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Nearly 50 years ago, Intel created the world's first commercially produced microprocessor--the 4004 (ref. .sup.1), a modest 4-bit CPU (central processing unit) with 2,300 transistors fabricated using 10 [mu]m process technology in silicon and capable only of simple arithmetic calculations. Since this ground-breaking achievement, there has been continuous technological development with increasing sophistication to the stage where state-of-the-art silicon 64-bit microprocessors now have 30 billion transistors (for example, the AWS Graviton2 (ref. .sup.2) microprocessor, fabricated using 7 nm process technology). The microprocessor is now so embedded within our culture that it has become a meta-invention--that is, it is a tool that allows other inventions to be realized, most recently enabling the big data analysis needed for a COVID-19 vaccine to be developed in record time. Here we report a 32-bit Arm (a reduced instruction set computing (RISC) architecture) microprocessor developed with metal-oxide thin-film transistor technology on a flexible substrate (which we call the PlasticARM). Separate from the mainstream semiconductor industry, flexible electronics operate within a domain that seamlessly integrates with everyday objects through a combination of ultrathin form factor, conformability, extreme low cost and potential for mass-scale production. PlasticARM pioneers the embedding of billions of low-cost, ultrathin microprocessors into everyday objects. Flexible electronic platforms would enable the integration of functional electronic circuitry with many everyday objects; here, a low-cost and fully flexible 32-bit microprocessor is produced., Author(s): John Biggs [sup.1] , James Myers [sup.1] , Jedrzej Kufel [sup.1] , Emre Ozer [sup.1] , Simon Craske [sup.1] , Antony Sou [sup.2] , Catherine Ramsdale [sup.2] , Ken [...]

BackgroundThe prevalence of neurocognitive deficits are reported to be high in HIV-1 positive patients, even with suppressive antiretroviral treatment, and it has been suggested that HIV can cause accelerated aging of the brain. In this study we measured phosphorylated tau (p-tau) in cerebrospinal fluid (CSF) as a potential marker for premature central nervous system (CNS) aging. P-tau increases with normal aging but is not affected by HIV-associated neurocognitive disorders.MethodsWith a cross-sectional retrospective design, p-tau, total tau (t-tau), neopterin and HIV-RNA were measured in CSF together with plasma HIV-RNA and blood CD4+ T-cells of 225 HIV-infected patients

BackgroundAlthough ischemic stroke risk is increased among people living with HIV infection, little is known about the epidemiology of ischemic stroke subtypes in contemporary HIV-infected cohorts. We examined the distribution of ischemic stroke subtypes among predominantly treated HIV-infected individuals to determine if and how the distribution differs from that of the general population.MethodsWe studied 60 HIV-infected and 60 HIV-uninfected adults with a history of first-ever ischemic stroke between 2000 and 2012. Ischemic strokes were classified as 1 of 5 subtypes based on established criteria. We used multinomial logistic regression models to compare the relative frequency of ischemic stroke subtypes by HIV status.ResultsLarge artery atherosclerosis (23%) and stroke of undetermined etiology (23%) were the most common stroke subtypes among HIV-infected individuals. The most recent plasma HIV viral load before the stroke event differed by subtype, with a median undetectable viral load for individuals with large artery stroke and stroke of undetermined etiology. Using cardioembolic stroke as the reference subtype, HIV-infected individuals were at higher proportional risk of stroke of undetermined etiology compared with uninfected individuals (relative risk ratio [RRR]: 8.6, 95% confidence interval [CI]: 1.2-63.7, P = .04). Among HIV-infected individuals with virologically suppressed infection, we observed a trend toward a greater proportion of strokes attributable to large artery atherosclerosis (RRR: 6.7, 95% CI: .8-57.9, P = .08).ConclusionsHIV-infected individuals may be at greater proportional risk of stroke of undetermined etiology compared with uninfected individuals. Further investigation is warranted to confirm this finding and determine underlying reasons for this greater risk.

BackgroundWe 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).MethodsThe 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.ResultsThe 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.ConclusionThe 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.

BackgroundCerebrovascular risk is increased in people living with HIV infection compared with age-matched uninfected individuals. Cerebrovascular endothelial dysfunction related to antiretroviral therapy (ART) and inflammation may contribute to higher stroke risk in HIV infection.MethodsWe compared cerebral vasoreactivity-a measure of cerebrovascular endothelial function assessed by the breath-holding index (BHI) using transcranial Doppler ultrasound-between virologically suppressed Chinese HIV-infected individuals followed in an HIV clinic in Beijing, China, and uninfected controls. We constructed mixed-effects models to evaluate the association of HIV, ART, and inflammatory markers with cerebral vasoreactivity.ResultsIn an unadjusted model, HIV infection was associated with a trend toward lower cerebral vasoreactivity (BHI 1.08 versus 1.26, P = 0.079). In multivariable analyses, cholesterol modified the association between HIV infection and cerebral vasoreactivity (P = 0.015 for interaction). At a lower total cholesterol of 4.15 mmol/L, HIV was associated with lower cerebral vasoreactivity (BHI -0.28, P = 0.019), whereas at a cholesterol of 5.15 mmol/L, the reduction in cerebral vasoreactivity associated with HIV was no longer statistically significant (BHI -0.05, P = 0.64). Among HIV-infected individuals, use of lopinavir/ritonavir compared with efavirenz was associated with lower cerebral vasoreactivity (BHI -0.24, P = 0.040). We did not find a significant association between inflammatory markers and cerebral vasoreactivity.ConclusionsCerebrovascular endothelial dysfunction associated with HIV infection may be most relevant for individuals with less traditional vascular risk, such as those with lower cholesterol. Further study of the impact of ART on cerebrovascular endothelial function is warranted to aid with ART selection in individuals at high cerebrovascular risk.

Although blood-brain barrier (BBB) impairment has been reported in HIV-infected individuals, characterization of this impairment has not been clearly defined.BBB integrity was measured by CSF/plasma albumin ratio in this cross-sectional study of 631 HIV-in

CSF HIV escape is a recently recognised phenomenon that suggests that despite suppressive treatment, HIV RNA may be detected in the CNS compartment in some individuals. In rare cases this is associated with clinical neurological disease, while in most case

The central nervous system (CNS) is an important target of HIV, and cerebrospinal fluid (CSF) can provide a window into host-virus interactions within the CNS. The goal of this study was to determine whether HIV-specific CD8(+) T cells are present in CSF of HIV controllers (HC), who maintain low to undetectable plasma viremia without antiretroviral therapy (ART). CSF and blood were sampled from 11 HC, defined based on plasma viral load (VL) consistently below 2,000 copies/ml without ART. These included nine elite controllers (EC, plasma VL 10,000 copies/ml, no ART); seven individuals with viremia suppressed due to ART (Tx, VL

ObjectiveLittle is known about the extent of cortical and subcortical volumetric alterations that may occur within the first year of HIV infection [primary HIV infection (PHI)].DesignWe used structural MRI in this prospective cross-sectional neuroimaging study to determine the extent of volumetric changes in early HIV infection.MethodsCerebrospinal fluid, blood, neuropsychological testing, and structural T1 MRI scans were acquired from 18 HIV and 47 PHI age-matched antiretroviral-naïve male participants. Using FreeSurfer 5.1, volumetric measurements were obtained from the caudate, amygdala, corpus callosum, ventricles, putamen, thalamus, cortical white matter, and total gray matter. Regional volumes were compared groupwise and related to biomarkers in cerebrospinal fluid (viral load, neopterin, and neurofilament light chain), blood (viral load, CD4, and CD8 T-cell count), and neuropsychometric tests (digit-symbol, grooved pegboard, finger-tapping, and timed gait).ResultsA trend-level moderate reduction of putamen volume (P = 0.076, adjusted Cohen's d = 0.5 after controlling for age) was observed for PHI compared with HIV-uninfected individuals. Within the PHI group, putamen volume associated with CD4 cell count (P = 0.03), CD4/CD8 ratio (P = 0.045), infection duration (P = 0.009), and worsening psychomotor performance on the digit-symbol (P = 0.028), finger-tapping (P = 0.039), and timed gait (P = 0.009) tests.ConclusionOur volumetric results suggest that the putamen is preferentially susceptible to early HIV-associated processes. Examining the natural course of early HIV infection longitudinally will allow for mapping of the trajectory of HIV-associated central nervous system changes, enabling creation of improved interventional strategies to potentially stabilize or reverse these observed structural changes.

ObjectiveTo compare cerebral vasoreactivity, a measure of cerebrovascular endothelial function, between treated, virally suppressed HIV-infected individuals and HIV-uninfected controls and to evaluate the effect of HIV-specific factors on cerebral vasoreactivity.MethodsCross-sectional study of 65 antiretroviral therapy-treated, virally suppressed HIV-infected individuals and 28 HIV-uninfected controls. Participants underwent noninvasive assessment of cerebral vasoreactivity using transcranial Doppler ultrasound and inhaled carbon dioxide (CO2). We used mixed effects multivariable linear regression to determine the association of HIV infection and HIV-specific factors with cerebral vasoreactivity.ResultsMean age was 57.2 years for HIV-infected participants and 53.5 years for HIV-uninfected controls. Most participants (95%) were men. Twenty-six per cent of HIV-infected participants were nonwhite compared to 32% of controls. Among HIV-infected participants, mean CD4 cell count was 596 cells/μl, and mean duration of viral suppression was 7.8 years. Cerebral vasoreactivity in response to hypercapnia (cerebral VRhyper) was lower in HIV-infected individuals compared to uninfected controls (3.23 versus 3.81%, P = 0.010). After adjusting for demographic and vascular risk factors, HIV infection was independently associated with lower cerebral vasoreactivity (-0.86%, 95% CI -1.30 to -0.42%, P

BackgroundCerebrospinal fluid (CSF) neurofilament light chain protein (NFL) is a sensitive marker of neuronal injury in a variety of neurodegenerative conditions, including the CNS dysfunction injury that is common in untreated HIV infection. However, an important limitation is the requirement for lumbar puncture. For this reason, a sensitive and reliable blood biomarker of CNS injury would represent a welcome advance in both clinical and research settings.MethodsTo explore whether plasma concentrations of NFL might be used to detect CNS injury in HIV infection, an ultrasensitive Single molecule array (Simoa) immunoassay was developed. Using a cross-sectional design, we measured NFL in paired CSF and plasma samples from 121 HIV-infected subjects divided into groups according to stage of their systemic disease, presence of overt HIV-associated dementia (HAD), and after antiretroviral treatment (ART)-induced viral suppression. HIV-negative controls were also examined.FindingsPlasma and CSF NFL concentrations were very highly correlated (r = 0.89, P < 0.0001). While NFL was more than 50-fold lower plasma than CSF it was within the quantifiable range of the new plasma assay in all subjects, including the HIV negatives and the HIV positives with normal CSF NFL concentrations. The pattern of NFL changes were almost identical in plasma and CSF, both exhibiting similar age-related increases in concentrations along with highest values in HAD and substantial elevations in ART-naïve neuroasymptomatic subjects with low blood CD4(+) T cells.InterpretationThese results show that plasma NFL may prove a valuable tool to evaluate ongoing CNS injury in HIV infection that may be applied in the clinic and in research settings to assess the presence if active CNS injury. Because CSF NFL is also elevated in a variety of other CNS disorders, sensitive measures of plasma NFL may similarly prove useful in other settings.

ObjectiveAlthough milder forms of HIV-associated neurocognitive disorder (HAND) remain prevalent, a correlation to neuronal injury has not been established in patients on antiretroviral therapy (ART). We examined the relationship between mild HAND and CSF neurofilament light protein (NFL), a biomarker of neuronal injury; and CSF neopterin, a biomarker of CNS immunoactivation, in virally suppressed patients on antiretroviral therapy (ART).Design and methodsWe selected 99 subjects on suppressive ART followed longitudinally from the CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) study. Based on standardized comprehensive neurocognitive performance (NP) testing, subjects were classified as neurocognitively normal (NCN; n = 29) or impaired (NCI; n = 70). The NCI group included subjects with asymptomatic (ANI; n = 37) or mild (MND; n = 33) HAND. CSF biomarkers were analyzed on two occasions.ResultsGeometric mean CSF neopterin was 25% higher in the NCI group (p = 0.04) and NFL and neopterin were significantly correlated within the NCI group (r = 0.30; p

UnlabelledHIV-1 is typically CCR5 using (R5) and T cell tropic (T-tropic), targeting memory CD4(+) T cells throughout acute and chronic infections. However, viruses can expand into alternative cells types. Macrophage-tropic (M-tropic) HIV-1 variants have evolved to infect macrophages, which have only low levels of surface CD4. Most M-tropic variants have been isolated from the central nervous system during late-stage chronic infection. We used the HIV-1 env genes of well-defined, subject-matched M-tropic and T-tropic viruses to characterize the phenotypic features of the M-tropic Env protein. We found that, compared to T-tropic viruses, M-tropic viruses infect monocyte-derived macrophages (MDMs) on average 28-fold more efficiently, use low-density CD4 more efficiently, have increased sensitivity to soluble CD4 (sCD4), and show trends toward sensitivity to some CD4 binding site antibodies but no difference in sensitivity to antibodies targeting the CD4-bound conformation. M-tropic viruses also displayed a trend toward resistance to neutralization by monoclonal antibodies targeting the V1/V2 region of Env, suggesting subtle changes in Env protein conformation. The paired M- and T-tropic viruses did not differ in autologous serum neutralization, temperature sensitivity, entry kinetics, intrinsic infectivity, or Env protein incorporation. We also examined viruses with modestly increased CD4 usage. These variants have significant sensitivity to sCD4 and may represent evolutionary intermediates. CD4 usage is strongly correlated with infectivity of MDMs over a wide range of CD4 entry phenotypes. These data suggest that emergence of M-tropic HIV-1 includes multiple steps in which a phenotype of increased sensitivity to sCD4 and enhanced CD4 usage accompany subtle changes in Env conformation.ImportanceHIV-1 typically replicates in CD4(+) T cells. However, HIV-1 can evolve to infect macrophages, especially within the brain. Understanding how CCR5-using macrophage-tropic viruses evolve and differ from CCR5-using T cell-tropic viruses may provide insights into viral evolution and pathogenesis within the central nervous system. We characterized the HIV-1 env viral entry gene from subject-matched macrophage-tropic and T cell-tropic viruses to identify entry features of macrophage-tropic viruses. We observed several differences between T cell-tropic and macrophage-tropic Env proteins, including functional differences with host CD4 receptor engagement and possible changes in the CD4 binding site and V1/V2 region. We also identified viruses with phenotypes between that of "true" macrophage-tropic and T cell-tropic viruses, which may represent evolutionary intermediates in a multistep process to macrophage tropism.