Variation in Structure and Process of Care in Traumatic Brain Injury: Provider Profiles of European Neurotrauma Centers Participating in the CENTER-TBI Study.

INTRODUCTION: The strength of evidence underpinning care and treatment recommendations in traumatic brain injury (TBI) is low. Comparative effectiveness research (CER) has been proposed as a framework to provide evidence for optimal care for TBI patients. The first step in CER is to map the existing variation. The aim of current study is to quantify variation in general structural and process characteristics among centers participating in the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study. METHODS: We designed a set of 11 provider profiling questionnaires with 321 questions about various aspects of TBI care, chosen based on literature and expert opinion. After pilot testing, questionnaires were disseminated to 71 centers from 20 countries participating in the CENTER-TBI study. Reliability of questionnaires was estimated by calculating a concordance rate among 5% duplicate questions. RESULTS: All 71 centers completed the questionnaires. Median concordance rate among duplicate questions was 0.85. The majority of centers were academic hospitals (n = 65, 92%), designated as a level I trauma center (n = 48, 68%) and situated in an urban location (n = 70, 99%). The availability of facilities for neuro-trauma care varied across centers; e.g. 40 (57%) had a dedicated neuro-intensive care unit (ICU), 36 (51%) had an in-hospital rehabilitation unit and the organization of the ICU was closed in 64% (n = 45) of the centers. In addition, we found wide variation in processes of care, such as the ICU admission policy and intracranial pressure monitoring policy among centers. CONCLUSION: Even among high-volume, specialized neurotrauma centers there is substantial variation in structures and processes of TBI care. This variation provides an opportunity to study effectiveness of specific aspects of TBI care and to identify best practices with CER approaches

Boosting care and knowledge about hereditary cancer: European Reference Network on Genetic Tumour Risk Syndromes

Approximately 27–36 million patients in Europe have one of the ~ 5.000–8.000 known rare diseases. These patients often do not receive the care they need or they have a substantial delay from diagnosis to treatment. In March 2017, twenty-four European Reference Networks (ERNs) were launched with the aim to improve the care for these patients through cross border healthcare, in a way that the medical knowledge and expertise travels across the borders, rather than the patients. It is expected that through the ERNs, European patients with a rare disease get access to expert care more often and more quickly, and that research and guideline development will be accelerated resulting in improved diagnostics and therapies. The ERN on Genetic Tumour Risk Syndromes (ERN GENTURIS) aims to improve the identification, genetic diagnostics, prevention of cancer, and treatment of European patients with a genetic predisposition for cancer. The ERN GENTURIS focuses on syndromes such as hereditary breast cancer, hereditary colorectal cancer and polyposis, neurofibromatosis and more rare syndromes e.g. PTEN Hamartoma Tumour Syndrome, Li Fraumeni Syndrome and hereditary diffuse gastric cancer

Fisiopatología de cálculos biliares de colesterol: la búsqueda de una diana terapéutica

In the physiopathology of cholesterol gallstones different imbalances are involved, among them are alterations in the secretion of biliary lipids, in the crystallization/nucleation of cholesterol, in the overproduction of mucins, which modify motility of gallbladder, and in the intestinal cholesterol transport. In all these processes many molecules are involved, for example ABCG5, ABCG8, ABCB11 and ABCB4 transporters, MUC genes, which are responsible for expressing mucin, cholecystokinin (CCK), cholecystokinin receptor 1 and Niemann-Pick C1L1 protein (NPC1L1). In this review, we discuss the findings of the studies of these molecules, which have a specific role in the formation of cholesterol gallstones. The modulation of the expression of these proteins can be an important guideline to find out a new therapeutic target for prevention and treatment and of this gallbladder disease.En la fisiopatología de los cálculos biliares de colesterol se involucran diferentes desajustes tales como, la alteración en la secreción de lípidos biliares, la cristalización o nucleación del colesterol, la sobreproducción de proteínas mucinas que modifican la motilidad de la vesícula biliar y la alteración en el transporte intestinal de colesterol. En estas fases intervienen numerosas moléculas por ejemplo, los transportadores ABCG5, ABCG8, ABCB11 y ABCB4, los genes MUC que se encargan de expresar las proteínas mucinas, la colecistocinina (CCK) y su receptor tipo 1 y la proteína de Niemann-Pick C1L1 intestinal (NPC1L1). En esta revisión, discutimos los resultados de estudios sobre estas moléculas que tienen una participación específica dentro de la formación de los cálculos biliares de colesterol. La modulación de la expresión de estas proteínas, puede ser una importante pauta de investigación para el hallazgo de una diana terapéutica para la prevención y el tratamiento de esta enfermedad de la vesícula biliar

Case-control Investigation of Previously Undiagnosed Diabetes in the Critically Ill

Context: The outcome of patients requiring intensive care can be influenced by the presence of previously undiagnosed diabetes (undiagDM). Objective: This work aimed to define the clinical characteristics, glucose control metrics, and outcomes of patients admitted to the intensive care unit (ICU) with undiagDM, and compare these to patients with known DM (DM). Methods: This case-control investigation compared undiagDM (glycated hemoglobin A1c [HbA1c] ≥ 6.5%, no history of diabetes) to patients with DM. Glycemic ratio (GR) was calculated as the quotient of mean ICU blood glucose (BG) and estimated preadmission glycemia, based on HbA1c ([28.7 × HbA1c]-46.7mg/dL). GR was analyzed by bands: less than 0.7, 0.7 to less than or equal to 0.9, 0.9 to less than 1.1, and greater than or equal to 1.1. Risk-adjusted mortality was represented by the Observed:Expected mortality ratio (OEMR), calculated as the quotient of observed mortality and mortality predicted by the severity of illness (APACHE IV prediction of mortality). Results: Of 5567 patients 294 (5.3%) were undiagDM. UndiagDM had lower ICU mean BG (P <. 0001) and coefficient of variation (P <. 0001) but similar rates of hypoglycemia (P =. 08). Mortality and risk-adjusted mortality were similar in patients with GR less than 1.1 comparing undiagDM and DM. However, for patients with GR greater than or equal to 1.1, mortality (38.5% vs 10.3% [P =. 0072]) and risk-adjusted mortality (OEMR 1.18 vs 0.52 [P <. 0001]) were higher in undiagDM than in DM. Conclusion: These data suggest that DM patients may develop tolerance to hyperglycemia that occurs during critical illness, a protective mechanism not observed in undiagDM, for whom hyperglycemia remains strongly associated with higher risk of mortality. These results may shed light on the natural history of diabetes.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Quantification of Target Volume Changes on Radiation Planning MRI in IDH-Wildtype Glioblastoma

IDH-wildtype glioblastoma (GBM) has an exceptionally poor prognosis due to its rapid growth. Delaying post-operative radiation therapy (RT) more than 6 weeks after surgery negatively impacts prognosis. Post-operative magnetic resonance imaging (MRI) is commonly used to assess the extent of surgical resection followed by a delayed MRI for RT planning. In a heterogeneous population of high-grade gliomas treated in the pre-molecular era, significant resolution of edema and a trend towards increase in surgical cavity sizes were observed. Post-operative volumetric changes in IDH-wildtype GBM have not been described and we suspect these tumors may demonstrate higher rates of recurrence or regrowth during the latent period before the initiation of RT. 30 patients with IDH-wildtype GBM treated with post-operative RT from our institution were identified. Patients with RT planning MRIs obtained between 3-6 weeks after biopsy or surgical resection were included. RT target volumes were contoured and compared between post-operative and RT planning MRIs. Volumetric changes in GTV2 (surgical cavity + residual enhancing disease) and GTV1 (edema + GTV2) were calculated. Progression-free survival (PFS) and overall survival (OS) were measured. The mean time between post-operative and RT planning MRI was 29.4 days (range: 21-42 days). When comparing post-operative and RT planning MRIs, the mean decrease in GTV1 was 25.8cc or 14.7% (P = 0.011) and the mean increase in GTV2 was 10.21cc or 39.6% (P = 0.0013). GTV1 decreased at an average rate of 0.5% per day and GTV2 increased at an average rate of 1.4% per day. The proportional growth was similar to a rate of historical controls of mixed high-grade gliomas. Median PFS and OS in our group were 5.6 and 11.2 months, respectively. A delay of more than one month between post-operative and planning MRI was associated with worse median OS of 8.0 months compared with 11.5 months (P = 0.044). To our knowledge, this is the largest volumetric study of the impact of post-operative MRIs in a uniform group of IDH-wildtype GBM. RT planning MRIs performed 3-6 weeks after biopsy or surgical resection of IDH-wildtype GBM demonstrate significant volumetric changes. Similar to previously published data on a heterogenous population of high-grade gliomas, decreases in GTV1 signify a resolution of edema, however, increases in GTV2 imply recurrence or regrowth of disease over a relatively short time. While this was not statistically significant in a previously published analysis of a heterogeneous population of high-grade gliomas, our analysis of a homogeneous population of IDH-wildtype GBM demonstrates a statistically significant increase in GTV2. Delaying planning MRI more than one month post-operatively was associated with worse OS. These findings support the need for RT planning MRIs and confirm the association between delayed treatment and worse survival. Radiomic analysis of cavity regression vs. tumor regrowth is forthcoming. J.B. Bell: None. B.J. Rich: None. I.B. Mihaylov: Research Grant; Philips Radiation Oncology Systems, NIH.C. Benjamin: None. E.A. Mellon: None. M.C. Abramowitz: None. G. Azzam: None. M. Guillermo Prieto Ei: None. M. De La Fuente: None. M. Butkus: None. T. Diwanji: None

Guidelines for the Li–Fraumeni and heritable TP53-related cancer syndromes

Fifty years after the recognition of the Li–Fraumeni syndrome (LFS), our perception of cancers related to germline alterations of TP53 has drastically changed: (i) germline TP53 alterations are often identified among children with cancers, in particular soft-tissue sarcomas, adrenocortical carcinomas, central nervous system tumours, or among adult females with early breast cancers, without familial history. This justifies the expansion of the LFS concept to a wider cancer predisposition syndrome designated heritable TP53-related cancer (hTP53rc) syndrome; (ii) the interpretation of germline TP53 variants remains challenging and should integrate epidemiological, phenotypical, bioinformatics prediction, and functional data; (iii) the penetrance of germline disease-causing TP53 variants is variable, depending both on the type of variant (dominant-negative variants being associated with a higher can

Dielectron and heavy-quark production in inelastic and high-multiplicity proton–proton collisions at √s = 13 TeV

The measurement of dielectron production is presented as a function of invariant mass and transverse momentum (pT) at midrapidity (|ye| < 0.8) in proton–proton (pp) collisions at a centre-of-mass energy of √s = 13 TeV. The contributions from light-hadron decays are calculated from their measured cross sections in pp collisions at √s = 7 TeV or 13 TeV. The remaining continuum stems from correlated semileptonic decays of heavy-flavour hadrons. Fitting the data with templates from two different MC event generators, PYTHIA and POWHEG, the charm and beauty cross sections at midrapidity are extracted for the first time at this collision energy: dσcc¯/dy|y=0 = 974 ± 138 (stat.) ± 140 (syst.) ± 214(BR) μb and dσbb¯ /dy|y=0 = 79 ± 14 (stat.) ± 11 (syst.) ± 5(BR) μb using PYTHIA simulations and dσcc¯/dy|y=0 = 1417 ± 184 (stat.) ± 204 (syst.) ± 312(BR) μb and dσbb¯ /dy|y=0 = 48 ± 14 (stat.) ± 7 (syst.) ± 3(BR) μb for POWHEG. These values, whose uncertainties are fully correlated between the two generators, are consistent with extrapolations from lower energies. The different results obtained with POWHEG and PYTHIA imply different kinematic correlations of the heavy-quark pairs in these two generators. Furthermore, comparisons of dielectron spectra in inelastic events and in events collected with a trigger on high charged-particle multiplicities are presented in various pT intervals. The differences are consistent with the already measured scaling of light-hadron and open-charm production at high charged-particle multiplicity as a function of pT. Upper limits for the contribution of virtual direct photons are extracted at 90% confidence level and found to be in agreement with pQCD calculations

Measurement of electrons from semileptonic heavy-flavour hadron decays at midrapidity in pp and Pb–Pb collisions at √sNN = 5.02 TeV

The differential invariant yield as a function of transverse momentum (pT) of electrons from semileptonic heavy-flavour hadron decays was measured at midrapidity in central (0–10%), semi-central (30–50%) and peripheral (60–80%) lead–lead (Pb–Pb) collisions at √sNN = 5.02 TeV in the pT intervals 0.5–26 GeV/c (0–10% and 30–50%) and 0.5–10 GeV/c (60–80%). The production cross section in proton–proton (pp) collisions at √s = 5.02 TeV was measured as well in 0.5 < pT < 10 GeV/c and it lies close to the upper band of perturbative QCD calculation uncertainties up to pT = 5 GeV/c and close to the mean value for larger pT. The modification of the electron yield with respect to what is expected for an incoherent superposition of nucleon–nucleon collisions is evaluated by measuring the nuclear modification factor RAA. The measurement of the RAA in different centrality classes allows in-medium energy loss of charm and beauty quarks to be investigated. The RAA shows a suppression with respect to unity at intermediate pT, which increases while moving towards more central collisions. Moreover, the measured RAA is sensitive to the modification of the parton distribution functions (PDF) in nuclei, like nuclear shadowing, which causes a suppression of the heavy-quark production at low pT in heavy-ion collisions at LHC