Phase Diagrams of Alloys and Their Hydrides via On-Lattice Graph Neural Networks and Limited Training Data.

Efficient prediction of sampling-intensive thermodynamic properties is needed to evaluate material performance and permit high-throughput materials modeling for a diverse array of technology applications. To alleviate the prohibitive computational expense of high-throughput configurational sampling with density functional theory (DFT), surrogate modeling strategies like cluster expansion are many orders of magnitude more efficient but can be difficult to construct in systems with high compositional complexity. We therefore employ minimal-complexity graph neural network models that accurately predict and can even extrapolate to out-of-train distribution formation energies of DFT-relaxed structures from an ideal (unrelaxed) crystallographic representation. This enables the large-scale sampling necessary for various thermodynamic property predictions that may otherwise be intractable and can be achieved with small training data sets. Two exemplars, optimizing the thermodynamic stability of low-density high-entropy alloys and modulating the plateau pressure of hydrogen in metal alloys, demonstrate the power of this approach, which can be extended to a variety of materials discovery and modeling problems.

Therapeutic amprenavir concentrations in cerebrospinal fluid.

Antiretrovirals that reach higher concentrations in cerebrospinal fluid (CSF) are associated with better control of HIV in CSF and possibly better neurocognitive performance. The objective of this study was to determine whether amprenavir (APV) concentrations in CSF are in the therapeutic range. Individuals were selected based on the use of regimens that included fosamprenavir (FPV), a prodrug of APV, and the availability of stored CSF and matched plasma. Total APV was measured in 119 matched CSF-plasma pairs from 75 subjects by high-performance liquid chromatography (HPLC) (plasma) or liquid chromatography tandem mass spectrometry (LC/MS/MS) (CSF). Concentrations were compared to the 50% inhibitory concentration (IC50) for wild-type HIV (5.6 ng/ml). Subjects were predominantly middle-aged (median 44 years) white (57%) men (78%) with AIDS (77%). APV was detected in all but 4 CSF specimens, with a median concentration of 24.8 ng/ml (interquartile range [IQR], 16.2 to 44.0). The median CSF-to-plasma ratio was 0.012 (IQR, 0.008 to 0.018). CSF concentrations correlated with plasma concentrations (rho = 0.61; P < 0.0001) and with postdose sampling interval (rho = -0.29; P = 0.0019). APV concentrations in CSF exceeded the median IC50 for wild-type HIV in more than 97% of CSF specimens with detectable APV by a median of 4.4-fold (IQR, 2.9 to 7.9). We conclude that administration of fosamprenavir should contribute to control of HIV replication in the central nervous system (CNS) as a component of effective antiretroviral regimens.

Hypertriglyceridemia in combination antiretroviral-treated HIV-positive individuals: potential impact on HIV sensory polyneuropathy.

OBJECTIVE: in HIV populations that are aging due to improved longevity with combination antiretroviral therapy (CART), both hypertriglyceridemia (hTRG) and sensory neuropathy have become increasingly common. Sensory neuropathy is associated with substantial long-term disability and frequently requires management with analgesics. Elevated serum triglycerides (TRGs) are associated with an increased risk for sensory neuropathy in diabetes mellitus. However, the contribution of hTRG to sensory neuropathy in HIV has not been carefully evaluated. DESIGN: prospective, comparative, single-center, cross-sectional cohort study. METHODS: clinical correlates of sensory neuropathy were assessed in HIV-positive and HIV-negative participants. HIV-sensory neuropathy was defined as one or more clinical signs of reduced distal sensation or ankle reflexes; symptoms were distal leg and foot pain, parasthesias or numbness. TRG levels were assessed along with concomitant metabolic and other risk factors including glucose, lipids, age, height, current and nadir CD4, and past or current use of protease inhibitors, dideoxynucleoside antiretrovirals (d-drugs), and statins in univariable and multivariable logistic regression. RESULTS: of 436 HIV patients (median age 52 years; 75% on CART), 27% had sensory neuropathy; 48% were symptomatic. TRG levels were significantly higher in HIV-positive than HIV-negative individuals (mean ± SD, 245 ± 242 versus 160 ± 97 mg/dl; P < 0.001). Among HIV-positive patients, those with TRG levels in the highest tertile (≥ 244 mg/dl) were more likely to have sensory neuropathy than those in the lowest tertile (reference, ≤ 142 mg/dl) after adjusting for concurrent predictors (adjusted odds ratio 2.7, 95% confidence interval 1.4-5.5). CONCLUSIONS: elevated triglyceride levels increased the risk for HIV-sensory neuropathy in HIV-positive individuals independently of other known risk factors.

Total raltegravir concentrations in cerebrospinal fluid exceed the 50-percent inhibitory concentration for wild-type HIV-1.

HIV-associated neurocognitive disorders continue to be common. Antiretrovirals that achieve higher concentrations in cerebrospinal fluid (CSF) are associated with better control of HIV and improved cognition. The objective of this study was to measure total raltegravir (RAL) concentrations in CSF and to compare them with matched concentrations in plasma and in vitro inhibitory concentrations. Eighteen subjects with HIV-1 infection were enrolled based on the use of RAL-containing regimens and the availability of CSF and matched plasma samples. RAL was measured in 21 CSF and plasma pairs by liquid chromatography-tandem mass spectrometry, and HIV RNA was detected by reverse transcription-PCR (RT-PCR). RAL concentrations were compared to the 50% inhibitory concentration (IC(50)) for wild-type HIV-1 (3.2 ng/ml). Volunteers were predominantly middle-aged white men with AIDS and without hepatitis C virus (HCV) coinfection. The median concurrent CD4(+) cell count was 276/µl, and 28% of CD4(+) cell counts were below 200/µl. HIV RNA was detectable in 38% of plasma specimens and 4% of CSF specimens. RAL was present in all CSF specimens, with a median total concentration of 14.5 ng/ml. The median concentration in plasma was 260.9 ng/ml, with a median CSF-to-plasma ratio of 0.058. Concentrations in CSF correlated with those in with plasma (r(2), 0.24; P, 0.02) but not with the postdose sampling time (P, >0.50). RAL concentrations in CSF exceeded the IC(50) for wild-type HIV in all specimens by a median of 4.5-fold. RAL is present in CSF and reaches sufficiently high concentrations to inhibit wild-type HIV in all individuals. As a component of effective antiretroviral regimens or as the main antiretroviral, RAL likely contributes to the control of HIV replication in the nervous system.