Expanding the phenotype associated to KMT2A variants: overlapping clinical signs between Wiedemann–Steiner and Rubinstein–Taybi syndromes

Lysine-specific methyltransferase 2A (KMT2A) is responsible for methylation of histone H3 (K4H3me) and contributes to chromatin remodeling, acting as \u201cwriter\u201d of the epigenetic machinery. Mutations in KMT2A were first reported in Wiedemann\u2013Steiner syndrome (WDSTS). More recently, KMT2A variants have been described in probands with a specific clinical diagnosis comprised in the so-called chromatinopathies. Such conditions, including WDSTS, are a group of overlapping disorders caused by mutations in genes coding for the epigenetic machinery. Among them, Rubinstein\u2013Taybi syndrome (RSTS) is mainly caused by heterozygous pathogenic variants in CREBBP or EP300. In this work, we used next generation sequencing (either by custom-made panel or by whole exome) to identify alternative causative genes in individuals with a RSTS-like phenotype negative to CREBBP and EP300 mutational screening. In six patients we identified different novel unreported variants in KMT2A gene. The identified variants are de novo in at least four out of six tested individuals and all of them display some typical RSTS phenotypic features but also WDSTS specific signs. This study reinforces the concept that germline variants affecting the epigenetic machinery lead to a shared molecular effect (alteration of the chromatin state) determining superimposable clinical conditions

Incidence and factors associated with the risk of sexually transmitted diseases in HIV-infected people seen for care in Italy: data from the Icona Foundation cohort.

Objectives: The aims of this study were to identify temporal trends in the incidence of sexually transmitted diseases (STDs) in a cohort of HIV-infected people and to evaluate factors associated with the risk of a new STD diagnosis. Methods: All HIV-infected patients in the Icona Foundation Study cohort enrolled after 1998 were included in this study. STD incidence rates (IRs) were calculated and stratified by calendar period. Predictors of STDs were identified using a Poisson regression model with sandwich estimates for standard errors. Results: Data for 9168 participants were analysed [median age 37.3 (range 18-81) years; 74% male; 30% men who have sex with men (MSM)]. Over 46 736 person-years of follow-up (PYFU), 996 episodes of STDs were observed [crude IR 21.3/1000 PYFU; 95% confidence interval (CI) 20.0-22.6/1000 PYFU]. In multivariable Poisson regression analysis, MSM [rate ratio (RR) 3.03; 95% CI 2.52-3.64 versus heterosexuals], calendar period (RR 1.67; 95% CI 1.42-1.97 for 2008-2012 versus 1998-2002), HIV RNA > 50 HIV-1 RNA copies/mL (RR 1.44; 95% CI 1.19-1.74 versus HIV RNA ≤ 50 copies/mL) and a current CD4 count < 100 cells/μL (RR 4.66; 95% CI 3.69-5.89; P < 0.001 versus CD4 count > 500 cells/μL) were associated with an increased risk of STDs. In contrast, older age (RR 0.82 per 10 years older; 95% CI 0.77-0.89) and being currently on ART (RR 0.38; 95% CI 0.33-0.45) compared with being ART-naïve or on a treatment interruption were associated with a lower risk of developing STDs. Conclusions: An increase in the incidence of STDs was observed in more recent years. Interventions to prevent STDs and potential spread of HIV should target the younger population, MSM and people currently not receiving ART

Is physician assessment of alcohol consumption useful in predicting risk of severe liver disease among people with HIV and HIV/HCV co-infection?

Background: Alcohol consumption is a known risk factor for liver disease in HIV-infected populations. Therefore, knowledge of alcohol consumption behaviour and risk of disease progression associated with hazardous drinking are important in the overall management of HIV disease. We aimed at assessing the usefulness of routine data collected on alcohol consumption in predicting risk of severe liver disease (SLD) among people living with HIV (PLWHIV) with or without hepatitis C infection seen for routine clinical care in Italy. Methods: We included PLWHIV from two observational cohorts in Italy (ICONA and HepaICONA). Alcohol consumption was assessed by physician interview and categorized according to the National Institute for Food and Nutrition Italian guidelines into four categories: abstainer; moderate; hazardous and unknown. SLD was defined as presence of FIB4 > 3.25 or a clinical diagnosis of liver disease or liver-related death. Cox regression analysis was used to evaluate the association between level of alcohol consumption at baseline and risk of SLD. Results: Among 9542 included PLWHIV the distribution of alcohol consumption categories was: abstainers 3422 (36%), moderate drinkers 2279 (23%), hazardous drinkers 637 (7%) and unknown 3204 (34%). Compared to moderate drinkers, hazardous drinking was associated with higher risk of SLD (adjusted hazard ratio, aHR = 1.45; 95% CI: 1.03-2.03). After additionally controlling for mode of HIV transmission, HCV infection and smoking, the association was attenuated (aHR = 1.32; 95% CI: 0.94-1.85). There was no evidence that the association was stronger when restricting to the HIV/HCV co-infected population. Conclusions: Using a brief physician interview, we found evidence for an association between hazardous alcohol consumption and subsequent risk of SLD among PLWHIV, but this was not independent of HIV mode of transmission, HCV-infection and smoking. More efforts should be made to improve quality and validity of data on alcohol consumption in cohorts of HIV/HCV-infected individuals

Search for Tensor, Vector, and Scalar Polarizations in the Stochastic Gravitational-Wave Background

The detection of gravitational waves with Advanced LIGO and Advanced Virgo has enabled novel tests of general relativity, including direct study of the polarization of gravitational waves. While general relativity allows for only two tensor gravitational-wave polarizations, general metric theories can additionally predict two vector and two scalar polarizations. The polarization of gravitational waves is encoded in the spectral shape of the stochastic gravitational-wave background, formed by the superposition of cosmological and individually unresolved astrophysical sources. Using data recorded by Advanced LIGO during its first observing run, we search for a stochastic background of generically polarized gravitational waves. We find no evidence for a background of any polarization, and place the first direct bounds on the contributions of vector and scalar polarizations to the stochastic background. Under log-uniform priors for the energy in each polarization, we limit the energy densities of tensor, vector, and scalar modes at 95% credibility to Ω0T<5.58×10-8, Ω0V<6.35×10-8, and Ω0S<1.08×10-7 at a reference frequency f0=25 Hz. © 2018 American Physical Society

The x-ray polarimetry view of the accreting pulsar Cen X-3

Galaxie

Non-AIDS defining cancers in the D:A:D Study-time trends and predictors of survival : a cohort study

BACKGROUND:Non-AIDS defining cancers (NADC) are an important cause of morbidity and mortality in HIV-positive individuals. Using data from a large international cohort of HIV-positive individuals, we described the incidence of NADC from 2004-2010, and described subsequent mortality and predictors of these.METHODS:Individuals were followed from 1st January 2004/enrolment in study, until the earliest of a new NADC, 1st February 2010, death or six months after the patient's last visit. Incidence rates were estimated for each year of follow-up, overall and stratified by gender, age and mode of HIV acquisition. Cumulative risk of mortality following NADC diagnosis was summarised using Kaplan-Meier methods, with follow-up for these analyses from the date of NADC diagnosis until the patient's death, 1st February 2010 or 6 months after the patient's last visit. Factors associated with mortality following NADC diagnosis were identified using multivariable Cox proportional hazards regression.RESULTS:Over 176,775 person-years (PY), 880 (2.1%) patients developed a new NADC (incidence: 4.98/1000PY [95% confidence interval 4.65, 5.31]). Over a third of these patients (327, 37.2%) had died by 1st February 2010. Time trends for lung cancer, anal cancer and Hodgkin's lymphoma were broadly consistent. Kaplan-Meier cumulative mortality estimates at 1, 3 and 5 years after NADC diagnosis were 28.2% [95% CI 25.1-31.2], 42.0% [38.2-45.8] and 47.3% [42.4-52.2], respectively. Significant predictors of poorer survival after diagnosis of NADC were lung cancer (compared to other cancer types), male gender, non-white ethnicity, and smoking status. Later year of diagnosis and higher CD4 count at NADC diagnosis were associated with improved survival. The incidence of NADC remained stable over the period 2004-2010 in this large observational cohort.CONCLUSIONS:The prognosis after diagnosis of NADC, in particular lung cancer and disseminated cancer, is poor but has improved somewhat over time. Modifiable risk factors, such as smoking and low CD4 counts, were associated with mortality following a diagnosis of NADC

On the progenitor of binary neutron star merger GW170817

On 2017 August 17 the merger of two compact objects with masses consistent with two neutron stars was discovered through gravitational-wave (GW170817), gamma-ray (GRB 170817A), and optical (SSS17a/AT 2017gfo) observations. The optical source was associated with the early-type galaxy NGC 4993 at a distance of just ∼40 Mpc, consistent with the gravitational-wave measurement, and the merger was localized to be at a projected distance of ∼2 kpc away from the galaxy's center. We use this minimal set of facts and the mass posteriors of the two neutron stars to derive the first constraints on the progenitor of GW170817 at the time of the second supernova (SN). We generate simulated progenitor populations and follow the three-dimensional kinematic evolution from binary neutron star (BNS) birth to the merger time, accounting for pre-SN galactic motion, for considerably different input distributions of the progenitor mass, pre-SN semimajor axis, and SN-kick velocity. Though not considerably tight, we find these constraints to be comparable to those for Galactic BNS progenitors. The derived constraints are very strongly influenced by the requirement of keeping the binary bound after the second SN and having the merger occur relatively close to the center of the galaxy. These constraints are insensitive to the galaxy's star formation history, provided the stellar populations are older than 1 Gyr

Biodiversit\ue0 e litofacies ai limiti Frasniano\u2013Famenniano e Permiano\u2013Triassico in Alpi Meridionali: indagine multidisciplinare su due dei \u201cCinque Grandi\u201d

Le estinzioni al tetto del Frasniano e del Permiano sono considerate due dei \u201cCinque grandi\u201d eventi di estinzione globale del Fanerozoico. La ricerca verter\ue0 su analisi paleontologiche associate ad analisi sedimentologiche e geochimiche su sezioni delle Alpi Meridionali in successioni comprendenti i limiti Frasniano\u2013Famenniano (Fr\u2013Fm) e Permiano\u2013Triassico (P\u2013T), caratterizzati da una drastica riduzione della biodiversit\ue0 globale. Lo studio, gi\ue0 intrapreso da alcuni anni dal gruppo di ricerca, sar\ue0 approfondito ed esteso a nuove sezioni. I dati paleontologici finora basati quasi esclusivamente sui conodonti saranno integrati da quelli di altri gruppi fossili. Sar\ue0 cos\uec possibile valutare la variazione della biodiversit\ue0 prima, durante e dopo gli eventi di estinzione, al variare delle condizioni ambientali dedotte dall\u2019analisi delle litofacies, il cui parametro pi\uf9 importante, finora poco valutato, \ue8 la stima dell\u2019entit\ue0 dei rimaneggiamenti. Dati isotopici e paleomagnetici associati a quelli paleontologici e sedimentologici forniranno informazioni sulla fluttuazione dei parametri ambientali. A) Sulle problematiche del limite Fr\u2013Fm \ue8 comparsa nell\u2019ultimo decennio un\u2019abbondante letteratura che non comprende dati inerenti le Alpi Meridionali. La lacuna potr\ue0 essere colmata dalla recente individuazione di due sezioni carbonatiche delle Alpi Carniche che, per mezzo di una analisi biostratigrafica a conodonti preliminare, hanno consentito di identificare l\u2019esatta posizione del limite Fr\u2013Fm, definito dalla prima comparsa di Palmatolepis triangularis conodonte marker del limite. L\u2019estinzione al tetto del Frasniano si realizza in due eventi (Lower e Upper Kellwasser events) molto ravvicinati nel tempo (c.a 500.000 anni) che spesso corrispondono a livelli di shales neri. In entrambe le sezioni Pramosio A (Pizzo Timau) e Freikofel T (Monte Freikofel) l\u2019intervallo critico, che in altre aree \ue8 caratterizzato dalla presenza degli shales neri, \ue8 costituito da carbonati bioturbati di mare basso. Lo studio sedimentologico sulla sezione Pramosio A \ue8 stato realizzato su una campionatura in continuo, per mezzo di un carotatore portatile, al fine di ottenere una successione inintettotta di sezioni sottili e lastre lucidate. L\u2019analisi cos\uec dettagliata ha permesso il riconoscimento di numerose sequenze deposizionali cicliche, alcune di spessore centimetrico-decimetrico, e la calibratura preliminare dei dati sedimentologici con quelli biostratigrafici a conodonti. Nell\u2019ambito della ricerca si prevede una campionatura di maggior dettaglio della sezione Pramosio A e l\u2019estensione dell\u2019indagine sia sedimentologica che paleontologica alla sezione Freikofel T che nella parte alta \ue8 caratterizzata da facies carbonatiche meno prossimali con intervalli nodulari rossastri intercalati a livelli di brecce con clasti di derivazione anche peritidale. B) La successione Permiano\u2013Triassico delle Alpi Meridionali rappresenta il margine occidentale della Paleotetide a latitudine equatoriale. E\u2019 costituita dalle formazioni a Bellerophon e di Werfen che presentano, a livello regionale, due unconformity, una in corrispondenza del limite formazionale e l\u2019altra subito sotto. La sezione di Bulla (Bolzano) si \ue8 rivelata eccellente sia per lo studio sedimentologico che biostratigrafico essendo l\u2019unica sezione in Italia dove \ue8 stato possibile individuare il limite P\u2013T sulla base della prima comparsa, all\u2019interno della sequenza evolutiva praeparvus\u2013parvus\u2013isarcica, del conodonte Hindeodus parvus, marker che definisce la base del Mesozoico. Si prevede di integrare i dati paleontologici sui conodonti con quelli inerenti foraminiferi, brachiopodi, lamellibranchi, gasteropodi e pollini al fine di una completa valutazione della variazione della biodiversit\ue0. Nella sezione Bulla verranno effettuate analisi isotopiche da correlare a quelle paleomagnetiche gi\ue0 disponibili e campionature sedimentologiche in continuo, realizzate con carotatore. Questo tipo di analisi sedimentolo..