Search

ONCR-177 is an engineered recombinant oncolytic herpes simplex virus (HSV) with complementary safety mechanisms, including tissue-specific miRNA attenuation and mutant UL37 to inhibit replication, neuropathic activity, and latency in normal cells. ONCR-177 is armed with five transgenes for IL12, FLT3LG (extracellular domain), CCL4, and antagonists to immune checkpoints PD-1 and CTLA-4. In vitro assays demonstrated that targeted miRNAs could efficiently suppress ONCR-177 replication and transgene expression, as could the HSV-1 standard-of-care therapy acyclovir. Although ONCR-177 was oncolytic across a panel of human cancer cell lines, including in the presence of type I IFN, replication was suppressed in human pluripotent stem cell–derived neurons, cardiomyocytes, and hepatocytes. Dendritic cells activated with ONCR-177 tumor lysates efficiently stimulated tumor antigen–specific CD8+ T-cell responses. In vivo, biodistribution analyses suggested that viral copy number and transgene expression peaked approximately 24 to 72 hours after injection and remained primarily within the injected tumor. Intratumoral administration of ONCR-177 mouse surrogate virus, mONCR-171, was efficacious across a panel of syngeneic bilateral mouse tumor models, resulting in partial or complete tumor regressions that translated into significant survival benefits and to the elicitation of a protective memory response. Antitumor effects correlated with local and distant intratumoral infiltration of several immune effector cell types, consistent with the proposed functions of the transgenes. The addition of systemic anti–PD-1 augmented the efficacy of mONCR-171, particularly for abscopal tumors. Based in part upon these preclinical results, ONCR-177 is being evaluated in patients with metastatic cancer (ONCR-177-101, NCT04348916).

Supplemental Tables and Figures

There are no studies comparing the prognosis for mature T-cell lymphoma (TCL) in people with HIV (PWH) to people without HIV (PWoH) and to AIDS-defining B-cell lymphomas (A-BCLs) in the modern antiretroviral therapy era. North American AIDS Cohort Collaboration on Research and Design and Comprehensive Oncology Measures for Peripheral T-cell Lymphoma Treatment are cohorts that enroll patients diagnosed with HIV and TCL, respectively. In our study, 52, 64, 101, 500, and 246 PWH with histologic confirmation of TCL, primary central nervous system lymphoma, Burkitt’s lymphoma, diffuse large B-cell lymphoma (DLBCL), and Hodgkin’s lymphoma (HL), respectively, and 450 TCLs without HIV were eligible for analysis. At the time of TCL diagnosis, anaplastic large-cell lymphoma (ALCL) was the most common TCL subtype within PWH. Although PWH with TCL diagnosed between 1996 and 2009 experienced a low 5-year survival probability at 0.23 (95% confidence interval [CI]: 0.13, 0.41), we observed a marked improvement in their survival when diagnosed between 2010 and 2016 (0.69; 95% CI: 0.48, 1; P = .04) in contrast to TCLs among PWoH (0.45; 95% CI: 0.41, 0.51; P = .53). Similarly, PWH with ALCLs diagnosed between 1996 and 2009 were associated with a conspicuously inferior 5-year survival probability (0.17; 95% CI: 0.07, 0.42) and consistently lagged behind A-BCL subtypes such as Burkitt’s (0.43; 95% CI:0.33, 0.57; P = .09) and DLBCL (0.17; 95% CI: 0.06, 0.46; P = .11) and behind HL (0.57; 95% CI: 0.50, 0.65; P < .0001). Despite a small number, those diagnosed between 2010 and 2016 experienced a remarkable improvement in survival (0.67; 95% CI: 0.3, 1) in comparison with PWoH (0.76; 95% CI: 0.66, 0.87; P = .58). Thus, our analysis confirms improved overall survival for aggressive B- and T-cell malignancies among PWH in the last decade.

Background Over 600,000 SARS-CoV-2 infections and 20,000 deaths have occurred among users of the Veterans Health Administration, the US’s largest integrated health care system. We explored early outcomes of SARS-COV-2 infection in Veterans. Methods An ongoing, prospective longitudinal cohort study of Veterans ages ≥ 18 enrolled 1,826 participants (29.0% inpatient; 49.1% vaccinated; 68.3% SARS-CoV-2-positive; 85.0% male, mean age = 57.1 years) seeking inpatient or outpatient care after SARS-CoV-2 testing at 15 Department of Veterans Affairs medical centers in July 2020 to February 13, 2022. Using multivariable regression, we estimated relationships of baseline demographic characteristics, COVID-19 vaccination, and clinical history to illness severity and cumulative length of hospital stay within 60 days of study entry. Illness severity was defined by a Veterans Affairs adaptation of the WHO COVID-19 severity scale and included 4 levels (mild, moderate, severe, or death). We derived the Charlson co-morbidity index (CCI) and other baseline characteristics from electronic health data and study questionnaires, and reported qualitative SARS-CoV-2 IgG responses using inpatients’ study-collected blood specimens. Results High CCI scores (≥ 5) occurred in 47 (42.7%) vaccinated SARS-CoV-2-positive inpatients and 47 (21.2%) unvaccinated. Severe illness occurred in 17 (15.5%) vaccinated inpatients, 37 (16.7%) unvaccinated inpatients, 4 (0.9%) vaccinated outpatients, and 3 (0.7%) unvaccinated outpatients. Eleven (10%) of 110 vaccinated SARS-CoV-2-positive inpatients died, as did 15 (6.8%) of the 222 unvaccinated. In SARS-CoV-2-positive inpatients, a one-step higher CCI was associated with more severe illness (aOR 1.10, 95% CI 1.01-1.20) and more hospitalization days (aIRR 1.06, 95% CI 1.03-1.10), adjusting for vaccination status. Respectively, 93% of vaccinated and 63% of unvaccinated SARS-CoV-2 positive inpatients with baseline antibody results had an anti-spike IgG response. Conclusion In an ongoing longitudinal cohort study of COVID-19 in US Veterans, comorbidity burden was higher among vaccinated than unvaccinated inpatients and was associated with more severe illness and hospitalization days, independent of vaccination status. Disclosures Christine M. Hunt, MD, MPH, Adaptive Phage Therapeutics: Advisor/Consultant|Akebia: Advisor/Consultant|Galmed: Advisor/Consultant|Otsuka: Advisor/Consultant|Palladio: Advisor/Consultant.

The therapeutic effectiveness of oncolytic viruses (OVs) delivered intravenously is limited by the development of neutralizing antibody responses against the virus. To circumvent this limitation and to enable repeated systemic administration of OVs, here we develop Synthetic RNA viruses consisting of a viral RNA genome (vRNA) formulated within lipid nanoparticles. For two Synthetic RNA virus drug candidates, Seneca Valley virus (SVV) and Coxsackievirus A21, we demonstrate vRNA delivery and replication, virus assembly, spread and lysis of tumor cells leading to potent anti-tumor efficacy, even in the presence of OV neutralizing antibodies in the bloodstream. Synthetic-SVV replication in tumors promotes immune cell infiltration, remodeling of the tumor microenvironment, and enhances the activity of anti-PD-1 checkpoint inhibitor. In mouse and non-human primates, Synthetic-SVV is well tolerated reaching exposure well above the requirement for anti-tumor activity. Altogether, the Synthetic RNA virus platform provides an approach that enables repeat intravenous administration of viral immunotherapy.

Background The World Health Organization’s Treat-All guidance recommends CD4 testing before initiating antiretroviral therapy (ART), and routine viral load (VL) monitoring (over CD4 monitoring) for patients on ART. Methods We used regression discontinuity analyses to estimate changes in CD4 testing and VL monitoring among 547 837 ART-naive patients enrolling in human immunodeficiency virus (HIV) care during 2006–2018 at 225 clinics in 26 countries where Treat-All policies were adopted. We examined CD4 testing within 12 months before and VL monitoring 6 months after ART initiation among adults (≥20 years), adolescents (10–19 years), and children (0–9 years) in low/lower-middle-income countries (L/LMICs) and high/upper-middle-income countries (H/UMICs). Results Treat-All adoption led to an immediate decrease in pre-ART CD4 testing among adults in L/LMICs, from 57.0% to 48.1% (−8.9 percentage points [pp]; 95% CI: −11.0, −6.8), and a small increase in H/UMICs, from 90.1% to 91.7% (+1.6pp; 95% CI: 0.2, 3.0), with no changes among adolescents or children; decreases in pre-ART CD4 testing accelerated after Treat-All adoption in L/LMICs. In L/LMICs, VL monitoring after ART initiation was low among all patients in L/LMICs before Treat-All; while there was no immediate change at Treat-All adoption, VL monitoring trends significantly increased afterwards. VL monitoring increased among adults immediately after Treat-All adoption, from 58.2% to 61.1% (+2.9pp; 95% CI: 0.5, 5.4), with no significant changes among adolescents/children. Conclusions While on-ART VL monitoring has improved in L/LMICs, Treat-All adoption has accelerated and disparately worsened suboptimal pre-ART CD4 monitoring, which may compromise care outcomes for individuals with advanced HIV., Adoption of Treat-All policies led to decreases in pre-antiretroviral therapy (ART) CD4 testing among adult ART initiators in low/lowermiddle income countries, with no immediate increase in viral load monitoring after ART initiation, potentially compromising appropriate care of individuals with advanced HIV.

The menopause transition (MT) is linked to adverse changes in lipids/lipoproteins. However, the related contributions of Anti-Müllerian hormone (AMH) and estradiol (E2) are not clear.To evaluate the independent associations of premenopausal AMH and E2 levels and their changes with lipids/lipoproteins levels [total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), apolipoprotein B (apoB) and apolipoprotein A-1 (apoA-1)] over the MT.SWAN participants who transitioned to menopause without exogenous hormone use, hysterectomy, or bilateral oophorectomy with data available on both exposure and outcomes when they were premenopausal until the 1st visit postmenopausal were studied.The study included 1,440 women (baseline-age:mean±SD=47.4±2.6) with data available from up to 9 visits (1997-2013). Lower premenopausal levels and greater declines in AMH were independently associated with greater TC and HDL-C, whereas lower premenopausal levels and greater declines in E2 were independently associated with greater TG and apo B and lower HDL-C. Greater declines in AMH were independently associated with greater apoA-1, and greater declines in E2 were independently associated with greater TC and LDL-C.AMH and E2 and their changes over the MT relate differently to lipids/lipoproteins profile in women during midlife. Lower premenopausal and/or greater declines in E2 over the MT were associated with an atherogenic lipid/lipoprotein profile. On the other hand, lower premenopausal AMH and/or greater declines in AMH over the MT were linked to higher apo A-1 and HDL-C; the later found previously to be related to a greater atherosclerotic risk after menopause.

OBJECTIVE: To assess differences in anal cancer incidence between racial/ethnic groups among a clinical cohort of men with HIV who have sex with men. DESIGN: Clinical cohort study METHODS: We studied men who have sex with men (MSM) in the Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) who initiated antiretroviral therapy (ART) under HIV care in CNICS. We compared anal cancer incidence between Black and non-Black men and calculated hazard ratios controlling for demographic characteristics (age, CNICS site, year of ART initiation), HIV disease indicators (nadir CD4(+), peak HIV RNA), and co-infection/behavioral factors including hepatitis B virus (HBV), hepatitis C virus (HCV), tobacco smoking and alcohol abuse. RESULTS: We studied 7473 MSM with HIV who contributed 41 810 person-years of follow-up after initiating ART between 1996 and 2014 in CNICS. Forty-one individuals had an incident diagnosis of anal cancer under observation. Crude rates of anal cancer were 204 versus 61 per 100 000 person-years among Black versus non-Black MSM. The weighted hazard ratio for anal cancer in Black MSM (adjusting for demographics, HIV disease factors, and co-infection/behavioral factors) was 2.37 (95% confidence interval: 1.17, 4.82) compared to non-Black MSM. CONCLUSIONS: In this large multicenter cohort, Black MSM were at significantly increased risk for anal cancer compared to non-Black MSM. Further detailed studies evaluating factors impacting anal cancer incidence and outcomes in Black men with HIV are necessary. Inclusion of more diverse study cohorts may elucidate modifiable factors associated with increased anal cancer risk experienced by Black MSM.

Development of next-generation oncolytic viruses requires the design of vectors that are potently oncolytic, immunogenic in human tumors, and well tolerated in patients. Starting with a joint-region deleted herpes simplex virus 1 (HSV-1) to create large transgene capability, we retained a single copy of the ICP34.5 gene, introduced mutations in UL37 to inhibit retrograde axonal transport, and inserted cell-type-specific microRNA (miRNA) target cassettes in HSV-1 genes essential for replication or neurovirulence. Ten miRNA candidates highly expressed in normal tissues and with low or absent expression in malignancies were selected from a comprehensive profile of 800 miRNAs with an emphasis on protection of the nervous system. Among the genes essential for viral replication identified using a small interfering RNA (siRNA) screen, we selected ICP4, ICP27, and UL8 for miRNA attenuation where a single miRNA is sufficient to potently attenuate viral replication. Additionally, a neuron-specific miRNA target cassette was introduced to control ICP34.5 expression. This vector is resistant to type I interferon compared to ICP34.5-deleted oncolytic HSVs, and in cancer cell lines, the oncolytic activity of the modified vector is equivalent to its parental virus. In vivo, this vector potently inhibits tumor growth while being well tolerated, even at high intravenous doses, compared to parental wild-type HSV-1., Graphical Abstract, Next-generation oncolytic viral immunotherapy is designed to promote greater oncolytic potency, be highly immunogenic in human tumors, and have an improved tolerability profile among patients. This article describes the design of a highly engineered novel oncolytic HSV-1 vector, ONCR-159, demonstrates its broad therapeutic index, and confirms its potent antitumor activity.

BACKGROUND: Use of electronic health records (EHRs) in health research may lead to the false assumption of complete event ascertainment. We present a systematic approach to estimate “observation windows” (OWs), defined as time periods within which the assumption of complete ascertainment of events is more likely to hold, as a quality control approach to reducing the likelihood of this false assumption. We demonstrate the impact of observation windows on estimating the rates of type 2 diabetes mellitus (diabetes) using EHR diagnosis, medication, and laboratory data from HIV clinical cohorts. METHODS: Data contributed by 16 HIV clinical cohorts to the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) were used to identify and evaluate OWs for an operationalized definition of diabetes occurrence as a case study. Procedures included: 1) gathering cohort-level data; 2) visualizing and summarizing gaps in observations; 3) systematically establishing start and stop dates during which complete ascertainment of diabetes events was reasonable; and 4) visualizing the diabetes OWs relative to the cohort open and close dates to identify periods of time during which immortal person time was accumulated and events were not fully ascertained. We estimated diabetes occurrence event rates and 95% confidence intervals ([,]) in the most recent decade that data were available (Jan 1, 2007 to Dec 31, 2016). RESULTS: The number of diabetes events decreased by 17% with the use of the diabetes OWs; immortal person-time was removed decreasing total person-years by 23%. Consequently, the diabetes rate increased from 1.23 (95% confidence interval [1.20, 1.25]) per 100 person-years to 1.32 ([1.29, 1.35] per 100 person-years with the use of diabetes OWs. CONCLUSIONS: As the use of EHR-curated data for event-driven health research continues to expand, OWs have utility as a quality control approach to complete event ascertainment, helping to improve accuracy of estimates by removing immortal person-time when ascertainment is incomplete.

Background The updated Veterans Aging Cohort Study (VACS) Index 2.0 combines general and human immunodeficiency virus (HIV)–specific biomarkers to generate a continuous score that accurately discriminates risk of mortality in diverse cohorts of persons with HIV (PWH), but a score alone is difficult to interpret. Using data from the North American AIDS Cohort Collaboration (NA-ACCORD), we translate VACS Index 2.0 scores into validated probability estimates of mortality. Methods Because complete mortality ascertainment is essential for accurate calibration, we restricted analyses to cohorts with mortality from the National Death Index or equivalent sources. VACS Index 2.0 components were ascertained from October 1999 to April 2018. Mortality was observed up to March 2019. Calibration curves compared predicted (estimated by fitting a gamma model to the score) to observed mortality overall and within subgroups: cohort (VACS/NA-ACCORD subset), sex, age 500 copies/mL, CD4 count Results Among 37230 PWH in VACS and 8061 PWH in the NA-ACCORD subset, median age was 53 and 44 years; 3% and 19% were women; and 48% and 39% were black. Discrimination in NA-ACCORD (C-statistic = 0.842 [95% confidence interval {CI}, .830–.854]) was better than in VACS (C-statistic = 0.813 [95% CI, .809–.817]). Predicted and observed mortality largely overlapped in VACS and the NA-ACCORD subset, overall and within subgroups. Conclusions Based on this validation, VACS Index 2.0 can reliably estimate probability of all-cause mortality, at various follow-up times, among PWH in North America.

Objective Describe the characteristics and pharmacological management of hypertensive patients in a Nicaraguan ambulatory care clinic. Methods The study analyzed a random sample of 349 charts of patients aged older than 18 years from an ambulatory care clinic in Nicaragua and analyzed those who were diagnosed or had a known history of hypertension. Results Out of 349 patients, 19.77% (n=69) had a history of hypertension. Hypertensive patients were 66.2% female (n=45) with mean age of 56.1 years (SD=13.7). The most common comorbid condition was type 2 diabetes mellitus, which was present in 18.8% (n=13) of hypertensive patients. Other comorbid conditions included 10% (n=7) with chronic kidney disease and 75.8% (n=50) who were either overweight or obese. The most commonly prescribed antihypertensive medications were losartan, captopril, and enalapril. Conclusions Hypertension is common in this clinic population and most commonly treated with angiotension-receptor blockers or angiotensin converting enzyme inhibitors.

Oncolytic viruses (OVs) are an emerging therapeutic approach for the treatment of cancer. Clinical benefit has been demonstrated for intratumoral administration. Still, the therapeutic effectiveness of intravenous delivery has been limited by neutralizing antibody responses against the virus. To circumvent this limitation, we developed Synthetic RNA viruses, a novel approach for intravenous and repeated administration of OVs, consisting of a viral RNA genome (vRNA) formulated within lipid nanoparticles. Systemic administration of ONCR-788, the Synthetic RNA virus drug candidate encoding the vRNA of Seneca Valley virus (SVV), led to potent anti-tumor efficacy, even in the presence of OV neutralizing antibodies in the bloodstream. After a single intravenous administration of ONCR-788, we demonstrated vRNA delivery, viral replication, spread, and lysis of tumor cells. Robust anti-tumor efficacy was observed across diverse neuroendocrine tumor models, including tumor CDX and PDX xenografts, lung orthotopic, and GEMM-derived models. In a syngeneic model, ONCR-788 stimulated both tumor lysis and modulation of the tumor microenvironment. Enhanced T cell recruitment and activation, increased expression of PD-L1 on tumor cells and myeloid cells, and M2 to M1 macrophage conversion were observed. Combination of ONCR-788 with anti-PD-1 resulted in improved anti-tumor activity versus the monotherapy arms. Altogether, ONCR-788 provides an innovative approach that enables repeat intravenous administration of viral immunotherapy. Citation Format: Edward M. Kennedy, Agnieszka Denslow, Jacqueline Hewett, Lingxin Kong, Ana De Almeida, Jeffrey Bryant, Jennifer S. Lee, Judy Jacques, Sonia Feau, Hayes Hayes, Elizabeth L. McMichael, Daniel Wambua, Sanmit Adhikari, Jessica Deterling, Matthew Scott, Brian H. Haines, Mitchel H. Finer, Ted Ashburn, Christophe Quéva, Lorena Lerner. Development of ONCR-788, a synthetic oncolytic virus based on Seneca Valley virus for the treatment of neuroendocrine tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3299.

Nonalcoholic fatty liver disease (NAFLD) is a growing cause of chronic liver disease. Using a proxy NAFLD definition of chronic elevation of alanine aminotransferase (cALT) levels without other liver diseases, we performed a multiancestry genome-wide association study (GWAS) in the Million Veteran Program (MVP) including 90,408 cALT cases and 128,187 controls. Seventy-seven loci exceeded genome-wide significance, including 25 without prior NAFLD or alanine aminotransferase associations, with one additional locus identified in European American-only and two in African American-only analyses (P < 5 × 10(−8)). External replication in histology-defined NAFLD cohorts (7,397 cases and 56,785 controls) or radiologic imaging cohorts (n = 44,289) replicated 17 single-nucleotide polymorphisms (SNPs) (P < 6.5 × 10(−4)), of which 9 were new (TRIB1, PPARG, MTTP, SERPINA1, FTO, IL1RN, COBLL1, APOH and IFI30). Pleiotropy analysis showed that 61 of 77 multiancestry and all 17 replicated SNPs were jointly associated with metabolic and/or inflammatory traits, revealing a complex model of genetic architecture. Our approach integrating cALT, histology and imaging reveals new insights into genetic liability to NAFLD.

From 2005 to 2018, among 32013 adults with human immunodeficiency virus entering care, median time to antiretroviral therapy (ART) prescription declined from 69 to 6 days, CD4 count at entry into care increased from 300 to 362 cells/μL, and CD4 count at ART prescription increased from 160 to 364 cells/μL.

Background People living with human immunodeficiency virus (HIV; PLWH) have a markedly elevated anal cancer risk, largely due to loss of immunoregulatory control of oncogenic human papillomavirus infection. To better understand anal cancer development and prevention, we determined whether recent, past, cumulative, or nadir/peak CD4+ T-cell count (CD4) and/or HIV-1 RNA level (HIV RNA) best predict anal cancer risk. Methods We studied 102 777 PLWH during 1996–2014 from 21 cohorts participating in the North American AIDS Cohort Collaboration on Research and Design. Using demographics-adjusted, cohort-stratified Cox models, we assessed associations between anal cancer risk and various time-updated CD4 and HIV RNA measures, including cumulative and nadir/peak measures during prespecified moving time windows. We compared models using the Akaike information criterion. Results Cumulative and nadir/peak CD4 or HIV RNA measures from approximately 8.5 to 4.5 years in the past were generally better predictors for anal cancer risk than their corresponding more recent measures. However, the best model included CD4 nadir (ie, the lowest CD4) from approximately 8.5 years to 6 months in the past (hazard ratio [HR] for Conclusions Our results are consistent with anal cancer promotion by severe, prolonged HIV-induced immunosuppression. Nadir and cumulative CD4 may represent useful markers for identifying PLWH at higher anal cancer risk.

Adults aged 50 years or older comprise a majority of people with HIV in the USA. Our objective was to describe observed differences by age in CD4 count at entry into HIV care, timing of antiretroviral therapy (ART) prescription, and CD4 count at time of ART prescription before (2004-11) and during (2012-18) the current era of universal treatment.For this descriptive study, we calculated median (IQR) CD4 count at entry into care, days from entry into care to ART prescription, and CD4 count at time of ART prescription among patients enrolled in US-based clinical cohorts of the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD; see appendix). We excluded participants with no CD4 count recorded at entry into care, medical records that suggested previous ART use, or previous AIDS diagnosis. All calculations were stratified by age (≥50 and 18-50 years) and calendar year.Of 35 293 ART-naive adult participants entering care between Jan 1, 2004 and Dec 31, 2018, 5794 (16%) were women and 29 499 (84%) were men; 15817 (45%) were Black, 11566 (33%) were White, 5538 (16%) were Hispanic (any race), 737 (2%) were Asian or Pacific Islander, 152 (0.4%) were Indigenous, and 98 (0.3%) were multiracial. Median age at entry into care was 39 years (IQR 29-49); 8004 (23%) were aged 50 years or older. Of 29 141 participants initially prescribed ART, 7274 (25%) were aged 50 years or older. From 2004 to 2018, median CD4 count at entry into care increased from 228 cells per µL (IQR 80-422) to 295 cells per µL (134-489) among adults aged 50 years and older, and from 297 cells per µL (119-480) to 378 cells per µL (202-564) among adults younger than 50 years. Median days from entry into care to ART prescription declined from 56 (IQR 17-658) to 6 (0-15) among adults older than 50 years, and from 61 (17-509) to 6 (0-16) among adults younger than 50 years. Median CD4 count at time of ART prescription increased from 139 cells per µL (IQR 59-257) to 311 cells per µL (137-504) among adults aged 50 years or older, and from 166 cells per µL (49-287) to 377 cells per µL (198-564) among adults younger than 50 years.Before the release of universal treatment guidelines by the US Department of Health and Human Services in 2012, median time to ART prescription was already falling, leading to increases in median CD4 count at ART prescription for both age groups; both measures continued to improve in the treat-all era. However, median CD4 counts, both at entry into care and at ART prescription, among adults aged 50 years and older were lower than those of adults younger than 50 years throughout the study period. Furthermore, even into the treat-all era, over half of adults aged 50 years and older entered care with CD4 counts of less than 350 cells per µL, potentially because of factors including immunosenescence, delayed HIV diagnosis, and late presentation to care. Given that age-related immunological changes might not be fully avoidable, targeted strategies for increasing HIV risk awareness, routine testing, and immediate linkage to HIV care at diagnosis are particularly essential for this population.US National Institutes of Health grant U01AI069918.

Objectives The lack of access to diagnostic imaging in resource-limited settings (RLSs) poses a worldwide problem. Advances in ultrasound (US) imaging technology bridge this gap, particularly when examinations are performed by physicians and integrated into the patient encounter, termed point-of-care ultrasound (POCUS). Because the number of physicians participating in short-term medical missions (STMMs) is increasing, the authors sought to characterize how the use of POCUS would affect care delivered as part of a 1-week outreach trip in rural Nicaragua. Methods In February 2017, as part of an ongoing collaboration among the University of South Carolina, the Medical University of South Carolina, and OneWorld Health, the authors conducted an observational prospective study of all of the patients who received a POCUS examination as part of standard clinical practice during an STMM to Sebaco, Nicaragua. The goal was to determine how often POCUS changed medical management. In addition, the number and types of scans performed were recorded to assess the most common reasons for POCUS use. Results More than 1100 patients were seen, and a total of 79 POCUS examinations were performed on 59 patients by 2 physicians with extensive POCUS training. Eighty percent of the patients were women, with an average age of 40.5 years (range 1.6-87 years). The use of US changed management for 35.6% of total patients examined (N = 21), divided among changes in diagnosis, pharmacotherapy, new referral, or referral not needed. The average time to perform a POCUS examination was 6.0 minutes. A wide range of POCUS examinations were performed, with lung, gallbladder, obstetric/gynecologic, and cardiac examinations performed most often. Conclusions Incorporating POCUS by trained physicians in an RLS as part of an STMM was successful and often changed management. As interest in nonemergency and noncritical care POCUS increases and proliferation of low-cost, accurate, handheld US devices continues, it is probable that more physicians traveling to RLSs will use POCUS as part of STMMs, positively affecting patient care.

We investigated type 2 diabetes (T2D) genetic susceptibility via multi-ancestry meta-analysis of 228,499 cases and 1,178,783 controls in the Million Veteran Program (MVP), DIAMANTE, Biobank Japan and other studies. We report 568 associations, including 286 autosomal, 7 X-chromosomal and 25 identified in ancestry-specific analyses that were previously unreported. Transcriptome-wide association analysis detected 3,568 T2D associations with genetically predicted gene expression in 687 novel genes; of these, 54 are known to interact with FDA-approved drugs. A polygenic risk score (PRS) was strongly associated with increased risk of T2D-related retinopathy and modestly associated with chronic kidney disease (CKD), peripheral artery disease (PAD) and neuropathy. We investigated the genetic etiology of T2D-related vascular outcomes in the MVP and observed statistical SNP-T2D interactions at 13 variants, including coronary heart disease (CHD), CKD, PAD and neuropathy. These findings may help to identify potential therapeutic targets for T2D and genomic pathways that link T2D to vascular outcomes.

BackgroundResearch is needed to better understand relations between immunosuppression and HIV viraemia and risk for non-Hodgkin lymphoma, a common cancer in people living with HIV. We aimed to identify key CD4 count and HIV RNA (viral load) predictors of risk for non-Hodgkin lymphoma, overall and by subtype.MethodsWe studied people living with HIV during 1996-2014 from 21 Canadian and US cohorts participating in the North American AIDS Cohort Collaboration on Research and Design. To determine key independent predictors of risk for non-Hodgkin lymphoma, we assessed associations with time-updated recent, past, cumulative, and nadir or peak measures of CD4 count and viral load, using demographics-adjusted, cohort-stratified Cox models, and we compared models using Akaike's information criterion.FindingsOf 102 131 people living with HIV during the study period, 712 people developed non-Hodgkin lymphoma. The key independent predictors of risk for overall non-Hodgkin lymphoma were recent CD4 count (ie, lagged by 6 months

PHQ-9 data from persons living with HIV (PLWH, n = 4099) being screened for depression in three clinics in the southeastern USA were used to determine the prevalence of suicidal ideation (SI). SI was reported by 352 (8.6 %); associated with3 years since HIV diagnosis (1.69; 95 %CI 1.35, 2.13), and HIV RNA50 copies/ml (1.70, 95 %CI 1.35, 2.14). Data from PLWH enrolled in a depression treatment study were used to determine the association between moderate-to-high risk SI (severity) and SI frequency reported on PHQ-9 screening. Over forty percent of persons reporting that SI occurred on "more than half the days" (by the PHQ-9) were assessed as having a moderate-to-high risk for suicide completion during the Mini International Neuropsychiatric Interview. SI, including moderate-to-high risk SI, remains a significant comorbid problem for PLWH who are not fully stabilized in care (as indicated by detectable HIV RNA or HIV diagnosis for less than 3 years).

Although oncolytic viruses have shown clinical efficacy for local treatment of cancerous tumors, the ability to induce immune-mediated regression to visceral lesions is not robust. Immune checkpoint modulation has been efficacious in a fraction of cancers associated with an inflamed microenvironment but is associated with toxicity due to nonspecific T-cell activation. Therefore, combining these two strategies has the exciting potential to be an effective cancer therapy. Oncolytic virus can be genetically modified to decrease pathogenicity to normal cells and to increase their lytic potential and ability to stimulate antitumor immunity, thus improving the risk-benefit ratio for cancer patients. Oncorus oHSV (ONCR) are novel oncolytic herpes simplex virus type-1 vectors developed for the treatment of solid tumors. ONCR utilizes a unique conditional-lethal strategy in which tissue-specific miRs binding sites are inserted into early genes essential for viral replication and in the neurovirulence gene ICP34.5. This strategy curtails viral replication in normal cells, including neurons, and limits the expression of g34.5 to tumor cells, thus promoting potent viral replication in presence of type I interferon. Fifteen immunostimulatory transgenes and combination thereof were systematically evaluated in dual flank syngeneic mouse tumor models to test both for oncolysis and abscopal efficacy on the contralateral noninjected tumor. Among the selected transgenes, IL-12 was found to elicit the most potent efficacy on the ipsilateral and contralateral tumors. We demonstrated that the replication of ONCR and the expression of IL-12 was limited to the injected tumors. By contrast, induction of systemic immunity as assessed by IFNg production in contralateral tumors and in plasma was observed. ONCR expressing IL-12 elicited efficacy in multiple subcutaneous and metastatic models. Additional payloads designed to stimulate antigen presentation, recruitment of immune cells and inhibition of tumor immune suppression were identified as further enhancing IL-12 activity. Data supporting the selection of a suite of payloads cloned into a single ONCR vector will be presented. ONCR represents a new class of oncolytic virus that promote antitumor responses through a multiprong mechanism of action dependent on selective tumor cell killing, the induction of systemic antitumor immunity and reversion of immune suppression. Citation Format: Lorena Lerner, Edward M. Kennedy, Terry Farkaly, Allison Colthart, Caity Montagna, Prajna Behera, Judith Jacques, Peter Grzesik, Jennifer Lee, Agnieszka Denslow, Jacqueline Gursha, Brian Haines, Michael Ball, Daniel Wambua, Cecilia Kwong, Lingxin Kong, Michael Paglia, Laura Viggiano Salta, Lorenz Ponce, Caroline Webb, Mitchell Finer, Christophe Quéva. microRNA attenuated oHSV-1 armed with multiple immunomodulatory payloads mediates robust and selective antitumor immune response in preclinical tumor models [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr B23.

Oncolytic viruses represent a new class of therapeutic agents for the treatment of cancers that poorly respond to immune checkpoint inhibitors. Oncorus is developing ONCR-177, an oncolytic herpes simplex virus engineered for enhanced oncolysis and antitumor immunity. ONCR-177 is replication competent in tumor cells, but its replication and neuropathic activities are attenuated in healthy cells using miRNA-dependent degradation of viral transcripts and by mutations in UL37 that prevent retrograde transport in neurons. Efficacy is enhanced by a gain of function in the fusogenic glycoprotein B to enhance viral entry and inactivation of US12 to restore antigen processing. ONCR-177 is armed with five immunostimulatory transgenes: IL-12, CCL4, FLT3LG, a PD-1 humanized antagonist VHH nanobody, and the CTLA4 blocking monoclonal antibody ipilimumab. The antitumor effect of ONCR-177 utilizes two distinct modalities of immune stimulation. First, ONCR-177 is specific for tumor cells where infection and replication result in direct tumor cell killing. Second, lysis of tumor cells and expression of ONCR-177 immune payloads stimulate the immune environment through multiple mechanisms: innate signaling through production of PAMP/DAMP signals, immune cell recruitment, exposure of tumor-specific antigens, and activation of the adaptive immune response. Tumor-specific immunogenicity was evaluated using mONCR-171, a mouse functional surrogate for ONCR-177, that is built on the same base vector ONCR-159 but expresses the immune transgenes suitable for murine studies. In a CT26 bilateral colon carcinoma tumor model, immune responses elicited by intratumoral injection of mONCR-171 and ONCR-159 were compared. Intratumoral T cells were evaluated for effector phenotype and function in response to a tumor-associated antigen. We observed a shift toward enhanced activation in the mONCR-171 treatment group. Treatment with mONCR-171 resulted in more tumor-associated CD8+ T cells, higher activation, and more effector cells. This group also had lower PD-1 expression, fewer Treg cells, and a favorable CD8:Treg ratio. The tumor-specific response was assessed using the CT26 tumor-associated antigen AH1, a peptide derived from envelope glycoprotein 70 (gp70) of endogenous murine leukemia virus (MuLV). Treatment with mONCR-171 elicited significantly more IFNγ and TNFα producing, intratumoral CD8+ T cells, producing significantly higher levels of IFNγ. The increase in antitumor immunogenicity with mONCR-171 treatment was further evidenced by the increase in polyfunctional CD8+ T cells, producing IFNγ, TNFα, and/or IL-2 in response to antigen stimulation. These results highlight the dual modality mechanism of action of mONCR-171 treatment though the direct tumor cell killing and immune stimulation through the antiviral response and their enhancement by the immune stimulatory transgenes. Citation Format: Melissa Hayes, Agnieska Denslow, Jacqueline Gurshaw, Daniel Wambua, Shreeya Khatiwada, Lingxin Kong, Jacob Spinale, Prajna Behera, Peter Grzesik, Jennifer Lee, Terry Farkaly, Edward Kennedy, Lorena Lerner, Christophe Quéva, Brian Haines, Sonia Feau. Dual mechanism of ONCR-177 enhances antitumor immunogenicity [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr B74.

Author(s): Lee, Jennifer S; Cole, Stephen R; Achenbach, Chad J; Dittmer, Dirk P; Richardson, David B; Miller, William C; Mathews, Christopher; Althoff, Keri N; Moore, Richard D; Eron, Joseph J; Center for AIDS Research (CFAR) Network of Integrated Clinical Systems (CNICS) | Abstract: BackgroundCancer causes significant morbidity and mortality among HIV patients in the US due to extended life expectancy with access to effective antiretroviral therapy. Low, detectable HIV RNA has been studied as a risk factor for adverse health outcomes, but its clinical impact on cancer risk remains unclear. The objective of this study was to determine whether HIV RNA l1,000 copies/mL six months after starting therapy was associated with 10-year first cancer risk.MethodsWe followed 7,515 HIV therapy initiators from a US-based multicenter clinical cohort from 1998 to 2014. We used nonparametric multiple imputation to account for viral loads that fell below assay detection limits, and categorized viral loads six months after therapy initiation into four groups: l20, 20-199, 200-999, and g999 copies/mL. We calculated estimates of the cumulative incidence of cancer diagnosis, accounting for death as a competing event. Inverse probability of exposure and censoring weights were used to control for confounding and differential loss to follow up, respectively.ResultsCrude 10-year first cancer risk in the study sample was 7.03% (95% CI: 6.08%, 7.98%), with the highest risk observed among patients with viral loads between 200 and 999 copies/mL six months after ART initiation (10.7%). After controlling for baseline confounders, 10-year first cancer risk was 6.90% (95% CI: 5.69%, 8.12%), and was similar across viral load categories.ConclusionOverall risk of first cancer was not associated with incomplete viral suppression; however, cancer remains a significant threat to HIV patients after treatment initiation. As more HIV patients gain access to treatment in the current "treat all" era, occurrences of incomplete viral suppression will be observed more frequently in clinical practice, which supports continued study of the role of low-level HIV RNA on cancer development.

Herpes simplex virus 1 (HSV-1) establishes latent infection in neurons via a variety of epigenetic mechanisms that silence its genome. The cellular CCCTC-binding factor (CTCF) functions as a mediator of transcriptional control and chromatin organization and has binding sites in the HSV-1 genome. We constructed an HSV-1 deletion mutant that lacked a pair of CTCF-binding sites (CTRL2) within the latency-associated transcript (LAT) coding sequences and found that loss of these CTCF-binding sites did not alter lytic replication or levels of establishment of latent infection, but their deletion reduced the ability of the virus to reactivate from latent infection. We also observed increased heterochromatin modifications on viral chromatin over the LAT promoter and intron. We therefore propose that CTCF binding at the CTRL2 sites acts as a chromatin insulator to keep viral chromatin in a form that is poised for reactivation, a state which we call poised latency., IMPORTANCE Herpes simplex virus 1 (HSV-1) is a human pathogen that persists for the lifetime of the host as a result of its ability to establish latent infection within sensory neurons. The mechanism by which HSV-1 transitions from the lytic to latent infection program is largely unknown; however, HSV-1 is able to coopt cellular silencing mechanisms to facilitate the suppression of lytic gene expression. Here, we demonstrate that the cellular CCCTC-binding factor (CTCF)-binding site within the latency associated transcript (LAT) region is critical for the maintenance of a specific local chromatin structure. Additionally, loss of CTCF binding has detrimental effects on the ability to reactivate from latent infection. These results argue that CTCF plays a critical role in epigenetic regulation of viral gene expression to establish and/or maintain a form of latent infection that can reactivate efficiently.

To determine whether there is a threshold of detectable HIV RNA under 1000 copies/ml after antiretroviral therapy initiation associated with 10-year all-cause mortality.This study included nearly 8000 patients from a US-based multicenter clinical cohort who started antiretroviral therapy between 1 January 1998 and 31 December 2013. Viral load was assessed 6 months after initiation of therapy. Patients were followed from 6 months after therapy initiation (between 1 July 1998 and 30 June 2014) until death, and data were administratively censored after 10 years or on 31 December 2014.We used nonparametric multiple imputation to account for left-censored viral load measurements, Cox proportional hazards models to estimate all-cause mortality hazard ratios, Nelson-Aalen cumulative hazard estimates to construct risk curves, and inverse probability of exposure weights to standardize estimated hazard ratios and risk curves to the total study population.Plots of standardized hazard ratio estimates and 95% confidence intervals indicated there was no demonstrable viral load threshold between 30 and 500 copies/ml associated with a marked increase in 10-year mortality. The standardized 10-year risk of mortality among patients with viral loads between 400 and 999 copies/ml 6 months after starting treatment was comparable with the risk of mortality among patients with viral loads between 1000 and 4 million copies/ml (20 vs. 23%).Incomplete suppression of plasma HIV RNA 6 months after starting therapy is associated with substantial 10-year all-cause mortality risk, highlighting the importance of rapid viral load suppression after therapy initiation.

Many viruses undergo an acute infection in the host organism and then are cleared by the ensuing host immune response, but other viruses establish a persistent infection involving a latent infection or a chronic infection. Latent infection by the herpesviruses or human immunodeficiency virus involves epigenetic silencing of the DNA genome or proviral genome, respectively. Latent infection was previously thought to be a default pathway resulting from infection of a nonpermissive cell, but recent studies have shown that viral gene products can promote epigenetic silencing and latent infection. This review will summarize the viral gene products that have been shown to promote epigenetic silencing of the genomes and their potential for therapeutics to target these viral gene products and disrupt or lock in latent infection.

ONCR-177 is a highly modified recombinant oncolytic Herpes Simplex Virus (oHSV) designed to be a safe and efficacious therapy for the treatment of solid tumor indications. Complementary safety mechanisms, such as tissue-specific miR attenuation of essential viral genes and UL37 mutation, were introduced to reduce replication, neuropathic activity, and latency in normal cells, while preserving oncolytic ability in tumor cells. In addition, ONCR-177 is armed with five transgenes: the NK and T cell activating cytokine IL-12, the chemokines CCL4 and FLT3LG (extracellular domain) to allow for expansion and recruitment of classical dendritic cells, and antagonists to the clinically validated immune checkpoint targets PD-1 and CTLA-4 to counter T cell exhaustion. Therefore, ONCR-177 is proposed to have a dual mechanism of action whereby the miR attenuation strategy allows for selective oncolysis of tumors cells and the transgenes mediate potent stimulation of systemic anti-tumor immunity. Since human IL-12 and the anti-CTLA-4 antagonist do not cross-react with the mouse targets, most nonclinical pharmacology studies were conducted with the mouse surrogate mONCR-171, which expresses within the same base vector as ONCR-177 the mouse equivalent to the ONCR-177 transgenes. Intra-tumoral administration of mONCR-171 in the oHSV-sensitive A20 BALB/c lymphoma bilateral tumor model resulted in response rates (partial and complete tumor regressions) of 100% and 80%, respectively, on the injected (ipsilateral) and distant (contralateral) tumor. mONCR-171 was also highly efficacious in the B16F10 melanoma model, an oHSV-resistant C57BL/6 based tumor model engineered to be permissive to oHSV by introduction of Nectin-1, and in the oHSV-resistant MC38 C57BL/6 colon carcinoma model. Abscopal anti-tumor activity could not be explained by propagation of the virus since viral DNA and transgenes were only detectable in the injected tumor. Rather, mONCR-171 treatment resulted in increased numbers of activated NK cells, CD8 and CD4 T cells, and classical dendritic cells. The proportion of Tregs decreased, resulting in large CD8/Treg ratios. These changes in immune contexture occurred in both the ipsilateral and contralateral tumor and were more pronounced with mONCR-171 treatment compared to the base vector without transgenes, indicating that the observed abscopal effects were due to the elicitation of systemic anti-tumor immunity mediated in part by the transgenes. These encouraging preclinical data warrant the clinical investigation of ONCR-177 in patients with metastatic cancer. Citation Format: Brian B. Haines, Agnieszka Denslow, Michael S. Ball, Jacqueline Gursha, Daniel Wambua, Cecilia Kwong, Lingxin Kong, Prajna Behera, Peter Grzesik, Caitlin Goshert, Allison Colthart, Jennifer S. Lee, Terry Farkaly, Edward M. Kennedy, Lorena Lerner, Christophe Queva. Development of ONCR-177, an miR-attenuated oncolytic HSV-1 designed to potently activate systemic antitumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 940.

This research describes the development and findings of a literature review and analysis meant to inform the international torture and trauma treatment community. The review focuses on interventions that have been used among populations affected by torture, based on a review of journals indexed in commonly used search engines. Work on the review began in September 2008 and continued to be updated until March 2014. In total, 88 studies of interventions for torture victims were identified. Studies ranged from randomized controlled trials utilizing evidence-based treatments to case studies employing non-structured, supportive therapies. Based on the results of the analysis, we have included recommendations for interventions that demonstrate effectiveness in treating survivors of torture and other systematic violence who suffer from PTSD, depression and anxiety. Priorities for mental health research for survivors of torture and other systematic violence are also recommended.

Latent infections by viruses usually involve minimizing viral protein expression so that the host immune system cannot recognize the infected cell through the viral peptides presented on its cell surface. Herpes simplex virus (HSV), for example, is thought to express noncoding RNAs such as latency-associated transcripts (LATs) and microRNAs (miRNAs) as the only abundant viral gene products during latent infection. Here we describe analysis of HSV-1 mutant viruses, providing strong genetic evidence that HSV-infected cell protein 0 (ICP0) is expressed during establishment and/or maintenance of latent infection in murine sensory neurons in vivo. Studies of an ICP0 nonsense mutant virus showed that ICP0 promotes heterochromatin and latent and lytic transcription, arguing that ICP0 is expressed and functional. We propose that ICP0 promotes transcription of LATs during establishment or maintenance of HSV latent infection, much as it promotes lytic gene transcription. This report introduces the new concept that a lytic viral protein can be expressed during latent infection and can serve dual roles to regulate viral chromatin to optimize latent infection in addition to its role in epigenetic regulation during lytic infection. An additional implication of the results is that ICP0 might serve as a target for an antiviral therapeutic acting on lytic and latent infections., Importance Latent infection by viruses usually involves minimizing viral protein synthesis so that the host immune system cannot recognize the infected cells and eliminate them. Herpes simplex virus has been thought to express only noncoding RNAs as abundant gene products during latency. In this study, we found genetic evidence that an HSV lytic protein is functional during latent infection, and this protein may provide a new target for antivirals that target both lytic and latent infections.

Herpesviruses must contend with host cell epigenetic silencing responses acting on their genomes upon entry into the host cell nucleus. In this study, we confirmed that unchromatinized herpes simplex virus 1 (HSV-1) genomes enter primary human foreskin fibroblasts and are rapidly subjected to assembly of nucleosomes and association with repressive heterochromatin modifications such as histone 3 (H3) lysine 9-trimethylation (H3K9me3) and lysine 27-trimethylation (H3K27me3) during the first 1 to 2 h postinfection. Kinetic analysis of the modulation of nucleosomes and heterochromatin modifications over the course of lytic infection demonstrates a progressive removal that coincided with initiation of viral gene expression. We obtained evidence for three phases of heterochromatin removal from an early gene promoter: an initial removal of histones and heterochromatin not dependent on ICP0, a second ICP0-dependent round of removal of H3K9me3 that is independent of viral DNA synthesis, and a third phase of H3K27me3 removal that is dependent on ICP0 and viral DNA synthesis. The presence of ICP0 in transfected cells is also sufficient to promote removal of histones and H3K9me3 modifications of cotransfected genes. Overall, these results show that ICP0 promotes histone removal, a reduction of H3K9me3 modifications, and a later indirect reduction of H3K27me3 modifications following viral early gene expression and DNA synthesis. Therefore, HSV ICP0 promotes the reversal of host epigenetic silencing mechanisms by several mechanisms., IMPORTANCE The human pathogen herpes simplex virus (HSV) has evolved multiple strategies to counteract host-mediated epigenetic silencing during productive infection. However, the mechanisms by which viral and cellular effectors contribute to these processes are not well defined. The results from this study demonstrate that HSV counteracts host epigenetic repression in a dynamic stepwise process to remove histone 3 (H3) and subsequently target specific heterochromatin modifications in two distinct waves. This provides the first evidence of a stepwise reversal of host epigenetic silencing by viral proteins. This work also suggests that targets capable of disrupting the kinetics of epigenetic regulation could serve as potential antiviral therapeutic agents.

A thorough understanding of the events during mammalian spermatogenesis requires studying specific molecular signatures of individual testicular cell populations as well as their interaction in co-cultures. However, most purification techniques to isolate specific testicular cell populations are timeconsuming, require large numbers of animals, and/or are only able to isolate a few cell types. Here we describe a cost-effective and timesaving approach that uses a single protocol to enrich multiple testicular cell populations (Sertoli, Leydig, and several spermatogenic cell populations) from as few as one mouse. Our protocol combines rigorous enzymatic digestion of seminiferous tubules with counter-current centrifugal elutriation, yielding specific testicular cell populations with >80%–95% purity.

BACKGROUND. Men who receive androgen-deprivation therapy (ADT) for prostate cancer experience several side effects from this treatment. A few recent studies have examined the cognitive implications of ADT and how they impact a patient's treatment decision-making, occupational pursuits, and quality of life. For this report, the authors explored possible mechanisms for this association, reviewed research in animal studies and aging men, and examined the growing literature focused on the relation between ADT and cognitive functioning in patients with prostate cancer. METHODS. A systematic literature search was conducted using the PubMed and Information Sciences Institute Web of Knowledge-Web of Science databases to identify relevant studies that investigated the relation between ADT in men with prostate cancer and its cognitive effects. RESULTS. Testosterone and its derivatives may have an impact on cognition through several mechanisms in the brain, as supported by studies of animals and in aging men. Studies that researched the impact of ADT on cognition in patients with prostate cancer patients were designed relatively well but suffered from small sample sizes. Between 47% and 69% of men on ADT declined in at least 1 cognitive area, most commonly in visuospatial abilities and executive functioning. Some studies reported contradictory results with increased functioning in verbal memory. CONCLUSIONS. There is a strong argument that androgen-ablation therapy is linked to subtle but significant cognitive declines in men with prostate cancer. The authors believe that clinicians should become aware of this correlation as the use of ADT increases and should inform and monitor patients for this possible side effect of treatment. Cancer 2008. ©2008 American Cancer Society.

This study demonstrates that experience and development interact to influence the "cross-race effect." In a multination study (n=245), Caucasian children and adults of European ancestry living in the United States, Norway, or South Africa, as well as biracial (Caucasian-African American) children and adults living in the United States, were tested for recognition of Asian, African, and Caucasian faces. Regardless of national or biracial background, 8- to 10-year-olds, 12- to 14-year-olds, and adults recognized own-race faces more accurately than other-race faces, and did so to a similar extent, whereas 5- to 7-year-olds recognized all face types equally well. This same developmental pattern emerged for biracial children and adults. Thus, early meaningful exposure did not substantially alter the developmental trajectory. During young childhood, developmental influences on face processing operate on a system sufficiently plastic to preclude, under certain conditions, the cross-race effect.

Introduction Tracheostomy decannulation in the paediatric patient is usually considered when there is resolution or significant improvement in the original indication for the tracheostomy. The child's cardiorespiratory function needs to be optimized and assessment of the readiness for decannulation is generally by endoscopic evaluation to confirm airway patency and vocal cord mobility. Functional airway assessment procedures include downsizing the tracheostomy, adding fenestration, speaking valves and capping the tracheostomy tube. Few objective measures have been demonstrated to accurately predict the likelihood of successful decannulation. This study aims to evaluate the usefulness of polysomnography (PSG) with a capped tracheostomy tube, as an adjunct to airway endoscopy and traditional decannulation procedures, to predict decannulation outcome. Methods A retrospective review was conducted for patients who underwent “capped” PSG prior to a trial of tracheostomy decannulation at the Sydney Children's Hospitals Network. The charts were reviewed for clinical data and PSG results. Results 30 children with a total of 40 PSG reports were included in this study. There was a statistically significant difference in mean oxygen saturation, minimum oxygen saturation, total apnoea/hypopnoea index, desaturations >3%, and desaturations >3% index between those that had successful decannulation compared to failed decannulation. The measures with the greatest significance, and therefore, the best predictors of decannulation outcome were total apnoea/hypopnoea index (3.35 events/h vs. 18.5 events/h, p = 0.004) and desaturation events (20.33 events vs. 192 events, p = 0.001). Conclusions PSG with a capped tracheostomy tube is a useful, objective tool to complement endoscopy and functional airway assessment in the consideration of decannulation in the paediatric population.

This study was designed to determine if vacuum-induced suction increased the number of blood vessels in healthy dog gingiva as a prelude to future studies testing vacuum therapy for improving local blood supply and controlling periodontal disease.The buccal gingiva of five dogs was treated with subatmospheric pressure for 5 days, with untreated tissues acting as controls. Biopsies were analyzed for vascular endothelial growth factors (VEGF) and blood vessels were counted.VEGF and vessel numbers were elevated in treatment groups compared to controls (P0.05).A single daily application of subatmospheric pressure might be beneficial for healing damaged or diseased gingival tissues. .

The high prevalence of Herpesviruses in the population and the maintenance of lifelong latent reservoirs are challenges to the control of herpetic diseases, despite the availability of antiviral pharmaceuticals that target viral DNA replication. In addition to oral and genital lesions, herpes simplex virus infections and recurrent reactivations from the latent pool can result in severe pathology including neonatal infection and mortality, blindness due to ocular keratitis, and viral-induced complications in immunosuppressed individuals. Herpesviruses, like their cellular hosts, are subject to the regulatory impacts of chromatin and chromatin modulation machinery that promotes or suppresses gene expression. The initiation of herpes simplex virus infection and reactivation from latency is dependent on a transcriptional coactivator complex that contains two required histone demethylases, LSD1 and JMJD2s. Inhibition of either of these enzymes results in heterochromatic suppression of the viral genome and a block to infection and reactivation in vitro. Here, the concept of epigenetic suppression of viral infection is demonstrated in three animal models of herpes simplex virus infection and disease. Inhibition of LSD1 via treatment of animals with the monoamine oxidase inhibitor tranylcypromine results in suppression of viral lytic infection, subclinical shedding, and reactivation from latency in vivo. Phenotypic suppression is correlated with enhanced epigenetic suppression of the viral genome and suggests that, even during latency, the chromatin state of the virus is dynamic. Given the expanding development of epipharmaceuticals, this approach has substantial potential for anti-herpetic treatments with distinct advantages over the present pharmaceutical options.