Miracle-dz/UniFAR-FTUs huggingface dataset:
Transparency and accuracy in funding investigator-initiated clinical trials: a systematic search in clinical trials databases

Objectives This study aims to identify the sources of funding for investigator-initiated clinical trials (IICTs) in Portugal, and to recommend ways to improve the quality of information collected from clinical trial databases about funding. Design and methods A systematic search of trial registrations over the last 13 years—using the WHO International Clinical Trials Registry Platform (WHO-ICTRP) and four clinical trials registries (CTRs)—was carried out to identify IICTs in Portugal, used as a case study. Data from the databases were compared with data contained in publications to evaluate the consistency of information on funding sources. The term ‘database’ is used in this study to refer to both the WHO-ICTRP and the CTRs. When mentioned separately, the WHO-ICTRP is referred to as a ‘platform’, while the CTRs are referred to as ‘registries’. Outcome Suggestions to improve clinical trials databases to clearly identify the funding sources and data ownership in IICTs. Results Two hundred and eighty-two IICTs were identified in Portugal. Twenty per cent of trials were supported by industry with unclear information on the ownership of the results. Inaccuracy was found in the information about sponsors and funders. The information about funding in all resulting publications (77 out of 133 completed studies) was also inconsistent between databases in 35 out of 77 (45%) of the studies. Notably, 23% of the trials funded by non-profit organisations (n=226) received funds from international and/or national funding agencies. Conclusions Identification of IICT funding and ownership of results is unclear in the databases used for this study, which may lead to misunderstandings about the independence of the obtained results. Transparency and accuracy are desirable so that public decision makers and strategic partners can accurately evaluate national performance in this particular type of clinical research.
Retrospective Analysis of Injuries and Hospitalizations of Patients Following the 2009 Earthquake of L’Aquila City

The aim of this study was to investigate the injury patterns and the hospitalizations of patients who were admitted to hospital following the 2009 earthquake in the city of L’Aquila, Central Italy. To the best of our knowledge, this is the first study to analyze the patterns of earthquake-related injuries in Italy. We reviewed the hospital discharge data of 171 patients admitted to hospital within the following 96 h from the mainshock. This is an observational and descriptive study: We controlled for variables such as patient demographics, primary and secondary ICD-9-CM (International Classification of Diseases) diagnosis codes in order to identify the multiple injured patients, main type of injury that resulted in the hospital admission, discharge disposition, and average length of stay (LOS). Seventy-three percent of the 171 patients were admitted to hospital on the first day. Multiple injuries accounted for 52% of all trauma admissions, with a female to male ratio of 63% versus 37%. The most common type of injuries involved bone fractures (46.8%), while lower extremities were the most frequently affected sites (38.75%). The average LOS was 12.11 days. This study allows the evaluation of the impact of earthquake-related injuries in relation both to the health needs of the victims and to the use of the health care resources and assistance.
The Cell Culture Medium Affects Growth, Phenotype Expression and the Response to Selenium Cytotoxicity in A549 and HepG2 Cells

Selenium compounds influence cell growth and are highly interesting candidate compounds for cancer chemotherapy. Over decades an extensive number of publications have reported highly efficient growth inhibitory effects with a number of suggested mechanisms f especially for redox-active selenium compounds. However, the studies are difficult to compare due to a high degree of variations in half-maximal inhibitor concentration (IC50) dependent on cultivation conditions and methods to assess cell viability. Among other factors, the variability in culture conditions may affect the experimental outcome. To address this, we have compared the maintenance effects of four commonly used cell culture media on two cell lines, A549 and HepG2, evaluated by the toxic response to selenite and seleno-methylselenocysteine, cell growth and redox homeostasis. We found that the composition of the cell culture media greatly affected cell growth and sensitivity to selenium cytotoxicity. We also provided evidence for change of phenotype in A549 cells when maintained under different culture conditions, demonstrated by changes in cytokeratin 18 (CK18) and vimentin expression. In conclusion, our results have shown the importance of defining the cell culture medium used when comparing results from different studies.
Long‐term population monitoring of the threatened and endemic black‐headed squirrel monkey (Saimiri vanzolinii) shows the importance of protected areas for primate conservation in Amazonia

Population monitoring of endangered species is essential to the improvement of their management and conservation plans. The black‐headed squirrel monkey (Saimiri vanzolinii) is a vulnerable species on the IUCN Red List and has extreme geographical endemism, exhibiting the smallest known distribution among Neotropical primates (ca. 870 km2), over 90% of which occurs in white‐water flooded forests within the Mamirauá Sustainable Development Reserve (MSDR), Brazilian Amazonia. To assess the effectiveness of this protected area in conserving the species, we conducted population monitoring of black‐headed squirrel monkeys across five consecutive years (2009–2013) on nine trails 2 km each. Each year samples included both low and high river water periods. We used the distance sampling method, recording the distance to each observed social group as well as counting component individuals. We also calculated annual encounter rates based on the number of individuals sighted every 10 km traveled. Densities ranged from 256 individuals/km2 (2011) to 453 individuals/km2 (2013), and no seasonal differences were detected. Population size was estimated to be 147,848 mature individuals. Encounter rates ranged from 100 individuals/10 km (2010) to 179 individuals/10 km (2013); no significant difference among years was found. We found that S. vanzolinii populations remained stable throughout the years, which indicates that the MSDR has been playing an essential role on protecting this species. Due to difficulties of fulfilling assumptions of the distance sampling method, we consider the encounter rate analysis to be more effective for monitoring this and other Saimiri species. Given the critical endemism and worrying conservation status of S. vanzolinii, we suggest that monitoring of the species population should be carried out regularly.
Trends in Primary Care Provision to Medicare Beneficiaries by Physicians, Nurse Practitioners, or Physician Assistants: 2008-2014

Objectives: To document the temporal trends in alternative primary care models in which physicians, nurse practitioners (NPs), or physician assistants (PAs) engaged in care provision to the elderly, and examine the role of these models in serving elders with multiple chronic conditions and those residing in rural and health professional shortage areas (HPSAs). Design: Serial cross-sectional analysis of Medicare claims data for years 2008, 2011, and 2014. Setting: Primary care outpatient setting. Participants: Medicare fee-for-service beneficiaries who had at least 1 primary care office visit in each study year. The sample size is 2 471 498. Measurements: Physician model—Medicare beneficiary’s primary care office visits in a year were conducted exclusively by physicians; shared care model—conducted by a group of professionals that included physicians and either NPs or PAs or both; NP/PA model: conducted either by NPs or PAs or both. Results: There was a decrease in the physician model (85.5% to 70.9%) and an increase in the shared care model (11.9% to 23.3%) and NP/PA model (2.7% to 5.9%) from 2008 to 2014. Compared with the physician model, the adjusted odds ratio (AOR) of receiving NP/PA care was 3.97 (95% CI 3.80-4.14) in rural and 1.26 (95% CI 1.23-1.29) in HPSAs; and the AOR of receiving shared care was 1.66 (95% CI 1.61-1.72) and 1.14 (95% CI 1.13-1.15), respectively. Beneficiaries with 3 or more chronic conditions were most likely to received shared care (AOR = 1.67, 95% CI 1.65-1.70). Conclusion: The increase in shared care practice signifies a shift toward bolstering capacity of the primary care delivery system to serve elderly populations with growing chronic disease burden and to improve access to care in rural and HPSAs.
Modeling of High Nanoparticle Exposure in an Indoor Industrial Scenario with a One-Box Model

Mass balance models have proved to be effective tools for exposure prediction in occupational settings. However, they are still not extensively tested in real-world scenarios, or for particle number concentrations. An industrial scenario characterized by high emissions of unintentionally-generated nanoparticles (NP) was selected to assess the performance of a one-box model. Worker exposure to NPs due to thermal spraying was monitored, and two methods were used to calculate emission rates: the convolution theorem, and the cyclic steady state equation. Monitored concentrations ranged between 4.2 × 104–2.5 × 105 cm−3. Estimated emission rates were comparable with both methods: 1.4 × 1011–1.2 × 1013 min−1 (convolution) and 1.3 × 1012–1.4 × 1013 min−1 (cyclic steady state). Modeled concentrations were 1.4-6 × 104 cm−3 (convolution) and 1.7–7.1 × 104 cm−3 (cyclic steady state). Results indicated a clear underestimation of measured particle concentrations, with ratios modeled/measured between 0.2–0.7. While both model parametrizations provided similar results on average, using convolution emission rates improved performance on a case-by-case basis. Thus, using cyclic steady state emission rates would be advisable for preliminary risk assessment, while for more precise results, the convolution theorem would be a better option. Results show that one-box models may be useful tools for preliminary risk assessment in occupational settings when room air is well mixed.
The separate and combined effects of KCa and KATP channel blockade with NOS inhibition on cutaneous vasodilation and sweating in older men during heat stress.

OBJECTIVE To examine the separate and combined effects of potassium (K+) channels and nitric oxide synthase (NOS) on cutaneous vasodilation and sweating in older men during rest and exercise in the heat. METHODS In thirteen habitually active men (61±4 years), cutaneous vascular conductance and local sweat rate were assessed at six dorsal forearm skin sites continuously perfused with either 1) lactated Ringer's (Control), 2) 10 mM NG-nitro-L-arginine methyl ester (L-NAME, NOS inhibitor), 3) 50 mM tetraethylammonium (TEA, Ca2+ activated K+ channel blocker), 4) 5 mM Glybenclamide (GLY, ATP-sensitive K+ channel blocker), 5) 50 mM TEA + 10 mM L-NAME and 6) 5 mM GLY + 10 mM L-NAME, via microdialysis. Participants rested in non-heat stress (25°C) and heat stress (35°C) conditions for ~60-min each, followed by 50-min of moderate intensity cycling (~55% VO2peak) and 30-min of recovery in the heat. RESULTS During rest and exercise in the heat L-NAME, TEA+L-NAME and GLY+L-NAME attenuated CVC relative to Control (all P≤0.05), although L-NAME was not different from TEA+L-NAME or GLY+L-NAME (all P>0.05). TEA attenuated CVC during rest, while GLY attenuated CVC during exercise (both P≤0.05). Additionally, while neither L-NAME nor TEA altered sweating throughout the protocol (all P>0.05), combined TEA+L-NAME attenuated sweating during exercise in the heat (P≤0.05). CONCLUSION In habitually active older men, blockade of KCa and KATP channels attenuates cutaneous vasodilation during rest and exercise in the heat, respectively, and these effects are NOS-dependent. Furthermore, combined NOS inhibition and KCa channel blockade attenuates sweating during exercise in the heat.
Murine epithelial sodium (Na+) channel regulation by biliary factors

The epithelial sodium channel (ENaC) mediates Na+ transport in several epithelia, including the aldosterone-sensitive distal nephron, distal colon, and biliary epithelium. Numerous factors regulate ENaC activity, including extracellular ligands, post-translational modifications, and membrane-resident lipids. However, ENaC regulation by bile acids and conjugated bilirubin, metabolites that are abundant in the biliary tree and intestinal tract and are sometimes elevated in the urine of individuals with advanced liver disease, remains poorly understood. Here, using a Xenopus oocyte-based system to express and functionally study ENaC, we found that, depending on the bile acid used, bile acids both activate and inhibit mouse ENaC. Whether bile acids were activating or inhibiting was contingent on the position and orientation of specific bile acid moieties. For example, a hydroxyl group at the 12-position and facing the hydrophilic side (12α-OH) was activating. Taurine-conjugated bile acids, which have reduced membrane permeability, affected ENaC activity more strongly than did their more membrane-permeant unconjugated counterparts, suggesting that bile acids regulate ENaC extracellularly. Bile acid–dependent activation was enhanced by amino acid substitutions in ENaC that depress open probability and was precluded by proteolytic cleavage that increases open probability, consistent with an effect of bile acids on ENaC open probability. Bile acids also regulated ENaC in a cortical collecting duct cell line, mirroring the results in Xenopus oocytes. We also show that bilirubin conjugates activate ENaC. These results indicate that ENaC responds to compounds abundant in bile and that their ability to regulate this channel depends on the presence of specific functional groups.
Misfolded GPI-anchored proteins are escorted through the secretory pathway by ER-derived factors

We have used misfolded prion protein (PrP*) as a model to investigate how mammalian cells recognize and degrade misfolded GPI-anchored proteins. While most misfolded membrane proteins are degraded by proteasomes, misfolded GPI-anchored proteins are primarily degraded in lysosomes. Quantitative flow cytometry analysis showed that at least 85% of PrP* molecules transiently access the plasma membrane en route to lysosomes. Unexpectedly, time-resolved quantitative proteomics revealed a remarkably invariant PrP* interactome during its trafficking from the endoplasmic reticulum (ER) to lysosomes. Hence, PrP* arrives at the plasma membrane in complex with ER-derived chaperones and cargo receptors. These interaction partners were critical for rapid endocytosis because a GPI-anchored protein induced to misfold at the cell surface was not recognized effectively for degradation. Thus, resident ER factors have post-ER itineraries that not only shield misfolded GPI-anchored proteins during their trafficking, but also provide a quality control cue at the cell surface for endocytic routing to lysosomes.
Redundancy and Complementarity between ERAP1 and ERAP2 Revealed by their Effects on the Behcet's Disease-associated HLA-B*51 Peptidome*

HLA-B*51 is the main risk factor for Behçet's disease. ERAP1 and ERAP2 trim peptides in the endoplasmic reticulum to be presented by MHC-I molecules. ERAP1, but not ERAP2, is also associated with this disorder in epistasis with B*51. Inhibition of each or both enzymes allowed the identification of the specific role of these proteins and their cooperation on shaping the HLA-B*51 peptidome and provide a basis for their differential association with Behçet's disease. Graphical Abstract Highlights HLA-B*51 and ERAP1, but not ERAP2, are risk factors for Behçet's disease. The HLA-B*51 peptidome and the effects of ERAP1 and ERAP2 on it are analyzed. ERAP1 and ERAP2 alter multiple features of the HLA-B*51 peptidome in distinct ways. Both enzymes act independently with complementary and partially redundant functions. The endoplasmic reticulum aminopeptidases ERAP1 and ERAP2 trim peptides to be loaded onto HLA molecules, including the main risk factor for Behçet's disease HLA-B*51. ERAP1 is also a risk factor among HLA-B*51-positive individuals, whereas no association is known with ERAP2. This study addressed the mutual relationships between both enzymes in the processing of an HLA-bound peptidome, interrogating their differential association with Behçet's disease. CRISPR/Cas9 was used to generate knock outs of ERAP1, ERAP2 or both from transfectant 721.221-HLA-B*51:01 cells. The surface expression of HLA-B*51 was reduced in all cases. The effects of depleting each or both enzymes on the B*51:01 peptidome were analyzed by quantitative label-free mass spectrometry. Substantial quantitative alterations of peptide length, subpeptidome balance, N-terminal residue usage, affinity and presentation of noncanonical ligands were observed. These effects were often different in the presence or absence of the other enzyme, revealing their mutual dependence. In the absence of ERAP1, ERAP2 showed similar and significant processing of B*51:01 ligands, indicating functional redundancy. The high overlap between the peptidomes of wildtype and double KO cells indicates that a large majority of B*51:01 ligands are present in the ER even in the absence of ERAP1/ERAP2. These results indicate that both enzymes have distinct, but complementary and partially redundant effects on the B*51:01 peptidome, leading to its optimization and maximal surface expression. The distinct effects of both enzymes on the HLA-B*51 peptidome provide a basis for their differential association with Behçet's disease and suggest a pathogenetic role of the B*51:01 peptidome.
Systematic review and analysis of efficacy of recombinant factor IX products for prophylactic treatment of hemophilia B in comparison with rIX-FP

Abstract Aims: Prophylaxis with standard-acting recombinant factor IX (rFIX) in hemophilia B patients requires frequent injections. Extended half-life (EHL) products allow for prolonged dosing intervals, and so reduce this treatment burden. Three technologies are employed to extend the half-life of FIX; glycopegylation, Fc-fusion, and albumin fusion. rIX-FP is a novel albumin fusion protein, which allows for a prolonged dosing interval of up to 14 days. A systematic review and indirect statistical comparison was performed to evaluate the efficacy of both EHL and standard-acting rFIX products compared with rIX-FP in Phase III trials for prophylaxis in adult hemophilia B patients. Materials and methods: A systematic search was conducted in both EMBASE and PubMed to identify Phase III trials of prophylactic rFIX treatment in previously treated hemophilia B patients aged ≥12 years (FIX ≤2%). Annualized bleeding rate (ABR), spontaneous ABR (AsBR), and joint ABR (AjBR) data were extracted from each study. A z-test was performed using the mean of each parameter, and the mean difference in outcome between studies was calculated. Results: Seven articles investigating six rFIX products were identified. Median ABR, AsBR, and AjBR ranged from 0–3.0, 0–1.0, and 0–1.1 (means = 0.8–4.26, 0.13–2.6, and 0.34–2.85), respectively. rIX-FP achieved the lowest median and mean values in all three parameters. Z-tests showed that mean ABR was significantly lower for rIX-FP 7-day prophylaxis compared with the majority of standard-acting and other EHL rFIX products. Limitations: The low number of appropriate trials available for comparison limits the quantity of data available for comparison, and restricts the use of methods of adjustment for variance in study design or patient characteristics. However, these limitations are shared with similar analyses published in this field. Conclusion: This indirect comparison of Phase III trials indicates that rIX-FP efficacy compares favorably vs other rFIX products for prophylaxis in hemophilia B.
BabyLux device: a diffuse optical system integrating diffuse correlation spectroscopy and time-resolved near-infrared spectroscopy for the neuromonitoring of the premature newborn brain

Abstract. The BabyLux device is a hybrid diffuse optical neuromonitor that has been developed and built to be employed in neonatal intensive care unit for the noninvasive, cot-side monitoring of microvascular cerebral blood flow and blood oxygenation. It integrates time-resolved near-infrared and diffuse correlation spectroscopies in a user-friendly device as a prototype for a future medical grade device. We present a thorough characterization of the device performance using test measurements in laboratory settings. Tests on solid phantoms report an accuracy of optical property estimation of about 10%, which is expected when using the photon diffusion equation as the model. The measurement of the optical and dynamic properties is stable during several hours of measurements within 3% of the average value. In addition, these measurements are repeatable between different days of measurement, showing a maximal variation of 5% in the optical properties and 8% for the particle diffusion coefficient on a liquid phantom. The variability over test/retest evaluation is <3 % . The integration of the two modalities is robust and without any cross talk between the two. We also perform in vivo measurements on the adult forearm during arterial cuff occlusion to show that the device can measure a wide range of tissue hemodynamic parameters. We suggest that this platform can form the basis of the next-generation neonatal neuromonitors to be developed for extensive, multicenter clinical testing.