High SMAD7 and p-SMAD2,3 expression is associated with environmental enteropathy in children

This work was supported by grants from the Bill & Melinda Gates Foundation (SAA: OPP1066200, PK: OPP1066118, GM: OPP1131242)

A combination of gemcitabine and 5-fluorouracil in advanced pancreatic cancer, a report from the Italian Group for the Study of Digestive Tract Cancer (GISCAD)

In a randomized clinical trial, gemcitabine (GEM) was more effective than 5-fluorouracil (5-FU) in advanced pancreatic cancer patients. GEM and 5-FU have different mechanisms of action and their combination, from a theoretical point of view, could result in a higher activity. To test activity and feasibility of such a combination, a multi-institutional phase II study was initiated in November 1996 by the Italian Group for the study of Digestive Tract Cancer (GISCAD). Primary objectives of this study were to determine the activity in terms of response rate and clinical benefit, while the secondary objective was toxicity. According to the optimal two-stage phase II design, 54 patients were enrolled. Schedule was: GEM 1000 mg m(-2) intravenous (i.v.), and 5-FU 600 mg m(-2) bolus i.v. weekly for 3 weeks out of every 4. All the 54 patients were symptomatic (pain, weight loss, dyspepsia). A clinical benefit was obtained in 28 patients (51\%) (95\% confidence interval (CI) 38-64\%). Two patients achieved a partial response and 34 a stable disease. Median survival for all the patients was 7 months. Side-effects were mild: no gastrointestinal or haematological grade 3-4 toxicity (WHO) were recorded. We observed only six episodes of grade 2 (WHO) leukopenia and seven episodes of thrombocytopenia. Although the non-randomized design of this study suggests caution in the interpretation of these data, in consideration of the low incidence of toxicity and the favourable results obtained in terms of clinical benefit, it may be worthwhile to test more active schedules of 5-FU (continuous infusion) in combination with gemcitabine

Equipping Health Professions Educators to Better Address Medical Misinformation

As part of a cooperative agreement with the US Centers for Disease Control and Prevention (Federal Award Identification Number [FAIN]: NU50CK000586), the Association of American Medical Colleges (AAMC) began a strategic initiative in 2022 both to increase confidence in COVID-19 vaccines and to address medical misinformation and mistrust through education in health professions contexts. Specifically, the AAMC solicited proposals for integrating competency-based, interprofessional strategies to mitigate health misinformation into new or existing curricula. Five Health Professions Education Curricular Innovations subgrantees received support from the AAMC in 2022 and reflected on the implementation of their ideas in a series of meetings over several months. Subgrantees included the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Florida International University Herbert Wertheim College of Medicine, the Jacobs School of Medicine and Biomedical Sciences at the University at Buffalo, the Maine Medical Center/Tufts University School of Medicine, and the University of Chicago Pritzker School of Medicine. This paper comprises insights from each of the teams and overarching observations regarding the challenges and opportunities involved with leveraging health professions education to address medical misinformation and improve patient health

Transthyretin Aggregation Pathway toward the Formation of Distinct Cytotoxic Oligomers

Characterization of small oligomers formed at an early stage of amyloid formation is critical to understanding molecular mechanism of pathogenic aggregation process. Here we identifed and characterized cytotoxic oligomeric intermediates populated during transthyretin (TTR) aggregation process. Under the amyloid-forming conditions, TTR initially forms a dimer through interactions between outer strands. The dimers are then associated to form a hexamer with a spherical shape, which serves as a building block to self-assemble into cytotoxic oligomers. Notably, wild-type (WT) TTR tends to form linear oligomers, while aTTR variant(G53A) prefers forming annular oligomers with pore-like structures. Structural analyses of the amyloidogenic intermediates using circular dichroism (CD) and solid-state NMR revealthatthe dimer and oligomers have a signifcant degree of native-like β-sheet structures (35–38%), but with more disordered regions (~60%)than those of nativeTTR.TheTTR variant oligomers are also less structured than WT oligomers. The partially folded nature of the oligomeric intermediates might be a common structural property of cytotoxic oligomers.The higher fexibility of the dimer and oligomers may also compensate for the entropic loss due to the oligomerization of the monomers

Abattoir-based estimates of mycobacterial infections in Cameroon

Mycobacteria cause major diseases including human tuberculosis, bovine tuberculosis and Johne’s disease. In livestock, the dominant species is M. bovis causing bovine tuberculosis (bTB), a disease of global zoonotic importance. In this study, we estimated the prevalence of Mycobacteria in slaughter cattle in Cameroon. A total of 2,346 cattle were examined in a cross-sectional study at four abattoirs in Cameroon. Up to three lesions per animal were collected for further study and a retropharyngeal lymph node was collected from a random sample of non-lesioned animals. Samples were cultured on Lowenstein Jensen media and the BACTEC MGIT 960 system, and identified using the Hain® Genotype kits. A total of 207/2,346 cattle were identified with bTB-like lesions, representing 4.0% (45/1,129), 11.3% (106/935), 23.8% (38/160) and 14.8% (18/122) of the cattle in the Bamenda, Ngaoundere, Garoua and Maroua abattoirs respectively. The minimum estimated prevalence of M. bovis was 2.8% (1.9–3.9), 7.7% (6.1–9.6), 21.3% (15.2–28.4) and 13.1% (7.7–20.4) in the four abattoirs respectively. One M. tuberculosis and three M. bovis strains were recovered from non-lesioned animals. The high prevalence of M. bovis is of public health concern and limits the potential control options in this setting without a viable vaccine as an alternative

The On-orbit Calibrations for the Fermi Large Area Telescope

The Large Area Telescope (LAT) on--board the Fermi Gamma ray Space Telescope began its on--orbit operations on June 23, 2008. Calibrations, defined in a generic sense, correspond to synchronization of trigger signals, optimization of delays for latching data, determination of detector thresholds, gains and responses, evaluation of the perimeter of the South Atlantic Anomaly (SAA), measurements of live time, of absolute time, and internal and spacecraft boresight alignments. Here we describe on orbit calibration results obtained using known astrophysical sources, galactic cosmic rays, and charge injection into the front-end electronics of each detector. Instrument response functions will be described in a separate publication. This paper demonstrates the stability of calibrations and describes minor changes observed since launch. These results have been used to calibrate the LAT datasets to be publicly released in August 2009.Comment: 60 pages, 34 figures, submitted to Astroparticle Physic

‘Hangry’ Drosophila: food deprivation increases male aggression

Aggressive interactions are costly, such that individuals should display modified aggression in response to environmental stress. Many organisms experience frequent periods of food deprivation, which can influence an individual's capacity and motivation to engage in aggression. However, because food deprivation can simultaneously decrease an individual's resource-holding potential and increase its valuation of food resources, its net impact on aggression is unclear. Here, we tested the influence of increasingly prolonged periods of adult food deprivation on intermale aggression in pairs of fruit flies, Drosophila melanogaster. We found that males displayed increased aggression following periods of food deprivation longer than a day. Increased aggression in food-deprived flies occurred despite their reduced mass. This result is probably explained by an increased attraction to food resources, as food deprivation increased male occupancy of central food patches, and food patch occupancy was positively associated with aggression. Our findings demonstrate that aggressive strategies in male D. melanogaster are influenced by nutritional experience, highlighting the need to consider past nutritional stresses to understand variation in aggression

Italian guidelines for primary headaches: 2012 revised version

The first edition of the Italian diagnostic and therapeutic guidelines for primary headaches in adults was published in J Headache Pain 2(Suppl. 1):105–190 (2001). Ten years later, the guideline committee of the Italian Society for the Study of Headaches (SISC) decided it was time to update therapeutic guidelines. A literature search was carried out on Medline database, and all articles on primary headache treatments in English, German, French and Italian published from February 2001 to December 2011 were taken into account. Only randomized controlled trials (RCT) and meta-analyses were analysed for each drug. If RCT were lacking, open studies and case series were also examined. According to the previous edition, four levels of recommendation were defined on the basis of levels of evidence, scientific strength of evidence and clinical effectiveness. Recommendations for symptomatic and prophylactic treatment of migraine and cluster headache were therefore revised with respect to previous 2001 guidelines and a section was dedicated to non-pharmacological treatment. This article reports a summary of the revised version published in extenso in an Italian version

The role of ETG modes in JET-ILW pedestals with varying levels of power and fuelling

We present the results of GENE gyrokinetic calculations based on a series of JET-ITER-like-wall (ILW) type I ELMy H-mode discharges operating with similar experimental inputs but at different levels of power and gas fuelling. We show that turbulence due to electron-temperature-gradient (ETGs) modes produces a significant amount of heat flux in four JET-ILW discharges, and, when combined with neoclassical simulations, is able to reproduce the experimental heat flux for the two low gas pulses. The simulations plausibly reproduce the high-gas heat fluxes as well, although power balance analysis is complicated by short ELM cycles. By independently varying the normalised temperature gradients (omega(T)(e)) and normalised density gradients (omega(ne )) around their experimental values, we demonstrate that it is the ratio of these two quantities eta(e) = omega(Te)/omega(ne) that determines the location of the peak in the ETG growth rate and heat flux spectra. The heat flux increases rapidly as eta(e) increases above the experimental point, suggesting that ETGs limit the temperature gradient in these pulses. When quantities are normalised using the minor radius, only increases in omega(Te) produce appreciable increases in the ETG growth rates, as well as the largest increases in turbulent heat flux which follow scalings similar to that of critical balance theory. However, when the heat flux is normalised to the electron gyro-Bohm heat flux using the temperature gradient scale length L-Te, it follows a linear trend in correspondence with previous work by different authors

Spectroscopic camera analysis of the roles of molecularly assisted reaction chains during detachment in JET L-mode plasmas

The roles of the molecularly assisted ionization (MAI), recombination (MAR) and dissociation (MAD) reaction chains with respect to the purely atomic ionization and recombination processes were studied experimentally during detachment in low-confinement mode (L-mode) plasmas in JET with the help of experimentally inferred divertor plasma and neutral conditions, extracted previously from filtered camera observations of deuterium Balmer emission, and the reaction coefficients provided by the ADAS, AMJUEL and H2VIBR atomic and molecular databases. The direct contribution of MAI and MAR in the outer divertor particle balance was found to be inferior to the electron-atom ionization (EAI) and electron-ion recombination (EIR). Near the outer strike point, a strong atom source due to the D+2-driven MAD was, however, observed to correlate with the onset of detachment at outer strike point temperatures of Te,osp = 0.9-2.0 eV via increased plasma-neutral interactions before the increasing dominance of EIR at Te,osp < 0.9 eV, followed by increasing degree of detachment. The analysis was supported by predictions from EDGE2D-EIRENE simulations which were in qualitative agreement with the experimental observations