David V. Glidden

Preexposure Chemoprophylaxis for HIV Prevention in Men Who Have Sex with Men

BACKGROUND Antiretroviral chemoprophylaxis before exposure is a promising approach for the prevention of human immunodeficiency virus (HIV) acquisition. METHODS We randomly assigned 2499 HIV-seronegative men or transgender women who have sex with men to receive a combination of two oral antiretroviral drugs, emtricitabine and tenofovir disoproxil fumarate (FTC-TDF), or placebo once daily. All subjects received HIV testing, risk-reduction counseling, condoms, and management of sexually transmitted infections. RESULTS The study subjects were followed for 3324 person-years (median, 1.2 years; maximum, 2.8 years). Of these subjects, 10 were found to have been infected with HIV at enrollment, and 100 became infected during follow-up (36 in the FTC-TDF group and 64 in the placebo group), indicating a 44% reduction in the incidence of HIV (95% confidence interval, 15 to 63; P=0.005). In the FTC-TDF group, the study drug was detected in 22 of 43 of seronegative subjects (51%) and in 3 of 34 HIV-infected subjects (9%) (P<0.001). Nausea was reported more frequently during the first 4 weeks in the FTC-TDF group than in the placebo group (P<0.001). The two groups had similar rates of serious adverse events (P=0.57). CONCLUSIONS Oral FTC-TDF provided protection against the acquisition of HIV infection among the subjects. Detectable blood levels strongly correlated with the prophylactic effect. (Funded by the National Institutes of Health and the Bill and Melinda Gates Foundation; ClinicalTrials.gov number, NCT00458393.).

Uptake of pre-exposure prophylaxis, sexual practices, and HIV incidence in men and transgender women who have sex with men: a cohort study

BACKGROUND The effect of HIV pre-exposure prophylaxis (PrEP) depends on uptake, adherence, and sexual practices. We aimed to assess these factors in a cohort of HIV-negative people at risk of infection. METHODS In our cohort study, men and transgender women who have sex with men previously enrolled in PrEP trials (ATN 082, iPrEx, and US Safety Study) were enrolled in a 72 week open-label extension. We measured drug concentrations in plasma and dried blood spots in seroconverters and a random sample of seronegative participants. We assessed PrEP uptake, adherence, sexual practices, and HIV incidence. Statistical methods included Poisson models, comparison of proportions, and generalised estimating equations. FINDINGS We enrolled 1603 HIV-negative people, of whom 1225 (76%) received PrEP. Uptake was higher among those reporting condomless receptive anal intercourse (416/519 [81%] vs 809/1084 [75%], p=0·003) and having serological evidence of herpes (612/791 [77%] vs 613/812 [75%] p=0·03). Of those receiving PrEP, HIV incidence was 1·8 infections per 100 person-years, compared with 2·6 infections per 100 person-years in those who concurrently did not choose PrEP (HR 0·51, 95% CI 0·26-1·01, adjusted for sexual behaviours), and 3·9 infections per 100 person-years in the placebo group of the previous randomised phase (HR 0·49, 95% CI 0·31-0·77). Among those receiving PrEP, HIV incidence was 4·7 infections per 100 person-years if drug was not detected in dried blood spots, 2·3 infections per 100 person-years if drug concentrations suggested use of fewer than two tablets per week, 0·6 per 100 person-years for use of two to three tablets per week, and 0·0 per 100 person-years for use of four or more tablets per week (p<0·0001). PrEP drug concentrations were higher among people of older age, with more schooling, who reported non-condom receptive anal intercourse, who had more sexual partners, and who had a history of syphilis or herpes. INTERPRETATION PrEP uptake was high when made available free of charge by experienced providers. The effect of PrEP is increased by greater uptake and adherence during periods of higher risk. Drug concentrations in dried blood spots are strongly correlated with protective benefit. FUNDING US National Institutes of Health.

Emtricitabine-Tenofovir Concentrations and Pre-Exposure Prophylaxis Efficacy in Men Who Have Sex with Men

PrEP drug concentrations associated with ≥90% reduction in HIV acquisition in men who have sex with men are achieved with daily dosing. PrEParing to Stop HIV Acquisition Pre-exposure prophylaxis (PrEP) using the antiretroviral drugs emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF) is a recently proven strategy for preventing HIV acquisition. These drugs require phosphorylation in mononuclear cells to the pharmacologically active triphosphate moieties, called emtricitabine-triphosphate (FTC-TP) and tenofovir-diphosphate (TFV-DP). The iPrEx study was a randomized placebo-controlled trial of daily oral doses of FTC-TDF as PrEP in HIV-negative men who have sex with men. Participants all received a comprehensive package of HIV prevention services. HIV infections were reduced by 44% overall in the FTC-TDF arm relative to placebo. HIV risk was reduced by more than 90% among those having detectable drug in blood, indicating that adherence was a powerful determinant of drug efficacy at preventing HIV acquisition. A new study by Anderson et al. estimates specific drug concentrations and adherence levels associated with protection from HIV-1 acquisition in the iPrEx trial. A regression analysis predicted that a TFV-DP concentration of 16 fmol/106 peripheral blood mononuclear cells (PBMCs) (95% confidence interval, 3 to 28) was associated with a 90% reduction in HIV acquisition relative to placebo in the iPrEx study. To determine the number of tablets required to achieve this drug concentration, TFV-DP concentrations from another study called STRAND were used to establish expected TFV-DP concentrations. TFV-DP was detected in the blood at all dosing levels in all participants with a median (interquartile range) TFV-DP concentration of 11 fmol/106 PBMCs (6 to 13) after two doses per week, 32 fmol/106 PBMCs (25 to 39) after four doses per week, and 42 fmol/106 PBMCs (31 to 47) after seven doses per week. When the iPrEx study’s regression model was used to analyze the STRAND TFV-DP concentrations, the predicted HIV risk reductions were 76, 96, and 99% for two, four, and seven doses per week, respectively. These findings suggest that PrEP using oral FTC-TDF tablets is a robust intervention for preventing HIV acquisition among men who have sex with men. Drug concentrations associated with protection from HIV-1 acquisition have not been determined. We evaluated drug concentrations among men who have sex with men in a substudy of the iPrEx trial (1). In this randomized placebo-controlled trial, daily oral doses of emtricitabine/tenofovir disoproxil fumarate were used as pre-exposure prophylaxis (PrEP) in men who have sex with men. Drug was detected less frequently in blood plasma and in viable cryopreserved peripheral blood mononuclear cells (PBMCs) in HIV-infected cases at the visit when HIV was first discovered compared with controls at the matched time point of the study (8% versus 44%; P < 0.001) and in the 90 days before that visit (11% versus 51%; P < 0.001). An intracellular concentration of the active form of tenofovir, tenofovir-diphosphate (TFV-DP), of 16 fmol per million PBMCs was associated with a 90% reduction in HIV acquisition relative to the placebo arm. Directly observed dosing in a separate study, the STRAND trial, yielded TFV-DP concentrations that, when analyzed according to the iPrEx model, corresponded to an HIV-1 risk reduction of 76% for two doses per week, 96% for four doses per week, and 99% for seven doses per week. Prophylactic benefits were observed over a range of doses and drug concentrations, suggesting ways to optimize PrEP regimens for this population.

Seizure-associated brain injury in term newborns with perinatal asphyxia

BackgroundThere is controversy over whether seizures, the most common manifestation of neonatal brain injury, may themselves damage the developing brain. ObjectiveTo determine if neonatal seizures are independently associated with brain injury in newborns with perinatal asphyxia. MethodsNinety term neonates were studied with MRI and single-voxel 1H-MRS on median day of life 6 (range 1 to 13 days). The severity of MR abnormality in the 1H-MRS regions of interest was scored using a validated scale. Seizure severity was scored based on seizure frequency and duration, EEG findings, and anticonvulsant administration. Multivariable linear regression tested the independent association of seizure severity with impaired cerebral metabolism measured by lactate/choline and compromised neuronal integrity measured by N-acetylaspartate/choline in both regions. ResultsClinical seizures occurred in 33 of 90 infants (37%). Seizure severity was associated with increased lactate/choline in both the intervascular boundary zone (p < 0.001) and the basal nuclei (p = 0.011) when controlling for potential confounders of MRI abnormalities and amount of resuscitation at birth. Each increase in seizure score was independently associated with a 21% increase in lactate/choline in the intervascular boundary zone (95% CI, 5.1–38.2%) and a 15% increase in the basal nuclei (95% CI, 0.1–31.7%). Seizure severity was independently associated with diminished N-acetylaspartate/choline in the intervascular boundary zone (p = 0.034). ConclusionThe severity of seizures in human newborns with perinatal asphyxia is independently associated with brain injury and is not limited to structural damage detectable by MRI.

High Prevalence of Peripheral Arterial Disease in Persons With Renal Insufficiency: Results From the National Health and Nutrition Examination Survey 1999–2000

Background—Although renal insufficiency is a recognized risk factor for coronary artery disease, little is known about the epidemiology of lower-extremity peripheral arterial disease (PAD) in persons with renal insufficiency. Methods and Results—We examined the cross-sectional association of PAD, defined as an ankle-brachial index (ABI) <0.9, and renal insufficiency, defined as an estimated creatinine clearance (CRCL) <60 mL · min−1 · 1.73 m−2, among 2229 eligible participants in the National Health and Nutrition Examination Survey (NHANES) 1999 to 2000. An estimated 1.2±0.3 million persons ≥40 years old with CRCL <60 mL · min−1 · 1.73 m−2 (24%) have PAD defined as an ABI <0.9 (versus 3.7% of persons with CRCL ≥60 mL · min−1 · 1.73 m−2). The association of ABI <0.9 with renal insufficiency was independent of potential confounders such as age, diabetes, hypertension, coronary artery disease, stroke history, and hypercholesterolemia (OR 2.5, 95% CI 1.2 to 5.1, P =0.011, referent category ABI 1.0 to 1.3). Conclusions—Clinicians should be aware of the remarkably high prevalence of PAD among patients with renal insufficiency. In the clinical setting, accurate identification of patients with renal insufficiency combined with routine ABI measurement in this group would greatly enhance efforts to detect subclinical PAD.

Temporal and Anatomic Risk Profile of Brain Injury With Neonatal Repair of Congenital Heart Defects

Background and Purpose— Brain injury is common in newborns with congenital heart disease (CHD) requiring neonatal surgery. The purpose of this study is to define the risk factors for preoperative and postoperative brain injuries and their association with functional cardiac anatomic groups. Methods— Sixty-two neonates with CHD were studied with preoperative MRI, and 53 received postoperative scans. Clinical and therapeutic characteristics were compared in newborns with and without newly acquired brain injuries. A subset of 16 consecutive patients was monitored with intraoperative cerebral near-infrared spectroscopy. Results— Brain injury was observed in 56% of patients. Preoperative brain injury, seen in 39%, was most commonly stroke and was associated with balloon atrial septostomy (P=0.002). Postoperative brain injury, seen in 35%, was most commonly white matter injury and was particularly common in neonates with single-ventricle physiology and aortic arch obstruction (P=0.001). Risk factors associated with acquired postoperative brain injury included cardiopulmonary bypass (CPB) with regional cerebral perfusion (P=0.01) and lower intraoperative cerebral hemoglobin oxygen saturation during the myocardial ischemic period of CPB (P=0.008). In a multivariable model, new postoperative white matter injury was specifically associated with low mean blood pressure during the first postoperative day (P=0.04). Conclusions— Specific modifiable risk factors can be identified for preoperative and postoperative white matter injury and stroke associated with neonatal surgery for CHD. The high incidence of postoperative injury observed despite new methodologies of CPB indicates the need for ongoing evaluation to optimize neurological outcome.

High-Resolution CT Imaging of Carotid Artery Atherosclerotic Plaques

BACKGROUND AND PURPOSE: Plaque morphologic features have been suggested as a complement to luminal narrowing measurements for assessing the risk of stroke associated with carotid atherosclerotic disease, giving rise to the concept of “vulnerable plaque.” The purpose of this study was to evaluate the ability of multidetector-row CT angiography (CTA) to assess the composition and characteristics of carotid artery atherosclerotic plaques with use of histologic examination as the gold standard. MATERIALS AND METHODS: Eight patients with transient ischemic attacks who underwent carotid CTA and “en bloc” endarterectomy were enrolled in a prospective study. An ex vivo micro-CT study of each endarterectomy specimen was obtained, followed by histologic examination. A systematic comparison of CTA images with histologic sections and micro-CT images was performed to determine the CT attenuation associated with each component of the atherosclerotic plaques. A computer algorithm was subsequently developed that automatically identifies the components of the carotid atherosclerotic plaques, based on the density of each pixel. A neuroradiologists reading of this computer analysis was compared with the interpretation of the histologic slides by a pathologist with respect to the types and characteristics of the carotid plaques. RESULTS: There was a 72.6% agreement between CTA and histologic examination in carotid plaque characterization. CTA showed perfect concordance for calcifications. A significant overlap between densities associated with lipid-rich necrotic core, connective tissue, and hemorrhage limited the reliability of individual pixel readings to identify these components. However, CTA showed good correlation with histologic examination for large lipid cores (κ = 0.796; P < .001) and large hemorrhages (κ = 0.712; P = .102). CTA performed well in detecting ulcerations (κ = 0.855) and in measuring the fibrous cap thickness (R2 = 0.77; P < .001). CONCLUSION: The composition of carotid atherosclerotic plaques determined by CTA reflects plaque composition defined by histologic examination.

Clinical Neonatal Seizures are Independently Associated with Outcome in Infants at Risk for Hypoxic-Ischemic Brain Injury

OBJECTIVE To examine whether neonatal seizures are associated with neurodevelopmental outcomes in infants with hypoxia-ischemia independent of the presence and severity of brain injury seen on magnetic resonance imaging (MRI). STUDY DESIGN We used multivariate regression to examine the independent effect of clinical neonatal seizures and their treatment on neurodevelopment in 77 term newborns at risk for hypoxic-ischemic brain injury. Clinical seizures were recorded prospectively, and high-resolution newborn MRI measured the severity of brain injury. The outcome measure was the Full-Scale Intelligence Quotient (FSIQ) of the Wechsler Preschool and Primary Scale of Intelligence-Revised and neuromotor score at age 4 years. RESULTS After controlling for severity of injury on MRI, the children with neonatal seizures had worse motor and cognitive outcomes compared with those without seizures. The magnitude of effect varied with seizure severity; children with severe seizures had a lower FSIQ than those with mild/moderate seizures (P < .0001). CONCLUSIONS Clinical neonatal seizures in the setting of birth asphyxia are associated with worse neurodevelopmental outcome, independent of the severity of hypoxic-ischemic brain injury. Randomized controlled trials are needed to determine whether differences in seizure treatment can improve outcome.

Evidence for α-synuclein prions causing multiple system atrophy in humans with parkinsonism

Significance Prions are proteins that assume alternate shapes that become self-propagating, and while some prions perform normal physiological functions, others cause disease. Prions were discovered while studying the cause of rare neurodegenerative diseases of animals and humans called scrapie and Creutzfeldt–Jakob disease, respectively. We report here the discovery of α-synuclein prions that cause a more common neurodegenerative disease in humans called multiple system atrophy (MSA). In contrast to MSA, brain extracts from Parkinson’s disease (PD) patients were not transmissible to genetically engineered cells or mice, although much evidence argues that PD is also caused by α-synuclein, suggesting that this strain (or variant) is different from those that cause MSA. Prions are proteins that adopt alternative conformations that become self-propagating; the PrPSc prion causes the rare human disorder Creutzfeldt–Jakob disease (CJD). We report here that multiple system atrophy (MSA) is caused by a different human prion composed of the α-synuclein protein. MSA is a slowly evolving disorder characterized by progressive loss of autonomic nervous system function and often signs of parkinsonism; the neuropathological hallmark of MSA is glial cytoplasmic inclusions consisting of filaments of α-synuclein. To determine whether human α-synuclein forms prions, we examined 14 human brain homogenates for transmission to cultured human embryonic kidney (HEK) cells expressing full-length, mutant human α-synuclein fused to yellow fluorescent protein (α-syn140*A53T–YFP) and TgM83+/− mice expressing α-synuclein (A53T). The TgM83+/− mice that were hemizygous for the mutant transgene did not develop spontaneous illness; in contrast, the TgM83+/+ mice that were homozygous developed neurological dysfunction. Brain extracts from 14 MSA cases all transmitted neurodegeneration to TgM83+/− mice after incubation periods of ∼120 d, which was accompanied by deposition of α-synuclein within neuronal cell bodies and axons. All of the MSA extracts also induced aggregation of α-syn*A53T–YFP in cultured cells, whereas none of six Parkinson’s disease (PD) extracts or a control sample did so. Our findings argue that MSA is caused by a unique strain of α-synuclein prions, which is different from the putative prions causing PD and from those causing spontaneous neurodegeneration in TgM83+/+ mice. Remarkably, α-synuclein is the first new human prion to be identified, to our knowledge, since the discovery a half century ago that CJD was transmissible.

Clinical characteristics of African Americans vs Caucasian Americans with multiple sclerosis

Background: African American (AA) individuals are thought to develop multiple sclerosis (MS) less frequently than Caucasian American (CA) individuals. Objective: To compare the clinical characteristics of AA and CA patients with MS. Methods: The clinical features of MS were compared in a large retrospective cohort of AA (n = 375) and CA (n = 427) subjects. Results: The proportion of women to men was similar in AA and CA subjects (81% [AA] vs 77% [CA]; p = 0.122). There were no differences in the proportions of subjects with relapsing-remitting, secondary progressive, primary progressive, and progressive relapsing MS. The median time to diagnosis was 1 year after symptom onset in AA subjects and 2 years after symptom onset in CA subjects (p = 0.0013). The age at onset was approximately 2.5 years later in AA than CA subjects (33.7 vs 31.1 years; p = 0.0001). AA subjects presented with multisite signs and symptoms at disease onset more often than CA subjects (p = 0.018). Clinical involvement restricted to the optic nerves and spinal cord (opticospinal MS) occurred in 16.8% of AA patients compared with 7.9% of CA patients (p < 0.001). Transverse myelitis also occurred more frequently in AA subjects (28 vs 18%; p = 0.001). Survival analysis revealed that AA subjects were at higher risk for development of ambulatory disability than CA subjects. After adjusting for baseline variations and differences in therapeutic interventions, AAs were at 1.67-fold greater risk for requiring a cane to ambulate than CA patients (p < 0.001). There was a trend suggesting that AAs were also at greater risk for development of wheelchair dependency (p = 0.099). Adjusted Cox proportional hazard models showed that this effect was in part attributable to the older age at onset in AAs (p < 0.001). Conclusions: Compared with multiple sclerosis (MS) in Caucasian Americans, African American patients with MS have a greater likelihood of developing opticospinal MS and transverse myelitis and have a more aggressive disease course.