Miracle-dz/UniFAR-FTUs huggingface dataset:
Allergen immunotherapy in allergic rhinitis: current use and future trends

ABSTRACT Introduction: Type-1 allergies are among the most chronic common diseases of humans. Allergen immunotherapy (AIT) is the only causative and disease-modifying treatment option besides allergen avoidance. Severe systemic adverse allergic reactions may be induced by every AIT treatment. Different approaches have been used to provide safer AIT preparations to lower or even totally overcome this risk. Areas covered: A structured literature recherche in Medline and Pubmed under inclusion of national and international guidelines and Cochrane meta-analyses has been performed aiming at reviewing clinical use of such approaches in AIT. New allergen preparations may include allergoids, recombinant allergens (recA) and modified recombinant allergens (recA) in subcutaneous as well as in mucosal immunotherapies (application e.g. using bronchial, nasal, oral and sublingual application) with sublingual being the established mucosal application route and new ways of application like intralymphatic and epicutaneous immunotherapy. Expert commentary: Immune-modifying agents like Virus-like particles and CpG-motifs, adjuvants like MPL and aluminum hydroxide are evaluated and found to increase and direct the immunological response toward immunological tolerance. New forms of allergen extracts can improve safety and efficacy of AIT and may change our way of performing allergen immunotherapy in the future.
The mechanical function of the periodontal ligament in the macaque mandible: a validation and sensitivity study using finite element analysis

Whilst the periodontal ligament (PDL) acts as an attachment tissue between bone and tooth, hypotheses regarding the role of the PDL as a hydrodynamic damping mechanism during intraoral food processing have highlighted its potential importance in finite element (FE) analysis. Although experimental and constitutive models have correlated the mechanical function of the PDL tissue with its anisotropic, heterogeneous, viscoelastic and non‐linear elastic nature, in many FE simulations the PDL is either present or absent, and when present is variably modelled. In addition, the small space the PDL occupies and the inability to visualize the PDL tissue using μCT scans poses issues during FE model construction and so protocols for the PDL thickness also vary. In this paper we initially test and validate the sensitivity of an FE model of a macaque mandible to variations in the Young’s modulus and the thickness of the PDL tissue. We then tested the validity of the FE models by carrying out experimental strain measurements on the same mandible in the laboratory using laser speckle interferometry. These strain measurements matched the FE predictions very closely, providing confidence that material properties and PDL thickness were suitably defined. The FE strain results across the mandible are generally insensitive to the absence and variably modelled PDL tissue. Differences are only found in the alveolar region adjacent to the socket of the loaded tooth. The results indicate that the effect of the PDL on strain distribution and/or absorption is restricted locally to the alveolar bone surrounding the teeth and does not affect other regions of the mandible.
Dried Blood Spots Combined With Ultra–High-Performance Liquid Chromatography–Mass Spectrometry for the Quantification of the Antipsychotics Risperidone, Aripiprazole, Pipamperone, and Their Major Metabolites

Background: Risperidone, aripiprazole, and pipamperone are antipsychotic drugs frequently prescribed for the treatment of comorbid behavioral problems in children with autism spectrum disorders. Therapeutic drug monitoring (TDM) could be useful to decrease side effects and to improve patient outcome. Dried blood spot (DBS) sample collection seems to be an attractive technique to develop TDM of these drugs in a pediatric population. The aim of this work was to develop and validate a DBS assay suitable for TDM and home sampling. Methods: Risperidone, 9-OH risperidone, aripiprazole, dehydroaripiprazole, and pipamperone were extracted from DBS and analyzed by ultra–high-performance liquid chromatography–tandem mass spectrometry using a C18 reversed-phase column with a mobile phase consisting of ammonium acetate/formic acid in water or methanol. The suitability of DBS for TDM was assessed by studying the influence of specific parameters: extraction solution, EDTA carryover, hematocrit, punching location, spot volume, and hemolysis. The assay was validated with respect to conventional guidelines for bioanalytical methods. Results: The method was linear, specific without any critical matrix effect, and with a mean recovery around 90%. Accuracy and imprecision were within the acceptance criteria in samples with hematocrit values from 30% to 45%. EDTA or hemolysis did not skew the results, and no punching carryover was observed. No significant influence of the spot volume or the punch location was observed. The antipsychotics were all stable in DBS stored 10 days at room temperature and 1 month at 4 or −80°C. The method was successfully applied to quantify the 3 antipsychotics and their metabolites in patient samples. Conclusions: A UHPLC-MS/MS method has been successfully validated for the simultaneous quantification of risperidone, 9-OH risperidone, aripiprazole, dehydroaripiprazole, and pipamperone in DBS. The assay provided good analytical performances for TDM and clinical research applications.
Determination of the Minimal Clinically Important Difference of the University of North Carolina Dry Eye Management Scale

Purpose: To establish an initial estimation of the MCID of the University of North Carolina Dry Eye Management Scale (UNC DEMS) and assess its association with patient perceptions of symptom change. Methods: Thirty-three patients (33.3% men, 67.7% women, mean age 60.5 yrs) with previous DEMS scores were recruited from a UNC ophthalmology clinic in spring 2014. We used anchor-based methods, categorizing important symptom change, to compare the change in the DEMS scores across visits to patient assessments of change; linear regression coefficients estimated the MCID. We correlated clinical assessments, patient perceptions, and DEMS scores. Results: DEMS score changes correlated with global anchors [−0.4229 (P = 0.014)]. Unadjusted linear regression yielded a beta coefficient of −0.54 (confidence interval, −0.97 to −0.12, R2 = 0.18, P = 0.014), which estimated the DEMS MCID. Adjusting the regression model for days since the last visit and DEMS score improved the association (beta = −0.56; confidence interval, −0.99 to −0.13; R2 = 0.43; P = 0.013). Descriptive statistics produced an MCID of 1 point. Patients said that 2 points would represent a significant change. The DEMS modestly correlated with the Schirmer test (−0.4045, P = 0.0266), Oxford Grading Scheme (+0.3713, P = 0.0364), and tear breakup time (−0.3559, P = 0.0456). Conclusions: The UNC DEMS is a valid, responsive patient-reported outcome measure instrument, which is easy to use in the clinic and capable of showing an MCID of 1 point.
miRNA92a targets KLF2 and the phosphatase PTEN signaling to promote human T follicular helper precursors in T1D islet autoimmunity

Significance The onset of type 1 diabetes autoimmunity is indicated by the development of multiple islet autoantibodies, produced by B cells with the help of T follicular helper (TFH) cells. MicroRNAs (miRNAs) are small noncoding RNAs that regulate cellular states, as immune activation, making them suitable targets for disease intervention. Here, we show an enrichment of insulin-specific C-X-C chemokine receptor type 5 (CXCR5)+CD4+ TFH precursors correlating with high miRNA92a abundance during onset of autoimmunity and identify Krueppel-like factor 2 (KLF2) as a target for miRNA92a. We demonstrate that miRNA92a inhibition blocks TFH induction and reduces murine islet autoimmunity in vivo. Therefore, we propose miRNA92a and the phosphatase and tension homolog-phosphoinositol-3-kinase-KLF2 signaling network as possible innovative precision medicine targets to interfere with aberrant immune activation in islet autoimmunity. Aberrant immune activation mediated by T effector cell populations is pivotal in the onset of autoimmunity in type 1 diabetes (T1D). T follicular helper (TFH) cells are essential in the induction of high-affinity antibodies, and their precursor memory compartment circulates in the blood. The role of TFH precursors in the onset of islet autoimmunity and signaling pathways regulating their differentiation is incompletely understood. Here, we provide direct evidence that during onset of islet autoimmunity, the insulin-specific target T-cell population is enriched with a C-X-C chemokine receptor type 5 (CXCR5)+CD4+ TFH precursor phenotype. During onset of islet autoimmunity, the frequency of TFH precursors was controlled by high expression of microRNA92a (miRNA92a). miRNA92a-mediated TFH precursor induction was regulated by phosphatase and tension homolog (PTEN) - phosphoinositol-3-kinase (PI3K) signaling involving PTEN and forkhead box protein O1 (Foxo1), supporting autoantibody generation and triggering the onset of islet autoimmunity. Moreover, we identify Krueppel-like factor 2 (KLF2) as a target of miRNA92a in regulating human TFH precursor induction. Importantly, a miRNA92a antagomir completely blocked induction of human TFH precursors in vitro. More importantly, in vivo application of a miRNA92a antagomir to nonobese diabetic (NOD) mice with ongoing islet autoimmunity resulted in a significant reduction of TFH precursors in peripheral blood and pancreatic lymph nodes. Moreover, miRNA92a antagomir application reduced immune infiltration and activation in pancreata of NOD mice as well as humanized NOD Scid IL2 receptor gamma chain knockout (NSG) human leucocyte antigen (HLA)-DQ8 transgenic animals. We therefore propose that miRNA92a and the PTEN-PI3K-KLF2 signaling network could function as targets for innovative precision medicines to reduce T1D islet autoimmunity.
Effect of Community Engagement Interventions on Patient Safety and Risk Reduction Efforts in Primary Health Facilities: Evidence from Ghana

Background Patient safety and quality care remain major challenges to Ghana’s healthcare system. Like many health systems in Africa, this is largely because demand for healthcare is outstripping available human and material resource capacity of healthcare facilities and new investment is insufficient. In the light of these demand and supply constraints, systematic community engagement (SCE) in healthcare quality assessment can be a feasible and cost effective option to augment existing quality improvement interventions. SCE entails structured use of existing community groups to assess healthcare quality in health facilities. Identified quality gaps are discussed with healthcare providers, improvements identified and rewards provided if the quality gaps are closed. Purpose This paper evaluates whether or not SCE, through the assessment of health service quality, improves patient safety and risk reduction efforts by staff in healthcare facilities. Methods A randomized control trail was conducted in 64 primary healthcare facilities in the Greater Accra and Western regions of Ghana. Patient risk assessments were conducted in 32 randomly assigned intervention and control facilities. Multivariate multiple regression test was used to determine effect of the SCE interventions on staff efforts towards reducing patient risk. Spearman correlation test was used to ascertain associations between types of community groups engaged and risk assessment scores of healthcare facilities. Findings Clinic staff efforts towards increasing patient safety and reducing risk improved significantly in intervention facilities especially in the areas of leadership/accountability (Coef. = 10.4, p<0.05) and staff competencies (Coef. = 7.1, p<0.05). Improvement in service utilization and health resources could not be attributed to the interventions because these were outside the control of the study and might have been influenced by institutional or national level developments between the baseline and follow-up period. Community groups that were gender balanced, religious/faith-based, and had structured leadership appeared to be better options for effective SCE in healthcare quality assessment. Conclusion Community engagement in healthcare quality assessment is a feasible client-centered quality improvement option that should be discussed for possible scale-up in Ghana and other resource poor countries in Africa.
Temporal Data Clustering via Weighted Clustering Ensemble with Different Representations

Temporal data clustering provides underpinning techniques for discovering the intrinsic structure and condensing information over temporal data. In this paper, we present a temporal data clustering framework via a weighted clustering ensemble of multiple partitions produced by initial clustering analysis on different temporal data representations. In our approach, we propose a novel weighted consensus function guided by clustering validation criteria to reconcile initial partitions to candidate consensus partitions from different perspectives, and then, introduce an agreement function to further reconcile those candidate consensus partitions to a final partition. As a result, the proposed weighted clustering ensemble algorithm provides an effective enabling technique for the joint use of different representations, which cuts the information loss in a single representation and exploits various information sources underlying temporal data. In addition, our approach tends to capture the intrinsic structure of a data set, e.g., the number of clusters. Our approach has been evaluated with benchmark time series, motion trajectory, and time-series data stream clustering tasks. Simulation results demonstrate that our approach yields favorite results for a variety of temporal data clustering tasks. As our weighted cluster ensemble algorithm can combine any input partitions to generate a clustering ensemble, we also investigate its limitation by formal analysis and empirical studies.
Psychometric evaluation of the Czech Beck Depression Inventory-II in a sample of depressed patients and healthy controls.

OBJECTIVE The goal of this study was to explore reliability and validity of the Czech revised Beck Depression Inventory (BDI-II) and to identify the best cut-off for a correct identification of a potentially depressed individual. METHOD Two groups of adult participants entered the study. The first group consisted of 177 patients with depression (F32x or F33x according to the ICD-10). Furthermore, there were 767 healthy controls. Each participant filled in BDI-II. A part of the patients also completed the Beck Anxiety Inventory (BAI), the Dissociative Experiences Scale (DES), and the subjective Clinical Global Impression scale (CGI). A part of the controls filled in the Adult Dispositional Hope Scale (ADHS) and the Satisfaction with Life Scale (SWLS). RESULT The average patients' BDI-II score was 30.8±10.3, the mean controls' score was 7.2±6.8. The internal consistency of the inventory was excellent (the ordinal alpha coefficient was 0.90 for the patients and 0.93 for the controls). The stability in time, measured two weeks apart, was also good (intra-class correlation coefficient r=0.83 for the patients and 0.77 for the controls). The exploratory factor analysis of the patients showed a three-factor solution, while the analysis of the controls' data identified two factors. As expected, BDI-II significantly positively correlated with BAI, DES, and CGI and was negatively connected to ADHS and SWLS. The cut-off score with the best sensitivity and specificity was 17. CONCLUSION The Czech BDI-II shows adequate psychometric characteristics.
OntoDiSENv1: an Ontology to Support Global Software Development

Global Software Development (GSD) brought competitive advantages to organizations, but it has also imposed some drawbacks due to the physical distribution. A critical aspect of this approach is related to communication. In order to p rovide the same semantic understanding about information exchanged on the environment to all team members it is necessary to minimize the ambiguity. This paper presents OntoDiSENv1, application ontology for a distributed software development environment. The goal of this ontology is support communication among geographically dispersed team members. The ontology is integrated to a contextual information dissemination model, which notifies the team members about the actions that occur on the shared workspace and can influence their work. The main contribution of OntoDiSENv1 is to support contextual information representation and processing, providing inference capability and sema ntic consistency of the information disseminated.
Rational design of a Kv1.3 channel-blocking antibody as a selective immunosuppressant

Significance There is considerable interest in developing immunosuppressants that can specifically target effector memory T cells which are key to the pathogenesis of many inflammatory disorders. The potassium channel Kv1.3 has been found to play an important role in TEM activation, but not in naive and central memory T cells. It has proven challenging to generate small molecules or antibodies that potently and selectively block Kv1.3 function. We generated antibody fusions by grafting potent Kv1.3 blocking peptides into complementary-determining regions (CDRs) of humanized antibodies, and among those, identified a candidate with high in vitro potency, excellent physiochemical and pharmacologic properties, and in vivo efficacy in a rat model. These novel toxin-antibody fusions have therapeutic potential for a variety of TEM-mediated inflammatory diseases. A variable region fusion strategy was used to generate an immunosuppressive antibody based on a novel “stalk-knob” structural motif in the ultralong complementary-determining region (CDR) of a bovine antibody. The potent Kv1.3 channel inhibitory peptides Moka1-toxin and Vm24-toxin were grafted into different CDRs of the humanized antibodies BVK and Synagis (Syn) using both β-sheet and coiled-coil linkers. Structure-activity relationship efforts led to generation of the fusion protein Syn-Vm24-CDR3L, which demonstrated excellent selectivity and potency against effector human memory T cells (subnanomolar to picomolar EC50 values). This fusion antibody also had significantly improved plasma half-life and serum stability in rodents compared with the parent Vm24 peptide. Finally, this fusion protein showed potent in vivo efficacy in the delayed type hypersensitivity in rats. These results illustrate the utility of antibody CDR fusions as a general and effective strategy to generate long-acting functional antibodies, and may lead to a selective immunosuppressive antibody for the treatment of autoimmune diseases.
Endocannabinoid system acts as a regulator of immune homeostasis in the gut

Significance Exogenous cannabinoids such as marijuana exert their influence through cannabinoid receptors. Endogenous cannabinoids such as anandamide (AEA) function through the same receptors, and their physiological roles are a subject of intense study. Here, we show that AEA plays a pivotal role in maintaining immunological health in the gut. The immune system in the gut actively tolerates the foreign antigens present in the gut through mechanisms that are only partially understood. We show that AEA contributes to this critical process by promoting the presence of CX3CR1hi macrophages, which are immunosuppressive. These results uncover a major conversation between the immune and nervous systems. In addition, with the increasing prevalence of ingestion of exogenous marijuana, our study has significant implications for public health. Endogenous cannabinoids (endocannabinoids) are small molecules biosynthesized from membrane glycerophospholipid. Anandamide (AEA) is an endogenous intestinal cannabinoid that controls appetite and energy balance by engagement of the enteric nervous system through cannabinoid receptors. Here, we uncover a role for AEA and its receptor, cannabinoid receptor 2 (CB2), in the regulation of immune tolerance in the gut and the pancreas. This work demonstrates a major immunological role for an endocannabinoid. The pungent molecule capsaicin (CP) has a similar effect as AEA; however, CP acts by engagement of the vanilloid receptor TRPV1, causing local production of AEA, which acts through CB2. We show that the engagement of the cannabinoid/vanilloid receptors augments the number and immune suppressive function of the regulatory CX3CR1hi macrophages (Mϕ), which express the highest levels of such receptors among the gut immune cells. Additionally, TRPV1−/− or CB2−/− mice have fewer CX3CR1hi Mϕ in the gut. Treatment of mice with CP also leads to differentiation of a regulatory subset of CD4+ cells, the Tr1 cells, in an IL-27–dependent manner in vitro and in vivo. In a functional demonstration, tolerance elicited by engagement of TRPV1 can be transferred to naïve nonobese diabetic (NOD) mice [model of type 1 diabetes (T1D)] by transfer of CD4+ T cells. Further, oral administration of AEA to NOD mice provides protection from T1D. Our study unveils a role for the endocannabinoid system in maintaining immune homeostasis in the gut/pancreas and reveals a conversation between the nervous and immune systems using distinct receptors.
The Neuroprotective Effects of Muscle-Derived Stem Cells via Brain-Derived Neurotrophic Factor in Spinal Cord Injury Model

Muscle-derived stem cells (MDSCs) possess multipotent differentiation and self-renewal capacities; however, the effects and mechanism in neuron injury remain unclear. The aim of this study was to investigate the effects of MDSCs on neuron secondary injury, oxidative stress-induced apoptosis. An in vivo study showed the Basso, Beattie, and Bresnahan (BBB) score and number of neurons significantly increased after MDSCs' transplantation in spinal cord injury (SCI) rats. An in vitro study demonstrated that MDSCs attenuated neuron apoptosis, and the expression of antioxidants was upregulated as well as the ratio of Bcl-2 and Bax in the MNT (MDSCs cocultured with injured neurons) group compared with the NT (injured neurons) group. Both LC3II/LC3I and β-catenin were enhanced in the MNT group, while XAV939 (a β-catenin inhibitor) decreased the expression of nuclear erythroid-related factor 2 (Nrf2) and LC3II/LC3I. Moreover, MDSCs became NSE- (neuron-specific enolase-) positive neuron-like cells with brain-derived neurotrophic factor (BDNF) treatment. The correlation analysis indicated that there was a significant relation between the level of BDNF and neuron injury. These findings suggest that MDSCs may protect the spinal cord from injury by inhibiting apoptosis and replacing injured neurons, and the increased BDNF and β-catenin could contribute to MDSCs' effects.