Alice J. Sheffet

Micronutrient profiles in HIV-1-infected heterosexual adults.

There is compelling evidence that micronutrients can profoundly affect immunity. We surveyed vitamin supplement use and circulating concentrations of 22 nutrients and glutathione in 64 HIV-1 seropositive men and women and 33 seronegative controls participating in a study of heterosexual HIV-1 transmission. We assayed antioxidants (vitamins A, C, and E; total carotenes), vitamins B6 and B12, folate, thiamin, niacin, biotin, riboflavin, pantothenic acid, free and total choline and carnitine, biopterin, inositol, copper, zinc, selenium, and magnesium. HIV-infected patients had lower mean circulating concentrations of magnesium (p < 0.0001), total carotenes (p = 0.009), total choline (p = 0.002), and glutathione (p = 0.045), and higher concentrations of niacin (p < 0.0001) than controls. Fifty-nine percent of HIV+ patients had low concentrations of magnesium, compared with 9% of controls (p < 0.0001). These abnormal concentrations were unrelated to stage of disease. Participants who took vitamin supplements had consistently fewer low concentrations of antioxidants, across HIV infection status and disease stage strata (p = 0.0006). Nevertheless, 29% of the HIV+ patients taking supplemental vitamins had subnormal levels of one or more antioxidants. The frequent occurrence of abnormal micronutrient nutriture, as found in these HIV+ subjects, may contribute to disease pathogenesis. The low magnesium concentrations may be particularly relevant to HIV-related symptoms of fatigue, lethargy, and impaired mentation.

Psychological distress, drug and alcohol use as correlates of condom use in HIV-serodiscordant heterosexual couples.

ObjectiveTo investigate the relationship between psychological distress, alcohol, drug and condom use in HIV-serodiscordant heterosexual couples. MethodsStructured interviews were conducted to collect demographic information, detailed data on psychological distress, drug and alcohol use and sexual behavior. ResultsAnalyses were based on 106 pairs of sexually active discordant couples. Significant differences among heterosexual condom users and non-users varied according to gender and HIV serostatus. Affect domains of interpersonal sensitivity and hostility were significant, as were the variables of regular drug or alcohol use and combining sex with drugs or alcohol. Employment was strongly associated with condom use in HIV-negative women whose regular sexual partners were HIV-positive men. ConclusionThe risk of vaginal sex without condoms in HIV-serodiscordant heterosexual couples may be reduced by specific psychological counseling and attention to drug and alcohol use as risk factors. Further research on the effect of employment of HIV-negative women is required.

Design of the Carotid Revascularization Endarterectomy vs. Stenting Trial (CREST)

Rationale Carotid endarterectomy (CEA) and medical therapy were shown superior to medical therapy alone for symptomatic (ge;50%) and asymptomatic (≥60%) stenosis. Carotid angioplasty stenting (CAS) offers a less invasive alternative. Establishing safety, efficacy, and durability of CAS requires rigorous comparison with CEA in symptomatic and asymptomatic patients. Aims The objective is to compare the efficacy of CAS versus CEA in patients with symptomatic (≥50%) or asymptomatic (≥60%) extracranial carotid stenosis. Design The Carotid Revascularization Endarterectomy vs. Stenting Trial (CREST) is a prospective, randomized, parallel, two-arm, multi-center trial with blinded endpoint adjudication. Primary endpoints are analyzed using standard time-to-event statistical modeling with adjustment for major baseline covariates. Primary analysis is on an intent-to-treat basis. Study Outcomes The primary outcome is the occurrence of any stroke, myocardial infarction, or death during a 30-day peri-procedural period, and ipsilateral stroke during follow-up of up to four years. Secondary outcomes include restenosis and health-related quality of life.

Mediators of the Age Effect in the Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST)

Background and Purpose— There is higher combined risk of stroke or death (S+D) at older ages with carotid stenting. We assess whether this can be attributed to patient or arterial characteristics that are in the pathway between older age and higher risk. Methods— Mediation analysis of selected patient (hypertension, diabetes mellitus, and dyslipidemia) and arterial characteristics assessed at the clinical sites and the core laboratory (plaque length, eccentric plaque, ulcerated plaque, percent stenosis, peak systolic velocity, and location) was performed in 1123 carotid artery stenting–treated patients in the Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST). We assessed the association of age with these characteristics, the association of these characteristics with stroke risk, and the amount of mediation of the association of age on the combined risk of periprocedural S+D with adjustment for these factors. Results— Only plaque length as measured at the sites increased with age, was associated with increased S+D risk and significantly mediated the association of age on S+D risk. However, adjustment for plaque length attenuated the increased risk per 10 years of age from 1.72 (95% confidence interval, 1.26–2.37) to 1.66 (95% confidence interval, 1.20–2.29), accounting for only 8% of the increased risk. Conclusions— Plaque length seems to be in the pathway between older age and higher risk of S+D among carotid artery stenting–treated patients, but it mediated only 8% of the age effect excess risk of carotid artery stenting in CREST. Other factors and mechanisms underlying the age effect need to be identified as plaque length will not identify elderly patients for whom stenting is safe relative to endarterectomy. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00004732.

Carotid endarterectomy and carotid artery stenting in the US Medicare population, 1999-2014

Importance Carotid endarterectomy and carotid artery stenting are the leading approaches to revascularization for carotid stenosis, yet contemporary data on trends in rates and outcomes are limited. Objective To describe US national trends in performance and outcomes of carotid endarterectomy and stenting among Medicare beneficiaries from 1999 to 2014. Design, Setting, and Participants Serial cross-sectional analysis of Medicare fee-for-service beneficiaries aged 65 years or older from 1999 to 2014 using the Medicare Inpatient and Denominator files. Spatial mixed models adjusted for age, sex, and race were fit to calculate county-specific risk-standardized revascularization rates. Mixed models were fit to assess trends in outcomes after adjustment for demographics, comorbidities, and symptomatic status. Exposures Carotid endarterectomy and carotid artery stenting. Main Outcomes and Measures Revascularization rates per 100 000 beneficiary-years of fee-for-service enrollment, in-hospital mortality, 30-day stroke or death, 30-day stroke, myocardial infarction, or death, 30-day all-cause mortality, and 1-year stroke. Results During the study, 937 111 unique patients underwent carotid endarterectomy (mean age, 75.8 years; 43% women) and 231 077 underwent carotid artery stenting (mean age, 75.4 years; 49% women). There were 81 306 patients who underwent endarterectomy in 1999 and 36 325 in 2014; national rates per 100 000 beneficiary-years decreased from 298 in 1999-2000 to 128 in 2013-2014 (P < .001). The number of patients who underwent stenting ranged from 10 416 in 1999 to 22 865 in 2006 (an increase per 100 000 beneficiary-years from 40 in 1999-2000 to 75 in 2005-2006; P < .001); by 2014, there were 10 208 patients who underwent stenting and the rate decreased to 38 per 100 000 beneficiary-years (P < .001). Outcomes improved over time despite increases in vascular risk factors (eg, hypertension prevalence increased from 67% to 81% among patients who underwent endarterectomy and from 61% to 70% among patients who underwent stenting) and the proportion of symptomatic patients (all P < .001). There were adjusted annual decreases in 30-day ischemic stroke or death of 2.90% (95% CI, 2.63% to 3.18%) among patients who underwent endarterectomy and 1.13% (95% CI, 0.71% to 1.54%) among patients who underwent stenting; an absolute decrease from 1999 to 2014 was observed for endarterectomy (1.4%; 95% CI, 1.2% to 1.5%) but not stenting (−0.1%; 95% CI, −0.5% to 0.4%). Rates for 1-year ischemic stroke decreased after endarterectomy (absolute decrease, 3.5% [95% CI, 3.2% to 3.7%]; adjusted annual decrease, 2.17% [95% CI, 2.00% to 2.34%]) and stenting (absolute decrease, 1.6% [95% CI, 1.2% to 2.1%]; adjusted annual decrease, 1.86% [95% CI, 1.45%-2.26%]). Additional improvements were noted for in-hospital mortality, 30-day stroke, myocardial infarction, or death, and 30-day all-cause mortality as well as within demographic subgroups. Conclusions and Relevance Among fee-for-service Medicare beneficiaries, the performance of carotid endarterectomy declined from 1999 to 2014, whereas the performance of carotid artery stenting increased until 2006 and then declined from 2007 to 2014. Outcomes improved despite increases in vascular risk factors.

Complication Rates and Center Enrollment Volume in the Carotid Revascularization Endarterectomy Versus Stenting Trial

Background and Purpose— Evidence indicates that center volume of cases affects outcomes for both carotid endarterectomy and stenting. We evaluated the effect of enrollment volume by site on complication rates in the Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST). Methods— The primary composite end point was any stroke, myocardial infarction, or death within 30 days or ipsilateral stroke in follow-up. The 477 approved surgeons performed >12 procedures per year with complication rates <3% for asymptomatic patients and <5% for symptomatic patients; 224 interventionists were certified after a rigorous 2 step credentialing process. CREST centers were divided into tertiles based on the number of patients enrolled into the study, with Group 1 sites enrolling <25 patients, Group 2 sites enrolling 25 to 51 patients, and Group 3 sites enrolling >51 patients. Differences in periprocedural event rates for the primary composite end point and its components were compared using logistic regression adjusting for age, sex, and symptomatic status within site-volume level. Results— The safety of carotid angioplasty and stenting and carotid endarterectomy did not vary by site-volume during the periprocedural period as indicated by occurrence of the primary end point (P=0.54) or by stroke and death (P=0.87). A trend toward an inverse relationship between center enrollment volume and complications was mitigated by adjustment for known risk factors. Conclusions— Complication rates were low in CREST and were not associated with center enrollment volume. The data are consistent with the value of rigorous training and credentialing in trials evaluating endovascular devices and surgical procedures. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00004732.

Lymphocyte Immunoregulatory Cells Present in Semen From Human Immunodeficiency Virus (HIV)-Infected Individuals: A Report From the HIV Heterosexual Transmission Study

The purpose of this study was to determine the types and distribution of immune subsets present in semen from human immunodeficiency virus (HIV)-infected (HIV+) individuals and to compare these values with those measures in semen from HIV-negative (HIV-) individuals. To accomplish this, a direct three-color monoclonal antibody labeling technique was employed to identify immune cells in fresh ejaculates. Once labeled, the percent of each immune subset present in the ejaculate was determined by flow cytometric analysis. The percent of CD3+ cells present in the semen of the HIV+ group showed no significant difference when compared with semen from the HIV- group. Analysis of the CD4+ subset yielded a significantly lower percent in the HIV+ group than in the HIV- group. The analysis of the CD8+ subset yielded a higher percent of cells present in semen from HIV+ individuals. The CD8 higher value along with lower CD4 value results in a lower CD4/CD8 ratio in the HIV+ group. Further subset studies showed that the percent of cells expressing naive (CD4+ CD45RA+) and memory (CD4+ CD45RO+) markers was lower in the HIV+ group. This study provides additional data supporting the utility of flow cytometry and monoclonal antibodies to immunophenotypic cells present in semen ejaculates. It is also the first reported application of the technique to a disease-based model and may be useful to better understand issues of mucosal immunity and transmission of sexually transmitted diseases such as HIV.

Challenge and Yield of Enrolling Racially and Ethnically Diverse Patient Populations in Low Event Rate Clinical Trials

Background and Purpose— We report patient enrollment and retention by race and ethnicity in the CREST (Carotid Revascularization Endarterectomy Versus Stent Trial) and assess potential effect modification by race/ethnicity. In addition, we discuss the challenge of detecting differences in study outcomes when subgroups are small and the event rate is low. Methods— We compared 2502 patients by race, ethnicity, baseline characteristics, and primary outcome (any periprocedural stroke, death, or myocardial infarction and subsequent ipsilateral stroke up to 10 years). Results— Two hundred forty (9.7%) patients were minority by race (6.1%) or ethnicity (3.6%); 109 patients (4.4%) were black, 32 (1.3%) Asian, 2332 (93.4%) white, 11 (0.4%) other, and 18 (0.7%) unknown. Ninety (3.6%) were Hispanic, 2377 (95%) non-Hispanic, and 35 (1.4%) unknown. The rate of the primary end point for all patients was 10.9%±0.9% at 10 years and did not differ by race or ethnicity (Pinter>0.24). Conclusions— The proportion of minorities recruited to CREST was below their representation in the general population, and retention of minority patients was lower than for whites. Primary outcomes did not differ by race or ethnicity. However, in CREST (like other studies), the lack of evidence of a racial/ethnic difference in the treatment effect should be interpreted with caution because of low statistical power to detect such a difference. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00004732.

Carotid Endarterectomy and Carotid Artery Stenting in the US Medicare Population, 1999-2014

Conclusions: Aortic neck diameter increases consistently over time following EVAR. The degree of neck dilatation correlates with degree of device oversize but not with device type. Summary: Implications of aortic neck dilatation following endovascular aneurysm repair (EVAR) are unclear. Previous studies are limited to comparisons of individual, early generation devices. The authors’ compared aortic neck dilatation among contemporary stent grafts in this retrospective study of a prospectively maintained single center database. They reviewed preoperative and postoperative computed tomographic angiograms (at least one > 6 months after implant) for elective EVARs performed from 2008-2014. Images were analyzed using three-dimensional centerline reconstructions. Aortic neck diameter was measured in orthogonal planes at and 10mm below the lowest renal artery. Device type and main body graft diameter were obtained from operative reports. Eighty-six patients were analyzed with a median radiologic follow-up of 21.9 months (range, 4-64 months) and 81.3% had imaging at one year. The cohort was predominantly male (86.1%) with a mean age of 75.6 years (range, 60-94 years) and comorbidities were notable for significant coronary disease (50.0%) and smoking history (76.7%). Stent grants implanted included 26 Cook Zenith, 26 Gore Excluder, 22 Medtronic Endurant, 10 Endologix Powerlink, and 2 Trivascular Ovation devices. Mean device oversizing was 13.6 6 11.5% and did not vary by device type (P 1⁄4 .54). Most patients (86.0%) experienced increases in aortic neck diameter during follow-up, with a mean increase of 1.3 6 2.2 mm (5.9 6 9.3 %) and 3.3 6 0.6 mm (8.9 6 2.5%) at 30 day and at latest follow-up scans, respectively. Repeated-measures analysis further demonstrated a significant increase in mean neck dilatation during follow-up (P < .001). Neck dilatation was not significantly different across different devices (P 1⁄4 .233). However, there was a moderate positive correlation between percent change in neck diameter and degree of oversizing, which was statistically significant (P < .001). Type IA endoleak was observed in two patients and was associated with greater mean neck dilatation (8.8 6 3.3 mm vs 3.35 6 2.71; P 1⁄4 .041). There was no relationship between changes in neck diameter and sac regression/expansion. Comments: This study demonstrates infrarenal aortic neck dilation after endograft repair, which is progressive over time and associated with endograft oversizing. Whether this is due to the radial force the device uses to secure water tight seal, which then ceases when this force vector reaches equilibrium as some studies suggest, or to progressive aneurysmal growth is still not completely understood. The latter event would, of course, be unfortunate since a wave of type IA endoleaks would be expected that fortunately has not be observed in current experience. This study would confirm this lack of clinical consequence but lacks longterm follow-up. A similar focus was reported in the Journal of Vascular Surgery but at 24 months there was a negative clinical impact with a higher risk of type IA endoleaks observed at 24 months. Much is yet to be learned regarding endograft repair of infrarenal abdominal aortic aneurysms in the long-term that being 10-15 years. Reference 1. Gargiulo M, Gallitto E, Wattez H, Verzini F, Massoni GB, Loschi D, et al. Outcomes of endovascular aneurysm repair performed in abdominal aortic aneurysms with large infrarenal necks. J Vasc Surg 2017;66:1065e1072.