Miracle-dz/UniFAR-FTUs huggingface dataset:
Genetic association between adiposity and gout: a Mendelian randomization study

Objective To investigate whether overall obesity (as measured by BMI) and abdominal obesity (as measured by waist-to-hip ratio adjusted for BMI) are associated with gout risk and serum urate concentrations using Mendelian randomization. Methods Single nucleotide polymorphisms associated with BMI (n = 97) and waist-to-hip ratio adjusted for BMI (n = 49) were analysed for association with gout risk in 2115 gout cases and 67 259 controls, and with serum urate concentrations in 110 347 individuals from the Global Urate Genetics Consortium. Results Genetically higher BMI, but not waist-to-hip ratio adjusted for BMI, was positively associated with risk of gout and serum urate concentrations. Each standard deviation (about 4.6 kg/m2) increase in genetically predicted BMI was associated with an odds ratio of gout of 2.24 (95% CI 1.70, 2.95; P = 8.4 × 10-9) and with a 0.30 mg/dl (95% CI 0.25, 0.35; P = 1.6 × 10-36) increase in serum urate concentrations. Conclusion These findings provide support that overall obesity may be a risk factor for gout and is associated with higher serum urate concentrations.
Active screening of gastrointestinal helminth infection in migrant workers in Thailand

Objective This study aimed to detect gastrointestinal helminth infection in migrant workers in Thailand. Methods A cross-sectional survey study was conducted in 403 migrant workers in the factories of Nakhon Ratchasima Province, northeastern Thailand during October 2016 to June 2017. Gastrointestinal helminth infections were detected by the formalin ether acetate concentration technique and microscopy. The data were analyzed using the χ2-test and logistic regression. Results The rate of gastrointestinal helminth infection was 24.07%. The most common species involved in infection was Opisthorchis viverrini (11.91%), followed by hookworm (5.46%), Trichuris trichiura (5.21%), Strongyloides stercoralis (0.5%), Ascaris lumbricoides (0.5%), and Taenia spp. (0.5%). The majority of infections were found in men aged ≥40 years, married participants, uneducated participants, laborers, those who worked for 1 year, and those who had an income of 9000 to 12,000 THB. Conclusions Gastrointestinal helminth infection is still found in migrant workers. Therefore, active surveillance is required in this large group for investigating and eradicating this type of infection.
Development of a Tetravalent Anti-GPA33/Anti-CD3 Bispecific Antibody for Colorectal Cancers

Despite progress in the treatment of colorectal cancer, curing metastatic colorectal cancer remains a major unmet medical need worldwide. Here, we describe a T-cell–engaging bispecific antibody (T-BsAb) to redirect polyclonal cytotoxic T cells to eradicate colorectal cancer. A33, a murine antibody specific for GPA33, was humanized to huA33 and reformatted to huA33-BsAb, based on a novel IgG(L)–scFv platform by linking the anti-CD3 huOKT3 scFv to the carboxyl end of the light chain. This T-BsAb was stably expressed in CHO cells and purified as a stable monomer by HPLC, retaining immunoreactivity by FACS through 30 days of incubation at 37°C. In vitro, it induced activation and expansion of unstimulated T cells and elicited potent T-cell–dependent cell-mediated cytotoxicity against colon and gastric cancer cells in an antigen-specific manner. In vivo, huA33-BsAb inhibited the colon and gastric cancer xenografts, in both subcutaneous and intraperitoneal tumor models. More importantly, both microsatellite instable and microsatellite stable colorectal cancer were effectively eliminated by huA33-BsAb. These preclinical results provide further support for the use of IgG(L)–scFv platform to build BsAb, and especially one targeting GPA33 for colorectal cancer. These preclinical results also support further development of huA33-BsAb as a potential immunotherapeutic. Mol Cancer Ther; 17(10); 2164–75. ©2018 AACR.
Safety and effectiveness, including intelligence prognosis, of diazoxide in pediatric patients with hyperinsulinemic hypoglycemia: special survey in Japan (long-term, all-case survey)

Abstract. To evaluate the safety and effectiveness of the long-term administration of diazoxide in patients with hyperinsulinemic hypoglycemia, a post-marketing surveillance study was conducted. Between 2008 and 2015, with a maximum observation period of 7 yr, 384 patients were monitored; 117 (30.5%) experienced at least one adverse drug reaction (ADR). The most commonly observed ADR was hypertrichosis (8.6%). The incidence of water retention-related ADRs and cardiac failure-related ADRs was 8.3% and 3.4%, respectively, and many of these occurred within the first 2 mo of treatment. The mean fasting blood glucose level was 44.9 mg/dL at baseline and was maintained at > 70 mg/dL, the control target, for 4 yr. A total of 113 infants < 1 yr of age were evaluated for the prognosis for intelligence, and a majority (77.9%) were assessed as “normal” at the final evaluation. Most ADRs occurred at an early stage of treatment and blood glucose levels were well controlled during long-term administration. The proportion of “normal” patients tended to be higher in those who started treatment at a younger age. However, because of the exploratory nature of this analysis, potential effects of coexisting or underlying diseases and the age of onset or diagnosis should not be ignored.
Illness pathways between eating disorder and post‐traumatic stress disorder symptoms: Understanding comorbidity with network analysis

Eating disorders (EDs) and post-traumatic stress disorder (PTSD) are highly comorbid. However, specific mechanisms by which PTSD-ED comorbidity is maintained are unknown. The current study constructed two PTSD-ED comorbidity networks (25 EDs and 17 PTSD symptoms) in two samples: a clinical (N = 158 individuals with an ED diagnosis) and a nonclinical sample (N = 300 college students). Glasso networks were constructed to identify (1) pathways between disorders (bridge symptoms) and (2) core symptoms. Three illness pathways emerged: between binge eating and irritability, between desire for a flat stomach and disturbing dreams, and between concentration problems and weight and shape-related concentration problems. Our findings suggest that pathways between binge eating and irritability, body dissatisfaction and trauma reminders, and concentration difficulties may be the mechanisms by which comorbidity is maintained. Interventions disrupting these pathways and targeting core and bridge symptoms may be more efficient than traditional treatment approaches.
A Three Component Synthetic Vaccine Containing a β-Mannan T-Cell Peptide Epitope and a β-Glucan Dendritic Cell Ligand

Glycoconjugates prepared from the capsular polysaccharide of several pathogenic bacteria and carrier proteins, such as CRM 197 or tetanus toxoid, have been one of the most successful public health measures to be implemented in the last quarter century. A crucial element in the success of conjugate vaccines has been the recruitment of T-cell help and systematic induction of a secondary immune response. The seminal discovery, that degraded polysaccharide fragments with attached peptide are presented to the T-cell receptor of carbohydrate specific T-cells by MHC-II molecules that bind to the peptide component of degraded vaccine, suggests potentially novel designs for conjugate vaccines. A fully synthetic conjugate vaccine was constructed from a 1,2-linked β-mannose trisaccharide conjugated to a T-cell peptide, previously shown to afford protection against Candida albicans. This combined B- and T-cell epitope was synthesized with a C-terminal azidolysine residue for subsequent conjugation by click chemistry. Four copies of a β-1,3 linked hexaglucan dendritic cell epitope were conjugated to an asymmetric dendrimer bearing an alkyne terminated tether. Click chemistry of these two components created a conjugate vaccine that induced antibodies to all three epitopes of the fully synthetic construct.
Replicate Once Per Cell Cycle: Replication Control of Secondary Chromosomes

Faithful vertical transmission of genetic information, especially of essential core genes, is a prerequisite for bacterial survival. Hence, replication of all the replicons is tightly controlled to ensure that all daughter cells get the same genome copy as their mother cell. Essential core genes are very often carried by the main chromosome. However they can occasionally be found on secondary chromosomes, recently renamed chromids. Chromids have evolved from non-essential megaplasmids, and further acquired essential core genes and a genomic signature closed to that of the main chromosome. All chromids carry a plasmidic replication origin, belonging so far to either the iterons or repABC type. Based on these differences, two categories of chromids have been distinguished. In this review, we focus on the replication initiation controls of these two types of chromids. We show that the sophisticated mechanisms controlling their replication evolved from their plasmid counterparts to allow a timely controlled replication, occurring once per cell cycle.
Successful Healthcare Improvements From Translating Evidence in complex systems (SHIFT-Evidence): simple rules to guide practice and research

Abstract Background Evidence translation and improvement research indicate that healthcare contexts are complex systems, characterized by uncertainty and surprise, which often defy orchestrated intervention attempts. This article reflects on the implications of complexity on attempts to translate evidence, and on a newly published framework for Successful Healthcare Improvements From Translating Evidence in complex systems (SHIFT-Evidence). Discussion SHIFT-Evidence positions the challenge of evidence translation within the complex and evolving context of healthcare, and recognizes the wider issues practitioners routinely face. It is empirically grounded, and designed to be comprehensive, practically relevant and actionable. SHIFT-evidence is summarized by three principles designed to be intuitive and memorable: ‘act scientifically and pragmatically’; ‘embrace complexity’; and ‘engage and empower’. Common challenges and strategies to overcome them are summarized in 12 ‘simple rules’ that provide actionable guidance. Conclusion SHIFT-Evidence provides a practical tool to guide practice and research of evidence translation and improvement within complex dynamic healthcare settings. Implications are that improvement initiatives and research study designs need to take into account the unique initial conditions in each local setting; conduct needs to respond to unpredictable effects and address dependent problems; and evaluation needs to be sensitive to evolving priorities and the emergent range of activities required to achieve improvement.
Efficacy and tolerability of trabectedin in elderly patients with sarcoma: subgroup analysis from a phase III, randomized controlled study of trabectedin or dacarbazine in patients with advanced liposarcoma or leiomyosarcoma

Background Treatment options for soft tissue sarcoma (STS) patients aged ≥65 years (elderly) can be limited by concerns regarding the increased risk of toxicity associated with standard systemic therapies. Trabectedin has demonstrated improved disease control in a phase III trial (ET743-SAR-3007) of patients with advanced liposarcoma or leiomyosarcoma after failure of anthracycline-based chemotherapy. Since previous retrospective analyses have suggested that trabectedin has similar safety and efficacy outcomes regardless of patient age, we carried out a subgroup analysis of the safety and efficacy observed in elderly patients enrolled in this trial. Patients and methods Patients were randomized 2 : 1 to trabectedin (n = 384) or dacarbazine (n = 193) administered intravenously every-3-weeks. The primary end point was overall survival (OS); secondary end points were progression-free survival (PFS), time-to-progression, objective response rate (ORR), duration of response, symptom severity, and safety. A post hoc analysis was conducted in the elderly patient subgroup. Results Among 131 (trabectedin = 94; dacarbazine = 37) elderly patients, disease characteristics were well-balanced and consistent with those of the total study population. Treatment exposure was longer in patients treated with trabectedin versus dacarbazine (median four versus two cycles, respectively), with a significantly higher proportion receiving prolonged therapy (≥6 cycles) in the trabectedin arm (43% versus 23%, respectively; P = 0.04). Elderly patients treated with trabectedin showed significantly improved PFS [4.9 versus 1.5 months, respectively; hazard ratio (HR)=0.40; P = 0.0002] but no statistically significant improvement in OS (15.1 versus 8.0 months, respectively; HR = 0.72; P = 0.18) or ORR (9% versus 3%, respectively; P = 0.43). The safety profile for elderly trabectedin-treated patients was comparable to that of the overall trabectedin-treated study population. Conclusions This subgroup analysis of the elderly population of ET743-SAR-3007 suggests that elderly patients with STS and good performance status can expect clinical benefit from trabectedin similar to that observed in younger patients. Trial registration www.clinicaltrials. gov, NCT01343277.
Next2Me: Capturing Social Interactions through Smartphone Devices using WiFi and Audio signals

Typical approaches in detecting social interactions consider the use of co-location as a proxy for real-world interactions. Such approaches can under-perform in challenging situations where multiple social interactions can occur in close proximity to each other. In this paper, we present a novel approach to detect co-located social interactions using smartphones. Next2Me relies on the use of WiFi signals and audio signals to accurately distinguish social groups interacting within a few meters from each other. Through a range of real-world experiments, we demonstrate a technique that utilises WiFi fingerprinting, along with sound fingerprinting to identify social groups. Experimental results show that Next2Me can achieve a precision of 88% within noisy environments, including smartphones that are placed in users' pockets, whilst maintaining a very low energy footprint (<3% of battery capacity per day).
Fast millimeter wave beam alignment

There is much interest in integrating millimeter wave radios (mmWave) into wireless LANs and 5G cellular networks to benefit from their multi-GHz of available spectrum. Yet, unlike existing technologies, e.g., WiFi, mmWave radios require highly directional antennas. Since the antennas have pencil-beams, the transmitter and receiver need to align their beams before they can communicate. Existing systems scan the space to find the best alignment. Such a process has been shown to introduce up to seconds of delay, and is unsuitable for wireless networks where an access point has to quickly switch between users and accommodate mobile clients. This paper presents Agile-Link, a new protocol that can find the best mmWave beam alignment without scanning the space. Given all possible directions for setting the antenna beam, Agile-Link provably finds the optimal direction in logarithmic number of measurements. Further, Agile-Link works within the existing 802.11ad standard for mmWave LAN, and can support both clients and access points. We have implemented Agile-Link in a mmWave radio and evaluated it empirically. Our results show that it reduces beam alignment delay by orders of magnitude. In particular, for highly directional mmWave devices operating under 802.11ad, the delay drops from over a second to 2.5 ms.
Characterization of diabetic neuropathy progression in a mouse model of type 2 diabetes mellitus

ABSTRACT Diabetes mellitus (DM) is one of most common chronic diseases with an increasing incidence in most countries. Diabetic neuropathy (DN) is one of the earliest and main complications of diabetic patients, which is characterized by progressive, distal-to-proximal degeneration of peripheral nerves. The cellular and molecular mechanisms that trigger DN are highly complex, heterogeneous and not completely known. Animal models have constituted a valuable tool for understanding diabetes pathophysiology; however, the temporal course of DN progression in animal models of type 2 diabetes (T2DM) is not completely understood. In this work, we characterized the onset and progression of DN in BKS diabetic (db/db) mice, including the main functional and histological features observed in the human disease. We demonstrated that diabetic animals display progressive sensory loss and electrophysiological impairments in the early-to-mid phases of the disease. Furthermore, we detected an early decrease in intraepidermal nerve fiber (IENF) density in 18-week-old diabetic mice, which is highly associated with sensory loss and constitutes a reliable marker of DN. Other common histological parameters of DN – like Schwann cells apoptosis and infiltration of CD3+ cells in the sciatic nerve – were altered in mid-to-late phases of the disease. Our results support the general consensus that DN evolves from initial functional to late structural changes. This work aimed to characterize the progression of DN in a reliable animal model sharing the main human disease features, which is necessary to assess new therapies for this complex disease. Finally, we also aimed to identify an effective temporal window where these potential treatments could be successfully applied. Summary: We characterized the main functional and structural diabetic neuropathy features during early-to-late phases of type 2 diabetes mellitus. This study aimed to identify a therapeutic window for new treatments.
Relationship between the Viable but Nonculturable State and Antibiotic Persister Cells

Bacteria have evolved numerous means of survival in adverse environments with dormancy, as represented by “persistence” and the “viable but nonculturable” (VBNC) state, now recognized to be common modes for such survival. VBNC cells have been defined as cells which, induced by some stress, become nonculturable on media that would normally support their growth but which can be demonstrated by various methods to be alive and capable of returning to a metabolically active and culturable state. ABSTRACT Bacteria have evolved numerous means of survival in adverse environments with dormancy, as represented by “persistence” and the “viable but nonculturable” (VBNC) state, now recognized to be common modes for such survival. VBNC cells have been defined as cells which, induced by some stress, become nonculturable on media that would normally support their growth but which can be demonstrated by various methods to be alive and capable of returning to a metabolically active and culturable state. Persister cells have been described as a population of cells which, while not being antibiotic resistant, are antibiotic tolerant. This drug-tolerant phenotype is thought to be a result of stress-induced and stochastic physiological changes as opposed to mutational events leading to true resistance. In this review, we describe these two dormancy strategies, characterize the molecular underpinnings of each state, and highlight the similarities and differences between them. We believe these survival modes represent a continuum between actively growing and dead cells, with VBNC cells being in a deeper state of dormancy than persister cells.
Acetylation of Mitochondrial Proteins in the Heart: The Role of SIRT3

A growing number of studies have demonstrated the role of post-translational modifications of proteins, particularly acetylation, in human diseases including neurodegenerative and cardiovascular diseases, diabetes, cancer, and in aging. Acetylation of mitochondrial proteins has been shown to be involved in the pathogenesis of cardiac diseases such as myocardial infarction (ischemia-reperfusion) and heart failure. Indeed, over 60% of mitochondrial proteins contain acetylation sites, and most of these proteins are involved in mitochondrial bioenergetics. Mitochondrial non-enzymatic acetylation is enabled by acetyl-coenzyme A abundance and serves as the primary pathway of acetylation in mitochondria. Hence, regulation of enzymatic deacetylation becomes the most important mechanism to control acetylation/deacetylation of mitochondrial proteins. Acetylation/deacetylation of mitochondrial proteins has been regarded as a key regulator of mitochondrial metabolism and function. Proteins are deacetylated by NAD+-dependent deacetylases known as sirtuins (SIRTs). Among seven sirtuin isoforms, only SIRT3, SIRT4, and SIRT5 are localized in the mitochondria. SIRT3 is the main mitochondrial sirtuin which plays a key role in maintaining metabolic and redox balance in the mitochondria under physiological and pathological conditions. SIRT3 regulates the enzymatic activity of proteins involved in fatty acid oxidation, tricarboxylic acid cycle, electron transport chain, and oxidative phosphorylation. Although many enzymes have been identified as targets for SIRT3, cardiac-specific SIRT3 effects and regulations could differ from those in non-cardiac tissues. Therefore, it is important to elucidate the contribution of SIRT3 and mitochondrial protein acetylation/deacetylation in mitochondrial metabolism and cardiac dysfunction. Here, we summarize previous studies and provide a comprehensive analysis of the role of SIRT3 in mitochondria metabolism and bioenergetics under physiological conditions and in cardiac diseases. In addition, the review discusses mitochondrial protein acetylation as a potential target for cardioprotection.
Meta-Prediction of MTHFR Gene Polymorphism and Air Pollution on the Risks of Congenital Heart Defects Worldwide: A Transgenerational Analysis

Congenital heart disease (CHD) is the leading cause of death in children, and is affected by genetic and environmental factors. To investigate the association of air pollution with methylene-tetrahydrofolate reductase (MTHFR) polymorphisms and the risk of CHD, we included 58 study groups of children and parents, with 12,347 cases and 18,106 controls worldwide. Both MTHFR C677T (rs 1801133) and A1298C (rs 1801131) gene polymorphisms were risks for CHD in children with transgenerational effects from their parents. Countries with greater risks of CHD with a pooled risk ratio (RR) > 2 from MTHFR 677 polymorphisms included Germany, Portugal, China, and Egypt for children; and Brazil, Puerto Rico, Mexico, China, and Egypt for mothers. Whereas, countries with greater risk of CHD with RR > 2 from MTHFR 1298 polymorphisms included Taiwan, Turkey, and Egypt for children; and Brazil, China, and Egypt for mothers. Additionally, meta-prediction analysis revealed that the percentages of MTHFR 677TT and TT plus CT polymorphisms together were increased in countries with higher levels of air pollution, with a trend of increased CHD risks with higher levels of air pollution for children (p = 0.07). Our findings may have significant implications for inflammatory pathways in association with MTHFR polymorphisms and future intervention studies to correct for folate-related enzyme deficits resulted from MTHFR polymorphisms to prevent CHDs for future generations.