The effects of age on associations between markers of HIV progression and markers of metabolic function including albumin, haemoglobin and lipid concentrations.

OBJECTIVES: We investigated whether age modified associations between markers of HIV progression, CD4 T lymphocyte count and HIV RNA viral load (VL), and the following markers of metabolic function: albumin, haemoglobin, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC). METHODS: A retrospective analysis of data from the United Kingdom Collaborative HIV Cohort was carried out. Analyses were limited to antiretroviral-naïve subjects to focus on the impact of HIV disease itself. A total of 16670 subjects were included in the analysis. Multilevel linear regression models assessed associations between CD4 count/VL and each of the outcomes. Statistical tests for interactions assessed whether associations differed among age groups. RESULTS: After adjustment for gender and ethnicity, there was evidence that lower CD4 count and higher VL were associated with lower TC, LDL-C, haemoglobin and albumin concentrations but higher triglyceride concentrations. Age modified associations between CD4 count and albumin (P 50 years, a 50 cells/μL lower CD4 count correlated with a 2.4 [95% confidence interval (CI) 1.7-3.0], 3.6 (95% CI 3.2-4.0) and 5.1 (95% CI 4.0-6.1) g/L lower haemoglobin concentration and a 0.09 (95% CI 0.07-0.11), 0.12 (95% CI 0.11-0.13) and 0.16 (95% CI 0.13-0.19) g/L lower albumin concentration, respectively. CONCLUSIONS: We present evidence that age modifies associations between CD4 count and plasma albumin and haemoglobin levels. A given reduction in CD4 count was associated with a greater reduction in haemoglobin and albumin concentrations among older people living with HIV. These findings increase our understanding of how the metabolic impact of HIV is influenced by age

Incomplete reversibility of estimated glomerular filtration rate decline following tenofovir disoproxil fumarate exposure.

BACKGROUND: Tenofovir disoproxil fumarate (TDF) has been linked to renal impairment, but the extent to which this impairment is reversible is unclear. We aimed to investigate the reversibility of renal decline during TDF therapy. METHODS: Cox proportional hazards models assessed factors associated with discontinuing TDF in those with an exposure duration of >6 months. In those who discontinued TDF therapy, linear piecewise regression models estimated glomerular filtration rate (eGFR) slopes before initiation of, during, and after discontinuation of TDF therapy. Factors associated with not achieving eGFR recovery 6 months after discontinuing TDF were assessed using multivariable logistic regression. RESULTS: We observed declines in the eGFR during TDF exposure (mean slopes, -15.7 mL/minute/1.73 m(2)/year [95% confidence interval {CI}, -20.5 to -10.9] during the first 3 months and -3.1 mL/minute/1.73 m(2)/year [95% CI, -4.6 to -1.7] thereafter) and evidence of eGFR increases following discontinuation of TDF therapy (mean slopes, 12.5 mL/minute/1.73 m(2)/year [95% CI, 8.9-16.1] during the first 3 months and 0.8 mL/minute/1.73 m(2)/year [95% CI,.1-1.5] thereafter). Following TDF discontinuation, 38.6% of patients with a decline in the eGFR did not experience recovery. A higher eGFR at baseline, a lower eGFR after discontinuation of TDF therapy, and more-prolonged exposure to TDF were associated with an increased risk of incomplete recovery 6 months after discontinuation of TDF therapy. CONCLUSIONS: This study shows that a decline in the eGFR during TDF therapy was not fully reversible in one third of patients and suggests that prolonged TDF exposure at a low eGFR should be avoided

Improved kidney function in patients who switch their protease inhibitor from atazanavir or lopinavir to darunavir

OBJECTIVE: Atazanavir (ATV) and lopinavir (LPV) have been associated with kidney disease progression in HIV positive patients, with no data reported for darunavir (DRV). We examined kidney function in patients who switched their protease inhibitor from ATV or LPV to DRV. DESIGN: Cohort study. METHODS: Data were from the UK CHIC study. We compared pre and post switch estimated glomerular filtration rate (eGFR) slopes (expressed in ml/min per 1.73 m2 per year) in all switchers and those with rapid eGFR decline (>5 ml/min per 1.73 m2 per year) on ATV or LPV. Mixed-effects models were adjusted for age, gender, ethnicity, eGFR at switch and time updated CD4þ cell count, HIV RNA and cumulative tenofovir (tenofovir disoproxil fumarate) exposure. RESULTS: Data from 1430 patients were included. At the time of switching to DRV, median age was 45 years, 79% were men, 76% had an undetectable viral load, and median eGFR was 93 ml/min per 1.73 m2 . Adjusted mean (95% confidence interval) pre and post switch eGFR slopes were 0.84 (1.31, 0.36) and 1.23 (0.80, 1.66) for ATV (P < 0.001), and 0.57 (1.09, 0.05) and 0.62 (0.28, 0.96) for LPV (P < 0.001). Stable or improved renal function was observed in patients with rapid eGFR decline on ATV or LPV who switched to DRV [15.27 (19.35, 11.19) and 3.72 (1.78, 5.66), P < 0.001 for ATV, 11.93 (14.60, 9.26) and 0.87 (0.54, 2.27), P < 0.001 for LPV]. Similar results were obtained if participants who discontinued tenofovir disoproxil fumarate at the time of switch were excluded. CONCLUSIONS: We report improved kidney function in patients who switched from ATV or LPV to DRV, suggesting that DRV may have a more favourable renal safety profile

Bounds on 4D Conformal and Superconformal Field Theories

We derive general bounds on operator dimensions, central charges, and OPE coefficients in 4D conformal and N=1 superconformal field theories. In any CFT containing a scalar primary phi of dimension d we show that crossing symmetry of implies a completely general lower bound on the central charge c >= f_c(d). Similarly, in CFTs containing a complex scalar charged under global symmetries, we bound a combination of symmetry current two-point function coefficients tau^{IJ} and flavor charges. We extend these bounds to N=1 superconformal theories by deriving the superconformal block expansions for four-point functions of a chiral superfield Phi and its conjugate. In this case we derive bounds on the OPE coefficients of scalar operators appearing in the Phi x Phi* OPE, and show that there is an upper bound on the dimension of Phi* Phi when dim(Phi) is close to 1. We also present even more stringent bounds on c and tau^{IJ}. In supersymmetric gauge theories believed to flow to superconformal fixed points one can use anomaly matching to explicitly check whether these bounds are satisfied.Comment: 47 pages, 9 figures; V2: small corrections and clarification

Renal impairment in a rural African antiretroviral programme

Background: There is little knowledge regarding the prevalence and nature of renal impairment in African populations initiating antiretroviral treatment, nor evidence to inform the most cost effective methods of screening for renal impairment. With the increasing availability of the potentially nephrotixic drug, tenofovir, such information is important for the planning of antiretroviral programmes Methods: (i) Retrospective review of the prevalence and risk factors for impaired renal function in 2189 individuals initiating antiretroviral treatment in a rural African setting between 2004 and 2007 (ii) A prospective study of 149 consecutive patients initiating antiretrovirals to assess the utility of urine analysis for the detection of impaired renal function. Severe renal and moderately impaired renal function were defined as an estimated GFR of ≤ 30 mls/min/1.73 m2 and 30–60 mls/min/1.73 m2 respectively. Logistic regression was used to determine odds ratio (OR) of significantly impaired renal function (combining severe and moderate impairment). Co-variates for analysis were age, sex and CD4 count at initiation. Results: (i) There was a low prevalence of severe renal impairment (29/2189, 1.3% 95% C.I. 0.8–1.8) whereas moderate renal impairment was more frequent (287/2189, 13.1% 95% C.I. 11.6–14.5) with many patients having advanced immunosuppression at treatment initiation (median CD4 120 cells/μl). In multivariable logistic regression age over 40 (aOR 4.65, 95% C.I. 3.54–6.1), male gender (aOR 1.89, 95% C.I. 1.39–2.56) and CD4<100 cells/ul (aOR 1.4, 95% C.I. 1.07–1.82) were associated with risk of significant renal impairment (ii) In 149 consecutive patients, urine analysis had poor sensitivity and specificity for detecting impaired renal function. Conclusion: In this rural African setting, significant renal impairment is uncommon in patients initiating antiretrovirals. Urine analysis alone may be inadequate for identification of those with impaired renal function where resources for biochemistry are limited

Effects of Fusion between Tactile and Proprioceptive Inputs on Tactile Perception

Tactile perception is typically considered the result of cortical interpretation of afferent signals from a network of mechanical sensors underneath the skin. Yet, tactile illusion studies suggest that tactile perception can be elicited without afferent signals from mechanoceptors. Therefore, the extent that tactile perception arises from isomorphic mapping of tactile afferents onto the somatosensory cortex remains controversial. We tested whether isomorphic mapping of tactile afferent fibers onto the cortex leads directly to tactile perception by examining whether it is independent from proprioceptive input by evaluating the impact of different hand postures on the perception of a tactile illusion across fingertips. Using the Cutaneous Rabbit Effect, a well studied illusion evoking the perception that a stimulus occurs at a location where none has been delivered, we found that hand posture has a significant effect on the perception of the illusion across the fingertips. This finding emphasizes that tactile perception arises from integration of perceived mechanical and proprioceptive input and not purely from tactile interaction with the external environment

Current OPEs in Superconformal Theories

It's well known that in conformal theories the two- and three-point functions of a subset of the local operators-the conformal primaries-suffice, via the operator product expansion (OPE), to determine all local correlation functions of operators. It's less well known that, in superconformal theories, the OPE of superdescendants is generally undetermined from those of the superprimaries, and there is no universal notion of superconformal blocks. We recall these and related aspects of 4d (S)CFTs, and then we focus on the super operator product expansion (sOPE) of conserved currents in 4d N=1 SCFTs. The current-current OPE J(x)J(0) has applications to general gauge mediation. We show how superconformal symmetry, when combined with current conservation, determines the OPE coefficients of superconformal descendants in terms of those of the superconformal primaries. We show that only integer-spin real superconformal primary operators of vanishing R-charge, and their descendants, appear in the sOPE. We also discuss superconformal blocks for four-point functions of the conserved currents.Comment: 37 pages, 1 figure. Corrected some formulas, added reference

Comparison of high versus low frequency cerebral physiology for cerebrovascular reactivity assessment in traumatic brain injury: a multi-center pilot study

Current accepted cerebrovascular reactivity indices suffer from the need of high frequency data capture and export for post-acquisition processing. The role for minute-by-minute data in cerebrovascular reactivity monitoring remains uncertain. The goal was to explore the statistical time-series relationships between intra-cranial pressure (ICP), mean arterial pressure (MAP) and pressure reactivity index (PRx) using both 10-s and minute data update frequency in TBI. Prospective data from 31 patients from 3 centers with moderate/severe TBI and high-frequency archived physiology were reviewed. Both 10-s by 10-s and minute-by-minute mean values were derived for ICP and MAP for each patient. Similarly, PRx was derived using 30 consecutive 10-s data points, updated every minute. While long-PRx (L-PRx) was derived via similar methodology using minute-by-minute data, with L-PRx derived using various window lengths (5, 10, 20, 30, 40, and 60 min; denoted L-PRx_5, etc.). Time-series autoregressive integrative moving average (ARIMA) and vector autoregressive integrative moving average (VARIMA) models were created to analyze the relationship of these parameters over time. ARIMA modelling, Granger causality testing and VARIMA impulse response function (IRF) plotting demonstrated that similar information is carried in minute mean ICP and MAP data, compared to 10-s mean slow-wave ICP and MAP data. Shorter window L-PRx variants, such as L-PRx_5, appear to have a similar ARIMA structure, have a linear association with PRx and display moderate-to-strong correlations (r ~ 0.700, p Peer reviewe

A phase I and pharmacological study of the matrix metalloproteinase inhibitor BB-3644 in patients with solid tumours.

BB-3644 is an oral, broad-spectrum matrix metalloproteinase inhibitor (MMPI) structurally related to marimastat and BB-94. It is also >10-fold more active than marimastat in inhibiting the processing of cell-bound TNF-alpha. Preclinical studies suggested a favourable toxicity profile when compared to marimastat, and therefore it was selected for clinical evaluation. Patients with advanced solid tumours against which established treatments had failed, or for which no satisfactory treatment exists and of good performance status, were eligible. Treatment consisted of twice daily (bd) oral BB-3644 for 84 days. The initial dose was 5 mg bd, and subsequent cohorts were treated with 10, 20 and 30 mg bd. In all, 22 patients were enrolled. The dose-limiting toxicity (DLT) was musculoskeletal pain. For 28 days of treatment with BB-3644, 20 mg bd was the maximum tolerated dose (MTD), as at 30 mg bd, six of nine patients developed significant musculoskeletal toxicity by day 28. Following chronic oral dosing (>28 days) with BB-3644, three of five patients treated at 10 mg bd developed musculoskeletal DLT by day 84, defining the MTD as 5 mg bd. As dose-limiting musculoskeletal toxicity was encountered at doses of BB-3644 unlikely to provide an advantage over currently available MMPIs, further evaluation is not recommended

Critical analysis of the influence of transnational capitalism on institutions and organizations

This paper aims to analyze the development of capitalism and its influences on institutions and organizations from its beginnings to reach the highest stage in the processes of neoliberal economic globalization and the New Economy version with support of information and communication technologies. In raising this development from a critical analysis, it examines the impacts and effects on individuals, communities and the nation state. Subsequently it is questioned the scope of the imposed transnational neoliberal capitalism model. Finally, it is concluded that it needs a cultural transformation for not accepting the forms of domination, power and alignment of globalizing capitalism and to reconstruct the identity of communities through individual action and asserting collective self-determination, independence and self-management