SF-TAR)-for predicting mortality in mechanically ventilated patients. METHODS Retrospective, observational cohort study of mechanically ventilated patients at 21 community and 2 academic hospitals. Association between the SF-TAR in the first 24 hours of ventilation and mortality was examined using multivariable logistic regression and compared with the worst recorded isolated partial pressure of arterial oxygen/fraction of inspired oxygen (P/F) ratio. RESULTS In 28,758 derivation cohort admissions, every 10% increase in SF-TAR was associated with a 24% increase in adjusted odds of hospital mortality (adjusted odds ratio = 1.24; 95% confidence interval [CI] = 1.23-1.26); a similar association was observed in validation cohorts. Discrimination for mortality modestly improved with SF-TAR (area under the receiver operating characteristic curve [AUROC] = 0.81; 95% CI = 0.81-0.82) vs the worst P/F ratio (AUROC = 0.78; 95% CI = 0.78-0.79) and worst SpO2/FiO2 ratio (AUROC = 0.79; 95% CI = 0.79-0.80). The SF-TAR in the first 6 hours offered comparable discrimination for hospital mortality (AUROC = 0.80; 95% CI = 0.79-0.80) to the 24-hour SF-TAR. CONCLUSION The SF-TAR can identify ventilated patients at increased risk of death, offering modest improvements compared with single SpO2/FiO2 and P/F ratios. This longitudinal, noninvasive, and broadly generalizable tool may have particular utility for early phenotyping and risk stratification using electronic health record data in ventilated patients.
Evaluation of Formulation Parameters on Permeation of Ibuprofen from Topical Formulations Using Strat-M® Membrane

Topical drug delivery is an attractive alternative to conventional methods because of advantages such as non-invasive delivery, by-pass of first pass metabolism, and improved patient compliance. However, several factors such as skin, physicochemical properties of the drug, and vehicle characteristics influence the permeation. Within a formulation, critical factors such as concentration of drug, physical state of drug in the formulation, and organoleptic properties affect the flux across the skin. The aim of the study was to develop and investigate topical semisolid preparations (creams and gels) with ibuprofen as the model drug and investigate the effect of various formulation parameters on the in-vitro performance across the Strat-M® membrane using flow-through cells. In addition, the physical stability of the developed formulations was investigated by studying viscosity, pH, and appearance. All the formulations developed in the study had appealing appearance with smooth texture and no signs of separation. Viscosity and pH of the formulations were acceptable. Cumulative amount of drug permeated at the end of 24 h was highest for clear gel (3% w/w ibuprofen; F6: 739.6 ± 36.1 µg/cm2) followed by cream with high concentration of ibuprofen in suspended form (5% w/w; F3: 320.8 ± 17.53 µg/cm2), emulgel (3% w/w ibuprofen; F5: 178.5 ± 34.5 µg/cm2), and cream with solubilized ibuprofen (3% w/w; F2A: 163.2 ± 9.36 µg/cm2). Results from this study showed that permeation of ibuprofen was significantly influenced by formulation parameters such as concentration of ibuprofen (3% vs. 5% w/w), physical state of ibuprofen (solubilized vs. suspended), formulation type (cream vs. gel), mucoadhesive agents, and viscosity (high vs. low). Thus, findings from this study indicate that pharmaceutical formulation scientists should explore these critical factors during the early development of any new topical drug product in order to meet pre-determined quality target product profile.