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To assess whether probiotic supplementation may reduce disease-linked systemic immune activation in people living with HIV with the immunologic nonresponder phenotype.Phase 2b, randomized, double-blind, placebo-controlled pilot trial.HIV-positive individuals with blood CD4+ T-cell counts350/mm3 despite viral suppression were randomized to 2:1 to receive De Simone Formulation Probiotic (DSFP; "Visbiome" commercially) or placebo for 48 weeks; target enrollment was 36 patients. The primary endpoint was the change in blood CD8+ T-cell coexpression of human leukocyte antigen-DR isotype and CD38 ("CD8 activation"). Secondary endpoints included biomarkers of inflammation, immune reconstitution, bacterial translocation, and gut permeability. Adjusted linear regression and linear mixed regression methods evaluated the differences between study arms from baseline to week 48. Study monitoring was performed by the CIHR Canadian HIV Trials Network Data Safety Monitoring Committee.Nineteen patients received DSFP, whereas 10 received placebo. One probiotic arm patient withdrew early. Blood CD8 activation increased 0.82 percentage points (pp) in the probiotic arm (95% confidence interval: -1.23 to 2.87;) and decreased by 2.06 pp in the placebo arm (-4.81 to 0.70; between arms P = 0.097). CD4+ T-cell activation (%HLA-DR+) decreased in the placebo arm [-3.79 pp (-7.32 to -0.26)] but increased in the probiotic arm [1.64 (-0.98 to 4.26); between arms P = 0.018]. No differences were observed in plasma or urine biomarkers of inflammation or microbial translocation.Blood immune activation markers in immunologic nonresponder individuals on effective antiretroviral treatment were not reduced by supplementation with DSFP; CD4+ T-cell activation may have been increased.

Introduction Antiretroviral therapy (ART) does not cure HIV infection due to the persistence of HIV reservoirs in long-lived memory CD4 T cells present in the blood, lymph nodes, intestinal tract, and other tissues. Interest grows in obtaining gut-tissue samples for HIV persistence studies, which poses an ethical challenge to provide study volunteers with adequate information on risks and benefits. Herein we assess the risks and benefits of undergoing gut biopsy procedures for HIV pathogenesis and reservoir studies. Methods A group discussion was organised with physicians and community representatives on performing either a flexible sigmoidoscopy or a colonoscopy. Consensus was reached on conducting colonoscopy in persons ≥50 years. Thirty HIV-infected, ART-treated and nine uninfected participants were recruited. Colonoscopy was performed to collect 30 gut mucosal biopsies. When present, polyps were removed and abnormal mucosal findings were biopsied for pathological analysis. Participants were interviewed on potential discomfort following colonoscopic examination. Results The HIV-infected and uninfected groups were comparable in terms of age and gender with more men who have sex with men (MSM) in the former group. Abnormal colonoscopic findings were observed in 43.6% of all the participants and did not differ by HIV status. In total, 24 polyps were removed with a higher mean number of polyps removed in HIV-infected versus uninfected participants (1.7 vs 1.0, P=0.013). The number of polyps marginally correlated with inverted CD4:CD8 ratio. Based on our findings, colonoscopic examination was safe to use for gut biopsy procedures where almost half of the participants had polyps removed. Conclusion Participation in the study provided colon cancer screening as an ancillary benefit that participants could have received in standard medical care, thus mitigating burdens of invasive procedures. Dialogue between community representatives and clinical researchers can increase participation and advance HIV cure research.

Supplemental Digital Content is Available in the Text., Background: Aging and increasing comorbidity is changing the end-of-life experience of people living with HIV (PLHIV) in the developed world. We quantified, at a population level, the receipt of health care services and associated costs across a comprehensive set of sectors among decedents with and without HIV. Methods: We conducted a retrospective population-level observational study of all decedents in Ontario and their receipt of health care services, captured through linked health administrative databases, between April 1, 2010 and March 31, 2013. We identified PLHIV using a validated algorithm. We described the characteristics of PLHIV and their receipt of health care services and associated costs by health care sector in the last year of life. Results: We observed 264,754 eligible deaths, 570 of whom had HIV. PLHIV were significantly younger than those without HIV (mean age of death 56.1 years vs. 76.6 years, [P < 0.01]). PLHIV spent a mean of 20.0 days in an acute care hospital in the last 90 days of life compared with 12.1 days for decedents without HIV (P < 0.01); after adjustment, HIV was associated with 4.5 more acute care days (P < 0.01). Mean cost of care in the last year was significantly higher among PLHIV ($80,885.62 vs. $53,869.77), mostly attributable to acute care costs. Interpretation: PLHIV in Ontario are dying younger, spending more time and dying more often in hospital, and incur significantly increased costs before death. Greater involvement of community-based palliative care may improve the dying experience for this complex population.

Despite substantial improvements in HIV outcomes with combination antiretroviral therapy (cART), morbidity and mortality remain above population norms. The gut mucosal immune system is not completely restored by cART, and the resultant microbial translocation may contribute to chronic inflammation, inadequate CD4 T-cell recovery, and increased rates of serious non-AIDS events. Since the microbial environment surrounding a CD4 T cell may influence its development and function, we hypothesize that probiotics provided during cART might reduce inflammation and improve gut immune health in HIV-positive treatment-naïve individuals (PROOV IT I) and individuals with suboptimal CD4 recovery on cART (PROOV IT II).These prospective, double-blinded, randomized, placebo-controlled, multicenter pilot studies will assess the impact of the probiotic Visbiome at 900 billion bacteria daily. Forty HIV positive cART-naïve men will be randomized in the PROOV IT I study, coincident with antiretroviral initiation, and be followed for 24 weeks. In PROOV IT II, 36 men on cART, but with a CD4 T-cell count below 350 cells/mm(3) will be followed for 48 weeks. The primary outcome for both studies is the comparison of blood CD8 T-cell immune activation. Secondary analyses will include comparison of blood inflammatory biomarkers, microbial translocation, blood and gut immunology and HIV levels, the bacterial community composition, diet, intestinal permeability, and the safety, adherence and tolerability of the study product.These studies will evaluate the ability of probiotics as a safe and tolerable therapeutic intervention to reduce systemic immune activation and to accelerate gut immune restoration in people living with HIV.

Several nitrobenzyl-based photosensitive phosphoramide mustards were synthesized. The nitrobenzyl moiety was structurally varied to find the most promising prodrug candidates in respect to photorelease and activity of the alkylating species. The synthesis of these compounds proved to be applicable even in regard to compounds with additional functionalization. The target molecules 13a,b to 14 exhibited the expected red shift in their absorption spectra maximum compared to the parent nitrobenzyl moiety. As seen by UV and (31)P NMR spectroscopy, the phosphoramide mustard was quickly liberated upon irradiation with mercury arc lamps. Assaying the structurally different prodrugs on their alkylating activity showed that compounds 13b and 14, derived from secondary benzyl alcohols, are promising prodrug candidates. Their water solubility and the possibility of attaching macromolecules are encouraging vis-à-vis future investigations on their in vitro cytotoxicity.

O-Sulfonylation of 2-oxomethylene-substituted 1-azaheterocycles 1 yields the 3-trifloxypropeniminium triflates 2a–e in high yield. Thermal β-elimination of triflic acid from these salts affords the propyniminium triflates (2-ethynylcycliminium triflates) 3a–e. The treatment of semicyclic enamino ketones 1f, g with triflic anhydride yields directly the propyniminium triflates 3f, g.

O-Sulfonylation of 2-oxomethylene-substituted 1-azaheterocycles 1 yields the 3-trifloxypropeniminium triflates 2a–e in high yield. Thermal β-elimination of triflic acid from these salts affords the propyniminium triflates (2-ethynylcycliminium triflates) 3a–e. The treatment of semicyclic enamino ketones 1f, g with triflic anhydride yields directly the propyniminium triflates 3f, g.

2-Aminodienes, in which the enamine function is incorporated in a five-, six-, or seven-membered ring, react with dimethyl acetylenedicarboxylate in a sequence of [2+2] cycloaddition and electrocyclic ring-opening to form the two-carbon ring expanded unsaturated heterocycles, i.e., 3,4- dicarboxylate substituted 6,7-dihydro-1H-azepines 3, 8 and 21, 1,6,7,8-tetrahydroazocines 22, and 6,7,8,9-tetrahydro-1H-azonines 13. Similarly, 2-[(2-thienyl)ethynyl]-4,5,6,7-tetrahydro-1H-azepine 9 is converted into 2-[(2-thienyl)ethynyl]-6,7,8,9-1H-azonine-3,4-dicarboxylate 10 which was characterized by X-ray structure determination. The eight- and nine-membered azaheterocycles 22 and 13, which have not been isolated, undergo thermal isomerization at elevated temperatures. Thus, ring contraction by a 6π-electrocyclic reaction takes place for N-methyl substituted azonine 13, while the N-allyl moiety of azocines 22 engages in an intramolecular Diels-Alder reaction or a 1,7- electrocyclization reaction

The authors deserve thanks for laying out decent principles of communication [1]. But serviceable consent language is insufficient to address all issues of protection. That was the point of recent workshops held by the National Institutes of Health to develop a genome-wide association studies program [2]. Risks associated with personal identification may be incurred if information is subject to code breaking. Legal means are available to compel identification, including across national boundaries. Privacy protections under the Health Insurance Portability and Accountability Act (HIPAA) are subject to exceptions, including for law enforcement, downstream data users, or for other reasons, and are not available internationally. Even with authorization, the complexities associated with a repository may frustrate attempts to achieve meaningful comprehension. Use of data for purposes other than pharmaceutical product development or biomedical interventions would be an abuse resulting perhaps in travel restrictions or discrimination. For these reasons, safeguards should be added, including: Amendments to prevent non-medical health access to personal identification information; Restrictions on recruitment of populations especially vulnerable to disclosure risks, such as prisoners or immigrants; Prohibitions on disclosure to or use by employers or third-party payors to deny medical coverage, assign differential premium risks, restrict access to therapies, or unfairly discriminate in employment. Another risk from creation of a genomics repository is the potential for unjust stigmatization (see for example [3]). A workable program would state that the data are appropriate only for limited public health purposes involving product development or professionally derived biomedical intervention, and are insupportable for other use or by political or non-medical entities. A researcher publishing results based on the genomic data should state affirmatively a boilerplate recognition of the abuse potential for stigmatization. This mechanism could prevent others from the wayward misappropriation of data for purposes other than those intended by professionals. The boilerplate could read: “Conclusions derived from the genotypic or phenotypic characterization of individuals, groups, or families in this [publication] are meaningful or supportable only for the purpose of biomedical intervention or treatment and are unethical, insupportable, or inappropriate for use in other purposes. Use of the data to support any result of stigmatization, discrimination, or adverse social harm would constitute a misuse or abuse of the data.” To increase the connection of benefits to participants, individuals should be given personal opportunities to receive news reports if they wish and learn of particular clinical trials directed at their characteristics. If the data are to be used in the development of pharmaceutical products, users should also be directed to plan and explain early on how targeted populations may have reasonable access to treatment or therapy if the product is successfully brought to market. These suggestions are consistent with the program outlined by Senator Barack Obama in the Genomics and Personalized Medicine Act of 2006 and Senator Olympia Snowe in the Genetic Information Nondiscrimination Act of 2007 [4,5]. Improved consent: Yes, but linked to and inseparable from strong protections and added benefits for participants.

The International AIDS Society (IAS) convened the Towards an HIV Cure Symposium on 18–19 July 2015 in Vancouver, Canada, bringing together researchers and community to discuss the most recent advances in our understanding of HIV latency, reservoirs and a summary of the current clinical approaches towards an HIV cure. The symposium objectives were to: (1) gather researchers and stakeholders to present, review, and discuss the latest research towards an HIV cure; (2) promote cross-disciplinary global interactions between basic, clinical and social scientists; and (3) provide a platform for sharing information among scientists, clinicians, funders, media and civil society. The symposium examined basic molecular science and animal model data, and emerging and ongoing clinical trial results to prioritise strategies and determine the viral and immune responses that could lead to HIV remission without antiretroviral therapy. This report summarises some of the major findings discussed during the symposium.