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Background A recent real-world study observed that 24% of patients with advanced non–small cell lung cancer (aNSCLC) with actionable driver oncogenes (ADOs) initiated nontargeted therapies before biomarker test results became available. This study assessed the clinical impact of the timing of first-line (1L) targeted therapies (TTs) in aNSCLC. Materials and Methods This retrospective analysis of a nationwide electronic health record–derived deidentified database included patients aged ≥18 years diagnosed with aNSCLC with ADOs (ALK, BRAF, EGFR, RET, MET, ROS-1, and NTRK) from January 1, 2015, to October 18, 2022, by biomarker testing within 90 days after advanced diagnosis and received 1L treatment. Cohorts were defined by treatment patterns ≤42 days after test results: "Upfront TT" received 1L TT ≤42 days; "Switchers" initiated 1L non-TT before or after testing but switched to TT ≤42 days; and "Non-switchers" initiated non-TT before or after testing and did not switch at any time. Adjusted multivariate Cox regression evaluated real-world progression-free survival, real-world time to next treatment or death, and real-world overall survival. Results A total of 3540 patients met the study criteria; 78% were treated in a community setting, and 50% underwent next-generation sequencing (NGS). There was no significant difference in outcomes between Switchers and Upfront TT; inferior outcomes were observed in Non-switchers versus Upfront TT. Conclusion Our findings demonstrated improved outcomes with upfront 1L TT versus non-TT in patients with aNSCLC with ADOs and observed timely switching to TT after biomarker test result had similar outcomes to Upfront TT. Opportunities remain to improve the use of NGS for early ADO identification and determination of 1L TT. [ABSTRACT FROM AUTHOR]

Human immunodeficiency virus (HIV) infection is associated with increased systemic microbial translocation, neuroinflammation, and occasionally, neuronal injury. Whether systemic lipopolysaccharide (LPS) penetrates into the brain and contributes to neuroinflammation remain unknown in HIV. Here, we measured plasma and cerebrospinal fluid (CSF) LPS levels along with biomarkers of neuroinflammation (white blood cell counts and 40 soluble markers) and neurofilament light chain (NfL). Notably, CSF LPS was undetectable in all samples, including 3 HIV-infected individuals with dementia. Increased plasma LPS, neuroinflammation, and blood-brain barrier (BBB) dysfunction were found in untreated HIV-infected individuals, but not in healthy or treated HIV-infected individuals. Plasma LPS levels were directly correlated with various markers of inflammation in both plasma and CSF, as well as with degree of BBB permeability but not with CSF NfL in HIV-infected subjects. These results suggest that the magnitude of microbial translocation associates with neuroinflammation and BBB permeability in HIV without direct penetration into the central nervous system. [ABSTRACT FROM AUTHOR]

Background Interactions between the endothelium and infected erythrocytes play a major role in the pathogenesis of falciparum malaria, with microvascular dysfunction and parasite sequestration associated with worsening outcomes. The glycocalyx is a carbohydrate-rich layer that lines the endothelium, with multiple roles in vascular homeostasis. The role of the glycocalyx in falciparum malaria and the association with disease severity has not been investigated. Methods We prospectively enrolled Indonesian inpatients (aged ≥18 years) with severe (SM) or moderately severe (MSM) falciparum malaria, as defined by World Health Organization criteria, and healthy controls (HCs). On enrollment, blood and urine samples were collected concurrently with measurements of vascular nitric oxide (NO) bioavailability. Urine was assayed for glycocalyx breakdown products (glycosaminoglycans) using a dimethylmethylene blue (GAG-DMMB) and liquid chromatography-tandem mass spectrometry (GAG-MS) assay. Results A total of 129 patients (SM = 43, MSM = 57, HC=29) were recruited. GAG-DMMB and GAG-MS (g/mol creatinine) were increased in SM (mean, 95% confidence interval: 3.98, 2.44–5.53 and 6.82, 5.19–8.44) compared to MSM patients (1.78, 1.27–2.29 and 4.87, 4.27–5.46) and HCs (0.22, 0.06–0.37 and 1.24, 0.89–1.59; P < 0.001). In SM patients, GAG-DMMB and GAG-MS were increased in those with a fatal outcome (n = 3; median, interquartile range: 6.72, 3.80–27.87 and 12.15, 7.88–17.20) compared to survivors (n = 39; 3.10, 0.46–4.5 and 4.64, 2.02–15.20; P = 0.03). Glycocalyx degradation was significantly associated with parasite biomass in both MSM (r = 0.48, GAG-DMMB and r = 0.43, GAG-MS; P < 0.001) and SM patients (r = 0.47, P = 0.002 and r = 0.33, P = 0.04) and inversely associated with endothelial NO bioavailability. Conclusions Increased endothelial glycocalyx breakdown is associated with severe disease and a fatal outcome in adults with falciparum malaria. [ABSTRACT FROM AUTHOR]

Background Human immunodeficiency virus type 1 (HIV-1) populations are detected in cerebrospinal fluid (CSF) of some people on suppressive antiretroviral therapy (ART). Detailed analysis of these populations may reveal whether they are produced by central nervous system (CNS) reservoirs. Methods We performed a study of 101 asymptomatic participants on stable ART. HIV-1 RNA concentrations were cross-sectionally measured in CSF and plasma. In participants with CSF HIV-1 RNA concentrations sufficient for analysis, viral populations were genetically and phenotypically characterized over multiple time points. Results For 6% of participants (6 of 101), the concentration of HIV-1 RNA in their CSF was ≥0.5 log copies/mL above that of plasma (ie, CSF escape). We generated viral envelope sequences from CSF of 3 participants. One had a persistent CSF escape population that was macrophage-tropic, partially drug resistant, genetically diverse, and closely related to a minor macrophage-tropic lineage present in the blood prior to viral suppression and enriched for after ART. Two participants (1 suppressed and 1 not) had transient CSF escape populations that were R5 T cell-tropic with little genetic diversity. Conclusions Extensive analysis of viral populations in 1 participant revealed that CSF escape was from a persistently replicating population, likely in macrophages/microglia, present in the CNS over 3 years of ART. CSF escape in 2 other participants was likely produced by trafficking and transient expansion of infected T cells in the CNS. Our results show that CNS reservoirs can persist during ART and that CSF escape is not exclusively produced by replicating CNS reservoirs. [ABSTRACT FROM AUTHOR]

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Background AIDS Clinical Trial Group 5199 compared neurological and neuropsychological test performance of human immunodeficiency virus type 1 (HIV-1)–infected participants in resource-limited settings treated with 3 World Health Organization–recommended antiretroviral (ART) regimens. We investigated the impact of tuberculosis (TB) on neurological and neuropsychological outcomes. Methods Standardized neurological and neuropsychological examinations were administered every 24 weeks. Generalized estimating equation models assessed the association between TB and neurological/neuropsychological performance. Results Characteristics of the 860 participants at baseline were as follows: 53% female, 49% African; median age, 34 years; CD4 count, 173 cells/μL; and plasma HIV-1 RNA, 5.0 log copies/mL. At baseline, there were 36 cases of pulmonary, 9 cases of extrapulmonary, and 1 case of central nervous system (CNS) TB. Over the 192 weeks of follow-up, there were 55 observations of pulmonary TB in 52 persons, 26 observations of extrapulmonary TB in 25 persons, and 3 observations of CNS TB in 2 persons. Prevalence of TB decreased with ART initiation and follow-up. Those with TB coinfection had significantly poorer performance on grooved pegboard (P <.001) and fingertapping nondominant hand (P <.01). TB was associated with diffuse CNS disease (P <.05). Furthermore, those with TB had 9.27 times (P <.001) higher odds of reporting decreased quality of life, and had 8.02 times (P =.0005) higher odds of loss of productivity. Conclusions TB coinfection was associated with poorer neuropsychological functioning, particularly the fine motor skills, and had a substantial impact on functional ability and quality of life. Clinical Trials Registration NCT00096824. [ABSTRACT FROM AUTHOR]

Peripheral arterial disease (PAD) is the leading cause of lower limb amputation and estimated to affect over 202 million people worldwide. PAD is caused by atherosclerotic lesions that occlude large arteries in the lower limbs, leading to insufficient blood perfusion of distal tissues. Given the severity of this clinical problem, there has been long-standing interest in both understanding how chronic arterial occlusions affect muscle tissue and vasculature and identifying therapeutic approaches capable of restoring tissue composition and vascular function to a healthy state. To date, the most widely utilized animal model for performing such studies has been the ischaemic mouse hindlimb. Despite not being a model of PAD per se, the ischaemic hindlimb model does recapitulate several key aspects of PAD. Further, it has served as a valuable platform upon which we have built much of our understanding of how chronic arterial occlusions affect muscle tissue composition, muscle regeneration and angiogenesis, and collateral arteriogenesis. Recently, there has been a global surge in research aimed at understanding how gene expression is regulated by epigenetic factors (i.e. non-coding RNAs, histone post-translational modifications, and DNA methylation). Thus, perhaps not unexpectedly, many recent studies have identified essential roles for epigenetic factors in regulating key responses to chronic arterial occlusion(s). In this review, we summarize the mechanisms of action of these epigenetic regulators and highlight several recent studies investigating the role of said regulators in the context of hindlimb ischaemia. In addition, we focus on how these recent advances in our understanding of the role of epigenetics in regulating responses to chronic arterial occlusion(s) can inform future therapeutic applications to promote revascularization and perfusion recovery in the setting of PAD. [ABSTRACT FROM AUTHOR]

The Alcurra Dolerite in the Musgrave Province, central Australia, is part of the c. 1075 Ma Warakurna large igneous province (LIP), which is interpreted to have been emplaced contemporaneously with intracontinental rifting. The Alcurra Dolerite in the eastern Musgrave Province comprises two types of continental tholeiite. Dominant Group 1 dolerites are mainly magnesian tholeiites, whereas subordinate Group 2 dolerites are normal tholeiites. These two groups have distinct chondrite-normalized rare earth element (REE) patterns, primordial mantle-normalized trace element patterns, and incompatible element ratios (e.g. Th/Yb, Nb/Yb, La/Yb and Zr/Y). Both groups are low-Ti and low-Zr, but Group 1 dolerites have higher Ti/Zr (>60) and Ti/Y (>310) values than those of Group 2. Group 1 mainly comprises olivine-microgabbros, and is volumetrically dominant, whereas Group 2 is proportionally minor and includes noritic-microgabbros. Dolerites from both groups plot in discrete fields in 143Nd/144Nd versus 147Sm/144Nd space, along a mixing trend between chondritic or depleted mantle and the c. 1·59 Ga Musgravian basement. Group 1 dolerites have low Rb, Th and K2O contents that preclude their contamination by Musgravian continental crust. They also have incompatible element ratios that overlap with mid-ocean ridge basalt or primitive mantle. Group 2 dolerites have more negative ɛNd values and are also the more incompatible element enriched group; they may have, to some extent, been directly contaminated by Musgravian basement. Low concentrations of light REE (LREE) in Group 1 dolerites indicate a moderate to high percentage of partial melting of a relatively depleted source. Mixing this partial melt with a small proportion of melt derived by a moderate percentage of partial melting of a more incompatible element enriched mantle source could have resulted in the low (La/Sm)N ratios and low absolute La contents seen in these dolerites. Group 1 is divided into two subgroups (1A and 1B) on the basis of LREE abundances and Nb/Yb ratios. These two subgroups may reflect different percentages of partial melting of the depleted source. Petrogenetic interpretations for the Alcurra Dolerite of the eastern Musgrave Province must address published geophysical evidence for asthenospheric mantle upwelling and underplating in the Musgrave Province, and for contemporaneous low- and high-Ti Alcurra Dolerites indicative of a plume to the west where they are associated with Giles Suite layered intrusions. The large proportion of probable asthenosphere-derived melt in the petrogenesis of the Group 1 dolerites from the eastern Musgrave Province indicates either substantial heat transfer, or significant decompression in the mantle. The Warakurna LIP could result from a complex interaction between a plume and mantle upwelling. [ABSTRACT FROM AUTHOR]

Background Human immunodeficiency virus (HIV) penetrates the brain in early infection. We used neuroimaging to longitudinally examine the impact of HIV and combination antiretroviral therapy (cART) on the brain in treated and untreated HIV-infected participants, starting in primary HIV infection (PHI). Methods Sixty-five participants, enrolled during PHI, underwent longitudinal magnetic resonance imaging, 30 of whom commenced cART during follow-up. Cross-sectional data from 16 patients with chronic HIV infection (CHI) and 19 HIV-uninfected participants were included for comparison. Brain volume and cortical thickness were estimated using tensor-based morphometry and cortical modeling, respectively. Mixed-effects models longitudinally mapped structural brain changes before and after cART. The relationship between brain morphometry estimates and blood and cerebrospinal fluid (CSF) biomarkers were also tested. Region-of-interest analyses were performed to compare brain morphometry estimates between the groups. Results Prior to cART, longer duration of untreated infection in PHI correlated with volume loss in the thalamus, caudate, and cerebellum, and with cortical thinning in the frontal and temporal lobes and cingulate cortex. After cART, no further volume loss was observed. However, small increases of cortical thickness in the frontal and temporal lobe correlated with longer cART duration. No correlations were observed with blood or CSF measures. The PHI group did not have different brain morphometric measures compared to the HIV-uninfected group, but had larger volumes in the thalamus, caudate, putamen, and cortical gray matter compared with CHI participants. Conclusions Subcortical atrophy and cortical thinning occur during untreated infection but may be arrested by cART. These findings emphasize the importance of early cART. [ABSTRACT FROM AUTHOR]

Background. Despite effective antiretroviral therapy (ART), human immunodeficiency virus (HIV) likely persists in the central nervous system (CNS) in treated individuals. We examined anti-HIV antibodies in cerebrospinal fluid (CSF) and blood as markers of persistence. Methods. Human immunodeficiency virus antibodies were measured in paired CSF and serum before and after long-term treatment of chronic (n = 10) and early infection (n = 12), along with untreated early infection (n = 10). Results. Treatment of chronic infection resulted in small reductions of anti-HIV antibodies in CSF and serum despite >10 years of suppressive ART. In untreated early infection, anti-HIV antibodies emerged in blood by day 30, whereas CSF antibodies reached similar levels 2 weeks later. Compared with long-term treatment of chronic infection, early ART initiation reduced CSF antibodies by 43-fold (P > .0001) and blood antibodies by 7-fold (P = .0003). Two individuals receiving pre-exposure prophylaxis and then ART early after infection failed to develop antibodies in CSF or blood, whereas CSF antibodies were markedly reduced in the Berlin patient. Conclusions. To the extent that differential CSF and blood antibodies indicate HIV persistence, these data suggest a relative delay in establishment of the CNS compared with the systemic HIV reservoir that provides an opportunity for early treatment to have a greater impact on the magnitude of long-term CNS infection. [ABSTRACT FROM AUTHOR]

Synthesis centers offer a unique amalgam of culture, infrastructure, leadership, and support that facilitates creative discovery on issues crucial to science and society. The combination of logistical support, postdoctoral or senior fellowships, complex data management, informatics and computing capability or expertise, and most of all, opportunity for group discussion and reflection lowers the "activation energy" necessary to promote creativity and the cross-fertilization of ideas. Synthesis centers are explicitly created and operated as community-oriented infrastructure, with scholarly directions driven by the ever-changing interests and needs of an open and inclusive scientific community. The last decade has seen a rise in the number of synthesis centers globally but also the end of core federal funding for several, challenging the sustainability of the infrastructure for this key research strategy. Here, we present the history and rationale for supporting synthesis centers, integrate insights arising from two decades of experience, and explore the challenges and opportunities for long-term sustainability. [ABSTRACT FROM AUTHOR]

Background: We explored the establishment of abnormal blood-brain barrier (BBB) permeability and its relationship to neuropathogenesis during primary human immunodeficiency virus (HIV) infection by evaluating the cerebrospinal fluid (CSF) to serum albumin quotient (QAlb) in patients with primary HIV infection. We also analyzed effects of initiating combination antiretroviral therapy (cART).Methods: The QAlb was measured in longitudinal observational studies of primary HIV infection. We analyzed trajectories of the QAlb before and after cART initiation, using mixed-effects models, and associations between the QAlb and the CSF level of neurofilament light chain (NFL), the ratio of N-acetylaspartate to creatinine levels (a magnetic resonance spectroscopy neuronal integrity biomarker), and neuropsychological performance.Results: The baseline age-adjusted QAlb was elevated in 106 patients with primary HIV infection (median time of measurement, 91 days after infection), compared with that in 64 controls (P = .02). Before cART initiation, the QAlb increased over time in 84 participants with a normal baseline QAlb (P = .006) and decreased in 22 with a high baseline QAlb (P = .011). The QAlb did not change after a median cART duration of 398 days, initiated at a median interval of 225 days after infection (P = .174). The QAlb correlated with the NFL level at baseline (r = 0.497 and P < .001) and longitudinally (r = 0.555 and P < .001) and with the ratio of N-acetylaspartate to creatinine levels in parietal gray matter (r = -0.352 and P < .001 at baseline and r = -0.387 and P = .008 longitudinally) but not with neuropsychological performance.Conclusion: The QAlb rises during primary HIV infection, associates with neuronal injury, and does not significantly improve over a year of treatment. BBB-associated neuropathogenesis in HIV-infected patients may initiate during primary infection. [ABSTRACT FROM AUTHOR]

The lithospheric mantle beneath West Antarctica has been characterized using petrology, whole-rock and mineral major element geochemistry, whole-rock trace element chemistry and Mössbauer spectroscopy data obtained on a suite of peridotite (lherzolite and harzburgite) and pyroxenite xenoliths from the Mount Morning eruptive centre, Southern Victoria Land. The timing of pyroxenite formation in Victoria Land overlaps with subduction of the Palaeo-Pacific plate beneath the Gondwana margin and pyroxenite is likely to have formed when fluids derived from, or modified by, melting of the subducting, eclogitic, oceanic crustal plate percolated through peridotite of the lithospheric mantle. Subsequent melting of lithospheric pyroxenite veins similar to those represented in the Mount Morning xenolith suite has contributed to the enriched trace element (and isotope) signatures seen in Cenozoic volcanic rocks from Mount Morning, elsewhere in Victoria Land and Zealandia. In general, the harzburgite xenoliths reflect between 20 and 30% melt depletion. Their depleted element budgets are consistent with Archaean cratonization ages and they have mantle-normalized trace element patterns comparable with typical subcontinental lithospheric mantle. The spinel lherzolite mineral data suggest a similar amount of depletion to that recorded in the harzburgites (20–30%), whereas plagioclase lherzolite mineral data suggest <15% melt depletion. The lherzolite (spinel and plagioclase) xenolith whole-rocks have compositions indicating <20% melt depletion, consistent with Proterozoic to Phanerozoic cratonization ages, and have mantle-normalized trace element patterns comparable with typical depleted mid-ocean ridge mantle. All peridotite xenoliths have undergone a number of melt–rock reaction events. Melting took place mainly in the spinel peridotite stability field, but one plagioclase peridotite group containing high-sodium clinopyroxenes is best modelled by melting in the garnet field. Median oxygen fugacity estimates based on Mössbauer spectroscopy measurements of spinel and pyroxene for spinel-facies conditions in the rifted Antarctic lithosphere are –0·6 Δlog fO2 at Mount Morning and –1·0 ± 0·1 (1σ) Δlog fO2 for all of Victoria Land, relative to the fayalite–magnetite–quartz buffer. These values are in good agreement with a calculated global median value of –0·9 ± 0·1 (1σ) Δlog fO2 for mantle spinel-facies rocks from continental rift systems. [ABSTRACT FROM AUTHOR]

Greek Yoghurt manufacturer's injunction is upheld by UK Supreme Court, preventing a US competitor from selling in the UK &#8220;Greek Yoghurt&#8221; made in the USA. UK national law can protect the public when registration of a geographical designation is not possible. [ABSTRACT FROM PUBLISHER]

We sequenced the genome of human immunodeficiency virus type 1 (HIV-1) recovered from 70 cerebrospinal fluid (CSF) specimens and 29 plasma samples and corresponding samples obtained before treatment initiation from 17 subjects receiving suppressive therapy. More CSF sequences than plasma sequences were hypermutants. We determined CSF sequences and plasma sequences in specimens obtained from 2 subjects after treatment initiation. In one subject, we found genetically distinct CSF and plasma sequences, indicating that they came from HIV-1 from 2 different compartments, one potentially the central nervous system, during suppressive therapy. In addition, there was little evidence of viral evolution in the CSF during therapy, suggesting that continuous virus replication is not the major cause of viral persistence in the central nervous system. [ABSTRACT FROM PUBLISHER]

Ulleung Island is the top of a 3000 m (from sea floor) intraplate alkalic volcanic edifice in the East Sea/Sea of Japan. The emergent 950 m consist of a basaltic lava and agglomerate succession (Stage 1, 1·37–0·97 Ma), intruded and overlain by a sequence of trachytic lavas and domes, which erupted in two episodes (Stage 2, 0·83–0·77 Ma; Stage 3, 0·73–0·24 Ma). The youngest eruptions, post 20 ka bp, were explosive, generating thick tephra sequences of phonolitic composition (Stage 4), which also entrained phaneritic, porphyritic and cumulate accidental lithics. Major element chemistry of the evolved products shows a continuous spectrum of trachyte to phonolite compositions, but these have discordant trace element trends and distinct isotopic characteristics, excluding a direct genetic relationship between the two end-members. Despite this, the Stage 3 trachytes and some porphyritic accidental lithics have chemical characteristics transitional between Stage 2 trachytes and Stage 4 phonolites. Within the phonolitic Stage 4 tephras three subgroups can be distinguished. The oldest, Tephra 5, is considerably enriched in incompatible elements and chondrite-normalized rare earth element (REE) patterns display negative Eu anomalies. The later tephras, Tephras 4–2, have compositions intermediate between the early units and the trachyte samples, and their REE patterns do not have significant Eu anomalies. The last erupted, Tephra 1, from a small intra-caldera structure, has a distinct tephriphonolite composition. Trace element and isotopic chemistry as well as textural characteristics suggest a genetic relationship between the phaneritic lithics and their host phonolitic pumices. The Stage 4 tephras are not related to earlier phases of basaltic to trachytic magmatism (Stages 1–3). They have distinct isotopic compositions and cannot be reliably modelled by fractional crystallization processes. The differences between the explosive phonolitic (Stage 4) and effusive trachytic (Stage 2–3) eruptions are mainly due to different pre-eruptive pressures and temperatures, causing closed- versus open-system degassing. Based on thermodynamic and thermobarometric modelling, the phonolites were derived from deeper (subcrustal) magma storage and rose quickly, with volatiles trapped until eruption. By contrast, the trachytes were stored at shallower crustal levels for longer periods, allowing open-system volatile exsolution and degassing before eruption. [ABSTRACT FROM PUBLISHER]

Background. Cerebrospinal fluid (CSF) and neuroimaging abnormalities demonstrate neuronal injury during chronic AIDS, but data on these biomarkers during primary human immunodeficiency virus (HIV) infection is limited.Methods. We compared CSF concentrations of neurofilament light chain, t-tau, p-tau, amyloid precursor proteins, and amyloid-beta 42 in 92 subjects with primary HIV infection and 25 controls. We examined relationships with disease progression and neuroinflammation, neuropsychological testing, and proton-magnetic resonance spectroscopy (MRS)–based metabolites.Results. Neurofilament light chain was elevated in primary HIV infection compared with controls (P = .0004) and correlated with CSF neopterin (r = 0.38; P = .0005), interferon gamma-induced protein 10 (r = 0.39; P = .002), white blood cells (r = 0.32; P = .004), protein (r = 0.59; P < .0001), and CSF/plasma albumin ratio (r = 0.60; P < .0001). Neurofilament light chain correlated with decreased N-acteylaspartate/creatine and glutamate/creatine in the anterior cingulate (r = −0.35, P = .02; r = −0.40, P = .009, respectively), frontal white matter (r = −0.43, P = .003; r = −0.30, P = .048, respectively), and parietal gray matter (r = −0.43, P = .003; r = −0.47, P = .001, respectively). Beta-amyloid was elevated in the primary infection group (P = .0005) and correlated with time infected (r = 0.34; P = .003). Neither marker correlated with neuropsychological abnormalities. T-tau and soluble amyloid precursor proteins did not differ between groups.Conclusions. Elevated neurofilament light chain and its correlation with MRS-based metabolites suggest early neuronal injury in a subset of participants with primary HIV infection through mechanisms involving central nervous system inflammation. [ABSTRACT FROM AUTHOR]

The advent of combination antiretroviral treatment has had a profound impact on CNS HIV infection and its clinical complications, but neurological impairment still occurs in patients on systemically effective combination therapy, and in some patients it may be important to consider antiretroviral drug entry and effects within the CNS. There are now data on the CNS exposure for most antiretroviral drugs. This review focuses on the CNS pharmacokinetics and pharmacodynamics of antiretroviral drugs in humans, and also discusses controversies in this field. [ABSTRACT FROM PUBLISHER]

Background. Despite suppression of plasma human immunodeficiency virus type 1 (HIV-1) RNA by antiretroviral therapy to levels below clinical assay detection, infection and immune activation may persist within the central nervous system and possibly lead to continued brain injury. We hypothesized that intensifying therapy would decrease cerebrospinal fluid (CSF) infection and immune activation. Methods. This was a 12-week, randomized, open-label pilot study comparing addition of the integrase inhibitor raltegravir to no treatment augmentation, with an option for rollover to raltegravir. CSF and plasma were analyzed for HIV-1 RNA using a single-copy assay. CSF and blood immune activation was assessed by neopterin concentrations and CD4+ and CD8+ T-cell surface antigen expression. Results. Primary analysis compared 14 intensified (including rollovers) to 9 nonintensified subject experiences. Median HIV-1 RNA levels in all samples were lower in CSF (<.3 copies/mL) than in plasma (<.9 copies/mL; P< .0001), and raltegravir did not reduce HIV-1 RNA, CSF neopterin, or CD4+ and CD8+ T-cell activation. Conclusions. Raltegravir intensification did not reduce intrathecal immunoactivation or alter CSF HIV-1 RNA levels in subjects with baseline viral suppression. With and without raltegravir intensification, HIV RNA levels in CSF were very low in the enrolled subjects. [ABSTRACT FROM AUTHOR]

In this article, the author discusses the possible adverse effects of administering combination antiretroviral therapy (CART) to HIV patients with severe neurocognitive disorders (SNCD). The author delineates the effectiveness of CART in alleviating the morbidity of SNCD to patients with HIV. The author cites the possibility of CART in protecting the central nervous system (CNS) from HIV-related injuries. The clinical studies for the CART are also discussed.

Background. Occasional cases of viral escape in cerebrospinal fluid (CSF) despite suppression of plasma human immunodeficiency virus type 1 (HIV-1) RNA have been reported. We investigated CSF viral escape in subjects treated with commonly used antiretroviral therapy regimens in relation to intrathecal immune activation and central nervous system penetration effectiveness (CPE) rank. Methods. Sixty-nine neurologically asymptomatic subjects treated with antiretroviral therapy 16 months and plasma HIV-1 RNA !50 copies/mL were cross-sectionally included in the analysis. Antiretroviral therapy regimens included efavirenz, lopinavir/ritonavir or atazanavir/ritonavir combined with tenofovir, abacavir, or zidovudine and emtricitabine or lamivudine. HIV-1 RNA was analyzed with real-time polymerase chain reaction assays. Neopterin was analyzed by enzyme-linked immunosorbent assay. Results. Seven (10%) of the 69 subjects had detectable CSF HIV-1 RNA, in median 121 copies/mL (interquartile range, 54-213 copies/mL). Subjects with detectable CSF virus had significantly higher CSF neopterin and longer duration of treatment. Previous treatment interruptions were more common in subjects with CSF escape. Central nervous system penetration effectiveness rank was not a significant predictor of detectable CSF virus or CSF neopterin levels. Conclusions. Viral escape in CSF is more common than previously reported, suggesting that low-grade central nervous system infection may continue in treated patients. Although these findings need extension in longitudinal studies, they suggest the utility of monitoring CSF responses, as new treatment combinations and strategies modify clinical practice. [ABSTRACT FROM AUTHOR]

John Searle and Susanna Siegel have argued that cases of aspect-switching show that visual experience represents a richer range of properties than colours, shapes, positions and sizes. I respond that cases of aspect-switching can be explained without holding that visual experience represents rich properties. I also argue that even if Searle and Siegel are right, and aspect-switching does require visual experience to represent rich properties, there is reason to think those properties do not include natural-kind properties, such as being a tomato. [ABSTRACT FROM AUTHOR]

Central nervous system (CNS) human immunodeficiency virus type 1 (HIV-1) infection begins during primary viremia and continues throughout the course of untreated systemic infection. Although frequently accompanied by local inflammatory reactions detectable in cerebrospinal fluid (CSF), CNS HIV-1 infection usually is not clinically apparent. In a minority of patients, CNS HIV-1 infection evolves into encephalitis during the late stages of systemic infection, which compromises brain function and presents clinically as acquired immunodeficiency syndrome dementia complex (ADC). Combination antiretroviral therapy (ART) has had a major impact on all aspects of CNS HIV-1 infection and disease. In those with asymptomatic infection, ART usually effectively suppresses HIV-1 in CSF and markedly reduces the incidence of symptomatic ADC. In those presenting with ADC, ART characteristically prevents neurological progression and leads to variable, and at times substantial, recovery. Similarly, treatment has reduced CNS opportunistic infections. With better control of these severe disorders, attention has turned to the possible consequences of chronic silent infection and the issue of whether indolent, low-grade brain injury might require earlier treatment intervention. [ABSTRACT FROM AUTHOR]

Highly active antiretroviral therapy (HAART) effectively reduces human immunodeficiency virus (HIV) RNA in cerebrospinal fluid (CSF), as well as in plasma. The effect on intrathecal immunoactivation is less well studied. We had earlier found that a substantial number of patients still have evidence of intrathecal immunoactivation after up to 2 years of treatment. We identified 15 patients treated with HAART for ⩾4 years who had plasma HIV-RNA levels of <50 copies/mL for ⩾3.5 years. CSF samples were available from 10 patients before treatment. We measured white-blood-cell count, HIVRNA level, neopterin level, and IgG index. During treatment, all patients had HIV-RNA levels of <50 copies/mL in plasma and CSF. In CSF, both neopterin level and IgG index decreased significantly. After 4 years, 9 (60%) of the 15 patients still had neopterin levels in CSF that were above the upper normal reference value (5.8 nmol/L). During HAART, 9 (60%) of the 15 patients had an abnormal IgG index (>0.63). HAART significantly decreases intrathecal immunoactivation, but, despite effective treatment for >4 years, with HIV-RNA levels <50 copies/mL for⩾3.5 years, a substantial proportion of patients continue to show signs of macrophage/microglia activation and intrathecal immunoglobulin production in the CNS. [ABSTRACT FROM AUTHOR]

The light subunit of neurofilament protein (NFL) is a sensitive indicator of central nervous system axonal injury. We retrospectively identified 9 subjects participating in a longitudinal cohort study who developed acquired immunodeficiency syndrome dementia complex (ADC) and who had had a lumbar puncture performed within 2 years before presentation. Elevated cerebrospinal fluid (CSF) NFL concentrations were found in 7 (78%) of the 9 case patients who later developed ADC, compared with 9 (33%) of 27 CD4 cell count-matched HIV-1-infected control subjects. By contrast, no differences were found in CSF HIV-1 RNA or neopterin concentrations between the 2 groups. CSF NFL may prove to be a useful predictive marker for ADC. [ABSTRACT FROM AUTHOR]

Objective. To characterize the effect of partially suppressive combination antiretroviral therapy on cerebrospinal fluid (CSF) human immunodeficiency virus (HIV)-1 RNA levels and CSF inflammation. Design. The study was a cross-sectional analysis of 139 HIV-1-infected subjects without active neurological disease, categorized as having successful therapy (plasma HIV-1 RNA level ⩽500 copies/mL), having failure of therapy (plasma HIV-1 RNA level >500 copies/mL), or not receiving therapy. The control group consisted of 48 HIV-negative subjects. CSF and plasma HIV-1 RNA assays had a lower limit of quantification of 2.5 copies/mL. Genotypic resistance testing was performed on a subset of subjects. Results. Of the 47 subjects with successful therapy, CSF HIV-1 RNA levels were <2.5 copies/mL in 34 (72%). Only 1 had an HIV-1 RNA level >500 copies/mL. Although plasma HIV-1 RNA levels were similar in 35 subjects with failed therapy and 57 of those not receiving therapy (P = .84), CSF HIV-1 RNA levels were at least 10-fold lower in subjects with failed therapy (P< .0001). This disproportionate effect of treatment on CSF HIV-1 RNA levels was found across the range of plasma HIV-1 RNA levels and was not explained by differences in levels of drug resistance in plasma or CSF. Therapy reduced CSF inflammation in both treated groups. Conclusions. In our cohort, antiretroviral therapy had a greater effect on HIV-1 RNA levels in CSF than in plasma and reduced intrathecal inflammation, even in the presence of drug resistance. [ABSTRACT FROM AUTHOR]

Although CXCR4-tropic viruses are relatively uncommon among untreated human immunodeficiency virus (HIV)-infected individuals except during advanced immunodeficiency, the prevalence of CXCR4-tropic viruses among treated patients with detectable viremia is unknown. To address this issue, viral coreceptor usage was measured with a single-cycle recombinant-virus phenotypic entry assay in treatment-naive and treated HIV-infected participants with detectable viremia sampled from 2 clinic-based cohorts. Of 182 treated participants, 75 (41%) harbored dual/mixed or X4-tropic viruses, compared with 178 (18%) of the 976 treatment-naive participants (P<.001). This difference remained significant after adjustment for CD4+ T cell count and CCR5 Δ32 genotype. Enrichment for dual/mixed/X4-tropic viruses among treated participants was largely but incompletely explained by lower pretreatment nadir CD4 + T cell counts. CCR5 inhibitors may thus be best strategically used before salvage therapy and before significant CD4 + T cell depletion. [ABSTRACT FROM AUTHOR]

The article presents a response by Richard Price on the commentary about his book "British Society 1680-1880: Dynamism, Containment and Change." Price stresses that it is not his intention to present the results of new research. He aims to address about the context and periodization and explained that his book was written as a kind of summing up of many years of engagement with some dominant themes in the historiography of modern Great Britain.

Background. Chemokine receptors serve as co receptors for human immunodeficiency virus type 1 (HIV- 1) entry, influence cell tropism, and may critically determine central nervous system infection pathogenesis. Using an in vitro functional entry assay, we examined utilization of 2 principal core ceptors in cerebrospinal fluid (CSF) and plasma in 46 subjects. Methods. Paired CSF and plasma samples were selected from subjects with a range of CD4 T cell counts. Amplified populations of em' sequences were characterized as using CCR5 (R5), CXCR4 (X4), or both receptors (R5+X4). Individual clones derived from 3 subjects were analyzed for viral tropism and phylogeny. Results. CSF and plasma pairs were mainly concordant for R5 (3 6/46) or R5+X4 (5/46) viruses. However, 5 pairs were discordant, 2 of which had the R5+X4 phenotype in CSF despite having the R5 phenotype in plasma. Although R5+X4 tropism was associated with advanced immunodeficiency, all 4 subjects with acquired immu- no deficiency syndrome dementia complex had R5 tropism in CSF. Clones derived from R5+X4-tropic populations revealed mixtures of R5 and X4 viruses and viruses able to utilize either core ceptor, suggesting both virus exchange between compartments and autonomous CSF virus evolution. Conclusions. Although R5 viruses predominate in the CSF, HIV-1 populations able to utilize CXCR4 are also present. Discordant tropism in CSF and plasma may have implications for R5 inhibitor therapy. [ABSTRACT FROM AUTHOR]

Background: The central nervous system (CNS) is a recognized target for human immunodeficiency virus type 1 (HIV-1). CD8(+) T cells may mediate viral clearance from the CNS but also may contribute to immune-mediated neuronal damage.Methods: Using 4- and 6-color flow cytometry, we investigated the role of adhesion molecules (very late antigen [VLA]-4 [ alpha 4 beta 1 integrin] and leukocyte function antigen [LFA]-1 [ alpha L beta 2 integrin]) and chemokine receptors (CXCR3 and CCR5) in CD8(+) T cell migration to cerebrospinal fluid (CSF) during HIV-1 infection.Results: CD8(+) T cells trafficking to CSF were uniformly VLA-4(high), LFA-1(high). CCR5 expression was significantly enhanced in T cells from CSF, compared with those from blood (P<.001), including HIV-1-specific CD8(+) T cells, and most T cells from CSF expressed both CXCR3 and CCR5. Interferon-inducible protein (IP)-10 (CXCL10) levels in CSF were significantly increased in HIV-1-positive individuals, relative to IP-10 levels in control subjects (P=.007), and a positive correlation was found between IP-10 levels and virus load in CSF (r2=.777; P=.0007).Conclusions: These findings suggest that LFA-1, CCR5 and CXCR3, and IP-10 play an important role in lymphocyte trafficking to CSF during HIV-1 infection. These observations suggest a "push-pull" model, in which lymphocyte extravasation is driven by lymphocyte activation, expression of adhesion molecules, and increased vascular permeability and is coupled with chemokine-mediated trafficking to inflammatory sites in the CNS. [ABSTRACT FROM AUTHOR]

ABSTRACT We explore the possibility that observational differences might exist between diffuse clouds which have been formed from the dissipation of unbound molecular clouds and those which have been formed from less dense atomic gas. Using single-point chemical models, we show that molecular-rich initial conditions will significantly enrich the gas-phase chemistry of diffuse clouds in the former scenario. An injection of hydrogenated grain mantles through photoevaporation will also enrich this chemistry further. If the population of interstellar diffuse clouds contains some members that are in contraction and others that are in expansion, then wide variations in atomic and molecular abundances are to be expected in this population. We predict several signatures of this effect. [ABSTRACT FROM AUTHOR]

To determine whether microbiologic cure of acquired immunodeficiency syndrome (AIDS)-related disseminated cryptococcosis is possible in patients receiving highly active antiretroviral therapy (HAART), antifungal therapy was discontinued in 6 patients with a history of disseminated cryptococcosis who had received ≥ 12 months of antifungal therapy. All were asymptomatic and had absolute CD4&sup+; T cell counts of >150 cells/μL (range, 178-525 cells/μL). Blood, cerebrospinal fluid (CSF), and urine samples were obtained for fungal culture. Serum and CSF cryptococcal antigen titers were also obtained. All 6 patients had CSF and blood cultures negative for Cryptococcus neoformans and were receiving HAART. All patients' subsequent cultures remained sterile, and all patients were clinically asymptomatic 24 months after ending antifungal therapy. Disseminated cryptococcal disease can be cured by prolonged antifungal therapy in some patients with AIDS who experience sustained CD4 lymphocyte increases while receiving HAART. [ABSTRACT FROM AUTHOR]

With the decline of violent geopolitical conflict as an overriding organizing principle in relations among advanced industrialized states, there is a growing gap between traditional conceptions and paradigms of security and the contemporary practice of security policy. Most advanced states increasingly define their security interests less in terms of war fighting and more in terms of crime fighting; less in terms of deterring military invasions and more in terms of deterring law evasions. This has involved a twofold transformation: an outward expansion of the portfolio of national security issues from domains previously associated with internal policing, and the deployment of the external military apparatus for a variety of international policing missions. Focusing on the United States, the essay examines how the coercive apparatus of the state has been reconfigured and redeployed, especially during the past decade. Specifically, it traces the growing fusion between law enforcement and national security. Among the numerous manifestations of these changes, the essay concentrates on four central developments: the heightened prominence of law enforcement issues in official security discourse and the exercise of U.S. power, the conversion of military hardware and technology for police missions, the increased overlap between law enforcement and intelligence communities, and the deployment of the military for internal and external police operations categorized as “Military Operations other than War.” Moreover, the essay explores the consequences of these changes for the traditional agenda of security studies and argues that these changes reflect both a militarization of policing and a domestication of soldiering. [ABSTRACT FROM AUTHOR]

Inoculation of mice with herpes simplex virus types 1 and 2 (HSV-I and HSV-2) by the vaginal route resulted in viral shedding during the acute phase of the infection and the development of a latent infection in vaginouterine tissue lasting up to one year in >25% of the animals. Immunization with either serotype of HSV markedly reduced viral shedding when animals were subsequently challenged with the homologous serotype, but immunization with HSV-2 was significantly less effective in preventing the development of a latent infection in the vaginouterine tissue after challenge than was immunization with HSV-l. [ABSTRACT FROM PUBLISHER]

Background. Central nervous system (CNS) human immunodeficiency virus (HIV) infection and immune activation lead to brain injury and neurological impairment. Although HIV enters the nervous system soon after transmission, the magnitude of infection and immunoactivation within the CNS during primary HIV infection (PHI) has not been characterized.Methods. This cross-sectional study analyzed cerebrospinal fluid (CSF) and blood from 96 participants with PHI and compared them with samples from neuroasymptomatic participants with chronic infection and ≥200 or <200 blood CD4 T cells/μL, and with samples from HIV-seronegative participants with respect to CSF and plasma HIV RNA, CSF to serum albumin ratio, and CSF white blood cell counts (WBC), neopterin levels, and concentrations of chemokines CXCL10 and CCL2.Results. The PHI participants (median 77 days post transmission) had CSF HIV RNA, WBC, neopterin, and CXCL10 concentrations similar to the chronic infection participants but uniquely high albumin ratios. 18 participants had ≤100 copies/mL CSF HIV RNA, which was associated with low CSF to plasma HIV ratios and levels of CSF inflammation lower than in other PHI participants but higher than in HIV-seronegative controls.Conclusions. Prominent CNS infection and immune activation is evident during the first months after HIV transmission, though a proportion of PHI patients demonstrate relatively reduced CSF HIV RNA and inflammation during this early period. [ABSTRACT FROM PUBLISHER]

Progressive dementia has been recognized as a complication of human immunodeficiency virus infection almost since the beginning of the epidemic. To many infectious diseases clinicians, however, the AIDS dementia complex remains ambiguous, and the clinical approach to this problem is less clearly defined than that for other infection-associated syndromes. Dr. Richard W. Price and his colleagues at Memorial Sloan-Kettering Cancer Center have, to a large extent, been responsible for defining this entity. In this AIDS Commentary they present their views of the current state of knowledge regarding the etiology, clinical presentation, and diagnostic and therapeutic approaches to the AIDS dementia complex. [ABSTRACT FROM PUBLISHER]

The article focuses on a study which investigated the effects of weightlessness on the digestion, growth and locomotion of the amoeba, Pelomyxa carolinensis. Following the recovery of package from the BIOSATELLITE, the modules with live amoebae were opened and the contents removed. The live organisms were counted, examined for the presence of miotic forms, food vacuoles counted and the general external morphology described. The amoebae were then studied under the light microscope for gross morphologic changes. In all control experiments, the presence of newly ingested paramecia indicated that feeding continued both in the fed and starved amoebae. No differences in the gross morphology were found in the live flight and live backup control organisms.

The article focuses on a study which investigated the effects of weightlessness on the nuclear or cellular division of the amoeba, Pelomyxa carolinensis. A three-compartment chamber was selected for the experiment since it is necessary to feed and fix the amoebae during weightlessness. Upon delivery of the flight chambers at Hickam Air Force Base in Honolulu, Hawaii, starved amoebae and fed amoebae were sub-cultured in separate dishes and amply fed for growth rate studies. The starved amoebae showed no evidence of division during flight. The study also found no significant difference in the rate of reproduction between the live fed flight amoebae and the controls.