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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.

IntroductionVoluntary medical male circumcision (VMMC), an effective HIV prevention programme for men, is implemented in East and Southern Africa. Approximately 50% of VMMC clients are aged below 15 years. More targeted interventions to reach older men and others at higher short-term HIV risk are needed.MethodsWe implemented a quality improvement project testing the effectiveness of an active referral-based VMMC recruitment approach, targeting men attending STI clinics and those escorting partners to antenatal care (ANC) clinics, at Bwaila Hospital in Lilongwe, Malawi. We compared the proportions aged older than 15 years among men who received VMMC following referral from STI and ANC clinics with those among men referred from standard community mobilisation. We also analysed referral cascades to VMMC.ResultsIn total, 330 clients were circumcised after referral from STI (242) and ANC (88) clinics, as compared with 3839 other clients attributed to standard community mobilisation. All clients from ANC and STI clinics were aged over 15 years, as compared with 69% from standard community mobilisation. STI clinics had a higher conversion rate from counselling to VMMC than ANC (12% vs 9%) and a higher contribution to total circumcisions performed at the VMMC clinic (6% vs 2%).ConclusionsIntegrating VMMC recruitment and follow-up in STI and ANC clinics co-located with VMMC services can augment demand creation and targeting of men at risk of HIV, based on age and STI history. This approach can be replicated at least in similar health facilities with ANC and STI services in close proximity to VMMC service delivery.

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.

Introduction Kenya started implementing voluntary medical male circumcision (VMMC) for HIV prevention in 2008 and adopted the use of decision makers program planning tool version 2 (DMPPT2) in 2016, to model the impact of circumcisions performed annually on the population prevalence of male circumcision (MC) in the subsequent years. Results of initial DMPPT2 modeling included implausible MC prevalence estimates, of up to 100%, for age bands whose sustained high uptake of VMMC pointed to unmet needs. Therefore, we conducted a cross-sectional survey among adolescents and men aged 10–29 years to determine the population level MC prevalence, guide target setting for achieving the goal of 80% MC prevalence and for validating DMPPT2 modelled estimates. Methods Beginning July to September 2019, a total of 3,569 adolescents and men aged 10–29 years from households in Siaya, Kisumu, Homa Bay and Migori Counties were interviewed and examined to establish the proportion already circumcised medically or non-medically. We measured agreement between self-reported and physically verified circumcision status and computed circumcision prevalence by age band and County. All statistical were test done at 5% level of significance. Results The observed MC prevalence for 15-29-year-old men was above 75% in all four counties; Homa Bay 75.6% (95% CI [69.0–81.2]), Kisumu 77.9% (95% CI [73.1–82.1]), Siaya 80.3% (95% CI [73.7–85.5]), and Migori 85.3% (95% CI [75.3–91.7]) but were 0.9–12.4% lower than DMPPT2-modelled estimates. For young adolescents 10–14 years, the observed prevalence ranged from 55.3% (95% CI [40.2–69.5]) in Migori to 74.9% (95% CI [68.8–80.2]) in Siaya and were 25.1–32.9% lower than DMMPT 2 estimates. Nearly all respondents (95.5%) consented to physical verification of their circumcision status with an agreement rate of 99.2% between self-reported and physically verified MC status (kappa agreement p-value Conclusion This survey revealed overestimation of MC prevalence from DMPPT2-model compared to the observed population MC prevalence and provided new reference data for setting realistic program targets and re-calibrating inputs into DMPPT2. Periodic population-based MC prevalence surveys, especially for established programs, can help reconcile inconsistencies between VMMC program uptake data and modeled MC prevalence estimates which are based on the number of procedures reported in the program annually.

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.

BACKGROUND Male circumcision (MC) offers men lifelong partial protection from heterosexually acquired HIV infection. The impact of MC on HIV incidence has not been quantified in nationally representative samples. Data from the population-based HIV impact assessments were used to compare HIV incidence by MC status in countries implementing voluntary medical MC (VMMC) programs. METHODS Data were pooled from population-based HIV impact assessments conducted in Eswatini, Lesotho, Malawi, Namibia, Tanzania, Uganda, Zambia, and Zimbabwe from 2015 to 2017. Incidence was measured using a recent infection testing algorithm and analyzed by self-reported MC status distinguishing between medical and nonmedical MC. Country, marital status, urban setting, sexual risk behaviors, and mean population HIV viral load among women as an indicator of treatment scale-up were included in a random-effects logistic regression model using pooled survey weights. Analyses were age stratified (15-34 and 35-59 years). Annualized incidence rates and 95% confidence intervals (CIs) and incidence differences were calculated between medically circumcised and uncircumcised men. RESULTS Men 15-34 years reporting medical MC had lower HIV incidence than uncircumcised men [0.04% (95% CI: 0.00% to 0.10%) versus 0.34% (95% CI: 0.10% to 0.57%), respectively; P value = 0.01]; whereas among men 35-59 years, there was no significant incidence difference [1.36% (95% CI: 0.32% to 2.39%) versus 0.55% (95% CI: 0.14% to 0.67%), respectively; P value = 0.14]. DISCUSSION Medical MC was associated with lower HIV incidence in men aged 15-34 years in nationally representative surveys in Africa. These findings are consistent with the expected ongoing VMMC program impact and highlight the importance of VMMC for the HIV response in Africa.

Early-career researchers (ECRs) make up a large portion of the academic workforce. Yet, most leadership positions in scientific societies are held by senior scientists, and ECRs have little to no say over the decisions that will shape the future of research. This article looks at the level of influence ECRs have in 20 scientific societies based in the US and UK, and provides guidelines on how societies can successfully include ECRs in leadership roles.

For over twenty years, reports from the National Academies of Science, Engineering, and Medicine and other groups have recommended changes to improve the training environments of graduate and postdoctoral trainees and promote a sustainable STEM workforce. In a hypercompetitive climate with a shortage of funds, academic institutions and departments have largely failed to prioritize and implement these recommendations, leading to a lack of change and exacerbation of problems. Here, we describe seven concrete and implementable changes, developed as part of a set of larger guidelines at a national meeting of stakeholders from across career stages, that departments and programs can make to improve their training environments.

Early career researchers (ECRs) represent a large proportion of the research enterprise, yet they are largely excluded from decision-making opportunities including conference organization, funding administration, and manuscript peer review. As organizers of the research community, scientific societies are particularly well-positioned to incorporate ECRs into leadership roles. To assess the landscape of scientific societies that include ECRs within their organizational structures, we surveyed executives, tenured faculty, and ECRs in leadership positions within these structures. Of the queried scientific societies, ECR involvement in leadership varied greatly; while some ECRs participated in specialized committees, others were incorporated as full board members with decisional voting responsibilities. Both senior and ECR members reported having had positive experiences within ECR-inclusive committees, in which both scientific societies and ECRs benefited from ECR inclusion. Here, we highlight the accomplishments of several societies in incorporating ECRs in leadership positions, summarize the mutualistic benefits of including ECRs within decision-making structures, and present recommendations for establishing these positions throughout different organizations. Taken together, this work underscores the contribution of ECR leaders to scientific societies and to the research enterprise despite the relative scarcity of these positions.

Background and Purpose: The ability to predict ischemic stroke outcomes in the first day of admission could be vital for patient counseling, rehabilitation, and care planning. The Blood and Clot Thrombectomy Registry and Collaboration (BACTRAC; clinicaltrials.gov NCT03153683) collects blood samples distal and proximal to the intracranial thrombus during mechanical thrombectomy. These samples are a novel resource in evaluating acute gene expression changes at the time of ischemic stroke. The purpose of this study was to identify inflammatory genes and patient demographics that are predictive of stroke outcomes (infarct and/or edema volume) in acute ischemic stroke patients. Methods: The BACTRAC study is a non-probability, convenience sampling of subjects (≥ 18 year olds) treated with mechanical thrombectomy for emergent large vessel occlusion. We evaluated relative concentrations of mRNA for gene expression in 84 inflammatory molecules in static blood distal and proximal to the intracranial thrombus from adults who underwent thrombectomy. We employed a machine learning method, Random Forest, utilizing the first set of enrolled subjects, to predict which inflammatory genes and patient demographics were important features for infarct and edema volumes. Results: We analyzed the first 28 subjects (age = 66 ± 15.48, 11 males) in the BACTRAC registry. Results from machine learning analyses demonstrate that the genes CCR4, IFNA2, IL9, CXCL3, Age, DM, IL7, CCL4, BMI, IL5, CCR3, TNF, and IL27 predict infarct volume. The genes IFNA2, IL5, CCL11, IL17C, CCR4, IL9, IL7, CCR3, IL27, DM, and CSF2 predict edema volume. There is an intersection of genes CCR4, IFNA2, IL9, IL7, IL5, CCR3 to both infarct and edema volumes. Overall, these genes depicts a microenvironment for chemoattraction and proliferation of autoimmune cells, particularly Th2 cells and neutrophils. Conclusions: Machine learning algorithms can be employed to develop predictive biomarker signatures for stroke outcomes in ischemic stroke patients, particularly in regard to identifying acute gene expression changes that occur during stroke.

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. Electronic supplementary material The online version of this article (10.1007/s10461-018-2313-0) contains supplementary material, which is available to authorized users.

Several neurotropic cytokines relay their signaling through the leukemia inhibitory factor receptor. This 190 kDa subunit couples with the 130 kDa gp130 subunit to transduce intracellular signaling in neurons and oligodendrocytes that leads to expression of genes associated with neurosurvival. Moreover, activation of this receptor alters the phenotype of immune cells to an anti-inflammatory one. Although cytokines that activate the leukemia inhibitory factor receptor have been studied in the context of neurodegenerative disease, therapeutic targeting of the specific receptor subunit has been understudied in by comparison. This review examines the role of this receptor in the CNS and immune system, and its application in the treatment in stroke and other brain pathologies.

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.

Aging is a major risk factor for Alzheimer’s disease (AD), the most common cause of dementia worldwide. TDP-43 proteinopathy is reported to be associated with AD pathology is almost 50% of cases. Our exploratory study examined near end-stage (28 months old) mice selectively driving expression of human TDP-43 in the hippocampus and cortex in an APP/PSEN1 background. We hypothesized that hippocampal neuropathology caused by β-amyloidosis with TDP-43 proteinopathy induced in this model, resembling the pathology seen in AD cases, manifest with changes in resting state functional connectivity. In vivo magnetic resonance imaging and post-mortem histology were performed on four genotypes: wild type, APP/PSEN1, Camk2a/TDP-43, and Camk2a/TDP-43/APP/PSEN1. Our results revealed loss of functional coupling in hippocampus and amygdala that was associated with severe neuronal loss in dentate gyrus of Camk2a/TDP-43/APP/PSEN1 mice compared to APP/PSEN1 and wild type mice. The loss of cells was accompanied by high background of β-amyloid plaques with sparse phosphorylated TDP-43 pathology. The survival rate was also reduced in Camk2a/TDP-43/APP/PSEN1 mice compared to other groups. This end-of-life study provides exploratory data to reach a better understanding of the role of TDP-43 hippocampal neuropathology in diseases with co-pathologies of TDP-43 proteinopathy and β-amyloidosis such as AD and limbic predominant age-related TDP-43 encephalopathy (LATE).

Voluntary medical male circumcision is a crucial HIV prevention program for men in sub-Saharan Africa. Kenya is one of the first countries to achieve high population coverage and seek to transition the program to a more sustainable structure designed to maintain coverage while making all aspects of service provision domestically owned and implemented. Using pre-defined metrics, we created and evaluated three models of circumcision service delivery (static, mobile and mixed) to identify which had potential for sustaining high circumcision coverage among 10-14-year-olds group, a historically high-demand and accessible age group, at the lowest possible cost. We implemented each model in two distinct geographic areas, one in Siaya and the other in Migori county, and assessed multiple aspects of each model’s sustainability. These included numerical achievements against targets designed to reach 80% coverage over two years; quantitative expenditure outcomes including unit expenditure plus its primary drivers; and qualitative community perception of program quality and sustainability based on Likert scale. Outcome values at baseline were compared with those for year one of model implementation using bivariate linear regression, unpaired t-tests and Wilcoxon rank tests as appropriate. Across models, numerical target achievement ranged from 45–140%, with the mixed models performing best in both counties. Unit expenditures varied from approximately $57 in both countries at baseline to $44-$124 in year 1, with the lowest values in the mixed and static models. Mean key informant perception scores generally rose significantly from baseline to year 1, with a notable drop in the area of community engagement. Consistently low scores were in the aspects of domestic financing for service provision. Sustainability-focused circumcision service delivery models can successfully achieve target volumes at lower unit expenditures than existing models, but strategies for domestic financing remain a crucial challenge to address for long-term maintenance of the program.

Introduction: Ischemic stroke remains one of the most debilitating diseases and is the fifth leading cause of death in the US. The ability to predict stroke outcomes within the acute period of stroke would be essential for care planning and rehabilitation. The Blood and Clot Thrombectomy Registry and Collaboration (BACTRAC; clinicaltrials.gov NCT03153683) study collects arterial blood immediately distal and proximal to the intracranial thrombus at the time of mechanical thrombectomy. These blood samples are an innovative resource in evaluating acute gene expression changes at the time of ischemic stroke. The purpose of this study was to identify inflammatory genes and important immune factors during mechanical thrombectomy for emergent large vessel occlusion (ELVO) and which patient demographics were predictors for stroke outcomes (infarct and/or edema volume) in acute ischemic stroke patients. Methods: The BACTRAC study is a non-probability sampling of male and female subjects (≥18 year old) treated with mechanical thrombectomy for ELVO. We evaluated 28 subjects (66 ± 15.48 years) relative concentrations of mRNA for gene expression in 84 inflammatory molecules in arterial blood distal and proximal to the intracranial thrombus who underwent thrombectomy. We used the machine learning method, Random Forest to predict which inflammatory genes and patient demographics were important features for infarct and edema volumes. To validate the overlapping genes with outcomes, we perform ordinary least squares regression analysis. Results: Machine learning analyses demonstrated that the genes and subject factors CCR4, IFNA2, IL-9, CXCL3, Age, T2DM, IL-7, CCL4, BMI, IL-5, CCR3, TNFα, and IL-27 predicted infarct volume. The genes and subject factor IFNA2, IL-5, CCL11, IL-17C, CCR4, IL-9, IL-7, CCR3, IL-27, T2DM, and CSF2 predicted edema volume. The overlap of genes CCR4, IFNA2, IL-9, IL-7, IL-5, CCR3, and IL-27 with T2DM predicted both infarct and edema volumes. These genes relate to a microenvironment for chemoattraction and proliferation of autoimmune cells, particularly Th2 cells and neutrophils. Conclusions: Machine learning algorithms can be employed to develop prognostic predictive biomarkers for stroke outcomes in ischemic stroke patients, particularly in regard to identifying acute gene expression changes that occur during stroke.

Background and purpose Mechanical thrombectomy (MT) is the standard of care for emergent large vessel occlusion (ELVO), one of the most severe subtypes of ischemic stroke, which accounts for 30–40% of all cases. Through MT, we can isolate distal blood within the artery immediately downstream from the clot and compare it to systemic arterial blood to provide insight into local intraluminal changes during ischemia. CXCL9 is in interferon gamma-inducible chemokine that binds CXCR3, degrading endothelial tight junctions, attracting T cells, and facilitating immune cell extravasation into brain parenchyma. We aimed to study local CXCL9 expression distal to the intracranial thrombus during large vessel occlusion in human patients. Methods Tissue samples of distal and proximal blood were collected as part of the BACTRAC tissue bank (www.clinicaltrials.gov NCT03153683). Adult subjects with ELVO were prospectively enrolled, and arterial blood distal (intracranial) and proximal (cervical) were collected and processed to optimize RNA quality. RNA were isolated and used to evaluate gene expression in both samples for each subject; proximal systemic blood was used as an internal control for each subject. Results 22 subjects were included in this preliminary analysis. 15 (68.2%) were female. 54.5% of subjects had a CTA collateral score of 1 (18.2% had a score of 0). 4.5% (1 subject) did not attain TICI 2B or 3 recanalization. Infarct time (last known normal to thrombectomy recanalization) was 491 ± 243 minutes. Mean change in NIHSS from admission to discharge was -8 ± 8. CXCL9 expression in distal blood was upregulated an average of 106-fold with a maximum upregulation of 805-fold in one subject. In plotting CXCL9 expression against infarct time, there was a clear negative correlation (Spearman coefficient -0.43, p=0.05). Conclusion For the first time, we evaluate chemokine alterations in human stroke patients in distal stagnant blood during ELVO. There is a significant variance in CXCL9 expression in distal blood in relationship to infarct time, which mirrors the known timing of blood-brain barrier disruption. Disclosures J. Fraser: None. S. Martha: None. L. Collier: None. S. Davis: None. A. Alhajeri: None. S. Grupke: None. K. Pennypacker: None.

Introduction Ischemic stroke is the one of the most severe and debilitating diseases, and despite animal models, there is much to learn about the neuropathology in humans in a way that could inform the development of therapies. We have developed a protocol to collect and evaluate arterial blood immediately distal and proximal from the removed intracranial thrombus during mechanical thrombectomy. These samples provide a unique resource in evaluating acute changes in acid/base and electrolyte concentrations at the time of ischemic stroke. The purpose of this study was to compare acid/base and electrolytes obtained proximal and distal to the occluded intracranial thrombi between male and female acute ischemic stroke subjects at the time of thrombectomy; and to determine whether arterial blood gas values predict outcomes in male and female subjects. Methods We analyzed the first 49 subjects (age = 67 ± 15.0, 21 males) in the BACTRAC registry. We compared arterial blood gas of blood distal versus proximal to the thrombus during thrombectomy which provided acid/base levels (pH, pCO2, pO2, BD, HCO3−) and electrolyte values (iCa2+, K+, and Na+). Comparisons were evaluated by one-way repeated measures ANOVA (p Results In general, distal intracranial luminal blood sample showed a compensated metabolic acidosis with an elevated oxygen concentration in both blood samples. Analysis indicated several significant differences in the proximal blood samples between sexes (pH, pCO2, and K+). Bicarbonate and base deficit were predictors of infarct time specifically in female subjects. Discussion and conclusion Acid/base and electrolyte response to ischemic conditions differ between men and women, and these early changes could be used to predict local acid/base changes and how they develop differently in men and women during ischemia. These findings provide a novel insight into the pathology of large vessel stroke in humans, particularly potential variations based on sex.

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.

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 minutes after occlusion), and at 72 hours 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 hours, 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 hours) and changes in sodium and ionized calcium (from post- to 72 hours) 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.

Background and Purpose: The Blood and Clot Thrombectomy Registry and Collaboration (BACTRAC) tissue bank collects blood proximal and distal to the intracranial thrombus during the process of mechanical thrombectomy in human stroke patients. These samples provide a unique resource in evaluating acute gene expression changes at the time of ischemic stroke. The purpose of this study was to evaluate gene expression changes occurring within the thrombus and across the occlusion in the intravascular space in acute ischemic stroke patients. Methods: We developed the BACTRAC protocol: an IRB-approved tissue banking approach for ELVO (clinicaltrials.gov NCT03153683). We evaluated relative concentrations of gene expression in 84 inflammatory molecules in thrombi removed from adults who received thrombectomy for ischemic stroke, in static blood distal to thrombus, and in peripheral circulation. Results: We analyzed the first 46 subjects (age = 67 ± 14.23, 20 males) in the BACTRAC registry. Results from qPCR gene expression analyses demonstrate that 21 genes (CCL1, CCL11, CCL13, CCL17, CCL26, CCL8, CSF3, CX3CL1, CXCL1, CXCL9, IFNA2, IL13, IL17C, IL17F, IL1A, IL27, IL3, IL33, LTA, TNFSF11, and TNFSF13) had at least 25 mean fold change in the distal blood compared to the peripheral blood. Fourteen genes (AIMP1, CCL11, CCL13, CCL15, CCL16, CCL23, CCR2, CCR4, CCR8, CD40LG, CXCL10, IL10RA, IL15, and TNFSF13B) had at least 10 mean fold change in the thrombus compared to the peripheral blood. Overall, these genes are associated with chemo-attraction and cell proliferation of monocytes, neutrophils, and T cells. Conclusions: These findings provide a novel insight into the initial pathology of large vessel stroke in humans, particularly in regard to identifying acute gene expression changes that occur during stroke.

Background and Purpose: In the setting of mechanical thrombectomy for emergent large vessel occlusion (ELVO), we have developed a protocol to collect and evaluate blood immediately distal and proximal from the removed intracranial thrombus. These samples provide a unique resource in evaluating acute changes in acid/base and electrolyte concentrations at the time of ischemic stroke. The purpose of this study is to compare acid/base and electrolyte differences obtained proximal and distal to the occluded intracranial thrombus in acute ischemic stroke patients. Methods: We developed the Blood and Clot Thrombectomy Registry and Collaboration (BACTRAC) protocol: an IRB-approved tissue banking strategy for ELVO (clinicaltrials.gov NCT03153683). We compared arterial blood gases (ABG) of blood distal versus proximal to the thrombus during thrombectomy. Comparisons were evaluated by Paired Samples T-Tests (p < 0.05). Results: We analyzed the first 46 subjects (age = 67 ± 14.23, 20 males) in the BACTRAC registry. Preliminary results demonstrate that, while pH is nonsignificant (p = 0.513), distal blood in relation to proximal blood showed significantly lower oxygen (p < 0.001), carbon dioxide (p < 0.001), bicarbonate (p < 0.001), ionized calcium (p < 0.001), and potassium (p < 0.001). Sodium concentration was significantly higher (p < 0.001) in distal blood. These results suggest alterations occurring intravascularly during ischemia. Conclusions: These preliminary findings provide a novel insight into the pathology of large vessel stroke in humans, particularly in regard to identifying acute changes in acid/base balance and electrolyte concentrations that occur during stroke.

Introduction Since 2011, Kenya has been evaluating ShangRing device for use in its voluntary medical male circumcision (VMMC) program according to World Health Organization (WHO) guidelines. Compared to conventional surgical circumcision, the ShangRing procedure is shorter, does not require suturing and gives better cosmetic outcomes. After a pilot evaluation of ShangRing in 2011, Kenya conducted an active surveillance for adverse events associated with its use from 2016-2018 to further assess its safety, uptake and to identify any operational bottlenecks to its widespread use based on data from a larger pool of procedures in routine health care settings. Methods From December 2017 to August 2018, HIV-negative VMMC clients aged 13 years or older seeking VMMC at six sites across five counties in Kenya were offered ShangRing under injectable local anesthetic as an alternative to conventional surgical circumcision. Providers described both procedures to clients before letting them make a choice. Outcome measures recorded for clients who chose ShangRing included the proportions who were clinically eligible, had successful device placement, experienced adverse events (AEs), or failed to return for device removal. Clients failing to return for follow up were sought through phone calls, text messages or home visits to ensure removal and complete information on adverse events. Results Out of 3,692 eligible clients 1,079 (29.2%) chose ShangRing; of these, 11 (1.0%) were excluded due to ongoing clinical conditions, 17 (1.6%) underwent conventional surgery due to lack of appropriate device size at the time of the procedure, 97.3% (1051/1079) had ShangRing placement. Uptake of ShangRing varied from 11% to 97% across different sites. There was one severe AE, a failed ShangRing placement (0.1%) managed by conventional wound suturing, plus two moderate AEs (0.2%), post removal wound dehiscence and bleeding, that resolved without sequelae. The overall AE rate was 0.3%. All clients returned for device removal from fifth to eleventh day after placement. Conclusion ShangRing circumcision is effective and safe in the Kenyan context but its uptake varies widely in different settings. It should be rolled out under programmatic implementation for eligible males to take advantage of its unique benefits and the freedom of choice beyond conventional surgical MMC. Public education on its availability and unique advantages is necessary to optimize its uptake and to actualize the benefit of its inclusion in VMMC programs.

Leukemia inhibitory factor (LIF) has been shown to protect oligodendrocytes from ischemia by upregulating endogenous antioxidants. The goal of this study was to determine whether LIF protects neurons during stroke by upregulating superoxide dismutase 3 (SOD3). Animals were administered phosphate-buffered saline (PBS) or 125 μg/kg LIF at 6, 24, and 48 h after middle cerebral artery occlusion or sham surgery. Neurons were isolated from rat pups on embryonic day 18 and used between 7 and 15 days in culture. Cells were treated with LIF and/or 10 μM Akt inhibitor IV with PBS and 0.1 % DMSO acting as vehicle controls. Neurons transfected with scrambled or SOD3 small interfering RNA (siRNA) were subjected to 24-h ischemia after PBS or LIF treatment. LIF significantly increased superoxide dismutase activity and SOD3 expression in ipsilateral brain tissue compared to PBS. Following 24-h ischemia, LIF reduced cell death and increased SOD3 messenger RNA (mRNA) in vitro compared to PBS. Adding Akt inhibitor IV with LIF counteracted the decrease in cell death. Partially silencing the expression of SOD3 using siRNA prior to LIF treatment counteracted the protective effect of LIF-alone PBS treatment. These results indicate that LIF protects neurons in vivo and in vitro via upregulation of SOD3.

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.

ObjectiveThis article provides an overview and interpretation of the performance of the US President’s Emergency Plan for AIDS Relief’s (PEPFAR’s) male circumcision programme which has supported the majority of voluntary medical male circumcisions (VMMCs) performed for HIV prevention, from its 2007 inception to 2017, and client characteristics in 2017.DesignLongitudinal collection of routine programme data and disaggregations.Setting14 countries in sub-Saharan Africa with low baseline male circumcision coverage, high HIV prevalence and PEPFAR-supported VMMC programmes.ParticipantsClients of PEPFAR-supported VMMC programmes directed at males aged 10 years and above.Main outcome measuresNumbers of circumcisions performed and disaggregations by age band, result of HIV test offer, procedure technique and follow-up visit attendance.ResultsPEPFAR supported a total of 15 269 720 circumcisions in 14 countries in Southern and Eastern Africa. In 2017, 45% of clients were under 15 years of age, 8% had unknown HIV status, 1% of those tested were HIV+ and 84% returned for a follow-up visit within 14 days of circumcision.ConclusionsOver 15 million VMMCs have been supported by PEPFAR since 2007. VMMC continues to attract primarily young clients. The non-trivial proportion of clients not testing for HIV is expected, and may be reassuring that testing is not being presented as mandatory for access to circumcision, or in some cases reflect test kit stockouts or recent testing elsewhere. While VMMC is extremely safe, achieving the highest possible follow-up rates for early diagnosis and intervention on complications is crucial, and programmes continue to work to raise follow-up rates. The VMMC programme has achieved rapid scale-up but continues to face challenges, and new approaches may be needed to achieve the new Joint United Nations Programme on HIV/AIDS goal of 27 million additional circumcisions through 2020.

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. 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. 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. Circumcision status at the time of HIV infection does not affect viral load in men. The original RCT which provided the samples was ClinicalTrials.gov trial NCT00059371 .

Background Mechanical thrombectomy offers a unique opportunity to examine neurophysiological changes occurring during stroke. We developed a tissue banking protocol to capture intracranial thrombi as well as the blood immediately proximal and distal. These tissues provide a rare resource to correlate changes occurring at the time of stroke to patient outcomes. The purpose of this study is to develop a tissue banking protocol in order to provide high-quality yields of RNA for gene expression analysis and protein for proteomics. Methods We instituted an IRB-approved protocol for tissue processing during mechanical thrombectomy (www.clinicaltrials.gov NCT03153683). The protocol is a joint clinical/basic science effort among multiple laboratories and the NeuroInterventional Radiology service line. We developed a step-by-step process for specimen retrieval, initial processing, and storage, which begins in a designated workspace constructed for the study in the angiography suite. Further processing and analysis is performed in our basic science laboratories, and includes extraction of RNA from thrombi with distal and proximal blood samples to assess RNA integrity number (RIN) values. To demonstrate viability of the collected plasma, proteomics of distal and proximal blood was evaluated through an outside vendor (Olink Proteomics). Results We have enrolled 34 subjects (age=66±13.3, 14 males) in the BACTRAC registry thusfar. In our preliminary dataset, the process yielded adequate RNA for gene expression analysis and protein for proteomics. RNA integrity analysis reveal mean RIN values (±SD) for distal arterial blood (n=8) were 8.89±0.41 (range from 8.30 to 9.60) and mean RIN values (±SD) for proximal arterial blood (n=8) were 6.98±0.29 (range from 6.60 to 7.50), indicating moderate to high quality RNA with minimal degradation. Mean RIN values for the thrombi (n=7) were undetectable. The first subject samples of distal and proximal blood were analyzed for proteomics. Duplicates of these samples passed quality control, and were run on all 11 of their proteomic panels (92 proteins/panel) for a total of 1012 proteins. 100% of proteins were detected on cardiovascular 3 and neurology panels. The organ damage panel detected the fewest, with 61% of this panel. The cardiometabolic and cardiovascular 3 panels each showed the most proteins with the greatest differences in expression. Conclusion We have developed a novel tissue banking protocol utilizing mechanical thrombectomy to capture thrombus along with arterial blood distal and proximal to it. The protocol provides high-quality specimens facilitating analysis of the initial molecular response to ischemic stroke in the human condition for the first time. In addition, preliminary integrity analyses demonstrated high-quality yields for RNA and protein in distal and proximal blood samples. Disclosures S. Martha: None. L. Collier: None. A. Gorman: None. K. Salmeron: None. A. Trout: None. D. Edwards: None. S. Davis: None. A. Alhajeri: None. S. Grupke: None. J. Roberts: None. G. Bix: None. K. Pennypacker: None. J. Fraser: None.

Introduction In the setting of mechanical thrombectomy for emergent large vessel occlusion (ELVO), we have for the first time developed a protocol to collect and evaluate blood immediately distal and proximal from the removed intracranial thrombus. These samples provide a unique resource in evaluating acute changes in acid/base and electrolyte concentrations at the time of ischemic stroke. The purpose of this study is to compare acid/base and electrolyte differences obtained proximal and distal to the occluded intracranial thrombus in acute ischemic stroke patients. Methods We developed the BACTRAC protocol: an IRB-approved tissue banking strategy for ELVO (clinicaltrials.gov NCT03153683). We compared arterial blood gases (ABG) of blood distal versus proximal to the thrombus during thrombectomy. Comparisons were evaluated by Paired Samples T-Tests (p Results We analyzed the first 24 subjects (age=65±0.54, 11 males) in the BACTRAC registry. Preliminary results demonstrate that, while pH is nonsignificant, distal blood in relation to proximal blood showed significantly lower oxygen (p=0.010), carbon dioxide (p=0.001), bicarbonate (p=0.002), ionized calcium (p=0.001), and potassium (p=0.001). Sodium concentration was significantly higher (p=0.002) in distal blood. These results suggest alterations occurring intravascularly during ischemia. Conclusion These findings provide a novel insight into the pathology of large vessel stroke in humans, particularly in regard to identifying acute changes in acid/base balance and electrolyte concentrations that occur during stroke. Disclosures J. Fraser: None. S. Martha: None. L. Collier: None. S. Davis: None. A. Abdulnasser: None. S. Grupke: None. K. Pennypacker: None.

BackgroundIschemic stroke research faces difficulties in translating pathology between animal models and human patients to develop treatments. Mechanical thrombectomy, for the first time, offers a momentary window into the changes occurring in ischemia. We developed a tissue banking protocol to capture intracranial thrombi and the blood immediately proximal and distal to it.ObjectiveTo develop and share a reproducible protocol to bank these specimens for future analysis.MethodsWe established a protocol approved by the institutional review board for tissue processing during thrombectomy (www.clinicaltrials.govNCT03153683). The protocol was a joint clinical/basic science effort among multiple laboratories and the NeuroInterventional Radiology service line. We constructed a workspace in the angiography suite, and developed a step-by-step process for specimen retrieval and processing.ResultsOur protocol successfully yielded samples for analysis in all but one case. In our preliminary dataset, the process produced adequate amounts of tissue from distal blood, proximal blood, and thrombi for gene expression and proteomics analyses. We describe the tissue banking protocol, and highlight training protocols and mechanics of on-call research staffing. In addition, preliminary integrity analyses demonstrated high-quality yields for RNA and protein.ConclusionsWe have developed a novel tissue banking protocol using mechanical thrombectomy to capture thrombus along with arterial blood proximal and distal to it. The protocol provides high-quality specimens, facilitating analysis of the initial molecular response to ischemic stroke in the human condition for the first time. This approach will permit reverse translation to animal models for treatment development.

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).

Background and Purpose: Monitoring for hypotension, hyperglycemia, hypoxia, and dehydration is key to reducing early death in stroke patients. Evaluation of physiological predictors of infarct volume and mortality may provide opportunities for effective interventions to improve outcomes. The purpose of this study is: 1) to describe and compare the predictive effects of venous blood gas (VBG) on infarct volume and mortality in acute stroke in rats; 2) and we have begun to collect arterial blood gas (ABG) to compare differences obtained proximal and distal to the occluded intracranial thrombi in acute ischemic stroke patients. Methods: 3-month old Sprague-Dawey rats (n = 9) underwent permanent or transient middle cerebral artery occlusion (MCAO). Pre- and post-MCAO venous samples provided pH, pCO 2 , pO 2 , and electrolyte values (iCa 2+ , K + , and Na + ). Linear regression determined predictors of infarct volume from these values, and Cox regression analyzed VBG changes between tMCAO (n = 28) and pMCAO (n = 29) to determine predictors of mortality. We compared mean proximal and distal pH, pCO 2 , pO 2 , and electrolytes (iCa 2+ , K + , and Na + ) in stroke patients (n = 7) arterial samples using Wilcoxon Signed Ranks test. Results: Animal studies demonstrated pH and iCa 2+ are predictors of infarct volume, but not mortality. After pMCAO (n = 9), change in pH or iCa 2+ significantly predicted infarct volume [F(1,7) = 7.351, β = -0.716, p = 0.03] and [F(1, 7) = 6.782, β = -0.701, p = 0.035]; as pH and calcium decreased, infarct volume increased. These variables explained 44% and 42% of the total variance in these models. In human patients (n = 7), there were significant differences in blood samples proximal and distal to the intracranial thrombus for pCO 2 (p = 0.018), HCO 3- (p = 0.028), iCa 2+ (p = 0.043), K + (p = 0.028), and Na + (p = 0.044). Conclusions: In conclusion, there are acute changes in acid/base balance and electrolytes during stroke in rodent models and humans. In cross-species comparison ionized calcium changes were significant in both, with iCa 2+ changes predicting stroke volume in the rat model. These preliminary findings are novel, and warrant further exploration in human patients.

Background: Research in ischemic stroke struggles from failures to translate stroke conditions between animal models and human patients. With mechanical thrombectomy, we have for the first time developed a protocol to facilitate tissue banking of intracranial thrombi as well as the blood immediately proximal and distal to it. These tissues provide a unique resource to correlate changes in the human condition to animal models. Our aim was to develop a reproducible protocol to bank these specimens for future gene expression and proteomic analysis. Methods: We developed an IRB-approved protocol for tissue processing during thrombectomy (www.clinicaltrials.gov NCT03153683). The protocol was a joint clinical/basic science effort among multiple laboratories and the Neurointerventional Radiology Service Line. We placed laboratory supplies in the angio suite, and developed a step-by-step protocol for specimen retrieval and processing. Results: Our protocol successfully yielded samples for analysis in all but one case. In our preliminary dataset, the protocol yielded adequate amounts of tissue for distal blood, proximal blood, and thrombus. We present the tissue banking protocol for dissemination, and highlight the training protocol and mechanics of on-call research staffing for 24/7 tissue processing. In addition, preliminary integrity analyses demonstrated high quality yields for RNA and protein. Conclusion: We have developed a novel tissue banking protocol to capture thrombus, and both proximal and distal blood to the intracranial thrombus in human stroke patients. The specimens are captured during the thrombectomy procedure, and allow us to study the initial molecular response to ischemic stroke in the human condition in ways previously unavailable.

Objective: To determine whether the anti-inflammatory effects of leukemia inhibitory factor (LIF) are altered in aged male and female rats. Methods: Focal ischemia was induced in 3 month old male and 18 month old male/female Sprague-Dawley using the middle cerebral artery occlusion (MCAO) procedure. Animals were treated with PBS or LIF at 6, 24, and 48 h after MCAO (125 μg/kg). Infarct volume in aged animals was quantified with T2-weighted MRI. Functional motor skills were assessed immediately prior to euthanization at 72 h post-MCAO. Protein levels of CD11b and IL-12 p40 in brain and spleen tissue were measured using immunoblotting. Results: At 72 h, there was a trend towards decreased infarct volume in aged male (189 ± 45OD; n=4) and female LIF-treated rats (104 ± 71 OD; n=4) compared to PBS-treated aged male (188 ± 45; n=4) and female rats (179 ± 72; n=5). LIF-treated aged female rats showed significant decreases in circling (p=0.0209) and body swing bias (p=0.05) compared to the PBS-treated aged females. Normalized CD11b levels were significantly in LIF-treated young males (1.1 ± 0.3 OD; n=5) compared to PBS-treated young males (2.5 ± 0.5 OD; n=6; p Conclusions: LIF is more effective at decreasing splenic IL-12 expression and immune cell infiltration in young rats compared to aged rats. However, LIF counteracts the post-stroke splenic response in aged females but not aged male rats.

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.

Summary Background Male circumcision reduces men's risk of acquiring HIV and some sexually transmitted infections from heterosexual exposure, and is essential for HIV prevention in sub-Saharan Africa. Studies have also investigated associations between male circumcision and risk of acquisition of HIV and sexually transmitted infections in women. We aimed to review all evidence on associations between male circumcision and women's health outcomes to benefit women's health programmes. Methods In this systematic review we searched for peer-reviewed and grey literature publications reporting associations between male circumcision and women's health outcomes up to April 11, 2016. All biomedical (not psychological or social) outcomes in all study types were included. Searches were not restricted by year of publication, or to sub-Saharan Africa. Publications without primary data and not in English were excluded. We extracted data and assessed evidence on each outcome as high, medium, or low consistency on the basis of agreement between publications; outcomes found in fewer than three publications were indeterminate consistency. Findings 60 publications were included in our assessment. High-consistency evidence was found for five outcomes, with male circumcision protecting against cervical cancer, cervical dysplasia, herpes simplex virus type 2, chlamydia, and syphilis. Medium-consistency evidence was found for male circumcision protecting against human papillomavirus and low-risk human papillomavirus. Although the evidence shows a protective association with HIV, it was categorised as low consistency, because one trial showed an increased risk to female partners of HIV-infected men resuming sex early after male circumcision. Seven outcomes including HIV had low-consistency evidence and six were indeterminate. Interpretation Scale-up of male circumcision in sub-Saharan Africa has public health implications for several outcomes in women. Evidence that female partners are at decreased risk of several diseases is highly consistent. Synergies between male circumcision and women's health programmes should be explored. Funding US Centers for Disease Control and Prevention and Jhpiego.

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. 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. 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. 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.

Objective: To identify how leukemia inhibitory factor (LIF) regulates antioxidant neuroprotective and anti-inflammatory signaling through the expression and trafficking of its receptor (LIFR). Hypothesis: LIF treatment after stroke confers neuroprotection by increasing protein expression and membrane localization of LIFR in neural cells and splenocytes. Methods: Genomatix software was used to identify binding sites for the LIF-dependent transcription factors specificity protein 1 (Sp1) and myeloid zinc finger-1 (MZF-1) in the LIFR promoter. Male Sprague-Dawley rats underwent middle cerebral artery occlusion or sham surgery and injected with PBS or LIF (125 μg/kg) (n=8 per group) at 6, 24 and 48 h post-MCAO. Levels of LIFR, MZF-1, and Sp1 were measured using western blotting. Immunohistochemistry was used to determine localization of Sp1, LIF receptor, MZF-1, and superoxide dismutase 3, a LIF-inducible enzyme. Results: LIF (1.494 OD ± 0.161) significantly increased brain LIFR levels in ipsilateral tissue at 72 h after stroke compared to sham surgery (0.299 OD ± 0.060) and PBS treatment (0.399 OD ± 0.154) (0.0281 OD ± 0.011, p Conclusions: Injury increases membrane localization of LIFR in neurons while LIF increases its receptor’s expression and Sp1/MZF-1 in stroke-injured neurons. As a part of its anti-inflammatory action, LIF causes downregulation of LIFR in the spleen after stroke.