Miracle-dz/UniFAR-FTUs huggingface dataset:
Brain Death-Induced Inflammatory Activity is Similar to Sepsis-Induced Cytokine Release

Brain death (BD) is associated with a systemic inflammation leading to worse graft outcomes. This study aimed to compare plasma cytokine values between brain-dead and critically ill patients, including septic and non-septic controls, and evaluate cytokine release kinetics in BD. Sixteen brain-dead and 32 control patients (16 with and 16 without sepsis) were included. Plasma cytokines were measured by magnetic bead assay after the first clinical exam consistent with BD and every 6 hours thereafter, and at the time of study entry in the control group. The values for IL-8 and IFN-γ were higher in brain-dead and septic patients than in non-septic patients [IL-8: 80.3 (18.7–169.6) vs. 68.2 (22.4–359.4) vs. 16.4 (9.2–42.7) pg/mL; P = 0.006; IFN-γ: 2.8 (1.6-6.1) vs. 3.4 (1.2–9.0) vs. 0.5 (0.5–1.8) pg/mL; P = 0.012]. TNF showed a clear tendency to increase in brain-dead patients [2.7 (1.0–4.8) vs. 1.0 (1.0–5.6) vs. 1.0 (1.0–1.0) pg/mL; P = 0.051], and IL-6 values were higher in brain-dead patients than in non-septic controls [174.5 (104.9–692.5) vs. 13.2 (7.3–38.6) pg/mL; P = 0.002]. These differences remained even after excluding brain-dead patients who also had sepsis (n = 3). IL-1β and IL-10 values increased from baseline to time point 2 (∼6 hours later) [IL-1β: 5.39 (1.93–16.89) vs. 7.11 (1.93–29.13) pg/mL; P = 0.012; IL-10: 8.78 (3.62–16.49) vs. 15.73 (5.49–23.98) pg/mL; P = 0.009]. BD-induced and sepsis-induced plasma cytokine values were similarly high, and both were higher than the observed in non-septic critically ill patients.
Relationship of a "Fundal Fluid Cap" and Vestibular Schwannoma Volume: Analysis of Preoperative Radiographic Findings and Outcomes.

OBJECTIVE To evaluate the relationship between radiographic fundal fluid cap in the lateral internal auditory canal, preoperative clinical characteristics, and postoperative outcomes in patients with vestibular schwannoma who underwent microsurgical excision. STUDY DESIGN Retrospective chart review. SETTING Academic tertiary referral center. PATIENTS Thirty-six consecutive patients (mean age 49.4 yr [range 29-74]) who underwent microsurgical vestibular schwannoma excision. INTERVENTIONS Microsurgical excision. MAIN OUTCOME MEASURES Linear fundal fluid size and tumor size calculated using volumetric analysis were measured on preoperative magnetic resonance imaging, and correlated to hearing status and postoperative facial nerve function. RESULTS Mean fundal fluid size was 2.18 mm (range 0-7.32). Mean tumor volume was 5.58 cm (range, 0.210-40.3 cm). Short- and long-term postoperative House-Brackmann scores were 2.4 and 1.4, respectively. Fundal fluid size was associated with tumor volume (rs = 0.488, p = 0.003) but not preoperative hearing status (p = 0.333). The presence of fundal fluid and larger tumor volumes were statistically associated with poorer short-term and long-term postoperative facial nerve function (p < 0.05). CONCLUSIONS Radiographic fundal fluid size is correlated to tumor volume.
Evolving techniques for endoscopic retrograde cholangiopancreatography in gastric bypass patients

Purpose of review The present review describes the current and evolving techniques available in approaching endoscopic retrograde cholangiopancreatography (ERCP) for patients with Roux-en-Y gastric bypass (RYGB) anatomy. Recent findings Recent studies have demonstrated that device-assisted enteroscopy (DAE) approaches have high failures rates when performing ERCP, but are currently considered the first-line approach for patients with RYGB anatomy because of lower costs and risks compared to surgery. In contrast, laparoscopicy-assisted-ERCP (LA-ERCP) exhibits high technical success rates but carries surgical risks and requires a high degree of scheduling coordination. A novel, completely endoscopic approach called endoscopic ultrasound directed transgastric ERCP (EDGE), also known as gastric access temporary for endoscopy (GATE), has in recent years shown high ERCP success rates comparable to LA-ERCPs while obviating the need for surgical assistance. Summary ERCP is technically difficult in patients with RYGB anatomy. Numerous approaches to ERCP exist, although availability of these techniques may be limited and depend on institutional expertise. The best initial approach should be considered based on patient history and institutional factors.
Anchoring and Adjustment in Uncertain Spatial Trajectory Prediction

Objective: The aim of this study was to explore the impact of prior information on spatial prediction and understanding of variability. Background: In uncertain spatial prediction tasks, such as hurricane forecasting or planning search-and-rescue operations, decision makers must consider the most likely case and the distribution of possible outcomes. Base performance on these tasks is varied (and in the case of understanding the distribution, often poor). Humans must update mental models and predictions with new information, sometimes under cognitive workload. Method: In a spatial-trajectory prediction task, participants were anchored on accurate or inaccurate information, or not anchored, regarding the future behavior of an object (both average behavior and the variability). Subsequently, they predicted an object’s future location and estimated its likelihood at multiple locations. In a second experiment, participants repeated the process under varying levels of external cognitive workload. Results: Anchoring influenced understanding of most likely predicted location, with fairly rapid adjustment following inaccurate anchors. Increasing workload resulted in decreased overall performance and an impact on the adjustment component of the task. Overconfidence was present in all conditions. Conclusion: Prior information exerted short-term influence on spatial predictions. Cognitive load impaired users’ ability to effectively adjust to new information. Accurate graphical anchors did not improve user understanding of variability. Application: Prior briefings or forecasts about spatiotemporal trajectories affect decisions even in the face of initial contradictory information. To best support spatial prediction tasks, efforts also need to be made to separate extraneous load-causing tasks from the process of integrating new information. Implications are discussed.
A gain of function variant in PIEZO1 (E756del) and sickle cell disease

The novel PIEZO1 E756del variant was recently identified in about 30% of Africans, and associated with significant red cell dehydration and protection against malaria. Erythrocytes from people with the E756del variant were found to have reduced infection by Plasmodium falciparum in in vitro studies, corresponding with equivalent findings in a mouse model. As such, it might be expected to be an important determinant of severity in sickle cell disease (SCD). We have studied the prevalence and significance of this PIEZO1 variant in 788 patients with SCD. Surprisingly, we found that it had little or no influence on red cell phenotype. All the complications of SCD arise from the polymerization of hemoglobin molecules incorporating a mutated β globin chain (HbS), βS (HBB, c.A20T, p.Glu7Val). The rate of HbS polymerization is very dependent on the intracellular concentration of HbS, with the lag time before the onset of polymerization increasing with the concentration of HbS raised to the power of 30. Small differences in red cell hydration, causing changes in HbS concentration therefore have a marked effect on the rate of HbS polymerization and consequent hematologic and clinical complications. In SCD, red cell cation loss and dehydration is thought to occur through three major transport pathways: K-Cl cotransport (KCC), the Gardos channel, and Psickle. 4 The interaction of these channels is complicated but results in a net loss of cations from the red cell, with subsequent loss of water, and increased hemoglobin concentration. Whereas the molecular basis of the Gardos channel (KCNN4) and KCC (KCC1, KCC3, KCC4) are known, Psickle is a pathophysiological entity, whose molecular basis is unknown. Psickle is a channel present only in sickle cell erythrocytes, which is activated by deoxygenation. It is nonselective, allowing the passage of ions and other small molecules; in particular, it is responsible for the entry of calcium into the deoxygenated sickle erythrocytes which causes the dehydration cascade. Various proteins have been proposed as the basis for Psickle, although recently it has been suggested that PIEZO1 is the likely origin of the Psickle channel. 4,6
Dietary supplementation of vitamin D prevents the development of western diet-induced metabolic, hepatic and cardiovascular abnormalities in rats

Background The western diet high in fat and fructose may cause metabolic disorders and cardiovascular diseases. Objective To evaluate whether long-term daily vitamin D3 supplementation prevents hepatic steatosis and cardiovascular abnormalities and restores insulin sensitivity caused by fat diet in rats without vitamin D deficiency. Methods Three groups of rats were fed for 6 months with standard diet (SD), western diet (WD) or WD containing 23 IU/day/rat vitamin D3, respectively. Tail-cuff systolic blood pressure (SBP)measurements in conscious rats and transthoracic echocardiography were performed in basal condition, and after 3 and 6 months of diet. Hepatic steatosis and myocardial fibrosis were assessed in liver and cardiac tissues using standard methods. Serum insulin and 25(OH)D3 concentrations were determined using rat-specific ELISA kits. Insulin resistance was determined according to the homeostasis model assessment of insulin resistance (HOMA-IR) method. Results Sixty-one per cent of hepatocytes in WD rats had steatotic vacuoles compared with just 27% in rats on a WD plus vitamin D3 (p < 0.05). HOMA-IR was reduced in rats with vitamin D supplementation compared with WD alone (19.4 ± 5.2 vs 41.9 ± 8.9, p < 0.05). Rat blood pressure and left ventricular mass were both reduced by vitamin D3 supplementation. Conclusion In animal models of liver and cardiovascular metabolic damage, the supplementation of vitamin D3 shows liver and cardio-protective effects.
Quantitative Extrapolation: An Approach to Validation of Adult Drug Efficacy in Pediatric Subjects

Confirmation of efficacy in pediatric drug development has traditionally required large, fully powered efficacy studies that have proven to have major feasibility and ethical challenges. Extrapolation of efficacy in the framework provided by the US Food and Drug Administration and European Medicines Agency is an appropriate solution when there is similarity of disease. When there is uncertainty regarding the degree of disease similarity, partial extrapolation may be utilized. The authors propose a more quantitative approach to partial extrapolation (ie, quantitative extrapolation), involving (1) integration of adult pharmacokinetic (PK), pharmacodynamic (PD), and clinical outcome data using pharmacometric models, (2) extrapolation using the adult pharmacometric model to predict PD and efficacy outcomes in pediatric subjects, and (3) validation of pediatric predictions with a streamlined plan of pediatric trials (ie, a quantitative extrapolation plan). A case study is presented for quantitative extrapolation using dipeptidyl peptidase 4 (DPP-4) inhibitors. In this example, the authors demonstrate how adult PK, PD, and HbA1c data can be integrated using a pharmacometric model for DPP-4 inhibitors with pediatric dose selection and efficacy validated with relatively few pediatric subjects.
Preference for the Workplace, Investment in Human Capital, and Gender

We use a hypothetical choice methodology to estimate preferences for workplace attributes from a sample of high-ability undergraduates attending a highly selective university. We estimate that women on average have a higher willingness to pay (WTP) for jobs with greater work flexibility and job stability, and men have a higher WTP for jobs with higher earnings growth. These job preferences relate to college major choices and to actual job choices reported in a follow-up survey four years after graduation. The gender differences in preferences explain at least a quarter of the early career gender wage gap.
Stromal vascular fraction cells plus sustained release VEGF/Ang‐1‐PLGA microspheres improve fat graft survival in mice

Autologous fat transplantation is increasingly applied in plastic and reconstructive surgery. Stromal vascular fraction cells (SVFs) combined with angiogenic factors, such as VEGF (vascular endothelial growth factor A) and Ang‐1 (angiogenin‐1), can improve angiogenesis, which is a critical factor for graft survival. However, direct transplant with such a mixture is insufficient owing to the short half‐life of angiogenic factors. In this study, we evaluated whether a double sustained release system of VEGF/ANG‐1‐PLGA (poly (lactic‐co‐glycolic acid)) microspheres plus SVFs can improve angiogenesis and graft survival after autologous fat transplantation. VEGF/ANG‐1‐PLGA‐sustained release microspheres were fabricated by a modified double emulsion–solvent evaporation technique. Human aspirated fat was mixed with SVF suspension plus VEGF/ANG‐1 sustained release microspheres (Group C), SVF suspension (Group B) alone, or Dulbecco’s modified Eagle’s medium as the control (Group A). Eighteen immunocompromised nude mice were injected with these three mixtures subcutaneously at random positions. After 8 weeks, the mean volume of grafts was greater in the SVFs plus VEGF/ANG‐1‐PLGA group than in the control and SVFs groups (1.08 ± 0.069 ml vs. 0.62 ± 0.036 ml, and 0.83 ± 0.059 ml, respectively). Histological assessments showed that lower fibrosis, but greater microvascular density in the SVFs plus VEGF/ANG‐1‐PLGA group than in the other groups, though the SVFs group also had an appropriate capillary density and reduced fibrosis. Our findings indicate that SVFs plus VEGF/ANG‐1‐PLGA‐sustained release microspheres can improve angiogenesis and graft survival after autologous fat transplantation.
Why Is It Hard to Obtain a Dichotomy for Consistent Query Answering?

A database may for various reasons become inconsistent with respect to a given set of integrity constraints. In the late 1990s, the formal approach of consistent query answering was proposed in order to query such databases. Since then, a lot of efforts have been spent to classify the complexity of consistent query answering under various classes of constraints. It is known that for the most common constraints and queries, the problem is in coNP and might be coNP-hard, yet several relevant tractable classes have been identified. Additionally, the results that emerged suggested that given a set of key constraints and a conjunctive query, the problem of consistent query answering is either in PTime or is coNP-complete. However, despite all the work, as of today this dichotomy remains a conjecture. The main contribution of this article is to explain why it appears so difficult to obtain a dichotomy result in the setting of consistent query answering. Namely, we prove that such a dichotomy with respect to common classes of constraints and queries is harder to achieve than a dichotomy for the constraint satisfaction problem, which is a famous open problem since the 1990s.
Gardner‐Diamond syndrome: a systematic review of treatment options for a rare psychodermatological disorder

Gardner‐Diamond syndrome (GDS) is a rare psychodermatological condition characterized by the formation of spontaneous, painful skin lesions that develop into ecchymosis following episodes of severe physiological or psychological stress. The majority of GDS cases occur in young adult females, and although the etiology of this rare disorder is unknown, there appears to be a psychological component correlated with the coexistence of previous psychiatric diagnoses. Due to the rare nature of this disorder, there exist few guidelines for prompt clinical diagnosis and optimal treatment. Here, a systematic review was conducted to include 45 cases of patients with GDS to better understand clinical presentation as well as current treatment options. Ultimately, GDS is a diagnosis of exclusion after other coagulopathies and causes of purpura are ruled out. High clinical suspicion following laboratory and clinical exclusion of known physiological causes is necessary for diagnosis. Selective serotonin reuptake inhibitors (SSRIs) and corticosteroids are cost effective first line treatments for GDS with proven efficacy in symptomatic relief. GDS refractory to initial treatment may require regular psychotherapy and titrated SSRI dosages to achieve long‐term success. This review of available case studies serves to comprehensively describe the clinical presentation and available treatment approaches to this rare psychodermatological disorder.
Biallelic mutations in human NHLRC2 enhance myofibroblast differentiation in FINCA disease

&NA; The development of tissue fibrosis is complex and at the present time, not fully understood. Fibrosis, neurodegeneration and cerebral angiomatosis (FINCA disease) have been described in patients with mutations in NHL repeat‐containing protein 2 (NHLRC2). However, the molecular functions of NHLRC2 are uncharacterized. Herein, we identified putative interacting partners for NHLRC2 using proximity‐labeling mass spectrometry. We also investigated the function of NHLRC2 using immortalized cells cultured from skin biopsies of FINCA patients and normal fibroblasts with NHLRC2 knock‐down and NHLRC2 overexpressing gene modifications. Transmission electron microscopy analysis of immortalized cell cultures from three FINCA patients demonstrated multilamellar bodies and distinctly organized vimentin filaments. Additionally, two of three cultures derived from patient skin biopsies contained cells that exhibited features characteristic of myofibroblasts. Altogether, the data presented in this study show for the first time that NHLRC2 is involved in cellular organization through regulation of the cytoskeleton and vesicle transport. We conclude that compound heterozygous p.Asp148Tyr and p.Arg201GlyfsTer6 mutations in NHLRC2 lead to severe tissue fibrosis in humans by enhancing the differentiation of fibroblasts to myofibroblasts.
Characterisation of maturation of photoreceptor cell subtypes during zebrafish retinal development

ABSTRACT Photoreceptor cells (PRCs) mature from simple epithelial cells, a process characterised by growth and compartmentalisation of the apical membrane into an inner and an outer segment. So far, a PRC subtype-specific description of morphological and cellular changes in the developing zebrafish retina is missing. Here, we performed an in-depth characterisation of four of the five PRC subtypes of the zebrafish retina between 51 and 120 h post fertilisation, including quantification of the size of different compartments, localisation of polarity proteins and positioning of organelles. One of the major findings was the anisotropic and subtype-specific growth of the different PRC compartments. In addition, a transient accumulation of endoplasmic reticulum in rod PRCs, changes in chromatin organisation in UV sensitive cones and differential expression of polarity proteins during the initial stages of PRC maturation were observed. The results obtained provide a developmental timeline that can be used as a platform for future studies on PRC maturation and function. This platform was applied to document that increased exposure to light leads to smaller apical domains of PRCs. Summary: We characterised subtype-specific growth of the different photoreceptor compartments, organelle distribution and the influence of light on the growth of the apical membrane.
Response from the authors

We would like to thank Dr Kawada for his interest in our work. In our cross-sectional study, we reported that urinary metabolites of polycyclic aromatic hydrocarbons (PAH) were associated with decreased %predicted FEV1 and %predicted FEV1/FVC in children with asthma and vitamin D insufficiency, but not in those with asthma and vitamin D sufficiency. Moreover, we showed that high levels of urinary Σmol3,4-PAH metabolites were associated with current asthma among participating children. We measured urinary metabolites of PAH, a component of diesel exhaust particles and particulate matter. Our findings for lung function are consistent with those from our previous study in Puerto Rican children with asthma. In that study, children who lived near a major highway (and thus were more exposed to trafficrelated air pollution) and had vitamin D insufficiency had nearly fivefold higher odds of severe asthma exacerbations than those who lived further from a major highway and had sufficient vitamin D levels. Some of Dr Kawada's comments are puzzling. It would be challenging—if not impossible—to measure all potential genetic and environmental determinants of lung function in a single study. As acknowledged in the Discussion, we did not measure several potential confounders, such as outdoor activity, diet, or exposure to individual pollutants. However, all our measures of lung function accounted for age, sex, race or ethnicity, and height. Moreover, we considered relevant confounders for inclusion in our multivariable models, including type of health insurance, body mass index, recent treatment with steroids, and second-hand smoke (SHS). Indeed, we adjusted for serum cotinine levels (a biomarker of exposure to SHS) in all multivariable analyses. Our results suggest that airway inflammation and oxidative stress due to air pollution is worsened by vitamin D insufficiency, ultimately leading to abnormal lung function. Ongoing clinical trials should help determine whether vitamin D supplementation has beneficial effects on lung function in children with asthma and vitamin D insufficiency.
Review of the Clinical Experiences of Feeding Infants Formula Containing the Human Milk Oligosaccharide 2′-Fucosyllactose

Human milk oligosaccharides (HMOs) are the third most abundant solid component in human milk after lactose and lipids. Preclinical research has demonstrated that HMOs and specifically 2′-fucosyllactose (2′-FL) are more than a prebiotic and have multiple functions, including immune, gut, and cognition benefits. Previously, human milk has been the only source for significant levels of HMOs. The most abundant HMO in most mothers’ breast milk is 2′-FL. Recently, 2′-FL has been synthesized and shown to be structurally identical to the 2′-FL found in human milk. 2′-FL HMO is now available in some commercial infant formulas. The purpose of this narrative review was to summarize the clinical experiences of feeding infant formula supplemented with the HMO, 2′-FL. Most of these studies investigated standard intact milk protein-based infant formulas containing 2′-FL, and one evaluated a partially hydrolyzed whey-based formula. Collectively, these clinical experiences demonstrated that 2′-FL being added to infant formula was safe, well-tolerated, and absorbed and excreted with similar efficiency to 2′-FL in human milk. Further, infants that were fed formula with 2′-FL had immune benefits, fewer parent-reported respiratory infections, and improved symptoms of formula intolerance. Ultimately, infant formula with 2′-FL supports immune and gut health and is closer compositionally and functionally to human milk.