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Abstract: Francisella tularensis is pathogenic for many mammalian species including humans, causing a spectrum of diseases called tularemia. The highly virulent Type A strains have associated mortality rates of up to 60% if inhaled. An attenuated live vaccine strain (LVS) is the only vaccine to show efficacy in humans, but suffers several barriers to licensure, including the absence of a correlate of protection. An immunoproteomics approach was used to survey the repertoire of antibodies in sera from individuals who had contracted tularemia during two outbreaks and individuals from two geographical areas who had been vaccinated with NDBR Lot 11 or Lot 17 LVS. These data showed a large overlap in the antibodies generated in response to tularemia infection or LVS vaccination. A total of seven proteins were observed to be reactive with 60% or more sera from vaccinees and convalescents. A further four proteins were recognised by 30–60% of the sera screened. These proteins have the potential to serve as markers of vaccination or candidates for subunit vaccines. [Copyright &y& Elsevier]

Abstract: A rapid and effective development of vaccines and other prophylactics, as well as novel therapeutics, against emerging threats requires the development and implementation of novel strategies. One such strategy is the integrator approach. This approach utilizes an integrated development team comprising expertise in program management, scientific management, clinical research, preclinical/nonclinical development, manufacturing, testing, risk management, quality assurance, and regulatory strategy and compliance. Key to the success of this approach is the successful management of subcontracted work, as well as the seamless integration of multiple systems and data inputs into a coherent development plan. [Copyright &y& Elsevier]

FLEX-module optical coherence tomography (OCT) - expanding the reach of OCT in evaluating childhood glaucoma Objective evaluation of glaucomatous optic neuropathy with OCT can be limited by very young age, inability to cooperate, or technical challenges. Childhood glaucoma patients undergoing examination under anesthesia and/or surgical intervention were included in this ongoing prospective study. [Extracted from the article]

The postoperative management of the nonvalved Baerveldt glaucoma drainage device (GDD) presents challenges in children due to widely variable intraocular pressure (IOP) often occurring perioperatively. Home tonometry-augmented GDD management in childhood glaucoma may improve care of these challenging patients. [Extracted from the article]

Purpose To identify and analyze cases of postoperative infection following strabismus surgery at a large referral center and to report the incidence, risk factors, and outcomes. Methods An electronic database search identified strabismus procedures at Duke Eye Center from July 1996 to October 2017. Diagnosis codes for periocular infections were used to further identify patients with possible infections following strabismus surgery. Results Of 9,111 strabismus surgeries, 13 (0.14%) met criteria for probable infection, all occurring since October 2012 (0/6580 before vs 13/2531 [0.51%] after; P < 0.0001). Mean age of infection cases was 11.4 years; 11 patients (85%) were under 18 years of age. Associated previous diagnoses were genetic abnormalities with associated developmental delay (n = 5 [38%]), previous skin or ear infection (n = 4 [31%]), and acute or chronic rhinitis (n = 3 [23%]). Infection site cultures revealed methicillin-resistant Staphylococcus aureus (n = 3 [23%]), methicillin-sensitive S. aureus (n = 3 [23%]), and Streptococcus pyogenes /group-A Streptococcus (n = 2 [15%]). Only 1 case had bilateral infection. Infection remained extraocular in all cases, but one eye lost light perception secondary to optic atrophy. No common surgeon/procedure/preparation-related risks were identified. Conclusions A unifying explanation for the increase in post–strabismus surgery infections at Duke Eye Center was not identified. Potential risk factors include age <18 years, developmental delay, immune compromise, preceding nonocular infection, and bacterial colonization. [ABSTRACT FROM AUTHOR]

Abstract: A recombinant botulinum vaccine (rBV A/B) is being developed to protect adults 18–55 years of age from fatal botulism caused by inhalational intoxication with botulinum neurotoxin complex (BoNT) serotype A, subtype A1 (BoNT/A1) and BoNT serotype B, subtype B1 (BoNT/B1). Fundamental to the advanced development process is an initial demonstration of product safety in animals. A comprehensive series of studies was conducted to evaluate the general toxicity, neurobehavioral toxicity and local reactogenicity of the rBV A/B vaccine prior to first use in humans. Toxicity was evaluated in CD-1 mice vaccinated with control material and three dosages of rBV A/B with or without Alhydrogel® by intramuscular (IM) injection on Study Days 0, 28, 56 and 70 in a volume of 100μL. Total immunizing protein given in each dose was either 0, 2, 4 or 8μg/animal. Local reactogenicity was evaluated in mice at the dosages given and in New Zealand white (NZW) rabbits using the same injection volume (0.5mL) and formulations (10, 20 and 40g/mL total antigen with 0.2% (w/v) Alhydrogel®) intended for human use. The rBV A/B vaccine produced no apparent systemic or neurobehavioral toxicity and only transient mild inflammation at the injection site. Together these results indicated a favorable safety profile for rBV A/B and supported its use in a Phase 1 clinical trial. [Copyright &y& Elsevier]

To assess macular vasculature in healthy infants and children using OCT angiography (OCTA). Prospective cross-sectional study. One hundred thirty-five normal maculae of 89 healthy infants and children (mean age, 8.5±5.3 years; range, 9 weeks–17 years) treated at the Duke University Eye Center. We imaged 135 maculae of 89 pediatric patients using the standard Spectralis tabletop and investigational Spectralis with Flex module devices, both equipped with investigational OCTA software (Heidelberg Engineering, Heidelberg, Germany). OCT angiography images of the superficial vascular complex (SVC) and deep vascular complex (DVC) were analyzed for foveal avascular zone (FAZ) area and superficial and deep vessel density. We assessed effects of age, gender, race, axial length (AL), and central subfield thickness on FAZ and vessel density. Patients with both eyes imaged were assessed for agreement between the FAZ and vessel densities of the left and right eyes. The FAZ area, as well as vessel area density (VAD) and vessel length density (VLD) in the SVC and DVC. The FAZ varied significantly with race; white patients showed a significantly smaller FAZ than black patients (mean difference, 0.11 mm2; P = 0.004). The FAZ did not vary with age, gender, or AL (P > 0.05). In the SVC, VAD and VLD varied significantly with age (P < 0.001) and AL (R 2 = 0.46; P < 0.001) but not gender (P > 0.05). The SVC VLD was significantly different between races and ethnicities (P = 0.037), but VAD was not (P < 0.05). In the DVC, VAD and VLD also varied significantly with age (P < 0.001) and AL (R 2 = 0.46; P < 0.001) but not gender or race (P > 0.05). There was excellent agreement between the right and left eyes for FAZ (intraclass correlation [ICC], 0.97), SVC VLD (ICC, 1.00), and DVC VLD (ICC, 1.00). Quantitative studies of pediatric perifoveal vasculature should consider age, race, and AL. In eyes with unilateral disease, the perifoveal vasculature in the unaffected eye may be used as a control comparison because there is excellent agreement between eyes. [ABSTRACT FROM AUTHOR]

Purpose To determine the personalized rate of uveal melanoma–related metastasis on the basis of individual tumor cytogenetic profile. Design Retrospective case series. Participants A total of 1059 patients with uveal melanoma. Methods Fine-needle aspiration biopsy (FNAB) for DNA amplification and whole genome array–based assay were performed for analysis of chromosomes 3, 6, and 8. Main Outcome Measures Melanoma-related metastasis. Results The mean patient age was 57 years, and most were white (1026/1059, 97%). The melanoma involved the choroid (938/1059, 89%), ciliary body (85/1059, 8%), or iris (36/1059, 3%), with 19% being macular in location. The mean largest basal diameter was 11 mm (median, 12 mm; range, 3–24 mm), and mean thickness was 5 mm (median, 4 mm; range, 1–20 mm). On the basis of individual chromosomal mutations, risk for metastasis was increased for chromosome 3 partial monosomy (hazard ratio [HR], 2.84; P = 0.001), 3 complete monosomy (HR, 6.7, P < 0.001), 6q loss (HR, 3.1, P = 0.003), 8p loss (HR, 21.5, P < 0.001), and 8q gain (HR, 9.8, P < 0.001). Kaplan–Meier estimate for melanoma-related metastasis in 1, 3, 5, and 7 years for 3 partial monosomy was 1%, 5%, 14%, and 17%; for 3 complete monosomy was 3%, 19%, 28%, and 37%; for 6q loss was 8%, 23%, 49%, and 49%; for 8p loss was 8%, 29%, not estimable (NE), and NE; and for 8q gain was 6%, 21%, 35%, 48%, respectively. On the basis of personalized cytogenetic profiles, Kaplan–Meier estimates (1, 3, and 5 years) for melanoma-related metastasis for 3, 6, and 8 disomy (1%, 1%, 4% [HR, 1]) were low compared with the higher-risk combinations of 3 complete monosomy, 6p gain, and 8q gain (0%, 29%, 29% [HR, 10.6, P = 0.02]); 3 complete monosomy, 6 disomy, 8q gain, and 8p gain (14%, 14%, NE [HR, 18.3, P = 0.02]); 3 complete monosomy, 6 disomy, and 8q gain (8%, 27%, 39% [HR, 19.5, P < 0.001]); and 3 complete monosomy, 6 disomy, 8q gain, and 8p loss (3%, 28%, NE [HR, 31.6, P < 0.001]), respectively. Conclusions Risk for melanoma-related metastasis strongly correlates with personalized cytogenetic profiles, with 5-year Kaplan–Meier estimates ranging from 4% with chromosomes 3, 6, and 8 disomy up to 39% for 3 complete monosomy, 6 disomy, and 8q gain. [ABSTRACT FROM AUTHOR]

Abstract: Francisella tularensis subspecies tularensis is a highly virulent facultative intracellular pathogen of humans and a potential biological weapon. A live vaccine strain, F. tularensis LVS, was developed more than 50 years ago by pragmatic attenuation of a strain of the less virulent holarctica subspecies. LVS was demonstrated to be highly effective in human volunteers who were exposed to intradermal challenge with fully virulent subsp. tularensis, but was less effective against aerosol exposure. LVS faces regulatory hurdles that to date have prevented its licensure for general use. Therefore, a better defined and more effective vaccine is being sought. To this end we have created gene deletion mutants in the virulent subsp. tularensis strain and tested them for their ability to elicit a protective immune response against systemic or aerosol challenge with the highly virulent wild-type subsp. tularensis strain, SCHU S4. Both oral and intradermal (ID) primary vaccination routes were assessed in BALB/c and C3H/HeN mice as was oral boosting. One SCHU S4 mutant missing the heat shock gene, clpB, was significantly more attenuated than LVS whereas a double deletion mutant missing genes FTT0918 and capB was as attenuated as LVS. In general mice immunized with SCHU S4ΔclpB were significantly better protected against aerosol challenge than mice immunized with LVS. A single ID immunization of BALB/c mice with SCHU S4ΔclpB was at least as effective as any other regimen examined. Mice immunized with SCHU S4Δ0918ΔcapB were generally protected to a similar degree as mice immunized with LVS. A preliminary examination of immune responses to vaccination with LVS, SCHU S4ΔclpB, or SCHU S4Δ0918ΔcapB provided no obvious correlate to their relative efficacies. [Copyright &y& Elsevier]

Abstract: Assessment of neurovirulence is a standard test for vaccines derived from virulent neurotropic viruses. This study evaluated the potential neurovirulence of V3526, a live attenuated vaccine derived from a full-length infectious clone of Venezuelan equine encephalitis virus (VEEV) Trinidad donkey strain (TrD), a comparator VEEV vaccine (TC-83), TrD, and process control material (PCM) in juvenile rhesus macaques. Following intrathalamic/intraspinal (IT/IS) or subcutaneous (SC) inoculations, animals were observed for periods of 18, 91 or 181 days for paresis, paralysis, neurological disorders and other signs of clinical illness. Blood was collected for measurement of viremia, VEEV neutralizing antibodies, hematologic parameters, and liver enzymes. Gross necropsies and histopathological examinations were conducted with emphasis on detecting lesions in the brain and spinal cord. Elevated temperatures (1–2°C) were noted in several of the TrD and vaccine inoculated animals on Day 6 following inoculation and mean temperatures for the V3526 IT/IS and TC-83 groups were higher than PCM group throughout the study Day 18. No significant differences were seen for weight or clinical chemistry results between vaccine and PCM inoculated groups. Clinically significant signs (Grades 3 or 4) were noted in three of 21 V3526 IT/IS and three of 12 TC-83 inoculated animals, however, these signs resolved within 3 weeks for all V3526 IT/IS and for two of three TC-83 inoculated animals. At Day 18 extensive lesions indicative of a viral infection were seen in brain sections of all four TrD inoculated animals and one of seven V3526 IT/IS inoculated animals. Only scattered lesions, characterized by foci of gliosis and vessels with perivascular inflammation, were found in the sections from four TC-83 and six V3526 IT/IS inoculated animals. The minimal histological changes observed at Day 18 resolved to baseline levels by Day 181 comparable to the PCM group. V3526 was immunogenic and essentially nonneurovirulent when administered via the clinically relevant subcutaneous route. [Copyright &y& Elsevier]

Summary: Tularemia is a severe disease for which there is no licensed vaccine. An attenuated F. tularensis live vaccine strain (LVS) was protective when administered to humans but safety concerns precluded its licensure and use in large-scale immunization. An improved F. tularensis LVS preparation was produced under current good manufacturing practice (cGMP) guidelines for evaluation in clinical trials. Preclinical safety, tolerability and immunogenicity were investigated in rabbits that received LVS in escalating doses (1×105–1×109 CFU) by the intradermal, subcutaneous or percutaneous (scarification) route. This improved LVS formulation was well tolerated at all doses; no death or adverse clinical signs were observed and necropsies showed no signs of pathology. No live organisms were detected in liver or spleen. Transient local reactogenicity was observed after scarification injection. Erythema and edema developed after intradermal injection in the highest dose cohorts. High levels of F. tularensis-specific IgM, IgG and IgA developed early after immunization, in a dose-dependent fashion. Scarification elicited higher levels of IgA. Antibodies elicited by LVS also recognized F. tularensis Schu-S4 antigens and there was a significant correlation between antibody titers measured against both LVS and Schu-S4. The ELISA titers also correlated closely with those measured by microagglutination. This is the first report describing comprehensive toxicological and immunological studies of F. tularensis LVS in rabbits. This animal model, which closely resembles human disease, proved adequate to assess safety and immunogenicity of F. tularensis vaccine candidates. This new LVS vaccine preparation is being evaluated in human clinical studies. [Copyright &y& Elsevier]

The recent report of P2–Na 2/3 Mg 0.28 Mn 0.72 O 2 (P2-NMM) demonstrated the possibility of utilizing the oxygen redox couple in a layered oxide cathode without the need for alkali ions or vacancies in the transition metal layer. In this work, we report the synthesis of a new P2-type compound, Na 2/3 Mg 1/4 Mn 7/12 Co 1/6 O 2 (P2-NMMC), which exhibits reversible specific capacities as high as 173 mAh g−1 and an improvement of the first cycle voltage hysteresis over P2-NMM. The material was characterised using a combination of ex-situ and operando techniques including X-ray diffraction (XRD), differential electrochemical mass spectrometry (DEMS) and X-ray spectroscopy (XAS) to identify potential sources for this improvement. • P2-NMMC exhibits specific capacities of ≈170 mAh g−1 after 40 cycles. • P2-NMMC has a lower voltage hysteresis (≈0.5 V) than P2-NMM. • Oxygen redox reaction is studied using various ex-situ and operando techniques. [ABSTRACT FROM AUTHOR]