In a small trial of boost immunization with the mRNA vaccine originally received or with heterologous boosting with spike proteins from the original strain or the beta variant, the beta-adjuvanted ...booster resulted in the highest titers of antibody and activated T cells 2 weeks later.
Background & Aims Parenteral methotrexate is an effective treatment for patients with Crohn’s disease, but has never been adequately evaluated in patients with ulcerative colitis (UC). We conducted a ...randomized controlled trial to determine its safety and efficacy in patients with steroid-dependent UC. Methods We performed a double-blind, placebo-controlled trial to evaluate the efficacy of parenteral methotrexate (25 mg/wk) in 111 patients with corticosteroid-dependent UC at 26 medical centers in Europe from 2007 through 2013. Patients were given prednisone (10 to 40 mg/d) when the study began and were randomly assigned to groups (1:1) given placebo or methotrexate (intramuscularly or subcutaneously, 25 mg weekly) for 24 weeks. The primary end point was steroid-free remission (defined as a Mayo score ≤2 with no item >1 and complete withdrawal of steroids) at week 16. Secondary endpoints included clinical remission (defined as a Mayo clinical subscore ≤2 with no item >1) and endoscopic healing without steroids at weeks 16 and/or 24, remission without steroids at week 24, and remission at both weeks 16 and 24. Results Steroid-free remission at week 16 was achieved by 19 of 60 patients given methotrexate (31.7%) and 10 of 51 patients given placebo (19.6%)—a difference of 12.1% (95% confidence interval CI: −4.0% to 28.1%; P = .15). The proportion of patients in steroid-free clinical remission at week 16 was 41.7% in the methotrexate group and 23.5% in the placebo group, for a difference of 18.1% (95% CI: 1.1% to 35.2%; P = .04). The proportions of patients with steroid-free endoscopic healing at week 16 were 35% in the methotrexate group and 25.5% in the placebo group—a difference of 9.5% (95% CI: −7.5% to 26.5%; P = .28). No differences were observed in other secondary end points. More patients receiving placebo discontinued the study because of adverse events (47.1%), mostly caused by UC, than patients receiving methotrexate (26.7%; P = .03). A higher proportion of patients in the methotrexate group had nausea and vomiting (21.7%) than in the placebo group (3.9%; P = .006). Conclusions In a randomized controlled trial, parenteral methotrexate was not superior to placebo for induction of steroid-free remission in patients with UC. However, methotrexate induced clinical remission without steroids in a significantly larger percentage of patients, resulting in fewer withdrawals from therapy due to active UC. ClinicalTrials.gov ID NCT00498589.
Intravenous (i.v.) thrombolysis with tissue plasminogen activator (rt-PA, i.v. 0.9 mg/kg body weight) has been approved by European health authorities in 2002, with a 3-hr time window. The ...meta-analysis of i.v. rt-PA trials suggests efficacy of rt-PA up to 4.5 to 6 hr. However, treatment efficacy declines rapidly over time: the numbers of patients needed to treat to prevent 1 death or dependency are respectively 7, 12, and > 30 in the 0-3 hr, 0-6 hr, and 3-6 hr time windows. Magnetic resonance imaging may be the best way to select candidates for thrombolysis beyond 3 hr, on the basis of the presence of arterial occlusion and mismatch between diffusion and perfusion images. New trials are testing the possibility of extending the time window. Trials with new thrombolytic agents, ultrasound thrombolysis, and mechanical thrombolysis also are running or planned in the 3- to 6-hr time window. The 3-hr limit is just a matter of safety. Patients should be treated as soon as possible, and the earliest is the best.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We investigated serum neutralizing activity against BA.1 and BA.2 Omicron sublineages and T cell response before and 3 months after administration of the booster vaccine in healthcare workers (HCWs).
...HCWs aged 18–65 years who were vaccinated and received booster doses of the BNT162b2 vaccine were included. Anti–SARS coronavirus 2 IgG levels and cellular response (through interferon γ ELISpot assay) were evaluated in all participants, and neutralizing antibodies against Delta, BA.1, and BA.2 were evaluated in participants with at least one follow-up visit 1 or 3 months after the administration of the booster dose.
Among 118 HCWs who received the booster dose, 102 and 84 participants attended the 1-month and 3-month visits, respectively. Before the booster vaccine dose, a low serum neutralizing activity against Delta, BA.1, and BA.2 was detectable in only 39/102 (38.2%), 8/102 (7.8%), and 12/102 (11.8%) participants, respectively. At 3 months, neutralizing antibodies against Delta, BA.1, and BA.2 were detected in 84/84 (100%), 79/84 (94%), and 77/84 (92%) participants, respectively. Geometric mean titres of neutralizing antibodies against BA.1 and BA.2 were 2.2-fold and 2.8-fold reduced compared with those for Delta. From 1 to 3 months after the administration of the booster dose, participants with a recent history of SARS coronavirus 2 infection (n = 21/84) had persistent levels of S1 reactive specific T cells and neutralizing antibodies against Delta and BA.2 and 2.2-fold increase in neutralizing antibodies against BA.1 (p 0.014). Conversely, neutralizing antibody titres against Delta (2.5-fold decrease, p < 0.0001), BA.1 (1.5-fold, p 0.02), and BA.2 (2-fold, p < 0.0001) declined from 1 to 3 months after the administration of the booster dose in individuals without any recent infection.
The booster vaccine dose provided significant and similar response against BA.1 and BA.2 Omicron sublineages; however, the immune response declined in the absence of recent infection.
The contribution of modifying non-low-density lipoprotein cholesterol (LDL-C) levels to reduce stroke risk remains uncertain. The aim of this study was to investigate the association between ...treatment-induced change in plasma triglyceride levels and risk of stroke and progression of carotid intima-media thickness (CIMT).
We performed a systematic review and meta-regression analyses of randomized controlled trials of lipid-modifying treatments selected from a PubMed search on literature published from 1966 to 2008.
We identified 64 randomized controlled trials (active groups, n=96,807; control groups, n=98,681) that tested lipid-modifying drugs and reported triglyceride levels and stroke outcome. Extracting data from placebo groups, we found a statistically significant association between baseline triglyceride levels and stroke risk (adjusted relative risk RR, 1.05 per 10-mg/dL increase; 95% CI, 1.03-1.07). Except for a trend in fibrate and niacin trials, there was no evidence of any relationship between degree of triglyceride change and stroke incidence. In multivariable meta-regression analysis including baseline and change in LDL-C, only change in LDL-C was associated with log risk ratio of all strokes (RR reduction, 4.5% per 10-mg/dL reduction; 95% CI, 1.7-7.2; P=.003). Similarly, taking into account 26 randomized controlled trials reporting CIMT outcome, LDL-C reduction was associated with reduced CIMT progression (-3.0 microm/y per 10-mg/dL reduction; 95% CI, -5.5 to -0.4; P=.03).
In view of the limitations of meta-regression analysis and CIMT measures as surrogate endpoints in lipid-lowering drugs trials, additional studies are needed to more precisely quantify the detrimental effect of triglyceride levels on stroke risk and to establish the efficacy of triglyceride-lowering therapy in addition to LDL-C reduction.
Statin therapy has became the most important advance in stroke prevention since the introduction of aspirin and blood pressure–lowering therapies. Other lipid-modifying drugs have been less ...successful in reducing the incidence of stroke, but because of evidence for the use of triglyceride-lowering drugs and treatments that raise concentrations of high-density lipoprotein (HDL) cholesterol, further investigations are needed, particularly in patients with an atherogenic dyslipidemia profile (high triglycerides and low HDL cholesterol levels). Furthermore, beyond reducing low-density lipoprotein cholesterol and possibly improving other lipids fractions in patients who are at high risk of stroke, the present review shoes that lipid-modifying drugs might have neuroprotective effects that should also be further explored.
Little is known on the association between clinical factors and coronavirus disease 2019 (COVID‐19) more than 15 days after diagnosis. We conducted a multicentric prospective cohort of COVID‐19 ...hospitalized patients to describe clinical, biological, and virological characteristics at hospital admission and over time, according to mortality up to Day 60 after admission. For the analysis of risk factors of survival, analyses assessing associations between mortality and demographic characteristics or comorbidities were performed using a Cox regression model. Between January 24 and March 15, 2020, 246 patients with reverse‐transcriptase polymerase chain reactions virologically confirmed COVID‐19 were enrolled. In multivariate analysis, mortality at Day 60 (n = 42 patients, 17.1% 95% confidence interval, 12.6–22.4) was associated with older age (adjusted hazard ratio aHR for age ≥ 65 years: 5.22 2.56–10.63, p < .001), gender (aHR for male: 2.97 1.47–5.99, p = .002), chronic pulmonary disease (aHR: 4.84 2.32–10.07, p < .001), obesity (aHR: 3.32 1.70–6.52, p < .001), and diabetes (aHR: 1.98 1.01–3.89, p = .048). The median nasopharyngeal viral load at admission was 6.4 log10 copies/ml and was associated with mortality regardless of clinical risk factors. Viral load decreased with time elapsed since symptoms onset. Our study confirmed that mortality was associated with clinical characteristics at admission. The viral load at admission was significantly lower in patients admitted late after the onset of symptoms in both dead and alive patients. Our results could improve earlier identification of patients with increased risk of mortality and adapted management.
Highlights
Older age, male gender, chronic pulmonary disease (not asthma), obesity, and diabetes were associated with mortality in COVID‐19 hospitalized patients.
Viral load at admission decreased with the time since symptom onset, with an association with mortality adjusted on clinical risk factors.
Early liver transplantation for severe alcohol-related hepatitis is an emerging treatment option. We aimed to assess the risk of alcohol relapse 2 years after early liver transplantation for ...alcohol-related hepatitis compared with liver transplantation for alcohol-related cirrhosis after at least 6 months of abstinence.
We conducted a multicentre, non-randomised, non-inferiority, controlled study in 19 French and Belgian hospitals. All participants were aged 18 years or older. There were three groups of patients recruited prospectively: patients with severe alcohol-related hepatitis who did not respond to medical treatment and were eligible for early liver transplantation according to a new selection scoring system based on social and addiction items that can be quantified in points (early transplantation group); patients with alcohol-related cirrhosis listed for liver transplantation after at least 6 months of abstinence (standard transplantation group); patients with severe alcohol-related hepatitis not responding to medical treatment not eligible for early liver transplantation according to the selection score (not eligible for early transplantation group), this group did not enter any further liver transplantation processes. We also defined a historical control group of patients with severe alcohol-related hepatitis unresponsive to medical therapy and non-transplanted. The primary outcome was the non-inferiority of 2-year rate of alcohol relapse after transplantation in the early transplantation group compared with the standard transplantation group using the alcohol timeline follow back (TLFB) method and a prespecified non-inferiority margin of 10%. Secondary outcomes were the pattern of alcohol relapse, 2-year survival rate post-transplant in the early transplantation group compared with the standard transplantation group, and 2-year overall survival in the early transplantation group compared with patients in the not eligible for early transplantation group and historical controls. This trial is registered with ClinicalTrials.gov, NCT01756794.
Between Dec 5, 2012, and June 30, 2016, we included 149 patients with severe alcohol-related hepatitis: 102 in the early transplantation group and 47 in the not eligible for early transplantation group. 129 patients were included in the standard transplantation group. 68 patients in the early transplantation group and 93 patients in the standard transplantation group received a liver transplant. 23 (34%) patients relapsed in the early transplantation group, and 23 (25%) patients relapsed in the standard transplantation group; therefore, the non-inferiority of early transplantation versus standard transplantation was not demonstrated (absolute difference 9·1% 95% CI -∞ to 21·1; p=0·45). The 2-year rate of high alcohol intake was greater in the early transplantation group than the standard transplantation group (absolute difference 16·7% 95% CI 5·8-27·6) The time spent drinking alcohol was not different between the two groups (standardised difference 0·24 95% CI -0·07 to 0·55), but the time spent drinking a large quantity of alcohol was higher in the early transplantation group than the standard transplantation group (standardised difference 0·50 95% CI 0·17-0·82). 2-year post-transplant survival was similar between the early transplantation group and the standard transplantation group (hazard ratio HR 0·87 95% CI 0·33-2·26); 2-year overall survival was higher in the early transplantation group than the not eligible for early transplantation group and historical controls (HR 0·27 95% CI 0·16-0·47 and 0·21 0·13-0·32).
We cannot conclude non-inferiority in terms of rate of alcohol relapse post-transplant between early liver transplantation and standard transplantation. High alcohol intake is more frequent after early liver transplantation. This prospective controlled study confirms the important survival benefit related to early liver transplantation for severe alcohol-related hepatitis; and this study provides objective data on survival and alcohol relapse to tailor the management of patients with severe alcohol-related hepatitis.
The present study has been granted by the French Ministry of Health-Programme Hospitalier de Recherche Clinique 2010.
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