Mapping Interests in Event-Driven and Long-Acting Pre-exposure Prophylaxis Formulations onto the HIV Risk Environment of Street-Based Female Sex Workers: A Latent Class Analysis

AIDS and Behavior - Despite growing availability, HIV pre-exposure prophylaxis (PrEP) uptake and adherence remains suboptimal among female sex workers (FSW) in the United States. Using...     

Altered protein tyrosine phosphorylation in asthmatic bronchial epithelium.

A disease-related, corticosteroid-insensitive increase in the expression of epidermal growth factor (EGF) receptor (EGFR) tyrosine kinase in asthmatic bronchial epithelium has been shown previously by the current authors. To determine whether this is associated with enhanced intracellular signalling, the aim of this study was to evaluate epithelial tyrosine phosphorylation. Bronchial biopsies were analysed for the presence of phosphotyrosine by immunohistochemistry. Bronchial epithelial cells were exposed to EGF, hydrogen peroxide or tumour necrosis factor-alpha in vitro for measurement of tyrosine phosphorylated signalling intermediates and interleukin (IL)-8 release. Phosphotyrosine was increased significantly in the epithelium of severe asthmatics when compared with controls or mild asthmatics; however, in mild asthma, phosphotyrosine levels were significantly decreased when compared with controls. There was no significant difference between phosphotyrosine levels before or after 8 weeks of treatment with budesonide. Stimulation of bronchial epithelial cells resulted in tyrosine phosphorylation of several proteins, including EGFR, Shc and p42/p44 mitogen-activated protein kinase. In the presence of salbutamol, a transient partial suppression of EGFR phosphorylation occurred, whereas dexamethasone was without effect. Neither salbutamol nor dexamethasone inhibited EGF-stimulated IL-8 release. These data indicate that regulation of protein tyrosine kinase activity is abnormal in severe asthma. The epidermal growth factor receptor and/or other tyrosine kinase pathways may contribute to persistent, corticosteroid-unresponsive inflammation in severe asthma.     

Validity of pedometers for measuring exercise adherence in heart failure patients

BACKGROUND: Measuring adherence to exercise is important to clinicians and researchers because inadequate adherence can adversely affect the effectiveness of an exercise program and cloud the relationship between exercise and clinical outcomes. Hence, assessment strategies for adherence to exercise, as with assessment strategies for other outcomes, must have demonstrated validity if they are to be employed with confidence. We conducted this study to determine the validity of pedometers as a measure of exercise adherence to a home-based walking program in heart failure patients. METHODS AND RESULTS: Exercise adherence was measured using pedometers in 38 patients (74% men) age 54.1 +/- 11.7 years who participated in a 12-month home-based walking program. A comparison of functional status as measured by the 6-minute walk distance and peak oxygen uptake (VO2 max) at 6 months into the exercise training program was made between 2 groups of participants who were thought to represent adherers and nonadherers: participants who demonstrated > or = 10% change in pedometer scores (n = 20) and those who showed no change in pedometer scores (n = 18) from baseline to 6 months. Patients who showed improvements in their pedometer scores over 6 months had better functional status at 6 months (6-minute walk distance 1718 +/- 46 versus 1012 +/- 25 meters, F = 5.699, P = .022; VO 2 max 17 +/- 0.7 versus 10 +/- 0.5 units, F = 7.162, P = .011) when compared with patients whose pedometers reflected minimal change in distance walked (ie, < or = 10%). CONCLUSION: Pedometers are inexpensive and readily available to both clinicians and researchers. The results of this study suggest that they may be a valid indicator of exercise adherence in heart failure patients who participate in a home-based walking program.     

The immune thrombocytopenic purpura (ITP) bleeding score: assessment of bleeding in patients with ITP

A method for objective quantification of bleeding symptoms in immune thrombocytopenic purpura (ITP) has not been established. The ITP Bleeding Scale (IBLS) is a novel bleeding assessment system comprising 11 site-specific grades. Implementation of the IBLS on 100 patient visits revealed that although platelet count and large platelet count correlated well with bleeding symptoms overall, this relationship disappeared in marked thrombocytopenia. The IBLS is a useful clinical tool for monitoring bleeding and may be used to aid the development of laboratory parameters that correlate with underlying bleeding propensity in thrombocytopenia.     

Spatial gradients in Clovis-age radiocarbon dates across North America suggest rapid colonization from the north

A key issue in the debate over the initial colonization of North America is whether there are spatial gradients in the distribution of the Clovis-age occupations across the continent. Such gradients would help indicate the timing, speed, and direction of the colonization process. In their recent reanalysis of Clovis-age radiocarbon dates, Waters and Stafford [Waters MR, Stafford TW, Jr (2007) Science 315:1122-1126] report that they find no spatial patterning. Furthermore, they suggest that the brevity of the Clovis time period indicates that the Clovis culture represents the diffusion of a technology across a preexisting pre-Clovis population rather than a population expansion. In this article, we focus on two questions. First, we ask whether there is spatial patterning to the timing of Clovis-age occupations and, second, whether the observed speed of colonization is consistent with demic processes. With time-delayed wave-of-advance models, we use the radiocarbon record to test several alternative colonization hypotheses. We find clear spatial gradients in the distribution of these dates across North America, which indicate a rapid wave of advance originating from the north. We show that the high velocity of this wave can be accounted for by a combination of demographic processes, habitat preferences, and mobility biases across complex landscapes. Our results suggest that the Clovis-age archaeological record represents a rapid demic colonization event originating from the north.     

C-reactive protein, an 'intermediate phenotype' for inflammation: human twin studies reveal heritability, association with blood pressure and the metabolic syndrome, and the influence of common polymorphism at catecholaminergic/beta-adrenergic pathway loci

BACKGROUND: C-reactive protein (CRP) both reflects and participates in inflammation, and its circulating concentration marks cardiovascular risk. Here we sought to understand the role of heredity in determining CRP secretion. METHODS: CRP, as well as multiple facets of the metabolic syndrome, were measured in a series of 229 twins, both monozygotic (MZ) and dizygotic (DZ), to estimate trait heritability (h2). Single nucleotide polymorphism (SNP) genotyping was done at adrenergic pathway loci. Haplotypes were inferred from genotypes by likelihood methods. Association of CRP with hypertension and the metabolic syndrome was studied in a larger series of 732 individuals, including 79 with hypertension. RESULTS: MZ and DZ twin variance components indicated substantial h2 for CRP, at approximately 56 +/- 7% (P < 0.001). CRP was significantly associated (P < 0.05) with multiple features of the metabolic syndrome in twins, including body mass index (BMI), blood pressure (BP), leptin and lipids. In established hypertension, elevated CRP was associated with increased BP, BMI, insulin, HOMA (index of insulin resistance), leptin, triglycerides and norepinephrine. Twin correlations indicated pleiotropy (shared genetic determination) for CRP with BMI (P = 0.0002), leptin (P < 0.001), triglycerides (P = 0.002) and systolic blood pressure (SBP) (P = 0.042). Approximately 9800 genotypes (43 genetic variants at 17 loci) were scored within catecholaminergic pathways: biosynthetic, receptor and signal transduction. Plasma CRP concentration in twins was predicted by polymorphisms at three loci in physiological series within the catecholamine biosynthetic/beta-adrenergic pathway: TH (tyrosine hydroxylase), ADRB1 (beta1-adrenergic receptor) and ADRB2 (beta2-adrenergic receptor). In the TH promoter, common allelic variation accounted for up to approximately 6.6% of CRP inter-individual variance. At ADRB1, variation at Gly389Arg predicted approximately 2.8% of CRP, while ADRB2 promoter variants T-47C and T-20C also contributed. Particular haplotypes and diplotypes at TH and ADRB1 also predicted CRP, though typically no better than single SNPs alone. Epistasis (gene-by-gene interaction) was demonstrated for particular combinations of TH and ADRB2 alleles, consistent with their actions in a pathway in series. In an illustration of pleiotropy, not only CRP but also plasma triglycerides were predicted by polymorphisms at TH (P = 0.0053) and ADRB2 (P = 0.027). CONCLUSIONS: CRP secretion is substantially heritable in humans, demonstrating pleiotropy (shared genetic determination) with other features of the metabolic syndrome, such as BMI, triglycerides or BP. Multiple, common genetic variants in the catecholaminergic/beta-adrenergic pathway contribute to CRP, and these variants (especially at TH and ADRB2) seem to interact (epistasis) to influence the trait. The results uncover novel pathophysiological links between the adrenergic system and inflammation, and suggest new strategies to probe the role and actions of inflammation within this setting.     

In vitro production of panton-valentine leukocidin among strains of methicillin-resistant Staphylococcus aureus causing diverse infections.

BACKGROUND: Community-acquired methicillin-resistant Staphylococcus aureus strains have recently been associated with severe necrotizing infections. Greater than 75% of these strains carry the genes for Panton-Valentine leukocidin (PVL), suggesting that this toxin may mediate these severe infections. However, to date, studies have not provided evidence of toxin production. METHODS: Twenty-nine community-acquired methicillin-resistant Staphylococcus aureus and 2 community-acquired methicillin-susceptible S. aureus strains were collected from patients with infections of varying severity. Strains were analyzed for the presence of lukF-PV and SCCmecA type. PVL production in lukF-PV gene-positive strains was measured by ELISA, and the amount produced was analyzed relative to severity of infection. RESULTS: Only 2 of the 31 strains tested, 1 methicillin-resistant Staphylococcus aureus abscess isolate and 1 nasal carriage methicillin-susceptible S. aureus isolate, were lukF-PV negative. All methicillin-resistant Staphylococcus aureus strains were SCCmec type IV. PVL was produced by all strains harboring lukF-PV, although a marked strain-to-strain variation was observed. Twenty-six (90%) of 29 strains produced 50-350 ng/mL of PVL; the remaining strains produced PVL in excess of 500 ng/mL. The quantity of PVL produced in vitro did not correlate with severity of infection. CONCLUSIONS: Although PVL likely plays an important role in the pathogenesis of these infections, its mere presence is not solely responsible for the increased severity. Factors that up-regulate toxin synthesis in vivo could contribute to more-severe disease and worse outcomes in patients with community-acquired methicillin-resistant Staphylococcus aureus infection.     

Unhealthy behaviours for self-management of HIV-related peripheral neuropathy

The prevalence of peripheral neuropathy is frequent in HIV disease and is often associated with antiretroviral therapy. Unhealthy behaviours, particularly substance-use behaviours, are utilized by many HIV-positive individuals to manage neuropathic symptoms. As part of a larger study on self-care for symptoms in HIV disease, this study analyzed the prevalence and characteristics of unhealthy behaviours to self-manage peripheral neuropathy in HIV disease. Sociodemographic and disease-related correlates and unhealthy behaviours were examined in a convenience sample of 1,217 respondents who were recruited from data collection sites in several US cities, Puerto Rico, Colombia, and Taiwan. Results of the study indicated that respondents with peripheral neuropathy (n=450) identified a variety of unhealthy self-care behaviours including injection drug use, oral drug use, smoking cigarettes and alcohol ingestion. Specific unhealthy behaviours that participants reported to alleviate peripheral neuropathy included use of marijuana (n=67), smoking cigarettes (n=139), drinking alcohol (n=81) and street drugs (n=30). A subset of those individuals (n=160), who identified high levels of neuropathy (greater than five on a scale of 1-10), indicated significantly higher use of amphetamines and injection drug use in addition to alcohol use and cigarette smoking. For participants from Norway, substance use (using alcohol: 56%) was one of the most frequent self-management strategies. Implications for clinical practice include assessment and education of persons with HIV for self-care management of the complex symptom of peripheral neuropathy.     

Inter‐ and Intraobserver Variability in LVH and RVH Reporting in Pediatric ECGs

Background: Physicians' diagnoses are often used as the gold standard for evaluating computer electrocardiogram (ECG) interpretation programs. As part of a larger study to evaluate the Glasgow pediatric ECG analysis program, inter‐ and intraobserver variability in the ECG reporting of two pediatric cardiologists was examined. Methods: The ECGs of 984 children were sent for reporting independently by two cardiologists with all identifying information except age and sex removed. Three hundred twenty ECGs had no clinical indication available, and they were thus reported “blind.” For 664 ECGs, the clinical indication was known and included with the ECG trace. All ECGs reported as right ventricular hypertrophy (RVH) or left ventricular hypertrophy (LVH) were returned to the cardiologists without their knowledge for reporting a second time “blind” as to the clinical indication. Results: When the cardiologists' reports were compared with each other, the provision of clinical information led to greater agreement between them for the diagnosis of LVH (kappa increased from 0.44 to 0.52) but did not substantially affect their agreement in diagnosing RVH (kappa fell from 0.66 to 0.63). Intraindividual comparisons in 166 ECGs revealed that one cardiologist was more consistent in diagnosing RVH and the other more consistent in diagnosing LVH. Conclusions: This study has demonstrated the difficulties in using cardiologists' diagnoses as the gold standard with which to evaluate pediatric ECGs.     

“The role of case management in HIV treatment adherence: HPTN 078”

AIDS and Behavior - Adherence to care and antiretroviral therapy is challenging, especially for people living with HIV (PLWH) with additional co-occurring risk factors. Case management...