Analyzing the errors of DFT approximations for compressed water systems.

We report an extensive study of the errors of density functional theory (DFT) approximations for compressed water systems. The approximations studied are based on the widely used PBE and BLYP exchange-correlation functionals, and we characterize their errors before and after correction for 1- and 2-body errors, the corrections being performed using the methods of Gaussian approximation potentials. The errors of the uncorrected and corrected approximations are investigated for two related types of water system: first, the compressed liquid at temperature 420 K and density 1.245 g/cm(3) where the experimental pressure is 15 kilobars; second, thermal samples of compressed water clusters from the trimer to the 27-mer. For the liquid, we report four first-principles molecular dynamics simulations, two generated with the uncorrected PBE and BLYP approximations and a further two with their 1- and 2-body corrected counterparts. The errors of the simulations are characterized by comparing with experimental data for the pressure, with neutron-diffraction data for the three radial distribution functions, and with quantum Monte Carlo (QMC) benchmarks for the energies of sets of configurations of the liquid in periodic boundary conditions. The DFT errors of the configuration samples of compressed water clusters are computed using QMC benchmarks. We find that the 2-body and beyond-2-body errors in the liquid are closely related to similar errors exhibited by the clusters. For both the liquid and the clusters, beyond-2-body errors of DFT make a substantial contribution to the overall errors, so that correction for 1- and 2-body errors does not suffice to give a satisfactory description. For BLYP, a recent representation of 3-body energies due to Medders, Babin, and Paesani [J. Chem. Theory Comput. 9, 1103 (2013)] gives a reasonably good way of correcting for beyond-2-body errors, after which the remaining errors are typically 0.5 mE(h) ≃ 15 meV/monomer for the liquid and the clusters.

Communication: energy benchmarking with quantum Monte Carlo for water nano-droplets and bulk liquid water.

We show the feasibility of using quantum Monte Carlo (QMC) to compute benchmark energies for configuration samples of thermal-equilibrium water clusters and the bulk liquid containing up to 64 molecules. Evidence that the accuracy of these benchmarks approaches that of basis-set converged coupled-cluster calculations is noted. We illustrate the usefulness of the benchmarks by using them to analyze the errors of the popular BLYP approximation of density functional theory (DFT). The results indicate the possibility of using QMC as a routine tool for analyzing DFT errors for non-covalent bonding in many types of condensed-phase molecular system.

First-principles energetics of water clusters and ice: a many-body analysis.

Standard forms of density-functional theory (DFT) have good predictive power for many materials, but are not yet fully satisfactory for cluster, solid, and liquid forms of water. Recent work has stressed the importance of DFT errors in describing dispersion, but we note that errors in other parts of the energy may also contribute. We obtain information about the nature of DFT errors by using a many-body separation of the total energy into its 1-body, 2-body, and beyond-2-body components to analyze the deficiencies of the popular PBE and BLYP approximations for the energetics of water clusters and ice structures. The errors of these approximations are computed by using accurate benchmark energies from the coupled-cluster technique of molecular quantum chemistry and from quantum Monte Carlo calculations. The systems studied are isomers of the water hexamer cluster, the crystal structures Ih, II, XV, and VIII of ice, and two clusters extracted from ice VIII. For the binding energies of these systems, we use the machine-learning technique of Gaussian Approximation Potentials to correct successively for 1-body and 2-body errors of the DFT approximations. We find that even after correction for these errors, substantial beyond-2-body errors remain. The characteristics of the 2-body and beyond-2-body errors of PBE are completely different from those of BLYP, but the errors of both approximations disfavor the close approach of non-hydrogen-bonded monomers. We note the possible relevance of our findings to the understanding of liquid water.

Therapeutic drug monitoring and TB treatment outcomes in patients with diabetes mellitus.

BACKGROUND: Diabetes mellitus (DM) increases the risk of TB disease and poor treatment outcomes such as delayed sputum culture conversion due to inadequate drug exposure. Therapeutic drug monitoring (TDM) has improved these outcomes in some settings.METHODS: To compare treatment outcomes in programs with routine TDM vs. programs that did not use TDM, we conducted a retrospective study among people with DM and TB at health departments in four US states.RESULTS: A total of 170 patients were enrolled (73 patients in the non-TDM group and 97 patients in the TDM group). Days to sputum culture conversion and total treatment duration were significantly shorter in the TDM group vs. the non-TDM group. In adjusted analyses, patients who underwent TDM were significantly more likely to achieve sputum culture conversion at 2 months (P = 0.007).CONCLUSION: TDM hastened microbiological cure from TB among people with DM and a high risk for poor treatment outcomes in the programmatic setting.

Tetrodotoxin blocks native cardiac L-type calcium channels but not CaV1.2 channels expressed in HEK cells.

Tetrodotoxin (TTX) has been believed for a long time to be a selective inhibitor of voltage-gated fast Na(+) channels in excitable tissues, including mammalian myocardium. Recently TTX has been shown to block cardiac L-type Ca(2+) current (ICa,L). Furthermore, this inhibition was ascribed to binding of TTX to the outer pore of the Ca(2+) channel, contributing to the selectivity filter region. In this study the TTX-sensitivity of Cav1.2 channels, expressed in HEK cells, was tested using the whole cell version of the patch clamp technique and compared to the TTX-sensitivity of native canine ICa,L. Cav1.2 channels mediate Ca(2+) current in ventricular myocardium of various mammalian species. Surprisingly, TTX failed to inhibit Cav1.2 current up to the concentration of 100 µM - in contrast to ICa,L - in spite of the fact that the kinetic properties of the ICa,L and Cav1.2 currents were similar. The possible reasons for this discrepancy are discussed. Present results may question the suitability of a single pore-forming channel subunit, expressed in a transfection system, for electrophysiological or pharmacological studies.

The association between cerebrovascular disease and smoking: a case-control study.

A retrospective case-control study was carried out to examine the relationship between cigarette smoking and cerebrovascular disease occurrence. Cases were obtained from the University of California-American Heart Association, San Diego Stroke Data Bank, and controls from selected Veterans Administration and University of California, San Diego, outpatient departments. When cigarette smoking was dichotomously coded into categories of low and high lifetime exposure, consistent significant positive associations were found with cerebrovascular disease occurrence in both bivariate and multivariate analysis when controlling for blood pressure. These associations, however, were not found when smoking was categorized as smoker, ex-smoker, and non-smoker. No association was found between passive smoking and cerebrovascular disease. The results indicate that a cumulative lifetime exposure to active cigarette smoking is directly associated with cerebrovascular disease.

Transient bacteremia due to Mycobacterium avium complex in patients with AIDS.

It is generally assumed that Mycobacterium avium complex (MAC) bacteremia, once it develops, is unremitting. On the basis of this presumption, changes in the level of mycobacteremia are used to gauge therapeutic response. In 7 (12%) of 60 patients enrolled in a prospective trial of MAC bacteremia and AIDS, bacteremia became undetectable before the initiation of antimycobacterial therapy. Patients with transient bacteremia reported fewer and shorter symptoms and survived longer than those with sustained bacteremia (59 vs. 31 weeks; P = .022). There was no difference in the duration of AIDS, CD4+ cell count, hematocrit, or body weight between groups. Two additional patients with transient bacteremia were identified outside this study setting. Despite disappearance of detectable mycobacteremia and subsequent administration of antimycobacterial agent(s), bacteremia once again became detectable in 6 patients 4-45 weeks after their negative pretreatment cultures. Patients with disseminated MAC may have fluctuating levels of mycobacteremia that become undetectable in the absence of antimycobacterial therapy.

Impact of Pneumocystis carinii and cytomegalovirus on the course and outcome of atypical pneumonia in advanced human immunodeficiency virus disease.

Patients undergoing bronchoscopy for possible pneumocystis pneumonia were studied retrospectively to characterize the impact of common viral pathogens on the course of advanced human immunodeficiency virus (HIV) disease and atypical pneumonia. In 327 episodes, Pneumocystis carinii was found in 220 (67%), cytomegalovirus (CMV) in 145 (44%), and herpes simplex virus in 16 (5%). Early deterioration in oxygenation and use of intensive care was less common in CMV-positive patients. Neither CMV nor P. carinii was a predictor of mortality in multivariate analyses. CMV was not associated with an increased prevalence of later CMV disease. Isolation of CMV from the bronchoalveolar lavage fluid of these patients was not an indication for antiviral therapy. Pulmonary shedding of CMV may be associated with a decreased inflammatory response to P. carinii. The outcome of HIV-associated atypical pneumonia where no clear pulmonary pathogen is found on routine evaluation was no better than that of treated P. carinii pneumonia.

The individual microbiologic effect of three antimycobacterial agents, clofazimine, ethambutol, and rifampin, on Mycobacterium avium complex bacteremia in patients with AIDS.

The individual antibacterial activities of clofazimine, ethambutol, and rifampin in the treatment of Mycobacterium avium complex bacteremia in patients with AIDS were determined. Sixty human immunodeficiency virus 1-infected patients who had at least one blood culture positive for M. avium complex were randomized to receive either clofazimine (200 mg), ethambutol (15 mg/kg), or rifampin (600 mg) once daily for 4 weeks. Only ethambutol resulted in a statistically significant reduction in the level of mycobacteremia. The median change in individual baseline colony counts was -0.60 log10 cfu/mL after 4 weeks of ethambutol (P = .046). In contrast, median changes in individual baseline colony counts were -0.2 log10 cfu/mL and +0.2 log10 cfu/mL for clofazimine and rifampin, respectively (both, P > .4). Ethambutol had greater antibacterial activity, as determined by changes in the level of mycobacteremia, than either rifampin or clofazimine, supporting its continued use in combination with other agents in the treatment of M. avium infection.

The impact of concomitant viral pathogens on the course of Pneumocystis carinii pneumonia.

A large retrospective study was conducted to evaluate the impact of culturing cytomegalovirus from the respiratory secretions of AIDS patients with Pneumocystis carinii pneumonia. Pneumocystis carinii was found in 220 (67%) of 327 episodes and cytomegalovirus was found in 106 (48%) of the P. carinii-positive patients. Cytomegalovirus-positive and -negative patients were similar at baseline and had a similar number of hospital days, but had a lower incidence of early deterioration in oxygenation, fewer intensive-care days, were less frequently intubated, and had a higher 30-day survival. The better short-term outcome of cytomegalovirus positive patients observed in this study may relate to the immunosuppressive effects of cytomegalovirus.

A controlled trial of early adjunctive treatment with corticosteroids for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. California Collaborative Treatment Group.

BACKGROUND: Pneumocystis carinii pneumonia remains a common cause of serious morbidity and mortality in patients with the acquired immunodeficiency syndrome (AIDS). The extensive lung injury that accompanies pneumocystis-associated respiratory failure and the reports of clinical benefit from the use of adjunctive corticosteroids provided the rationale for this prospective multicenter trial. METHODS: A total of 333 patients with AIDS and pneumocystis pneumonia received standard treatment and were randomly assigned to receive either corticosteroids (beginning with the equivalent of 40 mg of prednisone twice daily) or no additional therapy. The primary end points in this unblinded trial were the occurrence of respiratory failure (hypoxemia ratio [partial pressure of arterial oxygen divided by fraction of inspired oxygen] less than 75, intubation, or death), death, and dose-limiting toxicity of the initial standard therapy. RESULTS: Of the patients with confirmed or presumed pneumocystis pneumonia (n = 225 and n = 26, respectively), those assigned to treatment with corticosteroids had a lower cumulative risk at 31 days of respiratory failure (0.14 vs. 0.30, P = 0.004) and of death (0.11 vs. 0.23, P = 0.009), as well as a lower risk of death within 84 days (0.16 vs. 0.26, P = 0.026). The frequency of dose-limiting toxicity of the standard therapy was similar in the two treatment groups. Intention-to-treat analyses of the entire cohort confirmed these findings. Clinical benefit could not be demonstrated, however, for patients with mild disease (hypoxemia ratio, greater than 350), equivalent to a partial pressure of oxygen greater than 75 torr on room air. The patients assigned to corticosteroid treatment had an excess of localized herpetic lesions (26 percent vs. 15 percent, P = 0.04) but not of other infections or of neoplasms. CONCLUSIONS: Early adjunctive treatment with corticosteroids reduces the risks of respiratory failure and death in patients with AIDS and moderate-to-severe pneumocystis pneumonia. Because the adverse effects are few, corticosteroids should be included as part of the initial treatment for persons with AIDS who have moderate-to-severe pneumocystis pneumonia.

Examiner dependence on physical diagnostic tests for the detection of splenomegaly: a prospective study with multiple observers.

OBJECTIVE: To determine the reliability and validity of various physical diagnostic techniques (including three methods of palpation and three methods of percussion) in detecting ultrasonographically identified splenomegaly. DESIGN: Prospective, double-blind study. SETTING: University hospital. PATIENTS: Twenty-seven hospitalized male patients with suspected human immunodeficiency virus (HIV) infection. INTERVENTIONS: Three methods of palpation (bimanual, ballottement, and palpation from above) and three methods of percussion (as described by Nixon, Castell, and Barkun et al.) were performed on each patient by eight examiners. Splenic ultrasonography was performed within 96 hours of admission. MEASUREMENTS AND MAIN RESULTS: The prevalence of splenomegaly by ultrasonography (defined as a spleen > or = 13 cm on the longitudinal scan) in this population was 33.3%. The sensitivity and specificity of each method of palpation and percussion varied by examiner. The ranges of sensitivity across examiners for the three methods of palpation and the three methods of percussion were 0%-64.3% and 7.7%-75%, respectively. The ranges of specificity across examiners for the three methods of palpation and the three methods of percussion were 50%-100% and 60%-100%, respectively. Likelihood ratios pooled across observers revealed that for palpation, palpation from above, and percussion, Castell's method had the highest likelihood ratios [LR = 2.66 and 1.97, respectively; 95% CI = 1.52-4.64 and 1.22-3.19, respectively]. A combination of tests (either palpation or percussion) increased the diagnostic accuracy. CONCLUSION: Physical diagnostic techniques for the detection of splenomegaly are relatively insensitive but specific. In this study there was high interobserver variability, which did not appear to be associated to the level of experience. Combining tests increases diagnostic accuracy.

The evolution of lymphadenopathy and hypergammaglobulinemia are evidence for early and sustained polyclonal B lymphocyte activation during human immunodeficiency virus infection.

To examine whether polyclonal activation of B lymphocytes as measured by hypergammaglobulinemia contributes to lymphadenopathy in human immunodeficiency virus (HIV) infection, correlates of adenopathy were examined in 240 homosexual men. Lymph node size was measured in 12 sites semiannually over 4 years. Both adenopathy and hyperglobulinemia developed within 1 year after seroconversion and persisted at high levels. Adenopathy declined near diagnosis of AIDS whereas serum IgG decreased 8-16 months after diagnosis. Adenopathy attributable to HIV occurred in all palpable node groups. By logistic regression, HIV-positive men were best discriminated from HIV-negative men by size of posterior cervical nodes and the number of sites with enlarged nodes. In a repeated measures model of covariance, adenopathy in HIV-positive men was associated with more CD4+ cells (P less than .002), elevated serum globulins (P less than .01), and lower platelet counts (P less than .05). Adenopathy declined over time (P less than .001) and with diagnosis of AIDS or AIDS-related complex (P less than .03). Thus, adenopathy and hypergammaglobulinemia are correlated and follow a similar course through various stages of HIV infection, suggesting that both are caused by polyclonal B cell activation.

A randomized evaluation of ethambutol for prevention of relapse and drug resistance during treatment of Mycobacterium avium complex bacteremia with clarithromycin-based combination therapy. California Collaborative Treatment Group.

Patients with AIDS and Mycobacterium avium complex (MAC) bacteremia are at high risk for relapse and emergence of resistant isolates during monotherapy with clarithromycin. Ninety-five AIDS patients with MAC bacteremia received clarithromycin plus clofazimine, with or without ethambutol, in a prospective, multicenter, randomized open-label trial. Of 80 patients with positive baseline cultures, sterilization or a 2 log10 reduction in colony-forming units of MAC in two consecutive blood cultures occurred in 69% of both groups. There were nine relapses in the two-drug arm and three in the three-drug arm. Kaplan-Meier estimates of risk of relapse at 36 weeks were 68% and 12%, respectively (P = .004). All relapse isolates were resistant to clarithromycin. Median time to clarithromycin resistance was 16 weeks with two drugs and 40 weeks with three drugs (P = .004). Ethambutol reduced relapses and emergence of clarithromycin resistance and should be considered an essential component of clarithromycin-based therapies for MAC bacteremia.

Treatment of Mycobacterium avium complex bacteremia in AIDS with a four-drug oral regimen. Rifampin, ethambutol, clofazimine, and ciprofloxacin. The California Collaborative Treatment Group.

OBJECTIVE: To determine the quantitative microbiologic response and the clinical response of patients with Mycobacterium avium complex bacteremia and AIDS to an oral antimycobacterial regimen. DESIGN: A phase II, multicenter clinical trial. SETTING: Four university-affiliated medical centers. PATIENTS: Forty-one patients with HIV infection who had at least two consecutive blood cultures positive for M. avium complex and who had not received previous antimycobacterial therapy were enrolled in the study. Thirty-one patients were evaluable with regard to the efficacy of the oral regimen. INTERVENTIONS: Patients received a combination of orally administered rifampin (600 mg), ethambutol (15 mg/kg body weight), clofazimine (100 mg once daily), and ciprofloxacin (750 mg twice daily) for 12 weeks. Parenterally administered amikacin, 7.5 mg/kg daily for 4 weeks after the first 4 weeks of oral therapy, was used at the discretion of the individual investigator. MEASUREMENTS: Clinical symptoms, Karnofsky scores, and adverse events were monitored. Colony counts for M. avium complex were determined. MAIN RESULTS: The mean logarithmic (log) baseline colony count decreased from 2.1 to 0.7 after 4 weeks of oral therapy (P less than 0.001). Suppression of bacteremia was sustained throughout therapy. Thirteen patients (42%) became culture negative during therapy. The mean duration of treatment was 9.7 weeks. Nineteen evaluable patients (61%) completed 12 weeks of therapy. Adverse reactions to one or more agents were common. CONCLUSIONS: A rapid reduction in symptoms and bacteremia can be achieved as early as week 2 of therapy using an oral regimen of rifampin, ethambutol, clofazimine, and ciprofloxacin. Colony counts rose dramatically after therapy was discontinued, suggesting that more prolonged periods of therapy are necessary to eradicate systemic infection.