Urethrocutaneous fistulas after voluntary medical male circumcision for HIV prevention-15 African Countries, 2015-2019.

BACKGROUND: Voluntary medical male circumcision (VMMC) is an HIV prevention strategy recommended to partially protect men from heterosexually acquired HIV. From 2015 to 2019, the President's Emergency Plan for AIDS Relief (PEPFAR) has supported approximately 14.9 million VMMCs in 15 African countries. Urethrocutaneous fistulas, abnormal openings between the urethra and penile skin through which urine can escape, are rare, severe adverse events (AEs) that can occur with VMMC. This analysis describes fistula cases, identifies possible risks and mechanisms of injury, and offers mitigation actions. METHODS: Demographic and clinical program data were reviewed from all reported fistula cases during 2015 to 2019, descriptive analyses were performed, and an odds ratio was calculated by patient age group. RESULTS: In total, 41 fistula cases were reported. Median patient age for fistula cases was 11 years and 40/41 (98%) occurred in patients aged < 15 years. Fistulas were more often reported among patients < 15 compared to ≥ 15 years old (0.61 vs. 0.01 fistulas per 100,000 VMMCs, odds ratio 50.9 (95% confidence interval [CI] = 8.6-2060.0)). Median time from VMMC surgery to appearance of fistula was 20 days (interquartile range (IQR) 14-27). CONCLUSIONS: Urethral fistulas were significantly more common in patients under age 15 years. Thinner tissue overlying the urethra in immature genitalia may predispose boys to injury. The delay between procedure and symptom onset of 2-3 weeks indicates partial thickness injury or suture violation of the urethral wall as more likely mechanisms of injury than intra-operative urethral transection. This analysis helped to inform PEPFAR's recent decision to change VMMC eligibility policy in 2020, raising the minimum age to 15 years.

Early acid/base and electrolyte changes in permanent middle cerebral artery occlusion: Aged male and female rats.

BACKGROUND: Early changes in acid/base and electrolyte concentrations could provide insights into the development of neuropathology at the onset of stroke. We evaluated associations between acid/base and electrolyte concentrations, and outcomes in permanent middle cerebral artery occlusion (pMCAO) model. METHODS: 18-month-old male and female Sprague-Dawley rats underwent pMCAO. Pre-, post- (7 min after occlusion), and at 72 hr of pMCAO venous blood samples provided pH, carbon dioxide, oxygen, glucose, hematocrit, hemoglobin, and electrolyte values of ionized calcium, potassium, and sodium. Multiple linear regression determined predictors of infarct and edema volumes from these values, Kaplan-Meier curve analyzed morality between males and females at 72 hr, and a Cox regression model was used to determine predictors for mortality. RESULTS: Analysis indicated significant differences in acid/base balance and electrolyte levels in aged rats not dependent on sex between the three time points in the pMCAO model. Changes in pH (from pre- to post and post- to 72 hr) and changes in sodium and ionized calcium (from post- to 72 hr) were predictors of infarct volume and edema volume, respectively. Cox Regression revealed there is a 3.25 times increased risk for mortality based on changes in bicarbonate (pre- to post-MCAO). CONCLUSIONS: These early venous blood changes in acid/base balance and electrolytes can be used to predict stroke outcomes in our rat model of stroke. This study provides potential biomarkers to be examined in the human condition that could provide profound prognostic tools for stroke patients.

Correction to: Association of Male Circumcision with Women's Knowledge of its Biomedical Effects and With Their Sexual Satisfaction and Function: A Systematic Review.

The article Association of Male Circumcision with Women's Knowledge of its Biomedical Effects and With Their Sexual Satisfaction and Function: A Systematic Review, written by Jonathan M. Grund, Tyler S. Bryant, Carlos Toledo, Inimfon Jackson, Kelly Curran, Sheng Zhou, Jorge Martin del Campo, Ling Yang, Apollo Kivumbi, Peizi Li, Naomi Bock, Joanna Taliano, Stephanie M. Davis was originally published electronically on the publisher's internet portal (currently SpringerLink) on 24 October 2018 without open access.

Case series of glans injuries during voluntary medical male circumcision for HIV prevention - eastern and southern Africa, 2015-2018.

BACKGROUND: Male circumcision confers partial protection against heterosexual HIV acquisition among men. The President's Emergency Plan for AIDS Relief (PEPFAR) has supported > 18,900,000 voluntary medical male circumcisions (VMMC). Glans injuries (GIs) are rare but devastating adverse events (AEs) that can occur during circumcision. To address this issue, PEPFAR has supported multiple interventions in the areas of surveillance, policy, education, training, supply chain, and AE management. METHODS: Since 2015, PEPFAR has conducted surveillance of GIs including rapid investigation by the in-country PEPFAR team. This information is collected on standardized forms, which were reviewed for this analysis. RESULTS: Thirty-six GIs were reported from 2015 to 2018; all patients were < 15 years old (~ 0·7 per 100,000 VMMCs in this age group) with a decreasing annual rate (2015: 0.7 per 100,000 VMMCs; 2018: 0.4 per 100,000 VMMC; p = 0.02). Most (64%) GIs were partial or complete amputations. All amputations among 10-14 year-olds occurred using the forceps-guided (FG) method, as opposed to the dorsal-slit (DS) method, and three GIs among infants occurred using a Mogen clamp. Of 19 attempted amputation repairs, reattached tissue was viable in four (21%) in the short term. In some cases, inadequate DS method training and being overworked, were found. CONCLUSION: Following numerous interventions by PEPFAR and other stakeholders, GIs are decreasing; however, they have not been eliminated and remain a challenge for the VMMC program. Preventing further cases of complete and partial amputation will likely require additional interventions that prevent use of the FG method in young patients and the Mogen clamp in infants. Improving management of GIs is critical to optimizing outcomes.

Association of Male Circumcision with Women's Knowledge of its Biomedical Effects and With Their Sexual Satisfaction and Function: A Systematic Review.

Male circumcision (MC) is a key HIV prevention intervention for men in countries with high HIV prevalence. Women's understanding of MC is important but poorly understood. We conducted a systematic review including women's knowledge of MC's biomedical impacts and its association with female sexual satisfaction and function through October 2017. Thirty-eight articles were identified: thirty-two with knowledge outcomes, seven with sexual satisfaction, and four with sexual function (N = 38). Respondent proportions aware MC protects men from HIV were 9.84-91.8% (median 60.0%). Proportions aware MC protects men from STIs were 14.3-100% (72.6%). Proportions aware MC partially protects men from HIV were 37.5-82% (50.7%). Proportions aware MC is not proven to protect women from infection by an HIV-positive partner were 90.0-96.8% (93.0%). No increases over time were noted. Women's MC knowledge is variable. Education could help women support MC and make better-informed sexual decisions.

Neuroprotective activity of leukemia inhibitory factor is relayed through myeloid zinc finger-1 in a rat model of stroke.

The aim of this study was to determine whether leukemia inhibitory factor (LIF) exerts its neuroprotective effects through signal transduction of the transcription factor myeloid zinc finger-1 (MZF-1). According to the hypothesis of this study, MZF-1 mediates LIF-induced neuroprotective signaling during ELVO through increased expression and transcriptional activity. To determine the in vivo role of MZF-1 in LIF-induced neuroprotection, we used Genomatix software was used to MZF-1 sites in the promoter region of the rat superoxide dismutase 3 (SOD3) gene. Stroke was induced via middle cerebral artery occlusion, and animals were administered PBS or 125 µg/kg LIF at 6, 24, and 48 h after the injury. MZF-1 binding activity was measured using electrophoretic mobility shift assay (EMSA) and its expression/localization were determined using western blot and immunohistochemical analysis. To determine whether MZF-1 relays LIF-induced neuroprotection in vitro, primary cultured neurons were subjected to oxygen-glucose deprivation (OGD) after treatment with PBS or LIF. MZF-1 expression was measured in vitro using real time PCR and immunohistochemical staining. Transfection with siRNA was used to determine whether LIF protected cultured neurons against OGD after silencing MZF-1 expression. Four MZF-1 binding sites were identified by Genomatix, and EMSA confirmed in vivo binding activity in brain after MCAO. LIF significantly increased MZF-1 protein levels compared to PBS treatment at 72 h post-MCAO. In vivo nuclear localization of MZF-1 as well as co-localization of SOD3 and MZF-1 was observed in the cortical neurons of LIF-treated rats. Primary cultured neurons treated with LIF had significantly higher levels of MZF-1 mRNA and protein after LIF treatment compared to neurons treated with PBS. Finally, knockdown MZF-1 using siRNA counteracted the neuroprotective effects of LIF in vitro. These data demonstrate that LIF-mediated neuroprotection is dependent upon MZF-1 activity. Furthermore, these findings identify a novel neuroprotective pathway that employs MZF-1, a transcription factor associated with hematopoietic gene expression.

Leukemia inhibitory factor modulates the peripheral immune response in a rat model of emergent large vessel occlusion.

BACKGROUND: The migration of peripheral immune cells and splenocytes to the ischemic brain is one of the major causes of delayed neuroinflammation after permanent large vessel stroke. Other groups have demonstrated that leukemia inhibitory factor (LIF), a cytokine that promotes neural cell survival through upregulation of antioxidant enzymes, promotes an anti-inflammatory phenotype in several types of immune cells. The goal of this study was to determine whether LIF treatment modulates the peripheral immune response after stroke. METHODS: Young male (3 month) Sprague-Dawley rats underwent sham surgery or permanent middle cerebral artery occlusion (MCAO). Animals were administered LIF (125 µg/kg) or PBS at 6, 24, and 48 h prior to euthanization at 72 h. Bone marrow-derived macrophages were treated with LIF (20 ng/ml) or PBS after stimulation with interferon gamma + LPS. Western blot was used to measure protein levels of CD11b, IL-12, interferon inducible protein-10, CD3, and the LIF receptor in spleen and brain tissue. ELISA was used to measure IL-10, IL-12, and interferon gamma. Isolectin was used to label activated immune cells in brain tissue sections. Statistical analysis was performed using one-way ANOVA and Student's t test. A Kruskal-Wallis test followed by Bonferroni-corrected Mann-Whitney tests was performed if data did not pass the D'Agostino-Pearson normality test. RESULTS: LIF-treated rats showed significantly lower levels of the LIF receptor and interferon gamma in the spleen and CD11b levels in the brain compared to their PBS-treated counterparts. Fluorescence from isolectin-binding immune cells was more prominent in the ipsilateral cortex and striatum after PBS treatment compared to LIF treatment. MCAO + LIF significantly decreased splenic levels of CD11b and CD3 compared to sham surgery. MCAO + PBS treatment significantly elevated splenic levels of interferon inducible protein-10 at 72 h after MCAO, while LIF treatment after MCAO returned interferon inducible protein 10 to sham levels. LIF administration with interferon gamma + LPS significantly reduced the IL-12/IL-10 production ratio compared to macrophages treated with interferon gamma + LPS alone. CONCLUSIONS: These data demonstrate that LIF promotes anti-inflammatory signaling through alterations of the IL-12/interferon gamma/interferon inducible protein 10 pathway.

Bleeding and Blood Disorders in Clients of Voluntary Medical Male Circumcision for HIV Prevention - Eastern and Southern Africa, 2015-2016.

Male circumcision reduces the risk for female-to-male human immunodeficiency virus (HIV) transmission by approximately 60% (1) and has become a key component of global HIV prevention programs in countries in Eastern and Southern Africa where HIV prevalence is high and circumcision coverage is low. Through September 2017, the President's Emergency Plan for AIDS Relief (PEPFAR) had supported 15.2 million voluntary medical male circumcisions (VMMCs) in 14 priority countries in Eastern and Southern Africa (2). Like any surgical intervention, VMMC carries a risk for complications or adverse events. Adverse events during circumcision of males aged ≥10 years occur in 0.5% to 8% of procedures, though the majority of adverse events are mild (3,4). To monitor safety and service quality, PEPFAR tracks and reports qualifying notifiable adverse events. Data reported from eight country VMMC programs during 2015-2016 revealed that bleeding resulting in hospitalization for ≥3 days was the most commonly reported qualifying adverse event. In several cases, the bleeding adverse event revealed a previously undiagnosed or undisclosed bleeding disorder. Bleeding adverse events in men with potential bleeding disorders are serious and can be fatal. Strategies to improve precircumcision screening and performance of circumcisions on clients at risk in settings where blood products are available are recommended to reduce the occurrence of these adverse events or mitigate their effects (5).

Leukemia Inhibitory Factor-Loaded Nanoparticles with Enhanced Cytokine Metabolic Stability and Anti-Inflammatory Activity.

PURPOSE: To synthesize and assess the in vitro biological activity of nanoparticles containing leukemia inhibitory factor (LIF). These NanoLIF particles are designed to prolong the neuroprotective and anti-inflammatory actions of LIF in future preclinical studies of ischemic stroke. METHODS: LIF was packaged in nanoparticles made of poly(ethylene glycol)-poly(lactic acid) (PEG-PLA) polymer to form LIF-loaded nanoparticles (NanoLIF). The surface of NanoLIF was also modified with the CD11b antibody (CD11b-NanoLIF) targeting activated peripheral macrophages to increase cytokine delivery to inflammatory macrophages. ELISA was used to quantify bioactive cytokine inside and releasing from NanoLIF. NanoLIF biological activity was measured using the M1 murine leukemia cell proliferation assay. RESULTS: NanoLIF and CD11b-NanoLIF had diameters of approximately 30 nm, neutral surface charge, and physicochemical stability retaining biological activity of the cytokine during incubation at 25°C for 12 h. NanoLIF particles released LIF relatively fast from 0 to 6 h after incubation at 37°C followed by slow release from 24 to 72 h according to a two-phase exponential decay model. NanoLIF and CD11b-NanoLIF significantly decreased M1 cell proliferation over 72 h compared to free LIF. CONCLUSIONS: NanoLIF and CD11b-NanoLIF preserved the metabolic stability and biological activity of LIF in vitro. These results are promising to improve the therapeutic potential of LIF in treating neurodegenerative and inflammatory diseases.

Systematic review of the effect of economic compensation and incentives on uptake of voluntary medical male circumcision among men in sub-Saharan Africa.

Voluntary medical male circumcision (VMMC) prevalence in priority countries in sub-Saharan Africa, particularly among men aged ≥20 years, has not yet reached the goal of 80% coverage recommended by the World Health Organization. Determining novel strategies to increase VMMC uptake among men ≥20 years is critical to reach HIV epidemic control. We conducted a systematic review to analyze the effectiveness of economic compensation and incentives to increase VMMC uptake among older men in order to inform VMMC demand creation programs. The review included five qualitative, quantitative, and mixed methods studies published in peer reviewed journals. Data was extracted into a study summary table, and tables synthesizing study characteristics and results. Results indicate that cash reimbursements for transportation and food vouchers of small nominal amounts to partially compensate for wage loss were effective, while enrollment into lotteries offering prizes were not. Economic compensation provided a final push toward VMMC uptake for men who had already been considering undergoing circumcision. This was in settings with high circumcision prevalence brought by various VMMC demand creation strategies. Lottery prizes offered in the studies did not appear to help overcome barriers to access VMMC and qualitative evidence suggests this may partially explain why they were not effective. Economic compensation may help to increase VMMC uptake in priority countries with high circumcision prevalence when it addresses barriers to uptake. Ethical considerations, sustainability, and possible externalities should be carefully analyzed in countries considering economic compensation as an additional strategy to increase VMMC uptake.

Circumcision status at HIV infection is not associated with plasma viral load in men: analysis of specimens from a randomized controlled trial.

BACKGROUND: Male circumcision provides men with approximately 60% protection from acquiring HIV infection via heterosexual sex, and has become a key component of HIV prevention efforts in sub-Saharan Africa. Possible mechanisms for this protection include removal of the inflammatory anaerobic sub-preputial environment and the high concentration of Langerhans cells on the inside of the foreskin, both believed to promote local vulnerability to HIV infection. In people who do acquire HIV, viral load is partially determined by infecting partner viral load, potentially mediated by size of infecting inoculum. By removing a portal for virion entry, prior male circumcision could decrease infecting inoculum and thus viral load in men who become HIV-infected, conferring the known associated benefits of slower progression to disease and decreased infectiousness. METHODS: We performed an as-treated analysis of plasma samples collected under a randomized controlled trial of male circumcision for HIV prevention, comparing men based on their circumcision status at the time of HIV acquisition, to determine whether circumcision is associated with lower viral load. Eligible men were seroconverters who had at least one plasma sample available drawn at least 6 months after infection, reported no potential exposures other than vaginal sex and, for those who were circumcised, were infected more than 6 weeks after circumcision, to eliminate the open wound as a confounder. Initial viral load testing indicated that quality of pre-2007 samples might have been compromised during storage and they were excluded, as were those with undetectable or unquantifiable results. Log viral loads were compared between groups using univariable and multivariable linear regression, adjusting for sample age and sexually transmitted infection diagnosis with 3.5 months of seroconversion, with a random effect for intra-individual clustering for samples from the same man. A per-protocol analysis was also performed. RESULTS: There were no viral load differences between men who were circumcised and uncircumcised at the time of HIV infection (means 4.00 and 4.03 log10 copies/mL respectively, p = .88) in any analysis. CONCLUSION: Circumcision status at the time of HIV infection does not affect viral load in men. TRIAL REGISTRATION: The original RCT which provided the samples was ClinicalTrials.gov trial NCT00059371 .

Translational Evaluation of Acid/Base and Electrolyte Alterations in Rodent Model of Focal Ischemia.

BACKGROUND AND PURPOSE: Acid/base and electrolytes could provide clinically valuable information about cerebral infarct core and penumbra. We evaluated associations between acid/base and electrolyte changes and outcomes in 2 rat models of stroke, permanent, and transient middle cerebral artery occlusion. METHODS: Three-month old Sprague-Dawley rats underwent permanent or transient middle cerebral artery occlusion. Pre- and post-middle cerebral artery occlusion venous samples for permanent and transient models provided pH, carbon dioxide, oxygen, glucose, and electrolyte values of ionized calcium, potassium, and sodium. Multiple regression determined predictors of infarct volume from these values, and Kaplan-Meier curve analyzed morality between permanent and transient middle cerebral artery occlusion models. RESULTS: Analysis indicated significant differences in the blood gas and electrolytes between pre- to post-middle cerebral artery occlusion. A decrease in pH and sodium with increases in carbon dioxide, potassium, ionized calcium, and glucose changes were found in both middle cerebral artery occlusion models; while hematocrit and hemoglobin were significant in the transient model. pH and ionized calcium were predictors of infarct volume in the permanent model, as changes in pH and ionized calcium decreased, infarct volume increased. CONCLUSIONS: There are acute changes in acid/base balance and electrolytes during stroke in transient and permanent rodent models. Additionally, we found pH and ionized calcium changes predicted stroke volume in the permanent middle cerebral artery occlusion model. These preliminary findings are novel, and warrant further exploration in human conditions.

Scale-Up of Voluntary Medical Male Circumcision Services for HIV Prevention - 12 Countries in Southern and Eastern Africa, 2013-2016.

Countries in Southern and Eastern Africa have the highest prevalence of human immunodeficiency virus (HIV) infection in the world; in 2015, 52% (approximately 19 million) of all persons living with HIV infection resided in these two regions.* Voluntary medical male circumcision (VMMC) reduces the risk for heterosexually acquired HIV infection among males by approximately 60% (1). As such, it is an essential component of the Joint United Nations Programme on HIV/AIDS (UNAIDS) strategy for ending acquired immunodeficiency syndrome (AIDS) by 2030 (2). Substantial progress toward achieving VMMC targets has been made in the 10 years since the World Health Organization (WHO) and UNAIDS recommended scale-up of VMMC for HIV prevention in 14 Southern and Eastern African countries with generalized HIV epidemics and low male circumcision prevalence (3).† This has been enabled in part by nearly $2 billion in cumulative funding through the President's Emergency Plan for AIDS Relief (PEPFAR), administered through multiple U.S. governmental agencies, including CDC, which has supported nearly half of all PEPFAR-supported VMMCs to date. Approximately 14.5 million VMMCs were performed globally during 2008-2016, which represented 70% of the original target of 20.8 million VMMCs in males aged 15-49 years through 2016 (4). Despite falling short of the target, these VMMCs are projected to avert 500,000 HIV infections by the end of 2030 (4). However, UNAIDS has estimated an additional 27 million VMMCs need to be performed by 2021 to meet the Fast Track targets (2). This report updates a previous report covering the period 2010-2012, when VMMC implementing partners supported by CDC performed approximately 1 million VMMCs in nine countries (5). During 2013-2016, these implementing partners performed nearly 5 million VMMCs in 12 countries. Meeting the global target will require redoubling current efforts and introducing novel strategies that increase demand among subgroups of males who have historically been reluctant to undergo VMMC.

Non-muscle Mlck is required for ß-catenin- and FoxO1-dependent downregulation of Cldn5 in IL-1ß-mediated barrier dysfunction in brain endothelial cells.

Aberrant elevation in the levels of the pro-inflammatory cytokine interleukin-1ß (IL-1ß) contributes to neuroinflammatory diseases. Blood-brain barrier (BBB) dysfunction is a hallmark phenotype of neuroinflammation. It is known that IL-1ß directly induces BBB hyperpermeability but the mechanisms remain unclear. Claudin-5 (Cldn5) is a tight junction protein found at endothelial cell-cell contacts that are crucial for maintaining brain microvascular endothelial cell (BMVEC) integrity. Transcriptional regulation of Cldn5 has been attributed to the transcription factors ß-catenin and forkhead box protein O1 (FoxO1), and the signaling molecules regulating their nuclear translocation. Non-muscle myosin light chain kinase (nmMlck, encoded by the Mylk gene) is a key regulator involved in endothelial hyperpermeability, and IL-1ß has been shown to mediate nmMlck-dependent barrier dysfunction in epithelia. Considering these factors, we tested the hypothesis that nmMlck modulates IL-1ß-mediated downregulation of Cldn5 in BMVECs in a manner that depends on transcriptional repression mediated by ß-catenin and FoxO1. We found that treating BMVECs with IL-1ß induced barrier dysfunction concomitantly with the nuclear translocation of ß-catenin and FoxO1 and the repression of Cldn5. Most importantly, using primary BMVECs isolated from mice null for nmMlck, we identified that Cldn5 repression caused by ß-catenin and FoxO1 in IL-1ß-mediated barrier dysfunction was dependent on nmMlck.

Notes from the Field: Tetanus Cases After Voluntary Medical Male Circumcision for HIV Prevention--Eastern and Southern Africa, 2012-2015.

Voluntary medical male circumcision (VMMC) decreases the risk for female-to-male HIV transmission by approximately 60%, and the President's Emergency Plan for AIDS Relief (PEPFAR) is supporting the scale-up of VMMC for adolescent and adult males in countries with high prevalence of human immunodeficiency virus (HIV) and low coverage of male circumcision. As of September 2015, PEPFAR has supported approximately 8.9 million VMMCs.

Survey of obstetrician-gynecologists in the United States about toxoplasmosis: 2012 update.

PURPOSE: Toxoplasmosis, caused by the parasite Toxoplasma gondii, can have serious impacts on fetal development in the setting of acute maternal primary infection. The American College of Obstetricians and Gynecologists (ACOG) sought to determine current knowledge, practices, opinions, and educational preferences regarding T. gondii infection in pregnancy among ACOG members practicing prenatal care. METHODS: ACOG sent a survey to 1,056 members chosen by stratified random sampling from membership lists, including 370 participants and 686 non-participants in the Collaborative Ambulatory Research Network (CARN). Mailings were sent up to four times to nonresponders. RESULTS: Survey minimum response rates were 40.3% (CARN) and 19.7% (non-CARN); response rates adjusted for imputed non-eligibility were 59.7% (CARN) and 22.6% (non-CARN). Among providers, 80.2% had diagnosed no acute maternal T. gondii infections in the past 5 years, 12.7% correctly identified the screening role of the Toxoplasma avidity test, 42.6% performed serologic T. gondii screening for at least some asymptomatic pregnant women, and 62.1% of those who so did used appropriate approaches. Providers in the northeastern United States were 2.02 times more likely to routinely screen than those in the west (p = 0.025) and female providers were 1.48 times more likely than male providers (p = 0.047). The potential educational interventions considered useful by the most practitioners were updated ACOG guidelines on screening (81.4%) and management (71.7%) for acute T. gondii infection in pregnancy. CONCLUSIONS: ACOG members would benefit from educational efforts targeted at risk factor counseling and screening approaches.

Regurgitant valvular disease prevalence and progression found on echocardiogram in military aviators.

INTRODUCTION: The prevalence, progression rates, and outcomes affecting aviator valvular heart disease have not been extensively studied. METHODS: The U.S. Air Force (USAF) School of Aerospace Medicine's Clinical Sciences Database was used to determine prevalence and progression rates for regurgitant valvular disease. A subset of the initial population was further evaluated for risk factors that increased the likelihood of progression. Descriptive statistical analysis, analysis of variance, and t-test calculations were completed. RESULTS: There were 8475 unique aviators with some degree of valvular regurgitation for an overall prevalence of 3.0%. The mitral and aortic valves were most likely to have mild and moderate or greater regurgitation, respectively. Progression rates from mild to moderate were 8% in the aortic valve, 2% in the mitral valve, and less than 1% in the pulmonic and tricuspid valves. Progression rates from moderate to severe were over 20% for both the mitral and aortic valves. The only risk factors correlating to progression of valvular disease were lower levels of high-density lipoproteins in the mitral and aortic valves and triglycerides in the mitral valve. DISCUSSION: In USAF aviators, progression rates for mild or greater aortic valve regurgitation and moderate or greater mitral valve regurgitation are significant and should be followed closely. Classic risk factors of age, tobacco use, elevated blood pressure, and hyperlipidemia have no association with increased risk of valvular progression or rate of progression. Study outcomes validate the current USAF policy for valvular heart disease in aviators.

Interdependent nucleocytoplasmic trafficking and interactions of Dis3 with Rrp6, the core exosome and importin-alpha3.

Subcellular compartmentalization of exoribonucleases (RNAses) is an important control mechanism in the temporal and spatial regulation of RNA processing and decay. Despite much progress towards understanding RNAse substrates and functions, we know little of how RNAses are transported and assembled into functional, subcellularly restricted complexes. To gain insight into this issue, we are studying the exosome-binding protein Dis3, a processive 3' to 5' exoribonuclease. Here, we examine the interactions and subcellular localization of the Drosophila melanogaster Dis3 (dDis3) protein. N-terminal domain mutants of dDis3 abolish associations with the 'core' exosome, yet only reduce binding to the 'nuclear' exosome-associated factor dRrp6. We show that nuclear localization of dDis3 requires a C-terminal classic nuclear localization signal (NLS). Consistent with this, dDis3 specifically co-precipitates the NLS-binding protein importin-alpha3. Surprisingly, dDis3 constructs that lack or mutate the C-terminal NLS retain importin-alpha3 binding, suggesting that the interaction is indirect. Finally, we find that endogenous dDis3 and dRrp6 exhibit coordinated nuclear enrichment or exclusion, suggesting that dDis3, Rrp6 and importin-alpha3 interact in a complex independent of the core. We propose that the movement and deposition of this complex is important for the subcellular compartmentalization and regulation of the exosome core.

The Role of Nurses and Midwives in Expanding and Sustaining Voluntary Medical Male Circumcision Services for HIV Prevention: A Systematic and Policy Review.

ABSTRACT: Male circumcision reduces men's risk of acquiring HIV through heterosexual sex, and voluntary medical male circumcision (VMMC) is central to HIV prevention strategies in 15 sub-Saharan African countries. Nurses have emerged as primary VMMC providers; however, barriers remain to institutionalizing nurse-led VMMC. Patient safety concerns have hindered task sharing, and regulations governing nurse-performed VMMC are not always supportive or clear. We performed a systematic review on VMMC safety by provider cadre and a desk review of national policies governing the VMMC roles of nurses and midwives. Also, VMMC by nurses is safe and has become standard practice. Countries had multiple policy combinations among different documents, with only one disallowing VMMC by these cadres. Countries with alignment between policies often ensured that nursing workforces were equipped with clinical competencies through national certification. Regulatory clarity and formalized certification for nurse-performed VMMC can increase program sustainability and build nursing capacity to meet other critical basic surgical needs.

Brief Report: Modeling the Impact of Voluntary Medical Male Circumcision on Cervical Cancer in Uganda.

BACKGROUND: In addition to providing millions of men with lifelong lower risk for HIV infection, voluntary medical male circumcision (VMMC) also provides female partners with health benefits including decreased risk for human papillomavirus (HPV) and resultant cervical cancer (CC). SETTING: We modeled potential impacts of VMMC on CC incidence and mortality in Uganda as an additional benefit beyond HIV prevention. METHODS: HPV and CC outcomes were modeled using the CC model from the Spectrum policy tool suite, calibrated for Uganda, to estimate HPV infection incidence and progression to CC, using a 50-year (2018-2067) time horizon. 2016 Demographic Health Survey data provided baseline VMMC coverage. The baseline (no VMMC scale-up beyond current coverage, minimal HPV vaccination coverage) was compared with multiple scenarios to assess the varying impact of VMMC according to different implementations of HPV vaccination and HPV screening programs. RESULTS: Without further intervention, annual CC incidence was projected to rise from 16.9 to 31.2 per 100,000 women in 2067. VMMC scale-up alone decreased 2067 annual CC incidence to 25.3, averting 13,000 deaths between 2018 and 2067. With rapidly-achieved 90% HPV9 vaccination coverage for adolescent girls and young women, 2067 incidence dropped below 10 per 100,000 with or without a VMMC program. With 45% vaccine coverage, the addition of VMMC scaleup decreased incidence by 2.9 per 100,000 and averted 8000 additional deaths. Similarly, with HPV screen-and-treat without vaccination, the addition of VMMC scaleup decreased incidence by 5.1 per 100,000 and averted 10,000 additional deaths. CONCLUSIONS: Planned VMMC scale-up to 90% coverage from current levels could prevent a substantial number of CC cases and deaths in the absence of rapid scale-up of HPV vaccination to 90% coverage.