This is a cross-sectional, observational study to determine the frequency and associated features of HIV-associated neurocognitive disorders (HAND) in a large, diverse sample of infected individuals ...in the era of combination antiretroviral therapy (CART).
A total of 1,555 HIV-infected adults were recruited from 6 university clinics across the United States, with minimal exclusions. We used standardized neuromedical, psychiatric, and neuropsychological (NP) examinations, and recently published criteria for diagnosing HAND and classifying 3 levels of comorbidity (minimal to severe non-HIV risks for NP impairment).
Fifty-two percent of the total sample had NP impairment, with higher rates in groups with greater comorbidity burden (40%, 59%, and 83%). Prevalence estimates for specific HAND diagnoses (excluding severely confounded cases) were 33% for asymptomatic neurocognitive impairment, 12% for mild neurocognitive disorder, and only 2% for HIV-associated dementia (HAD). Among participants with minimal comorbidities (n = 843), history of low nadir CD4 was a strong predictor of impairment, and the lowest impairment rate on CART occurred in the subset with suppressed plasma viral loads and nadir CD4 ≥200 cells/mm(3) (30% vs 47% in remaining subgroups).
The most severe HAND diagnosis (HAD) was rare, but milder forms of impairment remained common, even among those receiving CART who had minimal comorbidities. Future studies should clarify whether early disease events (e.g., profound CD4 decline) may trigger chronic CNS changes, and whether early CART prevents or reverses these changes.
Across West Bengal and Bangladesh, concentrations of Cl in much groundwater exceed the natural, upper limit of 10mg/L. The Cl/Br mass ratios in groundwaters range up to 2500 and scatter along mixing ...lines between waste-water and dilute groundwater, with many falling near the mean end-member value for waste-water of 1561 at 126mg/L Cl. Values of Cl/Br exceed the seawater ratio of 288 in uncommon NO3-bearing groundwaters, and in those containing measurable amounts of salt-corrected SO4 (SO4 corrected for marine salt). The data show that shallow groundwater tapped by tube-wells in the Bengal Basin has been widely contaminated by waste-water derived from pit latrines, septic tanks, and other methods of sanitary disposal, although reducing conditions in the aquifers have removed most evidence of NO3 additions from these sources, and much evidence of their additions of SO4. In groundwaters from wells in palaeo-channel settings, end-member modelling shows that >25% of wells yield water that comprises ≥10% of waste-water. In palaeo-interfluvial settings, only wells at the margins of the palaeo-interfluvial sequence contain detectable waste water. Settings are identifiable by well-colour survey, owner information, water composition, and drilling.
Values of Cl/Br and faecal coliform counts are both inversely related to concentrations of pollutant As in groundwater, suggesting that waste-water contributions to groundwater in the near-field of septic-tanks and pit-latrines (within 30m) suppress the mechanism of As-pollution and lessen the prevalence and severity of As pollution. In the far-field of such sources, organic matter in waste-water may increase groundwater pollution by As.
► Groundwater in the Bengal Basin is widely polluted by domestic waste-water. ► The impact on groundwater can be quantified using Cl/Br mass ratios. ► Both NO3 and SO4 in groundwater are sourced from waste-water. ► Pollution of groundwater by arsenic is decreased adjacent to sources of waste-water. ► Distally from its source, waste-water may exacerbate As-pollution of groundwater.
in groundwaters from 145 wells across central West Bengal, India, those from Pleistocene aquifers at depths >70 m beneath paleo-interfluves contain <10 μg/L As. Pleistocene aquifers beneath deep ...paleo-channels typically host groundwaters containing 10–100 μg/L As at depths between 120 and 180 m. The depth profiles of As and SO4 and the conservative tracers Cl/Br, δ18O, and δ2H show that the As in Pleistocene groundwater beneath deep paleo-channels is relict and does not arise from migration downward of As-polluted groundwater in overlying aquifers. We postulate that the As was liberated in situ by reduction of minimal iron oxyhydroxides in the gray Pleistocene sands by organic matter infiltrating from riverbeds during late Pleistocene or earliest Holocene times. Mitigation of the widespread As-pollution in shallow aquifers through exploitation of deep Pleistocene aquifers would improve if guided by an understanding of the distribution of buried paleo-channels and paleo-interfluves and the knowledge that As may be present naturally in groundwater at depths >150 m beneath deep paleo-channels.
Acquired resistance to PARP inhibitors (PARPi) is a major challenge for the clinical management of high grade serous ovarian cancer (HGSOC). Here, we demonstrate CX-5461, the first-in-class inhibitor ...of RNA polymerase I transcription of ribosomal RNA genes (rDNA), induces replication stress and activates the DNA damage response. CX-5461 co-operates with PARPi in exacerbating replication stress and enhances therapeutic efficacy against homologous recombination (HR) DNA repair-deficient HGSOC-patient-derived xenograft (PDX) in vivo. We demonstrate CX-5461 has a different sensitivity spectrum to PARPi involving MRE11-dependent degradation of replication forks. Importantly, CX-5461 exhibits in vivo single agent efficacy in a HGSOC-PDX with reduced sensitivity to PARPi by overcoming replication fork protection. Further, we identify CX-5461-sensitivity gene expression signatures in primary and relapsed HGSOC. We propose CX-5461 is a promising therapy in combination with PARPi in HR-deficient HGSOC and also as a single agent for the treatment of relapsed disease.
Kolkata, the capital city of West Bengal, exploits groundwater for public water-supply. The groundwater has been reported to be widely polluted by arsenic (As). Analysis for As in 280 groundwaters ...from across Kolkata, failed to detect As concentrations >10 μg/L from natural processes. Arsenic concentrations between 10 and 79 μg/L found in 14 of the 280 groundwaters are remnant from a pollution-plume emanating from a single factory site where Paris Green, an arsenical pesticide, was manufactured between 1965 and 1985. In 45% of groundwaters sampled, concentrations of Mn exceed 0.4 mg/L, a putative health guideline value for drinking water. Sporadic minor hazards are posed by Pb > 10 μg/L introduced into groundwater from well-fittings, from 4% of groundwaters with F concentrations between 0.75 and 1 mg/L, and the 14% of groundwaters containing more than 500 mg/L Na, concentrations that might contribute to excessive daily intake of Na. Compounding hazards from As, F, Mn, Na, and Pb, shows that 64% of public wells and 40% of municipal wells supply groundwater of suspect quality. Groundwaters comply with WHO Guideline Values for drinking water in terms of Cr, Cu, Co, NO2, NO3, Sb, Se, and U. Aesthetic guideline values for Fe, Mn, SO4, and Cl are exceeded for many groundwaters.
A prospective study explored the heterogeneous nature of metastatic melanoma using Multiplex immunohistochemistry (IHC) and flow cytometry (FACS). Multiplex IHC data quantitated immune subset number ...present intra-tumoral (IT) vs the tumor stroma, plus distance of immune subsets from the tumor margin (TM). In addition, mIHC showed a close association between the presence of IT CD8
T cells and PDL1 expression in melanoma, which was more prevalent on macrophages than on melanoma cells. In contrast, FACS provided more detailed information regarding the T cell subset differentiation, their activation status and expression of immune checkpoint molecules. Interestingly, mIHC detected significantly higher Treg numbers than FACS and showed preferential CD4
T cell distribution in the tumor stroma. Based on the mIHC and FACS data, we provide a model which defines metastatic melanoma immune context into four categories using the presence or absence of PDL1
melanoma cells and/or macrophages, and their location within the tumor or on the periphery, combined with the presence or absence of IT CD8
T cells. This model interprets melanoma immune context as a spectrum of tumor escape from immune control, and provides a snapshot upon which interpretation of checkpoint blockade inhibitor (CBI) therapy responses can be built.
We report the detection of pulsed gamma rays from the Crab pulsar at energies above 100 giga—electron volts (GeV) with the Very Energetic Radiation Imaging Telescope Array System (VERITAS) array of ...atmospheric Cherenkov telescopes. The detection cannot be explained on the basis of current pulsar models. The photon spectrum of pulsed emission between 100 mega—electron volts and 400 GeV is described by a broken power law that is statistically preferred over a power law with an exponential cutoff. It is unlikely that the observation can be explained by invoking curvature radiation as the origin of the observed gamma rays above 100 GeV. Our findings require that these gamma rays be produced more than 10 stellar radii from the neutron star.
In order to investigate the mechanism of As release to anoxic ground water in alluvial aquifers, the authors sampled ground waters from 3 piezometer nests, 79 shallow (<45 m) wells, and 6 deep (>80 ...m) wells, in an area 750 m by 450 m, just north of Barasat, near Kolkata (Calcutta), in southern West Bengal. High concentrations of As (200–1180 μg
L
−1) are accompanied by high concentrations of Fe (3–13.7 mg
L
−1) and PO
4 (1–6.5 mg
L
−1). Ground water that is rich in Mn (1–5.3 mg
L
−1) contains <50 μg
L
−1 of As. The composition of shallow ground water varies at the 100-m scale laterally and the metre-scale vertically, with vertical gradients in As concentration reaching 200 μg
L
−1
m
−1. The As is supplied by reductive dissolution of FeOOH and release of the sorbed As to solution. The process is driven by natural organic matter in peaty strata both within the aquifer sands and in the overlying confining unit. In well waters, thermo-tolerant coliforms, a proxy for faecal contamination, are not present in high numbers (<10 cfu/100 ml in 85% of wells) showing that faecally-derived organic matter does not enter the aquifer, does not drive reduction of FeOOH, and so does not release As to ground water.
Arsenic concentrations are high (≫50 μg
L
−1) where reduction of FeOOH is complete and its entire load of sorbed As is released to solution, at which point the aquifer sediments become grey in colour as FeOOH vanishes. Where reduction is incomplete, the sediments are brown in colour and resorption of As to residual FeOOH keeps As concentrations below 10 μg
L
−1 in the presence of dissolved Fe. Sorbed As released by reduction of Mn oxides does not increase As in ground water because the As resorbs to FeOOH. High concentrations of As are common in alluvial aquifers of the Bengal Basin arise because Himalayan erosion supplies immature sediments, with low surface-loadings of FeOOH on mineral grains, to a depositional environment that is rich in organic mater so that complete reduction of FeOOH is common.
The Early Toarcian, organic-rich, black shales of the Cleveland Basin, Yorkshire UK, are the type sediments for the supposed early Toarcian oceanic anoxic event. The sediments have values of Cd/Mo ...that are <0.1 and values of Co (mg/kg) × Mn (%) that are >0.4. These values are typical of sediment deposited in modern basins that are hydrographically restricted and show that the Cleveland Basin was hydrographically restricted when depositing organic-rich sediments. These palaeo-proxies confirm earlier interpretations, based on Mo/TOC values, that argued for hydrographic restriction. The term Toarcian oceanic anoxic event can now be discarded.
In 49 samples of groundwater, sampled in Muzaffargarh District of south-western Punjab, central Pakistan, concentrations of As exceeded the World Health Organisation provisional guideline value, and ...United States Environmental Protection Agency (USEPA) Maximum Contaminant Level (MCL), of 10 μg
L
−1 in 58% of samples and reached up to 906 μg
L
−1. In this semi-arid region canal irrigation has lead to widespread water-logging, and evaporative concentration of salts has the potential to raise As concentrations in shallow groundwater well above 10 μg
L
−1. In fact, in rural areas, concentrations stay below 25 μg
L
−1 because As in the oxic shallow groundwater, and in recharging water, is sorbed to aquifer sediments. In some urban areas, however, shallow groundwater is found to contain elevated levels of As. The spatial distribution of As-rich shallow groundwater indicates either direct contamination with industrial or agricultural chemicals, or some other anthropogenic influence. Geochemical evidence suggests that pollutant organics from unconfined sewage and other sources drives reduction of hydrous ferric oxide (HFO) releasing sorbed As to shallow groundwater. The situation is slightly less clear for seven wells sampled which tap deeper groundwater, all of which were found with >50 μg
L
−1 As. Here As concentrations seem to increase with depth and differing geochemical signatures are seen, suggesting that As concentrations in older groundwater may be governed by different processes. Other data on parameters of potential concern in drinking water are discussed briefly at the end of the paper.
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