Summary Background c-kit-positive, lineage-negative cardiac stem cells (CSCs) improve post-infarction left ventricular (LV) dysfunction when administered to animals. We undertook a phase 1 trial ...(Stem Cell Infusion in Patients with Ischemic cardiOmyopathy SCIPIO) of autologous CSCs for the treatment of heart failure resulting from ischaemic heart disease. Methods In stage A of the SCIPIO trial, patients with post-infarction LV dysfunction (ejection fraction EF ≤40%) before coronary artery bypass grafting were consecutively enrolled in the treatment and control groups. In stage B, patients were randomly assigned to the treatment or control group in a 2:3 ratio by use of a computer-generated block randomisation scheme. 1 million autologous CSCs were administered by intracoronary infusion at a mean of 113 days (SE 4) after surgery; controls were not given any treatment. Although the study was open label, the echocardiographic analyses were masked to group assignment. The primary endpoint was short-term safety of CSCs and the secondary endpoint was efficacy. A per-protocol analysis was used. This study is registered with ClinicalTrials.gov , number NCT00474461. Findings This study is still in progress. 16 patients were assigned to the treatment group and seven to the control group; no CSC-related adverse effects were reported. In 14 CSC-treated patients who were analysed, LVEF increased from 30·3% (SE 1·9) before CSC infusion to 38·5% (2·8) at 4 months after infusion (p=0·001). By contrast, in seven control patients, during the corresponding time interval, LVEF did not change (30·1% 2·4 at 4 months after CABG vs 30·2% 2·5 at 8 months after CABG). Importantly, the salubrious effects of CSCs were even more pronounced at 1 year in eight patients (eg, LVEF increased by 12·3 ejection fraction units 2·1 vs baseline, p=0·0007). In the seven treated patients in whom cardiac MRI could be done, infarct size decreased from 32·6 g (6·3) by 7·8 g (1·7; 24%) at 4 months (p=0·004) and 9·8 g (3·5; 30%) at 1 year (p=0·04). Interpretation These initial results in patients are very encouraging. They suggest that intracoronary infusion of autologous CSCs is effective in improving LV systolic function and reducing infarct size in patients with heart failure after myocardial infarction, and warrant further, larger, phase 2 studies. Funding University of Louisville Research Foundation and National Institutes of Health.
Summary Background Innate immunity contributes to the pathogenesis of autoimmune diseases, such as type 1 diabetes, but until now no randomised, controlled trials of blockade of the key innate immune ...mediator interleukin-1 have been done. We aimed to assess whether canakinumab, a human monoclonal anti-interleukin-1 antibody, or anakinra, a human interleukin-1 receptor antagonist, improved β-cell function in recent-onset type 1 diabetes. Methods We did two randomised, placebo-controlled trials in two groups of patients with recent-onset type 1 diabetes and mixed-meal-tolerance-test-stimulated C peptide of at least 0·2 nM. Patients in the canakinumab trial were aged 6–45 years and those in the anakinra trial were aged 18–35 years. Patients in the canakinumab trial were enrolled at 12 sites in the USA and Canada and those in the anakinra trial were enrolled at 14 sites across Europe. Participants were randomly assigned by computer-generated blocked randomisation to subcutaneous injection of either 2 mg/kg (maximum 300 mg) canakinumab or placebo monthly for 12 months or 100 mg anakinra or placebo daily for 9 months. Participants and carers were masked to treatment assignment. The primary endpoint was baseline-adjusted 2-h area under curve C-peptide response to the mixed meal tolerance test at 12 months (canakinumab trial) and 9 months (anakinra trial). Analyses were by intention to treat. These studies are registered with ClinicalTrials.gov , numbers NCT00947427 and NCT00711503 , and EudraCT number 2007-007146-34. Findings Patients were enrolled in the canakinumab trial between Nov 12, 2010, and April 11, 2011, and in the anakinra trial between Jan 26, 2009, and May 25, 2011. 69 patients were randomly assigned to canakinumab (n=47) or placebo (n=22) monthly for 12 months and 69 were randomly assigned to anakinra (n=35) or placebo (n=34) daily for 9 months. No interim analyses were done. 45 canakinumab-treated and 21 placebo-treated patients in the canakinumab trial and 25 anakinra-treated and 26 placebo-treated patients in the anakinra trial were included in the primary analyses. The difference in C peptide area under curve between the canakinumab and placebo groups at 12 months was 0·01 nmol/L (95% CI −0·11 to 0·14; p=0·86), and between the anakinra and the placebo groups at 9 months was 0·02 nmol/L (–0·09 to 0·15; p=0·71). The number and severity of adverse events did not differ between groups in the canakinumab trial. In the anakinra trial, patients in the anakinra group had significantly higher grades of adverse events than the placebo group (p=0·018), which was mainly because of a higher number of injection site reactions in the anakinra group. Interpretation Canakinumab and anakinra were safe but were not effective as single immunomodulatory drugs in recent-onset type 1 diabetes. Interleukin-1 blockade might be more effective in combination with treatments that target adaptive immunity in organ-specific autoimmune disorders. Funding National Institutes of Health and Juvenile Diabetes Research Foundation.
•Approximately one in five femoral fragility fracture patients take an anticoagulant medication, primarily DOACs.•Anticoagulated patients differ in several demographic and comorbidity ...characteristics.•Time to surgery was longer for anticoagulated patients and fewer received surgery within 36 h of admission.•Differences in time to surgery were similar between countries however there was some variation between hospitals.•Adjusted 30-day mortality from admission was higher in anticoagulated patients.
Due to their hypocoagulable state on presentation, anticoagulated patients with femoral fragility fractures typically experience delays to surgery. There are no large, multicentre studies previously carried out within the United Kingdom (UK) evaluating the impact of anticoagulant use in this patient population. This study aimed to evaluate the current epidemiology and compare the perioperative management of anticoagulated and non-anticoagulated femoral fragility fracture patients.
Data was prospectively collected through a collaborative, multicentre approach involving hospitals across the United Kingdom. Femoral fragility fracture patients aged ≥60 years and admitted to hospital between 1st May to 31st July 2023 were included. Main outcomes under investigation included time to surgery, receipt of blood transfusion between admission and 48 h following surgery, length of stay, and 30-day mortality. These were assessed using multivariable linear and logistic regression, and Cox proportional hazards models. Only data from hospitals ≥90 % case ascertainment with reference to figures from the National Hip Fracture Database (NHFD) were analysed.
Data on 10,197 patients from 78 hospitals were analysed. 18.5 % of patients were taking anticoagulants. Compared to non-anticoagulated patients, time to surgery was longer by 7.59 h (95 %CI 4.83–10.36; p < 0.001). 42.41 % of anticoagulated patients received surgery within 36 h (OR 0.54, 95 %CI 0.48–0.60, p < 0.001). Differences in time to surgery were similar between countries however there was some variation across units. There were no differences in blood transfusion and length of stay between groups (OR 1.03, 95 %CI 0.88–1.22, p = 0.646 and 0.22 days, 95 %CI -0.45–0.89; p = 0.887 respectively). Mortality within 30 days of admission was higher in anticoagulated patients (HR 1.27, 95 %CI 1.03–1.57, p = 0.026).
Anticoagulated femoral fragility fracture patients comprise a substantial number of patients, and experience relatively longer delays to surgery with less than half receiving surgery within 36 h of admission. This may have resulted in their comparatively higher mortality rate. Inclusion of anticoagulation status in the minimum data set for the NHFD to enable routine auditing of performance, and development of a national guideline on the management of this growing and emerging patient group is likely to help standardise practice in this area and improve outcomes.
•Only around half of hospitals have dedicated protocols for the perioperative management of patients taking warfarin and DOAC medications.•Substantial variation in guidance exists among protocols of ...different hospitals with a lack of consistency in guidance within the Trauma Network.•A large proportion of protocols lacked guidance on several important aspects of management including type of anaesthesia during surgery.•Existence of dedicated hospital protocols did not improve attainment of the defined targets for time to surgery from admission.
Approximately 20 % of femoral fragility fracture patients take anticoagulants, typically warfarin or Direct Oral AntiCoagulant (DOAC). These can impact timing of surgery affecting patient survival. Due to several possible approaches and numerous factors to consider in the preoperative workup of anticoagulated patients, potential for variations in clinical practice exist. Some hospitals employ dedicated anticoagulation management protocols to address this issue, and to improve time to surgery. This study aimed to determine the proportion of hospitals with such protocols, compare protocol guidance between hospitals, and evaluate the effectiveness of protocols in facilitating prompt surgery.
Data was prospectively collected through a collaborative, multicentre approach involving hospitals across the UK. Femoral fragility fracture patients aged ≥60 years and admitted to hospital between 1st May to 31st July 2023 were included. Information from dedicated anticoagulation management protocols were collated on several domains relating to perioperative care including administration of reversal agents and instructions on timing of surgery as well as others. Logistic regression was used to evaluate effects of dedicated protocols on time to surgery.
Dedicated protocols for management of patients taking warfarin and DOACs were present at 41 (52.6 %) and 43 (55.1 %) hospitals respectively. For patients taking warfarin, 39/41 (95.1 %) protocols specified the dose of vitamin k and the most common was 5 milligrams intravenously (n=21). INR threshold values for proceeding to surgery varied between protocols; 1.5 (n=28), 1.8 (n=6), and 2 (n=6). For patients taking DOACs, 35/43 (81.4 %) and 8/43 (18.6 %) protocols advised timing of surgery based on renal function and absolute time from last dose respectively. Analysis of 10,197 patients from 78 hospitals showed fewer patients taking DOACs received surgery within 36 h of admission at hospitals with a dedicated protocol compared to those without (adjusted OR 0.73, 95% CI 0.54–0.99, p=0.040), while there were no differences among patients taking warfarin (adjusted OR 1.64, 95% CI 0.75–3.57, p=0.219).
Around half of hospitals employed a dedicated anticoagulation management protocol for femoral fragility fracture patients, and substantial variation was observed in guidance between protocols. Dedicated protocols currently being used at hospitals were ineffective at improving the defined targets for time to surgery.
Pollutants originating from the destruction of the World Trade Center (WTC) in New York City on 11 September 2001 have been reported to cause adverse respiratory responses in rescue workers and ...nearby residents. We examined whether WTC-derived fine particulate matter particulate matter with a mass median aerodynamic diameter < 2.5 μm ( PM2.5) has detrimental respiratory effects in mice to contribute to the risk assessment of WTC-derived pollutants. Samples of WTC PM2.5were derived from settled dust collected at several locations around Ground Zero on 12 and 13 September 2001. Aspirated samples of WTC PM2.5induced mild to moderate degrees of pulmonary inflammation 1 day after exposure but only at a relatively high dose (100 μg). This response was not as great as that caused by 100 μg PM2.5derived from residual oil fly ash (ROFA) or Washington, DC, ambient air PM National Institute of Standards and Technology, Standard Reference Material (SRM) 1649a. However, this same dose of WTC PM2.5caused airway hyperresponsiveness to methacholine aerosol comparable to that from SRM 1649a and to a greater degree than that from ROFA. Mice exposed to lower doses by aspiration or inhalation exposure did not develop significant inflammation or hyperresponsiveness. These results show that exposure to high levels of WTC PM2.5can promote mechanisms of airflow obstruction in mice. Airborne concentrations of WTC PM2.5that would cause comparable doses in people are high (∼ 425 μ g/ m3for 8 hr) but conceivable in the aftermath of the collapse of the towers when rescue and salvage efforts were in effect. We conclude that a high-level exposure to WTC PM2.5could cause pulmonary inflammation and airway hyperresponsiveness in people. The effects of chronic exposures to lower levels of WTC PM2.5, the persistence of any respiratory effects, and the effects of coarser WTC PM are unknown and were not examined in these studies. Degree of exposure and respiratory protection, individual differences in sensitivity to WTC PM2.5, and species differences in responses must be considered in assessing the risks of exposure to WTC PM2.5.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, IZUM, KILJ, NMLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK