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Abstract Background Minocycline is a tetracycline antibiotic that has been shown to attenuate central nervous system (CNS) lentivirus infection, immune activation, and brain injury in model systems. To initiate assessment of minocycline as an adjuvant therapy in human CNS HIV infection, we conducted an open-labelled pilot study of its effects on cerebrospinal fluid (CSF) and blood biomarkers of infection and immune responses in 7 viremic subjects not taking antiretroviral therapy. Results There were no discernable effects of minocycline on CSF or blood HIV-1 RNA, or biomarkers of immune activation and inflammation including: CSF and blood neopterin, CSF CCL2, CSF white blood cell count, and expression of cell-surface activation markers on CSF and blood T lymphocytes and monocytes. Conclusions This pilot study of biological responses to minocycline suggests little potential for its use as adjunctive antiviral or immunomodulating therapy in chronic untreated HIV infection.

Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory tract infections (LRTIs) and hospital admissions in early childhood. Recent advancements in novel preventive therapies, including extended half‐life monoclonal antibodies and antenatal vaccination, have afforded new opportunities to significantly reduce the burden of this infection. Nirsevimab is a novel monoclonal antibody that provides sustained protection against RSV for at least 5 months among newborns and young children. It has received regulatory approval in numerous countries and is being implemented across various settings. Two pivotal Phase 3 trials (MELODY, HARMONIE) demonstrated significant reductions in RSV‐associated LRTI hospitalisations following nirsevimab administration, with treatment efficacy of 62.1% and 83.2%. Emerging real‐world data from early adopters of nirsevimab corroborates these findings. Studies from Spain, Luxembourg, France and the USA report effectiveness rates between 82% and 90% in preventing RSV‐associated hospitalisations among infants entering their first RSV season. Current implementation strategies for nirsevimab have primarily focused on seasonal administration for all infants, aligned to local RSV seasons, and often include catch‐up doses for those born before the season begins. Available cost‐effectiveness analyses indicate that while nirsevimab offers significant potential public health benefits, its adoption must carefully consider economic factors such as treatment costs, implementation strategies tailored to local viral epidemiology, and logistics for vaccine delivery. Overall, nirsevimab presents a promising opportunity to alleviate the burden of severe RSV infections in young children. However, ongoing surveillance and refinements in implementation strategies are crucial to optimise its impact and ensure sustainability across diverse health‐care settings. [ABSTRACT FROM AUTHOR]

Objectives: This study assessed the use and perceptions of physician associates/assistants (PAs) and NPs at liver transplant centers and sought to determine their financial effect. Methods: Leaders of liver transplant programs performing 25 or more transplants in 2020 were contacted to complete an 11-question survey about the role and effect of PAs and NPs in liver transplant. A single-center retrospective analysis compared length of stay (LOS) and readmission rates for primary liver transplants and simultaneous liver-kidney transplants before and after a dedicated PA team was established. Chi-square and t-test analyses were performed. Results: The survey achieved a 77% response rate, and 98% of institutions reported using PAs and NPs. The single-center study found the mean LOS post-transplant was significantly shorter in the post-PA cohort (P = .0005). No significant difference was found in 30-day readmission rates. Conclusions: PAs and NPs are used broadly across the postliver transplant care continuum. Using LOS as a surrogate financial marker suggests that a dedicated PA and NP team may contribute to cost savings. [ABSTRACT FROM AUTHOR]

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.

Kinase inhibitors are used widely to treat various cancers, but adaptive reprogramming of kinase cascades and activation of feedback loop mechanisms often contribute to therapeutic resistance. Determining comprehensive, accurate maps of kinase circuits may therefore help elucidate mechanisms of response and resistance to kinase inhibitor therapies. In this study, we identified and validated phosphorylatable target sites across human cell and tissue types to generate PhosphoAtlas, a map of 1,733 functionally interconnected proteins comprising the human phospho-reactome. A systematic curation approach was used to distill protein phosphorylation data cross-referenced from 38 public resources. We demonstrated how a catalog of 2,617 stringently verified heptameric peptide regions at the catalytic interface of kinases and substrates could expose mutations that recurrently perturb specific phospho-hubs. In silico mapping of 2,896 nonsynonymous tumor variants identified from thousands of tumor tissues also revealed that normal and aberrant catalytic interactions co-occur frequently, showing how tumors systematically hijack, as well as spare, particular subnetworks. Overall, our work provides an important new resource for interrogating the human tumor kinome to strategically identify therapeutically actionable kinase networks that drive tumorigenesis. Cancer Res; 76(7); 1733-45. ©2016 AACR.

BackgroundLimited data exist comparing viral quasispecies between cerebrospinal fluid (CSF) and plasma compartments during primary HIV infection. Deep sequencing is a new method to examine the HIV plasma and CSF quasispecies.MethodsIn this pilot study, deep sequencing of protease (PR) and reverse transcriptase (RT) was performed in plasma and CSF from participants during primary HIV infection. Estimated mutational load was calculated by mutant variant frequency multiplied by HIV-RNA level.ResultsPaired plasma and CSF samples were studied from five antiretroviral therapy-naïve male participants with median 109 days post estimated transmission, age 32 years, CD4 cell count 580 cells/μL, HIV-RNA 5.18 log10 copies/mL in plasma and 3.67 log10 copies/mL in CSF. Plasma samples averaged 7,124 reads of PR and 2,448 reads of RT, whereas CSF samples averaged 7,082 and 2,792 reads, respectively. A distinct drug-resistance pattern with linked mutations present at significant levels (5-10%) was detected in one participant in CSF. Other low abundance variants (>0.2%) were detected in plasma and CSF of four out of five participants.ConclusionsDeep sequencing of CSF HIV is technically possible with sufficient HIV-RNA levels. Differences between the quasispecies in the two compartments detected in one participant, which were present with a high mutational load in CSF at an estimated 3.6 months after HIV infection, suggest that early CNS compartmentalisation may be revealed by sensitive deep-sequencing methods. The presence of distinct low abundance (

ObjectiveInflammation and infection within the central nervous system is initiated during primary HIV infection (PHI), but the association of these processes with the integrity of brain white matter during PHI is unknown.DesignWe used diffusion tensor imaging (DTI) in this prospective cross-sectional neuroimaging study to determine the extent of white matter involvement in early HIV infection.MethodsAntiretroviral-naive PHI (defined as

BackgroundCentral nervous system (CNS) inflammation is a mediator of brain injury in HIV infection. To study the natural course of CNS inflammation in the early phase of infection, we analyzed longitudinal levels of soluble and cellular markers of inflammation in cerebrospinal fluid (CSF) and blood, beginning with primary HIV-1 infection (PHI).MethodsAntiretroviral-naïve subjects identified as having PHI (less than one year since HIV transmission) participated in phlebotomy and lumbar puncture at baseline and at variable intervals thereafter. Mixed-effects models were used to analyze longitudinal levels of CSF neopterin and percentages of activated cluster of differentiation (CD)4+ and CD8+ T-cells (co-expressing CD38 and human leukocyte antigen-D-related (HLA-DR)) in blood and CSF.ResultsA total of 81 subjects were enrolled at an average of 100 days after HIV transmission and had an average follow-up period of 321 days, with the number of visits ranging from one to 13. At baseline, the majority of subjects had CSF neopterin concentrations above the upper limit of normal. The baseline concentration was associated with the longitudinal trajectory of CSF neopterin. In subjects with baseline levels of less than 21 nmol/L, a cutoff value obtained from a mixed-effects model, CSF neopterin increased by 2.9% per 10 weeks (n = 33; P

ObjectiveWe examined the longitudinal effects of primary HIV infection (PHI) and responses to early antiretroviral therapy (ART) on the brain using high-field magnetic resonance spectroscopy (MRS).MethodsCerebral metabolites were measured longitudinally with 4T proton MRS and assessed for ART effects in participants with PHI. Levels of glutamate (Glu), N-acetylaspartate (NAA), myo-inositol (MI), and choline-containing metabolites (Cho) were measured relative to creatine + phosphocreatine (Cr) in anterior cingulate, basal ganglia, frontal white matter, and parietal gray matter.ResultsFifty-three participants recruited at median 3.7 months post HIV transmission were followed a median 6.0 months. A total of 23 participants initiated ART during follow-up. Prior to ART, increases per month were observed in Cho/Cr (slope = 0.0012, p = 0.005) and MI/Cr (slope = 0.0041, p = 0.005) in frontal white matter as well as increases in MI/Cr (slope = 0.0041, p < 0.001) and NAA/Cr (slope = 0.0024, p = 0.030) in parietal gray matter. After initiation of ART, prior positive slopes were no longer significantly different from zero, while Glu/Cr in basal ganglia decreased (slope = -0.0038, p = 0.031).ConclusionsEarly in HIV infection, increases of Cho/Cr and MI/Cr in treatment-naive participants suggest progressive inflammation and gliosis in the frontal white matter and parietal gray matter, which is attenuated after initiation of ART. Elevated baseline Glu/Cr in basal ganglia may signal excitotoxicity; its subsequent stabilization and downward trajectory with ART may lend further support for early ART initiation.

BackgroundPeripheral neuropathy (PN) is a frequent complication of chronic HIV infection. We prospectively studied individuals with primary HIV infection (

Though depression is known to frequently afflict those with chronic HIV, mood during the early course of HIV is not well characterized. In a prospective study we assessed mood during primary HIV infection [primary HIV infection (PHI),

BackgroundCerebrospinal 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.MethodsWe 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.ResultsNeurofilament 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.ConclusionsElevated 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.

ObjectiveElite controllers are a rare subset of HIV-1-infected individuals who maintain HIV-1 RNA concentrations in plasma below the lower limit of quantification of clinical assays (

ObjectiveTo characterize HIV-infected patients with neurosymptomatic cerebrospinal fluid (CSF) 'escape', defined as detectable CSF HIV RNA in the setting of treatment-suppressed plasma levels or CSF RNA more than 1-log higher than plasma RNA.DesignRetrospective case series.SettingFour urban medical centers in the United States and Europe.ParticipantsVirologically controlled HIV-infected patients on antiretroviral therapy (ART) with progressive neurologic abnormalities who were determined to have CSF 'escape'. INTERVENTION Optimization of ART based upon drug susceptibility and presumed central nervous system exposure.Main outcome measuresLevels of CSF HIV RNA and inflammatory markers, clinical signs and symptoms, and MRI findings.ResultsTen patients presented with new neurologic abnormalities, which included sensory, motor, and cognitive manifestations. Median CSF HIV RNA was 3900 copies/ml (range 134-9056), whereas median plasma HIV RNA was 62 copies/ml (range

Abstract Background Minocycline is a tetracycline antibiotic that has been shown to attenuate central nervous system (CNS) lentivirus infection, immune activation, and brain injury in model systems. To initiate assessment of minocycline as an adjuvant therapy in human CNS HIV infection, we conducted an open-labelled pilot study of its effects on cerebrospinal fluid (CSF) and blood biomarkers of infection and immune responses in 7 viremic subjects not taking antiretroviral therapy. Results There were no discernable effects of minocycline on CSF or blood HIV-1 RNA, or biomarkers of immune activation and inflammation including: CSF and blood neopterin, CSF CCL2, CSF white blood cell count, and expression of cell-surface activation markers on CSF and blood T lymphocytes and monocytes. Conclusions This pilot study of biological responses to minocycline suggests little potential for its use as adjunctive antiviral or immunomodulating therapy in chronic untreated HIV infection.