Miracle-dz/UniFAR-FTUs huggingface dataset:
This Work Is Licensed under a Creative Commons Attribution 3.0 Unported License Predictors of Participation of Adolescents with Cerebral Palsy: a European Multi-centre Longitudinal Study

of participation of adolescents with cerebral palsy: A European multi-centre longitudinal study. A B S T R A C T We investigated whether childhood factors that are amenable to intervention (parenting stress, child psychological problems and pain) predicted participation in daily activities and social roles of adolescents with cerebral palsy (CP). We randomly selected 1174 children aged 8–12 years from eight population-based registers of children with CP in six European countries; 743 (63%) agreed to participate. One further region recruited 75 children from multiple sources. These 818 children were visited at home at age 8–12 years, 594 (73%) agreed to follow-up at age 13–17 years. We used the following measures: parent reported stress (Parenting Stress Index Short Form), their child's psychological difficulties (Strength and Difficulties Questionnaire) and frequency and severity of pain; either child or parent reported the child's participation (LIFE Habits questionnaire). We fitted a structural equation model to each of the participation domains, regressing participation in childhood and adolescence on parenting stress, child psychological problems and pain, and regressing adolescent factors on the corresponding childhood factors; models were adjusted for impairment, region, age and gender.
A Culturally Tailored Community Health Worker Intervention Leads to Improvement in Patient-Centered Outcomes for Immigrant Patients With Type 2 Diabetes

IN BRIEF This article reports results from a patient-centered intervention to improve management of type 2 diabetes in the New York City Bangladeshi community. The DREAM (Diabetes Research, Education, and Action for Minorities) intervention is a randomized trial among Bangladeshi immigrants with type 2 diabetes comparing those enrolled in a community health worker (CHW) intervention to those in usual care. Participants in the intervention group received five group-based educational sessions and two one-on-one visits delivered by a trained CHW, whereas those in the control group received only the first group educational session. Main outcomes include changes in A1C, systolic and diastolic blood pressure, cholesterol, triglycerides, weight, BMI, and patient-centered outcomes such as knowledge and behavior related to type 2 diabetes management.
Human CCR4+CCR6+Th17 Cells Suppress Autologous CD8+ T Cell Responses

The role of Th17 cells in cancer patients remains unclear and controversial. In this study, we have analyzed the phenotype of in vitro primed Th17 cells and further characterized their function on the basis of CCR4 and CCR6 expression. We show a novel function for a subset of IL-17–secreting CD4+ T cells, namely, CCR4+CCR6+Th17 cells. When cultured together, CCR4+CCR6+Th17 cells suppressed the lytic function, proliferation, and cytokine secretion of both Ag-specific and CD3/CD28/CD2-stimulated autologous CD8+ T cells. In contrast, CCR4−CCR6+ CD4+ T cells, which also secrete IL-17, did not affect the CD8+ T cells. Suppression of CD8+ T cells by CCR4+CCR6+Th17 cells was partially dependent on TGF-β, because neutralization of TGF-β in cocultures reversed their suppressor function. In addition, we also found an increase in the frequency of CCR4+CCR6+, but not CCR4−CCR6+ Th17 cells in peripheral blood of hepatocellular carcinoma patients. Our study not only underlies the importance of analysis of subsets within Th17 cells to understand their function, but also suggests Th17 cells as yet another immune evasion mechanism in hepatocellular carcinoma. This has important implications when studying the mechanisms of carcinogenesis, as well as designing effective immunotherapy protocols for patients with cancer.
Maternal Vitamin B12 Status and Risk of Neural Tube Defects in a Population With High Neural Tube Defect Prevalence and No Folic Acid Fortification

OBJECTIVE. Folic acid fortification has reduced neural tube defect prevalence by 50% to 70%. It is unlikely that fortification levels will be increased to reduce neural tube defect prevalence further. Therefore, it is important to identify other modifiable risk factors. Vitamin B12 is metabolically related to folate; moreover, previous studies have found low B12 status in mothers of children affected by neural tube defect. Our objective was to quantify the effect of low B12 status on neural tube defect risk in a high-prevalence, unfortified population. METHODS. We assessed pregnancy vitamin B12 status concentrations in blood samples taken at an average of 15 weeks’ gestation from 3 independent nested case-control groups of Irish women within population-based cohorts, at a time when vitamin supplementation or food fortification was rare. Group 1 blood samples were from 95 women during a neural tube defect–affected pregnancy and 265 control subjects. Group 2 included blood samples from 107 women who had a previous neural tube defect birth but whose current pregnancy was not affected and 414 control subjects. Group 3 samples were from 76 women during an affected pregnancy and 222 control subjects. RESULTS. Mothers of children affected by neural tube defect had significantly lower B12 status. In all 3 groups those in the lowest B12 quartiles, compared with the highest, had between two and threefold higher adjusted odds ratios for being the mother of a child affected by neural tube defect. Pregnancy blood B12 concentrations of <250 ng/L were associated with the highest risks. CONCLUSIONS. Deficient or inadequate maternal vitamin B12 status is associated with a significantly increased risk for neural tube defects. We suggest that women have vitamin B12 levels of >300 ng/L (221 pmol/L) before becoming pregnant. Improving B12 status beyond this level may afford a further reduction in risk, but this is uncertain.
Sorafenib-induced eruptive melanocytic lesions.

We report 2 cases of eruptive melanocytic lesions associated with sorafenib, a multikinase inhibitor FDA-approved for the treatment of advanced renal cell carcinoma. Understanding the development of this previously unknown side effect may provide further insight into sorafenib’s mechanistic effects on tumors and normal tissues and into the development of pigmented lesions.
Clinical practice. Primary ovarian insufficiency.

A 30-year-old woman presents with a history of no menses since she stopped taking oral contraceptives 6 months ago in order to conceive. She had undergone puberty that was normal in both timing and development, with menarche at 12 years of age. At 18 years of age, she started taking oral contraceptives for irregular menses. She reports stress at work. Her weight is 59 kg, and her height 1.66 m; her body-mass index (the weight in kilograms divided by the square of the height in meters) is 21.3. There is no galactorrhea, hirsutism, or acne. The pelvic examination is normal, a pregnancy test is negative, the prolactin level is normal, and the follicle-stimulating hormone (FSH) level is in the menopausal range. How should she be evaluated and treated?
Combustion-derived nanoparticle exposure and household solid fuel use in Xuanwei and Fuyuan, China

Combustion-derived nanoparticles (CDNPs) have not been readably measurable until recently. We conducted a pilot study to determine CDNP levels during solid fuel burning. The aggregate surface area of CDNP (μm2/cm3) was monitored continuously in 15 Chinese homes using varying fuel types (i.e. bituminous coal, anthracite coal, wood) and stove types (i.e. portable stoves, stoves with chimneys, firepits). Information on fuel burning activities was collected and PM2.5 levels were measured. Substantial exposure differences were observed during solid fuel burning (mean: 228.1 μm2/cm3) compared to times without combustion (mean: 14.0 μm2/cm3). The observed levels during burning were reduced by about four-fold in homes with a chimney (mean: 92.1 μm2/cm3; n = 9), and effects were present for all fuel types. Each home's CDNP measurement was only moderately correlated with the respective PM2.5 measurements (r 2 = 0.43; p = 0.11). Our results indicate that household coal and wood burning contributes to indoor nanoparticle levels, which are not fully reflected in PM2.5 measurements.
The use of neurocognitive methods in assessing health communication messages: A systematic review

We review 20 studies that examined persuasive processing and outcomes of health messages using neurocognitive measures. The results suggest that cognitive processes and neural activity in regions thought to reflect self-related processing may be more prominent in the persuasive process of self-relevant messages. Furthermore, activity in the medial prefrontal cortex, the superior temporal gyrus and the middle frontal gyrus were identified as predictors of message effectiveness, with the medial prefrontal cortex accounting for additional variance in behaviour change beyond that accounted for by self-report measures. Incorporating neurocognitive measures may provide a more comprehensive understanding of the processing and outcomes of health messages.
Controlled and Extended In Vitro Release of Bioactive Anti-Vascular Endothelial Growth Factors from a Microsphere-Hydrogel Drug Delivery System

ABSTRACT Purpose: To demonstrate controlled and extended release of bioactive anti-vascular endothelial growth factor (VEGF) agents (ranibizumab or aflibercept) from an injectable microsphere-hydrogel drug delivery system (DDS). Methods: Anti-VEGF agents were radiolabeled with iodine-125 and loaded into poly(lactic-co-glycolic acid) (PLGA) 75:25 microspheres using a modified double-emulsion, solvent evaporation technique. Microspheres were then suspended in an injectable poly(N-isopropylacrylamide)-based thermo-responsive hydrogel to create a microsphere-hydrogel DDS. Release profiles were performed in phosphate buffered saline at 37°C and at predetermined intervals, release samples were collected. Microspheres were also made using non-radiolabeled anti-VEGFs to determine the bioactivity of the DDS throughout release. Bioactivity and cytotoxicity of release samples were determined using human umbilical vascular endothelial cells (HUVECs) under VEGF-induced proliferation. Results: The DDS is capable of releasing either ranibizumab or aflibercept for 196 days with an initial burst (first 24 h) of 22.2 ± 2.2 and 13.1 ± 0.5 μg, respectively, followed by controlled release of 0.153 and 0.065 μg/day, respectively. Release samples showed no toxicity in HUVECs at any time. Both anti-VEGFs remained bioactive throughout release with significant inhibition of HUVEC proliferation compared to the drug-free DDS, which showed no inhibitory effect on HUVEC proliferation. Conclusions: Controlled, extended, and bioactive release for approximately 200 days was achieved for both ranibizumab and aflibercept in vitro. The use of anti-VEGF-loaded microspheres suspended within an injectable, thermo-responsive hydrogel may be an advantageous ocular DDS with the potential to improve upon current therapies.
Using cases to strengthen inference on the association between single nucleotide polymorphisms and a secondary phenotype in genome‐wide association studies

Case‐control genome‐wide association studies provide a vast amount of genetic information that may be used to investigate secondary phenotypes. We study the situation in which the primary disease is rare and the secondary phenotype and genetic markers are dichotomous. An analysis of the association between a genetic marker and the secondary phenotype based on controls only (CO) is valid, whereas standard methods that also use cases result in biased estimates and highly inflated type I error if there is an interaction between the secondary phenotype and the genetic marker on the risk of the primary disease. Here we present an adaptively weighted (AW) method that combines the case and control data to study the association, while reducing to the CO analysis if there is strong evidence of an interaction. The possibility of such an interaction and the misleading results for standard methods, but not for the AW or CO approaches, are illustrated by data from a case‐control study of colorectal adenoma. Simulations and asymptotic theory indicate that the AW method can reduce the mean square error for estimation with a prespecified SNP and increase the power to discover a new association in a genome‐wide study, compared to CO analysis. Further experience with genome‐wide studies is needed to determine when methods that assume no interaction gain precision and power, thereby can be recommended, and when methods such as the AW or CO approaches are needed to guard against the possibility of nonzero interactions. Genet. Epidemiol. 34:427–433, 2010. Published 2010 Wiley‐Liss, Inc.
On the remarkable mechanostability of scaffoldins and the mechanical clamp motif

Protein mechanostability is a fundamental biological property that can only be measured by single-molecule manipulation techniques. Such studies have unveiled a variety of highly mechanostable modules (mainly of the Ig-like, β-sandwich type) in modular proteins subjected to mechanical stress from the cytoskeleton and the metazoan cell–cell interface. Their mechanostability is often attributed to a “mechanical clamp” of secondary structure (a patch of backbone hydrogen bonds) fastening their ends. Here we investigate the nanomechanics of scaffoldins, an important family of scaffolding proteins that assembles a variety of cellulases into the so-called cellulosome, a microbial extracellular nanomachine for cellulose adhesion and degradation. These proteins anchor the microbial cell to cellulose substrates, which makes their connecting region likely to be subjected to mechanical stress. By using single-molecule force spectroscopy based on atomic force microscopy, polyprotein engineering, and computer simulations, here we show that the cohesin I modules from the connecting region of cellulosome scaffoldins are the most robust mechanical proteins studied experimentally or predicted from the entire Protein Data Bank. The mechanostability of the cohesin modules studied correlates well with their mechanical kinetic stability but not with their thermal stability, and it is well predicted by computer simulations, even coarse-grained. This extraordinary mechanical stability is attributed to 2 mechanical clamps in tandem. Our findings provide the current upper limit of protein mechanostability and establish shear mechanical clamps as a general structural/functional motif widespread in proteins putatively subjected to mechanical stress. These data have important implications for the scaffoldin physiology and for protein design in biotechnology and nanotechnology.
Bilateral sternal infusion of ropivacaine and length of stay in ICU after cardiac surgery with increased respiratory risk: A randomised controlled trial

BACKGROUND The continuous bilateral infusion of a local anaesthetic solution around the sternotomy wound (bilateral sternal) is an innovative technique for reducing pain after sternotomy. OBJECTIVE To assess the effects of the technique on the need for intensive care in cardiac patients at increased risk of respiratory complications. DESIGN Randomised, observer-blind controlled trial. SETTING Single centre, French University Hospital. PATIENTS In total, 120 adults scheduled for open-heart surgery, with one of the following conditions: age more than 75 years, BMI >30 kg m−2, chronic obstructive pulmonary disease, active smoking habit. INTERVENTION Either a bilateral sternal infusion of 0.2% ropivacaine (3 ml h−1 through each catheter; ‘intervention’ group), or standardised care only (‘control’ group). Analgesia was provided with paracetamol and self-administered intravenous morphine. MAIN OUTCOME MEASURES The length of time to readiness for discharge from ICU, blindly assessed by a committee of experts. RESULTS No effect was found between groups for the primary outcome (P = 0.680, intention to treat); the median values were 42.4 and 37.7 h, respectively for the control and intervention groups (P = 0.873). Similar nonsignificant trends were noted for other postoperative delays. Significant effects favouring the intervention were noted for dynamic pain, patient satisfaction, occurrence of nausea and vomiting, occurrence of delirium or mental confusion and occurrence of pulmonary complications. In 12 patients, although no symptoms actually occurred, the total ropivacaine plasma level exceeded the lowest value for which neurological symptoms have been observed in healthy volunteers. CONCLUSION Because of a small size effect, and despite significant analgesic effects, this strategy failed to reduce the time spent in ICU. TRIAL REGISTRATION EudraCT (N°: 2012-005225-69); ClinicalTrials.gov (NCT01828788).
Localization of P-gp (Abcb1) and Mrp2 (Abcc2) in Freshly Isolated Rat Hepatocytes

Freshly isolated hepatocytes are widely accepted as the “gold standard” for providing reliable data on drug uptake across the sinusoidal (basolateral) membrane. However, the suitability of freshly isolated hepatocytes in suspension to assess efflux by canalicular (apical) proteins or predict biliary excretion in the intact organ is unclear. After collagenase digestion, hepatocytes rapidly lose polarity, but localization of canalicular transport proteins in the first few hours after isolation has not been well characterized. In this study, immunostaining and confocal microscopy have provided, for the first time, a detailed examination of canalicular transport protein localization in freshly isolated rat hepatocytes fixed within 1 h of isolation and in cells cultured for 1 h. Organic anion transporting polypeptide 1a1 (Oatp1a1) was expressed in all hepatocytes and distributed evenly across the basolateral membrane; there was no evidence for colocalization of Oatp1a1 with P-glycoprotein (P-gp) or multidrug resistance-associated protein 2 (Mrp2). In contrast, P-gp and Mrp2 expression was lower than Oatp1a1 and confined to junctions between adjacent cells, intracellular compartments, and “legacy” network structures at or near the cell surface. P-gp and Mrp2 staining was more predominant in regions adjacent to former canalicular spaces, identified by zonula occludens-1 staining. Functional analysis of rat hepatocytes cultured for 1 h demonstrated that the fluorescent anion and Mrp2 substrate, 5-(and-6)-carboxy-2′,7′-dichlorofluorescein (CDF), accumulated in cellular compartments; compartmental accumulation of CDF was sensitive to (E)-3-[[[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-[[3-dimethylamino)-3-oxopropyl]thio]methyl]thio]-propanoic acid (MK571, Mrp inhibitor) and was not observed in hepatocytes isolated from Mrp2-deficient rats. Drug efflux from freshly isolated hepatocytes as an estimate of apical efflux/biliary excretion would give an inaccurate assessment of true apical elimination and, as such, should not be used to make in vivo extrapolations.
N-terminal pro-brain natriuretic peptide levels and risk of death in sickle cell disease.

CONTEXT Thirty percent of patients with sickle cell disease (SCD) develop pulmonary hypertension, a major risk factor for death in this population. A validated blood biomarker of pulmonary hypertension in SCD could provide important prognostic and diagnostic information and allow the exploration of the prevalence of pulmonary hypertension in participants in the 1996 Multicenter Study of Hydroxyurea in Sickle Cell Anemia (MSH) Patients' Follow-up Study. Levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) provide such information in patients with idiopathic pulmonary arterial hypertension. OBJECTIVE To determine the relationship between NT-proBNP levels and severity of pulmonary hypertension and prospective mortality in patients with SCD. DESIGN, SETTING, AND PARTICIPANTS NT-proBNP levels were measured in 230 participants in the National Institutes of Health (NIH) Sickle Cell Disease-Pulmonary Hypertension Screening Study (enrollment between February 2001 and March 2005) and in 121 samples from patients enrolled starting in 1996 in the MSH Patients' Follow-up Study. A threshold level predictive of high pulmonary artery pressure and mortality was identified in the NIH Sickle Cell Disease-Pulmonary Hypertension Screening Study and used to define an a priori analytical plan to determine the prevalence and associated mortality of pulmonary hypertension in the MSH follow-up study. MAIN OUTCOME MEASURES Severity of pulmonary hypertension and risk of all-cause mortality. RESULTS NT-proBNP levels were higher in patients with sickle cell pulmonary hypertension and correlated directly with tricuspid regurgitant jet velocity in the NIH cohort (R = 0.50, P<.001). An NT-proBNP level of 160 pg/mL or greater had a 78% positive predictive value for the diagnosis of pulmonary hypertension and was an independent predictor of mortality (21 deaths at 31 months' median follow-up; risk ratio, 5.1; 95% confidence interval, 2.1-12.5; P<.001; 19.5% absolute increase in risk of death). In the MSH cohort, 30% of patients had an NT-proBNP level of 160 pg/mL or greater. An NT-proBNP level of 160 pg/mL or greater in the MSH cohort was independently associated with mortality by Cox proportional hazards regression analysis (24 deaths at 47 months' median follow-up; risk ratio, 2.87; 95% confidence interval, 1.2-6.6; P = .02; 11.9% absolute increase in risk of death). CONCLUSIONS Pulmonary hypertension, as indicated by an NT-proBNP level of 160 pg/mL or greater, was very common in patients in the NIH study and in the MSH cohort. The MSH analysis suggests that rates of vaso-occlusive pain episodes in these patients were unrelated to risk of death; this risk was largely determined by occult hemolytic anemia-associated pulmonary hypertension.
Quality assessment and transfusion efficacy of buffy coat-derived platelet concentrates washed with platelet additive solution.

BACKGROUND Transfusion of washed platelet concentrates (W-PC) is recommended for some patients, such as those who have had previous severe allergic transfusion reactions. However, we still lack a standardised method for preparing these products. Here, we assessed the effect of a manual washing procedure on in vitro platelet quality and on the transfusion efficacy of W-PCs. MATERIALS AND METHODS Buffy coat-derived W-PC in Composol solution were prepared by one-step centrifugation. Platelet activation and function were evaluated before and after washing by means of: (i) CD62 expression by flow cytometry; (ii) platelet aggregation (LTA); and (iii) the VerifyNow® P2Y12 test. A pilot prospective transfusion study was carried out in 11 onco-hematology patients receiving, in a short time, two consecutive transfusions: one with standard PC (S-PC) and one with W-PC. The post-transfusion platelet increment, the 1 h and 24 h corrected count increment (CCI) and occurrence of bleeding events were used as indices of transfusion efficacy. RESULTS Platelet recovery in W-PC was 84.8±5.4%. Washing slightly increased platelet activation in W-PC vs pre-washed samples (% CD62+ platelets 23.6±7 vs 14.8±1; p=0.03). As compared to prewash samples, platelet reactivity of W-PC as measured by VerifyNow® P2Y12 was significantly lower with ADP (PRU 32.2±37.7 vs 4.2±2.4, p=0.027), but similar using TRAP. Platelet aggregation responses to TRAP, collagen, ristocetin and arachidonic acid were maintained in W-PC. The pilot transfusion trial showed similar 1 h (13.5±5.6 vs 11.5±7.3, p=0.49) and 24 h (11±7.2 vs 9±6.5, p=0.48) CCI for S-PC and W-PC. Transfusion of W-PC was not associated with an increased number of bleeding events. DISCUSSION We have set up a simple method to obtain buffy-coat-derived W-PC, which has minor effects on in vitro platelet quality and transfusion effectiveness. This procedure can be easily implemented in transfusion centres for on-demand preparation of washed platelets.