The relationship between adverse neighborhood socioeconomic context and HIV continuum of care outcomes in a diverse HIV clinic cohort in the Southern United States

Retention in care and viral suppression are critical to delaying HIV progression and reducing transmission. Neighborhood socioeconomic context (NSEC) may affect HIV care receipt. We therefore assessed NSEC's impact on retention and viral suppression in a diverse HIV clinical cohort. HIV-positive adults with ≥1 visit at the Vanderbilt Comprehensive Care Clinic and 5-digit ZIP code tabulation area (ZCTA) information between 2008 and 2012 contributed. NSEC z-score indices used neighborhood-level socioeconomic indicators for poverty, education, labor-force participation, proportion of males, median age, and proportion of residents of black race by ZCTA. Retention was defined as ≥2 HIV care visits per calendar year, >90 days apart. Viral suppression was defined as an HIV-1 RNA <200 copies/mL at last measurement per calendar year. Modified Poisson regression was used to estimate risk ratios (RR) and 95% confidence intervals (CI). Among 2272 and 2541 adults included for retention and viral suppression analyses, respectively, median age and CD4 count at enrollment were approximately 38 (1st and 3rd quartile: 30, 44) years and 351 (176, 540) cells/μL, respectively, while 24% were female, and 39% were black. Across 243 ZCTAs, median NSEC z-score was 0.09 (-0.66, 0.48). Overall, 79% of person-time contributed was retained and 74% was virally suppressed. In adjusted models, NSEC was not associated with retention, though being in the 4th vs. 1st NSEC quartile was associated with lack of viral suppression (RR = 0.88; 95% CI: 0.80-0.97). Residing in the most adverse NSEC was associated with lack of viral suppression. Future studies are needed to confirm this finding

Functional diversity of marine ecosystems after the Late Permian mass extinction event

Article can be accessed from http://www.nature.com/ngeo/journal/v7/n3/full/ngeo2079.htmlThe Late Permian mass extinction event was the most severe such crisis of the past 500 million years and occurred during an episode of global warming. It is assumed to have had significant ecological impact, but its effects on marine ecosystem functioning are unknown and the patterns of marine recovery are debated. We analysed the fossil occurrences of all known Permian-Triassic benthic marine genera and assigned each to a functional group based on their inferred life habit. We show that despite the selective extinction of 62-74% of marine genera there was no significant loss of functional diversity at the global scale, and only one novel mode of life originated in the extinction aftermath. Early Triassic marine ecosystems were not as ecologically depauperate as widely assumed, which explains the absence of a Cambrian-style Triassic radiation in higher taxa. Functional diversity was, however, significantly reduced in particular regions and habitats, such as tropical reefs, and at these scales recovery varied spatially and temporally, probably driven by migration of surviving groups. Marine ecosystems did not return to their pre-extinction state, however, and radiation of previously subordinate groups such as motile, epifaunal grazers led to greater functional evenness by the Middle Triassic

Modelling the impact of improving screening and treatment of chronic hepatitis C virus infection on future hepatocellular carcinoma rates and liver-related mortality.

BACKGROUND: The societal, clinical and economic burden imposed by the complications of chronic hepatitis C virus (HCV) infection - including cirrhosis and hepatocellular carcinoma (HCC) - is expected to increase over the coming decades. However, new therapies may improve sustained virological response (SVR) rates and shorten treatment duration. This study aimed to estimate the future burden of HCV-related disease in England if current management strategies remain the same and the impact of increasing diagnosis and treatment of HCV as new therapies become available. METHODS: A previously published model was adapted for England using published literature and government reports, and validated through an iterative process of three meetings of HCV experts. The impact of increasing diagnosis and treatment of HCV as new therapies become available was modelled and compared to the base-case scenario of continuing current management strategies. To assess the 'best case' clinical benefit of new therapies, the number of patients treated was increased by a total of 115% by 2018. RESULTS: In the base-case scenario, total viraemic (HCV RNA-positive) cases of HCV in England will decrease from 144,000 in 2013 to 76,300 in 2030. However, due to the slow progression of chronic HCV, the number of individuals with cirrhosis, decompensated cirrhosis and HCC will continue to increase over this period. The model suggests that the 'best case' substantially reduces HCV-related hepatic disease and HCV-related liver mortality by 2020 compared to the base-case scenario. The number of HCV-related HCC cases would decrease 50% by 2020 and the number progressing from infection to decompensated cirrhosis would decline by 65%. Therefore, compared to projections of current practices, increasing treatment numbers by 115% by 2018 would reduce HCV-related mortality by 50% by 2020. CONCLUSIONS: This analysis suggests that with current treatment practices the number of patients developing HCV-related cirrhosis, decompensated cirrhosis and HCC will increase substantially, with HCV-related liver deaths likely to double by 2030. However, increasing diagnosis and treatment rates could optimise the reduction in the burden of disease produced by the new therapies, potentially halving HCV-related liver mortality and HCV-related HCC by 2020

Just-in-Time Information Improved Decision-Making in Primary Care: A Randomized Controlled Trial

BACKGROUND: The "Just-in-time Information" (JIT) librarian consultation service was designed to provide rapid information to answer primary care clinical questions during patient hours. This study evaluated whether information provided by librarians to answer clinical questions positively impacted time, decision-making, cost savings and satisfaction. METHODS AND FINDING: A randomized controlled trial (RCT) was conducted between October 2005 and April 2006. A total of 1,889 questions were sent to the service by 88 participants. The object of the randomization was a clinical question. Each participant had clinical questions randomly allocated to both intervention (librarian information) and control (no librarian information) groups. Participants were trained to send clinical questions via a hand-held device. The impact of the information provided by the service (or not provided by the service), additional resources and time required for both groups was assessed using a survey sent 24 hours after a question was submitted. The average time for JIT librarians to respond to all questions was 13.68 minutes/question (95% CI, 13.38 to 13.98). The average time for participants to respond their control questions was 20.29 minutes/question (95% CI, 18.72 to 21.86). Using an impact assessment scale rating cognitive impact, participants rated 62.9% of information provided to intervention group questions as having a highly positive cognitive impact. They rated 14.8% of their own answers to control question as having a highly positive cognitive impact, 44.9% has having a negative cognitive impact, and 24.8% with no cognitive impact at all. In an exit survey measuring satisfaction, 86% (62/72 responses) of participants scored the service as having a positive impact on care and 72% (52/72) indicated that they would use the service frequently if it were continued. CONCLUSIONS: In this study, providing timely information to clinical questions had a highly positive impact on decision-making and a high approval rating from participants. Using a librarian to respond to clinical questions may allow primary care professionals to have more time in their day, thus potentially increasing patient access to care. Such services may reduce costs through decreasing the need for referrals, further tests, and other courses of action. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN96823810

Contemporary Homozygous Familial Hypercholesterolemia in the United States: Insights From the CASCADE FH Registry

Erratum in: J Am Heart Assoc. 2023 Jun 6;12(11):e027706. doi: 10.1161/JAHA.122.027706. Epub 2023 Jun 1.Free PMC article: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10227232/Background: Homozygous familial hypercholesterolemia (HoFH) is a rare, treatment-resistant disorder characterized by earlyonset atherosclerotic and aortic valvular cardiovascular disease if left untreated. Contemporary information on HoFH in the United States is lacking, and the extent of underdiagnosis and undertreatment is uncertain. Methods and Results: Data were analyzed from 67 children and adults with clinically diagnosed HoFH from the CASCADE (Cascade Screening for Awareness and Detection) FH Registry. Genetic diagnosis was confirmed in 43 patients. We used the clinical characteristics of genetically confirmed patients with HoFH to query the Family Heart Database, a US anonymized payer health database, to estimate the number of patients with similar lipid profiles in a “real-world” setting. Untreated lowdensity lipoprotein cholesterol levels were lower in adults than children (533 versus 776mg/dL; P=0.001). At enrollment, atherosclerotic cardiovascular disease and supravalvular and aortic valve stenosis were present in 78.4% and 43.8% and 25.5% and 18.8% of adults and children, respectively. At most recent follow-up, despite multiple lipid-lowering treatment, low-density lipoprotein cholesterol goals were achieved in only a minority of adults and children. Query of the Family Heart Database identified 277 individuals with profiles similar to patients with genetically confirmed HoFH. Advanced lipid-lowering treatments were prescribed for 18%; 40% were on no lipid-lowering treatment; atherosclerotic cardiovascular disease was reported in 20%; familial hypercholesterolemia diagnosis was uncommon. Conclusions: Only patients with the most severe HoFH phenotypes are diagnosed early. HoFH remains challenging to treat. Results from the Family Heart Database indicate HoFH is systemically underdiagnosed and undertreated. Earlier screening, aggressive lipid-lowering treatments, and guideline implementation are required to reduce disease burden in HoFH.Dr Martin is supported by grants/contracts from the American Heart Association (20SFRN35380046, 20SFRN35490003, 878924, and 882415), Patient‐Centered Outcomes Research Institute (PCORI) (ME‐2019C1‐15328), National Institutes of Health (NIH) (R01AG071032 and P01 HL108800), the David and June Trone Family Foundation, Pollin Digital Health Innovation Fund, and Sandra and Larry Small; Dr Knowles is supported by the NIH through grants P30 DK116074 (to the Stanford Diabetes Research Center), R01 DK116750, R01 DK120565, and R01 DK106236; and by a grant from the Bilateral Science Foundation. Dr Linton is supported by NIH grants P01HL116263, HL148137, HL159487, and HL146134.info:eu-repo/semantics/publishedVersio

Magnitude and Complexity of Rectal Mucosa HIV-1-Specific CD8+ T-Cell Responses during Chronic Infection Reflect Clinical Status

The intestinal mucosa displays robust virus replication and pronounced CD4+ T-cell loss during acute human immunodeficiency virus type 1 (HIV-1) infection. The ability of HIV-specific CD8+ T-cells to modulate disease course has prompted intensive study, yet the significance of virus-specific CD8+ T-cells in mucosal sites remains unclear.We evaluated five distinct effector functions of HIVgag-specific CD8+ T-cells in rectal mucosa and blood, individually and in combination, in relationship to clinical status and antiretroviral therapy (ART). In subjects not on ART, the percentage of rectal Gag-specific CD8+ T-cells capable of 3, 4 or 5 simultaneous effector functions was significantly related to blood CD4 count and inversely related to plasma viral load (PVL) (p<0.05). Polyfunctional rectal CD8+ T-cells expressed higher levels of MIP-1beta and CD107a on a per cell basis than mono- or bifunctional cells. The production of TNFalpha, IFN-gamma, and CD107a by Gag-specific rectal CD8+ T-cells each correlated inversely (p<0.05) with PVL, and MIP-1beta expression revealed a similar trend. CD107a and IFN-gamma production were positively related to blood CD4 count (p<0.05), with MIP-1beta showing a similar trend. IL-2 production by rectal CD8+ T-cells was highly variable and generally low, and showed no relationship to viral load or blood CD4 count.The polyfunctionality of rectal Gag-specific CD8+ T-cells appears to be related to blood CD4 count and inversely related to PVL. The extent to which these associations reflect causality remains to be determined; nevertheless, our data suggest a potentially important role for mucosal T-cells in limiting virus replication during chronic infection

Expression of Constitutively Active CDK1 Stabilizes APC-Cdh1 Substrates and Potentiates Premature Spindle Assembly and Checkpoint Function in G1 Cells

Mitotic progression in eukaryotic cells depends upon the activation of cyclin-dependent kinase 1 (CDK1), followed by its inactivation through the anaphase-promoting complex (APC)/cyclosome-mediated degradation of M-phase cyclins. Previous work revealed that expression of a constitutively active CDK1 (CDK1AF) in HeLa cells permitted their division, but yielded G1 daughter cells that underwent premature S-phase and early mitotic events. While CDK1AF was found to impede the sustained activity of APC-Cdh1, it was unknown if this defect improperly stabilized mitotic substrates and contributed to the occurrence of these premature M phases. Here, we show that CDK1AF expression in HeLa cells improperly stabilized APC-Cdh1 substrates in G1-phase daughter cells, including mitotic kinases and the APC adaptor, Cdc20. Division of CDK1AF-expressing cells produced G1 daughters with an accelerated S-phase onset, interrupted by the formation of premature bipolar spindles capable of spindle assembly checkpoint function. Further characterization of these phenotypes induced by CDK1AF expression revealed that this early spindle formation depended upon premature CDK1 and Aurora B activities, and their inhibition induced rapid spindle disassembly. Following its normal M-phase degradation, we found that the absence of Wee1 in these prematurely cycling daughter cells permitted the endogenous CDK1 to contribute to these premature mitotic events, since expression of a non-degradable Wee1 reduced the number of cells that exhibited premature cyclin B1oscillations. Lastly, we discovered that Cdh1-ablated cells could not be forced into a premature M phase, despite cyclin B1 overexpression and proteasome inhibition. Together, these results demonstrate that expression of constitutively active CDK1AF hampers the destruction of critical APC-Cdh1 targets, and that this type of condition could prevent newly divided cells from properly maintaining a prolonged interphase state. We propose that this more subtle type of defect in activity of the APC-driven negative-feedback loop may have implications for triggering genome instability and tumorigenesis

Genomic attributes of airway commensal bacteria and mucosa

Microbial communities at the airway mucosal barrier are conserved and highly ordered, in likelihood reflecting co-evolution with human host factors. Freed of selection to digest nutrients, the airway microbiome underpins cognate management of mucosal immunity and pathogen resistance. We show here the initial results of systematic culture and whole-genome sequencing of the thoracic airway bacteria, identifying 52 novel species amongst 126 organisms that constitute 75% of commensals typically present in heathy individuals. Clinically relevant genes encode antimicrobial synthesis, adhesion and biofilm formation, immune modulation, iron utilisation, nitrous oxide (NO) metabolism and sphingolipid signalling. Using whole-genome content we identify dysbiotic features that may influence asthma and chronic obstructive pulmonary disease. We match isolate gene content to transcripts and metabolites expressed late in airway epithelial differentiation, identifying pathways to sustain host interactions with microbiota. Our results provide a systematic basis for decrypting interactions between commensals, pathogens, and mucosa in lung diseases of global significance

First Phase 1 Double-Blind, Placebo-Controlled, Randomized Rectal Microbicide Trial Using UC781 Gel with a Novel Index of Ex Vivo Efficacy

Objectives: Successful control of the HIV/AIDS pandemic requires reduction of HIV-1 transmission at sexually-exposed mucosae. No prevention studies of the higher-risk rectal compartment exist. We report the first-in-field Phase 1 trial of a rectally-applied, vaginally-formulated microbicide gel with the RT-inhibitor UC781 measuring clinical and mucosal safety, acceptability and plasma drug levels. A first-in-Phase 1 assessment of preliminary pharmacodynamics was included by measuring changes in ex vivo HIV-1 suppression in rectal biopsy tissue after exposure to product in vivo. Methods: HIV-1 seronegative, sexually-abstinent men and women (N = 36) were randomized in a double-blind, placebo-controlled trial comparing UC781 gel at two concentrations (0.1%, 0.25%) with placebo gel (1:1:1). Baseline, single-dose exposure and a separate, 7-day at-home dosing were assessed. Safety and acceptability were primary endpoints. Changes in colorectal mucosal markers and UC781 plasma drug levels were secondary endpoints; ex vivo biopsy infectibility was an ancillary endpoint. Results: All 36 subjects enrolled completed the 7-14 week trial (100% retention) including 3 flexible sigmoidoscopies, each with 28 biopsies (14 at 10 cm; 14 at 30 cm). There were 81 Grade 1 adverse events (AEs) and 8 Grade 2; no Grade 3, 4 or procedure-related AEs were reported. Acceptability was high, including likelihood of future use. No changes in mucosal immunoinflammatory markers were identified. Plasma levels of UC781 were not detected. Ex vivo infection of biopsies using two titers of HIV-1 BaL showed marked suppression of p24 in tissues exposed in vivo to 0.25% UC781; strong trends of suppression were seen with the lower 0.1% UC781 concentration. Conclusions: Single and 7-day topical rectal exposure to both concentrations of UC781 were safe with no significant AEs, high acceptability, no detected plasma drug levels and no significant mucosal changes. Ex vivo biopsy infections demonstrated marked suppression of HIV infectibility, identifying a potential early biomarker of efficacy. (Registered at ClinicalTrials.gov; #NCT00408538). © 2011 Anton et al