Risk factors for fatality in HIV-infected patients with dideoxynucleoside-induced severe hyperlactataemia or lactic acidosis.

BACKGROUND: Lactic acidosis (LA) and severe hyperlactataemia (HL) are infrequent but serious complications of antiretroviral therapy that have been associated with a high fatality rate. METHODS: In a multinational retrospective cohort study, LA was defined as arterial blood pH5 mmol/l. Logistic regression was used to identify factors associated with fatality. Sensitivity and specificity of different case definitions as predictors of death were compared. RESULTS: The overall case-fatality rate was 19/110 (17.3%), but among acidotic patients it was 33% (16/49 cases). There were 10 asymptomatic patients and none of them died as a consequence of the event. The median lactate for fatal, non-fatal and all patients was 8.3 mmol/l (IQR 7.2-13.1), 6.4 mmol/l (IQR 5.4-7.8) and 6.7 mmol/l (IQR 5.5-8.1), respectively. After adjusting for age and current CD4(+) T-cell count, lactate >7 mmol/l (OR 6.27, 95% CI 1.13-34.93), blood bicarbonate 18 mmol/l, 95% CI 1.33-75.65) and concurrent opportunistic infections (OR 8.69, 95% CI 1.45-52.22) were independently associated with case fatality. Blood lactate >7 mmol/l showed a sensitivity of 84% for fatality with a specificity of 60%, whereas bicarbonate 7 mmol/l and blood bicarbonate <18 mmol/l appear to predict death and might help clinicians in selecting patients who may benefit from more intense monitoring

Exisulind and CP248 induce growth inhibition and apoptosis in human esophageal adenocarcinoma and squamous carcinoma cells

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75468/1/j.1359-4117.2003.01076.x.pd

Incorporating social determinants of health in infectious disease models: a systematic review of guidelines

Background Infectious disease (ID) models have been the backbone of policy decisions during the COVID-19 pandemic. However, models often overlook variation in disease risk, health burden, and policy impact across social groups. Nonetheless, social determinants are becoming increasingly recognized as fundamental to the success of control strategies overall and to the mitigation of disparities. Methods To underscore the importance of considering social heterogeneity in epidemiological modeling, we systematically reviewed ID modeling guidelines to identify reasons and recommendations for incorporating social determinants of health into models in relation to the conceptualization, implementation, and interpretations of models. Results After identifying 1,372 citations, we found 19 guidelines, of which 14 directly referenced at least 1 social determinant. Age (n = 11), sex and gender (n = 5), and socioeconomic status (n = 5) were the most commonly discussed social determinants. Specific recommendations were identified to consider social determinants to 1) improve the predictive accuracy of models, 2) understand heterogeneity of disease burden and policy impact, 3) contextualize decision making, 4) address inequalities, and 5) assess implementation challenges. Conclusion This study can support modelers and policy makers in taking into account social heterogeneity, to consider the distributional impact of infectious disease outbreaks across social groups as well as to tailor approaches to improve equitable access to prevention, diagnostics, and therapeutics

Neurocognitive function in HIV infected patients on antiretroviral therapy

OBJECTIVE To describe factors associated with neurocognitive (NC) function in HIV-positive patients on stable combination antiretroviral therapy. DESIGN We undertook a cross-sectional analysis assessing NC data obtained at baseline in patients entering the Protease-Inhibitor-Monotherapy-Versus-Ongoing-Triple therapy (PIVOT) trial. MAIN OUTCOME MEASURE NC testing comprised of 5 domains. Raw results were z-transformed using standard and demographically adjusted normative datasets (ND). Global z-scores (NPZ-5) were derived from averaging the 5 domains and percentage of subjects with test scores >1 standard deviation (SD) below population means in at least two domains (abnormal Frascati score) calculated. Patient characteristics associated with NC results were assessed using multivariable linear regression. RESULTS Of the 587 patients in PIVOT, 557 had full NC results and were included. 77% were male, 68% Caucasian and 28% of Black ethnicity. Mean (SD) baseline and nadir CD4+ lymphocyte counts were 553(217) and 177(117) cells/µL, respectively, and HIV RNA was <50 copies/mL in all. Median (IQR) NPZ-5 score was -0.5 (-1.2/-0) overall, and -0.3 (-0.7/0.1) and -1.4 (-2/-0.8) in subjects of Caucasian and Black ethnicity, respectively. Abnormal Frascati scores using the standard-ND were observed in 51%, 38%, and 81%, respectively, of subjects overall, Caucasian and Black ethnicity (p<0.001), but in 62% and 69% of Caucasian and Black subjects using demographically adjusted-ND (p = 0.20). In the multivariate analysis, only Black ethnicity was associated with poorer NPZ-5 scores (P<0.001). CONCLUSIONS In this large group of HIV-infected subjects with viral load suppression, ethnicity but not HIV-disease factors is closely associated with NC results. The prevalence of abnormal results is highly dependent on control datasets utilised. TRIAL REGISTRY ClinicalTrials.gov, NCT01230580

Targeting of the mitochondrion by dinuclear thiolato-bridged arene ruthenium complexes in cancer cells and in the apicomplexan parasite Neospora caninum

A library of 18 dinuclear-thiolato bridged arene ruthenium complexes, some of which with demonstrated activity against cancer cells, was screened for activity against a transgenic Neospora caninum strain that constitutively expresses beta-galactosidase. Initial assessments were done at concentrations of 2500, 250, 25 and 2.5 nM, and 5 compounds were further evaluated with regard to their half maximal proliferation-inhibiting concentration (IC50). Among those, [(η6-p-MeC6H4Pri)2Ru2(μ2-SC6H4-p-CH3)3]Cl (1), [(η6-p-MeC6H4Pri)2Ru2(μ2-SC6H4-p-But)3]Cl (2) and [(η6-p-MeC6H4Pri)2Ru2(μ2-SCH2C6H4-p-But)2(μ2-SC6H4-p-OH)]BF4 (9) inhibited N. caninum proliferation with low C50 values of 15, 5 and 1 nM, respectively, while [(η6-p-MeC6H4Pri)2Ru2(μ2-SC6H4-p-OH)3]Cl (3) and [(η6-p-MeC6H4Pri)2Ru2(μ2-SC6H4-p-mco)3]Cl (5, mco = 4-methylcoumarinyl) were less active (IC50 = 280 and 108 nM, respectively). These compounds did not affect human foreskin fibroblast (HFF) host cells at dosages of 5 μM and above, but impaired proliferation of the human ovarian carcinoma cell line A2780 (IC50 values of 130 nM (1), 30 nM (2), 530 nM (3), 7730 nM (5), 130 nM (9)). A2780 cancer cells were treated with complexes 1, 2, and 5, and biodistribution analysis using inductively coupled plasma mass spectrometry (ICP-MS) showed that most of the drugs accumulated in the mitochondrial fractions. Transmission electron microscopy showed that the parasite mitochondrion is the primary target also in N. caninum tachyzoites, but these compounds, when applied at 200 nM for 15 days in vitro, did not act parasiticidal. Complexes 1, 2 and 9 applied orally at 2 and 10 mg kg−1 day−1 during 5 days in a neosporosis mouse model did not reduce parasite load and did not limit parasite dissemination to the central nervous system. In accordance with these results, ICP-MS carried out on different organs of mice orally administrated with complexes 1 and 9, demonstrated that the drugs were readily absorbed, and after 3 and 48 h, were mainly detected in liver and kidney, but were largely absent from the brain. Thus, dinuclear thiolato-bridged arene ruthenium complexes exhibit interesting activities against N. caninum in vitro, but further modifications of these promising molecules are required to improve their bioavailability and pharmacokinetic properties in order to exert a pronounced and selective effect against N. caninum in vivo

LSST Science Book, Version 2.0

A survey that can cover the sky in optical bands over wide fields to faint magnitudes with a fast cadence will enable many of the exciting science opportunities of the next decade. The Large Synoptic Survey Telescope (LSST) will have an effective aperture of 6.7 meters and an imaging camera with field of view of 9.6 deg^2, and will be devoted to a ten-year imaging survey over 20,000 deg^2 south of +15 deg. Each pointing will be imaged 2000 times with fifteen second exposures in six broad bands from 0.35 to 1.1 microns, to a total point-source depth of r~27.5. The LSST Science Book describes the basic parameters of the LSST hardware, software, and observing plans. The book discusses educational and outreach opportunities, then goes on to describe a broad range of science that LSST will revolutionize: mapping the inner and outer Solar System, stellar populations in the Milky Way and nearby galaxies, the structure of the Milky Way disk and halo and other objects in the Local Volume, transient and variable objects both at low and high redshift, and the properties of normal and active galaxies at low and high redshift. It then turns to far-field cosmological topics, exploring properties of supernovae to z~1, strong and weak lensing, the large-scale distribution of galaxies and baryon oscillations, and how these different probes may be combined to constrain cosmological models and the physics of dark energy.Comment: 596 pages. Also available at full resolution at http://www.lsst.org/lsst/sciboo

Depressive symptoms during early adulthood and the development of physical multimorbidity in the UK: an observational cohort study

Background An understanding of whether early-life depression is associated with physical multimorbidity could be instrumental for the development of preventive measures and the integrated management of depression. We therefore aimed to map out the cumulative incidence of physical multimorbidity over adulthood, and to determine the association between the presence of depressive symptoms during early adulthood and the development of physical multimorbidity in middle age. Methods In this observational cohort study, we used pooled data from the 1958 National Child Development Study (NCDS) and the 1970 British Cohort Study (BCS). Cohort waves were pooled in each decade of adult life available (when cohort members were aged 26 years in the BCS and 23 years in the NCDS [baseline]; 34 years in the BCS and 33 years in the NCDS [age 34 BCS/33 NCDS]; 42 years in the BCS and NCDS [age 42 BCS/NCDS]; and 46 years in the BCS and 50 years in the NCDS [age 46 BCS/50 NCDS]). We included participants who had completed the nine-item Malaise Inventory at baseline, and did not have a history of physical multimorbidity, any physical multimorbidity at baseline, or the presence of depressive symptoms before the development of physical multimorbidity. The presence of depressive symptoms was determined using the nine-item Malaise Inventory (cutoff score ≥4). Physical multimorbidity was defined as having at least two measures of any of the following ten self-reported groups of long-term conditions: asthma or bronchitis; backache; bladder or kidney conditions; cancer; cardiovascular conditions; convulsions or epilepsy; diabetes; hearing conditions; migraine; and stomach, bowel, or gall conditions. Cumulative incidence (with 95% CI) of physical multimorbidity was calculated for each decade considered after baseline, with physical multimorbidity being assessed as both a dichotomous and categorical variable. The association between depressive symptoms and the development of physical multimorbidity was assessed using adjusted relative risk ratios (with 95% CIs). Findings Analyses included 15 845 participants, of whom 4001 (25·25%; 95% CI 24·57–25·93) had depressive symptoms at baseline and 11 844 (74·75%; 74·07–75·42) did not. The cumulative incidence of physical multimorbidity (dichotomous) ranged over the study period from 2263 (18·44%; 95% CI 17·75–18·14) of 12 273 participants at age 34 BCS/33 NCDS, to 4496 (42·90%; 41·95–43·85) of 10 481 participants at age 46 BCS/50 NCDS, and was consistently higher in participants with depressive symptoms at baseline. The adjusted relative risk of physical multimorbidity was higher in participants with depressive symptoms than in those without and remained stable over the study period (adjusted relative rate ratio 1·67, 95% CI 1·50–1·87, at age 34 BCS/33 NCDS; 1·63, 1·48–1·79, at age 42 BCS/NCDS; and 1·58, 1·43–1·73, at age 46 BCS/50 NCDS). Interpretation The presence of depressive symptoms during early adulthood is associated with an increased risk of the development of physical multimorbidity in middle age. Although further research about the drivers of this relationship is needed, these results could help to enhance the integrated management of individuals with depressive symptoms and the development of preventive strategies to reduce the effect and burden of physical multimorbidity