Miracle-dz/UniFAR-FTUs huggingface dataset:
Are newly launched pharmacotherapies efficacious in treating idiopathic pulmonary fibrosis? Or is there still more work to be done?

ABSTRACT Introduction: Idiopathic pulmonary fibrosis (IPF) is a challenging and multifactorial disease that has been thought for some time to lack effective treatments. The approval of two drugs, nintedanib and pirfenidone, has heralded a new era in its management. Areas covered: Currently, there is a growing interest on therapeutic strategies. Many studies have been designed and performed, although few of them turned out to be successful. Nowadays, nintedanib and pirfenidone are considered disease modifying drugs, recommended treatments by current evidence-based guidelines. A combined approach with more than one drug could be an effective strategy in IPF. However, data on combination therapy of the two approved drugs are still scarce, and ongoing trials are evaluating pharmacodynamic interactions and safety. The approved disease modifying drugs are also being assessed in combination with new molecules, showing promising results in preclinical models. Expert opinion: A deeper understanding of pathogenesis and key molecular mechanisms driving disease inception and progression will be key to identify novel agents to be tested both pre-clinically and clinically, possibly in combination with approved treatments. Looking at the near future, it is likely that clinical trials will adopt a phenotype-specific and pathway-specific approach, thus leading towards a personalized approach to IPF management.
Size‐ and shape‐dependent effects of microplastic particles on adult daggerblade grass shrimp (Palaemonetes pugio)

The incidence of microplastics in marine environments has been increasing over the past several decades. The objective of the present study was to characterize the size‐ and shape‐dependent effects of microplastic particles (spheres, fibers, and fragments) on the adult daggerblade grass shrimp (Palaemonetes pugio). Grass shrimp were exposed to 11 sizes of plastic: spheres (30, 35, 59, 75, 83, 116, and 165 μm), fragments (34 and 93 μm), and fibers (34 and 93 μm) at a concentration of 2000 particles/400 mL (= 50 000 particles/L) for 3 h. Following exposure, grass shrimp were monitored for survival, ingested and ventilated microplastics, and residence time. Mortality ranged from 0% to 55%. Spheres and fragments <50 μm were not acutely toxic. Mortality rates in experiments with spheres and fragments >50 μm ranged from 5% to 40%. Mortality was significantly higher in the exposure to 93‐μm fibers than other sizes tested (p < 0.001). The shape of the particle had a significant influence on the number of particles ingested by the shrimp (p < 0.001). The residence time of particles in the gut ranged from 27 to 75 h, with an average of 43.0 ± 13.8 h. Within the gills, the residence time ranged from 27 to 45 h, with an average of 36.9 ± 5.4 h. The results suggest that microplastic particles of various sizes and shapes can be ingested and ventilated by adult daggerblade grass shrimp, resulting in acute toxicity. Environ Toxicol Chem 2017;36:3074–3080. © 2017 SETAC
Safety and efficacy of long-term treatment with teneligliptin: Interim analysis of a post-marketing surveillance of more than 10,000 Japanese patients with type 2 diabetes mellitus

ABSTRACT Background: This post-marketing surveillance examined the safety and efficacy of long-term teneligliptin therapy in Japanese patients. Research design and methods: We report interim results (cut-off date: 28 June 2017) of a 3-year PMS undertaken in subjects with type 2 diabetes mellitus (T2DM). Survey items included demographics, treatments, adverse drug reactions (ADRs), and laboratory variables. A subgroup analysis was also performed across three age groups (<65 years; 65 to <75 years; ≥75 years). Main outcome measures were incidence of ADRs, laboratory variables, and change in glycated hemoglobin (HbA1c) from baseline over time. Results: Of 11,677 patients registered, data from 10,532 patients (6,338 males/4,194 females) were analyzed for the safety analysis set; the median administration period was 731 days. Overall, ADRs and serious ADRs were reported in 364 (3.46%) and 91 patients (0.86%), respectively. The most common ADRs were all hypoglycemia (0.32%), constipation (0.27%), and hepatic function abnormal (0.24%). No change in mean body weight occurred, and a reduction in mean HbA1c was observed until 2 years. The safety and efficacy profiles did not differ markedly among the three age groups. Conclusions: These interim results show that teneligliptin was well tolerated and improved hyperglycemia in Japanese patients with T2DM in clinical practice.
The effect of pH on the uptake and toxicity of the bivalent weak base chloroquine tested on Salix viminalis and Daphnia magna

The uptake and accumulation of most electrolytes will change with pH because of the different speciation states of these compounds at various pH. Non‐ionized compounds will partition into fatty and organic phases (such as cell membranes) more readily than the corresponding charged compounds, and therefore a higher toxicity can be expected. The current study examines the pH‐dependent toxicity and bioaccumulation of the bivalent weak base chloroquine (pKa: 10.47 and 6.33, log KOW 4.67) tested on Salix viminalis (basket willow) and Daphnia magna (water flea). The transpiration rates of hydroponically grown willow cuttings were used to determine the toxicity of chloroquine at pH levels of 6, 7, 8, and 9. Root concentration factors were calculated from solution measurements. Results showed more than 10‐fold higher toxicity and four to seven times higher root concentration factor at pH 9 than at pH 6. The toxicity of chloroquine was tested on Daphnia magna using the standard Organisation for Economic Co‐operation and Development acute toxicity test modified to accommodate testing at pH levels of 7, 8, and 9. Increasing toxicity was seen at higher pH. The results of the current study confirm that the toxicity of weak bases with intermediate pKa values is higher at high pH levels. Environ. Toxicol. Chem. 2011;30:354–359. © 2010 SETAC
Testicular oocytes in smallmouth bass in northeastern Minnesota in relation to varying levels of human activity

Testicular oocytes (TOs) have been found in black bass (Micropterus spp.) from many locations in North America. The presence of TOs is often assumed to imply exposure to estrogenic endocrine disrupting compounds (EDCs); however, a definitive causal relationship has yet to be established, and TO prevalence is not consistently low in fish from areas lacking evident EDC sources. This might indicate any of a number of situations: 1) unknown or unidentified EDCs or EDC sources, 2) induction of TOs by other stressors, or 3) testicular oocytes occurring spontaneously during normal development. In the present study, we analyzed TO occurrence in smallmouth bass (Micropterus dolomieu) from 8 populations in northeastern Minnesota watersheds with differing degrees of human development and, hence, presumed likelihood of exposure to anthropogenic chemicals. Three watersheds were categorized as moderately developed, based on the presence of municipal wastewater discharges and higher human population density (4–81 per km2), and 5 watersheds were minimally developed, with very low human population density (0–1 per km2) and minimal built environment. Testicular tissues from mature fish were evaluated using a semiquantitative method that estimated TO density, normalized by cross‐sectional area. Testicular oocyte prevalence and density among populations from moderately developed watersheds was higher than in populations from minimally developed watersheds. However, TO prevalence was unexpectedly high and variable (7–43%) in some populations from minimally developed watersheds, and only weak evidence was found for a relationship between TO density and watershed development, suggesting alternative or more complex explanations for TO presence in smallmouth bass from this region. Environ Toxicol Chem 2017;36:3424–3435. © 2017 SETAC
Nonbiological therapeutic management of ulcerative colitis

ABSTRACT Introduction: Treatment of ulcerative colitis (UC) is constantly evolving. In the last two decades, new therapeutic strategies have been implemented by addressing specific disease mechanisms: biological agents against tumor necrosis factor-α and integrins are now widely used, and more agents targeting different pathological pathways are being marketed. Despite these novel therapies, nonbiological drugs are still the mainstay of treatment, especially in mild-to-moderate disease, since a proven safety and tolerability profile is observed. Excellent efficacy both in induction and maintenance of remission is obtained, with a lower cost compared to biological agents. Areas covered: The purpose of this review is to summarize the current knowledge and the latest clinical evidence regarding nonbiological therapies for UC. Expert opinion: Concomitant administration of oral and rectal 5-aminosalicylates acid is more effective in the treatment of UC in remission. Corticosteroids are the treatment of choice in patients with moderately severe or severe UC. The association of azathioprine with biological treatments is more effective than monotherapy. Cyclosporine is an effective drug in severe UC, but its poor management must be considered. Probiotics are very popular; however, evidence on their actual role in UC still must be demonstrated; cytapheresis plays only a niche role at this time.
Mercury contamination in bats from the central United States

Mercury (Hg) is a highly toxic metal that has detrimental effects on wildlife. We surveyed Hg concentrations in 10 species of bats collected at wind farms in the central United States and found contamination in all species. Mercury concentration in fur was highly variable both within and between species (range: 1.08–10.52 µg/g). Despite the distance between sites (up to 1200 km), only 2 of the 5 species sampled at multiple locations had fur Hg concentrations that differed between sites. Mercury concentrations observed in the present study all fell within the previously reported ranges for bats collected from the northeastern United States and Canada, although many of the bats we sampled had lower maximum Hg concentrations. Juvenile bats had lower concentrations of Hg in fur compared with adult bats, and we found no significant effect of sex on Hg concentrations in fur. For a subset of 2 species, we also measured Hg concentration in muscle tissue; concentrations were much higher in fur than in muscle, and Hg concentrations in the 2 tissue types were weakly correlated. Abundant wind farms and ongoing postconstruction fatality surveys offer an underutilized opportunity to obtain tissue samples that can be used to assess Hg contamination in bats. Environ Toxicol Chem 2018;37:160–165. © 2018 SETAC
Acute exposure to an environmentally relevant concentration of diclofenac elicits oxidative stress in the culturally important galaxiid fish Galaxias maculatus

Diclofenac is a nonsteroidal anti‐inflammatory drug (NSAID) of growing concern in aquatic environments worldwide; nevertheless, knowledge of its effects on aquatic biota is restricted to a few model species with limited information regarding its mechanisms of impact. In the present study, diclofenac accumulation, its effects on metabolic rate, ionoregulation, and oxidative stress were examined at environmentally relevant (0.17 µg L−1) and elevated (763 µg L−1) concentrations in a culturally and economically important galaxiid fish, inanga (Galaxias maculatus), from the Southern Hemisphere. This species is among the most widespread freshwater fish in the world but its sensitivity to emerging contaminants is unknown. Following an acute 96‐h exposure, bioconcentration of diclofenac was measured in the inanga whole‐body, resulting in an estimated bioconcentration factor of 87 for the 0.17‐µg L−1 exposure concentration, approaching values where transfer through the food chain should be considered. Lipid peroxidation in the liver was significantly elevated at both 0.17‐ and 763‐µg L−1 exposure concentrations but lipid peroxidation in the kidney and gill decreased after diclofenac exposure. Catalase activity was also elevated in the liver of inanga but activity decreased in the gill. There were no effects of diclofenac on metabolic rate or ion (sodium and calcium) influx rates. These data indicate that toxicologically relevant adverse outcomes and bioconcentration of diclofenac at environmentally relevant levels warrant additional study in this important fish. Environ Toxicol Chem 2018;37:224–235. © 2017 SETAC
Evaluation of pediatric cochlear implant care throughout Europe: Is European pediatric cochlear implant care performed according to guidelines?

Objectives: International guidelines indicate that children with profound hearing loss should receive a cochlear implant (CI) soon after diagnosis in order to optimize speech and language rehabilitation. Although prompt rehabilitation is encouraged by current guidelines, delays in cochlear implantation are still present. This study investigated whether European countries establish timely pediatric CI care based on epidemiological, commercial, and clinical data. Methods: An estimation of the number of pediatric CI candidates in European countries was performed and compared to epidemiological (Euro-CIU), commercial (Cochlear®), and clinical (institutional) age-at-implantation data. The ages at implantation of pediatric patients in eight countries (the Netherlands, Belgium, Germany, the United Kingdom, France, Turkey, Portugal, and Italy) between 2005 and 2015 were evaluated. Results: From 2010 onwards, over 30% of the pediatric CI candidates were implanted before 24 months of age. Northern European institutions implanted children on average around 12 months of age, whereas southern European institutions implanted children after 18 months of age. The Netherlands and Germany implanted earliest (between 6 and 11 months). Discussion: Implemented newborn hearing screening programs and reimbursement rates of CIs vary greatly within Europe due to local, social, financial, and political differences. However, internationally accepted recommendations are applicable to this heterogeneous European CI practice. Although consensus on early pediatric cochlear implantation exists, this study identified marked delays in European care. Conclusion: Regardless of the great heterogeneity in European practice, reasons for latency should be identified on a national level and possibilities to prevent avoidable future implantation delays should be explored to provide national recommendations.
Measuring the toxicity of alkyl‐phenanthrenes to early life stages of medaka (Oryzias latipes) using partition‐controlled delivery

Alkyl‐phenanthrenes are a class of compounds present in crude oil and toxic to developing fish. Most research on alkyl‐phenanthrenes has focused on retene (7‐isopropyl‐1‐methyl‐phenanthrene), but little is known about the chronic toxicity of related congeners to the early life stages of fish. This project is the first to describe the chronic toxicity of a series of alkyl‐phenanthrenes to the embryos of Japanese medaka (Oryzias latipes) using the partition‐controlled delivery (PCD) method of exposure and is the first to establish a relationship between toxicity of alkyl‐phenanthrenes and log P. With PCD, test concentrations were maintained by equilibrium partitioning of test chemicals from polydimethylsiloxane (PDMS) films containing various concentrations of C1 to C4 phenanthrenes. Log film:solution partition constants (log Kfs) and aqueous solubility limits were determined for each alkyl‐phenanthrene. The prevalence of abnormalities in fish embryos increased in an exposure‐dependent manner, with median effective concentration (EC50) values lower than experimental solubility limits of the compounds, and typical of environmental concentrations. Alkyl‐phenanthrenes were more toxic to medaka embryos than unsubstituted phenanthrene, with effects resembling those of dioxin and indicating a specific receptor‐based mechanism of toxicity. These results extend conclusions for the Exxon Valdez oil spill, suggest a specific mechanism of toxicity for alkyl‐phenanthrenes, and provide a model for assessing the risks of mixture toxicity. Environ. Toxicol. Chem. 2011;30:487–495. © 2010 SETAC
Developing a competency framework to support training in evidence‐based healthcare

This paper focuses on the practice of evidence‐based healthcare by doctors, nurses, midwives and the professions allied to medicine in four NHS Trusts in and around London. This qualitative study, based on interviews and self‐efficiency ratings uncovered the extent of evidence based practice between different groups and between acute and community Trusts, the perceived obstacles to the adoption and implementation of EBHC, and throws light on the knowledge, skills and attitudes required for such practice. Five clusters of competencies were identified – personal attributes, interpersonal, self‐management, information management and technical knowledge skills – and these form the basis of a competency framework of measurable criteria to assess proficiency as well as staff training needs which it is hoped will enable NHS Trusts to devise strategies to meet the requirements and challenges of clinical governance from April 1999.
Efficacy and safety of otelixizumab use in new-onset type 1 diabetes mellitus

ABSTRACT Introduction: Type 1 diabetes (T1DM) is an immune-mediated disease induced by antigen-specific T cells infiltrating pancreatic beta cells leading to the progressive loss of endogenous insulin secretion. Areas covered: The identification of specific components of the autoimmune response favoured the implementation of several immunomodulatory therapies including antiCD3 monoclonal antibody (mAb) called otelixizumab. Otelixizumab is a chimeric monoclonal antibody that targets the ε-chain of the CD3T-lymphocyte surface receptor that has been developed with the aim of short therapeutic courses capable of inducing a remission of T1DM. Clinical trials have been carried out with otelixizumab to evaluate its safety and efficacy, but despite positive results of Phase I and II studies, the results of Phase III studies have been contradictory. Expert opinion: High doses of otelixizumab have shown beneficial effects on beta cell function whereas a lower dose, which was tested to avoid the adverse effects associated with higher doses, was not effective on beta cells preservation. We believe that otelixizumab is a drug of potential interest for treating new onset T1DM patients and its use in combination with other immunomodulatory agents should be considered as a solution to circumvent adverse effects while maintaining efficacy.
Technical, economic and consumer barriers to the consumption of reduced fat bakery products

Qualitative research with both consumers and industry representatives, in this MAFF‐funded project, allowed assessment of current barriers to the production and consumption of reduced fat bakery products. In addressing the way forward, there were four key areas where barriers existed: consumer attitudes, product quality (technical), economic and legislative issues. These must be tackled if reduced fat bakery products are to succeed in the marketplace.
Bioaccumulation and toxicity of uranium, arsenic, and nickel to juvenile and adult Hyalella azteca in spiked sediment bioassays

Uranium (U) mining and milling release arsenic (As), nickel (Ni) and U to receiving waters, which accumulate in sediments. The objective of the present study was to investigate if As, Ni, and U concentrations in tissue residue of Hyalella azteca, overlying water, sediment porewater, and solids could predict juvenile and adult survival and growth in conditions similar to lake sediments downstream of U mines and mills. We conducted 14‐d static sediment toxicity tests spiked with U, As, and Ni salts. For U, we spiked uranyl nitrate with sodium bicarbonate to limit U precipitation once in contact with circumneutral sediment. The median lethal concentrations for As, Ni, and U of juveniles and adults based on measured concentrations in sediments were 134 and 165 μg/g, 370 and 787 μg/g, and 48 and 214 μg/g, respectively. Adult survival and growth linearly decreased with increasing bioaccumulation. For juveniles, metal accumulation linearly predicted survival. We calculated median lethal body concentrations for juveniles and adults of 5 and 36 μg As/g, 14 and 49 μg Ni/g, and 0.4 and 1.0 μg U/g. The concentrations of As, Ni, and U in tissue residue leading to a 20% decrease in adult growth were 32 μg As/g, 44 μg Ni/g, and 1 μg U/g. Overall, the present study showed that U was the most toxic element, followed by As and Ni; that juveniles were more sensitive to the 3 metals tested than adults; and that threshold body concentrations can support assessment of benthic invertebrate community impairment. Environ Toxicol Chem 2018;37:2340–2349. © 2018 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals, Inc. on behalf of SETAC.
Single vs. combination immunotherapeutic strategies for glioma

ABSTRACT Introduction: Malignant gliomas are highly invasive tumors, associated with a dismal survival rate despite standard of care, which includes surgical resection, radiotherapy and chemotherapy with temozolomide (TMZ). Precision immunotherapies or combinations of immunotherapies that target unique tumor-specific features may substantially improve upon existing treatments. Areas covered: Clinical trials of single immunotherapies have shown therapeutic potential in high-grade glioma patients, and emerging preclinical studies indicate that combinations of immunotherapies may be more effective than monotherapies. In this review, the authors discuss emerging combinations of immunotherapies and compare efficacy of single vs. combined therapies tested in preclinical brain tumor models. Expert opinion: Malignant gliomas are characterized by a number of factors which may limit the success of single immunotherapies including inter-tumor and intra-tumor heterogeneity, intrinsic resistance to traditional therapies, immunosuppression, and immune selection for tumor cells with low antigenicity. Combination of therapies which target multiple aspects of tumor physiology are likely to be more effective than single therapies. While a limited number of combination immunotherapies are described which are currently being tested in preclinical and clinical studies, the field is expanding at an astounding rate, and endless combinations remain open for exploration.
Promising immunotherapies for esophageal cancer

ABSTRACT Introduction: Esophageal cancer (EC) is the eighth most common cancer in the world, and the prognosis of EC is still poor. Although immunotherapy has been developed in melanoma and lung cancer, it is also expected to show efficacy in EC. Currently, several clinical trials are ongoing to evaluate the safety and efficacy of immunotherapies, immune checkpoint inhibitors, adoptive T cell transfer, and therapeutic cancer vaccines in EC. Areas covered: This review provides an overview and the status of immunotherapy in EC. Clinical significance of molecules related immune checkpoints, especially PD-1 and PD-L1 is presented and the designs, results and future directions of clinical trials using immunotherapy in EC are provided. Expert opinion: To bring immunotherapy to the forefront of treatment for EC, it is necessary to select patients who can obtain a high efficacy of immunotherapy and to also elucidate the correct timing for administration. Moreover, combination therapies of immunotherapy with existing chemotherapy or radiation or other immunotherapy with different mechanisms of action must be evaluated to achieve excellent outcomes in patients with EC.