SARS-CoV-2 Infection and Death Rates Among Maintenance Dialysis Patients During Delta and Early Omicron Waves - United States, June 30, 2021-September 27, 2022.

Persons receiving maintenance dialysis are at increased risk for SARS-CoV-2 infection and its severe outcomes, including death. However, rates of SARS-CoV-2 infection and COVID-19-related deaths in this population are not well described. Since November 2020, CDC's National Healthcare Safety Network (NHSN) has collected weekly data monitoring incidence of SARS-CoV-2 infections (defined as a positive SARS-CoV-2 test result) and COVID-19-related deaths (defined as the death of a patient who had not fully recovered from a SARS-CoV-2 infection) among maintenance dialysis patients. This analysis used NHSN dialysis facility COVID-19 data reported during June 30, 2021-September 27, 2022, to describe rates of SARS-CoV-2 infection and COVID-19-related death among maintenance dialysis patients. The overall infection rate was 30.47 per 10,000 patient-weeks (39.64 among unvaccinated patients and 27.24 among patients who had completed a primary COVID-19 vaccination series). The overall death rate was 1.74 per 10,000 patient-weeks. Implementing recommended infection control measures in dialysis facilities and ensuring patients and staff members are up to date with recommended COVID-19 vaccination is critical to limiting COVID-19-associated morbidity and mortality.

Effectiveness of a COVID-19 Additional Primary or Booster Vaccine Dose in Preventing SARS-CoV-2 Infection Among Nursing Home Residents During Widespread Circulation of the Omicron Variant - United States, February 14-March 27, 2022.

Nursing home residents have experienced disproportionally high levels of COVID-19-associated morbidity and mortality and were prioritized for early COVID-19 vaccination (1). Following reported declines in vaccine-induced immunity after primary series vaccination, defined as receipt of 2 primary doses of an mRNA vaccine (BNT162b2 [Pfizer-BioNTech] or mRNA-1273 [Moderna]) or 1 primary dose of Ad26.COV2 (Johnson & Johnson [Janssen]) vaccine (2), CDC recommended that all persons aged ≥12 years receive a COVID-19 booster vaccine dose.* Moderately to severely immunocompromised persons, a group that includes many nursing home residents, are also recommended to receive an additional primary COVID-19 vaccine dose.† Data on vaccine effectiveness (VE) of an additional primary or booster dose against infection with SARS-CoV-2 (the virus that causes COVID-19) among nursing home residents are limited, especially against the highly transmissible B.1.1.529 and BA.2 (Omicron) variants. Weekly COVID-19 surveillance and vaccination coverage data among nursing home residents, reported by skilled nursing facilities (SNFs) to CDC's National Healthcare Safety Network (NHSN)§ during February 14-March 27, 2022, when the Omicron variant accounted for >99% of sequenced isolates, were analyzed to estimate relative VE against infection for any COVID-19 additional primary or booster dose compared with primary series vaccination. After adjusting for calendar week and variability across SNFs, relative VE of a COVID-19 additional primary or booster dose was 46.9% (95% CI = 44.8%-48.9%). These findings indicate that among nursing home residents, COVID-19 additional primary or booster doses provide greater protection against Omicron variant infection than does primary series vaccination alone. All immunocompromised nursing home residents should receive an additional primary dose, and all nursing home residents should receive a booster dose, when eligible, to protect against COVID-19. Efforts to keep nursing home residents up to date with vaccination should be implemented in conjunction with other COVID-19 prevention strategies, including testing and vaccination of nursing home staff members and visitors.

Association between prevalence of laboratory-identified Clostridioides difficile infection (CDI) and antibiotic treatment for CDI in US acute-care hospitals, 2019.

OBJECTIVE: To evaluate hospital-level variation in using first-line antibiotics for Clostridioides difficile infection (CDI) based on the burden of laboratory-identified (LabID) CDI. METHODS: Using data on hospital-level LabID CDI events and antimicrobial use (AU) for CDI (oral/rectal vancomycin or fidaxomicin) submitted to the National Healthcare Safety Network in 2019, we assessed the association between hospital-level CDI prevalence (per 100 patient admissions) and rate of CDI AU (days of therapy per 1,000 days present) to generate a predicted value of AU based on CDI prevalence and CDI test type using negative binomial regression. The ratio of the observed to predicted AU was then used to identify hospitals with extreme discordance between CDI prevalence and CDI AU, defined as hospitals with a ratio outside of the intervigintile range. RESULTS: Among 963 acute-care hospitals, rate of CDI prevalence demonstrated a positive dose-response relationship with rate of CDI AU. Compared with hospitals without extreme discordance (n = 902), hospitals with lower-than-expected CDI AU (n = 31) had, on average, fewer beds (median, 106 vs 208), shorter length of stay (median, 3.8 vs 4.2 days), and higher proportion of undergraduate or nonteaching medical school affiliation (48% vs 39%). Hospitals with higher-than-expected CDI AU (n = 30) were similar overall to hospitals without extreme discordance. CONCLUSIONS: The prevalence rate of LabID CDI had a significant dose-response association with first-line antibiotics for treating CDI. We identified hospitals with extreme discordance between CDI prevalence and CDI AU, highlighting potential opportunities for data validation and improvements in diagnostic and treatment practices for CDI.

Ecological Analysis of the Decline in Incidence Rates of COVID-19 Among Nursing Home Residents Associated with Vaccination, United States, December 2020-January 2021.

OBJECTIVE: To evaluate if facility-level vaccination after an initial vaccination clinic was independently associated with COVID-19 incidence adjusted for other factors in January 2021 among nursing home residents. DESIGN: Ecological analysis of data from the CDC's National Healthcare Safety Network (NHSN) and from the CDC's Pharmacy Partnership for Long-Term Care Program. SETTING AND PARTICIPANTS: CMS-certified nursing homes participating in both NHSN and the Pharmacy Partnership for Long-Term Care Program. METHODS: A multivariable, random intercepts, negative binomial model was applied to contrast COVID-19 incidence rates among residents living in facilities with an initial vaccination clinic during the week ending January 3, 2021 (n = 2843), vs those living in facilities with no vaccination clinic reported up to and including the week ending January 10, 2021 (n = 3216). Model covariates included bed size, resident SARS-CoV-2 testing, staff with COVID-19, cumulative COVID-19 among residents, residents admitted with COVID-19, community county incidence, and county social vulnerability index (SVI). RESULTS: In December 2020 and January 2021, incidence of COVID-19 among nursing home residents declined to the lowest point since reporting began in May, diverged from the pattern in community cases, and began dropping before vaccination occurred. Comparing week 3 following an initial vaccination clinic vs week 2, the adjusted reduction in COVID-19 rate in vaccinated facilities was 27% greater than the reduction in facilities where vaccination clinics had not yet occurred (95% confidence interval: 14%-38%, P < .05). CONCLUSIONS AND IMPLICATIONS: Vaccination of residents contributed to the decline in COVID-19 incidence in nursing homes; however, other factors also contributed. The decline in COVID-19 was evident prior to widespread vaccination, highlighting the benefit of a multifaced approach to prevention including continued use of recommended screening, testing, and infection prevention practices as well as vaccination to keep residents in nursing homes safe.

Effectiveness of Pfizer-BioNTech and Moderna Vaccines in Preventing SARS-CoV-2 Infection Among Nursing Home Residents Before and During Widespread Circulation of the SARS-CoV-2 B.1.617.2 (Delta) Variant - National Healthcare Safety Network, March 1-August 1, 2021.

Nursing home and long-term care facility residents live in congregate settings and are often elderly and frail, putting them at high risk for infection with SARS-CoV-2, the virus that causes COVID-19, and severe COVID-19-associated outcomes; therefore, this population was prioritized for early vaccination in the United States (1). Following rapid distribution and administration of the mRNA COVID-19 vaccines (Pfizer-BioNTech and Moderna) under an Emergency Use Authorization by the Food and Drug Administration (2), observational studies among nursing home residents demonstrated vaccine effectiveness (VE) ranging from 53% to 92% against SARS-CoV-2 infection (3-6). However, concerns about the potential for waning vaccine-induced immunity and the recent emergence of the highly transmissible SARS-CoV-2 B.1.617.2 (Delta) variant† highlight the need to continue to monitor VE (7). Weekly data reported by the Centers for Medicaid & Medicare (CMS)-certified skilled nursing facilities or nursing homes to CDC's National Healthcare Safety Network (NHSN)§ were analyzed to evaluate effectiveness of full vaccination (2 doses received ≥14 days earlier) with any of the two currently authorized mRNA COVID-19 vaccines during the period soon after vaccine introduction and before the Delta variant was circulating (pre-Delta [March 1-May 9, 2021]), and when the Delta variant predominated¶ (Delta [June 21-August 1, 2021]). Using 17,407 weekly reports from 3,862 facilities from the pre-Delta period, adjusted effectiveness against infection for any mRNA vaccine was 74.7% (95% confidence interval [CI] = 70.0%-78.8%). Analysis using 33,160 weekly reports from 11,581 facilities during an intermediate period (May 10-June 20) found that the adjusted effectiveness was 67.5% (95% CI = 60.1%-73.5%). Analysis using 85,593 weekly reports from 14,917 facilities during the Delta period found that the adjusted effectiveness was 53.1% (95% CI = 49.1%-56.7%). Effectiveness estimates were similar for Pfizer-BioNTech and Moderna vaccines. These findings indicate that mRNA vaccines provide protection against SARS-CoV-2 infection among nursing home residents; however, VE was lower after the Delta variant became the predominant circulating strain in the United States. This analysis assessed VE against any infection, without being able to distinguish between asymptomatic and symptomatic presentations. Additional evaluations are needed to understand protection against severe disease in nursing home residents over time. Because nursing home residents might remain at some risk for SARS-CoV-2 infection despite vaccination, multiple COVID-19 prevention strategies, including infection control, testing, and vaccination of nursing home staff members, residents, and visitors, are critical. An additional dose of COVID-19 vaccine might be considered for nursing home and long-term care facility residents to optimize a protective immune response.

Rates of COVID-19 Among Residents and Staff Members in Nursing Homes - United States, May 25-November 22, 2020.

During the beginning of the coronavirus disease 2019 (COVID-19) pandemic, nursing homes were identified as congregate settings at high risk for outbreaks of COVID-19 (1,2). Their residents also are at higher risk than the general population for morbidity and mortality associated with infection with SARS-CoV-2, the virus that causes COVID-19, in light of the association of severe outcomes with older age and certain underlying medical conditions (1,3). CDC's National Healthcare Safety Network (NHSN) launched nationwide, facility-level COVID-19 nursing home surveillance on April 26, 2020. A federal mandate issued by the Centers for Medicare & Medicaid Services (CMS), required nursing homes to commence enrollment and routine reporting of COVID-19 cases among residents and staff members by May 25, 2020. This report uses the NHSN nursing home COVID-19 data reported during May 25-November 22, 2020, to describe COVID-19 rates among nursing home residents and staff members and compares these with rates in surrounding communities by corresponding U.S. Department of Health and Human Services (HHS) region.* COVID-19 cases among nursing home residents increased during June and July 2020, reaching 11.5 cases per 1,000 resident-weeks (calculated as the total number of occupied beds on the day that weekly data were reported) (week of July 26). By mid-September, rates had declined to 6.3 per 1,000 resident-weeks (week of September 13) before increasing again, reaching 23.2 cases per 1,000 resident-weeks by late November (week of November 22). COVID-19 cases among nursing home staff members also increased during June and July (week of July 26 = 10.9 cases per 1,000 resident-weeks) before declining during August-September (week of September 13 = 6.3 per 1,000 resident-weeks); rates increased by late November (week of November 22 = 21.3 cases per 1,000 resident-weeks). Rates of COVID-19 in the surrounding communities followed similar trends. Increases in community rates might be associated with increases in nursing home COVID-19 incidence, and nursing home mitigation strategies need to include a comprehensive plan to monitor local SARS-CoV-2 transmission and minimize high-risk exposures within facilities.

Risk Factors for Community-Associated Clostridium difficile Infection in Adults: A Case-Control Study.

BACKGROUND: An increasing proportion of Clostridium difficile infections (CDI) in the United States are community-associated (CA). We conducted a case-control study to identify CA-CDI risk factors. METHODS: We enrolled participants from 10 US sites during October 2014-March 2015. Case patients were defined as persons age ≥18 years with a positive C. difficile specimen collected as an outpatient or within 3 days of hospitalization who had no admission to a health care facility in the prior 12 weeks and no prior CDI diagnosis. Each case patient was matched to one control (persons without CDI). Participants were interviewed about relevant exposures; multivariate conditional logistic regression was performed. RESULTS: Of 226 pairs, 70.4% were female and 52.2% were ≥60 years old. More case patients than controls had prior outpatient health care (82.1% vs 57.9%; P < .0001) and antibiotic (62.2% vs 10.3%; P < .0001) exposures. In multivariate analysis, antibiotic exposure-that is, cephalosporin (adjusted matched odds ratio [AmOR], 19.02; 95% CI, 1.13-321.39), clindamycin (AmOR, 35.31; 95% CI, 4.01-311.14), fluoroquinolone (AmOR, 30.71; 95% CI, 2.77-340.05) and beta-lactam and/or beta-lactamase inhibitor combination (AmOR, 9.87; 95% CI, 2.76-340.05),-emergency department visit (AmOR, 17.37; 95% CI, 1.99-151.22), white race (AmOR 7.67; 95% CI, 2.34-25.20), cardiac disease (AmOR, 4.87; 95% CI, 1.20-19.80), chronic kidney disease (AmOR, 12.12; 95% CI, 1.24-118.89), and inflammatory bowel disease (AmOR, 5.13; 95% CI, 1.27-20.79) were associated with CA-CDI. CONCLUSIONS: Antibiotics remain an important risk factor for CA-CDI, underscoring the importance of appropriate outpatient prescribing. Emergency departments might be an environmental source of CDI; further investigation of their contribution to CDI transmission is needed.

Genetic Evidence of Contemporary Dispersal of the Intermediate Snail Host of Schistosoma japonicum: Movement of an NTD Host Is Facilitated by Land Use and Landscape Connectivity.

BACKGROUND: While the dispersal of hosts and vectors-through active or passive movement-is known to facilitate the spread and re-emergence of certain infectious diseases, little is known about the movement ecology of Oncomelania spp., intermediate snail host of the parasite Schistosoma japonicum, and its consequences for the spread of schistosomiasis in East and Southeast Asia. In China, despite intense control programs aimed at preventing schistosomiasis transmission, there is evidence in recent years of re-emergence and persistence of infection in some areas, as well as an increase in the spatial extent of the snail host. A quantitative understanding of the dispersal characteristics of the intermediate host can provide new insights into the spatial dynamics of transmission, and can assist public health officials in limiting the geographic spread of infection. METHODOLOGY/PRINCIPAL FINDINGS: Oncomelania hupensis robertsoni snails (n = 833) were sampled from 29 sites in Sichuan, China, genotyped, and analyzed using Bayesian assignment to estimate the rate of recent snail migration across sites. Landscape connectivity between each site pair was estimated using the geographic distance distributions derived from nine environmental models: Euclidean, topography, incline, wetness, land use, watershed, stream use, streams and channels, and stream velocity. Among sites, 14.4% to 32.8% of sampled snails were identified as recent migrants, with 20 sites comprising >20% migrants. Migration rates were generally low between sites, but at 8 sites, over 10% of the overall host population originated from one proximal site. Greater landscape connectivity was significantly associated with increased odds of migration, with the minimum path distance (as opposed to median or first quartile) emerging as the strongest predictor across all environmental models. Models accounting for land use explained the largest proportion of the variance in migration rates between sites. A greater number of irrigation channels leading into a site was associated with an increase in the site's propensity to both attract and retain snails. CONCLUSIONS/SIGNIFICANCE: Our findings have important implications for controlling the geographic spread of schistosomiasis in China, through improved understanding of the dispersal capacity of the parasite's intermediate host.

Circulating progenitor cells and coronary microvascular dysfunction: Results from the NHLBI-sponsored Women's Ischemia Syndrome Evaluation - Coronary Vascular Dysfunction Study (WISE-CVD).

BACKGROUND AND AIMS: Ischemia stimulates a reparative response resulting in mobilization of circulating progenitor cells (CPCs). We hypothesized that women with chronic myocardial ischemia from coronary microvascular disease (CMD) will mobilize CPCs. METHODS: In 123 women with ischemic symptoms and signs but no obstructive coronary artery disease (CAD) enrolled in the Women's Ischemia Syndrome Evaluation - Coronary Vascular Dysfunction Study (WISE-CVD), we measured coronary flow reserve (CFR) in response to intracoronary adenosine. Peripheral blood CPCs were measured using flow cytometry for expression of CD34, CD133, CXCR4, and VEGFR2. RESULTS: Subjects were 53 ± 11 years, BMI 30 ± 8; 44% hypertensive, 11% diabetic, 23% hyperlipidemic and 7% smokers. Lower CFR correlated inversely with higher levels of hematopoietic-enriched CD34+ (r = -0.23, p = 0.011), CD34+/CD133+ (r = -0.24, p = 0.008), and CD34+/CXCR4+ (r = -0.19, p = 0.036) cells. In multivariable regression analyses, after adjusting for traditional cardiovascular risk factors, lower CFR remained significantly associated with elevated levels of CD34+ (ß -0.18, p = 0.042), CD34+/CD133+ (ß -0.24, p = 0.036), and CD34+/CXCR4+ (ß -0.22, p = 0.050) cells. We found no association between CFR and CD34+/VEGFR2+ cells. CONCLUSIONS: In women with non-obstructive CAD, impaired CFR is associated with higher levels of CPCs, suggesting that chronic myocardial ischemia from CMD stimulates CPC mobilization. The functional significance of elevated CPCs in these subjects requires further investigation as a potential biomarker and treatment target.

Incidence and Characteristics of Ventilator-Associated Events Reported to the National Healthcare Safety Network in 2014.

OBJECTIVE: Ventilator-associated event surveillance was introduced in the National Healthcare Safety Network in 2013, replacing surveillance for ventilator-associated pneumonia in adult inpatient locations. We determined incidence rates and characteristics of ventilator-associated events reported to the National Healthcare Safety Network. DESIGN, SETTING, AND PATIENTS: We analyzed data reported from U.S. healthcare facilities for ventilator-associated events that occurred in 2014, the first year during which ventilator-associated event surveillance definitions were stable. We used negative binomial regression modeling to identify healthcare facility and inpatient location characteristics associated with ventilator-associated events. We calculated ventilator-associated event incidence rates, rate distributions, and ventilator utilization ratios in critical care and noncritical care locations and described event characteristics. MEASUREMENTS AND MAIN RESULTS: A total of 1,824 healthcare facilities reported 32,772 location months of ventilator-associated event surveillance data to the National Healthcare Safety Network in 2014. Critical care unit pooled mean ventilator-associated event incidence rates ranged from 2.00 to 11.79 per 1,000 ventilator days, whereas noncritical care unit rates ranged from 0 to 14.86 per 1,000 ventilator days. The pooled mean proportion of ventilator-associated events defined as infection-related varied from 15.38% to 47.62% in critical care units. Pooled mean ventilator utilization ratios in critical care units ranged from 0.24 to 0.47. CONCLUSIONS: We found substantial variability in ventilator-associated event incidence, proportions of ventilator-associated events characterized as infection-related, and ventilator utilization within and among location types. More work is needed to understand the preventable fraction of ventilator-associated events and identify patient care strategies that reduce ventilator-associated events.

Age and Human Regenerative Capacity Impact of Cardiovascular Risk Factors.

RATIONALE: We investigated aging of human endogenous reparative capacity and aimed to clarify whether it is affected by presence of cardiovascular disease or its risk factors (RFs). OBJECTIVE: Circulating progenitor cell (PC) levels reflect endogenous regenerative potential. The effect on PC of healthy aging compared with aging with RFs or cardiovascular disease (CVD) is unknown. We examined whether exposure to RF and CVD leads to an accelerated decline in circulating PC with increasing age. METHODS AND RESULTS: In 2792 adult subjects, 498 were free of RFs (smoking, diabetes mellitus, hypertension, or hyperlipidemia), 1036 subjects had 1 to 2 RF, and 1253 had ≥3 RFs or CVD. PC were enumerated by flow cytometry as CD45(med+) mononuclear cells expressing CD34 and subsets coexpressing CD133, CXCR4, and vascular endothelial growth factor receptor-2 epitopes. Younger age, male sex, and larger body size correlated with higher PC counts (P<0.01). After multivariable adjustment, both age and RF categories were independently associated with PC counts (P<0.05), with lower PC counts in older subjects and those with higher RF burden or CVD. PC counts remained unchanged with increasing age in healthy individuals. There were significant interactions between age and RF categories (P≤0.005), such that for younger subjects (<40 years), RFs were associated with increased PC counts, whereas for older subjects (>60 years), RFs and CVD were associated with lower PC counts. CONCLUSIONS: Circulating PC levels do not decline with healthy aging; RF exposure at a younger age stimulates PC mobilization, whereas continued exposure is associated with lower PC levels in later life. Over the lifespan, exposure to RFs and CVD is associated with an initial stimulation and subsequent decline in circulating PC levels, which reflect endogenous regenerative capacity.

Outcomes After Surgery in High-Risk Patients With Early Stage Lung Cancer.

BACKGROUND: Patients with early stage lung cancer considered high risk for surgery are increasingly being treated with nonsurgical therapies. However, consensus on the classification of high risk does not exist. We compared clinical outcomes of patients considered to be high risk with those of standard-risk patients, after lung cancer surgery. METHODS: A total of 490 patients from our institutional Society of Thoracic Surgeons data from 2009 to 2013 underwent resection for clinical stage I lung cancer. High-risk patients were identified by ACOSOG z4032/z4099 criteria: major: forced expiratory volume in 1 second (FEV1) 50% or less or diffusing capacity of lung for carbon monoxide (Dlco) 50% or less; and minor: (two of the following), age 75 years or more, FEV1 51% to 60%, or Dlco 51% to 60%. Demographics, perioperative outcomes, and survival between high-risk and standard-risk patients undergoing lobectomy and sublobar resection were compared. Univariate analysis was performed using the χ(2) test/Fisher's exact test and the t test/Mann-Whitney U test. Survival was studied using a Cox regression model to calculate hazard ratios, and Kaplan-Meier survival curves were drawn. RESULTS: In all, 180 patients (37%) were classified as high risk. These patients were older than standard-risk patients (70 years versus 65 years, respectively; p < 0.0001) and had worse FEV1 (57% versus 85%, p < 0.0001), and Dlco (47% versus 77%, p < 0.0001). High-risk patients also had more smoking pack-years than standard-risk patients (46 versus 30, p < 0.0001) and a greater incidence of chronic obstructive pulmonary disease (72% versus 32%, p < 0.0001), and were more likely to undergo sublobar resection (32% versus 20%, p = 0.001). Length of stay was longer in the high-risk group (5 versus 4 days, p < 0.0001), but there was no difference in postoperative mortality (2% versus 1%, p = 0.53). Nodal upstaging occurred in 20% of high-risk patients and 21% of standard-risk patients (p = 0.79). Three-year survival was 59% for high-risk patients and 76% for standard-risk patients (p < 0.0001). CONCLUSIONS: Good clinical outcomes after surgery for early stage lung cancer can be achieved in patients classified as high risk. In our study, surgery led to upstaging in 20% of patients and acceptable 1-, 2-, and 3-year survival as compared with historical rates for nonsurgical therapies. This study suggests that empiric selection criteria may deny patients optimal oncologic therapy.

Differential effects of nebivolol and metoprolol on arterial stiffness, circulating progenitor cells, and oxidative stress.

Unlike traditional beta receptor antagonists, nebivolol activates nitric oxide. We hypothesized that therapy with nebivolol compared with metoprolol would improve arterial stiffness, increase levels of circulating progenitor cells (PC), and decrease oxidative stress (OS). In a randomized, double-blind, cross-over study, 30 hypertensive subjects received either once daily nebivolol or metoprolol succinate for 3 months each. Pulse wave velocity and augmentation index were measured using tonometry. Flow cytometry was used to measure circulating PC. OS was measured as plasma aminothiols. Measurements were performed at baseline, and repeated at 3 and 6 months. No significant differences were present between the levels of OS, arterial stiffness, and PC numbers during treatment with metoprolol compared with nebivolol. In subgroup analyses of beta-blocker naïve subjects (n = 19), nebivolol reduced pulse wave velocity significantly compared with metoprolol (-1.4 ± 1.9 vs. -0.1 ± 2.2; P = .005). Both nebivolol and metoprolol increased circulating levels of CD34+/CD133 + PC similarly (P = .05), suggesting improved regenerative capacity.

Circulating CD34+ progenitor cells and risk of mortality in a population with coronary artery disease.

RATIONALE: Low circulating progenitor cell numbers and activity may reflect impaired intrinsic regenerative/reparative potential, but it remains uncertain whether this translates into a worse prognosis. OBJECTIVES: To investigate whether low numbers of progenitor cells associate with a greater risk of mortality in a population at high cardiovascular risk. METHODS AND RESULTS: Patients undergoing coronary angiography were recruited into 2 cohorts (1, n=502 and 2, n=403) over separate time periods. Progenitor cells were enumerated by flow cytometry as CD45(med+) blood mononuclear cells expressing CD34, with additional quantification of subsets coexpressing CD133, vascular endothelial growth factor receptor 2, and chemokine (C-X-C motif) receptor 4. Coefficient of variation for CD34 cells was 2.9% and 4.8%, 21.6% and 6.5% for the respective subsets. Each cohort was followed for a mean of 2.7 and 1.2 years, respectively, for the primary end point of all-cause death. There was an inverse association between CD34(+) and CD34(+)/CD133(+) cell counts and risk of death in cohort 1 (ß=-0.92, P=0.043 and ß=-1.64, P=0.019, respectively) that was confirmed in cohort 2 (ß=-1.25, P=0.020 and ß=-1.81, P=0.015, respectively). Covariate-adjusted hazard ratios in the pooled cohort (n=905) were 3.54 (1.67-7.50) and 2.46 (1.18-5.13), respectively. CD34(+)/CD133(+) cell counts improved risk prediction metrics beyond standard risk factors. CONCLUSIONS: Reduced circulating progenitor cell counts, identified primarily as CD34(+) mononuclear cells or its subset expressing CD133, are associated with risk of death in individuals with coronary artery disease, suggesting that impaired endogenous regenerative capacity is associated with increased mortality. These findings have implications for biological understanding, risk prediction, and cell selection for cell-based therapies.

Circadian variation in vascular function and regenerative capacity in healthy humans.

BACKGROUND: Progenitor cells (PCs) are mobilized in response to vascular injury to effect regeneration and repair. Recruitment of PCs requires intact nitric oxide (NO) synthesis by endothelial cells, and their number and activity correlate with cardiovascular disease risk burden and future outcomes. Whereas cardiovascular vulnerability exhibits a robust circadian rhythm, the 24-hour variation of PCs and their inter-relation with vascular function remain unknown. We investigated the circadian variation of PCs and vascular function with the hypothesis that this will parallel the pattern observed for cardiovascular events (CVEs). METHODS AND RESULTS: In 15 healthy subjects (9 men, 37±16 years), circulating PCs and vascular function were measured at 8 am, noon, 4 pm, 8 pm, midnight, 4 am (only PCs counts), and 8 am the following day. Circulating PCs were enumerated as mononuclear cells (MNCs; CD45(med)) that express CD34 as well as CD133, and their activity was assessed as the number of colonies formed by culturing MNCs. Vascular function was evaluated by measurement of endothelium-dependent, flow-mediated vasodilation (FMD) of the brachial artery and tonometry-derived indices of arterial stiffness. Higher CD34(+) and CD34(+)/CD133(+) cell counts were observed at 8 pm than any other time of the day (P-ANOVA=0.038 and <0.001; respectively) and were lowest at 8 am. PC colony formation was highest at midnight (P-ANOVA=0.045) and lowest in the morning hours. FMD was highest at midnight and lowest at 8 am and 8 pm, and systemic arterial stiffness was greatest at 8 am and lowest at 4 pm and midnight (P-ANOVA=0.03 and 0.01; respectively). CONCLUSION: A robust circadian variation in PC counts and vascular function occurs in healthy humans and both exhibit an unfavorable profile in the morning hours that parallels the preponderance of CVEs at these times. Whether these changes are precipitated by awakening and time-dependent physical activity or governed by the endogenous circadian clock needs to be further investigated.

Effect of progenitor cell mobilization with granulocyte-macrophage colony-stimulating factor in patients with peripheral artery disease: a randomized clinical trial.

IMPORTANCE: Many patients with peripheral artery disease (PAD) have walking impairment despite therapy. Experimental studies in animals demonstrate improved perfusion in ischemic hind limb after mobilization of bone marrow progenitor cells (PCs), but whether this is effective in patients with PAD is unknown. OBJECTIVE: To investigate whether therapy with granulocyte-macrophage colony-stimulating factor (GM-CSF) improves exercise capacity in patients with intermittent claudication. DESIGN, SETTING, AND PARTICIPANTS: In a phase 2 double-blind, placebo-controlled study, 159 patients (median [SD] age, 64 [8] years; 87% male, 37% with diabetes) with intermittent claudication were enrolled at medical centers affiliated with Emory University in Atlanta, Georgia, between January 2010 and July 2012. INTERVENTIONS: Participants were randomized (1:1) to received 4 weeks of subcutaneous injections of GM-CSF (leukine), 500 µg/day 3 times a week, or placebo. Both groups were encouraged to walk to claudication daily. MAIN OUTCOMES AND MEASURES: The primary outcome was peak treadmill walking time (PWT) at 3 months. Secondary outcomes were PWT at 6 months and changes in circulating PC levels, ankle brachial index (ABI), and walking impairment questionnaire (WIQ) and 36-item Short-Form Health Survey (SF-36) scores. RESULTS: Of the 159 patients randomized, 80 were assigned to the GM-CSF group. The mean (SD) PWT at 3 months increased in the GM-CSF group from 296 (151) seconds to 405 (248) seconds (mean change, 109 seconds [95% CI, 67 to 151]) and in the placebo group from 308 (161) seconds to 376 (182) seconds (change of 56 seconds [95% CI, 14 to 98]), but this difference was not significant (mean difference in change in PWT, 53 seconds [95% CI, -6 to 112], P = .08). At 3 months, compared with placebo, GM-CSF improved the physical functioning subscore of the SF-36 questionnaire by 11.4 (95% CI, 6.7 to 16.1) vs 4.8 (95% CI, -0.1 to 9.6), with a mean difference in change for GM-CSF vs placebo of 7.5 (95% CI, 1.0 to 14.0; P = .03). Similarly, the distance score of the WIQ improved by 12.5 (95% CI, 6.4 to 18.7) vs 4.8 (95% CI, -0.2 to 9.8) with GM-CSF compared with placebo (mean difference in change, 7.9 [95% CI, 0.2 to 15.7], P = .047). There were no significant differences in the ABI, WIQ distance and speed scores, claudication onset time, or mental or physical component scores of the SF-36 between the groups. CONCLUSIONS AND RELEVANCE: Therapy with GM-CSF 3 times a week did not improve treadmill walking performance at the 3-month follow-up. The improvements in some secondary outcomes with GM-CSF suggest that it may warrant further study in patients with claudication. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01041417.

Estrogen up-regulates ATBF1 transcription but causes its protein degradation in estrogen receptor-alpha-positive breast cancer cells.

The proper level of estrogen-estrogen receptor (ER) signaling is important for the maintenance of epithelial homeostasis in the breast. In a previous study we demonstrated that ATBF1, which has been suggested as a tumor suppressor in breast cancer, inhibited estrogen-mediated cell proliferation by selectively competing with AIB1 for binding to the ER. However, the expression of ATBF1 mRNA was shown to positively correlate with ER in breast cancer specimens. We, therefore, examined whether estrogen regulates ATBF1. We demonstrated that estrogen up-regulated the transcription of ATBF1, which was mediated by the direct binding of the ER onto the ATBF1 promoter, and that a half-estrogen-responsive element in the ATBF1 promoter was essential for ER direct binding. Furthermore, we found that estrogen at lower levels increased, but at higher levels decreased the expression of ATBF1 protein, which involved the degradation of ATBF1 protein by the estrogen-responsive proteasome system. ATBF1 protein levels fluctuate with estrogen levels. Although lower levels of estrogen increased ATBF1 protein expression, ATBF1 still inhibited cell proliferation caused by lower levels of estrogen. These findings not only reveal an autoregulatory feedback loop between ATBF1 and estrogen-ER signaling but also suggest that ATBF1 plays a role in both the maintenance of breast epithelial homeostasis and breast tumorigenesis caused by elevated estrogen levels.

ATBF1 inhibits estrogen receptor (ER) function by selectively competing with AIB1 for binding to the ER in ER-positive breast cancer cells.

Loss of the q22 band of chromosome 16 is a frequent genetic event in breast cancer, and the candidate tumor suppressor gene, ATBF1, has been implicated in breast cancer by genomic deletion, transcriptional down-regulation, and association with better prognostic parameters. In addition, estrogen receptor (ER)-positive breast cancer expresses a higher level of ATBF1, suggesting a role of ATBF1 in ER-positive breast cancer. In this study, we examined whether and how ATBF1 affects the ER function in breast cancer cells. We found that ATBF1 inhibited ER-mediated gene transcription, cell growth, and proliferation in ER-positive breast cancer cells. In vitro and in vivo immunoprecipitation experiments revealed that ATBF1 interacted physically with the ER and that multiple domains in both ATBF1 and ER proteins mediated the interaction. Furthermore, we demonstrated that ATBF1 inhibited ER function by selectively competing with the steroid receptor coactivator AIB1 but not GRIP1 or SRC1 for binding to the ER. These findings not only support the concept that ATBF1 plays a tumor-suppressive role in breast cancer, they also provide a mechanism for how ATBF1 functions as a tumor suppressor in breast cancer.