The Receptor Slamf1 on the Surface of Myeloid Lineage Cells Controls Susceptibility to Infection by Trypanosoma cruzi

Trypanosoma cruzi, the protozoan parasite responsible for Chagas' disease, causes severe myocarditis often resulting in death. Here, we report that Slamf1−/− mice, which lack the hematopoietic cell surface receptor Slamf1, are completely protected from an acute lethal parasite challenge. Cardiac damage was reduced in Slamf1−/− mice compared to wild type mice, infected with the same doses of parasites, as a result of a decrease of the number of parasites in the heart even the parasitemia was only marginally less. Both in vivo and in vitro experiments reveal that Slamf1-defIcient myeloid cells are impaired in their ability to replicate the parasite and show altered production of cytokines. Importantly, IFN-γ production in the heart of Slamf1 deficient mice was much lower than in the heart of wt mice even though the number of infiltrating dendritic cells, macrophages, CD4 and CD8 T lymphocytes were comparable. Administration of an anti-Slamf1 monoclonal antibody also reduced the number of parasites and IFN-γ in the heart. These observations not only explain the reduced susceptibility to in vivo infection by the parasite, but they also suggest human Slamf1 as a potential target for therapeutic target against T. cruzi infection

Metabolic development of necrotic bone in the femoral head following resurfacing arthroplasty: A clinical [18F]fluoride-PET study in 11 asymptomatic hips

Background and purpose One concern regarding resurfacing arthroplasty is the viability of the diminished femoral head and the postoperative risk of collapse, or a femoral neck fracture. (18)F-fluoride positron emission tomography (F-PET) enables us to assess bone viability despite there being a covering metal component. By F-PET studies, we recently showed the absence of metabolism in the remaining part of femoral heads, 1-4 years after surgery in 11 of 46 consecutive cases. We now present the further development of bone metabolism in these 11 cases. Patients and methods 10 patients (11 chips) with previously shown loss of femoral head metabolism were evaluated by radiography and repeated F-PET scans, 3-6.5 years after surgery. The size of the area with low (18)F-fluoride PET uptake in the femoral head was compared to that in earlier PET images. Results No patients had any clinical symptoms; nor was any necrotic bone area visible in plain radiographs. On F-PET scans, 2 patients showed a diminished area with low uptake, 4 were unchanged, and 5 had enlarged areas. Interpretation Bone metabolism surrounding a volume of bone with no metabolic activity changes dynamically even 5 years after surgery. The presence of bone with minor uptake of F-tracer, indicating low or no bone metabolism, with further progression in 5 of 11 cases leads us to conclude that resurfacing THA should be used restrictively.</p

A study assessing the association of glycated hemoglobin a1C (HbA1C) associated variants with HbA1C, chronic kidney disease and diabetic retinopathy in populations of asian ancestry

10.1371/journal.pone.0079767PLoS ONE811-POLN

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

A phase II study of the bispecific antibody MDX-H210 (anti-HER2 × CD64) with GM-CSF in HER2+ advanced prostate cancer

The proto-oncogene HER2 presents a novel therapeutic target. We report results in 25 patients with HER2+ advanced prostate cancer treated with the bispecific antibody MDX-H210 15 μg m−2by intravenous infusion plus GM-CSF 5 μg kg−1day−1by subcutaneous injection for 4 days repeated weekly for 6 weeks. Patients with stable disease or better received further cycles of treatment until disease progression or study withdrawal. 1 patient received no treatment and 4 received less than 1 cycle and are included in the toxicity analysis only. Median duration of follow up was 105+ (range 21–188) days. Toxicity was generally NCI-CTG 0–2. There were 2 grade 4 adverse events (heart failure and dyspnoea) and 1 grade 3 event (allergic reaction) resulting in discontinuation of the study medication. There were 9 further grade 3 events not resulting in trial withdrawal. There were no treatment-related deaths. 7/20 (35%) evaluable patients had a >50% PSA response of median duration 128 (range 71–184+) days. 7/12 (58%) patients with evaluable pain had improvements in pain scores. The PSA relative velocity on therapy decreased in 15/18 (83%) assessable patients compared to pre-study. GM-CSF and MDX-H210 is active in hormone refractory prostate carcinoma with acceptable toxicity; further studies are warranted. © 2001 Cancer Research Campaign http://www.bjcancer.co

Understanding high pressure hydrogen with a hierarchical machine-learned potential

The hydrogen phase diagram has a number of unusual features which are generally well reproduced by density functional calculations. Unfortunately, these calculations fail to provide good physical insights into why those features occur. In this paper, we parameterize a model potential for molecular hydrogen which permits long and large simulations. The model shows excellent reproduction of the phase diagram, including the broken-symmetry Phase II, an efficiently-packed phase III and the maximum in the melt curve. It also gives an excellent reproduction of the vibrational frequencies, including the maximum in the vibrational frequency $\nu(P)$ and negative thermal expansion. By detailed study of lengthy molecular dynamics, we give intuitive explanations for observed and calculated properties. All solid structures approximate to hexagonal close packed, with symmetry broken by molecular orientation. At high pressure, Phase I shows significant short-ranged correlations between molecular orientations. The turnover in Raman frequency is due to increased coupling between neighboring molecules, rather than weakening of the bond. The liquid is denser than the close-packed solid because, at molecular separations below 2.3\AA, the favoured relative orientation switches from quadrupole-energy-minimising to steric-repulsion-minimising. The latter allows molecules to get closer together, without atoms getting closer but this cannot be achieved within the constraints of a close-packed layer

A core outcome set for future male infertility research: development of an international consensus

\ua9 The Author(s). Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.STUDY QUESTION: Can a core outcome set be developed through a global consensus to standardize outcome selection, collection, comparison, and reporting in future male infertility trials? SUMMARY ANSWER: A minimum dataset, known as a \u27core outcome set\u27, has been developed for randomized controlled trials (RCTs) and systematic reviews evaluating potential interventions for male infertility. WHAT IS KNOWN ALREADY: Numerous factors, including a failure to consider the perspectives of men with lived experiences of infertility or their partners when developing and conducting RCTs can limit their clinical utility. Selection of outcomes, variations in outcome definitions, and the selective reporting of outcomes based on statistical analysis make the results of infertility research challenging to interpret, compare, and implement. For male infertility, this is further compounded by there being potentially three participants, the male, their female partner, and any offspring born, all with outcomes to be reported. This has led to significant heterogeneity in trial design and reporting. While a core outcome set for general infertility trials has been developed, there is no such outcome set for male infertility trials. STUDY DESIGN, SIZE, DURATION: A two-round Delphi survey (334 participants from 39 countries) and consensus development workshops (44 participants from 21 countries). PARTICIPANTS/MATERIALS, SETTING, METHODS: Healthcare professionals, researchers, and men and women with infertility were brought together in a transparent process using formal consensus science methods. MAIN RESULTS AND THE ROLE OF CHANCE: The core outcome set for male infertility trials has been developed by the inclusion of specific male-factor outcomes in addition to the general infertility core outcome set. These outcomes include assessment of semen using the World Health Organization recommendations for semen analysis; viable intrauterine pregnancy confirmed by ultrasound (accounting for singleton, twin, and higher multiple pregnancies); pregnancy loss (accounting for ectopic pregnancy, miscarriage, stillbirth, and termination of pregnancy); live birth; gestational age at delivery; birthweight; neonatal mortality; and major congenital anomaly. Although not a requirement as part of the core outcome set, other outcomes were identified as potentially useful in certain study settings. LIMITATIONS, REASONS FOR CAUTION: We used consensus development methods in this work, which have inherent limitations, including the representativeness of the participant sample, Delphi survey attrition, and an arbitrary consensus threshold. WIDER IMPLICATIONS OF THE FINDINGS: Embedding the core outcome set within RCTs and systematic reviews should ensure the comprehensive selection, collection, and reporting of core outcomes, which are inconsistently reported at present. Research funding bodies, the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) statement, and over 80 specialty journals, including the Cochrane Gynaecology and Fertility Group, Fertility and Sterility and Human Reproduction, have committed to implementing this core outcome set for male infertility trials

Team climate, intention to leave and turnover among hospital employees: Prospective cohort study

<p>Abstract</p> <p>Background</p> <p>In hospitals, the costs of employee turnover are substantial and intentions to leave among staff may manifest as lowered performance. We examined whether team climate, as indicated by clear and shared goals, participation, task orientation and support for innovation, predicts intention to leave the job and actual turnover among hospital employees.</p> <p>Methods</p> <p>Prospective study with baseline and follow-up surveys (2–4 years apart). The participants were 6,441 (785 men, 5,656 women) hospital employees under the age of 55 at the time of follow-up survey. Logistic regression with generalized estimating equations was used as an analysis method to include both individual and work unit level predictors in the models.</p> <p>Results</p> <p>Among stayers with no intention to leave at baseline, lower self-reported team climate predicted higher likelihood of having intentions to leave at follow-up (odds ratio per 1 standard deviation decrease in team climate was 1.6, 95% confidence interval 1.4–1.8). Lower co-worker assessed team climate at follow-up was also association with such intentions (odds ratio 1.8, 95% confidence interval 1.4–2.4). Among all participants, the likelihood of actually quitting the job was higher for those with poor self-reported team climate at baseline. This association disappeared after adjustment for intention to leave at baseline suggesting that such intentions may explain the greater turnover rate among employees with low team climate.</p> <p>Conclusion</p> <p>Improving team climate may reduce intentions to leave and turnover among hospital employees.</p

Resistance of a Rodent Malaria Parasite to a Thymidylate Synthase Inhibitor Induces an Apoptotic Parasite Death and Imposes a Huge Cost of Fitness

BACKGROUND: The greatest impediment to effective malaria control is drug resistance in Plasmodium falciparum, and thus understanding how resistance impacts on the parasite's fitness and pathogenicity may aid in malaria control strategy. METHODOLOGY/PRINCIPAL FINDINGS: To generate resistance, P. berghei NK65 was subjected to 5-fluoroorotate (FOA, an inhibitor of thymidylate synthase, TS) pressure in mice. After 15 generations of drug pressure, the 2% DT (the delay time for proliferation of parasites to 2% parasitaemia, relative to untreated wild-type controls) reduced from 8 days to 4, equalling the controls. Drug sensitivity studies confirmed that FOA-resistance was stable. During serial passaging in the absence of drug, resistant parasite maintained low growth rates (parasitaemia, 15.5%±2.9, 7 dpi) relative to the wild-type (45.6%±8.4), translating into resistance cost of fitness of 66.0%. The resistant parasite showed an apoptosis-like death, as confirmed by light and transmission electron microscopy and corroborated by oligonucleosomal DNA fragmentation. CONCLUSIONS/SIGNIFICANCE: The resistant parasite was less fit than the wild-type, which implies that in the absence of drug pressure in the field, the wild-type alleles may expand and allow drugs withdrawn due to resistance to be reintroduced. FOA resistance led to depleted dTTP pools, causing thymineless parasite death via apoptosis. This supports the tenet that unicellular eukaryotes, like metazoans, also undergo apoptosis. This is the first report where resistance to a chemical stimulus and not the stimulus itself is shown to induce apoptosis in a unicellular parasite. This finding is relevant in cancer therapy, since thymineless cell death induced by resistance to TS-inhibitors can further be optimized via inhibition of pyrimidine salvage enzymes, thus providing a synergistic impact. We conclude that since apoptosis is a process that can be pharmacologically modulated, the parasite's apoptotic machinery may be exploited as a novel drug target in malaria and other protozoan diseases of medical importance