Miracle-dz/UniFAR-FTUs huggingface dataset:
Effect of Tinnitus Retraining Therapy vs Standard of Care on Tinnitus-Related Quality of Life: A Randomized Clinical Trial.

Importance Tinnitus retraining therapy (TRT) is an internationally recognized, but controversial, protocol of uncertain efficacy that uses tinnitus-specific educational counseling (TC) and sound therapy (ST) to reduce the patient's tinnitus-evoked negative reaction to, and awareness of, tinnitus. Objective To compare the efficacy of TRT and its components, ST and TC, with the standard of care (SoC) in reducing the negative effect of tinnitus on quality of life. Design, Setting, and Participants A randomized, placebo-controlled, multicenter phase 3 trial was conducted from August 4, 2011, to June 20, 2017, at 6 US military hospitals, the study chairs' office, and a data coordinating center, among 151 active-duty and retired military personnel and dependents with functionally adequate hearing sensitivity and moderate to severe subjective tinnitus. All analyses were based on intention to treat. Interventions Central randomized allocation to TRT (TC and ST with conventional sound generators), partial TRT (TC with placebo sound generators), or SoC. Main Outcomes and Measures The primary outcome was mean change on the Tinnitus Questionnaire (TQ), assessed longitudinally between baseline and 18 months after start of therapy. The secondary outcomes were changes in TQ subscales, Tinnitus Functional Index (TFI), and Tinnitus Handicap Inventory (THI) total and subscales, as well as a 10-point visual analog scale (VAS). Results Among the 151 participants in the study (44 women and 107 men; mean [SD] age, 50.6 [11.3] years), 51 were randomized to receive TRT, 51 to receive partial TRT, and 49 to receive standard of care. Longitudinal analyses showed no difference between partial TRT or TRT compared with SoC, or partial TRT compared with TRT, on TQ, TFI, or THI total scores. Comparison of changes in mean score from baseline to the 18-month visit also showed no difference between treatment groups. Significant improvement was observed at 18 months in all treatment groups on TQ scores for TRT (effect size, -1.32; 95% CI, -1.78 to -0.85), partial TRT (effect size, -1.16; 95% CI, -1.56 to -0.76), and SoC (effect size, -1.01; 95% CI, -1.41 to -0.61). Compared with baseline scores, at 18 months there were reductions in scores by 7 points or more on the TQ score for 86 of 111 participants (77.55%; 95% CI, 69.7%-85.2%), 13 points or more on the TFI for 52 of 111 participants (46.8%; 95% CI, 37.6%-56.1%), 7 points or more on the THI for 63 of 111 participants (56.8%; 95% CI, 47.5%-66.0%), and 2 points or more on the VAS for 45 of 93 participants (48.4%; 95% CI, 38.2%-58.5%). Conclusions and Relevance There were few differences between treatment groups. About half of participants showed clinically meaningful reductions in the effect of tinnitus. Trial Registration ClinicalTrials.gov identifier: NCT01177137.
A systematic review and meta-analysis of interventions incorporating behaviour change techniques to promote breastfeeding among postpartum women

ABSTRACT The benefits of exclusive breastfeeding are well documented, yet few women adhere to recommendations. We report the Behaviour Change Techniques (BCTs) within interventions trialled internationally after pregnancy to promote exclusive and mixed breastfeeding as well as evidence of effectiveness. PsycINFO, EMBASE and MEDLINE databases were screened. Twenty-three (n = 23) studies met inclusion criteria. Three authors independently extracted data, coded interventions using the BCT v.1 taxonomy, and assessed study quality. There was a moderate significant effect of the interventions promoting exclusive breastfeeding up to four weeks postpartum (OR 1.77, [95% CI: 1.47–2.13]) but this effect slightly declined beyond thirteen weeks (OR 1.63, [95% CI: 1.07–2.47]). Twenty-nine BCTs were identified within interventions. ‘Credible source’ and ‘instruction on how to perform the behaviour’ were the most prevalent and ‘social support (unspecified)’ contributed to the effectiveness of exclusive breastfeeding interventions five to eight weeks postpartum. Using BCTs with cognitive and behavioural aspects may help women develop coping mechanisms promoting exclusive breastfeeding. Further trials are needed in countries with low breastfeeding rates such as the UK. The use of programme theory during intervention development and clear description of intervention components is recommended. This meta-analysis provides guidance for trials evaluating postpartum breastfeeding interventions.
Effects of a Medial Knee Unloading Implant on Tibiofemoral Joint Mechanics During Walking

The Atlas™ unicompartmental knee system is a second‐generation extra‐articular unloading implant for patients with mild to moderate medial knee osteoarthritis. The technology acts to reduce a portion of the weight‐bearing load exerted on the medial knee during physical activity thereby, reducing the mechanical stress imposed on a degenerative joint. The purpose of the present study was to evaluate the effects of the Atlas™ on tibiofemoral joint mechanics during walking. A computer‐aided design assembly of the Atlas™ was virtually implanted on the medial aspect of a previously validated finite element tibiofemoral joint model. Data for knee joint forces and moments from an anthropometrically matched male were applied to the model to quasi‐statically simulate the stance phase of gait. Predictions of tibiofemoral joint mechanics were computed pre‐ and post‐virtual implantation of the Atlas™. Compressive force in the medial tibiofemoral compartment was reduced by a mean of 53%, resulting in the decrement of mean cartilage–cartilage and cartilage–meniscus von Mises stress by 31% and 32%, respectively. The Atlas™ was not predicted to transfer net loading to the lateral compartment. The tibiofemoral joint model exhibited less internal–external rotation and anterior–posterior translation post‐Atlas™, indicating a change in the kinematic environment of the knee. From a biomechanical perspective, extra‐articular joint unloading may serve as a treatment option for patients recalcitrant to conservative care. Evaluation of mechanical changes in the tibiofemoral joint demonstrate the potential treatment mechanism of the Atlas™, in accordance with the available clinical data. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:2149–2156, 2019
TIMP2 Polymorphisms Association With Curve Initiation and Progression of Thoracic Idiopathic Scoliosis in the Caucasian Females

Idiopathic scoliosis (IS) etiology remains unclear, but strong genetic background is suggested. Previously reported TIMP2 study indicates an association of genic rs8179090 with IS progression in a Han Chinese population. However, there has been a lack of investigation into intragenic TIMP2 polymorphisms in IS patients. We recruited 100 Caucasian females with IS and 100 controls. Patients were subdivided accordingly to: progression rate, curve severity, joint mobility, and curve pattern. Allele‐specific‐polymerase chain reaction based on fluorescence resonance energy transfer was applied to evaluate nine TIMP2 polymorphisms. Distribution of genotype and allele frequency in only one polymorphism (rs11658743) differed in case–control study. Four of the polymorphisms (rs2277700, rs11077401, rs2376999, and rs4789934) showed non‐equal distributions either in genotype or/and allele distributions in the patients of different progression rates. The rs11077401 was related to curve severity patients distinction and the rs8179090 distinguished patients with different joint mobility level. Two polymorphisms either differed statistically in case of curve patterns subgrouping (rs8068674 and rs8179090) or showed a slight tendency toward significance in the recessive model of allele distributions (rs9916809 and rs8179090). The remaining two polymorphisms (rs2377005, rs11658743) showed no association with either clinical or radiographic IS characteristics. The influence of the G allele of the rs8179090 on the clinical course of IS has not yet been confirmed. We identified four TIMP2 polymorphisms (rs11077401, rs2376999, rs2277700, and rs4789934) that were associated with a higher risk of the progressive IS form. Further genetic association studies based on suggested clinical criteria would be necessary to validate TIMP2 polymorphisms associated with the curve progression. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:2217–2225, 2019
A Qualitative Study on Danish Student Pharmacists’ Attitudes Towards and Experience of Communication Skills Training

As the pharmacy profession evolves, good communication skills are vital for securing the safer and more rational use of medicines. Currently there is a lack of qualitative studies researching European student pharmacists’ and their experience with communication skills training (CST). This qualitative study aimed to fill this gap by exploring Danish student pharmacists’ attitudes towards, and experiences of, CST. Focus group interviews were conducted with a heterogeneous sample of Danish student pharmacists in 2016. Interviews were audio recorded, transcribed verbatim and analyzed inductively. Fifteen students participated in three focus groups. Five categories identified as key aspects were: professional communication vs. normal conversation, motivation to engage in training, how to learn communication skills, experience with CST and universities’ role in teaching communication skills. In conclusion, there were both positive and negative attitudes towards CST among the participants. However, they had little experience with CST. Bloom’s taxonomy of the affective domain and Kolb’s experiential learning model appear to be useful in understanding students’ attitudes towards CST. Pharmacy educators can use this study to structure and improve their CST curricula by knowing what influences students’ attitudes towards CST.
A genome‐wide association study‐derived polygenic score for interleukin‐1β is associated with hippocampal volume in two samples

Accumulating research suggests that the pro‐inflammatory cytokine interleukin‐1β (IL‐1β) has a modulatory effect on the hippocampus, a brain structure important for learning and memory as well as linked with both psychiatric and neurodegenerative disorders. Here, we used an imaging genetics strategy to test an association between an IL‐1β polygenic score and hippocampal volume in two independent samples. Our polygenic score was derived using summary statistics from a recent genome‐wide association study of circulating cytokines that included IL‐1β (N = 3,309). In the first sample of 512 non‐Hispanic Caucasian university students (274 women, mean age 19.78 ± 1.24 years) from the Duke Neurogenetics Study, we identified a significant positive correlation between IL‐1β polygenic scores and hippocampal volume. This positive association was successfully replicated in a second sample of 7,960 white British volunteers (4,158 women, mean age 62.63 ± 7.45 years) from the UK Biobank. Our results lend further support in humans, to the link between IL‐1β and the structure of the hippocampus.
Design, manufacture, and fatigue analysis of lightweight hip implants

Background: This study aims to design, analyze and manufacture lightweight hip implants which have sufficient fatigue performance to enable use in total hip arthroplasty (THA). Methods: The lattice structure was applied on an implant geometry, which is frequently used in THA, to provide a reduction in mass and increase flexibility. The implant surfaces were roughened using semispherical pores to improve the osseointegration. The specimens were manufactured by means of direct metal laser sintering (DMLS) and fatigue tests were performed according to ISO 7206-4:2010. Moreover, fatigue analyses of the designed implants were numerically carried out using the finite element method. Results: The applied lattice structure on implant geometry leads to 15–17% reduction in the masses of implants compared to a solid one. It has also been determined that the lightweight implants show more flexible behavior with increasing pore diameter used on the implant surfaces while keeping the lattice structure geometry constant. The fatigue test and finite element analysis (FEA) results are in reasonable agreement. In addition, additively manufactured solid implants have exhibited similar fatigue performance with one produced by conventional methods. Conclusions: This paper presents design, analysis, manufacturing and fatigue test processes of lightweight hip implants. The lattice structure and the semispherical pores were applied on a reference implant geometry and they were manufactured by DMLS. The fatigue tests and FEA were performed to evaluate newly designed implant performance. All the implants successfully completed the fatigue tests without any damage.
WIP-1 and DBN-1 promote scission of endocytic vesicles by bridging actin and Dynamin-1 in the C. elegans intestine

ABSTRACT There has been a consensus that actin plays an important role in scission of the clathrin-coated pits (CCPs) together with large GTPases of the dynamin family in metazoan cells. However, the recruitment, regulation and functional interdependence of actin and dynamin during this process remain inadequately understood. Here, based on small-scale screening and in vivo live-imaging techniques, we identified a novel set of molecules underlying CCP scission in the multicellular organism Caenorhabditis elegans. We found that loss of Wiskott−Aldrich syndrome protein (WASP)-interacting protein (WIP-1) impaired CCP scission in a manner that is independent of the C. elegans homolog of WASP/N-WASP (WSP-1) and is mediated by direct binding to G-actin. Moreover, the cortactin-binding domain of WIP-1 serves as the binding interface for DBN-1 (also known in other organisms as Abp1), another actin-binding protein. We demonstrate that the interaction between DBN-1 and F-actin is essential for Dynamin-1 (DYN-1) recruitment at endocytic sites. In addition, the recycling regulator RME-1, a homolog of mammalian Eps15 homology (EH) domain-containing proteins, is increasingly recruited at the arrested endocytic intermediates induced by F-actin loss or DYN-1 inactivation, which further stabilizes the tubular endocytic intermediates. Our study provides new insights into the molecular network underlying F-actin participation in the scission of CCPs. This article has an associated First Person interview with the first author of the paper. Summary: WIP-1 and DBN-1, two actin-binding proteins, link the actin assembly to endocytic sites and cooperate with DYN-1 for clathrin-coated vesicle scission in the C. elegans intestine.
In Vivo Gene Essentiality and Metabolism in Bordetella pertussis

Our study describes the first in vivo transposon sequencing (Tn-seq) analysis of B. pertussis and identifies genes predicted to be essential for in vivo growth in a murine model of intranasal infection, generating key resources for future investigations into B. pertussis pathogenesis and vaccine design. ABSTRACT Bordetella pertussis is the causative agent of whooping cough, a serious respiratory illness affecting children and adults, associated with prolonged cough and potential mortality. Whooping cough has reemerged in recent years, emphasizing a need for increased knowledge of basic mechanisms of B. pertussis growth and pathogenicity. While previous studies have provided insight into in vitro gene essentiality of this organism, very little is known about in vivo gene essentiality, a critical gap in knowledge, since B. pertussis has no previously identified environmental reservoir and is isolated from human respiratory tract samples. We hypothesize that the metabolic capabilities of B. pertussis are especially tailored to the respiratory tract and that many of the genes involved in B. pertussis metabolism would be required to establish infection in vivo. In this study, we generated a diverse library of transposon mutants and then used it to probe gene essentiality in vivo in a murine model of infection. Using the CON-ARTIST pipeline, 117 genes were identified as conditionally essential at 1 day postinfection, and 169 genes were identified as conditionally essential at 3 days postinfection. Most of the identified genes were associated with metabolism, and we utilized two existing genome-scale metabolic network reconstructions to probe the effects of individual essential genes on biomass synthesis. This analysis suggested a critical role for glucose metabolism and lipooligosaccharide biosynthesis in vivo. This is the first genome-wide evaluation of in vivo gene essentiality in B. pertussis and provides tools for future exploration. IMPORTANCE Our study describes the first in vivo transposon sequencing (Tn-seq) analysis of B. pertussis and identifies genes predicted to be essential for in vivo growth in a murine model of intranasal infection, generating key resources for future investigations into B. pertussis pathogenesis and vaccine design.
An essential role of the mouse synapse-associated protein Syap1 in circuits for spontaneous motor activity and rotarod balance

ABSTRACT Synapse-associated protein 1 (Syap1) is the mammalian homologue of synapse-associated protein of 47 kDa (Sap47) in Drosophila. Genetic deletion of Sap47 leads to deficiencies in short-term plasticity and associative memory processing in flies. In mice, Syap1 is prominently expressed in the nervous system, but its function is still unclear. We have generated Syap1 knockout mice and tested motor behaviour and memory. These mice are viable and fertile but display distinct deficiencies in motor behaviour. Locomotor activity specifically appears to be reduced in early phases when voluntary movement is initiated. On the rotarod, a more demanding motor test involving control by sensory feedback, Syap1-deficient mice dramatically fail to adapt to accelerated speed or to a change in rotation direction. Syap1 is highly expressed in cerebellar Purkinje cells and cerebellar nuclei. Thus, this distinct motor phenotype could be due to a so-far unknown function of Syap1 in cerebellar sensorimotor control. The observed motor defects are highly specific since other tests in the modified SHIRPA exam, as well as cognitive tasks like novel object recognition, Pavlovian fear conditioning, anxiety-like behaviour in open field dark-light transition and elevated plus maze do not appear to be affected in Syap1 knockout mice. Summary: Knockout of the Syap1 gene in mice causes a distinct motor behaviour phenotype characterised by reduced initial locomotor activity and impaired rotarod performance.
Physiological and transcriptomic analyses reveal the molecular networks of responses induced by exogenous trehalose in plant

It is well known that exogenous trehalose can improve resistances of plants to some abiotic and biotic stresses. Nonetheless, information respecting the molecular responses of tobacco leaves to Tre treatment is limited. Here we show that exogenous Tre can rapidly reduce stomatal aperture, up-regulate NADPH oxidase genes and increase O2•-andH2O2 on tobacco leaves at 2 h after treatment. We further demonstrated that imidazole and DPI, inhibitors of NADPH oxidase, can promote recovery of stomatal aperture of tobacco leaves upon trehalose treatment. Exogenous trehalose increased tobacco leaf resistance to tobacco mosaic disease significantly in a concentration-dependent way. To elucidate the molecular mechanisms in response to exogenous trehalose, the transcriptomic responses of tobacco leaves with 10 (low concentration) or 50 (high concentration) mM of trehalose treatment at 2 or 24h were investigated through RNA-seq approach. In total, 1288 differentially expressed genes (DEGs) were found with different conditions of trehalose treatments relative to control. Among them, 1075 (83.5%) were triggered by low concentration of trehalose (10mM), indicating that low concentration of Tre is a better elicitor. Functional annotations with KEGG pathway analysis revealed that the DEGs are involved in metabolic pathway, biosynthesis of secondary metabolites, plant hormone signal transduction, plant-pathogen interaction, protein processing in ER, flavonoid synthesis and circadian rhythm and so on. The protein-protein interaction networks generated from the core DEGs regulated by all conditions strikingly revealed that eight proteins, including ClpB1, HSP70, DnaJB1-like protein, universal stress protein (USP) A-like protein, two FTSH6 proteins, GolS1-like protein and chloroplastics HSP, play a core role in responses to exogenous trehalose in tobacco leaves. Our data suggest that trehalose triggers a signal transduction pathway which involves calcium and ROS-mediated signalings. These core components could lead to partial resistance or tolerance to abiotic and biotic stresses. Moreover, 19 DEGs were chosen for analysis of quantitative real-time polymerase chain reaction (qRT-PCR). The qRT-PCR for the 19 candidate genes coincided with the DEGs identified via the RNA-seq analysis, sustaining the reliability of our RNA-seq data.
Whole Genome Sequencing of Giant Schnauzer Dogs with Progressive Retinal Atrophy Establishes NECAP1 as a Novel Candidate Gene for Retinal Degeneration

Canine progressive retinal atrophies (PRA) are genetically heterogeneous diseases characterized by retinal degeneration and subsequent blindness. PRAs are untreatable and affect multiple dog breeds, significantly impacting welfare. Three out of seven Giant Schnauzer (GS) littermates presented with PRA around four years of age. We sought to identify the causal variant to improve our understanding of the aetiology of this form of PRA and to enable development of a DNA test. Whole genome sequencing of two PRA-affected full-siblings and both unaffected parents was performed. Variants were filtered based on those segregating appropriately for an autosomal recessive disorder and predicted to be deleterious. Successive filtering against 568 canine genomes identified a single nucleotide variant in the gene encoding NECAP endocytosis associated 1 (NECAP1): c.544G>A (p.Gly182Arg). Five thousand one hundred and thirty canids of 175 breeds, 10 cross-breeds and 3 wolves were genotyped for c.544G>A. Only the three PRA-affected GS were homozygous (allele frequency in GS, excluding proband family = 0.015). In addition, we identified heterozygotes belonging to Spitz and Dachshund varieties, demonstrating c.544G>A segregates in other breeds of German origin. This study, in parallel with the known retinal expression and role of NECAP1 in clathrin mediated endocytosis (CME) in synapses, presents NECAP1 as a novel candidate gene for retinal degeneration in dogs and other species.
HIV-1 integrase tetramers are the antiviral target of pyridine-based allosteric integrase inhibitors

Allosteric HIV-1 integrase (IN) inhibitors (ALLINIs) are a promising new class of antiretroviral agents that disrupt proper viral maturation by inducing hyper-multimerization of IN. Here we show that lead pyridine-based ALLINI KF116 exhibits striking selectivity for IN tetramers versus lower order protein oligomers. IN structural features that are essential for its functional tetramerization and HIV-1 replication are also critically important for KF116 mediated higher-order IN multimerization. Live cell imaging of single viral particles revealed that KF116 treatment during virion production compromises the tight association of IN with capsid cores during subsequent infection of target cells. We have synthesized the highly active (-)-KF116 enantiomer, which displayed EC50 of ~7 nM against wild type HIV-1 and ~10 fold higher, sub-nM activity against a clinically relevant dolutegravir resistant mutant virus suggesting potential clinical benefits for complementing dolutegravir therapy with pyridine-based ALLINIs.