Improving global vaccine accessibility.

Although the beneficial impact of vaccination is well established, developing countries often rely upon humanitarian support to obtain access to routine immunization schedules. Furthermore, philanthropic funders require that vaccines be supplied at prices that are drastically lower than that charged in developed nations. This pricing requirement arises due to both the massive volume of vaccines needed and the logistics necessary to ensure their integrity (i.e. the cold chain). Cost-prohibitive vaccine formulation strategies, especially for newer vaccines, along with the lack of infrastructure in developing nations can further complicate this process. Extensive research is being conducted to develop novel technological platforms that overcome each of these accessibility impediments. This review provides an overview of the humanitarian organizations and technological developments that are dedicated to improving global healthcare by increasing vaccine accessibility.

Exploring the Potential Health Impact and Cost-Effectiveness of AIDS Vaccine within a Comprehensive HIV/AIDS Response in Low- and Middle-Income Countries.

BACKGROUND: The Investment Framework Enhanced (IFE) proposed in 2013 by the Joint United Nations Programme on HIV/AIDS (UNAIDS) explored how maximizing existing interventions and adding emerging prevention options, including a vaccine, could further reduce new HIV infections and AIDS-related deaths in low- and middle-income countries (LMICs). This article describes additional modeling which looks more closely at the potential health impact and cost-effectiveness of AIDS vaccination in LMICs as part of UNAIDS IFE. METHODS: An epidemiological model was used to explore the potential impact of AIDS vaccination in LMICs in combination with other interventions through 2070. Assumptions were based on perspectives from research, vaccination and public health experts, as well as observations from other HIV/AIDS interventions and vaccination programs. Sensitivity analyses varied vaccine efficacy, duration of protection, coverage, and cost. RESULTS: If UNAIDS IFE goals were fully achieved, new annual HIV infections in LMICs would decline from 2.0 million in 2014 to 550,000 in 2070. A 70% efficacious vaccine introduced in 2027 with three doses, strong uptake and five years of protection would reduce annual new infections by 44% over the first decade, by 65% the first 25 years and by 78% to 122,000 in 2070. Vaccine impact would be much greater if the assumptions in UNAIDS IFE were not fully achieved. An AIDS vaccine would be cost-effective within a wide range of scenarios. INTERPRETATION: Even a modestly effective vaccine could contribute strongly to a sustainable response to HIV/AIDS and be cost-effective, even with optimistic assumptions about other interventions. Higher efficacy would provide even greater impact and cost-effectiveness, and would support broader access. Vaccine efficacy and cost per regimen are critical in achieving cost-effectiveness, with cost per regimen being particularly critical in low-income countries and at lower efficacy levels.

A novel optic nerve photograph alignment and subtraction technique for the detection of structural progression in glaucoma.

PURPOSE: To highlight changing features over time within a single static image through the auto-alignment and subtraction of serial optic nerve photographs. METHODS: Subtraction maps were generated from auto-aligned (EyeIC, Narbeth, PA) baseline and follow-up images using Adobe Photoshop software. They demonstrated progressive retinal nerve fibre layer (RNFL) defects, optic disc haemorrhage (DH), neuroretinal rim loss (RL) and peripapillary atrophy (PPA). A masked glaucoma specialist identified features of progression on subtraction map first, then assessed feature strength by comparison with original images using alternation flicker. Control images with no progression and parallax-only images (as determined by flicker) were included. RESULTS: Eighty eyes of 67 patients were used to generate subtraction maps that detected glaucoma progression in 87% of DH (n = 28, sensitivity (Se) 82%, specificity (Sp) 98%) and 84% of PPA (n = 30, Se 80%, Sp 98%) cases. The lowest rate of detection was seen with RL at 67% (n = 31, Se 65%, Sp 100%). The subtraction technique was most sensitive for detecting parallax (n = 39, Se 98%, Sp 94%). Features of glaucoma progression appeared equally strong in flicker and subtraction images, but parallax was often enhanced on subtraction maps. Among control images selected for absence of features of glaucomatous change (n = 9) in original flicker images, no features were detected on subtraction maps. CONCLUSIONS: Auto-alignment and subtraction of serial optic nerve photographs reliably detects features of glaucoma progression with a single static image. Parallax identification may also be facilitated. Auto-alignment and subtraction of serial optic nerve photographs may prove especially useful in education and printed publications when dynamic imaging is not feasible.

Neuro-ophthalmologic features of chordoid glioma.

Chordoid glioma is a rare intracranial tumor typically arising in the third ventricle, particularly along the anterior aspect of the hypothalamic wall. We describe the clinical, neuroimaging, and pathologic factors of this neoplasm in a patient presenting with a chiasmal syndrome.

Association of blood and ocular perfusion pressure with structural glaucomatous progression by flicker chronoscopy.

BACKGROUND: Vascular risk factors have been associated with glaucomatous visual field progression. AIM: We determined the relationship between vascular risk factors and structural glaucomatous progression using serial flicker chronoscopy images. METHODS: Two glaucoma fellowship-trained ophthalmologists, masked to temporal sequence, independently graded serial flicker chronoscopy images from one eye of a cohort of glaucoma patients for features of structural progression in this retrospective cohort study. After adjudication, simple and multiple logistic models were constructed to determine variables associated with increased odds of progression, including systolic blood pressure (BP), diastolic BP and mean ocular perfusion pressure. RESULTS: Seventy-two eyes of 72 patients were analysed. Patients with any form of structural progression (n=40) were older (67.0 vs 58.8 years; p=0.005) and had lower diastolic BP (71.8 vs 76.5 mm Hg; p=0.02) than patients without progression (n=32). In the univariable model, diastolic BP was associated with progressive retinal nerve fibre layer (RNFL) loss (OR=0.2 per 10 mm Hg, 95% CI 0.1 to 0.6, p<0.006) and neuroretinal rim loss (OR=0.4 per 10 mm Hg, 95% CI 0.2 to 0.8, p<0.01). Diastolic BP was also significant in the multivariable model for RNFL loss (p=0.009) and neuroretinal rim loss (p=0.003). CONCLUSIONS: This study is the first to use structural progression and flicker chronoscopy to identify vascular glaucoma risk factors. Older age and lower diastolic BP were associated with progression. By multivariable analysis diastolic BP was associated with RNFL and neuroretinal rim loss. These findings suggest that diastolic BP is associated with structural glaucomatous progression which may have implications for management.

Accelerating the development of a safe and effective HIV vaccine: HIV vaccine case study for the Decade of Vaccines.

Human immunodeficiency virus (HIV), the etiologic agent that causes AIDS, is the fourth largest killer in the world today. Despite the remarkable achievements in development of anti-retroviral therapies against HIV, and the recent advances in new prevention technologies, the rate of new HIV infections continue to outpace efforts on HIV prevention and control. Thus, the development of a safe and effective vaccine for prevention and control of AIDS remains a global public health priority and the greatest opportunity to eventually end the AIDS pandemic. Currently, there is a renaissance in HIV vaccine development, due in large part to the first demonstration of vaccine induced protection, albeit modest, in human efficacy trials, a generation of improved vaccine candidates advancing in the clinical pipeline, and newly defined targets on HIV for broadly neutralizing antibodies. The main barriers to HIV vaccine development include the global variability of HIV, lack of a validated animal model, lack of correlates of protective immunity, lack of natural protective immune responses against HIV, and the reservoir of infected cells conferred by integration of HIV's genome into the host. Some of these barriers are not unique to HIV, but generic to other variable viral pathogens such as hepatitis C and pandemic influenza. Recommendations to overcome these barriers are presented in this document, including but not limited to expansion of efforts to design immunogens capable of eliciting broadly neutralizing antibodies against HIV, expansion of clinical research capabilities to assess multiple immunogens concurrently with comprehensive immune monitoring, increased support for translational vaccine research, and engaging industry as full partners in vaccine discovery and development.

Desmoid fibromatosis in children and adolescents: a conservative approach to management.

PURPOSE: Desmoid fibromatosis is associated with frequent recurrence and significant morbidity, but no metastases. To examine the impact of initial non-operative management on event-free survival (EFS) in children, we reviewed our institutional experience with this tumor. METHODS: We retrospectively reviewed our institutional database for pediatric cases of desmoid fibromatosis treated between 1970 and 2010. Survival was analyzed using the Kaplan-Meier method and log-rank test. RESULTS: Ninety-three patients were identified, with a median follow-up of 6 years. Median age at diagnosis was 16 years. Forty-seven patients presented with primary tumors, and forty-six had recurrent or progressing disease. Five-year OS was 100%, and 5-year EFS was 31.8%, with a median time to event of 1.48 years. There was no significant difference in 5-year EFS between patients who were managed expectantly and those who initially received treatment (21% versus 34%, P=.09). Sex, race, history of trauma, or familial adenomatous polyposis, multifocality, tumor size, tumor location, and resection status did not correlate with EFS. CONCLUSION: Our findings support a conservative initial approach in the management of desmoid fibromatosis. In patients at risk for morbid procedures, upfront resection should be reserved for select tumors that demonstrate aggressive growth or cause serious symptoms.

Posttraumatic Chondrocyte Apoptosis in the Murine Xiphoid.

OBJECTIVE: To demonstrate posttraumatic chondrocyte apoptosis in the murine xiphoid after a crush-type injury and to ultimately determine the pathway (i.e., intrinsic or extrinsic) by which chondrocytes undergo apoptosis in response to mechanical injury. DESIGN: The xiphoids of adult female wild-type mice were injured with the use of a modified Kelly clamp. Postinjury xiphoid cartilage was analyzed via 3 well-described independent means of assessing apoptosis in chondrocytes: hematoxylin and eosin staining, terminal deoxynucleotidyl transferase dUTP nick end labeling assay, and activated caspase-3 staining. RESULTS: Injured specimens contained many chondrocytes with evidence of apoptosis, which is characterized by cell shrinkage, chromatin condensation, nuclear fragmentation, and the liberation of apoptotic bodies. There was a statistically significant increase in the number of chondrocytes undergoing apoptosis in the injured specimens as compared with the uninjured specimens. CONCLUSIONS: Chondrocytes can be stimulated to undergo apoptosis as a result of mechanical injury. These experiments involving predominantly cartilaginous murine xiphoid in vivo establish a baseline for future investigations that employ the genetic and therapeutic modulation of chondrocyte apoptosis in response to mechanical injury.

IL-7 promotes T cell viability, trafficking, and functionality and improves survival in sepsis.

Sepsis is a highly lethal disorder characterized by widespread apoptosis-induced depletion of immune cells and the development of a profound immunosuppressive state. IL-7 is a potent antiapoptotic cytokine that enhances immune effector cell function and is essential for lymphocyte survival. In this study, recombinant human IL-7 (rhIL-7) efficacy and potential mechanisms of action were tested in a murine peritonitis model. Studies at two independent laboratories showed that rhIL-7 markedly improved host survival, blocked apoptosis of CD4 and CD8 T cells, restored IFN-gamma production, and improved immune effector cell recruitment to the infected site. Importantly, rhIL-7 also prevented a hallmark of sepsis (i.e., the loss of delayed-type hypersensitivity), which is an IFN-gamma- and T cell-dependent response. Mechanistically, rhIL-7 significantly increased the expression of the leukocyte adhesion markers LFA-1 and VLA-4, consistent with its ability to improve leukocyte function and trafficking to the infectious focus. rhIL-7 also increased the expression of CD8. The potent antiapoptotic effect of rhIL-7 was due to increased Bcl-2, as well as to a dramatic decrease in sepsis-induced PUMA, a heretofore unreported effect of IL-7. If additional animal studies support its efficacy in sepsis and if current clinical trials continue to confirm its safety in diverse settings, rhIL-7 should be strongly considered for clinical trials in sepsis.