Post-exposure intranasal IFNα suppresses replication and neuroinvasion of Venezuelan Equine Encephalitis virus within olfactory sensory neurons.

BACKGROUND: Venezuelan Equine Encephalitis virus (VEEV) may enter the central nervous system (CNS) within olfactory sensory neurons (OSN) that originate in the nasal cavity after intranasal exposure. While it is known that VEEV has evolved several mechanisms to inhibit type I interferon (IFN) signaling within infected cells, whether this inhibits virologic control during neuroinvasion along OSN has not been studied. METHODS: We utilized an established murine model of intranasal infection with VEEV and a repository of scRNAseq data from IFN-treated OSN to assess the cellular targets and IFN signaling responses after VEEV exposure. RESULTS: We found that immature OSN, which express higher levels of the VEEV receptor LDLRAD3 than mature OSN, are the first cells infected by VEEV. Despite rapid VEEV neuroinvasion after intranasal exposure, olfactory neuroepithelium (ONE) and olfactory bulb (OB) IFN responses, as assessed by evaluation of expression of interferon signaling genes (ISG), are delayed for up to 48 h during VEEV neuroinvasion, representing a potential therapeutic window. Indeed, a single intranasal dose of recombinant IFNα triggers early ISG expression in both the nasal cavity and OB. When administered at the time of or early after infection, IFNα treatment delayed onset of sequelae associated with encephalitis and extended survival by several days. VEEV replication after IFN treatment was also transiently suppressed in the ONE, which inhibited subsequent invasion into the CNS. CONCLUSIONS: Our results demonstrate a critical and promising first evaluation of intranasal IFNα for the treatment of human encephalitic alphavirus exposures.

Comparative bone histology of two thalattosaurians (Diapsida: Thalattosauria): Askeptosaurus italicus from the Alpine Triassic (Middle Triassic) and a Thalattosauroidea indet. from the Carnian of Oregon (Late Triassic).

Here, we present the first bone histological and microanatomical study of thalattosaurians, an enigmatic group among Triassic marine reptiles. Two taxa of thalattosaurians, the askeptosauroid Askeptosaurus italicus and one as yet undescribed thalattosauroid, are examined. Both taxa have a rather different microanatomy, tissue type, and growth pattern. Askeptosaurus italicus from the late Anisian middle Besano Formation of the southern Alpine Triassic shows very compact tissue in vertebrae, rib, a gastralium, and femora, and all bones are without medullary cavities. The tissue shows moderate to low vascularization, dominated by highly organized and very coarse parallel-fibred bone, resembling interwoven tissue. Vascularization is dominated by simple longitudinal vascular canals, except for the larger femur of Askeptosaurus, where simple vascular canals dominate in a radial arrangement. Growth marks stratify the cortex of femora. The vertebrae and humeri from the undescribed thalattosauroid from the late Carnian of Oregon have primary and secondary cancellous bone, resulting in an overall low bone compactness. Two dorsal vertebral centra show dominantly secondary trabeculae, whereas a caudal vertebral centrum shows much primary trabecular bone, globuli ossei, and cartilage, indicating an earlier ontogenetic stage of the specimens or paedomorphosis. The humeri of the thalattosauroid show large, simple vascular canals that are dominantly radially oriented in a scaffold of woven and loosely organized parallel-fibred tissue. Few of the simple vascular canals are thinly but only incompletely lined by parallel-fibered tissue. In the Oregon material, changes in growth rate are only indicated by changes in vascular organization but no distinct growth marks were identified. The compact bone of Askeptosaurus is best comparable to some pachypleurosaurs, whereas its combination of tissue and vascularity is similar to eosauropterygians in general, except for the coarse nature of its parallel-fibred tissue. The cancellous bone of the Oregon thalattosauroid resembles what is documented in ichthyosaurs and plesiosaurs. However, in contrast to these its tissue does not consist of fibro-lamellar bone type. Tissue types of both thalattosaurian taxa indicate rather different growth rates and growth patterns, associated with different life history strategies. The microanatomy reflects different life styles that fit to the different environments in which they had been found (intraplatform basin vs. open marine). Both thalattosaurian taxa differ from each other but in sum also from all other marine reptile taxa studied so far. Thalattosaurian bone histology documents once more that bone histology provides for certain groups (i.e., Triassic Diapsida) only a poor phylogenetic signal and is more influenced by exogenous factors. Differences in lifestyle, life history traits, and growth rate and pattern enabled all these Triassic marine reptiles to live contemporaneously in the same habitat managing to avoid substantial competition.

Post-exposure intranasal IFNα suppresses replication and neuroinvasion of Venezuelan Equine Encephalitis virus within olfactory sensory neurons.

Venezuelan Equine Encephalitis virus (VEEV) may enter the central nervous system (CNS) within olfactory sensory neurons (OSN) that originate in the nasal cavity after intranasal exposure. While it is known that VEEV has evolved several mechanisms to inhibit type I interferon (IFN) signaling within infected cells, whether this inhibits virologic control during neuroinvasion along OSN has not been studied. Here, we utilized an established murine model of intranasal infection with VEEV to assess the cellular targets and IFN signaling responses after VEEV exposure. We found that immature OSN, which express higher levels of the VEEV receptor LDLRAD3 than mature OSN, are the first cells infected by VEEV. Despite rapid VEEV neuroinvasion after intranasal exposure, olfactory neuroepithelium (ONE) and olfactory bulb (OB) IFN responses, as assessed by evaluation of expression of interferon signaling genes (ISG), are delayed for up to 48 hours during VEEV neuroinvasion, representing a potential therapeutic window. Indeed, a single intranasal dose of recombinant IFNα triggers early ISG expression in both the nasal cavity and OB. When administered at the time of or early after infection, IFNα treatment delayed onset of sequelae associated with encephalitis and extended survival by several days. VEEV replication after IFN treatment was also transiently suppressed in the ONE, which inhibited subsequent invasion into the CNS. Our results demonstrate a critical and promising first evaluation of intranasal IFNα for the treatment of human encephalitic alphavirus exposures.

The Gantzer transfer - Assessment of the feasibility of using the nerve supplying the Gantzer muscle for end-to-side supercharging of the ulnar nerve.

Our study aimed at assessing the anatomical feasibility of using the nerve supplying the Gantzer muscle (GM) to supercharge the ulnar nerve following injury. The GM nerve was dissected and measured in 36 forearms. The distance between its origin and the lateral epicondyle of humerus and between the GM nerve and the ulnar nerve was measured. The GM was present in 15 forearms (47%). The average distance between the origin of the GM nerve and the lateral epicondyle was 7.34 cm (range 3.3-9.1 cm). The average length of the GM nerve was 3.05 cm (range 1.6-4.5 cm) from origin to neuromuscular junction. The average distance from the ulnar nerve was 2.56 cm (range 1.8-13 3.4 cm). The length of the GM nerve was significantly greater (p < 0.05) than the perpendicular distance between its origin and the ulnar nerve, allowing ample margin for side-to-side or end-to-side supercharging of the ulnar nerve with minimal or no need for further translocation or dissection. The use of the GM nerve as donor following ulnar nerve injury may provide an alternative to the pronator quadratus nerve for supercharged end-to-side transfer, or as an addition, thus supercharging the ulnar nerve twice.

Arterial Stiffness in a Cohort of Young People Living With Perinatal HIV and HIV Negative Young People in England.

Background: Antiretroviral therapy (ART) has increased life expectancy and consequently the risk of cardiovascular disease (CVD) in adults living with HIV. We investigated the levels and predictors of arterial stiffness in young people (YP) living with perinatal HIV (PHIV) and HIV negative YP in the Adolescents and Adults Living with Perinatal HIV (AALPHI) study. Methods: AALPHI was a prospective study evaluating the impact of HIV infection and exposure to ART on YP living with PHIV (aged 13-21 years) who had known their HIV status for at least 6 months, and HIV negative YP (aged 13-23 years) who either had a sibling, friend or parent living with HIV. Participants were enrolled from HIV clinics and community services in England. Two hundred and thirteen PHIV and 65 HIV negative YP (42% siblings of PHIV) had pulse wave velocity (PWV) measurements taken (Vicorder software) from the supra-sternal notch to the middle of the thigh cuff, at their second interview in the study between 2015 and 2017. Average PWV was calculated from the three closest readings (≥3 and ≤ 12 m/s) within 0.6 m/s of each other. Linear regression examined predictors of higher (worse) PWV, including age, sex, HIV status and height as a priori, ethnicity, born outside UK/Ireland, alcohol/nicotine/drug use, weight, waist-to-hip-ratio, mean arterial pressure (MAP), caffeine 2 h before PWV and nicotine on day of PWV. A separate PHIV model included CD4, viral load, years taking ART and ART regimen. Findings: One hundred and twenty eight (60%) PHIV and 45 (69%) HIV negative YP were female (p = 0.18), with median (IQR) age 18 (16, 20) and 18 (16, 21) years (p = 0.48) respectively. Most PHIV were taking a combination of three ART drugs from two classes. There was a trend toward higher (worse) mean PWV in the PHIV group than the HIV negative group [unvariable analysis 6.15 (SD 0.83) m/s vs. 5.93 (0.70) m/s, respectively, unadjusted p = 0.058], which was statistically significant in the multivariable analysis [adjusted p (ap) = 0.020]. In multivariable analysis being male (ap = 0.002), older age (ap < 0.001), higher MAP (ap < 0.001) and nicotine use on day of measurement (ap = 0.001) were also predictors of higher PWV. The predictors were the same in the PHIV model. Interpretation: By late adolescence PHIV had worse PWV in comparison to HIV negative peers, and traditional risk factors for CVD (higher arterial pressure, being male and older age) were associated with higher PWV values. Regular detailed monitoring of cardiovascular risk factors should become standard of care for every young person with PHIV worldwide.

Long-term clinical, virological and immunological outcomes following planned treatment interruption in HIV-infected children.

OBJECTIVES: Planned treatment interruption (PTI) of antiretroviral therapy (ART) in adults is associated with adverse outcomes. The PENTA 11 trial randomized HIV-infected children to continuous ART (CT) vs. CD4-driven PTIs. We report 5 years' follow-up after the end of main trial. METHODS: Post-trial, all children resumed ART. Clinical, immunological, virological and treatment data were collected annually. A sub-study investigated more detailed immunophenotype. CT and PTI arms were compared using intention-to-treat. Laboratory parameters were compared using linear regression, adjusting for baseline values; mixed models were used to include all data over time. RESULTS: In all, 101 children (51 CT, 50 PTI) contributed a median of 7.6 years, including 5.1 years of post-trial follow-up. Post-trial, there were no deaths, one pulmonary tuberculosis and no other CDC stage B/C events. At 5 years post-trial, 90% of children in the CT vs. 82% in the PTI arm had HIV RNA < 50 copies/mL (P = 0.26). A persistent increase in CD8 cells was observed in the PTI arm. The sub-study (54 children) suggested that both naïve and memory populations contributed to higher CD8 cells following PTI. Mean CD4/CD8 ratios at 5 years post-trial were 1.22 and 1.08 in CT and PTI arms, respectively [difference (CT - PTI) = -0.15; 95% CI: -0.34-0.05), P = 0.14]. The sub-study also suggested that during the trial and at early timepoints after the end of the trial, reduction in CD4 in the PTI arm was mainly from loss of CD4 memory cells. CONCLUSIONS: Children tolerated PTI with few long-term clinical, virological or immunological consequences.

Barriers and facilitators to infection prevention and control in a neonatal unit in Zimbabwe - a theory-driven qualitative study to inform design of a behaviour change intervention.

BACKGROUND: Hospital-acquired infection (HAI) is an increasing cause of neonatal morbidity/mortality in low-income settings. Hospital staff behaviours (e.g., hand hygiene) are key contributors to HAI. Understanding the drivers of these can inform interventions to improve infection prevention and control (IPC). AIM: To explore barriers/facilitators to IPC in a neonatal unit in Harare, Zimbabwe. METHODS: Interviews were conducted with 15 staff members of neonatal and maternity units alongside ethnographic observations. The interview guide and data analysis were informed by the COM-B (Capability, Opportunity, Motivation-Behaviour) model and explored individual, socio-cultural, and organizational barriers/facilitators to IPC. Potential interventions were identified using the Behaviour-Change Wheel. FINDINGS: Enablers within Capability included awareness of IPC, and within Motivation beliefs that IPC was crucial to one's role, and concerns about consequences of poor IPC. Staff were optimistic that IPC could improve, contingent upon resource availability (Opportunity). Barriers included: limited knowledge of guidelines, no formal feedback on performance (Capability), lack of resources (Opportunity), often leading to improvization and poor habit formation. Further barriers included the unit's hierarchy, e.g., low engagement of cleaners and mothers in IPC, and staff witnessing implementation of poor practices by other team members (Opportunity). Potential interventions could include role-modelling, engaging mothers and staff across cadres, audit and feedback and flexible protocols (adaptable to water/handrub availability). CONCLUSIONS: Most barriers to IPC fell within Opportunity, whilst most enablers fell under Capability and Motivation. Theory-based investigation provides the basis for systematically identifying and developing interventions to address barriers and enablers to IPC in low-income settings.

Auditing use of antibiotics in Zimbabwean neonates.

BACKGROUND: Neonatal sepsis is a major cause of morbidity and mortality in low-income settings. As signs of sepsis are non-specific and deterioration precipitous, antibiotics are often used profusely in these settings where diagnostics may not be readily available. Harare Central Hospital, Zimbabwe, delivers 12000 babies per annum admitting ∼4800 to the neonatal unit. Overcrowding, understaffing and rapid staff turnover are consistent problems. Suspected sepsis is highly prevalent, and antibiotics widely used. We audited the impact of training and benchmarking intervention on rationalizing antibiotic prescription using local, World Health Organization-derived, guidelines as the standard. METHODS: An initial audit of admission diagnosis and antibiotic use was performed between 8th May - 6th June 2018 as per the audit cycle. An intern training programme, focusing on antimicrobial stewardship and differentiating between babies 'at risk of' versus 'with' clinically-suspected sepsis was instituted post-primary audit. Re-audit was conducted after 5 months. RESULTS: Sepsis was the most common admitting diagnosis by interns at both time points but reduced at repeat audit (81% versus 59%, P<0.0001). Re-audit after 5 months demonstrated a decrease in antibiotic prescribing at admission and discharge. Babies prescribed antibiotics at admission decreased from 449 (98%) to 96 (51%), P<0.0001. Inpatient days of therapy (DOT) reduced from 1243 to 1110/1000 patient-days. Oral amoxicillin prescription at discharge reduced from 349/354 (99%) to 1% 1/161 (P<0.0001). CONCLUSION: A substantial decrease in antibiotic use was achieved by performance feedback, training and leadership, although ongoing performance review will be key to ensuring safety and sustainability.

Persistence of HIV reservoir following successful haematopoietic stem cell transplant for juvenile myelomonocytic leukaemia in a child with perinatally acquired HIV.

This report describes a case of juvenile myelomonocytic leukaemia (JMML) on a background of both perinatally acquired HIV infection and congenital cytomegalovirus, and management of antiretroviral therapy during haematopoietic stem cell transplant. Peripheral blood HIV viral load remained below the lower limit of detection throughout and following transplant and is currently <20 RNA copies/mL. The child is currently in remission from JMML, but HIV DNA remains detectable despite myeloablative conditioning and sustained plasma HIV viral suppression.

Assessing the relationship between markers of glycemic control through flexible copula regression models.

Glycated haemoglobin (HbA1c) is a sensitive marker of blood glucose in patients with diabetes. However, levels can vary considerably, even amongst individuals with similar mean blood glucose concentrations. Other glycated proteins, such as fructosamine, can also act as blood sugar markers, but estimating HbA1c and fructosamine via independent models may lead to errors of interpretation regarding disease severity. From a clinical standpoint, it would be of great interest to know the factors that affect the mean concentration of both HbA1c and fructosamine, which influence the variability in the concentrations of these glycated markers and cause HbA1c/fructosamine discordance. Flexible models are required to illustrate the behaviour of these variables as well as the association between them. This work reviews existing models that might serve in this regard. Flexible copula regression models using splines were used to provide a better understanding of the behaviour of both glycated proteins and the relationship between them under the possible influence of different covariates. This work shows the usefulness of this type of models in practise and provides a basis for their clinical interpretation by means of an understandable case study. Ultimately, to better understand the effects of each continuous covariate, they are represented at the true scale of the response variables.

Prostate cancer treatment with Irreversible Electroporation (IRE): Safety, efficacy and clinical experience in 471 treatments.

BACKGROUND: Irreversible Electroporation (IRE) is a novel image-guided tissue ablation technology that induces cell death via very short but strong pulsed electric fields. IRE has been shown to have preserving properties towards vessels and nerves and the extracellular matrix. This makes IRE an ideal candidate to treat prostate cancer (PCa) where other treatment modalities frequently unselectively destroy surrounding structures inducing severe side effects like incontinence or impotence. We report the retrospective assessment of 471 IRE treatments in 429 patients of all grades and stages of PCa with 6-year maximum follow-up time. MATERIAL AND FINDINGS: The patient cohort consisted of low (25), intermediate (88) and high-risk cancers (312). All had multi-parametric magnetic resonance imaging, and 199 men had additional 3D-mapping biopsy for diagnostic work-up prior to IRE. Patients were treated either focally (123), sub-whole-gland (154), whole-gland (134) or for recurrent disease (63) after previous radical prostatectomy, radiation therapy, etc. Adverse effects were mild (19.7%), moderate (3.7%) and severe (1.4%), never life-threatening. Urinary continence was preserved in all cases. IRE-induced erectile dysfunction persisted in 3% of the evaluated cases 12 months post treatment. Mean transient IIEF-5-Score reduction was 33% within 12-month post IRE follow-up and 15% after 12 months. Recurrences within the follow-up period occurred in 10% of the treated men, 23 in or adjacent to the treatment field and 18 outside the treatment field (residuals). Including residuals for worst case analysis, Kaplan Maier estimation on recurrence rate at 5 years resulted in 5.6% (CI95: 1.8-16.93) for Gleason 6, 14.6% (CI95: 8.8-23.7) for Gleason 7 and 39.5% (CI95: 23.5-61.4) for Gleason 8-10. CONCLUSION: The results indicate comparable efficacy of IRE to standard radical prostatectomy in terms of 5-year recurrence rates and better preservation of urogenital function, proving the safety and suitability of IRE for PCa treatment. The data also shows that IRE, besides focal therapy of early PCa, can also be used for whole-gland ablations, in patients with recurrent PCa, and as a problem-solver for local tumor control in T4-cancers not amenable to surgery and radiation therapy anymore.

Habenula-prefrontal resting-state connectivity in reactive aggressive men - A pilot study.

Disproportionate anger and reactive aggression in response to provocation are core symptoms of intermittent-explosive disorder (IED). Previous research shows a link between the propensity for aggression in healthy individuals and altered functioning of prefrontal-limbic and default-mode networks (DMN) at rest when no provocation is present. In a pilot study, we used resting-state functional magnetic resonance imaging to investigate the effects of pronounced reactive aggression in men, exemplified by IED, on the functional organization of resting-state brain networks including subcortical nodes such as the habenula previously implicated in aggression in preclinical models. Graph theory was applied to resting-state networks to determine alterations in global efficiency and clustering in high reactive aggressive men compared to low reactive aggressive men (controls). Further, we computed within-group correlations between trait aggression and graph measures, as well as within-group whole-brain seed-to-voxel regression analyses between trait aggression and habenula resting-state functional connectivity (rsFC). Reactive aggressive men compared to controls showed higher global efficiency in the left habenula, the left pulvinar in the thalamus, the left dorso-lateral prefrontal cortex, and the right temporal pole, as well as a trend for decreased clustering in DMN nodes. In the reactive aggressive group, high levels of trait aggression were linked to lower global efficiency of the left habenula, and to lower rsFC between the left habenula and the left ventro-lateral prefrontal cortex, a core region involved in inhibitory control. Together with preclinical evidence, our findings in men underline the relevance of aberrant habenula-prefrontal connectivity for the severity of aggressive behavior. This article is part of the Special Issue entitled 'Current status of the neurobiology of aggression and impulsivity'.

Post-licensure safety surveillance study of routine use of quadrivalent meningococcal diphtheria toxoid conjugate vaccine (MenACWY-D) in infants and children.

BACKGROUND: Menactra® vaccine (MenACWY-D) was licensed in the United States in 2005 for persons 11-55 years of age, in 2007 for children 2-10 years of age, and in 2011 for infants/toddlers 9-23 months of age. We conducted two studies at Kaiser Permanente Northern California (KPNC), an integrated health care organization, to assess the safety of MenACWY-D in 2-10-year-olds and 9-23-month-olds receiving the vaccine during routine clinical care. METHODS: We conducted observational, retrospective studies of MenACWY-D in 2-10-year-olds (October 2007-October 2010) and in 9-23-month-olds (June 2011-June 2014). We monitored all subjects for non-elective hospitalizations, emergency department visits, and selected outpatient outcomes (specified neurological conditions, hypersensitivity reactions and new-onset autoimmune diseases) up to 6 months after vaccination, depending on the study. Using a self-control risk-interval design, we calculated incidence rate ratios (IRRs) comparing outcomes during the post-vaccination risk interval (0-30 days) with those during more remote post-vaccination comparison intervals (31-60 and 31-180 days [children] or 31-75 days [infants/toddlers]). RESULTS: There were 1421 children aged 2-10 years and 116 infants/toddlers aged 9-23 months who received MenACWY-D. Approximately 30% of the 2-10-year-olds and 67% of the 9-23-month-olds were considered at increased risk of meningococcal disease. Among 2-10-year-olds, there was 1 hospitalization on post-vaccination day 5 for fever, which was considered possibly related to vaccination. The only significantly elevated outcome among 2-10-year-olds was cellulitis/abscess (2 cases occurred during the risk interval versus 0 during comparison interval; IRR not evaluable [NE], 95% CI: 1.42, NE). After medical record review, the 2 cases were considered unrelated to vaccination. Among 9-23-month-olds, no outcomes were significantly elevated after vaccination and there were no hospitalizations. There were no deaths observed during the three-year accrual and subsequent six-month surveillance period for either study. CONCLUSIONS: Immunization of infants and young children with MenACWY-D vaccine was not associated with any new safety concerns; however, these small studies had limited power to detect rare or uncommon safety events. ClinicalTrials.gov Identifiers are NCT00728260 and NCT01689155.

Paediatric European Network for Treatment of AIDS (PENTA) guidelines for treatment of paediatric HIV-1 infection 2015: optimizing health in preparation for adult life.

The 2015 Paediatric European Network for Treatment of AIDS (PENTA) guidelines provide practical recommendations on the management of HIV-1 infection in children in Europe and are an update to those published in 2009. Aims of treatment have progressed significantly over the last decade, moving far beyond limitation of short-term morbidity and mortality to optimizing health status for adult life and minimizing the impact of chronic HIV infection on immune system development and health in general. Additionally, there is a greater need for increased awareness and minimization of long-term drug toxicity. The main updates to the previous guidelines include: an increase in the number of indications for antiretroviral therapy (ART) at all ages (higher CD4 thresholds for consideration of ART initiation and additional clinical indications), revised guidance on first- and second-line ART recommendations, including more recently available drug classes, expanded guidance on management of coinfections (including tuberculosis, hepatitis B and hepatitis C) and additional emphasis on the needs of adolescents as they approach transition to adult services. There is a new section on the current ART 'pipeline' of drug development, a comprehensive summary table of currently recommended ART with dosing recommendations. Differences between PENTA and current US and World Health Organization guidelines are highlighted and explained.

Periapical infection may affect birth outcomes via systemic inflammation.

OBJECTIVES: Maternal dental periapical infections are associated with preterm birth and intrauterine growth restriction. This study investigates whether the association is mediated through bacterial spread from periapical lesions to placenta (direct pathway) or systemic inflammatory reaction (indirect pathway). MATERIALS AND METHODS: We compared birth outcomes in Malawian mothers with and without periapical infection. As markers of a direct pathway, we identified placental bacteria using a 16S rDNA approach and assessed histological evidence of inflammation in the placenta and amniotic membranes. We measured C-reactive protein, alpha-1-acid glycoprotein, and salivary cortisol as markers of an indirect pathway. We used regression models to associate the predictor variables with duration of pregnancy and newborn size. RESULTS: Of 1,024 women, 23.5% had periapical infection. There was no association of periapical infection with either bacterial DNA or histological inflammation in placenta or membranes. Periapical infection was associated with C-reactive protein, alpha-1-acid glycoprotein, and cortisol concentrations in a dose-dependent manner at 36 weeks. Addition of alpha-1-acid glycoprotein or cortisol concentration into regression models attenuated the association between periapical infection and pregnancy outcomes. CONCLUSION: There was no evidence of direct spread of periapical bacteria to the placenta. Periapical infections and adverse pregnancy outcomes are in part mediated through systemic inflammation.

Post-licensure safety surveillance study of routine use of quadrivalent meningococcal diphtheria toxoid conjugate vaccine.

BACKGROUND: Menactra® vaccine (MenACWY-D) was licensed in the United States in 2005 for persons 11-55years of age. The aim of this study was to assess the safety of MenACWY-D administered as part of routine clinical care to patients at Kaiser Permanente Northern California (KPNC). METHODS: This was an observational, retrospective study that included all KPNC members who received MenACWY-D during the study period. We monitored all vaccine recipients for non-elective hospitalizations, emergency department visits, and selected outcomes captured in the clinic setting (Bell's palsy, seizures, neuritis, Guillain-Barré syndrome, encephalopathy, encephalitis, epilepsy, transverse myelitis, multiple sclerosis, hypersensitivity reactions, idiopathic thrombocytopenic purpura, diabetes, arthritis, hemolytic anemia, collagen-vascular disease) through 6months after vaccination. Using vaccine recipients as their own controls, we calculated incidence rate ratios (IRRs) of outcomes during the post-vaccination risk interval and compared these with rates during a comparison interval more remote from vaccination. We also compared rates of outcomes in MenACWY-D recipients with those in matched controls who received selected vaccines in the prior year. We reviewed medical records for selected outcomes. RESULTS: From April 2005 through April 2006, 31,561 KPNC patients (>99% of whom were 11-55years of age) received MenACWY-D. Overall, there were 21 outcomes with significantly elevated IRRs and 44 outcomes with significantly reduced IRRs. Medical record review of outcomes with significantly elevated IRRs did not suggest any relationship with MenACWY-D. Two serious adverse events were considered possibly related to vaccination by the study investigator. CONCLUSIONS: This study did not detect any safety concerns following MenACWY-D and provides reassurance that MenACWY-D administered as part of routine care was not associated with unexpected safety risks. ClinicalTrials.gov Identifier is NCT00254995.

Risk in the "Red Zone": Outcomes for Children Admitted to Ebola Holding Units in Sierra Leone Without Ebola Virus Disease.

We collected data on 1054 children admitted to Ebola Holding Units in Sierra Leone and describe outcomes of 697/1054 children testing negative for Ebola virus disease (EVD) and accompanying caregivers. Case-fatality was 9%; 3/630 (0.5%) children discharged testing negative were readmitted EVD-positive. Nosocomial EVD transmission risk may be lower than feared.