Charity J. Morgan

High Multiplicity Infection by HIV-1 in Men Who Have Sex with Men.

Elucidating virus-host interactions responsible for HIV-1 transmission is important for advancing HIV-1 prevention strategies. To this end, single genome amplification (SGA) and sequencing of HIV-1 within the context of a model of random virus evolution has made possible for the first time an unambiguous identification of transmitted/founder viruses and a precise estimation of their numbers. Here, we applied this approach to HIV-1 env analyses in a cohort of acutely infected men who have sex with men (MSM) and found that a high proportion (10 of 28; 36%) had been productively infected by more than one virus. In subjects with multivariant transmission, the minimum number of transmitted viruses ranged from 2 to 10 with viral recombination leading to rapid and extensive genetic shuffling among virus lineages. A combined analysis of these results, together with recently published findings based on identical SGA methods in largely heterosexual (HSX) cohorts, revealed a significantly higher frequency of multivariant transmission in MSM than in HSX [19 of 50 subjects (38%) versus 34 of 175 subjects (19%); Fishers exact p = 0.008]. To further evaluate the SGA strategy for identifying transmitted/founder viruses, we analyzed 239 overlapping 5′ and 3′ half genome or env-only sequences from plasma viral RNA (vRNA) and blood mononuclear cell DNA in an MSM subject who had a particularly well-documented virus exposure history 3–6 days before symptom onset and 14–17 days before peak plasma viremia (47,600,000 vRNA molecules/ml). All 239 sequences coalesced to a single transmitted/founder virus genome in a time frame consistent with the clinical history, and a molecular clone of this genome encoded replication competent virus in accord with model predictions. Higher multiplicity of HIV-1 infection in MSM compared with HSX is consistent with the demonstrably higher epidemiological risk of virus acquisition in MSM and could indicate a greater challenge for HIV-1 vaccines than previously recognized.

Wide Variation in the Multiplicity of HIV-1 Infection among Injection Drug Users

ABSTRACT Recent studies indicate that sexual transmission of human immunodeficiency virus type 1 (HIV-1) generally results from productive infection by only one virus, a finding attributable to the mucosal barrier. Surprisingly, a recent study of injection drug users (IDUs) from St. Petersburg, Russia, also found most subjects to be acutely infected by a single virus. Here, we show by single-genome amplification and sequencing in a different IDU cohort that 60% of IDU subjects were infected by more than one virus, including one subject who was acutely infected by at least 16 viruses. Multivariant transmission was more common in IDUs than in heterosexuals (60% versus 19%; odds ratio, 6.14; 95% confidence interval [CI], 1.37 to 31.27; P = 0.008). These findings highlight the diversity in HIV-1 infection risks among different IDU cohorts and the challenges faced by vaccines in protecting against this mode of infection.

Beta-blocker use and 30-day all-cause readmission in medicare beneficiaries with systolic heart failure

BACKGROUND Beta-blockers improve outcomes in patients with systolic heart failure. However, it is unknown whether their initial negative inotropic effect may increase 30-day all-cause readmission, a target outcome for Medicare cost reduction and financial penalty for hospitals under the Affordable Care Act. METHODS Of the 3067 Medicare beneficiaries discharged alive from 106 Alabama hospitals (1998-2001) with a primary discharge diagnosis of heart failure and ejection fraction <45%, 2202 were not previously on beta-blocker therapy, of which 383 received new discharge prescriptions for beta-blockers. Propensity scores for beta-blocker use, estimated for each of the 2202 patients, were used to assemble a matched cohort of 380 pairs of patients receiving and not receiving beta-blockers who were balanced on 36 baseline characteristics (mean age 73 years, mean ejection fraction 27%, 45% women, 33% African American). RESULTS Beta-blocker use was not associated with 30-day all-cause readmission (hazard ratio [HR] 0.87; 95% confidence interval [CI], 0.64-1.18) or heart failure readmission (HR 0.95; 95% CI, 0.57-1.58), but was significantly associated with lower 30-day all-cause mortality (HR 0.29; 95% CI, 0.12-0.73). During 4-year postdischarge, those in the beta-blocker group had lower mortality (HR 0.81; 95% CI, 0.67-0.98) and combined outcome of all-cause mortality or all-cause readmission (HR 0.87; 95% CI, 0.74-0.97), but not with all-cause readmission (HR 0.89; 95% CI, 0.76-1.04). CONCLUSIONS Among hospitalized older patients with systolic heart failure, discharge prescription of beta-blockers was associated with lower 30-day all-cause mortality and 4-year combined death or readmission outcomes without higher 30-day readmission.

Breast cancer subtypes predispose the site of distant metastases.

OBJECTIVES The distant organs to which breast cancer preferentially metastasizes are of significant clinical importance. METHODS We explored the relationship between the clinicopathologic factors and the common sites of distant metastasis in 531 consecutive patients with advanced breast cancer. RESULTS Breast cancer subtype as a variable was significantly associated with all five common sites of relapse by multivariate analysis. The luminal tumors were remarkable for their significant bone-seeking phenotype and were less frequently observed in lung, brain, and pleural metastases and less likely to be associated with multiorgan relapse. The HER2 subtype demonstrated a significant liver-homing characteristic. African Americans were significantly less likely to have brain-only metastasis in patients with brain relapse. CONCLUSIONS These findings further articulate that breast cancer subtypes differ not only in tumor characteristics but also in their metastatic behavior, thus raising the possibility that this knowledge could potentially be used in determining the appropriate strategy for follow-up of patients with newly diagnosed breast cancer.

Early coagulopathy is an independent predictor of mortality in children after severe trauma.

ABSTRACT To determine whether early coagulopathy affects the mortality associated with severe civilian pediatric trauma, trauma patients younger than 18 years admitted to a pediatric intensive care unit from 2001 to 2010 were evaluated. Patients with burns, primary asphyxiation, preexisting bleeding diathesis, lack of coagulation studies, or transferred from other hospitals more than 24 h after injury were excluded. Age, sex, race, mechanism of injury, initial systolic blood pressure, Glasgow Coma Scale score, Injury Severity Score, prothrombin time, partial thromboplastin time, platelet count, and international normalized ratio were recorded. An arterial or venous blood gas was performed, if clinically indicated. Coagulopathy was defined as an international normalized ratio greater than 1.2. The primary outcome was in-hospital mortality. Secondary outcomes were lengths of intensive care unit and hospital stay. Eight hundred three patients were included in the study. Overall mortality was 13.4%. The incidence of age-adjusted hypotension was 5.4%. Early coagulopathy was observed in 37.9% of patients. High Injury Severity Score and/or hypotension were associated with early coagulopathy and higher mortality. Early coagulopathy was associated with a modest increase in mortality in pediatric trauma patients without traumatic brain injury (TBI). In contrast, the combination of TBI and early coagulopathy was associated with a fourfold increase in mortality in this patient population. Early coagulopathy is an independent predictor of mortality in civilian pediatric patients with severe trauma. The increase in mortality was particularly significant in patients with TBI either isolated or combined with other injuries, suggesting that a rapid correction of this coagulopathy could substantially decrease the mortality after TBI in pediatric trauma patients.

Digoxin Use and Lower 30-day All-cause Readmission for Medicare Beneficiaries Hospitalized for Heart Failure

BACKGROUND Heart failure is the leading cause for hospital readmission, the reduction of which is a priority under the Affordable Care Act. Digoxin reduces 30-day all-cause hospital admission in chronic systolic heart failure. Whether digoxin is effective in reducing readmission after hospitalization for acute decompensation remains unknown. METHODS Of the 5153 Medicare beneficiaries hospitalized for acute heart failure and not receiving digoxin, 1054 (20%) received new discharge prescriptions for digoxin. Propensity scores for digoxin use, estimated for each of the 5153 patients, were used to assemble a matched cohort of 1842 (921 pairs) patients (mean age, 76 years; 56% women; 25% African American) receiving and not receiving digoxin, who were balanced on 55 baseline characteristics. RESULTS Thirty-day all-cause readmission occurred in 17% and 22% of matched patients receiving and not receiving digoxin, respectively (hazard ratio [HR] for digoxin, 0.77; 95% confidence interval [CI], 0.63-0.95). This beneficial association was observed only in those with ejection fraction <45% (HR 0.63; 95% CI, 0.47-0.83), but not in those with ejection fraction ≥ 45% (HR 0.91; 95% CI, 0.60-1.37; P for interaction, .145), a difference that persisted throughout the first 12 months postdischarge (P for interaction, .019). HRs (95% CIs) for 12-month heart failure readmission and all-cause mortality were 0.72 (0.61-0.86) and 0.83 (0.70-0.98), respectively. CONCLUSIONS In Medicare beneficiaries with systolic heart failure, a discharge prescription of digoxin was associated with lower 30-day all-cause hospital readmission, which was maintained at 12 months, and was not at the expense of higher mortality. Future randomized controlled trials are needed to confirm these findings.

Clinical Characteristics and Outcomes of Intravenous Inotropic Therapy in Advanced Heart Failure

Background—Inotrope use in heart failure treatment was associated with improved symptoms, but worse survival in clinical trials. However, these studies predated use of modern heart failure therapies. This study evaluates contemporary outcomes on long-term inotropes. Methods and Results—We collected baseline and postinotrope data on 197 patients discharged on inotropes between January 2007 and March 2013. Baseline characteristics, hemodynamic and clinical changes on inotropes, and survival were evaluated. Patients initiated on inotropes had refractory heart failure, with median baseline New York Heart Association class IV, cardiac index of 1.7 L/min per m2, pulmonary capillary wedge pressure of 25.6 mm Hg, and left ventricular ejection fraction of 18.7%. Inotropes were used in patients listed for transplant or scheduled for left ventricular assist device (LVAD; 60 patients), in patients being evaluated for LVAD/transplant (20 patients), for stabilization pending cardiac resynchronization therapy/percutaneous coronary intervention (4 patients), in patients who were offered LVAD but chose inotropes (15 patients), and for palliation (98 patients). Milrinone was used in 84.8% and dobutamine in 15.2%. At the end of the study, 68 patients had died, 24 were weaned off inotropes, 23 were transplanted, 32 received LVADs, and 50 remained on inotropes. Patients who received inotropes for palliation or those who preferred inotropes over LVAD had median survival of 9.0 months (interquartile range, 3.1–37.1 months), actuarial 1-year survival of 47.6%, and 2-year survival of 38.4%. Of 60 patients who were placed on inotropes as a bridge to transplant/LVAD, 55 were successfully maintained on inotropes until transplant/LVAD. Conclusions—Survival on inotropes for patients who are not candidates for transplant/LVAD is modestly better than previously reported, but remains poor. Inotropes are effective as a bridge to transplant/LVAD.

Pancreatitis with vascular endothelial growth factor receptor tyrosine kinase inhibitors

A trial-level meta-analysis was conducted to determine the relative risk (RR) of pancreatitis associated with multi-targeted vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKI). Eligible studies included randomized phase 2 and 3 trials comparing arms with and without an FDA-approved VEGFR TKI (sunitinib, sorafenib, pazopanib, axitinib, vandetanib, cabozantinib, ponatinib, regorafenib). Statistical analyses calculated the RR and 95% confidence intervals (CI). A total of 10,578 patients from 16 phase III trials and 6 phase II trials were selected. The RR for all grade and high-grade pancreatitis for the TKI vs. no TKI- arms was 1.95 (p=0.042, 95% CI: 1.02 to 3.70) and 1.89 (p=0.069, 95% CI: 0.95 to 373), respectively. No differential impact of malignancy type or specific TKI agent was seen on RR of all grade of high grade pancreatitis. Better patient selection and monitoring may mitigate the risk of severe pancreatitis.

Clinical correlates of chronic cerebrospinal venous insufficiency in multiple sclerosis

BackgroundChronic cerebrospinal venous insufficiency (CCSVI) is a vascular condition characterized by anomalies of the primary veins outside the skull that has been reported to be associated with MS. In the blinded Combined Transcranial (TCD) and Extracranial Venous Doppler Evaluation (CTEVD) study, we found that prevalence of CCSVI was significantly higher in multiple sclerosis (MS) vs. healthy controls (HC) (56.1% vs. 22.7%, p < 0.001).The objective was to evaluate the clinical correlates of venous anomalies indicative of CCSVI in patients with MS.MethodsThe original study enrolled 499 subjects; 163 HC, 289 MS, 21 CIS and 26 subjects with other neurological disorders who underwent a clinical examination and a combined Doppler and TCD scan of the head and neck. This analysis was restricted to adult subjects with MS (RR-MS: n = 181, SP-MS: n = 80 and PP-MS: n = 12). Disability status was evaluated by using the Kurtzke Expanded Disability Status Scale (EDSS) and MS severity scale (MSSS).ResultsDisability was not associated with the presence (≥2 venous hemodynamic criteria) or the severity of CCSVI, as measured with venous hemodynamic insufficiency severity score (VHISS). However, the severity of CCSVI was associated with the increased brainstem functional EDSS sub-score (p = 0.002). In logistic regression analysis, progressive MS (SP-MS or PP-MS) vs. non-progressive status (including RR-MS) was associated with CCSVI diagnosis (p = 0.004, OR = 2.34, CI = 1.3–4.2).ConclusionsThe presence and severity of CCVSI in multiple sclerosis correlate with disease status but has no or very limited association with clinical disability.

Discharge Hospice Referral and Lower 30-Day All-Cause Readmission in Medicare Beneficiaries Hospitalized for Heart Failure

Background—Heart failure (HF) is the leading cause for hospital readmission. Hospice care may help palliate HF symptoms but its association with 30-day all-cause readmission remains unknown. Methods and Results—Of the 8032 Medicare beneficiaries hospitalized for HF in 106 Alabama hospitals (1998–2001), 182 (2%) received discharge hospice referrals. Of the 7850 patients not receiving hospice referrals, 1608 (20%) died within 6 months post discharge (the hospice-eligible group). Propensity scores for hospice referral were estimated for each of the 1790 (182+1608) patients and were used to match 179 hospice-referral patients with 179 hospice-eligible patients who were balanced on 28 baseline characteristics (mean age, 79 years; 58% women; 18% non-white). Overall, 22% (1742/8032) died in 6 months, of whom 8% (134/1742) received hospice referrals. Among the 358 matched patients, 30-day all-cause readmission occurred in 5% and 41% of hospice-referral and hospice-eligible patients, respectively (hazard ratio associated with hospice referral, 0.12; 95% confidence interval, 0.06–0.24). Hazard ratios (95% confidence intervals) for 30-day all-cause readmission associated with hospice referral among the 126 patients who died and 232 patients who survived 30-day post discharge were 0.03 (0.04–0.21) and 0.17 (0.08–0.36), respectively. Although 30-day mortality was higher in the hospice referral group (43% versus 27%), it was similar at 90 days (64% versus 67% among hospice-eligible patients). Conclusions—A discharge hospice referral was associated with lower 30-day all-cause readmission among hospitalized patients with HF. However, most patients with HF who died within 6 months of hospital discharge did not receive a discharge hospice referral.