Association Between Intraoperative Arterial Hypotension and Postoperative Delirium After Noncardiac Surgery: A Retrospective Multicenter Cohort Study.

BACKGROUND: It is unclear whether intraoperative arterial hypotension is associated with postoperative delirium. We hypothesized that intraoperative hypotension within a range frequently observed in clinical practice is associated with increased odds of delirium after surgery. METHODS: Adult noncardiac surgical patients undergoing general anesthesia at 2 academic medical centers between 2005 and 2017 were included in this retrospective cohort study. The primary exposure was intraoperative hypotension, defined as the cumulative duration of an intraoperative mean arterial pressure (MAP) <55 mm Hg, categorized into and short (<15 minutes; median [interquartile range {IQR}], 2 [1-4] minutes) and prolonged (≥15 minutes; median [IQR], 21 [17-31] minutes) durations of intraoperative hypotension. The primary outcome was a new diagnosis of delirium within 30 days after surgery. In secondary analyses, we assessed the association between a MAP decrease of >30% from baseline and postoperative delirium. Multivariable logistic regression adjusted for patient- and procedure-related factors, including demographics, comorbidities, and markers of procedural severity, was used. RESULTS: Among 316,717 included surgical patients, 2183 (0.7%) were diagnosed with delirium within 30 days after surgery; 41.7% and 2.6% of patients had a MAP <55 mm Hg for a short and a prolonged duration, respectively. A MAP <55 mm Hg was associated with postoperative delirium compared to no hypotension (short duration of MAP <55 mm Hg: adjusted odds ratio [ORadj], 1.22; 95% confidence interval [CI], 1.11-1.33; P < .001 and prolonged duration of MAP <55 mm Hg: ORadj, 1.57; 95% CI, 1.27-1.94; P < .001). Compared to a short duration of a MAP <55 mm Hg, a prolonged duration of a MAP <55 mm Hg was associated with greater odds of postoperative delirium (ORadj, 1.29; 95% CI, 1.05-1.58; P = .016). The association between intraoperative hypotension and postoperative delirium was duration-dependent (ORadj for every 10 cumulative minutes of MAP <55 mm Hg: 1.06; 95% CI, 1.02-1.09; P =.001) and magnified in patients who underwent surgeries of longer duration (P for interaction = .046; MAP <55 mm Hg versus no MAP <55 mm Hg in patients undergoing surgery of >3 hours: ORadj, 1.40; 95% CI, 1.23-1.61; P < .001). A MAP decrease of >30% from baseline was not associated with postoperative delirium compared to no hypotension, also when additionally adjusted for the cumulative duration of a MAP <55 mm Hg (short duration of MAP decrease >30%: ORadj, 1.13; 95% CI, 0.91-1.40; P = .262 and prolonged duration of MAP decrease >30%: ORadj, 1.19; 95% CI, 0.95-1.49; P = .141). CONCLUSIONS: In patients undergoing noncardiac surgery, a MAP <55 mm Hg was associated with a duration-dependent increase in odds of postoperative delirium. This association was magnified in patients who underwent surgery of long duration.

Neurophysiologic Intraoperative Monitoring for Spine Surgery: A Practical Guide From Past to Present.

Intraoperative neuromonitoring was introduced in the second half of the 20th century with the goal of preventing patient morbidity for patients undergoing complex operations of the central and peripheral nervous system. Since its early use for scoliosis surgery, the growth and utilization of IOM techniques expanded dramatically over the past 50 years to include spinal tumor resection and evaluation of cerebral ischemia. The importance of IOM has been broadly acknowledged, and in 1989, the American Academy of Neurology (AAN) released a statement that the use of SSEPs should be standard-of-care during spine surgery. In 2012, both the AAN and the American Clinical Neurophysiology Society (ACNS) recommended that: "Intraoperative monitoring (IOM) using SSEPs and transcranial MEPs be established as an effective means of predicting an increased risk of adverse outcomes, such as paraparesis, paraplegia, and quadriplegia, in spinal surgery." With a multimodal approach that combines SSEPs, MEPs, and sEMG with tEMG and D waves, as appropriate, sensitivity and specificity can be maximized for the diagnosis of reversible insults to the spinal cord, nerve roots, and peripheral nerves. As with most patient safety efforts in the operating room, IOM requires contributions from and communication between a number of different teams. This comprehensive review of neuromonitoring techniques for surgery on the central and peripheral nervous system will highlight the technical, surgical and anesthesia factors required to optimize outcomes. In addition, this review will discuss important trouble shooting measures to be considered when managing ION changes concerning for potential injury.

Effect of Intraoperative Arterial Hypotension on the Risk of Perioperative Stroke After Noncardiac Surgery: A Retrospective Multicenter Cohort Study.

BACKGROUND: Intraoperative cerebral blood flow is mainly determined by cerebral perfusion pressure and cerebral autoregulation of vasomotor tone. About 1% of patients undergoing noncardiac surgery develop ischemic stroke. We hypothesized that intraoperative hypotension within a range frequently observed in clinical practice is associated with an increased risk of perioperative ischemic stroke within 7 days after surgery. METHODS: Adult noncardiac surgical patients undergoing general anesthesia at Beth Israel Deaconess Medical Center and Massachusetts General Hospital between 2005 and 2017 were included in this retrospective cohort study. The primary exposure was intraoperative hypotension, defined as a decrease in mean arterial pressure (MAP) below 55 mm Hg, categorized into no intraoperative hypotension, short (<15 minutes, median [interquartile range {IQR}], 2 minutes [1-5 minutes]) and prolonged (≥15 minutes, median [IQR], 21 minutes [17-31 minutes]) durations. The primary outcome was a new diagnosis of early perioperative ischemic stroke within 7 days after surgery. In secondary analyses, we assessed the effect of a MAP decrease by >30% from baseline on perioperative stroke. Analyses were adjusted for the preoperative STRoke After Surgery (STRAS) prediction score, work relative value units, and duration of surgery. RESULTS: Among 358,391 included patients, a total of 1553 (0.4%) experienced an early perioperative ischemic stroke. About 42% and 3% of patients had a MAP of below 55 mm Hg for a short and a prolonged duration, and 49% and 29% had a MAP decrease by >30% from baseline for a short and a prolonged duration, respectively. In an adjusted analysis, neither a MAP <55 mm Hg (short duration: adjusted odds ratio [ORadj], 0.95; 95% confidence interval [CI], 0.85-1.07; P = .417 and prolonged duration: ORadj, 1.18; 95% CI, 0.91-1.55; P = .220) nor a MAP decrease >30% (short duration: ORadj, 0.97; 95% CI, 0.67-1.42; P = .883 and prolonged duration: ORadj, 1.30; 95% CI, 0.89-1.90; P = .176) was associated with early perioperative stroke. A high a priori stroke risk quantified based on preoperatively available risk factors (STRAS prediction score) was associated with longer intraoperative hypotension (adjusted incidence rate ratio, 1.04; 95% CI, 1.04-1.05; P < .001 per 5 points of the STRAS prediction score). CONCLUSIONS: This study found no evidence to conclude that intraoperative hypotension within the range studied was associated with early perioperative stroke within 7 days after surgery. These findings emphasize the importance of perioperative cerebral blood flow autoregulation to prevent ischemic stroke.

Unplanned hospital admission after ambulatory surgery: a retrospective, single cohort study.

PURPOSE: We estimated the rate of unplanned hospital and intensive care unit (ICU) admissions following ambulatory surgery centre (ASC) procedures, and identified factors associated with their occurrence. METHODS: This retrospective cohort included adult patients who underwent ASC procedures within a large community practice from January 2010 to December 2014. Patients were categorized into two groups: unplanned postoperative hospital/ICU admission within 24 hr of procedure or uneventful discharge. Demographics, comorbidities, anesthesia type, procedure type, procedure group, and ASC facility were assessed. RESULTS: Of the 211,389 patients included, there were 211,147 uneventful discharges (99.89%) and 242 unplanned hospital admissions (0.11%), of which 75 were ICU admissions (0.04%). The multivariable logistic regression model for hospital admission showed an increased risk associated with age > 50 yr (odds ratio [OR], 1.53); American Society of Anesthesiologists (ASA) physical status (III vs II: OR, 1.45; IV vs II: OR, 1.88), comorbidity (chronic obstructive pulmonary disease: OR, 2.63; diabetes mellitus: OR, 1.62; transient ischemic attack: OR, 2.48) procedure (respiratory: OR, 2.92; digestive: OR, 2.66; musculoskeletal system: OR, 2.53), anesthetic management (general anesthesia [GA] and peripheral nerve block vs GA: OR, 1.79), and ASC facility (189BB: OR, 2.29; 30E9A: OR, 7.41; and BD21F: OR, 1.69). The multivariable logistic regression model for ICU admission showed increased risk of unplanned ICU admission associated with ASA physical status (ASA III vs II: OR, 3.0; ASA IV vs II: OR, 8.52), procedure (musculoskeletal system: OR, 2.45), and ASC facility (00E6C: OR, 3.14; 189BB: OR, 2.77; 30E9A: OR, 2.59; and BD21F: OR, 3.71). CONCLUSION: While a small percentage of adult patients who underwent ASC procedures required unplanned hospital admission (0.07%), approximately one-third of these admissions were to the ICU (0.04%). Facility was at least as strong a predictor of hospital admission as the patient- and/or procedure-specific variables.

RéSUMé: OBJECTIF: Nous avons estimé le taux d'admissions non planifiées à l'hôpital et à l'unité de soins intensifs (USI) après des interventions dans des centres de chirurgie ambulatoire (CCA), et identifié les facteurs associés à leur survenue. MéTHODE: Cette étude de cohorte rétrospective a porté sur des patients adultes ayant subi une intervention dans un CCA appartenant à une grande pratique communautaire entre janvier 2010 et décembre 2014. Les patients ont été catégorisés en deux groupes : admission postopératoire non planifiée à l'hôpital/USI dans les 24 h suivant l'intervention ou congé sans incident. Les données démographiques, les comorbidités, le type d'anesthésie, le type d'intervention, le groupe d'intervention et l'établissement de CCA ont été évalués. RéSULTATS: Parmi les 211 389 patients inclus, il y a eu 211 147 congés sans incident (99,89 %) et 242 admissions non planifiées à l'hôpital (0,11 %), 75 desquelles étaient des admissions à l'USI (0,04 %). Le modèle de régression logistique multivariée des admissions hospitalières a montré un risque accru associé à un âge > 50 ans (rapport de cotes [RC], 1,53); au statut physique ASA (American Society of Anesthesiologists) (III vs II : RC, 1,45; IV vs II : RC, 1,88), aux comorbidités (maladie pulmonaire obstructive chronique : RC, 2,63; diabète: RC, 1,62; accident ischémique transitoire : RC, 2,48); à l'intervention (respiratoire : RC, 2,92; digestive : RC, 2,66; appareil locomoteur : RC, 2,53); à la prise en charge anesthésique (anesthésie générale [AG] et bloc nerveux périphérique vs AG : RC, 1,79) et établissement de CCA (189BB : RC, 2,29; 30E9A : RC, 7,41; et BD21F : RC, 1,69). Le modèle de régression logistique multivariée des admissions à l'USI a montré un risque accru d'admission non planifiée à l'USI associé au statut physique ASA (ASA III vs II: RC, 3,0; ASA IV vs II: RC, 8,52), à l'intervention (appareil locomoteur : RC, 2,45), et à l'établissement de CCA (00E6C: RC, 3,14; 189BB: RC, 2,77; 30E9A: RC, 2,59; et BD21F: RC, 3,71). CONCLUSION: Alors qu'un faible pourcentage de patients adultes ayant subi des interventions en CCA ont nécessité une admission non planifiée à l'hôpital (0,11 %), environ un tiers de ces admissions étaient à l'USI (0,04 %). L'établissement était un prédicteur au moins aussi puissant d'admission à l'hôpital que les variables spécifiques au patient et/ou à l'intervention.

Anesthetic management of unruptured intracranial aneurysms: a qualitative systematic review.

Intracranial aneurysms (IA) occur in 3-5% of the general population and may require surgical or endovascular obliteration if the patient is symptomatic or has an increased risk of rupture. These procedures carry an inherent risk of neurological complications, and the outcome can be influenced by the physiological and pharmacological effects of the administered anesthetics. Despite the critical role of anesthetic agents, however, there are no current studies to systematically assess the intraoperative anesthetic risks, benefits, and outcome effects in this population. In this systematic review of the literature, we carefully examine the existing evidence on the risks and benefits of common anesthetic agents during IA obliteration, their physiological and clinical characteristics, and effects on neurological outcome. The initial search strategy captured a total of 287 published studies. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, 28 studies were included in the final report. Our data showed that both volatile and intravenous anesthetics are commonly employed, without evidence that either is superior. Although no specific anesthetic regimens are promoted, their unique neurological, cardiovascular, and physiological properties may be critical to the outcome in vulnerable patients. In particular, patients at risk for perioperative ischemia may benefit from timely administration of anesthetic agents with neuroprotective properties and optimization of their physiological parameters. Further studies are warranted to examine if these anesthetic regimens can reduce the risk of neurological injury and improve the overall outcome in these patients.

Correction: Effects of Combined CCR5/Integrase Inhibitors-Based Regimen on Mucosal Immunity in HIV-Infected Patients Naïve to Antiretroviral Therapy: A Pilot Randomized Trial.

[This corrects the article DOI: 10.1371/journal.ppat.1005381.].

Effects of Combined CCR5/Integrase Inhibitors-Based Regimen on Mucosal Immunity in HIV-Infected Patients Naïve to Antiretroviral Therapy: A Pilot Randomized Trial.

Whether initiation of antiretroviral therapy (ART) regimens aimed at achieving greater concentrations within gut associated lymphoid tissue (GALT) impacts the level of mucosal immune reconstitution, inflammatory markers and the viral reservoir remains unknown. We included 12 HIV- controls and 32 ART-naïve HIV patients who were randomized to efavirenz, maraviroc or maraviroc+raltegravir, each with fixed-dose tenofovir disoproxil fumarate/emtricitabine. Rectal and duodenal biopsies were obtained at baseline and at 9 months of ART. We performed a comprehensive assay of T-cell subsets by flow cytometry, T-cell density in intestinal biopsies, plasma and tissue concentrations of antiretroviral drugs by high-performance liquid chromatography/mass spectroscopy, and plasma interleukin-6 (IL-6), lipoteichoic acid (LTA), soluble CD14 (sCD14) and zonulin-1 each measured by ELISA. Total cell-associated HIV DNA was measured in PBMC and rectal and duodenal mononuclear cells. Twenty-six HIV-infected patients completed the follow-up. In the duodenum, the quadruple regimen resulted in greater CD8+ T-cell density decline, greater normalization of mucosal CCR5+CD4+ T-cells and increase of the naïve/memory CD8+ T-cell ratio, and a greater decline of sCD14 levels and duodenal HIV DNA levels (P = 0.004 and P = 0.067, respectively), with no changes in HIV RNA in plasma or tissue. Maraviroc showed the highest drug distribution to the gut tissue, and duodenal concentrations correlated well with other T-cell markers in duodenum, i.e., the CD4/CD8 ratio, %CD4+ and %CD8+ HLA-DR+CD38+ T-cells. Maraviroc use elicited greater activation of the mucosal naïve CD8+ T-cell subset, ameliorated the distribution of the CD8+ T-cell maturational subsets and induced higher improvement of zonulin-1 levels. These data suggest that combined CCR5 and integrase inhibitor based combination therapy in ART treatment naïve patients might more effectively reconstitute duodenal immunity, decrease inflammatory markers and impact on HIV persistence by cell-dependent mechanisms, and show unique effects of MVC in duodenal immunity driven by higher drug tissue penetration and possibly by class-dependent effects.

Temporal Trends in Difficult and Failed Tracheal Intubation in a Regional Community Anesthetic Practice.

BACKGROUND: When tracheal intubation is difficult or unachievable before surgery or during an emergent resuscitation, this is a critical safety event. Consensus algorithms and airway devices have been introduced in hopes of reducing such occurrences. However, evidence of improved safety in clinical practice related to their introduction is lacking. Therefore, we selected a large perioperative database spanning 2002 to 2015 to look for changes in annual rates of difficult and failed tracheal intubation. METHODS: Difficult (more than three attempts) and failed (unsuccessful, requiring awakening or surgical tracheostomy) intubation rates in patients 18 yr and older were compared between the early and late periods (pre- vs. post-January 2009) and by annual rate join-point analysis. Primary findings from a large, urban hospital were compared with combined observations from 15 smaller facilities. RESULTS: Analysis of 421,581 procedures identified fourfold reductions in both event rates between the early and late periods (difficult: 6.6 of 1,000 vs. 1.6 of 1,000, P < 0.0001; failed: 0.2 of 1,000 vs. 0.06 of 1,000, P < 0.0001), with join-point analysis identifying two significant change points (2006, P = 0.02; 2010, P = 0.03) including a pre-2006 stable period, a steep drop between 2006 and 2010, and gradual decline after 2010. Data from 15 affiliated practices (442,428 procedures) demonstrated similar reductions. CONCLUSIONS: In this retrospective assessment spanning 14 yr (2002 to 2015), difficult and failed intubation rates by skilled providers declined significantly at both an urban hospital and a network of smaller affiliated practices. Further investigations are required to validate these findings in other data sets and more clearly identify factors associated with their occurrence as clues to future airway management advancements. VISUAL ABSTRACT: An online visual overview is available for this article at http://links.lww.com/ALN/B635.

Is Compliance With Surgical Care Improvement Project Cardiac (SCIP-Card-2) Measures for Perioperative ß-Blockers Associated With Reduced Incidence of Mortality and Cardiovascular-Related Critical Quality Indicators After Noncardiac Surgery?

BACKGROUND: While continuation of ß-blockers (BBs) perioperatively has become a national quality improvement measure, the relationship between BB withdrawal and mortality and cardiovascular-related critical quality indicators has not been studied in a contemporary cohort of patients undergoing noncardiac surgery. METHODS: For this retrospective study, the quality assurance database of a large community-based anesthesiology group practice was used to identify 410,288 surgical cases, 18 years of age or older, who underwent elective or emergent noncardiac surgical procedures between January 1, 2009, and December 31, 2014. Each surgical case that was withdrawn from BBs perioperatively was propensity matched by clinical and surgical characteristics to 4 cases that continued BBs perioperatively. Subsequently, multivariable conditional logistic regression analyses were performed in the matched cohort to determine the extent to which withdrawal of perioperative BBs was independently associated with mortality as the primary outcome and cardiovascular-related critical quality indicators as the secondary outcome (need for vasopressor, electrocardiographic changes requiring treatment, unplanned admission to intensive care unit, postanesthesia care unit stay >2 hours, and a combination of cardiac arrest and myocardial infarction) within 48 hours postoperatively. RESULTS: Of the 66,755 (16%) cases in the cohort admitted on BB therapy, BBs were withdrawn in 3829 (6%) and continued in 62,926 (94%). Propensity score matching resulted in an analysis cohort of 19,145 cases. Withdrawal of perioperative BBs in the multivariable conditional logistic regression analysis was significantly associated with an increased risk for mortality (odds ratio [OR], 3.61; 95% confidence interval [CI], 1.75-7.35; P = .0003), but a significantly decreased risk for need of blood pressure support requiring vasopressor initiation (OR, 0.84; 95% CI, 0.76-0.92; P = .0003) and extended postanesthesia care unit stay (OR, 0.69; 95% CI, 0.54-0.88; P = .004) within 48 hours after noncardiac surgery. CONCLUSIONS: Perioperative withdrawal of BBs was associated with increased risk for mortality within 48 hours after noncardiac surgery and with decreased risk for need of vasopressor during the early postoperative period and a shorter stay in the postanesthesia care unit.

Perianesthetic and Anesthesia-Related Mortality in a Southeastern United States Population: A Longitudinal Review of a Prospectively Collected Quality Assurance Data Base.

BACKGROUND: Perianesthetic mortality (death occurring within 48 hours of an anesthetic) continues to vary widely depending on the study population examined. The authors study in a private practice physician group that covers multiple anesthetizing locations in the Southeastern United States. This group has in place a robust quality assurance (QA) database to follow all patients undergoing anesthesia. With this study, we estimate the incidence of anesthesia-related and perianesthetic mortality in this QA database. METHODS: Following institutional review board approval, data from 2011 to 2016 were obtained from the QA database of a large, community-based anesthesiology group practice. The physician practice covers 233 anesthetizing locations across 20 facilities in 2 US states. All detected cases of perianesthetic death were extracted from the database and compared to the patients' electronic medical record. These cases were further examined by a committee of 3 anesthesiologists to determine whether the death was anesthesia related (a perioperative death solely attributable to either the anesthesia provider or anesthetic technique), anesthetic contributory (a perioperative death in which anesthesia role could not be entirely excluded), or not due to anesthesia. RESULTS: A total of 785,467 anesthesia procedures were examined from the study period. A total of 592 cases of perianesthetic deaths were detected, giving an overall death rate of 75.37 in 100,000 cases (95% CI, 69.5-81.7). Mortality judged to be anesthesia related was found in 4 cases, giving a mortality rate of 0.509 in 100,000 (95% CI, 0.198-1.31). Mortality judged to be anesthesia contributory were found in 18 cases, giving a mortality of 2.29 in 100,000 patients (95% CI, 1.45-3.7). A total of 570 cases were judged to be nonanesthesia related, giving an incidence of 72.6 per 100,000 anesthetics (95% CI, 69.3-75.7). CONCLUSIONS: In a large, comprehensive database representing the full range of anesthesia practices and locations in the Southeastern United States, the rate of perianesthestic death was 0.509 in 100,000 (95% CI, 0.198-1.31). Future in-depth analysis of the epidemiology of perianesthetic deaths will be reported in later studies.

Associations of Plasma Cytokine and Microbial Translocation Biomarkers With Immune Reconstitution Inflammatory Syndrome.

A nested case-cohort study was performed in participants of a clinical trial of first-line human immunodeficiency virus treatments to investigate plasma biomarkers of inflammation and microbial translocation for their association with immune reconstitution inflammatory syndrome (IRIS). Fifty-one of 1452 participants with baseline CD4 count <350 cells/µL developed IRIS. Plasma from 51 IRIS cases, including 6 stratified by preenrollment CD4 count ≤200 cells/µL, were analyzed and compared to 94 non-IRIS controls. At baseline, CXCL10, lipopolysaccharide, soluble CD14, 16S ribosomal DNA, and interferon-α2 were associated with greater risk of IRIS. Systemic inflammation through persistent monocyte activation and microbial translocation appear to be important in IRIS pathogenesis.

Tissue Pharmacologic and Virologic Determinants of Duodenal and Rectal Gastrointestinal-Associated Lymphoid Tissue Immune Reconstitution in HIV-Infected Patients Initiating Antiretroviral Therapy.

Plasma, duodenal, and rectal tissue antiretroviral therapy (ART) drug concentrations, human immunodeficiency virus (HIV) RNA and HIV DNA copy numbers, and recovery of mucosal immunity were measured before and 9 months after initiation of 3 different ART regimens in 26 subjects. Plasma and tissue HIV RNA correlated at baseline and when 9-month declines were compared, suggesting that these compartments are tightly associated. Antiretroviral tissue:blood penetration ratios were above the 50% inhibitory concentration values in almost 100% of cases. There were no correlations between drug concentrations and HIV DNA/RNA. Importantly, no evidence was found for residual viral replication or deficient tissue drug penetration to account for delayed gastrointestinal-associated lymphoid tissue immune recovery.

Comparison of Home Advantage in College and Professional Team Sports in the United States.

Home advantage in seven American college team sports (baseball, basketball, football, hockey, lacrosse, soccer and women's basketball) was compared with professional leagues in the United States for the same sports and for the same time period. A total of 81,063 college games and 22,477 professional games were analyzed for the four seasons 2006-07 to 2009-10. There was a significant home advantage, as measured by home winning percentage, in all sports, both college and professional. The overall home advantage in college sports was significantly greater than in professional sports (p<0.015). The mean difference was 3.73 home winning percentage points, being greatest for baseball, basketball, and hockey (all p<0.001). Plausible explanations for these results include differences in college and professional competition in terms of familiarity with local conditions, referee bias, territoriality and psychological factors. However, the influence of travel fatigue was inconclusive. Only for soccer was the home advantage greater for professionals. This was the only sport where crowd size appeared to be having an effect. In addition the rules of college soccer allow more substitution and hence greater coach intervention than in professional soccer, a factor that could also be reducing home advantage.

Clinical and immunologic predictors of death after an acute opportunistic infection: results from ACTG A5164.

BACKGROUND: In the pre-antiretroviral therapy (ART) era, markers of increased disease severity during an acute opportunistic infection (OI) were associated with mortality. Even with ART, mortality remains high during the first year after an OI in persons with advanced HIV infection, but it is unclear whether previous predictors of mortality remain valid in the current era. OBJECTIVE: To determine clinical and immunological predictors of death after an OI. METHODS: We used clinical data and stored plasma from ACTG A5164, a multicenter study evaluating the optimal timing of ART during a nontuberculous OI. We developed Cox models evaluating associations between clinical parameters and plasma marker levels at entry and time to death over the first 48 weeks after the diagnosis of OI. We developed multivariable models incorporating only clinical parameters, only plasma marker levels, or both. RESULTS: The median CD4+ T-cell count in study participants at baseline was 29 cells/µL. Sixty-four percent of subjects had Pneumocystis jirovecii pneumonia (PCP). Twenty-three of 282 (8.2%) subjects died. In univariate analyses, entry mycobacterial infection, OI number, hospitalization, low albumin, low hemoglobin, lower CD4, and higher IL-8 and sTNFrII levels and lower IL-17 levels were associated with mortality. In the combined model using both clinical and immunologic parameters, the presence of an entry mycobacterial infection and higher sTNFrII levels were significantly associated with death. CONCLUSIONS: In the ART era, clinical risk factors for death previously identified in the pre-ART era remain predictive. Additionally, activation of the innate immune system is associated with an increased risk of death following an acute OI.

HIV disease activity as a modulator of lipoprotein(a) and allele-specific apolipoprotein(a) levels.

OBJECTIVE: Mechanisms underlying the cardiovascular risk of lipoprotein(a) are poorly understood. We investigated the relationship of apolipoprotein(a) (apo(a)) size, lipoprotein(a), and allele-specific apo(a) levels with HIV disease activity parameters in a biethnic population. METHODS AND RESULTS: Lipoprotein(a) and allele-specific apo(a) levels were determined in 139 white and 168 black HIV-positive patients. Plasma HIV RNA viral load and CD4+ T-cell count were used as surrogates for disease activity. Lipoprotein(a) and allele-specific apo(a) levels were higher in blacks than whites (for both P<0.001). Apo(a) allele size distribution was similar between the 2 ethnic groups, with a median apo(a) size of 28 kringle 4 repeats. Allele-specific apo(a) levels were positively associated with CD4+ T-cell count (P=0.027) and negatively with plasma HIV RNA viral load (P<0.001). Further, allele-specific apo(a) levels associated with smaller (<28 kringle 4) atherogenic apo(a) sizes were higher in subjects with CD4+ T-cell counts of ≥350 (P=0.002). CONCLUSIONS: Allele-specific apo(a) levels were higher in subjects with high CD4+ T-cell count or low plasma HIV RNA viral load. The findings suggest that HIV disease activity reduced allele-specific apo(a) levels. Higher allele-specific apo(a) levels associated with atherogenic small apo(a) sizes might contribute to increased cardiovascular risk in HIV-positive subjects with improved disease status.

A genotypic HIV-1 proviral DNA coreceptor tropism assay: characterization in viremic subjects.

BACKGROUND: HIV-1 coreceptor tropism testing is used to evaluate eligibility for CCR5 antagonist therapy. However, HIV-1 RNA-based tests are not suitable for virologically suppressed patients, therefore the use of proviral DNA tropism testing has been investigated. We describe a novel proviral DNA-based genotypic tropism assay and compare its performance to that of a sensitive HIV-1 RNA-based genotypic test. METHODS: Tropism was determined using HIV-1 plasma RNA and proviral DNA from 42 paired samples from patients with plasma viral loads ≥1000 HIV-1 RNA copies/mL. Proviral DNA sample types included whole blood, separated peripheral blood mononuclear cells resuspended in phosphate-buffered saline and peripheral blood mononuclear cells resuspended in spun plasma. The HIV-1 envelope V3 region was PCR-amplified, sequenced in triplicate, and analyzed for tropism with the geno2pheno algorithm using a 10% false-positive rate (FPR). RESULTS: Amplicons were obtained from proviral DNA and plasma RNA in 41/42 samples. Tropism predictions were highly concordant (93%-98%) between proviral DNA and plasma RNA, regardless of the proviral DNA isolation method. Non-R5 proviral DNA results were obtained for 100% of patients with detectable non-R5 plasma HIV-1 RNA results. Geno2pheno FPRs for proviral DNA and plasma RNA were highly correlated (Spearman rho = 0.86). CONCLUSIONS: Our findings demonstrate that proviral DNA tropism determinations from whole blood or peripheral blood mononuclear cells were highly concordant with plasma HIV-1 RNA tropism determinations. This assay may be useful for screening virologically suppressed patients for CCR5-antagonist eligibility and for research purposes.

Generation of an HIV-1-resistant immune system with CD34(+) hematopoietic stem cells transduced with a triple-combination anti-HIV lentiviral vector.

HIV gene therapy has the potential to offer an alternative to the use of current small-molecule antiretroviral drugs as a treatment strategy for HIV-infected individuals. Therapies designed to administer HIV-resistant stem cells to an infected patient may also provide a functional cure, as observed in a bone marrow transplant performed with hematopoietic stem cells (HSCs) homozygous for the CCR5-Δ32-bp allele. In our current studies, preclinical evaluation of a combination anti-HIV lentiviral vector was performed, in vivo, in humanized NOD-RAG1(-/-) IL2rγ(-/-) knockout mice. This combination vector, which displays strong preintegration inhibition of HIV-1 infection in vitro, contains a human/rhesus macaque TRIM5α isoform, a CCR5 short hairpin RNA (shRNA), and a TAR decoy. Multilineage hematopoiesis from anti-HIV lentiviral vector-transduced human CD34(+) HSCs was observed in the peripheral blood and in various lymphoid organs, including the thymus, spleen, and bone marrow, of engrafted mice. Anti-HIV vector-transduced CD34(+) cells displayed normal development of immune cells, including T cells, B cells, and macrophages. The anti-HIV vector-transduced cells also displayed knockdown of cell surface CCR5 due to the expression of the CCR5 shRNA. After in vivo challenge with either an R5-tropic BaL-1 or X4-tropic NL4-3 strain of HIV-1, maintenance of human CD4(+) cell levels and a selective survival advantage of anti-HIV gene-modified cells were observed in engrafted mice. The data provided from our study confirm the safety and efficacy of this combination anti-HIV lentiviral vector in a hematopoietic stem cell gene therapy setting for HIV and validates its potential application in future clinical trials.