Individual Endpoints Research Articles

Outcomes of transcatheter mitral valve repair for secondary mitral regurgitation by severity of left ventricular dysfunction.

In the COAPT trial, transcatheter mitral valve repair with the MitraClip plus maximally tolerated guideline-directed medical therapy (GDMT) improved clinical outcomes compared with GDMT alone in symptomatic patients with heart failure (HF) and 3+ or 4+ secondary mitral regurgitation (SMR) due to left ventricular (LV) dysfunction. In this COAPT substudy, we sought to evaluate two-year outcomes in HF patients with reduced LV ejection fraction (HFrEF; LVEF ≤40%) versus preserved LVEF (HFpEF; LVEF >40%) and in those with severe (LVEF ≤30%) versus moderate (LVEF >30%) LV dysfunction. The principal effectiveness outcome was the two-year rate of death from any cause or HF hospitalisations (HFH). Subgroup analysis with interaction testing was performed according to baseline LVEF; 472 patients (82.1%) had HFrEF (mean LVEF 28.0%±6.2%; range 12% to 40%) and 103 (17.9%) had HFpEF (mean LVEF 46.6%±4.9%; range 41% to 65%), while 292 (50.7%) had severely depressed LVEF (LVEF ≤30%; mean LVEF 23.9%±3.8%) and 283 (49.3%) had moderately depressed LVEF (LVEF >30%; mean LVEF 39.0%±6.8%). The two-year rate of death or HFH was 56.7% in patients with HFrEF and 53.4% with HFpEF (HR 1.16, 95% CI: 0.86-1.57, p=0.32). MitraClip reduced the two-year rate of death or HFH in patients with HFrEF (HR 0.50, 95% CI: 0.39-0.65) and HFpEF (HR 0.60, 95% CI: 0.35-1.05), pint=0.55. MitraClip was consistently effective in reducing the individual endpoints of mortality and HFH, improving MR severity, quality of life, and six-minute walk distance in patients with HFrEF, HFpEF, LVEF ≤30%, and LVEF >30%. In the COAPT trial, among patients with HF and 3+ or 4+ SMR who remained symptomatic despite maximally tolerated GDMT, the MitraClip was consistently effective in improving survival and health status in patients with severe and moderate LV dysfunction and those with preserved LVEF.

Multivariate Efficacy Analysis of a Randomized, Phase 3 Study of CPX-351 Versus 7+3 in Older Adults with Treatment-Related Acute Myeloid Leukemia (AML) or AML with Myelodysplasia-Related Changes

Multivariate Efficacy Analysis of a Randomized, Phase 3 Study of CPX-351 Versus 7+3 in Older Adults with Treatment-Related Acute Myeloid Leukemia (AML) or AML with Myelodysplasia-Related Changes

Ten-year clinical outcomes of polymer-free versus durable polymer new-generation drug-eluting stent in patients with coronary artery disease with and without diabetes mellitus

BackgroundVery long-term outcomes according to diabetic status of patients with coronary artery disease (CAD) undergoing percutaneous coronary intervention (PCI) with new-generation drug-eluting stents (DES) are scant. Both, the durable polymer zotarolimus-eluting stent (DP-ZES), the first DES to gain FDA-approval for specific use in patients with diabetes mellitus, and the polymer-free sirolimus- and probucol-eluting stent (PF-SES), with a unique design that enables effective drug release without the need of a polymer offer the potential to enhance clinical long-term outcomes especially in patients with diabetes mellitus.MethodsWe investigate 10-year clinical outcomes of the prespecified subgroups of patients with and without diabetes mellitus, randomly assigned to treatment with PF-SES versus DP-ZES in the ISAR-TEST 5 trial. The primary endpoint of interest was major adverse cardiac events (MACE), defined as the composite of all-cause death, any myocardial infarction or any revascularization. Further endpoints of interest were cardiac death, myocardial infarction related to the target vessel and target lesion revascularization as well as the individual components of the primary composite endpoint and the incidence of definite or probable stent thrombosis at 10 years.ResultsThis analysis includes a total of 3002 patients randomly assigned to PF-SES (n = 2002) or DP-ZES (n = 1000). Prevalence of diabetes mellitus was high and comparable, 575 Patients (28.7%) in PF-SES group and 295 patients (29.5%) in DP-ZES group (P = 0.66). At 10 years 53.5% of patients with diabetes mellitus and 68.5% of patients without diabetes mellitus were alive. Regarding major adverse cardiac events, PF-SES as compared to DP-ZES showed comparable event rates in patients with diabetes mellitus (74.8% vs. 79.6%; hazard ratio 0.86; 95% CI 0.73–1.02; P = 0.08) and in patients without diabetes (PF-SES 62.5% vs. DP-ZES 62.2%; hazard ratio 0.99; 95% CI 0.88–1.11; P = 0.88).ConclusionAt 10 years, both new-generation DES show comparable clinical outcome irrespective of diabetic status or polymer strategy. Event rates after PCI in patients with diabetes mellitus are considerable higher than in patients without diabetes mellitus and continue to accrue over time.Trial registrationClinicalTrials.gov, NCT00598533, Registered 10 January 2008, https://clinicaltrials.gov/ct2/show/NCT00598533?term=NCT00598533Graphic abstractKaplan-Meier estimates of endpoints of interest for patients with vs. without diabetes mellitus treated with PF-SES vs. DP-ZES. Bar graphs: Kaplan-Meier estimates as percentages. PF-SES: polymer-free sirolimus-eluting stent; DP-ZES: durable polymer zotarolimus-eluting stent; DM: diabetes mellitus. Comparison of event rates of individual endpoints in patients with and without diabetes mellitus treated with PF-SES vs. DP-ZES all without statistically significant differences. Comparison of event rates of individual endpoints in overall patients with vs. without diabetes mellitus significantly different (P ≤ 0.01 for all comparisons).

Global longitudinal strain and long-term outcome in patients presenting to the emergency department with suspected acute coronary syndrome.

We have previously shown that 2-dimentional strain is not a useful tool for ruling out acute coronary syndrome (ACS) in the emergency department (ED). The aim of the present study was to determine whether in patients with suspected ACS, global longitudinal strain (GLS), measured in the ED using 2-dimensional strain imaging, can predict long-term outcome. Long-term (median 7.7years [IQR 6.7-8.2]) major adverse cardiac events (MACE; cardiac death, ACS, revascularization, hospitalization for heart failure, or atrial fibrillation) and all-cause mortality data were available in 525/605 patients (87%) enrolled in the Two-Dimensional Strain for Diagnosing Chest Pain in the Emergency Room (2DSPER) study. The study prospectively enrolled patients presenting to the ED with chest pain and suspected ACS but without a diagnostic ECG or elevated troponin. GLS was computed using echocardiograms performed within 24hours of chest pain. MACE of patients with worse GLS (>median GLS) were compared to patients with better GLS (≤ median GLS). Median GLS was -18.7%. MACE occurred in 47/261 (18%) of patients with worse GLS as compared with 45/264 (17%) with better GLS, adjusted HR 0.87 (95% CI 0.57-1.33, P=.57). There was no significant difference in all-cause mortality or individual endpoints between groups. GLS did not predict MACE even in patients with optimal 2-dimensional image quality (n=164, adjusted HR=1.51, 95% CI 0.76-3.0). Global longitudinal strain did not predict long-term outcome in patients presenting to the ED with chest pain and suspected ACS, supporting our findings in the 2DSPER study.

Stenting versus balloon angioplasty alone in patients with below-the-knee disease: A propensity score-matched analysis.

Percutaneous transluminal angioplasty (PTA) is considered an effective treatment in patients with critical limb ischemia (CLI). However, the long-term durability of below-the-knee (BTK) PTA is known to be limited. This study sought to compare the 1-year clinical outcomes following stenting versus balloon angioplasty alone in BTK lesions. This study included 357 consecutive patients (400 limbs, 697 lesions) with BTK lesions who underwent PTA from September 2010 to December 2016. All enrolled patients were treated either by stenting (stent group; 111 limbs of 102 patients) or plain old balloon angioplasty (POBA group; 289 limbs of 255 patients). Stent group includes both primary and provisional stenting. Angiographic outcomes, procedural success, complications, and clinical outcomes were compared between the two groups up to 1 year. After propensity score matching (PSM) analysis, 56 pairs were generated, and the baseline and angiographic characteristics were balanced. The procedural success and complications were similar between the two groups; however, the incidence of procedure-related perforation was higher in the POBA group than in the stenting group [5(11.9%) vs.1 (0.9%), P = 0.009]. Six- to 9-month computed tomography or angiographic follow-up showed similar incidences of binary restenosis, primary patency, and secondary patency. In the 1-year clinical follow-up, there were similar incidences of individual hard endpoints, including mortality, myocardial infarction, limb salvage, and amputation rate, with the exception of target extremity revascularization (TER), which tended to be higher in the stenting group than in the POBA group [21 (20.8%) vs. 11 (10.9%), P = 0.054]. Although there was a trend toward a higher incidence of TER risk in the stenting group, stent implantation, particularly in bail-out stenting seemed to have acceptable 1-year safety and efficacy compared to POBA alone in patients undergoing BTK PTA.

Multi-generational exposure to fipronil, 2,4-D, and their mixtures in Chironomus sancticaroli: Biochemical, individual, and population endpoints

Conventional farming delivers a range of pesticides to aquatic ecosystems leading to implications for the indigenous species. Due to the multiple applications and persistence of molecules, organisms may be exposed for a prolonged period over multiple generations. The present study outlines a full life-cycle design over three generations of Chironomus sancticaroli exposed to the insecticide fipronil, the herbicide 2,4-D, and their mixtures. The experiment started with newly hatched larvae from the parental generation and lasted with the emerged adults from the second generation. Five nominal concentrations of fipronil and 2,4-D were tested, as well as six combinations of both pesticides. As additional responses, the total carbohydrates and the lipid classes were evaluated in the parental generation. The first and second generations were more susceptible to the tested compounds compared with the parental ones. Survival of larvae and pupae was decreased by both pesticides and their mixtures along with the generations. Only fipronil impaired the survival of emerged adults. Both pesticides (isolated and in the mixture) altered the emergence and the fraction of males and females. Moreover, the number of eggs produced, and their hatchability decreased. Only one combination of the pesticides increased the content of carbohydrates. Fipronil, 2,4-D, and its mixture altered the profile of the lipid classes. All mixture treatments and the three highest concentrations of fipronil extinguished the population of C. sancticaroli at the end of the first generation. In the remaining treatments with the insecticide, the population did not survive the second generation. Only three concentrations of 2,4-D and the control persisted until the end of the experiment. The results indicate that a prolonged exposition to these pesticides may disrupt the natural populations of exposed organisms with consequences to ecosystems' functioning, considering the importance of chironomids to aquatic and terrestrial environments.

Does lipoprotein(a) predict cardiovascular events in a long-term follow-up?

Abstract Funding Acknowledgements Type of funding sources: None. Background Elevated plasma lipoprotein(a) [Lp(a)] concentrations are associated with an increased risk of atherosclerotic cardiovascular disease and its role in risk categorizing was recognized in the new ESC guidelines for the management of dyslipidaemias. We investigated 1) the association between baseline Lp(a) levels and incident long-term cardiovascular (CV) events and 2) its relationship with type 2 diabetes mellitus (T2DM) in a Southern European population. Methods We retrospectively assessed baseline Lp(a) concentrations in a total of 499 patients of a primary prevention cohort followed at the Lipidology Clinic of our hospital, with a median follow-up time of 15 (IQR 12-17) years. Lp(a) was analysed as a continuous variable, as a categorical variable with a 180mg/dL cut-off and by quartiles. We collected data on major CV events (CV death, myocardial infarction, stroke) as a composite outcome. Cox proportional hazard regression analyses were used to estimate hazard ratios (HR) and 95% confidence interval (CI). Results Mean age was 48.30 ± 14.41 years and 61.70% were male (n = 499). Median Lp(a) was 36.60 (IQR 0-396) mg/dL and 12.4% of patients had very high Lp(a) (≥180mg/dL); T2DM prevalence was 13.60%. The composite outcome incidence was 10%. At the baseline, individuals with T2DM had lower Lp(a) levels (11.85 IQR 3-330 mg/dL vs. 46.40 IQR 0-396, p < 0.01 mg/dL). There was a moderate inverse correlation between Lp(a) and HbA1c (r = -0.67, p < 0.01) but no significant correlations with lipid profile (total, LDL or HDL), risk scores (SCORE or the ACC pooled cohort equation), age nor gender. We found no relationship between baseline Lp(a) quartiles and composite outcome’s incidence (age-, sex-, and diabetes-adjusted HR: 1.15, 95%CI: 0.71-1.87, p = 0.57) (Figure 1), neither with the individual CV endpoints. Exploratory analysis showed that patients on aspirin had lower Lp(a) levels (29.55 IQR 0-264 mg/dL vs. 63.60 IQR 1-396 mg/dL, p < 0.01). Conclusion In a single centre cohort of a primary prevention southern European population, we did not find an association between Lp(a) levels and incident CV events in a 15-year median follow-up time.

Digital PCR for Genotype Quantification: A Case Study in a Pasta Production Chain.

Simple SummaryDigital polymerase chain reaction (dPCR) is a breakthrough technology able to provide an absolute quantification of the target sequence through the compartmentalization of the sample and independent amplifications of the numerous separate compartments. Such technology has recently found several applications in plant science; however, to the best of our knowledge, it has never been applied until now for the detection and quantification of a specific plant variety along a production chain. As proof of concept, a dPCR assay targeted to the quantification of a durum wheat variety routinely used in an Italian premium pasta production chain has been developed.Digital polymerase chain reaction (dPCR) is a breakthrough technology based on the partitioning of the analytical sample and detection of individual end-point amplifications into the separate compartments. Among the numerous applications of this technology, its suitability in mutation detection is relevant and characterized by unprecedented levels of precision. The actual applicability of this analytical technique to quantify the presence of a specific plant genotype, in both raw materials and transformed products, by exploiting a point polymorphism has been evaluated. As proof of concept, an Italian premium pasta production chain was considered and a dPCR assay based on a durum wheat target variety private point mutation was designed and evaluated in supply-chain samples. From the results obtained, the assay can be applied to confirm the presence of a target variety and to quantify it in raw materials and transformed products, such as commercial grain lots and pasta. The performance, costs, and applicability of the assay has been compared to analytical alternatives, namely simple sequence repeats (SSRs) and genotype-by-sequencing based on Diversity Arrays Technology sequencing (DArTseqTM).

Cancer Patients Have a Higher Risk of Thrombotic and Ischemic Events After Percutaneous Coronary Intervention.

This study sought to define the risk of stent thrombosis (ST) and myocardial infarction (MI) in cancer patients compared with noncancer patients after percutaneous coronary intervention (PCI). Cancer patients are considered to be at high thrombotic risk, but data on whether this is the case after PCI remain inconclusive. Cancer patients undergoing PCI at Mayo Clinic Rochester from January 1, 2003, to December 31, 2013, were identified by cross-linking institutional cancer and PCI databases and by propensity score matching to noncancer patients. The combined primary endpoint was all-cause mortality, MI, and revascularization rate at 5-year follow-up. Secondary endpoints were the individual primary endpoint components, cause of mortality, ST, and Bleeding Academic Research Consortium 2+ bleeding. The primary endpoint occurred in 48.6% of 416 cancer and in 33.0% of 768 noncancer patients (p<0.001). In competing risk analyses, cancer patients had a higher rate of noncardiac death (24.0% vs. 10.5%; p<0.001) and a lower rate of cardiac death (5.0% vs. 11.7%; p<0.001). Cancer patients had a higher rate of MI (16.1% vs. 8.0%; p<0.001), ST (6.0% vs. 2.3%; p<0.001), repeat revascularization (21.2% vs. 10.0%; p<0.001), and bleeding (6.7% vs. 3.9%; p=0.03). The most critical period for ST in cancer patients was in the first year after PCI. The dual antiplatelet therapy score was predictive of thrombotic and ischemic events in both groups. Cancer patients have a higher risk of thrombotic and ischemic events after PCI, identifiable by a high dual antiplatelet therapy score. These findings have important implications for antiplatelet therapy decisions.

Predictive Value of Bowel Ultrasound in Crohn’s Disease: A 12-Month Prospective Study

Mucosal healing is associated with better outcomes in Crohn's disease (CD). Colonoscopy is invasive and poorly tolerated. Bowel ultrasound (US) is a noninvasive tool that increasingly is being used for CD assessment. We assessed the predictive role of baseline bowel US findings on disease course in a large prospective cohort of CD patients for 12 months. Ileocolonic CD consecutive patients were followed up for 12 months after performing bowel US. The negative course of CD, defined as the need for steroids and/or change of therapy and/or hospitalization and/or the need for surgery, was assessed. We evaluated this composite end point and subsequently considered each individual end point separately. Predictors of negative disease course were analyzed by logistic regression analysis. There were 225 ileal and/or colonic CD consecutive patients included in the study. We analyzed the association between baseline bowel US parameters and endoscopic activity (defined as a Simplified Endoscopic Activity score for CD > 2) to set up a noninvasive quantitative ultrasound-based score (bowel ultrasound score). The multivariable analysis identified the following independent predictors of a worse outcome throughout the 12-month period as follows: bowel ultrasound score greater than 3.52 (odds ratio [OR], 6.97; 95% CI, 2.87-16.93; P < .001), presence of at least 1 disease complication (stricture, fistula, abscess) at baseline bowel US (OR, 3.90; 95% CI, 1.21-12.53; P= .021), fecal calprotectin value of 250 μg/g or greater at baseline (OR, 5.43; 95% CI, 2.25-13.11; P < .001), and male sex (OR, 2.60; 95% CI, 1.12-6.02; P= .025). Bowel US predicts the 12-month course in CD.

Assessing natural recovery from contaminants in a river using sediment chemistry and toxicity from different depth ranges

To determine whether natural recovery was occurring in a depositional area of the St. Marys River (Ontario, Canada) known as East Bellevue Marine Park (EBMP), sediment was collected from two depth ranges, 0–5 cm and 0–10 cm, and subjected to a series of laboratory toxicity tests and chemical analysis. Toxicological responses (survival, growth, reproduction, development) of four benthic invertebrates and the fathead minnow were compared at test vs. reference sites using univariate and multivariate (ordination) techniques. Temporal trends in sediment chemistry and invertebrate toxicity were examined with time series data from 2008 through to 2018. Polycyclic aromatic hydrocarbons (PAHs; ≤ 37 mg/kg) and petroleum hydrocarbons (PHCs; ≤ 6266 mg/kg) were elevated in EBMP compared to reference sites (PAHs, ≤ 1.6 mg/kg; PHCs ≤ 180 mg/kg). Comparatively, the 0–5 cm sediment layer had lower concentrations of all contaminants than the 0–10 cm layer at three of four test sites. Over time, contaminant concentrations have mostly remained stable or have decreased. There were no significant differences in survival, growth, or development of the larval fish in EBMP compared to the upstream reference sites, and no differences between sampling depths. However, most EBMP sediments were toxic to invertebrates, driven by reduced reproduction by the worm Tubifex and reduced survival by the amphipod Hyalella. Among habitat variables, a combination of different classes of compounds based on ordination scores (PHCs, oil and grease, metals) was most strongly correlated to toxicological response. There was little to no difference in toxicity between sampling depths based on integrated endpoint response; however, individual endpoints showed mostly greater toxicity from exposure to the 0–10 cm layer. Over time, toxicity has mostly remained stable or showed improvement. These results provided some positive indications that gradual natural recovery is occurring in EBMP.

From environmental bioavailability of metal(loid)s to their ecogenotoxicological effects in land snails.

To date, no study has linked the environmental and the ecogenotoxicological bioavailability of contaminants to land snails. Yet, understanding the specific ecotoxicological mechanisms from bioaccumulation to genotoxicity is necessary e.g., to build an adverse outcome pathway relevant to risk assessment. Consequently, the aim of our study is to look for relationships between accumulated concentrations of As, Cd and Hg in sub-adult snails and ecotoxicological effects at the individual (survival and growth) and molecular (genomic stability) levels. This study combines random amplified polymorphic DNA (RAPD) coupled with high-resolution capillary electrophoresis system (HRS) and micronucleus (MN) assay on haemocytes to consider various types of cytogenomic damage, such as chromosomal aberrations, breakages, adducts and mutations. The results showed alteration of the individual endpoints at higher accumulation quotients (AQs) that reflect the excess of transfers to snails, especially with decreased survival for As. In addition, genotoxic effects were observed with an increased occurrence of MN in haemocytes for the three meta(loid)s considered (R2 from 0.57 to 0.61 as a function of the meta(loid)s). No concentration-dependent decrease in genome stability was highlighted by RAPD-HRS in snails exposed to As and Cd but not Hg. Our results demonstrate the complementarity of the RAPD-HRS and the MN assay for understanding the different genotoxic mechanisms of the three metal(loid)s studied in land snails. They show a way to better assess environmental risks of contaminated soils by associating ecotoxicity, genotoxicity and bioaccumulation assays (ISO 24032), i.e., ecogenotoxicological bioavailability. Convergences highlighted here between the bioaccumulation of metal(loid)s in viscera and genotoxic effects in haemocytes constitute a way to better assess the bioavailability of contaminants in soils to the land snail and the subsequent environmental risk.

Insulin‐like growth factor‐1, growth hormone and disease outcomes in acromegaly: A population study

A lack of consensus remains about the relative importance of insulin-like growth factor-1 (IGF-1) and growth hormone (GH) in predicting adverse outcomes in patients with acromegaly. To describe the differing association between IGF-1 and GH and major disease outcomes in acromegaly. Retrospective cohort study. United Kingdom National Health Service patients with acromegaly who had an IGF-1 and/or a GH measurement recorded following diagnosis, prior to December 2019. A composite endpoint including all-cause mortality (ACM), type 2 diabetes (DM), major adverse cardiovascular events (MACE) or cancer was the primary outcome. These outcomes were also analysed individually. Follow-up period was capped at 5years. A maximum of 417 cases and 332 cases were eligible for the IGF-1 and GH analyses, respectively, comprising 1041.5 and 938.9years of follow-up. There was a direct association between increased IGF-1 concentration and adjusted event risk for the composite endpoint (hazard ratio [HR]=1.2; 95% confidence interval [CI]=1.02-1.5); in GH, the HR was 1.1 (1.0-1.2). For the individual endpoints in relation to IGF-1 level, the HRs were ACM (1.2; 0.93-1.5), MACE (1.2; 0.64-2.1), DM (1.53; 1.09-2.2) and cancer (1.3; 0.95-1.7). For GH, the HRs were ACM (1.1; 0.97-1.2), MACE (0.99; 0.73-1.3), DM (1.1; 0.99-1.2) and cancer (0.90; 0.66-1.2). In this contemporary data set with extended follow-up, IGF-1 and GH concentrations showed an association with major adverse outcomes from acromegaly.

Five-Year Comparative Efficacy of Everolimus-Eluting vs. Resolute Zotarolimus-Eluting Stents in Patients with Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention.

Among drug-eluting stents (DESs), the durable polymer everolimus-eluting stent (EES) and resolute zotarolimus-eluting stent (R-ZES) are widely used in clinical practice and have contributed to improve the outcomes of patients undergoing percutaneous coronary intervention (PCI). Few studies addressed their long-term comparative performance in patients with acute coronary syndrome (ACS). We aimed to investigate the 5 year comparative efficacy of EES and R-ZES in ACS. We queried ACTION-ACS, a large-scale database of ACS patients undergoing PCI. The treatment groups were analyzed using propensity score matching. The primary endpoint was a composite of mortality, myocardial infarction (MI), stroke, repeat PCI, and definite or probable stent thrombosis, which was addressed at the five-year follow-up. A total of 3497 matched patients were analyzed. Compared with R-ZES, a significant reduction in the primary endpoint at 5 years was observed in patients treated with EES (hazard ratio (HR) [95%CI] = 0.62 [0.54–0.71], p < 0.001). By landmark analysis, differences between the two devices emerged after the first year and were maintained thereafter. The individual endpoints of mortality (HR [95%CI] = 0.70 [0.58–0.84], p < 0.01), MI (HR [95%CI] = 0.55 [0.42–0.74], p < 0.001), and repeat PCI (HR [95%CI] = 0.65 [0.53–0.73], p < 0.001) were all significantly lower in the EES-treated patients. Stroke risk did not differ between EES and R-ZES. In ACS, a greater long-term clinical efficacy with EES vs. R-ZES was observed. This difference became significant after the first year of the ACS episode and persisted thereafter.

Poor long-term prognosis in patients admitted with strong suspicion of acute myocardial infarction but discharged with another diagnosis.

Characteristics and prognosis of patients admitted with strong suspicion of myocardial infarction (MI) but discharged without an MI diagnosis are not well-described. To compare background characteristics and cardiovascular outcomes in patients discharged with or without MI diagnosis. The DETermination of the role of Oxygen in suspected Acute Myocardial Infarction (DETO2X-AMI) trial compared 6629 patients with strong suspicion of MI randomized to oxygen or ambient air. The main composite end-point of this subgroup analysis was the incidence of all-cause death, rehospitalization with MI, heart failure (HF) or stroke during a follow-up of 2.1years (median; range: 1-3.7years) irrespective of randomized treatment. 1619 (24%) received a non-MI discharge diagnosis, and 5010 patients (76%) were diagnosed with MI. Groups were similar in age, but non-MI patients were more commonly female and had more comorbidities. At thirty days, the incidence of the composite end-point was 2.8% (45 of 1619) in non-MI patients, compared to 5.0% (250 of 5010) in MI patients with lower incidences in all individual end-points. However, for the long-term follow-up, the incidence of the composite end-point increased in the non-MI patients to 17.7% (286 of 1619) as compared to 16.0% (804 of 5010) in MI patients, mainly driven by a higher incidence of all-cause death, stroke and HF. Patients admitted with a strong suspicion of MI but discharged with another diagnosis had more favourable outcomes in the short-term perspective, but from one year onwards, cardiovascular outcomes and death deteriorated to a worse long-term prognosis.

Ethnic variance on long term clinical outcomes of concomitant use of proton pump inhibitors and clopidogrel in patients with stent implantation: A PRISMA-complaint systematic review with meta-analysis.

Background:Pharmacokinetic and pharmacodynamic study showed a lower clopidogrel response when coprescribed with proton pump inhibitors (PPIs). Despite this, PPIs is necessary for patients treated with long term dual antiplatelet therapy (DAPT). Ethnic variance also played a different effect on clopidogrel response. Our study evaluated the effect of concomitant use of DAPT and PPIs and assessed whether ethnic variance exert different effect on clinical outcomes.Methods:We carefully searched EMBASE, PubMed/Medline databases, and the Cochrane library in April 2019. The primary endpoint was major adverse cardiovascular and cerebrovascular events (MACCE) and individual endpoints reported. We also focused on bleeding events. Studies were excluded if the follow-up were <12 months and patients were not treated with clopidogrel after stent implantation.Results:A total of 18 studies were included in the systematic review (involving 79,670 patients). No randomized controlled trials (RCTs) were included. PPIs comedication were associated with increased MACCE (odds ratio [OR] = 1.38; 95% confidence interval [CI] = 1.28–1.49) while not associated with decreased bleeding risks, such as gastrointestinal bleeding (OR = 1.05; 95% CI = 0.53–2.11). PPIs comedication were associated with increased risk for all endpoints among Caucasian population while not with increased risk for MACE (OR = 1.20; 95% CI = 0.99–1.39), all-cause death (OR = 1.24; 95% CI = 0.74–2.06), cardiac-death (OR = 1.29; 95% CI = 0.64–2.57) among Asian population.Conclusion:PPIs comedication were associated with adverse clinical outcomes, and ethnic variance may exert different effect on clinical outcomes. Subgroup analysis indicated that concomitant use of PPI might be suitable for Asian patients after stent implantation.

Non-Animal Strategies for Toxicity Assessment of Nanoscale Materials: Role of Adverse Outcome Pathways in the Selection of Endpoints.

Faster, cheaper, sensitive, and mechanisms-based animal alternatives are needed to address the safety assessment needs of the growing number of nanomaterials (NM) and their sophisticated property variants. Specifically, strategies that help identify and prioritize alternative schemes involving individual test models, toxicity endpoints, and assays for the assessment of adverse outcomes, as well as strategies that enable validation and refinement of these schemes for the regulatory acceptance are needed. In this review, two strategies 1) the current nanotoxicology literature review and 2) the adverse outcome pathways (AOPs) framework, a systematic process that allows the assembly of available mechanistic information concerning a toxicological response in a simple modular format, are presented. The review highlights 1) the most frequently assessed and reported ad hoc in vivo and in vitro toxicity measurements in the literature, 2) various AOPs of relevance to inhalation toxicity of NM that are presently under development, and 3) their applicability in identifying key events of toxicity for targeted in vitro assay development. Finally, using an existing AOP for lung fibrosis, the specific combinations of cell types, exposure and test systems, and assays that are experimentally supported and thus, can be used for assessing NM-induced lung fibrosis, are proposed.

Tracking Major Sources of Water Contamination Using Machine Learning.

Current microbial source tracking techniques that rely on grab samples analyzed by individual endpoint assays are inadequate to explain microbial sources across space and time. Modeling and predicting host sources of microbial contamination could add a useful tool for watershed management. In this study, we tested and evaluated machine learning models to predict the major sources of microbial contamination in a watershed. We examined the relationship between microbial sources, land cover, weather, and hydrologic variables in a watershed in Northern California, United States. Six models, including K-nearest neighbors (KNN), Naïve Bayes, Support vector machine (SVM), simple neural network (NN), Random Forest, and XGBoost, were built to predict major microbial sources using land cover, weather and hydrologic variables. The results showed that these models successfully predicted microbial sources classified into two categories (human and non-human), with the average accuracy ranging from 69% (Naïve Bayes) to 88% (XGBoost). The area under curve (AUC) of the receiver operating characteristic (ROC) illustrated XGBoost had the best performance (average AUC = 0.88), followed by Random Forest (average AUC = 0.84), and KNN (average AUC = 0.74). The importance index obtained from Random Forest indicated that precipitation and temperature were the two most important factors to predict the dominant microbial source. These results suggest that machine learning models, particularly XGBoost, can predict the dominant sources of microbial contamination based on the relationship of microbial contaminants with daily weather and land cover, providing a powerful tool to understand microbial sources in water.

Estimates of Alpha/Beta (α/β) Ratios for Individual Late Rectal Toxicity Endpoints: An Analysis of the CHHiP Trial

PurposeChanges in fraction size of external beam radiation therapy exert nonlinear effects on subsequent toxicity. Commonly described by the linear-quadratic model, fraction size sensitivity of normal tissues is expressed by the α/β ratio. We sought to study individual α/β ratios for different late rectal effects after prostate external beam radiation therapy.Methods and MaterialsThe CHHiP trial (ISRCTN97182923) randomized men with nonmetastatic prostate cancer 1:1:1 to 74 Gy/37 fractions (Fr), 60 Gy/20 Fr, or 57 Gy/19 Fr. Patients in the study had full dosimetric data and zero baseline toxicity. Toxicity scales were amalgamated to 6 bowel endpoints: bleeding, diarrhea, pain, proctitis, sphincter control, and stricture. Lyman-Kutcher-Burman models with or without equivalent dose in 2 Gy/Fr correction were log-likelihood fitted by endpoint, estimating α/β ratios. The α/β ratio estimate sensitivity was assessed using sequential inclusion of dose modifying factors (DMFs): age, diabetes, hypertension, inflammatory bowel or diverticular disease (IBD/diverticular), and hemorrhoids. 95% confidence intervals (CIs) were bootstrapped. Likelihood ratio testing of 632 estimator log-likelihoods compared the models.ResultsLate rectal α/β ratio estimates (without DMF) ranged from bleeding (G1 + α/β = 1.6 Gy; 95% CI, 0.9-2.5 Gy) to sphincter control (G1 + α/β = 3.1 Gy; 95% CI, 1.4-9.1 Gy). Bowel pain modelled poorly (α/β, 3.6 Gy; 95% CI, 0.0-840 Gy). Inclusion of IBD/diverticular disease as a DMF significantly improved fits for stool frequency G2+ (P = .00041) and proctitis G1+ (P = .00046). However, the α/β ratios were similar in these no-DMF versus DMF models for both stool frequency G2+ (α/β 2.7 Gy vs 2.5 Gy) and proctitis G1+ (α/β 2.7 Gy vs 2.6 Gy). Frequency-weighted averaging of endpoint α/β ratios produced: G1 + α/β ratio = 2.4 Gy; G2 + α/β ratio = 2.3 Gy.ConclusionsWe estimated α/β ratios for several common late adverse effects of rectal radiation therapy. When comparing dose-fractionation schedules, we suggest using late a rectal α/β ratio ≤ 3 Gy.

Utility and safety of systematic coronary angiogram in patients with acute infective endocarditis who required surgery: Single centre experience and comprehensive meta-analysis

The benefit/risk ratio to perform a systematic coronary angiogram (CA) before surgery for infective endocarditis (IE) is poorly reported and largely unknown. Recommendations are derived from studies on aortic stenosis management in stable patients where the prevalence of coronary artery disease may be much higher (vs. IE). Patients with IE usually do not present acute coronary issues and acute renal failure is frequent in such patients. We assessed the benefit/risk ratio to perform a CA before surgery for IE. We conducted a single-centre prospective registry including 272 patients with acute IE intended for surgery and compared patients who underwent a preoperative CA ( n = 160) to those who did not ( n = 112). A comprehensive meta-analysis was also conducted and included 551 patients: 342 who underwent a CA and 209 who did not. In our registry, a combined bypass surgery (CABG) was performed in 17.3% of the patients with preoperative CA. At 2 years, the rate of the primary composite endpoint (all-cause death, new systemic embolism, stroke, new hemodialysis) was similar in the CA (37.5%) and no-CA (36.6%) groups. In-hospital and 2-year individual endpoints were all similar between groups. There were only 2 episodes of systemic embolism after CA and only one possibly related to a vegetation dislodgement. In the meta-analysis, a combined CABG was performed in 18.6% of the patients with preoperative CA. All-cause death was similar in the CA (19.1%) and no-CA groups (20.2%). Only 5 cases of systemic embolism possibly related to a vegetation dislodgement were reported. New hemodialysis was numerically more frequent in the CA group: 18.4% vs. 13.7% ( P = 0.179). In daily practice, 2/3 of the patients with acute IE who required surgery have a preoperative CA leading to a combined CABG in 18% of the patients. Our results suggest that to perform a preoperative CA in this context is not associated with improved prognosis.