Electronic health records to facilitate clinical research

Electronic health records (EHRs) provide opportunities to enhance patient care, embed performance measures in clinical practice, and facilitate clinical research. Concerns have been raised about the increasing recruitment challenges in trials, burdensome and obtrusive data collection, and uncertain generalizability of the results. Leveraging electronic health records to counterbalance these trends is an area of intense interest. The initial applications of electronic health records, as the primary data source is envisioned for observational studies, embedded pragmatic or post-marketing registry-based randomized studies, or comparative effectiveness studies. Advancing this approach to randomized clinical trials, electronic health records may potentially be used to assess study feasibility, to facilitate patient recruitment, and streamline data collection at baseline and follow-up. Ensuring data security and privacy, overcoming the challenges associated with linking diverse systems and maintaining infrastructure for repeat use of high quality data, are some of the challenges associated with using electronic health records in clinical research. Collaboration between academia, industry, regulatory bodies, policy makers, patients, and electronic health record vendors is critical for the greater use of electronic health records in clinical research. This manuscript identifies the key steps required to advance the role of electronic health records in cardiovascular clinical research

Numeričko i eksperimentalno modeliranje nosivih elemenata teške metalurške opreme

Carrying structures of heavy metallurgical equipments are during their operation often exposed to extreme loading. The short-term overloading of the structure results to high stresses in locations of their concentrations. By repeating of these phenomena is decreased the life-time of the structure and eventually this leads to local failures in their carrying elements. In the paper are on examples described advantages of using numerical and experimental methods of mechanical system modelling that is exploited for identification of overloading in carrying elements of metallurgical equipments or for detection of damage causes.Nosivi elementi teške metalurške opreme tijekom eksploatacije često su izloženi ekstremnim opterećenjima. Njihova kratkotrajna preopterećenja izazivaju visoka naprezanja na mjestima koncentracije. Ponavljanje ove pojave izaziva skraćenje životnog vijeka konstrukcije i moguća lokalna oštećenja nosivih elemenata. U ovom članku, na dva primjera su prikazane prednosti primjene numeričkih i eksperimentalnih metoda modeliranja mehaničkog sustava u otkrivanju preopterećenja ili uzroka oštećenja nosivih elemenata metalurške opreme

Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p<0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (<1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (<1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

Fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin with gemtuzumab ozogamicin improves event-free survival in younger patients with newly diagnosed aml and overall survival in patients with npm1 and flt3 mutations

Purpose To determine the optimal induction chemotherapy regimen for younger adults with newly diagnosed AML without known adverse risk cytogenetics. Patients and Methods One thousand thirty-three patients were randomly assigned to intensified (fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin [FLAG-Ida]) or standard (daunorubicin and Ara-C [DA]) induction chemotherapy, with one or two doses of gemtuzumab ozogamicin (GO). The primary end point was overall survival (OS). Results There was no difference in remission rate after two courses between FLAG-Ida + GO and DA + GO (complete remission [CR] + CR with incomplete hematologic recovery 93% v 91%) or in day 60 mortality (4.3% v 4.6%). There was no difference in OS (66% v 63%; P = .41); however, the risk of relapse was lower with FLAG-Ida + GO (24% v 41%; P < .001) and 3-year event-free survival was higher (57% v 45%; P < .001). In patients with an NPM1 mutation (30%), 3-year OS was significantly higher with FLAG-Ida + GO (82% v 64%; P = .005). NPM1 measurable residual disease (MRD) clearance was also greater, with 88% versus 77% becoming MRD-negative in peripheral blood after cycle 2 (P = .02). Three-year OS was also higher in patients with a FLT3 mutation (64% v 54%; P = .047). Fewer transplants were performed in patients receiving FLAG-Ida + GO (238 v 278; P = .02). There was no difference in outcome according to the number of GO doses, although NPM1 MRD clearance was higher with two doses in the DA arm. Patients with core binding factor AML treated with DA and one dose of GO had a 3-year OS of 96% with no survival benefit from FLAG-Ida + GO. Conclusion Overall, FLAG-Ida + GO significantly reduced relapse without improving OS. However, exploratory analyses show that patients with NPM1 and FLT3 mutations had substantial improvements in OS. By contrast, in patients with core binding factor AML, outcomes were excellent with DA + GO with no FLAG-Ida benefit

Effect of darapladib treatment on endarterectomy carotid plaque lipoprotein-associated phospholipase A2 activity: a randomized, controlled trial.

BACKGROUND: The aim of this study was to assess the effects of darapladib, a selective oral investigational lipoprotein-associated phospholipase A2 inhibitor, on both plasma and plaque lipoprotein-associated phospholipase A2 activity. METHODS: Patients undergoing elective carotid endarterectomy were randomized to darapladib 40 mg (n = 34), 80 mg (n = 34), or placebo (n = 34) for 14 days, followed by carotid endarterectomy 24 hours after the last dose of study medication. RESULTS: Darapladib 40 mg and 80 mg reduced plasma lipoprotein-associated phospholipase A2 activity by 52% and 81%, respectively, versus placebo (both P<0.001). Significant reductions in plaque lipoprotein-associated phospholipase A2 activity were also observed compared with placebo (P<0.0001), which equated to a 52% and 80% decrease compared with placebo. No significant differences were observed between groups in plaque lysophosphatidylcholine content or other biomarkers, although a dose-dependent decrease in plaque matrix metalloproteinase-9 mRNA expression was observed with darapladib 80 mg (P = 0.053 vs placebo). In a post-hoc analysis, plaque caspase-3 (P<0.001) and caspase-8 (P<0.05) activity were found to be significantly lower in the darapladib 80-mg group versus placebo. No major safety concerns were identified in the study. CONCLUSIONS: Short-term treatment (14 ± 4 days) with darapladib produced a robust, dose-dependent reduction in plasma lipoprotein-associated phospholipase A2 activity. More importantly, darapladib demonstrated placebo-corrected reductions in carotid plaque lipoprotein-associated phospholipase A2 activity of similar magnitude. Darapladib was generally well tolerated and no safety concerns were identified. Additional studies of longer duration are needed to explore whether these pharmacodynamic effects are associated with improved clinical outcomes, as might be hypothesized

Impact of the 2019 Food and Drug Administration Guidance for Uncomplicated Urinary Tract Infection on Treatment Response Rates : A Reanalysis of a Clinical Trial of Nitrofurantoin vs Fosfomycin

Background: Current US Food and Administration (FDA) guidance recommends that the primary efficacy endpoint for uncomplicated urinary tract infection (uUTI) clinical trials be a composite of clinical and microbiological responses. We applied these criteria to a previous clinical trial to determine the impact on treatment outcomes. Methods: We conducted a patient-level reanalysis of a randomized clinical trial of nitrofurantoin versus fosfomycin for treatment of uUTI in nonpregnant adult women. Women were included in the reanalysis if they had 2 or more signs/symptoms of uUTI and a single bacterial species isolated from baseline urine culture at ≥105 colony-forming units (CFU)/mL. The applied primary efficacy endpoint-therapeutic response-required both clinical resolution of signs/symptoms and reduction of the infecting bacterial pathogen to &lt;103 CFU/mL at day 14 post-treatment completion. Results: Two hundred eleven of 513 (41%) patients were eligible for inclusion in the reanalysis. Among these patients, 74% (76/103) and 69% (75/108) in the nitrofurantoin and fosfomycin groups, respectively, achieved clinical resolution by day 14. Similarly, 70% (72/103) and 67% (72/108) in each group achieved microbiological success at day 14. As such, 59% (61/103) and 57% (62/108) of women in each group met the primary efficacy endpoint-therapeutic success-at day 14. In comparison, 75% and 66% of patients in each group achieved clinical resolution at day 14 in the initial clinical trial. Conclusions: Applying current FDA guidance resulted in lower composite efficacy rates than clinical resolution alone as observed in the initial clinical trial. This may limit the ability to compare antibiotic treatment effects between historical and future clinical trials.</p

Summary of adverse experiences during treatment (14±4 days) in the carotid endarterectomy study.

<p>Summary of adverse experiences during treatment (14±4 days) in the carotid endarterectomy study.</p

Disposition of patients throughout the carotid endarterectomy study.

<p>Disposition of patients throughout the carotid endarterectomy study.</p

The influence of darapladib treatment (14±4 days) on plaque (A) caspase-3 activity and (B) caspase-8 activity (mean ± SEM).

<p><i>P</i> values represent comparisons of darapladib 80 mg with placebo. AU, activity units.</p