Publications by authors named "Jennifer A White"

61 Publications

Preventing potential pitfalls of a liberalized potassium diet in the hemodialysis population.

Semin Dial 2021 Aug 10. Epub 2021 Aug 10.

University of California, Irvine, School of Medicine, Irvine, California, USA.

Emerging research suggests that a more liberalized diet, specifically a more plant-based diet resulting in liberalization of potassium intake, for people receiving hemodialysis is necessary and the benefits outweigh previously thought risks. If the prescribed hemodialysis diet is to be liberalized, the need to illuminate and prevent potential pitfalls of a liberalized potassium diet is warranted. This paper explores such topics as partial to full adherence to a liberalized diet and its consequences if any, the advantages of a high-fiber intake, the theoretical risk of anemia when consuming a more plant-dominant diet, the potential benefits against renal acid load and effect on metabolic acidosis with increased fruit and vegetable intake, the putative change in serum potassium levels, carbohydrate quality, and the healthfulness of meat substitutes. The benefits of a more plant-based diet for the hemodialysis population are multifold; however, the possible pitfalls of this type of diet must be reviewed and addressed upon meal planning in order to be avoided.
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http://dx.doi.org/10.1111/sdi.13006DOI Listing
August 2021

Nonsterile immunity to cryptosporidiosis in infants is associated with mucosal IgA against the sporozoite and protection from malnutrition.

PLoS Pathog 2021 Jun 28;17(6):e1009445. Epub 2021 Jun 28.

Department of Medicine, University of Virginia, Charlottesville, Virginia, United States of America.

We conducted a longitudinal study of cryptosporidiosis from birth to three years of age in an urban slum of Dhaka Bangladesh. Fecal DNA was extracted from monthly surveillance samples and diarrheal stool samples collected from 392 infants from birth to three years. A pan-Cryptosporidium qPCR assay was used to identify sub-clinical and symptomatic cryptosporidiosis. Anthropometric measurements were collected quarterly to assess child nutritional status. 31% (121/392) of children experienced a single and 57% (222/392) multiple infections with Cryptosporidium. Repeat infections had a lower burden of parasites in the stool (Cq slope = -1.85; p<0.0001) and were more likely to be sub-clinical (Chi square test for trend; p = 0.01). Repeat infections were associated with the development of growth faltering (Pearson correlation = -0.18; p = 0.0004). High levels of fecal IgA antibodies against the Cryptosporidium Cp23 sporozoite protein at one year of life were associated with a delay in reinfection and amelioration of growth faltering through three years of life (HAZ IgA high responders -1.323 ± 0.932 versus HAZ -1.731 ± 0.984 p = 0.0001). We concluded that nonsterile immunity to cryptosporidiosis in young children was associated with high levels of mucosal IgA anti-Cp23 and protection from diarrhea and growth faltering. Trial Registration: NCT02764918.
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http://dx.doi.org/10.1371/journal.ppat.1009445DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8270466PMC
June 2021

Antigen-driven clonal selection shapes the persistence of HIV-1-infected CD4+ T cells in vivo.

J Clin Invest 2021 02;131(3)

Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Clonal expansion of infected CD4+ T cells is a major mechanism of HIV-1 persistence and a barrier to achieving a cure. Potential causes are homeostatic proliferation, effects of HIV-1 integration, and interaction with antigens. Here, we show that it is possible to link antigen responsiveness, the full proviral sequence, the integration site, and the T cell receptor β-chain (TCRβ) sequence to examine the role of recurrent antigenic exposure in maintaining the HIV-1 reservoir. We isolated CMV- and Gag-responding CD4+ T cells from 10 treated individuals. Proviral populations in CMV-responding cells were dominated by large clones, including clones harboring replication-competent proviruses. TCRβ repertoires showed high clonality driven by converging adaptive responses. Although some proviruses were in genes linked to HIV-1 persistence (BACH2, STAT5B, MKL1), the proliferation of infected cells under antigenic stimulation occurred regardless of the site of integration. Paired TCRβ and integration site analysis showed that infection could occur early or late in the course of a clone's response to antigen and could generate infected cell populations too large to be explained solely by homeostatic proliferation. Together, these findings implicate antigen-driven clonal selection as a major factor in HIV-1 persistence, a finding that will be a difficult challenge to eradication efforts.
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http://dx.doi.org/10.1172/JCI145254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843227PMC
February 2021

Endosymbionts facilitate rapid evolution in a polyphagous herbivore.

J Evol Biol 2020 10 30;33(10):1507-1511. Epub 2020 Sep 30.

Department of Entomology, S-225 Agricultural Science Center N, University of Kentucky, Lexington, KY, USA.

Maternally transmitted bacterial symbionts can be important mediators of the interactions between insect herbivores and their foodplants. These symbionts are often facultative (present in some host individuals but not others) and can have large effects on their host's phenotype, thus giving rise to heritable variation upon which selection can act. In the cowpea aphid (Aphis craccivora), it has been established that the facultative endosymbiont Arsenophonus improves aphid performance on black locust trees (Robinia pseudoacacia) but not on fava (Vicia faba). Here, we tested whether this fitness differential translated into contemporaneous evolution of aphid populations associated with the different plants. In a laboratory study lasting 16 weeks, we found that the frequency of Arsenophonus-infected individuals significantly increased over time for aphid populations on black locust but declined for aphid populations on fava. By the end of the experiment, Arsenophonus infection was >3× more common on black locust than fava, which is comparable to previously described infection frequencies in natural field populations. Our results clearly demonstrate that aphid populations with mixed facultative symbiont infection status can rapidly evolve in response to the selective environments imposed by different host plants. This selection differential may be a sufficient explanation for the global association between Arsenophonus-infected cowpea aphids and black locust trees, without invoking additional assortative mechanisms. Because the aphid and plant originate from different parts of the world, we further hypothesize that Arsenophonus infection may have acted as a preadaptation that has promoted functional specialization of infected aphids on a novel host plant.
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http://dx.doi.org/10.1111/jeb.13697DOI Listing
October 2020

Intact proviral DNA assay analysis of large cohorts of people with HIV provides a benchmark for the frequency and composition of persistent proviral DNA.

Proc Natl Acad Sci U S A 2020 08 20;117(31):18692-18700. Epub 2020 Jul 20.

Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205.

A scalable approach for quantifying intact HIV-1 proviruses is critical for basic research and clinical trials directed at HIV-1 cure. The intact proviral DNA assay (IPDA) is a novel approach to characterizing the HIV-1 reservoir, focusing on the genetic integrity of individual proviruses independent of transcriptional status. It uses multiplex digital droplet PCR to distinguish and separately quantify intact proviruses, defined by a lack of overt fatal defects such as large deletions and APOBEC3G-mediated hypermutation, from the majority of proviruses that have such defects. This distinction is important because only intact proviruses cause viral rebound on ART interruption. To evaluate IPDA performance and provide benchmark data to support its implementation, we analyzed peripheral blood samples from 400 HIV-1 adults on ART from several diverse cohorts, representing a robust sample of treated HIV-1 infection in the United States. We provide direct quantitative evidence that defective proviruses greatly outnumber intact proviruses (by >12.5 fold). However, intact proviruses are present at substantially higher frequencies (median, 54/10 CD4 T cells) than proviruses detected by the quantitative viral outgrowth assay, which requires induction and in vitro growth (∼1/10 CD4 T cells). IPDA amplicon signal issues resulting from sequence polymorphisms were observed in only 6.3% of individuals and were readily apparent and easily distinguished from low proviral frequency, an advantage of the IPDA over standard PCR assays which generate false-negative results in such situations. The large IPDA dataset provided here gives the clearest quantitative picture to date of HIV-1 proviral persistence on ART.
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http://dx.doi.org/10.1073/pnas.2006816117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414172PMC
August 2020

Endosymbiotic causes cytoplasmic incompatibility in a spider host.

Proc Biol Sci 2020 07 8;287(1930):20201107. Epub 2020 Jul 8.

Department of Entomology, University of Kentucky, S-225 Agricultural Science Center N, Lexington, KY, USA.

Many arthropod hosts are infected with bacterial endosymbionts that manipulate host reproduction, but few bacterial taxa have been shown to cause such manipulations. Here, we show that a bacterial strain in the genus causes cytoplasmic incompatibility (CI) between infected and uninfected hosts. We first surveyed the bacterial community of the agricultural spider (Linyphiidae) using high throughput sequencing and found that individual spiders can be infected with up to five different strains of maternally inherited symbiont from the genera , , and . The strain was pervasive, found in all 23 tested spider matrilines. We used antibiotic curing to generate uninfected matrilines that we reciprocally crossed with individuals infected only with . We found that only 13% of eggs hatched when uninfected females were mated with -infected males; in contrast, at least 83% of eggs hatched in the other cross types. This is the first documentation of , or any Gammaproteobacteria, causing CI. We speculate that induction of CI may be much more widespread among maternally inherited bacteria than previously appreciated. Further, our results reinforce the importance of thoroughly characterizing and assessing the inherited microbiome before attributing observed host phenotypes to well-characterized symbionts such as .
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http://dx.doi.org/10.1098/rspb.2020.1107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7423472PMC
July 2020

Cardiac remodeling after large ST-elevation myocardial infarction in the current therapeutic era.

Am Heart J 2020 05 26;223:87-97. Epub 2020 Feb 26.

Duke University Medical Center, Durham, NC; Clinical Research Institute, Durham, NC.

Background: The evolution and clinical impact of cardiac remodeling after large ST-elevation myocardial infarction (STEMI) is not well delineated in the current therapeutic era.

Methods: The PRESERVATION I trial longitudinally assessed cardiac structure and function in STEMI patients receiving primary percutaneous coronary intervention (PCI). Echocardiograms were performed immediately post-PCI and at 1, 3, 6 and 12 months after STEMI. The extent of cardiac remodeling was assessed in patients with ejection fraction (EF) ≤ 40% after PCI. Patients were stratified by the presence or absence of reverse remodeling, defined as an increase in end-diastolic volume (EDV) of ≤10 mL or decrease in EDV at 1 month, and evaluated for an association with adverse events at 1 year.

Results: Of the 303 patients with large STEMI enrolled in PRESERVATION I, 225 (74%) had at least moderately reduced systolic function (mean EF 32 ± 5%) immediately after primary PCI. In the following year, there were significant increases in EF and LV volumes, with the greatest magnitude of change occurring in the first month. At 1 month, 104 patients (46%) demonstrated reverse remodeling, which was associated with a significantly lower rate of death, recurrent myocardial infarction and repeat cardiovascular hospitalization at 1 year (HR 0.44; 95% CI: 0.19-0.99).

Conclusion: Reduced EF after large STEMI and primary PCI is common in the current therapeutic era. The first month following primary reperfusion is a critical period during which the greatest degree of cardiac remodeling occurs. Patients demonstrating early reverse remodeling have a significantly lower rate of adverse events in the year after STEMI.
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http://dx.doi.org/10.1016/j.ahj.2020.02.017DOI Listing
May 2020

Morphine and Cardiovascular Outcomes Among Patients With Non-ST-Segment Elevation Acute Coronary Syndromes Undergoing Coronary Angiography.

J Am Coll Cardiol 2020 01;75(3):289-300

Thrombosis In Myocardial Infarction Study Group-Brigham and Women's Hospital, Boston, Massachusetts. Electronic address:

Background: Mechanistic studies have shown that morphine blunts the antiplatelet effects of oral adenosine diphosphate receptor blockers. However, the clinical relevance of this interaction is controversial.

Objectives: This study sought to explore the association between morphine and ischemic events in 5,438 patients treated with concomitant clopidogrel presenting with non-ST-segment elevation acute coronary syndromes (NSTEACS) in the EARLY ACS (Early Glycoprotein IIb/IIIa Inhibition in Patients With Non-ST-Segment Elevation Acute Coronary Syndrome) trial. Patients not treated with clopidogrel (n = 3,462) were used as negative controls.

Methods: Endpoints were the composite of death, myocardial infarction (MI), recurrent ischemia, or thrombotic bailout at 96 h (4-way endpoint) and the composite of death or MI at 30 days.

Results: In patients treated with clopidogrel, morphine use was associated with higher rates of the 4-way endpoint at 96 h (adjusted odds ratio [OR]: 1.40; 95% confidence interval [CI]: 1.04 to 1.87; p = 0.026). There was a trend for higher rates of death or MI at 30 days (adjusted OR: 1.29; 95% CI: 0.98 to 1.70; p = 0.072), driven by events in the first 48 h (adjusted hazard ratio: 1.54; 95% CI: 1.07 to 2.23; p = 0.021). In patients not treated with clopidogrel, morphine was not associated with either the 4-way endpoint at 96 h (adjusted OR: 1.05; 95% CI: 0.74 to 1.49; p = 0.79; p = 0.36 ) or death or MI at 30 days (adjusted OR: 1.07; 95% CI: 0.77 to 1.48; p = 0.70; p = 0.46).

Conclusions: When used concomitantly with clopidogrel pre-treatment, morphine was associated with higher rates of ischemic events in patients with NSTEACS. (EARLY ACS: Early Glycoprotein IIb/IIIa Inhibition in Patients With Non-ST-Segment Elevation Acute Coronary Syndrome; NCT00089895).
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http://dx.doi.org/10.1016/j.jacc.2019.11.035DOI Listing
January 2020

Effect of Simvastatin-Ezetimibe Compared With Simvastatin Monotherapy After Acute Coronary Syndrome Among Patients 75 Years or Older: A Secondary Analysis of a Randomized Clinical Trial.

JAMA Cardiol 2019 09;4(9):846-854

Duke Clinical Research Institute, Division of Cardiology, Department of Medicine, Duke University, Durham, North Carolina.

Importance: Limited evidence is available regarding the benefit and hazard of higher-intensity treatment to lower lipid levels among patients 75 years or older. As a result, guideline recommendations differ for this age group compared with younger patients.

Objective: To determine the effect on outcomes and risks of combination ezetimibe and simvastatin compared with simvastatin monotherapy to lower lipid levels among patients 75 years or older with stabilized acute coronary syndrome (ACS).

Design, Setting, Participants: In this prespecified secondary analysis of the global, multicenter, prospective clinical randomized Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT), outcomes and risks were compared by age among patients 50 years or older after a hospitalization for ACS. Data were collected from October 26, 2005, through July 8, 2010, with the database locked October 21, 2014. Data were analyzed May 29, 2015, through March 13, 2018, using Kaplan-Meier curves and Cox proportional hazards models.

Interventions: Double-blind randomized assignment to combined simvastatin and ezetimibe or simvastatin and placebo with follow-up for a median of 6 years (interquartile range, 4.3-7.1 years).

Main Outcomes And Measures: The primary composite end point consisted of death due to cardiovascular disease, myocardial infarction (MI), stroke, unstable angina requiring hospitalization, and coronary revascularization after 30 days. Individual adverse ischemic and safety end points and lipid variables were also analyzed.

Results: Of 18 144 patients enrolled (13 728 men [75.7%]; mean [SD] age, 64.1 [9.8] years), 5173 (28.5%) were 65 to 74 years old, and 2798 (15.4%) were 75 years or older at randomization. Treatment with simvastatin-ezetimibe resulted in lower rates of the primary end point than simvastatin-placebo, including 0.9% for patients younger than 65 years (HR, 0.97; 95% CI, 0.90-1.05) and 0.8% for patients 65 to 74 years of age (hazard ratio [HR], 0.96; 95% CI, 0.87-1.06), with the greatest absolute risk reduction of 8.7% for patients 75 years or older (HR, 0.80; 95% CI, 0.70-0.90) (P = .02 for interaction). The rate of adverse events did not increase with simvastatin-ezetimibe vs simvastatin-placebo among younger or older patients.

Conclusions And Relevance: In IMPROVE-IT, patients hospitalized for ACS derived benefit from higher-intensity therapy to lower lipid levels with simvastatin-ezetimibe compared with simvastatin monotherapy, with the greatest absolute risk reduction among patients 75 years or older. Addition of ezetimibe to simvastatin was not associated with any significant increase in safety issues among older patients. These results may have implications for guideline recommendations regarding lowering of lipid levels in the elderly.

Trial Registration: ClinicalTrials.gov identifier: NCT00202878.
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http://dx.doi.org/10.1001/jamacardio.2019.2306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6647004PMC
September 2019

Endosymbiotic Bacteria Are Prevalent and Diverse in Agricultural Spiders.

Microb Ecol 2020 Feb 12;79(2):472-481. Epub 2019 Jul 12.

Department of Entomology, University of Kentucky, Lexington, KY, 40546, USA.

Maternally inherited bacterial endosymbionts are common in arthropods, but their distribution and prevalence are poorly characterized in many host taxa. Initial surveys have suggested that vertically transmitted symbionts may be particularly common in spiders (Araneae). Here, we used diagnostic PCR and high-throughput sequencing to evaluate symbiont infection in 267 individual spiders representing 14 species (3 families) of agricultural spiders. We found 27 operational taxonomic units (OTUs) that are likely endosymbiotic, including multiple strains of Wolbachia, Rickettsia, and Cardinium, which are all vertically transmitted and frequently associated with reproductive manipulation of arthropod hosts. Additional strains included Rickettsiella, Spiroplasma, Rhabdochlamydia, and a novel Rickettsiales, all of which could range from pathogenic to mutualistic in their effects upon their hosts. Seventy percent of spider species had individuals that tested positive for one or more endosymbiotic OTUs, and specimens frequently contained multiple symbiotic strain types. The most symbiont-rich species, Idionella rugosa, had eight endosymbiotic OTUs, with as many as five present in the same specimen. Individual specimens within infected spider species had a variety of symbiotypes, differing from one another in the presence or absence of symbiotic strains. Our sample included both starved and unstarved specimens, and dominant bacterial OTUs were consistent per host species, regardless of feeding status. We conclude that spiders contain a remarkably diverse symbiotic microbiota. Spiders would be an informative group for investigating endosymbiont population dynamics in time and space, and unstarved specimens collected for other purposes (e.g., food web studies) could be used, with caution, for such investigations.
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http://dx.doi.org/10.1007/s00248-019-01411-wDOI Listing
February 2020

Medication Discontinuation in the IMPROVE-IT Trial.

Circ Cardiovasc Qual Outcomes 2019 01;12(1):e005041

Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC (A.M.N., M.T.R., J.A.W., Y.L., L.K.N., M.A.B.).

Background: Although cholesterol-lowering medications can reduce the risk of recurrent cardiovascular events, premature discontinuation limits effectiveness. Discontinuation rates have not been systematically reported for lipid-lowering trials.

Methods And Results: We evaluated medication discontinuation in IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial), which evaluated placebo+simvastatin versus ezetimibe+simvastatin in patients hospitalized with the acute coronary syndrome and followed longitudinally postdischarge. Reasons for discontinuation were evaluated from randomization through study end (median 71.9 [interquartile range 51.8-85.8] months). Kaplan-Meier (KM) discontinuation rates were evaluated at 30 days, 1 year, and through year 7, and compared by treatment arm and region, with Cox proportional hazards modeling used to evaluate predictors of discontinuation. Overall, 46.7% of subjects discontinued study medication (KM rate by study end 50.9% [95% CI, 50.1%-51.7%]). The risk of discontinuation was highest early in the trial but decreased with increasing time, with a terminal KM rate per 100 person-years of 8.4 (8.2-8.6) from years 1 to 7. Discontinuation was higher in the placebo+simvastatin versus ezetimibe+simvastatin arm (KM rate 52.0% versus 49.8%, P=0.049) and was highest in the United States (7-year KM rate 57.4%). In multivariable modeling, smoking, prior revascularization, hypertension, unstable angina, female sex, nonwhite race, and US location were associated with higher discontinuation rates.

Conclusions: Although discontinuation was highest early and stabilized to 8% per year, because of prolonged follow-up, most discontinuation occurred after year 1. Adding ezetimibe to statin therapy did not increase discontinuation risk. Geographic differences and patient-level factors should be considered in trial design and analysis.

Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00202878.
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http://dx.doi.org/10.1161/CIRCOUTCOMES.118.005041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6541480PMC
January 2019

Photoperiodic Induction of Adult Diapause in North American Populations of the Convergent Lady Beetle (Coleoptera: Coccinellidae).

Environ Entomol 2018 12;47(6):1596-1600

Department of Entomology, University of Kentucky, Lexington, KY.

Characterization of intraspecific variation is required to assess the potential nontarget effects of augmentative releases of Hippodamia convergens (Guerin) (Coleoptera: Coccinellidae) from the Western United States on local populations of this species in the Eastern United States. Adults of this predatory lady beetle species overwinter in adult reproductive diapause, thus examining responses to photoperiods can characterize geographic variation influencing their seasonal biology. This laboratory study quantified the induction and duration of adult reproductive diapause in five North American populations of H. convergens in response to four constant photoperiods (16:8, 14:10, 12:12, and 10:14 [L:D] h) at 22°C. Three populations were collected over a range of latitudes (31° N to 42° N) in the central portion of the United States (Texas, Kansas, and Iowa); two populations were purchased from commercial sources in the Western United States. All populations exhibited a long-day response to photoperiods: ≤17% of females reared at 16:8 (L:D) h entered diapause, whereas shorter photoperiods (12:12 and 10:14 [L:D] h) induced diapause in 82 to 100% of females. The response to 14:10 (L:D) h showed significant variation among the populations, ranging from 0 to 89% of females in reproductive diapause. Both the phenotypic variation in response to diapause inducing photoperiods and the genetic variation in North American populations of H. convergens document the geographic variability in this widely distributed predatory species.
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http://dx.doi.org/10.1093/ee/nvy128DOI Listing
December 2018

Heritable variation in prey defence provides refuge for subdominant predators.

Proc Biol Sci 2018 05;285(1879)

Department of Entomology, S-225 Agricultural Science Center N, University of Kentucky, Lexington, KY, USA.

Generalist predators with broadly overlapping niches commonly coexist on seemingly identical sets of prey. Here, we provide empirical demonstration that predators can differentially exploit fine-grained niches generated by variable, heritable and selective defences within a single prey species. Some, but not all, clones of the aphid are toxic towards the dominant invasive predatory ladybeetle, However, other less competitive ladybeetle species are not affected by the aphid's toxic trait. In laboratory and open field experiments, we show: (i) that subdominant ladybeetle species were able to exploit the toxic aphids, benefitting from the suppression of the dominant predator; and (ii) that this narrow-spectrum toxicity can function as an anti-predator defence for the aphid, but depends on enemy community context. Our results demonstrate that niche differentiation among generalist predators may hinge upon previously underappreciated heritable variation in prey defence, which, in turn, may promote diversity and stability of enemy communities invaded by a dominant predator.
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http://dx.doi.org/10.1098/rspb.2018.0523DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5998095PMC
May 2018

Benefit of Adding Ezetimibe to Statin Therapy on Cardiovascular Outcomes and Safety in Patients With Versus Without Diabetes Mellitus: Results From IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial).

Circulation 2018 04 20;137(15):1571-1582. Epub 2017 Dec 20.

TIMI Study Group, Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (R.P.G., C.P.C., J.-G.P., E.A.B., E.B.).

Background: Ezetimibe, when added to simvastatin, reduces cardiovascular events after acute coronary syndrome. We explored outcomes stratified by diabetes mellitus (DM).

Methods: In IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial), 18 144 patients after acute coronary syndrome with low-density lipoprotein cholesterol 50 to 125 mg/dL were randomized to 40 mg ezetimibe/simvastatin (E/S) or 40 mg placebo/simvastatin. The primary composite end point was cardiovascular death, major coronary events, and stroke. DM was a prespecified subgroup.

Results: The 4933 (27%) patients with DM were more often older and female, had had a prior myocardial infarction and revascularization, and presented more frequently with non-ST segment elevation acute coronary syndrome compared with patients without DM (each <0.001). The median admission low-density lipoprotein cholesterol was lower among patients with DM (89 versus 97 mg/dL, <0.001). E/S achieved a significantly lower median time-weighted average low-density lipoprotein cholesterol compared with placebo/simvastatin, irrespective of DM (DM: 49 versus 67 mg/dL; no DM: 55 versus 71 mg/dL; both <0.001). In patients with DM, E/S reduced the 7-year Kaplan-Meier primary end point event rate by 5.5% absolute (hazard ratio, 0.85; 95% confidence interval, 0.78-0.94); in patients without DM, the absolute difference was 0.7% (hazard ratio, 0.98; 95% confidence interval, 0.91-1.04; =0.02). The largest relative reductions in patients with DM were in myocardial infarction (24%) and ischemic stroke (39%). No differences in safety outcomes by treatment were present regardless of DM. When stratified further by age, patients ≥75 years of age had a 20% relative reduction in the primary end point regardless of DM (=0.91), whereas patients <75 years of age with DM had greater benefit than those without (=0.011). When stratified by the TIMI (Thrombolysis in Myocardial Infarction) Risk Score for Secondary Prevention, all patients with DM demonstrated benefit with E/S regardless of risk. In contrast, among patients without DM, those with a high risk score experienced a significant (18%) relative reduction in the composite of cardiovascular death, myocardial infarction, and ischemic stroke with E/S compared with placebo/simvastatin, whereas patients without DM at low or moderate risk demonstrated no benefit with the addition of ezetimibe to simvastatin ( =0.034).

Conclusions: In IMPROVE-IT, the benefit of adding ezetimibe to statin was enhanced in patients with DM and in high-risk patients without DM.

Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00202878.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.117.030950DOI Listing
April 2018

Efficacy and Safety of Adding Ezetimibe to Statin Therapy Among Women and Men: Insight From IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial).

J Am Heart Assoc 2017 Nov 18;6(11). Epub 2017 Nov 18.

TIMI (Thrombolysis in Myocardial Infarction) Study Group, Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA

Background: IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) showed that adding the nonstatin ezetimibe to statin therapy further reduced cardiovascular events in patients after an acute coronary syndrome. In a prespecified analysis, we explore results stratified by sex.

Methods And Results: In IMPROVE-IT, patients with acute coronary syndrome and low-density lipoprotein cholesterol of 50 to 125 mg/dL were randomized to placebo/simvastatin 40 mg or ezetimibe/simvastatin 10/40 mg. They were followed up for a median of 6 years for the primary composite of cardiovascular death, myocardial infarction, hospitalization for unstable angina, coronary revascularization ≥30 days, and stroke. Among 18 144 patients in IMPROVE-IT, 4416 (24%) were women. At 12 months, the addition of ezetimibe to simvastatin significantly reduced low-density lipoprotein cholesterol from baseline compared with simvastatin monotherapy in men and women equally (absolute reduction, 16.7 mg/dL in men and 16.4 mg/dL in women). Women receiving ezetimibe/simvastatin had a 12% risk reduction over those receiving placebo/simvastatin for the primary composite end point (hazard ratio, 0.88; 95% confidence interval, 0.79-0.99) compared with a 5% reduction for men (hazard ratio, 0.95; 95% confidence interval, 0.90-1.01; =0.26 for interaction). When the total number of primary events was considered, women had an 18% reduction with the addition of ezetimibe (relative risk, 95% confidence interval, 0.81; 0.71-0.94) and men had a 6% reduction (relative risk, 0.94; 95% confidence interval, 0.87-1.02; =0.08 for interaction). The addition of ezetimibe did not increase the rates of safety events in either women or men.

Conclusions: IMPROVE-IT demonstrated that the benefit of adding ezetimibe to statin is present in both women and men, with a good safety profile supporting the use of intensive, combination, lipid-lowering therapy to optimize cardiovascular outcomes.

Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00202878.
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http://dx.doi.org/10.1161/JAHA.117.006901DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5721774PMC
November 2017

Prevention of Stroke with the Addition of Ezetimibe to Statin Therapy in Patients With Acute Coronary Syndrome in IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial).

Circulation 2017 Dec 30;136(25):2440-2450. Epub 2017 Sep 30.

TIMI Study Group, Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (E.A.B., S.D.W., R.P.G., J.-G.P., S.A.M., C.P.C., E.B.).

Background: Patients who experience an acute coronary syndrome are at heightened risk of recurrent ischemic events, including stroke. Ezetimibe improved cardiovascular outcomes when added to statin therapy in patients stabilized after acute coronary syndrome. We investigated the efficacy of the addition of ezetimibe to simvastatin for the prevention of stroke and other adverse cardiovascular events in IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial), with a focus on patients with a stroke before randomization.

Methods: Patients who experienced acute coronary syndrome were randomized to a placebo/simvastatin or ezetimibe/simvastatin regimen and followed for a median of 6 years. Treatment efficacy was assessed for the entire population and by subgroups for the first and total (first and subsequent) events for the end points of stroke of any etiology, stroke subtypes, and the primary trial end point at 7 years.

Results: Of 18 144 patients, 641 (3.5%) experienced at least 1 stroke; most were ischemic (527, 82%). Independent predictors of stroke included prior stroke, older age, atrial fibrillation, congestive heart failure, diabetes mellitus, myocardial infarction, and renal dysfunction. There was a nonsignificant reduction in the first event of stroke of any etiology (4.2% versus 4.8%; hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.73-1.00; =0.052) with ezetimibe/simvastatin versus placebo/simvastatin, driven by a significant 21% reduction in ischemic stroke (3.4% versus 4.1%; HR, 0.79; 95% CI, 0.67-0.94; =0.008) and a nonsignificant increase in hemorrhagic stroke (0.8% versus 0.6%; HR, 1.38; 95% CI, 0.93-2.04; =0.11). Evaluating total events, including the first and all recurrent strokes, ezetimibe/simvastatin reduced stroke of any etiology (HR, 0.83; 95% CI, 0.70-0.98; =0.029) and ischemic stroke (HR, 0.76; 95% CI, 0.63-0.91; =0.003). Patients who had experienced a stroke prior to randomization were at a higher risk of recurrence and demonstrated an absolute risk reduction of 8.6% for stroke of any etiology (10.2% versus 18.8%; number needed to treat=12; HR, 0.60; 95% CI, 0.38-0.95; =0.030) and 7.6% for ischemic stroke (8.7% versus 16.3%; number needed to treat=13; HR, 0.52; 95% CI, 0.31-0.86; =0.011) with ezetimibe added to simvastatin therapy.

Conclusions: The addition of ezetimibe to simvastatin in patients stabilized after acute coronary syndrome reduces the frequency of ischemic stroke, with a particularly large effect seen in patients with a prior stroke.

Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00202878.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.117.029095DOI Listing
December 2017

A window of opportunity: Subdominant predators can use suboptimal prey.

Ecol Evol 2017 07 7;7(14):5269-5275. Epub 2017 Jun 7.

Department of Entomology University of Kentucky Lexington KY USA.

Introduced species have been linked to declines of native species through mechanisms including intraguild predation and exploitative competition. However, coexistence among species may be promoted by niche partitioning if native species can use resources that the invasive species cannot. Previous research has shown that some strains of the aphid are toxic to a competitively dominant invasive lady beetle, . Our objective was to investigate whether these aphids might be an exploitable resource for other, subdominant, lady beetle species. We compared larval development rate, survival, and adult weight of five lady beetle species in no-choice experiments with two different strains of , one of which is toxic to and one that is nontoxic. Two lady beetle species, and were able to complete larval development when feeding on the aphid strain that is toxic to , experiencing only slight developmental delays relative to beetles feeding on the other aphid strain. One species, also was able to complete larval development, but experienced a slight reduction in adult weight. The other two lady beetle species, and , demonstrated generally low survivorship when consuming , regardless of aphid strain. All five species showed increased survival and/or development relative to on the "toxic" aphid strain. Our results suggest that this toxic trait may act as a narrow-spectrum defense for the aphids, providing protection against only some lady beetle enemies. For other less-susceptible lady beetles, these aphids have the potential to provide competitive release from the otherwise dominant .
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http://dx.doi.org/10.1002/ece3.3139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5528202PMC
July 2017

Long-term Safety and Efficacy of Achieving Very Low Levels of Low-Density Lipoprotein Cholesterol : A Prespecified Analysis of the IMPROVE-IT Trial.

JAMA Cardiol 2017 05;2(5):547-555

Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, TIMI Study Group, Boston, Massachusetts.

Importance: In the Improved Reduction of Outcomes: Vytorin Efficacy International Trial, intensive low-density lipoprotein cholesterol (LDL-C)-reducing therapy with ezetimibe/simvastatin compared with simvastatin alone was associated with a significant reduction in cardiovascular events in 18 144 patients after acute coronary syndrome. The safety of very low LDL-C levels over the long-term is unknown.

Objective: To assess the safety and clinical efficacy of achieving a very low (<30 mg/dL) level of LDL-C at 1 month using data from the Improved Reduction of Outcomes: Vytorin Efficacy International Trial.

Design, Setting, And Participants: This prespecified analysis compared outcomes in patients stratified by achieved LDL-C level at 1 month in the Improved Reduction of Outcomes: Vytorin Efficacy International Trial and adjusted for baseline characteristics during 6 years' median follow-up. Patients were enrolled from October 26, 2005, to July 8, 2010, and the data analysis was conducted from December 2014 to February 2017.

Main Outcomes And Measures: Safety end points included adverse events leading to drug discontinuation; adverse muscle, hepatobiliary, and neurocognitive events; and hemorrhagic stroke, heart failure, cancer, and noncardiovascular death. Efficacy events were as specified in the overall trial.

Results: Among the 15 281 patients included in the study, 11 645 (76.2%) were men and the median age was 63 years (interquartile range, 56.6-70.7 years). In these patients without an event in the first month, the achieved LDL-C values at 1 month were less than 30 mg/dL, 30 to 49 mg/dL, 50 to 69 mg/dL, and 70 mg/dL or greater in 6.4%, 31%, 36%, and 26% of patients, respectively. Patients with LDL-C values less than 30 mg/dL (median, 25 mg/dL; interquartile range, 21-27 mg/dL) at 1 month were more likely randomized to ezetimibe/simvastatin (85%), had lower baseline LDL-C values, and were more likely older, male, nonwhite, diabetic, overweight, statin naive, and presenting with a first myocardial infarction. After multivariate adjustment, there was no significant association between the achieved LDL-C level and any of the 9 prespecified safety events. The adjusted risk of the primary efficacy composite of cardiovascular death, major coronary events, or stroke was significantly lower in patients achieving an LDL-C level less than 30 mg/dL at 1 month (adjusted hazard ratio, 0.79; 95% CI, 0.69-0.91; P = .001) compared with 70 mg/dL or greater.

Conclusions And Relevance: Patients achieving an LDL-C level less than 30 mg/dL at 1 month had a similar safety profile (and numerically the lowest rate of cardiovascular events) over a 6-year period compared with patients achieving higher LDL-C concentrations. These data provide reassurance regarding the longer-term safety and efficacy of the continuation of intensive lipid-lowering therapy in very higher-risk patients resulting in very low LDL-C levels.

Trial Registration: clinicaltrials.gov Identifier: NCT00202878.
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http://dx.doi.org/10.1001/jamacardio.2017.0083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5814987PMC
May 2017

Atherothrombotic Risk Stratification and Ezetimibe for Secondary Prevention.

J Am Coll Cardiol 2017 Feb;69(8):911-921

TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

Background: Ezetimibe improves cardiovascular (CV) outcomes in patients stabilized after acute coronary syndrome (ACS) when added to statin therapy. After ACS, patients vary considerably in their risk for recurrent CV events.

Objectives: This study tested the hypothesis that atherothrombotic risk stratification may be useful to identify post-ACS patients who have the greatest potential for benefit from the addition of ezetimibe to statin therapy.

Methods: The TIMI (Thrombolysis In Myocardial Infarction) Risk Score for Secondary Prevention (TRS 2°P) is a simple 9-point risk stratification tool, previously developed in a large population with atherothrombosis to predict CV death, myocardial infarction (MI), and ischemic stroke (CV death/MI/ischemic cerebrovascular accident [iCVA]). The current study applied this tool prospectively to 17,717 post-ACS patients randomized either to ezetimibe and simvastatin or to placebo and simvastatin in IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial). Treatment efficacy was assessed by baseline risk for CV death/MI/iCVA, the IMPROVE-IT composite endpoints (CE), and individual component endpoints at 7 years.

Results: All 9 clinical variables in the TRS 2°P were independent risk indicators for CV death/MI/iCVA (p < 0.001). The integer-based scheme showed a strong graded relationship with the rate of CV death/MI/iCVA, the trial CE, and the individual components (p trend <0.0001 for each). High-risk patients (n = 4,393; 25%), defined by ≥3 risk indicators, had a 6.3% (95% confidence interval: 2.9% to 9.7%) absolute risk reduction in CV death/MI/iCVA at 7 years with ezetimibe/simvastatin, thus translating to a number-needed-to-treat of 16. Intermediate-risk patients (2 risk indicators; n = 5,292; 30%) had a 2.2% (95% confidence interval: -0.3% to 4.6%) absolute risk reduction. Low-risk patients (0 to 1 risk indicators; n = 8,032; 45%) did not appear to derive benefit from the addition of ezetimibe (p interaction = 0.010). Similar findings were observed for the IMPROVE-IT primary CE.

Conclusions: Atherothrombotic risk stratification using the TRS 2°P identifies high-risk patients who derive greatest benefit from the addition of ezetimibe to statin therapy for secondary prevention after ACS. (Improved Reduction of Outcomes: Vytorin Efficacy International Trial [IMPROVE-IT]; NCT00202878).
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http://dx.doi.org/10.1016/j.jacc.2016.11.070DOI Listing
February 2017

On-treatment analysis of the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT).

Am Heart J 2016 Dec 23;182:89-96. Epub 2016 Sep 23.

TIMI Study Group, Boston, MA.

Background: We aimed to determine the efficacy and safety of adding ezetimibe (Ez) to simvastatin (S) in a post-acute coronary syndrome (ACS) population in a prespecified on-treatment analysis.

Methods: We evaluated 17,706 post-ACS patients from the IMPROVE-IT trial who had low-density lipoprotein cholesterol values between 50 and 125 mg/dL and who received Ez 10 mg/d with S 40 mg/d (Ez/S) or placebo with simvastatin 40 mg/d (P/S). The primary composite end point was cardiovascular death, myocardial infarction, unstable angina, coronary revascularization ≥30 days postrandomization, or stroke. The on-treatment analysis included patients who received study drug for the duration of the trial or experienced a primary end point or noncardiovascular death within 30 days of drug discontinuation.

Results: Mean low-density lipoprotein cholesterol values at 1 year were 71 mg/dL for P/S and 54 mg/dL for Ez/S (absolute difference -17 mg/dL = -24%; P < .001). The 7-year Kaplan-Meier estimate of the primary end point occurred in 32.4% in the P/S arm and 29.8% in the Ez/S arm (absolute difference 2.6%; HR 0.92 [95% CI 0.87-0.98]; P = .01). The absolute treatment effect favoring Ez/S was 30% greater than in the intention-to-treat analysis of IMPROVE-IT.

Conclusions: This analysis provides additional support for the efficacy and safety of adding Ez to S in this high-risk, post-ACS population.
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http://dx.doi.org/10.1016/j.ahj.2016.09.004DOI Listing
December 2016

The benefit of adding ezetimibe to statin therapy in patients with prior coronary artery bypass graft surgery and acute coronary syndrome in the IMPROVE-IT trial.

Eur Heart J 2016 Dec 28;37(48):3576-3584. Epub 2016 Aug 28.

TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, 350 Longwood Avenue, 1st Floor Offices, Boston, MA 02115, USA

Aims: To examine the efficacy and safety of ezetimibe added to statin in patients with prior coronary artery bypass graft surgery (CABG) following hospitalization for an acute coronary syndrome (ACS).

Methods And Results: In the IMPROVE-IT trial, post-ACS patients with mean low density lipoprotein cholesterol (LDL-C) of 93.8 mg/dL at presentation were randomized to simvastatin/ezetimibe or simvastatin/placebo. The primary endpoint was cardiovascular death, major coronary event or stroke, and the median follow-up was 6 years. Efficacy and safety endpoints were examined by prior CABG status. Among 18 134 patients, 1684 (9.3%) had a prior CABG (median age 69 years, 82% male). During the trial, the median time-weighted LDL-C level was 55.0 mg/dL with simvastatin/ezetimibe vs. 69.9 mg/dL with simvastatin/placebo in patients with prior CABG (P < 0.001), and it was 53.6 mg/dL vs. 69.5 mg/dL, respectively, in patients without prior CABG (P < 0.001). The rate of the primary endpoint was higher in patients with vs. without prior CABG [56% vs. 32%, adj. hazard ratio 1.45, 95% confidence interval (CI) 1.33-1.58]. Patients with prior CABG receiving simvastatin/ezetimibe had an 8.8% (95% CI 3.1-14.6%) lower absolute risk over simvastatin/placebo in the primary endpoint, whereas patients without prior CABG had a 1.3% (95% CI 0-2.6%) lower absolute risk (P-interaction = 0.02). There were no between-group significant differences in safety endpoints.

Conclusion: The clinical benefit of adding ezetimibe to statin appears to be enhanced in patients with prior CABG, supporting the use of intensive lipid lowering therapy in these high-risk patients following ACS.
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http://dx.doi.org/10.1093/eurheartj/ehw377DOI Listing
December 2016

Bioabsorbable Intracoronary Matrix for Prevention of Ventricular Remodeling After Myocardial Infarction.

J Am Coll Cardiol 2016 08;68(7):715-23

Duke Clinical Research Institute, Durham, North Carolina.

Background: Bioabsorbable cardiac matrix (BCM) is a novel device that attenuates adverse left ventricular (LV) remodeling after large myocardial infarctions in experimental models.

Objectives: This study aimed to analyze whether BCM, compared with saline control, would result in less LV dilation and fewer adverse clinical events between baseline and 6 months.

Methods: In an international, randomized, double-blind, controlled trial, 303 subjects with large areas of infarction despite successful primary percutaneous coronary intervention (PCI) of ST-segment elevation myocardial infarction (STEMI) were randomized 2:1 to BCM or saline injected into the infarct-related artery 2 to 5 days after primary PCI. The primary outcome was mean change from baseline in LV end-diastolic volume index (LVEDVI) at 6 months. Secondary outcomes included change in Kansas City Cardiomyopathy Questionnaire score, 6-minute walk time, and New York Heart Association functional class at 6 months. The primary safety endpoint was a composite of cardiovascular death, recurrent MI, target-vessel revascularization, stent thrombosis, significant arrhythmia requiring therapy, or myocardial rupture through 6 months.

Results: In total, 201 subjects were assigned to BCM and 102 to saline control. There was no significant difference in change in LVEDVI from baseline to 6 months between the groups (mean change ± SD: BCM 14.1 ± 28.9 ml/m(2) vs. saline 11.7 ± 26.9 ml/m(2); p = 0.49). There was also no significant difference in the secondary endpoints. The rates of the primary safety outcome were similar between the 2 groups (BCM 11.6% vs. saline 9.1%; p = 0.37).

Conclusions: Intracoronary deployment of BCM 2 to 5 days after successful reperfusion in subjects with large myocardial infarction did not reduce adverse LV remodeling or cardiac clinical events at 6 months. (IK-5001 for the Prevention of Remodeling of the Ventricle and Congestive Heart Failure After Acute Myocardial Infarction [PRESERVATION I]; NCT01226563).
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http://dx.doi.org/10.1016/j.jacc.2016.05.053DOI Listing
August 2016

A randomized, double-blind, placebo controlled safety, tolerability, and pharmacokinetic dose escalation study of a gentamicin vancomycin gel in patients undergoing colorectal surgery.

Perioper Med (Lond) 2016 16;5:17. Epub 2016 Jun 16.

Dr. Reddy's Laboratories, Inc., Princeton, NJ USA.

Background: Despite numerous interventions promulgated by the Surgical Care Improve Project (SCIP) and other organizations, surgical site infection (SSI) continues to be a significant medical problem. DFA-02 is a novel bioresorbable modified-release gel consisting of both gentamicin (16.8 mg/mL) and vancomycin (18.8 mg/mL) to be applied during surgical incision closure for the prevention of SSIs. The following double-blind phase 2a trial was designed to test the safety and tolerability of DFA-02.

Methods: At six US sites, the study planned to randomize 40 subjects undergoing colorectal surgery (30 with DFA-02, and eight with placebo gel) in four ascending dose cohorts (10-, 20-, 30-, and 40-mL study drug per wound). Safety was ascertained and serum pharmacokinetics (PK) was determined.

Results: Study enrollment was discontinued after the first three dose cohorts (10, 20, and 30 mL) as even very large incisions could not accommodate more than 20 mL of gel, leaving no scientific justification for the 40-mL cohort. DFA-02 was well tolerated and showed no evidence of local tissue reaction or impairment of wound healing. No serious AEs were deemed related to study drug. Systemic exposure to gentamicin and vancomycin remained well below levels considered to be at higher risk for oto- or nephrotoxicity. The maximal gentamicin and vancomycin levels observed were 2.36 and 0.684 μg/mL at 6 h, which were well below the prespecified stopping criteria of 12 and 20 μg/mL, respectively.

Conclusions: In this small phase 2a study, the study drug was well tolerated and appeared to be free of serious adverse effects. Consistent with these findings, the PK values were consistent with gradual release of the antibiotics from the gel in the surgical site.

Trial Registration: ClinicalTrials.gov, NCT01496352.
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http://dx.doi.org/10.1186/s13741-016-0043-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4910209PMC
June 2016

Reduction in Total Cardiovascular Events With Ezetimibe/Simvastatin Post-Acute Coronary Syndrome: The IMPROVE-IT Trial.

J Am Coll Cardiol 2016 Feb;67(4):353-361

TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.

Background: Intensive low-density lipoprotein cholesterol therapy with ezetimibe/simvastatin in IMPROVE-IT (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial) significantly reduced the first primary endpoint (PEP) in patients post-acute coronary syndrome (ACS) compared to placebo/simvastatin.

Objectives: This analysis tested the hypothesis that total events, including those beyond the first event, would also be reduced with ezetimibe/simvastatin therapy.

Methods: All PEP events (cardiovascular [CV] death, myocardial infarction [MI], stroke, unstable angina [UA] leading to hospitalization, coronary revascularization ≥30 days post-randomization) during a median 6-year follow-up were analyzed in patients randomized to receive ezetimibe/simvastatin or placebo/simvastatin in IMPROVE-IT. Negative binomial regression was used for the primary analysis.

Results: Among 18,144 patients, there were 9,545 total PEP events (56% were first events and 44% subsequent events). Total PEP events were significantly reduced by 9% with ezetimibe/simvastatin vs placebo/simvastatin (incidence-rate ratio [RR]: 0.91; 95% confidence interval [CI]: 0.85 to 0.97; p = 0.007), as were the 3 pre-specified secondary composite endpoints and the exploratory composite endpoint of CV death, MI, or stroke (RR: 0.88; 95% CI: 0.81 to 0.96; p = 0.002). The reduction in total events was driven by decreases in total nonfatal MI (RR: 0.87; 95% CI: 0.79 to 0.96; p = 0.004) and total NF stroke (RR: 0.77; 95% CI: 0.65 to 0.93; p = 0.005).

Conclusions: Lipid-lowering therapy with ezetimibe plus simvastatin improved clinical outcomes. Reductions in total PEP events, driven by reductions in MI and stroke, more than doubled the number of events prevented compared with examining only the first event. These data support continuation of intensive combination lipid-lowering therapy after an initial CV event. (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial [IMPROVE-IT]; NCT00202878).
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http://dx.doi.org/10.1016/j.jacc.2015.10.077DOI Listing
February 2016

Surveys for maternally-inherited endosymbionts reveal novel and variable infections within solitary bee species.

J Invertebr Pathol 2015 Nov 26;132:111-114. Epub 2015 Sep 26.

Department of Entomology, University of Kentucky, S-225 Agricultural Sciences Center North, Lexington, KY 40546, USA. Electronic address:

Maternally-inherited bacteria can affect the fitness and population dynamics of their host insects; for solitary bees, such effects have the potential to influence bee efficacy as pollinators. We screened bee species for bacterial associates using 454-pyrosequencing (4 species) and diagnostic PCR (183 specimens across 29 species). The endosymbiont Wolbachia was abundant, infecting 18 species, including all specimens from the family Halictidae. Among commercially-supplied orchard bees (family Megachilidae), only 2/7 species were Wolbachia-infected, but one species showed variable infection among specimens. Two other maternally-inherited bacteria, Arsenophonus and Sodalis, were also detected, neither of which was fixed in infection frequency. Differential endosymbiont infection could potentially compromise fitness and reproductive compatibility among commercially redistributed pollinator populations.
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http://dx.doi.org/10.1016/j.jip.2015.09.011DOI Listing
November 2015

Achievement of dual low-density lipoprotein cholesterol and high-sensitivity C-reactive protein targets more frequent with the addition of ezetimibe to simvastatin and associated with better outcomes in IMPROVE-IT.

Circulation 2015 Sep 1;132(13):1224-33. Epub 2015 Sep 1.

From TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (E.A.B., R.P.G., C.P.C., J.Z., S.A.M., E.B.); Duke Clinical Research Institute, Durham, NC (J.W., M.A.B.); and Merck, Kenilworth, NJ (A.M.T.).

Background: Statins lower low-density lipoprotein cholesterol (LDL-C) and high-sensitivity C-reactive protein (hs-CRP); addition of ezetimibe to statins further reduces LDL-C and hs-CRP. An analysis of the relationship between achieved LDL-C and hs-CRP targets and outcomes for simvastatin and ezetimibe/simvastatin was prespecified in Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT).

Methods And Results: The IMPROVE-IT trial randomly assigned 18 144 patients stabilized after acute coronary syndrome to simvastatin or ezetimibe/simvastatin. LDL-C and hs-CRP were measured at baseline and 1 month after randomization. Outcomes were assessed in those achieving one or both of the prespecified targets of LDL-C<70 mg/dL and hs-CRP<2 mg/L versus achieving neither target, adjusting for differences in baseline characteristics. An exploratory analysis examined targets of LDL-C<50 mg/dL and hs-CRP<1 mg/L. Patients meeting both targets at baseline, with no 1-month values, or with end points before 1 month were excluded. Of 15 179 patients, 39% achieved the dual LDL-C (<70 mg/dL) and hs-CRP (<2 mg/L) targets at 1 month, 14% met neither target, 14% met only the hs-CRP target, and 33% met only the LDL-C target. Those achieving dual targets had lower primary end point rates than those meeting neither target (cardiovascular death, major coronary event, or stroke; 38.9% versus 28.0%; adjusted hazard ratio, 0.73; 0.66-0.81; P<0.001). More patients treated with ezetimibe/simvastatin met dual targets than those treated with simvastatin alone (50% versus 29%, P<0.001). The association of dual-target attainment with improved outcomes was similar irrespective of treatment assignment (P-interaction=0.65). Similar findings were observed using the exploratory targets.

Conclusions: Significantly more patients treated with ezetimibe/simvastatin met prespecified and exploratory dual LDL-C and hs-CRP targets than patients treated with simvastatin alone. Reaching both LDL-C and hs-CRP targets was associated with improved outcomes after multivariable adjustment.

Clinical Trial Registration: URL: http://www.clinicaltrials.gov; Unique identifier: NCT00202878.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.115.018381DOI Listing
September 2015

The Endosymbiont Arsenophonus Provides a General Benefit to Soybean Aphid (Hemiptera: Aphididae) Regardless of Host Plant Resistance (Rag).

Environ Entomol 2015 Jun 31;44(3):574-81. Epub 2015 Mar 31.

Department of Entomology, University of Kentucky, Lexington, KY 40546, USA.

Soybean aphid, Aphis glycines Matsumura (Hemiptera: Aphididae), invokes substantial chemical treatment and economic cost in North America. Resistant soybean genotypes hold promise as a low-impact control methodology, but soybean aphid "biotypes" capable of development on resistant soy cast doubt on the durability of soy resistance. We hypothesized that variation in soybean aphid ability to colonize resistant soy is partially attributable to a bacterial symbiont of soybean aphid, Arsenophonus. We used microinjection to manipulate Arsenophonus infection in both virulent and avirulent aphid biotypes, resulting in five pairs of infected versus uninfected isolines. These isolines were subjected to various population growth rate assays on resistant Rag versus susceptible soybean. We found that aphid virulence on Rag soybean was not dependent on Arsenophonus: virulent aphid biotypes performed well on Rag soybean, and avirulent aphid biotypes performed poorly on Rag soybean, regardless of whether Arsenophonus was present or not. However, we did find that Arsenophonus-infected clones on average performed significantly better than their paired uninfected isolines. This pattern was not consistently evident on every date for every clone, either in the population assays nor when we compared lifetime fecundity of individual aphids in a separate experiment. Nevertheless, this overall benefit for infected aphids may be sufficient to explain the high frequency of Arsenophonus infection in soybean aphids.
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http://dx.doi.org/10.1093/ee/nvv031DOI Listing
June 2015

Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes.

N Engl J Med 2015 Jun 3;372(25):2387-97. Epub 2015 Jun 3.

From the Thrombolysis in Myocardial Infarction (TIMI) Study Group, Brigham and Women's Hospital, and Harvard Medical School, Boston (C.P.C., R.P.G., A.M., K.I., E.A.B., S.D.W., E.B.); Duke Clinical Research Institute (DCRI), Durham, NC (M.A.B., J.A.W., C.R., R.M.C.); Montreal Heart Institute, Montreal (P.T.); Vivantes Neukölln Medical Center, Berlin (H.D.); Lady Davis Carmel Medical Center, Haifa, Israel (B.S.L.); Canisius-Wilhelmina Ziekenhuis, Nijmegen (T.O.O.), and the Netherlands Leiden University Medical Center, Leiden (J.W.J.) - both in the Netherlands; Fondazione IRCCS Policlinico San Matteo and University of Pavia, Pavia, Italy (G.M.D.F.); National Institute of Cardiology, Warsaw, Poland (W.R.); and Merck, Kenilworth, NJ (P.D.L., A.M.T., T.A.M.).

Background: Statin therapy reduces low-density lipoprotein (LDL) cholesterol levels and the risk of cardiovascular events, but whether the addition of ezetimibe, a nonstatin drug that reduces intestinal cholesterol absorption, can reduce the rate of cardiovascular events further is not known.

Methods: We conducted a double-blind, randomized trial involving 18,144 patients who had been hospitalized for an acute coronary syndrome within the preceding 10 days and had LDL cholesterol levels of 50 to 100 mg per deciliter (1.3 to 2.6 mmol per liter) if they were receiving lipid-lowering therapy or 50 to 125 mg per deciliter (1.3 to 3.2 mmol per liter) if they were not receiving lipid-lowering therapy. The combination of simvastatin (40 mg) and ezetimibe (10 mg) (simvastatin-ezetimibe) was compared with simvastatin (40 mg) and placebo (simvastatin monotherapy). The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, unstable angina requiring rehospitalization, coronary revascularization (≥30 days after randomization), or nonfatal stroke. The median follow-up was 6 years.

Results: The median time-weighted average LDL cholesterol level during the study was 53.7 mg per deciliter (1.4 mmol per liter) in the simvastatin-ezetimibe group, as compared with 69.5 mg per deciliter (1.8 mmol per liter) in the simvastatin-monotherapy group (P<0.001). The Kaplan-Meier event rate for the primary end point at 7 years was 32.7% in the simvastatin-ezetimibe group, as compared with 34.7% in the simvastatin-monotherapy group (absolute risk difference, 2.0 percentage points; hazard ratio, 0.936; 95% confidence interval, 0.89 to 0.99; P=0.016). Rates of prespecified muscle, gallbladder, and hepatic adverse effects and cancer were similar in the two groups.

Conclusions: When added to statin therapy, ezetimibe resulted in incremental lowering of LDL cholesterol levels and improved cardiovascular outcomes. Moreover, lowering LDL cholesterol to levels below previous targets provided additional benefit. (Funded by Merck; IMPROVE-IT ClinicalTrials.gov number, NCT00202878.).
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http://dx.doi.org/10.1056/NEJMoa1410489DOI Listing
June 2015
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