Risultati per: Quali armi contro l'infiammazione alla base dell'artite psoriasica?

Circulation, Volume 150, Issue Suppl_1, Page A4139206-A4139206, November 12, 2024. Introduction:Maintaining LDL-C at goal levels is critical in populations at high risk for cardiovascular events, including people with heterozygous familial hypercholesterolemia (HeFH) and/or premature coronary artery disease (CAD). Despite multiple approved LDL-C lowering therapies for these populations, most patients are not at guideline-directed treatment goal.In vivobase editing to inactivate hepaticPCSK9has the potential to provide lifelong LDL-C lowering after a single course of treatment. Success of the base editing approach is contingent on safe and effective hepatocyte delivery and precise, consistentPCSK9editing.Aim:We set out to develop a base editing medicine to inactivatePCSK9with broad utility across diverse genetic backgrounds. Here we describe the investigational therapy, VERVE-102, and the design of the ongoing, phase 1b Heart-2 trial.Approach:VERVE-102 consists of an mRNA encoding an adenine base editor and guide RNA (gRNA) targetingPCSK9packaged in a novel, proprietary GalNAc lipid nanoparticle (LNP). VERVE-102 creates a precise A-to-G DNA edit to introduce a premature stop codon and thereby inactivatePCSK9in hepatocytes. In a DNA sequence analysis of 784,318 individuals from diverse ancestries, the 20 base-pair sequence targeted by the gRNA was identical in 99.97% of individuals. LNP delivery to hepatocytesin vivooccurs through either endogenous LDL receptor (LDLR) uptake or GalNAc-mediated endocytosis via the asialoglycoprotein receptor (ASGPR) and as such, may address the LDLR deficiency seen in a fraction of patients with HeFH. Heart-2 is a single ascending dose trial of VERVE-102 in males and females aged 18–65 with HeFH and/or premature CAD who require additional LDL-C lowering despite maximally tolerated oral lipid-lowering therapies. Participants receive a single intravenous infusion of VERVE-102 with 3 to 9 participants per dose cohort. The primary endpoint is safety and tolerability. Secondary endpoints include pharmacokinetics of VERVE-102 and changes from baseline in blood PCSK9 and LDL-C.Discussion:VERVE-102 was designed to access hepatocytes via either LDLR- or ASGPR-mediated uptake to enable robust LNP delivery and subsequentPCSK9editing. Consistency of the gRNA target site suggests that potential therapeutic benefits should apply broadly across ancestries. The ongoing Heart-2 clinical trial is intended to support selection of a safe and effective dose for future clinical investigation of VERVE-102.

Circulation, Volume 150, Issue Suppl_1, Page ASu904-ASu904, November 12, 2024. Background:The relationship between base-excess (BE) values, which take into account the time interval from cardiac arrest to blood test, and neurological outcome after out-of-hospital cardiac arrest (OHCA) is not well understood. The purpose of this study was to evaluate the association between BE on arrival at the hospital and neurological outcomes in OHCA patients.Methods:The CRITICAL study, a prospective, multicenter observational study in Osaka, Japan, registered consecutive OHCA patients who were transported to 16 participating critical care centers from 2012 to 2021. We included adult patients aged 18 years with witnessed OHCA whose BE values on hospital arrival was available, and divided patients into quartiles based on BE values of initial blood test on arrival at the hospital: Q1 (BE ≤ −21.1 mmol/L), Q2 (−21.1 < BE ≤ −15.7 mmol/L), Q3 (−15.7 < BE ≤ −10.4 mmol/L), and Q4 (BE > −10.4 mmol/L). The primary outcome was one-month survival with favorable neurological outcome, defined as cerebral performance category scale 1 or 2.Results:A total of 23,854 patients were registered, and 6,066 of them were eligible for analyses. Neurologically favorable outcome was the lowest in the Q1 group (3.2% [49/1,528]), followed by the Q2 (4.7% [70/1,493]), Q3 (9.8% [148/1,515]), and Q4 (23.5% [359/1,530]) group. In the multivariable logistic regression analysis, the adjusted odds ratio of Q1 compared with Q4 for one-month favorable neurological outcome was 0.13 (95% CI 0.090–0.18). The proportion of one-month favorable neurological outcome decreased progressively across decreasing quartiles (p for trend < 0.001). In subgroup analysis, there was an interaction between presence of return of spontaneous circulation (ROSC) before blood test and neurological outcome (p for interaction < 0.001). The neurological outcome worsened as the BE values decreased among those who achieved ROSC before the blood test (p for trend < 0.001), but not in those without ROSC (p for trend = 0.078). There was not a significant interaction between BE values without ROSC before blood test and time from witness to blood test (p for interaction = 0.501).Conclusions:We demonstrated that lower BE values at hospital arrival were associated with worse neurological outcome. The BE values may be one of the effective prognostic indications for neurological outcome, especially in OHCA patients with ROSC before hospital arrival.

‘Altre 2 aggressioni in 24 ore. E’ un’emergenza costituzionale’

‘Bisogna rivedere il loro ruolo in riforma medicina territorio’

Utile per nuove terapie e diagnosi precoce

We welcome the excellent discussion from Mandarino et al regarding whether thermal ablation of resection base is warranted after endoscopic mucosal resection (EMR) of large non-pedunculated colorectal polyps.1 2 We agree with many of the points raised by the authors. Indeed, a perfect resection technique as evidenced by Mandarino et al is likely to reduce the need for base ablation; however, such perfect technique is not always possible be it due to polyp-related or endoscopist-related factors. Furthermore, perfect overlapping resections with wide margins would also theoretically preclude the need for snare tip soft coagulation (STSC) of the margins. However, if the theory of microscopic polyp remnants at the margins despite overlapping and wide resection holds true, then the same should be considered possible for the base. Several Randomised controlled trials (RCTs) comparing hot versus cold snare EMR have recently been presented.3 4

Marti, ‘massima convergenza’ in Commissione Istruzione al Senato

Attivo da anni, il percorso culturale, organizzativo e istituzionale ha fatto registrare risultati positivi sia dal punto di vista terapeutico sia sulla spesa sanitaria

Il 13enne soffre di una rara malattia che ha deteriorato cornee

Il 13enne soffre di una rara malattia che ha deteriorato cornee

Se ben trattata ha un decorso benigno ma possibili le recidive

L’intervento sull’umore ‘cura’ le malattie infiammatorie intestinali

Bozza milleproroghe, misure anche per specializzandi pediatria