A homozygous MED11 C-terminal variant causes a lethal neurodegenerative disease.

Purpose: The mediator (MED) multisubunit-complex modulates the activity of the transcriptional machinery, and genetic defects in different MED subunits (17, 20, 27) have been implicated in neurologic diseases. In this study, we identified a recurrent homozygous variant in MED11 (c.325C>T; p.Arg109Ter) in 7 affected individuals from 5 unrelated families. Methods: To investigate the genetic cause of the disease, exome or genome sequencing were performed in 5 unrelated families identified via different research networks and Matchmaker Exchange. Deep clinical and brain imaging evaluations were performed by clinical pediatric neurologists and neuroradiologists. The functional effect of the candidate variant on both MED11 RNA and protein was assessed using reverse transcriptase polymerase chain reaction and western blotting using fibroblast cell lines derived from 1 affected individual and controls and through computational approaches. Knockouts in zebrafish were generated using clustered regularly interspaced short palindromic repeats/Cas9. Results: The disease was characterized by microcephaly, profound neurodevelopmental impairment, exaggerated startle response, myoclonic seizures, progressive widespread neurodegeneration, and premature death. Functional studies on patient-derived fibroblasts did not show a loss of protein function but rather disruption of the C-terminal of MED11, likely impairing binding to other MED subunits. A zebrafish knockout model recapitulates key clinical phenotypes. Conclusion: Loss of the C-terminal of MED subunit 11 may affect its binding efficiency to other MED subunits, thus implicating the MED-complex stability in brain development and neurodegeneration

A homozygous MED11 C-terminal variant causes a lethal neurodegenerative disease

Purpose: The mediator (MED) multisubunit-complex modulates the activity of the transcriptional machinery, and genetic defects in different MED subunits (17, 20, 27) have been implicated in neurologic diseases. In this study, we identified a recurrent homozygous variant in MED11 (c.325C>T; p.Arg109Ter) in 7 affected individuals from 5 unrelated families. Methods: To investigate the genetic cause of the disease, exome or genome sequencing were performed in 5 unrelated families identified via different research networks and Matchmaker Exchange. Deep clinical and brain imaging evaluations were performed by clinical pediatric neurologists and neuroradiologists. The functional effect of the candidate variant on both MED11 RNA and protein was assessed using reverse transcriptase polymerase chain reaction and western blotting using fibroblast cell lines derived from 1 affected individual and controls and through computational approaches. Knockouts in zebrafish were generated using clustered regularly interspaced short palindromic repeats/Cas9. Results: The disease was characterized by microcephaly, profound neurodevelopmental impairment, exaggerated startle response, myoclonic seizures, progressive widespread neurodegeneration, and premature death. Functional studies on patient-derived fibroblasts did not show a loss of protein function but rather disruption of the C-terminal of MED11, likely impairing binding to other MED subunits. A zebrafish knockout model recapitulates key clinical phenotypes. Conclusion: Loss of the C-terminal of MED subunit 11 may affect its binding efficiency to other MED subunits, thus implicating the MED-complex stability in brain development and neurodegeneration

Analysis of 339 pregnancies in 181 women with 13 different forms of inherited thrombocytopenia

Pregnancy in women with inherited thrombocytopenias is a major matter of concern as both the mothers and the newborns are potentially at risk of bleeding. However, medical management of this condition cannot be based on evidence because of the lack of consistent information in the literature. To advance knowledge on this matter, we performed a multicentric, retrospective study evaluating 339 pregnancies in 181 women with 13 different forms of inherited thrombocytopenia. Neither the degree of thrombocytopenia nor the severity of bleeding tendency worsened during pregnancy and the course of pregnancy did not differ from that of healthy subjects in terms of miscarriages, fetal bleeding and pre-term births. The degree of thrombocytopenia in the babies was similar to that in the mother. Only 7 of 156 affected newborns had delivery-related bleeding, but 2 of them died of cerebral hemorrhage. The frequency of delivery-related maternal bleeding ranged from 6.8% to 14.2% depending on the definition of abnormal blood loss, suggesting that the risk of abnormal blood loss was increased with respect to the general population. However, no mother died or had to undergo hysterectomy to arrest bleeding. The search for parameters predicting delivery-related bleeding in the mother suggested that hemorrhages requiring blood transfusion were more frequent in women with history of severe bleedings before pregnancy and with platelet count at delivery below 50 x 109/L

Medico-legal assessment of personal damage in older people: report from a multidisciplinary consensus conference

Ageing of the global population represents a challenge for national healthcare systems and healthcare professionals, including medico-legal experts, who assess personal damage in an increasing number of older people. Personal damage evaluation in older people is complex, and the scarcity of evidence is hindering the development of formal guidelines on the subject. The main objectives of the first multidisciplinary Consensus Conference on Medico-Legal Assessment of Personal Damage in Older People were to increase knowledge on the subject and establish standard procedures in this field. The conference, organized according to the guidelines issued by the Italian National Institute of Health (ISS), was held in Bologna (Italy) on June 8, 2019 with the support of national scientific societies, professional organizations, and stakeholders. The Scientific Technical Committee prepared 16 questions on 4 thematic areas: (1) differences in injury outcomes in older people compared to younger people and their relevance in personal damage assessment; (2) pre-existing status reconstruction and evaluation; (3) medico-legal examination procedures; (4) multidimensional assessment and scales. The Scientific Secretariat reviewed relevant literature and documents, rated their quality, and summarized evidence. During conference plenary public sessions, 4 pairs of experts reported on each thematic area. After the last session, a multidisciplinary Jury Panel (15 members) drafted the consensus statements. The present report describes Conference methods and results, including a summary of evidence supporting each statement, and areas requiring further investigation. The methodological recommendations issued during the Conference may be useful in several contexts of damage assessment, or to other medico-legal evaluation fields

A new measurement of the K-+/- -> pi(+/-)gamma gamma decay at the NA48/2 experiment

The NA48/2 experiment at CERN collected two data samples with minimum bias trigger conditions in 2003 and 2004. A measurement of the rate and dynamic properties of the rare decay K-+/- -> pi(+/-)gamma gamma from these data sets based on 149 decay candidates with an estimated background of 15.5 +/- 0.7 events is reported. The model-independent branching ratio in the kinematic range z = (m(gamma gamma)/m(K))(2) > 0.2 is measured to be B-MI(z > 0.2) = (0.877 +/- 0.089) x 10(-6), and the branching ratio in the full kinematic range assuming a particular Chiral Perturbation Theory description to be B(K-pi gamma gamma) = (0.910 +/- 0.075) x 10(-6). (C) 2014 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/3.0/)

Search for the dark photon in pi(0) decays

A sample of 1.69 x 10(7) fully reconstructed pi(0) -> gamma e(+)e(-) decay candidates collected by the NA48/2 experiment at CERN in 2003-2004 is analyzed to search for the dark photon (A') production in the pi(0) -> gamma A' decay followed by the prompt A' -> e(+)e(-) decay. No signal is observed, and an exclusion region in the plane of the dark photon mass m(A') and mixing parameter epsilon(2) is established. The obtained upper limits on epsilon(2) are more stringent than the previous limits in the mass range 9 MeV/c(2) pi(+/-)A' decay is also evaluated. (C) 2015 The Authors. Published by Elsevier B.V

Determination of gamma and-2 beta(s) from charmless two-body decays of beauty mesons

Using the latest LHCb measurements of time-dependent CP violation in the B-s(0) -> K+K- decay, a U-spin relation between the decay amplitudes of B-s(0) -> K+K- and B-0 -> p(+)p(-) decay processes allows constraints to be placed on the angle gamma of the unitarity triangle and on the B-s(0) mixing phase -2 beta(s). Results from an extended approach, which uses additional inputs on B-0 -> pi(0)pi(0) and B+ -> pi(+)pi(0) decays from other experiments and exploits isospin symmetry, are also presented. The dependence of the results on the maximum allowed amount of U-spin breaking is studied. At 68% probability, the value gamma =( 63.5(-6.7)(+7.2))degrees modulo 180 degrees is determined. In an alternative analysis, the value -2 beta(s)= - 0.12(-0.16)(+ 0.14) rad is found. In both measurements, the uncertainties due to U-spin breaking effects up to 50% are included. (C) 2014 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/3.0/)

Identification of beauty and charm quark jets at LHCb

Identification of jets originating from beauty and charm quarks is important for measuring Standard Model processes and for searching for new physics. The performance of algorithms developed to select b- and c-quark jets is measured using data recorded by LHCb from proton-proton collisions at root s = 7TeV in 2011 and at root s = 8TeV in 2012. The efficiency for identifying a b (c) jet is about 65%(25%) with a probability for misidentifying a light-parton jet of 0.3% for jets with transverse momentum pT > 20GeV and pseudorapidity 2 : 2 < eta < 4.2. The dependence of the performance on the pT and eta of the jet is also measured

B flavour tagging using charm decays at the LHCb experiment

An algorithm is described for tagging the flavour content at production of neutral B mesons in the LHCb experiment. The algorithm exploits the correlation of the flavour of a B meson with the charge of a reconstructed secondary charm hadron from the decay of the other b hadron produced in the proton-proton collision. Charm hadron candidates are identified in a number of fully or partially reconstructed Cabibbo-favoured decay modes. The algorithm is calibrated on the self-tagged decay modes B+ -> J/psi K+ and B-0 -> J/psi K*(0) using 3.0fb(-1) of data collected by the LHCb experiment at pp centre-of-mass energies of 7TeV and 8TeV. Its tagging power on these samples of B -> J/psi X decays is (0.30 +/- 0.01 +/- 0.01) %

The association of indwelling urinary catheter with delirium in hospitalized patients and nursing home residents: an explorative analysis from the "Delirium Day 2015"

BackroundUse of indwelling urinary catheter (IUC) in older adults has negative consequences, including delirium.AimThis analysis, from the Delirium Day 2015, a nationwide multicenter prevalence study, aim to evaluate the association of IUC with delirium in hospitalized and Nursing Homes (NHs) patients.MethodsPatients underwent a comprehensive geriatric assessment, including the presence of IUC; inclusion criteria were age>65 years, being Italian speaker and providing informed consent; exclusion criteria were coma, aphasia, end-of-life status. Delirium was assessed using the 4AT test (score4: possible delirium; scores 1-3: possible cognitive impairment).ResultsAmong 1867 hospitalized patients (mean age 82.07.5 years, 58% female), 539 (28.9%) had IUC, 429 (22.9%) delirium and 675 (36.1%) cognitive impairment. IUC was significantly associated with cognitive impairment (OR 1.60, 95% CI 1.19-2.16) and delirium (2.45, 95% CI 1.73-3.47), this latter being significant also in the subset of patients without dementia (OR 2.28, 95% CI 1.52-3.43). Inattention and impaired alertness were also independently associated with IUC. Among 1454 NHs residents (mean age 84.47.4 years, 70.% female), 63 (4.3%) had IUC, 535 (36.8%) a 4AT score4, and 653 (44.9%) a 4AT score 1-3. The multivariate logistic regression analysis did not show a significant association between 4AT test or its specific items with IUC, neither in the subset of patients without dementia.DiscussionWe confirmed a significant association between IUC and delirium in hospitalized patients but not in NHs residents.ConclusionEnvironmental and clinical factors of acute setting might contribute to IUC-associated delirium occurrence