Miracle-dz/UniFAR-FTUs huggingface dataset:
Short- and long-term real-world effectiveness of omalizumab in severe allergic asthma: systematic review of 42 studies published 2008-2018

ABSTRACT Introduction: Omalizumab is a recombinant monoclonal anti-IgE antibody approved in the US as add-on treatment in moderate-to-severe allergic asthma (in severe allergic asthma [SAA] in Europe). A 2016 review of 24 real-world effectiveness studies in SAA published between 2008–2015 concluded that omalizumab was associated with significant improvements in objective and subjective outcomes with benefits extending beyond 2 years. Several new real-world studies have been published since, bringing the total to 42 studies. Areas covered: This systematic review of 42 studies published since 2008 updates and extends the 2016 review on the real-word evidence on omalizumab in SAA. It offers greater granularity as to time windows within which outcomes are reported and includes studies extending well beyond 4 years post omalizumab initiation. Expert commentary: This review firmly establishes the short-term effectiveness of omalizumab in adolescent and adult patients with SAA at 1 year, and provides strong evidence of long-term effectiveness up to 4 years and emergent evidence of effectiveness beyond 4 years. In the aggregate, these 42 studies underscore the long-term effectiveness of omalizumab in terms of: reducing exacerbations and symptoms, achieving asthma control, improving lung function, enhancing quality of life, decreasing emergency department visits and hospitalizations, and promoting concomitant medication-sparing.
Cancer statistics, 2014

Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths that will occur in the United States in the current year and compiles the most recent data on cancer incidence, mortality, and survival. Incidence data were collected by the National Cancer Institute, the Centers for Disease Control and Prevention, and the North American Association of Central Cancer Registries and mortality data were collected by the National Center for Health Statistics. A total of 1,665,540 new cancer cases and 585,720 cancer deaths are projected to occur in the United States in 2014. During the most recent 5 years for which there are data (2006‐2010), delay‐adjusted cancer incidence rates declined slightly in men (by 0.6% per year) and were stable in women, while cancer death rates decreased by 1.8% per year in men and by 1.4% per year in women. The combined cancer death rate (deaths per 100,000 population) has been continuously declining for 2 decades, from a peak of 215.1 in 1991 to 171.8 in 2010. This 20% decline translates to the avoidance of approximately 1,340,400 cancer deaths (952,700 among men and 387,700 among women) during this time period. The magnitude of the decline in cancer death rates from 1991 to 2010 varies substantially by age, race, and sex, ranging from no decline among white women aged 80 years and older to a 55% decline among black men aged 40 years to 49 years. Notably, black men experienced the largest drop within every 10‐year age group. Further progress can be accelerated by applying existing cancer control knowledge across all segments of the population. CA Cancer J Clin 2014;64:9–29. © 2014 American Cancer Society, Inc.
Combination Anthelmintic/Antioxidant Activity Against Schistosoma Mansoni

Schistosomiasis is a major neglected tropical disease. Treatment for schistosomiasis with praziquantel (PZQ), which is effective against the parasite, by itself is not capable to counteract infection-associated disease lesions including hepatic fibrosis. There is a pressing need for novel therapies. Due to their biological properties, antioxidant biomolecules might be useful in treating and reverting associated pathological sequelae. Here, we investigated a novel therapy approach based on a combination of anthelmintic drugs with antioxidant biomolecules. We used a host-parasite model involving Bioamphalaria glabrata and newly transformed schistosomula (NTS) of Schistosoma mansoni. For in vitro drug screening assays, was selected several antioxidants and evaluated not only antischistosomal activity but also ability to enhance activity of the anthelmintic drugs praziquantel (PZQ) and artesunate (AS). The morphological alterations induced by compounds alone/combined were assessed on daily basis using an inverted and automated microscope to quantify NTS viability by a fluorometric-based method. The findings indicated that not only do some antioxidants improve antischistosomal activity of the two anthelmintics, but they exhibit activity per se, leading to high mortality of NTS post-exposure. The combination index (CI) of PZQ + Mel (CI = 0.80), PZQ + Resv (CI = 0.74), AS + Resv (CI = 0.34), AS + NAC (CI = 0.89), VDT + Flav (CI = 1.03) and VDT + Resv (CI = 1.06) reveal that they display moderate to strong synergism. The combination of compounds with discrete mechanisms of action might provide a valuable adjunct to contribution for treatment of schistosomiasis-associated disease.
Prevotella copri in individuals at risk for rheumatoid arthritis

Objectives Rheumatoid arthritis (RA) has been associated with a relative expansion of faecal Prevotellaceae. To determine the microbiome composition and prevalence of Prevotella spp. in a group of individuals at increased risk for RA, but prior to the development of the disease. Methods In an ongoing cohort study of first-degree relatives (FDRs) of patients with RA, we identified ‘FDR controls’, asymptomatic and without autoantibodies, and individuals in pre-clinical RA stages, who had either developed anticitrullinated peptide antibodies or rheumatoid factor positivity and/or symptoms and signs associated with possible RA. Stool sampling and culture-independent microbiota analyses were performed followed by descriptive statistics and statistical analyses of community structures. Results A total of 133 participants were included, of which 50 were categorised as ‘FDR controls’ and 83 in ‘pre-clinical RA stages’. The microbiota of individuals in ‘pre-clinical RA stages’ was significantly altered compared with FDR controls. We found a significant enrichment of the bacterial family Prevotellaceae, particularly Prevotella spp. , in the ‘pre-clinical RA’ group (p=0.04). Conclusions Prevotella spp. enrichment in individuals in pre-clinical stages of RA, before the onset of RA, suggests a role of intestinal dysbiosis in the development of RA.
Generation of Potent T-cell Immunotherapy for Cancer Using DAP12-Based, Multichain, Chimeric Immunoreceptors

Wang and colleagues describe a new multichain, chimeric antigen receptor (CAR) that uses portions of KIR2DS2 to engage DAP12, mimicking natural NK- and T-cell signaling. This new CAR triggers potent T-cell antitumor responses in vivo due to improved retention of CAR surface expression and effector function. Chimeric antigen receptors (CAR) bearing an antigen-binding domain linked in cis to the cytoplasmic domains of CD3ζ and costimulatory receptors have provided a potent method for engineering T-cell cytotoxicity toward B-cell leukemia and lymphoma. However, resistance to immunotherapy due to loss of T-cell effector function remains a significant barrier, especially in solid malignancies. We describe an alternative chimeric immunoreceptor design in which we have fused a single-chain variable fragment for antigen recognition to the transmembrane and cytoplasmic domains of KIR2DS2, a stimulatory killer immunoglobulin-like receptor (KIR). We show that this simple, KIR-based CAR (KIR-CAR) triggers robust antigen-specific proliferation and effector function in vitro when introduced into human T cells with DAP12, an immunotyrosine-based activation motifs-containing adaptor. T cells modified to express a KIR-CAR and DAP12 exhibit superior antitumor activity compared with standard first- and second-generation CD3ζ-based CARs in a xenograft model of mesothelioma highly resistant to immunotherapy. The enhanced antitumor activity is associated with improved retention of chimeric immunoreceptor expression and improved effector function of isolated tumor-infiltrating lymphocytes. These results support the exploration of KIR-CARs for adoptive T-cell immunotherapy, particularly in immunotherapy-resistant solid tumors. Cancer Immunol Res; 3(7); 815–26. ©2015 AACR.
Comparison of the Transcriptomes and Proteomes of Serum Exosomes from Marek’s Disease Virus-Vaccinated and Protected and Lymphoma-Bearing Chickens

Marek’s disease virus (MDV) is the causative agent of Marek’s disease (MD), a complex pathology of chickens characterized by paralysis, immunosuppression, and T-cell lymphomagenesis. MD is controlled in poultry production via vaccines administered in ovo or at hatch, and these confer protection against lymphoma formation, but not superinfection by MDV field strains. Despite vaccine-induced humoral and cell-mediated immune responses, mechanisms eliciting systemic protection remain unclear. Here we report the contents of serum exosomes to assess their possible roles as indicators of systemic immunity, and alternatively, tumor formation. We examined the RNA and protein content of serum exosomes from CVI988 (Rispens)-vaccinated and protected chickens (VEX), and unvaccinated tumor-bearing chickens (TEX), via deep-sequencing and mass spectrometry, respectively. Bioinformatic analyses of microRNAs (miRNAs) and predicted miRNA targets indicated a greater abundance of tumor suppressor miRNAs in VEX compared to TEX. Conversely, oncomiRs originating from cellular (miRs 106a-363) and MDV miRNA clusters were more abundant in TEX compared to VEX. Most notably, mRNAs mapping to the entire MDV genome were identified in VEX, while mRNAs mapping to the repeats flanking the unique long (IRL/TRL) were identified in TEX. These data suggest that long-term systemic vaccine-induced immune responses may be mediated at the level of VEX which transfer viral mRNAs to antigen presenting cells systemically. Proteomic analyses of these exosomes suggested potential biomarkers for VEX and TEX. These data provide important putative insight into MDV-mediated immune suppression and vaccine responses, as well as potential serum biomarkers for MD protection and susceptibility.
Adaptive Sampling for Sound Propagation

Precomputed sound propagation samples acoustics at discrete scene probe positions to support dynamic listener locations. An offline 3D numerical simulation is performed at each probe and the resulting field is encoded for runtime rendering with dynamic sources. Prior work place probes on a uniform grid, requiring high density to resolve narrow spaces. Our adaptive sampling approach varies probe density based on a novel “local diameter” measure of the space surrounding a given point, evaluated by stochastically tracing paths in the scene. We apply this measure to layout probes so as to smoothly adapt resolution and eliminate undersampling in corners, narrow corridors and stairways, while coarsening appropriately in more open areas. Coupled with a new runtime interpolator based on radial weights over geodesic paths, we achieve smooth acoustic effects that respect scene boundaries as both the source or listener move, unlike existing visibility-based solutions. We consistently demonstrate quality improvement over prior work at fixed cost.
Factors influencing practices among ward nurses that support ongoing independent community living after discharge: a cross-sectional study

Background:It is not clear which personal factors and experiences affect ward nurses’ practice in supporting patients to return home after discharge. Aims: To explore the practices among ward nurses that help them support patients to continue to live independently in the community; and the influence on these of personal experience of providing home care, approaches to discharge planning, and understanding about patients after discharge. Design: Cross-sectional study. Methods: The study included 178 ward nurses in three hospitals. We used a t-test to analyze differences in ward nursing practices focusing on community living by nurses’ characteristics, experience in providing home-based care, discharge planning approaches, and understanding of patient situations after discharge, and a stepwise multi-regression analysis with ward nursing practices focusing on community living as the dependent variable. Results: Respondents included 167 female and 11 male nurses, with 34.8% in their 40s. Their mean length of nursing experience was 14.2 ± 9.8 years. Only 45.5% of the ward nurses recognized that discharge planning should commence on admission. The most common area of ward nursing practice focusing on community living was educating patients and their families. Cooperation with community healthcare workers was seen least frequently. The highest rate of contribution was observed in a model including recognition of the importance of discharge planning, number of conferences attended with community care service providers, experience of caring for a family member, and length of nursing experience (Adjusted R2 = 0.301). Impact statement: Improved ward nursing practice can help nurses to focus on enabling ongoing independent community living. Conclusions: Nurses were most focused on educating patients and their families to help them to manage after discharge. Recognizing the importance of discharge planning, holding conferences with community care service providers, and experience in caring for a family member affected ward nursing practice supporting community living.
Generalized tonic-clonic seizures: aberrant interhemispheric functional and anatomical connectivity.

PURPOSE To characterize interhemispheric functional and anatomic connectivity in patients with idiopathic generalized epilepsy and generalized tonic-clonic seizures (GTCS). MATERIALS AND METHODS This retrospective study was approved by the local institutional review board and was HIPAA compliant. All participants provided written informed consent. Resting-state functional and structural magnetic resonance images were acquired in 52 patients with GTCS and 65 healthy control subjects. The functional connectivity between bilateral homotopic voxels was calculated. Homotopic regions showing abnormal functional connectivity in patients were adopted as regions of interest for an analysis of diffusion-tensor imaging tractography. The fractional anisotropy and fiber length were compared between groups. Two-sample t test and nonparametric correlation analysis were used. RESULTS Compared with control subjects, patients showed increased interhemispheric functional connectivity between the bilateral cuneus (P = .0008, corrected) and anterior cingulate cortex (P = .0003, corrected) and decreased functional connectivity between the bilateral olfactory cortex (P = .00005, corrected), inferior frontal gyrus (P = .00005, corrected), supramarginal gyrus (P = .0002, corrected), and temporal pole (P = .0003, corrected). Furthermore, the fiber length of the commissural fiber bundles connecting the bilateral anterior cingulate cortex (t = -2.30; P = .03, uncorrected) and the bilateral cuneus was shorter in patients than in control subjects (t = -3.19; P = .002, uncorrected). CONCLUSION Our findings show that the bilateral anterior cingulate cortex may be critical to the pathophysiology of patients with GTCS and suggest that the corresponding commissural fiber bundle in the genu of the corpus callosum is a potential target for future surgical treatment in patients with intractable GTCS.
Adolescents’ Cognitive Capacity Reaches Adult Levels Prior to Their Psychosocial Maturity: Evidence for a “Maturity Gap” in a Multinational, Cross-Sectional Sample

All countries distinguish between minors and adults for various legal purposes. Recent U.S. Supreme Court cases concerning the legal status of juveniles have consulted psychological science to decide where to draw these boundaries. However, little is known about the robustness of the relevant research, because it has been conducted largely in the U.S. and other Western countries. To the extent that lawmakers look to research to guide their decisions, it is important to know how generalizable the scientific conclusions are. The present study examines 2 psychological phenomena relevant to legal questions about adolescent maturity: cognitive capacity, which undergirds logical thinking, and psychosocial maturity, which comprises individuals’ ability to restrain themselves in the face of emotional, exciting, or risky stimuli. Age patterns of these constructs were assessed in 5,227 individuals (50.7% female), ages 10–30 (M = 17.05, SD = 5.91) from 11 countries. Importantly, whereas cognitive capacity reached adult levels around age 16, psychosocial maturity reached adult levels beyond age 18, creating a “maturity gap” between cognitive and psychosocial development. Juveniles may be capable of deliberative decision making by age 16, but even young adults may demonstrate “immature” decision making in arousing situations. We argue it is therefore reasonable to have different age boundaries for different legal purposes: 1 for matters in which cognitive capacity predominates, and a later 1 for matters in which psychosocial maturity plays a substantial role.
The Relationship between Player's Value Systems and Their In-Game Behavior in a Massively Multiplayer Online Role-Playing Game

This study examines the relationship between player’s value systems and their actions in playing a massively multiplayer online role-playing game. Online survey data from 1,577 players were paired with their behavioral metrics within the game. A number of correlations were found between the scores of value system and the in-game metrics. Participants that scored high on the Red value system tend to spend more real money in the game, level up their character and ability as quickly as possible, and seek other achievements in the forms offered by game world. These characteristics for fun, power, and immediate gratification are also predicted by the Red value system. The finding provides valuable information on how to better design, evaluate, and understand enjoyment in games. The results also show the possibility of using the game as a platform in inferring players’ value systems and in training people to develop certain skills.
Phenology and growth of Fagus sylvatica and Quercus robur seedlings in response to temperature variation in the parental versus offspring generation.

Plants are known to respond to warming temperatures. Few studies, however, have included the temperature experienced by the parent plant in the experimental design, in spite of the importance of this factor for population dynamics. We investigated the phenological and growth responses of seedlings of two key temperate tree species (Fagus sylvatica and Quercus robur) to spatiotemporal temperature variation during the reproductive period (parental generation) and experimental warming of the offspring. To this end, we sampled oak and beech seedlings of different ages (1-5 years) from isolated mother trees and planted the seedlings in a common garden. Warming of the seedlings advanced bud burst in both species. In oak seedlings, higher temperatures experienced by mother trees during the reproductive period delayed bud burst in control conditions, but advanced bud burst in heated seedlings. In beech seedlings, bud burst timing advanced both with increasing temperatures during the reproductive period of the parents and with experimental warming of the seedlings. Relative diameter growth was enhanced in control oak seedlings but decreased with warming when the mother plant experienced higher temperatures during the reproductive period. Overall, oak displayed more plastic responses to temperatures than beech. Our results emphasise that temperature during the reproductive period can be a potential determinant of tree responses to climate change.
Cross-linguistic generalization in the treatment of two sequential Spanish–English bilingual children with speech sound disorders

Abstract Purpose. The effect of bilingual service delivery on treatment of speech sound disorders (SSDs) in bilingual children is largely unknown. Bilingual children with SSDs are typically provided intervention in only one language, although research suggests dual-language instruction for language disorders is best practice for bilinguals. This study examined cross-linguistic generalization of bilingual intervention in treatment of two 5-year-old sequential bilingual boys with SSDs (one with Childhood Apraxia of Speech), hypothesizing that selecting and treating targets in both languages would result in significant overall change in their English and Spanish speech systems. Method. A multiple baseline across behaviours design was used to measure treatment effectiveness for two targets per child. Children received treatment 2–3 times per week for 8 weeks and in Spanish for at least 2 of every 3 days. Ongoing treatment performance was measured in probes in both languages; overall speech skills were compared pre- and post-treatment. Result. Both children's speech improved in both languages with similar magnitude; there was improvement in some non-treated errors. Conclusion. Treating both languages had an overall positive effect on these bilingual children's speech. Future bilingual intervention research should explore alternating treatments designs, efficiency of monolingual vs bilingual treatment, different language and bilingual backgrounds, and between-group comparisons.
HDAC Inhibitors Rescue Multiple Disease-Causing CFTR Variants

Understanding the role of the epigenome in protein misfolding diseases remains a challenge in light of genetic diversity found in the world-wide population revealed by human genome sequencing efforts and the highly variable respond of the disease population to any therapeutic. An ever-growing body of evidence has shown that histone deacetylase (HDAC) inhibitors (HDACi) can have significant benefit in correcting protein misfolding diseases that occur in response to both familial and somatic mutation. Cystic fibrosis (CF) is a familial autosomal recessive disease, caused by genetic diversity in the CF transmembrane conductance regulator (CFTR) gene, a cAMP-dependent chloride channel expressed at the apical plasma membrane of epithelial cells in multiple tissues. The potential utility of HDACi in correcting F508del as well as the over 2000 CF-associated variants remains controversial. To address this concern, we examined the impact of FDA-approved HDACi on the trafficking and function of a panel of CFTR variants. Our data reveal that panobinostat (LBH-589) and romidepsin (FK-228) provide functional correction of class II and III CFTR variants, restoring cell surface chloride channel activity in primary human bronchial epithelial (hBE) cells. We further demonstrate a synergistic effect of these HDACi with Vx809, that together can significantly restore channel activity for multiple CFTR variants. These data suggest that HDACi can serve to level the cellular playing field for correcting CF-causing mutations, a leveling effect that might also extend to other protein misfolding diseases.