The Time Is Now to End the HIV Epidemic.

In his State of the Union Address on February 5, 2019, President Donald J. Trump announced his administration's goal to end the domestic HIV epidemic. Following the announcement of the Ending the HIV Epidemic: A Plan for America initiative, the president proposed $291 million in new funding for the fiscal year 2020 Department of Health and Human Services (HHS) budget to implement a new initiative to reduce the number of new HIV infections by 75% in the next five years (2025) and by 90% in the next 10 years (2030). This is in addition to the $20 billion the US government already spends each year, domestically, for HIV prevention and care.With this initiative, HHS recognizes that the time to end the HIV epidemic is now: we have the right data, the right biomedical and behavioral tools, and the right leadership. With the new resources, the goal is achievable.This article outlines how this initiative will be accomplished through the implementation of four fundamental strategies that will be tailored by local communities on the basis of their own needs and strengths.

Racial/Ethnic and Age Group Differences in Opioid and Synthetic Opioid-Involved Overdose Deaths Among Adults Aged ≥18 Years in Metropolitan Areas - United States, 2015-2017.

Among the 47,600 opioid-involved overdose deaths in the United States in 2017, 59.8% (28,466) involved synthetic opioids (1). Since 2013, synthetic opioids, particularly illicitly manufactured fentanyl (IMF), including fentanyl analogs, have been fueling the U.S. overdose epidemic (1,2). Although initially mixed with heroin, IMF is increasingly being found in supplies of cocaine, methamphetamine, and counterfeit prescription pills, which increases the number of populations at risk for an opioid-involved overdose (3,4). With the proliferation of IMF, opioid-involved overdose deaths have increased among minority populations including non-Hispanic blacks (blacks) and Hispanics, groups that have historically had low opioid-involved overdose death rates (5). In addition, metropolitan areas have experienced sharp increases in drug and opioid-involved overdose deaths since 2013 (6,7). This study analyzed changes in overdose death rates involving any opioid and synthetic opioids among persons aged ≥18 years during 2015-2017, by age and race/ethnicity across metropolitan areas. Nearly all racial/ethnic groups and age groups experienced increases in opioid-involved and synthetic opioid-involved overdose death rates, particularly blacks aged 45-54 years (from 19.3 to 41.9 per 100,000) and 55-64 years (from 21.8 to 42.7) in large central metro areas and non-Hispanic whites (whites) aged 25-34 years (from 36.9 to 58.3) in large fringe metro areas. Comprehensive and culturally tailored interventions are needed to address the rise in drug overdose deaths in all populations, including prevention strategies that address the risk factors for substance use across each racial/ethnic group, public health messaging to increase awareness about synthetic opioids in the drug supply, expansion of naloxone distribution for overdose reversal, and increased access to medication-assisted treatment.

ENHANCE: results of a global open-label trial of drotrecogin alfa (activated) in children with severe sepsis.

OBJECTIVE: To gather additional 28-day all-cause mortality data and safety information for pediatric patients with severe sepsis who received drotrecogin alfa (activated) (DrotAA). DESIGN AND SETTING: Single-arm, open-label, multicentered study conducted in 59 study sites in 15 countries. PATIENTS: One-hundred eighty-eight children (term newborn to <18 yrs old) with severe sepsis were consecutively enrolled in the study. INTERVENTION: Administration of DrotAA, 24 microg/kg/hr for 96 hrs. MAIN OUTCOME MEASURES: Four-day and 28-day all-cause mortality, safety information, and protein C levels. RESULTS: : One-hundred eighty-seven patients completed the study. The 4-day mortality rate was 7.0%, and the 28-day mortality rate was 13.4%. At baseline, 57.6% of patients were severely deficient in protein C (a level < or = 40% of normal). There was a statistically significant association between increased 28-day mortality and decreased end-of-infusion protein C levels (p < .001), greater number of baseline organ dysfunctions (p < .001), and greater baseline ventilator use (p = .03). Bleeding was the most significant complication observed. Serious bleeding events (including anemia without a bleeding source) were experienced by 27.7% of patients (n = 52). Six of the serious bleeding events (3.2%) were considered related to administration of DrotAA. During infusion, serious bleeding events with an identified source of bleeding were experienced by 5.9% of patients (n = 11). Central nervous system bleeding was experienced by 2.7% (n = 5). Two of the intracranial hemorrhages were fatal and occurred postinfusion. CONCLUSIONS: Without a placebo control, no efficacy conclusions are possible. Subgroups at higher risk of death were identified, and the change in protein C level from baseline was predictive of survival. The most significant complication observed was bleeding. Risk factors for serious bleeding appear to be multiple organ failure, thrombocytopenia, and coagulopathy.

The Pediatric Multiple Organ Dysfunction Score (P-MODS): development and validation of an objective scale to measure the severity of multiple organ dysfunction in critically ill children.

OBJECTIVE: To develop and then prospectively validate an objective scale to grade multiple organ system dysfunction in a large population of critically ill children. DESIGN: Prospective, observational cohort study. SETTING: A pediatric intensive care unit at a tertiary care pediatric teaching hospital. PATIENTS: A total of 6,456 pediatric consecutive admissions (mean age 4.62 yrs) admitted to the pediatric intensive care unit. INTERVENTIONS: a) Identification of variables that could define organ dysfunction in children; b) development of a Pediatric Multiple Organ Dysfunction Score (P-MODS); c) correlation of the score with outcome at pediatric intensive care unit discharge; d) subsequent prospective validation. MEASUREMENTS AND MAIN RESULTS: A computer system randomly separated patients into two groups: a development set to create the scoring system and a validation set to evaluate score performance and reproducibility. Survivors and nonsurvivors were compared to define variables that were significantly more abnormal in nonsurvivors. Those variables were correlated with pediatric intensive care unit mortality rate. Optimal intervals for each variable were defined on the development set, and their performance was evaluated in the validation set. Descriptors for organ dysfunction were identified in five organ systems: cardiovascular (lactic acid), respiratory (Pa(O(2))/Fi(O(2)) ratio), hepatic (bilirubin), hematologic (fibrinogen), and renal (blood urea nitrogen). A grading scale for each variable was set from 0 to 4, corresponding to mortality rates of <5% and >50%, respectively. P-MODS was calculated by summing the worst score for all variables. Overall performance of the score was evaluated by generating receiver operating characteristic curves for both study sets. The score correlated strongly and in a graded fashion with pediatric intensive care unit mortality rate. In both sets (development and validation), mortality rate was <5% when the score was 0 and >70% at the highest score. Overall mortality rate was 5.9% (development set) and 5.3% (validation set). The score showed excellent discrimination reflected in areas under the curve: 0.81 (development set) and 0.78 (validation set). CONCLUSIONS: P-MODS correlated strongly with pediatric intensive care unit mortality in both study sets and can provide an objective measure for assessing organ dysfunction in the pediatric intensive care unit. With further study and validation across many centers, it is likely that P-MODS could function as a quantitative, clinically relevant surrogate outcome measure for future therapeutic trials.

Tumor necrosis factor-alpha-induced caspase activation mediates endotoxin-related cardiac dysfunction.

OBJECTIVE: Sepsis-induced cardiac dysfunction is a serious clinical syndrome characterized by hypotension, decreased systemic vascular resistance, and elevated cardiac index. Although cytokines such as tumor necrosis factor (TNF)-alpha have been shown to play a significant role early in this response, the downstream effects of TNF-alpha signaling on cardiac function, specifically its relationship to apoptosis, have not been fully elucidated. DESIGN: Previous studies from our laboratory have identified endotoxin-induced apoptosis in cardiac cells in vitro. To further determine the role of lipopolysaccharide-induced apoptosis in vivo, mice were injected intraperitoneally with lipopolysaccharide (4 mg/kg), and cardiac apoptosis was detected and inhibited using a broad-spectrum caspase inhibitor. SETTING: University research laboratory. SUBJECTS: Adult male wild-type (B6:129PF1/J) and TNF receptor 1/receptor 2 (TNFR-1/2) knockout mice (B6;129S-Tnfrsf1aTnfrsf1b). INTERVENTIONS: We sought to determine the dependence of cardiac apoptosis on TNF-alpha signaling and determine the physiologic role of caspase activation on lipopolysaccharide-induced cardiac dysfunction. MEASUREMENTS AND MAIN RESULTS: Cardiac apoptosis was determined at baseline and at 2, 4, 8, and 24 hrs by detection of capase-3 and -8 activity, cytoplasmic levels of Bax/Bcl-2, cleaved caspase-3 immunohistochemistry, and terminal deoxynucleotidyl transferase UTP nick-end labeling (TUNEL) staining of histologic sections in wild-type and TNFR-1/2 knockout mice. To determine the role of caspase activation in lipopolysaccharide-induced cardiac dysfunction, a broad-spectrum caspase inhibitor Z-Val-Ala-Asp (ome)-FMK (sad) was given, and cardiac function was determined in isolated beating hearts (Langendorff preparation). Our experiments determined that caspase-3-dependent apoptosis was active in cardiac tissue by 2 hrs and that this activation was completely mediated by TNFR-1/2. The Bax/Bcl-2 ratios supported the finding and time course of apoptosis, whereas TUNEL staining of cardiac tissue sections identified sporadic apoptotic ventricular cells. The administration of zVAD significantly inhibited myocardial caspase-3 activity and preserved cardiac physiologic function (Langendorff preparation). CONCLUSIONS: Endotoxin induces a TNF-alpha-dependent apoptotic cascade in the myocardium, which contributes to the development of cardiac dysfunction.

Macrophage migration inhibitory factor mediates late cardiac dysfunction after burn injury.

We have recently demonstrated that macrophage migration inhibitory factor (MIF) is a myocardial depressant protein and that MIF mediates late, prolonged cardiac dysfunction after endotoxin challenge in mice. Because many factors, including endotoxin, have been implicated in the pathogenesis of cardiac dysfunction after burn injury, we tested the hypothesis that MIF might also be the mediator of prolonged cardiac dysfunction in this model. At 4 h after 40% total body surface area burn in anesthetized mice, serum MIF levels increased significantly compared with baseline (2.2-fold). This increase was accompanied by a significant decrease in cardiac tissue MIF levels (2.1-fold decrease compared with controls). This pattern was consistent with MIF release from preformed cytoplasmic stores in the heart and other organs. To determine whether MIF mediates cardiac dysfunction after burn injury, mice were pretreated with anti-MIF neutralizing monoclonal antibodies or isotype control antibodies. Beginning 4 h after burn injury (and continuing through 48 h), burned mice demonstrated a significantly depressed left ventricular shortening fraction of 38.6 +/- 1.8%, compared with the normal controls (56.0 +/- 2.6%). Mice treated with anti-MIF displayed an initial depression of cardiac function similar to nontreated animals but then showed rapid restoration of cardiac function with complete recovery by 24 h, which persisted for the duration of the protocol. This study is the first to demonstrate that MIF mediates late, prolonged cardiac dysfunction after burn injury and suggests that MIF blockade should be considered a therapeutic target for the treatment of burn injury.

Fresh whole blood versus reconstituted blood for pump priming in heart surgery in infants.

BACKGROUND: In an attempt to reduce the coagulopathic and inflammatory responses seen after cardiopulmonary bypass, the use of fresh whole blood during heart operations has become the standard of care for neonates and infants at many institutions. We compared the use of fresh whole blood with the use of a combination of packed red cells and fresh-frozen plasma (reconstituted blood) for priming of the cardiopulmonary bypass circuit. METHODS: We conducted a single-center, randomized, double-blind, controlled trial involving children less than one year of age who underwent open-heart surgery. Patients were assigned to receive either fresh whole blood that had been collected not more than 48 hours previously (96 patients) or reconstituted blood (104 patients) for bypass-circuit priming. Clinical outcomes and serologic measures of systemic inflammation and myocardial injury were compared between the groups. RESULTS: The group that received reconstituted blood had a shorter stay in the intensive care unit than the group that received fresh whole blood (70.5 hours vs. 97.0 hours, P=0.04). The group that received reconstituted blood also had a smaller cumulative fluid balance at 48 hours (-6.9 ml per kilogram of body weight vs. 28.8 ml per kilogram, P=0.003). Early postoperative chest-tube output, blood-product transfusion requirements, and levels of serum mediators of inflammation and cardiac troponin I were similar in the two groups. CONCLUSIONS: The use of fresh whole blood for cardiopulmonary bypass priming has no advantage over the use of a combination of packed red cells and fresh-frozen plasma during surgery for congenital heart disease. Moreover, circuit priming with fresh whole blood is associated with an increased length of stay in the intensive care unit and increased perioperative fluid overload.

Safety, pharmacokinetics, and pharmacodynamics of drotrecogin alfa (activated) in children with severe sepsis.

OBJECTIVE: In a phase 3 trial, recombinant human activated protein C (drotrecogin alfa [activated]) significantly reduced mortality in adult patients with severe sepsis. We have now performed a preliminary analysis of the safety, pharmacokinetics, and pharmacodynamics of drotrecogin alfa (activated) in pediatric patients with severe sepsis. DESIGN AND SETTING: Open-label, nonrandomized, sequential, 2-part study conducted in 11 medical centers in the United States and United Kingdom. PATIENTS: Eighty-three pediatric patients with severe sepsis aged term newborn (>or=38 weeks' gestation) to <18 years old. INTERVENTION: In part 1, drotrecogin alfa (activated) was administered as escalating doses of 6, 12, 24, and 36 micro g/kg per hour for 6 hours for each patient (n = 21). In part 2, drotrecogin alfa (activated) was infused at a rate of 24 micro g/kg per hour for 96 hours in 62 patients. MAIN OUTCOME MEASURES: Plasma clearance, plasma concentration, D-dimer, protein C, and antithrombin levels were measured, and adverse events were monitored. RESULTS: The trial enrolled 83 pediatric patients with severe sepsis, aged term newborn (>or=38 weeks' gestation) to <18 years. In part 1, a dose of 24 micro g/kg per hour produced steady-state plasma concentrations of activated protein C similar to those attained in equivalently dosed adult severe sepsis patients. For all pediatric patients dosed at 24 micro g/kg per hour, the median weight-normalized clearance was 0.45 L/hour/kg and the median steady-state concentration was 51.3 ng/mL. The mean plasma half-life was 30 minutes. Weight-normalized clearance in pediatric and adult patients did not differ significantly with age or weight. D-dimer levels decreased 26% from baseline to end of infusion. Baseline levels of protein C and antithrombin increased 79% and 24%, respectively, over the 96-hour treatment period in part 2. The incidence of serious bleeding during infusion and during the entire study period was 2.4% and 4.8%, respectively. CONCLUSIONS: Pediatric patients with severe sepsis manifest sepsis-induced coagulopathy including protein C deficiency comparable to that seen in adults with severe sepsis. The pharmacokinetics, pharmacodynamic effects, and safety profile of drotrecogin alfa (activated) in pediatric patients are similar to those previously published for adult patients. A large, phase 3, randomized, placebo-controlled study is ongoing to confirm these results and formally assess the safety and efficacy of drotrecogin alfa (activated) in children.

Macrophage migration inhibitory factor is a cardiac-derived myocardial depressant factor.

Macrophage migration inhibitory factor (MIF) is a pluripotent proinflammatory cytokine that is ubiquitously expressed in organs, including the heart. However, no specific role for MIF in modulating cardiac performance has yet been described. Therefore, we examined cardiac MIF expression in mice after LPS challenge (4 mg/kg) and tested the hypothesis that MIF is a mediator of LPS-induced cardiac dysfunction. Western blots of whole heart lysates, as well as immunohistochemistry, documented constitutive MIF protein expression in the heart. Cardiac MIF protein levels significantly decreased after LPS challenge, reaching a nadir at 12 h, and then returned to baseline by 24 h. This pattern was consistent with MIF release from cytoplasmic stores after endotoxin challenge. After release of protein, MIF mRNA levels increased 24-48 h postchallenge. To determine the functional consequences of MIF release, we treated LPS-challenged mice with anti-MIF neutralizing antibodies or isotype control antibodies. Anti-MIF-treated animals had significantly improved cardiac function, as evidenced by a significant improvement in left ventricular (LV) fractional shortening percentage at 8, 12, 24, and 48 h after endotoxin challenge. In support of these findings, perfusion of isolated beating mouse hearts (Langendorff preparation) with recombinant MIF (20 ng/ml) led to a significant decrease in both systolic and diastolic performance [LV pressure (LVP), positive and negative first derivative of LVP with respect to time, and rate of LVP rise at developed pressure of 40 mmHg]. This study demonstrates that MIF mediates LPS-induced cardiac dysfunction and suggests that MIF should be considered a pharmacological target for the treatment of cardiac dysfunction in sepsis and potentially other cardiac diseases.