Purpose of Review
We discuss recent advances in understanding of gut bacterial microbiota composition in HIV-infected subjects and comment on controversies. We discuss the putative effects of ...microbiota shifts on systemic inflammation and HIV disease progression and potential mechanisms, as well as ongoing strategies being developed to modulate the gut microbiota in humans for amelioration of infectious and inflammatory diseases.
Recent Findings
Lifestyle and behavioral factors relevant to HIV infection studies have independent effects on the microbiota. Microbial metabolism of immunomodulatory compounds and direct immune stimulation by translocation of microbes are putative mechanisms contributing to HIV disease. Fecal microbiota transplantation, microbial enzyme inhibition, phage therapy, and rationally selected probiotic cocktails have emerged as promising strategies for microbiota modulation.
Summary
Numerous surveys of the HIV gut microbiota matched for lifestyle factors suggest consistent shifts in gut microbiota composition among HIV-infected subjects. Evidence exists for a complex pathogenic role of the gut microbiota in HIV disease progression, warranting further study.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Colorectal Cancer Screening and COVID-19 Patel, Shreya; Issaka, Rachel B; Chen, Ellen ...
The American journal of gastroenterology,
02/2021, Volume:
116, Issue:
2
Journal Article
Peer reviewed
Open access
Routine outpatient visits were converted to telehealth appointments, and nonurgent endoscopic procedures were cancelled, resulting in dramatic declines in colorectal cancer (CRC) screening. ...Electronic medical records and registries can identify patients not up to date with screening, use of at-home FIT kits mailed directly to patients can be expanded, and positive tests can be followed up with automated calls and text prompts from direct patient messaging platforms—all strategies that have proven effective at increasing screening rates and follow-up. R.B.I. receives funding from National Institutes of Health/National Cancer Institute award number K08 CA241296.
We examined the utility of the International Classification of Disease, Tenth Revision (ICD-10) code, R19.5, for a positive or abnormal fecal immunochemical test (FIT) and its association with ...colonoscopy completion.
We identified all patients in a safety-net health system who underwent FITs from January 1, 2020, to August 31, 2021, and extracted the FIT date, FIT result, and ICD-10 code (R19.5) and colonoscopy procedures for each patient.
FIT-positive patients who had an R19.5 designation within 90 days (n = 383) were significantly more likely than all other FIT-positive patients (n = 273) to complete a colonoscopy within 6 months (40.9% vs 16.8%, P <0.001).
We found that less than two-thirds of patients had an ICD-10 code designated in their chart within 30 days of an abnormal FIT. When coding occurred in a timely manner, patients were more likely to complete their colonoscopy within 6 months.
Sustained, drug-free control of HIV-1 replication is naturally achieved in less than 0.5% of infected individuals (here termed 'elite controllers'), despite the presence of a replication-competent ...viral reservoir
. Inducing such an ability to spontaneously maintain undetectable plasma viraemia is a major objective of HIV-1 cure research, but the characteristics of proviral reservoirs in elite controllers remain to be determined. Here, using next-generation sequencing of near-full-length single HIV-1 genomes and corresponding chromosomal integration sites, we show that the proviral reservoirs of elite controllers frequently consist of oligoclonal to near-monoclonal clusters of intact proviral sequences. In contrast to individuals treated with long-term antiretroviral therapy, intact proviral sequences from elite controllers were integrated at highly distinct sites in the human genome and were preferentially located in centromeric satellite DNA or in Krüppel-associated box domain-containing zinc finger genes on chromosome 19, both of which are associated with heterochromatin features. Moreover, the integration sites of intact proviral sequences from elite controllers showed an increased distance to transcriptional start sites and accessible chromatin of the host genome and were enriched in repressive chromatin marks. These data suggest that a distinct configuration of the proviral reservoir represents a structural correlate of natural viral control, and that the quality, rather than the quantity, of viral reservoirs can be an important distinguishing feature for a functional cure of HIV-1 infection. Moreover, in one elite controller, we were unable to detect intact proviral sequences despite analysing more than 1.5 billion peripheral blood mononuclear cells, which raises the possibility that a sterilizing cure of HIV-1 infection, which has previously been observed only following allogeneic haematopoietic stem cell transplantation
, may be feasible in rare instances.
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FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Abstract
Background
Colorectal cancer (CRC) screening remains underused, especially in safety-net systems. The objective of this study was to determine the effectiveness, costs, and ...cost-effectiveness of organized outreach using fecal immunochemical tests (FITs) compared with usual care.
Methods
Patients age 50–75 years eligible for CRC screening from eight participating primary care safety-net clinics were randomly assigned to outreach intervention with usual care vs usual care alone. The intervention included a mailed postcard and call, followed by a mailed FIT kit, and a reminder phone call if the FIT kit was not returned. The primary outcome was screening participation at 1 year and a microcosting analysis of the outreach activities with embedded long-term cost-effectiveness of outreach. All statistical tests were two-sided.
Results
A total of 5386 patients were randomly assigned to the intervention group and 5434 to usual care. FIT screening was statistically significantly higher in the intervention group than in the control group (57.9% vs 37.4%, P < .001; difference = 20.5%, 95% confidence interval = 18.6% to 22.4%). In the intervention group, FIT completion rate was higher in patients who had previously completed a FIT vs those who had not (71.9% vs 35.7%, P < .001). There was evidence of effect modification of the intervention by language, and clinic. Outreach cost approximately $23 per patient and $112 per additional patient screened. Projecting long-term outcomes, outreach was estimated to cost $9200 per quality-adjusted life-year gained vs usual care.
Conclusion
Population-based management with organized FIT outreach statistically significantly increased CRC screening and was cost-effective in a safety-net system. The sustainability of the program and any impact of economies of scale remain to be determined.
Mucosal-associated invariant T (MAIT) cells are an evolutionarily conserved antimicrobial MR1-restricted T-cell subset. MAIT cells are CD161+, express a Vα7.2 TCR, are primarily CD8+ and numerous in ...blood and mucosal tissues. However, their role in HIV-1 infection is unknown. In this study, we found levels of MAIT cells to be severely reduced in circulation in patients with chronic HIV-1 infection. Residual MAIT cells were highly activated and functionally exhausted. Their decline was associated with time since diagnosis, activation levels, and the concomitant expansion of a subset of functionally impaired CD161− Vα7.2+ T cells. Such cells were generated in vitro by exposure of MAIT cells to Escherichia coli. Notably, whereas the function of residual MAIT cells was at least partly restored by effective antiretroviral therapy, levels of MAIT cells in peripheral blood were not restored. Interestingly, MAIT cells in rectal mucosa were relatively preserved, although some of the changes seen in blood were recapitulated in the mucosa. These findings are consistent with a model in which the MAIT-cell compartment, possibly as a result of persistent exposure to microbial material, is engaged, activated, exhausted, and progressively and persistently depleted during chronic HIV-1 infection.
•Antimicrobial CD8+ MAIT cells are activated, exhausted, and progressively and persistently depleted during chronic HIV-1 infection.•This decline in MAIT cell level and function may seriously impair the ability to mount immune responses to bacterial and fungal pathogens.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Microbial translocation and innate immune action characterize HIV infection. Continued gut mucosal dysfunction during treatment and its relationship to CD4 T-cell recovery has not been well ...described.
A cross-sectional study was performed of antiretroviral therapy (ART)-suppressed (immunologic responders with CD4 > 500 cells/μl and immunologic nonresponders with CD4 < 350 cells/μl), untreated HIV-infected, and seronegative participants consenting to gut biopsies and a blood draw.
Neutrophil infiltration as a surrogate response to epithelial breach, colorectal epithelial proliferation as a measure of repair, and mucosal apoptosis by immunohistochemistry were determined in gut biopsies. Plasma markers of monocyte activation (sCD14), immune activation (interleukin-6), and indoleamine 2,3-dioxygenase-1 activity (plasma kynurenine/tryptophanratio) were concurrently measured.
Each HIV-infected group had greater neutrophil infiltration than controls. Similarly, untreated HIV-infected participants and ART-suppressed immunologic responders had increased epithelial proliferation compared with controls, but immunologic nonresponders had no appreciable increase in epithelial proliferation despite elevated neutrophil infiltration. The CD4 T-cell count was positively correlated with epithelial proliferation and was modestly negatively correlated with neutrophil infiltration in ART-suppressed patients. Epithelial proliferation was inversely correlated with mucosal apoptosis, and apoptosis was linked to plasma sCD14 and modestly to kynurenine/tryptophan ratio.
Neutrophil infiltration and mucosal apoptosis remain abnormally high despite ART. Epithelial proliferation increases in HIV, but may be impaired in immunologic nonresponders. Whether mucosal apoptosis is a cause or consequence of epithelial proliferative defects is unclear, but appears to be associated with systemic inflammation. The impact of ART and interventions targeting the gut epithelial barrier in treated HIV infection warrant further investigation.
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