Using the Indirect Cohort Design to Estimate the Effectiveness of the Seven Valent Pneumococcal Conjugate Vaccine in England and Wales

BACKGROUND: The 7-valent pneumococcal conjugate vaccine (PCV-7) was introduced in the United Kingdom in 2006 with a 2, 3 and 13 month schedule, and has led to large decreases in invasive pneumococcal disease (IPD) caused by the vaccine serotypes in both vaccinated and unvaccinated cohorts. We estimated the effectiveness of PCV-7 against IPD. METHODS AND FINDINGS: We used enhanced surveillance data, collated at the Health Protection Agency, on vaccine type (n = 153) and non vaccine type (n = 919) IPD cases eligible for PCV-7. The indirect cohort method, a case-control type design which uses non vaccine type cases as controls, was used to estimate effectiveness of various numbers of doses as well as for each vaccine serotype. Possible bias with this design, caused by differential serotype replacement in vaccinated and unvaccinated individuals, was estimated after deriving formulae to quantify the bias. The results showed good effectiveness, increasing from 56% (95% confidence interval (CI): -7-82) for a single dose given under one year of age to 93% (95% CI: 70-98) for two doses under one year of age plus a booster dose in the second year of life. Serotype specific estimates indicated higher effectiveness against serotypes 4, 14 and 18C and lower effectiveness against 6B. Under the assumption of complete serotype replacement by non vaccine serotypes in carriage, we estimated that effectiveness estimates may be overestimated by about 2 to 5%. CONCLUSIONS: This study shows high effectiveness of PCV-7 under the reduced schedule used in the UK. This finding agrees with the large reductions seen in vaccine type IPD in recent years in England and Wales. The formulae derived to assess the bias of the indirect cohort method for PCV-7 can also be used when using the design for other vaccines that affect carriage such as the recently introduced 13 valent pneumococcal conjugate vaccine

Recommendations for reducing energy consumption and improving air quality through energy efficiency in Indian Country: Working paper series--04-04

The strongest recommendation stemming from the Air Pollution Prevention forum of the Western Regional Air Partnership (WRAP) was for tribes to develop and implement energy plans. This paper provides a discussion of the benefits of any such plan and itemized a variety of components of any said plan. A brief discussion of the WRAP is presented is the framework of improving air quality. Based on the background of Jacobs (2000) and Smith (2000), the primary and secondary benefits of energy efficiency plans are then discussed. Then a series of specific recommendations are itemized. These include tribally sponsored programs, collaborative opportunities, and tribal leadership programs

Economic analysis of energy efficiency measures: Tribal case studies with The Confederated Salish and Kootenai Tribes of The Flathead Reservation, The Pascua Yaqui Tribe, and The Yurok Tribe: Working paper series--04-02

The best way to reduce air pollution from the production of electricity is not to produce it in the first place. This paper presents three cases studies explaining how energy efficiency programs can be beneficial to tribes from a purely cost-saving basis, The Yurok, Flathead and Pascua Yaqui Reservations graciously provided an opportunity to investigate energy efficiency for their tribes. In each case the consumption of electricity was reduced such that a positive net present value was present following an initial capital investment. In the case of the irrigation systems on the Flathead Reservation, the savings were substantial even though no explicit savings of water was accounted for. It is estimated that tribes can reduce electricity costs by 10-50% by following energy efficiency programs. Many programs can be very simple involving small upfront capital outlays, such as changing light bulbs or installing motion sensors. The Yurok case showed a return of 7.5% after simply changing bulbs and the Pasqua Yaqui case showed a possible return of 10-80%. Other tribes could make similar investments and realize similar benefits in addition to improved air quality. The strongest recommendation from the Air Pollution Prevention Forum to tribes was to develop an energy plan. These cases show that some fairly simple analysis can make a plan very beneficial

Identification and implementation of potential energy efficiency programs in Indian Country: Working paper series--04-03

The strongest recommendation stemming from the Air Pollution Prevention forum of the Western Regional Air Partnership (WRAP) was for tribes to develop and implement energy plans. This paper provides a discussion of the benefits of any such plan and itemized a variety of components of any said plan. A brief discussion of the WRAP is presented is the framework of improving air quality. Based on the background of Jacobs (2000) and Smith (2000), the primary and secondary benefits of energy efficiency plans are then discussed. Then a series of specific recommendations are itemized. These include tribally sponsored programs, collaborative opportunities, and tribal leadership programs

Asymmetric Upwarp of the Asthenosphere beneath the Baikal Rift Zone, Siberia

In the summer of 1991 we installed 27 seismic stations about lake Baikal, Siberia, aimed at obtaining accurately timed digital seismic data to investigate the deep structure and geodynamics of the Baikal rift zone and adjacent regions. Sixty-six teleseismic events with high signal-to-noise ratio were recorded. Travel time and Q analysis of teleseisms characterize an upwarp of the lithosphere-asthenosphere boundary under Baikal. Theoretical arrival times were calculated by using the International Association of Seismology and Physics of the Earth\u27s interior 1991 Earth model, and travel time residuals were found by subtracting computed arrival times from observed ones. A three-dimensional downward projection inversion method is used to invert the P wave velocity structure with constraints from deep seismic sounding data. Our results suggest that (1) the lithosphere-asthenosphere transition upwarps beneath the rift zone, (2) the upwarp has an asymmetric shape, (3) the velocity contrast is -4.9% in the asthenosphere, (4) the density contrast is -0.6%, and (5) the P wave attenuation contrast t* is 0.1 s

Haemophilus influenzae Type b Vaccine Failure in Children Is Associated with Inadequate Production of High-Quality Antibody

Background. Despite the excellent immunogenicity of Haemophilus influenzae type b (Hib) conjugate vaccines, breakthrough cases of Hib disease still affect a small proportion of vaccinated children in the United Kingdom. We performed a retrospective study to compare the avidity of antibody directed against the Hib polysaccharide capsule (PRP) in children who experienced Hib vaccine failure in the United Kingdom among 3 historical cohorts and with age-matched healthy control subjects. Methods. Serum samples from vaccinated children with invasive Hib disease were collected beginning in 1992 as part of enhanced surveillance for Hib disease following vaccine introduction. A total of 251 children who experienced Hib vaccine failure were identified from 3 historical cohorts (1992-1995, 1996-1999, and 2000-2003). The anti-PRP antibody concentration and avidity from healthy age-matched control subjects was obtained for the 3 contemporary time points (1995, 1999, and 2002). Serum anti-PRP antibody concentration was measured in each of the samples using a standard Hib ELISA, and antibody avidity was determined using thiocyanate elution. Results. Within the first 60 days after disease onset, there was no change in the anti-PRP antibody avidity, and there was no statistically significant difference in the geometric mean Hib antibody avidity over the 3 study periods. However, the children who experienced Hib vaccine failure had significantly lower Hib antibody avidity than did healthy control subjects, despite a marked antibody response following infection. Conclusions. Children who experience Hib disease despite vaccination appear to have a defect in immunological priming, leading to a qualitative difference in Hib-specific memory B cells. Low anti-PRP antibody avidity decreases the functional activity of anti-PRP antibody in the sera of these children experiencing vaccine failure, leading to disease susceptibilit

A positron emission tomography imaging study to confirm target engagement in the lungs of patients with idiopathic pulmonary fibrosis following a single dose of a novel inhaled αvβ6 integrin inhibitor

© 2020 The Author(s). Background: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease with poor prognosis and a significant unmet medical need. This study evaluated the safety, pharmacokinetics (PK) and target engagement in the lungs, of GSK3008348, a novel inhaled alpha-v beta-6 (αvβ6) integrin inhibitor, in participants with IPF. Methods: This was a phase 1b, randomised, double-blind (sponsor unblind) study, conducted in the UK (two clinical sites, one imaging unit) between June 2017 and July 2018 (NCT03069989). Participants with a definite or probable diagnosis of IPF received a single nebulised dose of 1000 mcg GSK3008348 or placebo (ratio 5:2) in two dosing periods. In period 1, safety and PK assessments were performed up to 24 h post-dose; in period 2, after a 7-day to 28-day washout, participants underwent a total of three positron emission tomography (PET) scans: Baseline, Day 1 (~ 30 min post-dosing) and Day 2 (~ 24 h post-dosing), using a radiolabelled αvβ6-specific ligand, [18F]FB-A20FMDV2. The primary endpoint was whole lung volume of distribution (VT), not corrected for air volume, at ~ 30 min post-dose compared with pre-dose. The study success criterion, determined using Bayesian analysis, was a posterior probability (true % reduction in VT > 0%) of ≥80%. Results: Eight participants with IPF were enrolled and seven completed the study. Adjusted posterior median reduction in uncorrected VT at ~ 30 min after GSK3008348 inhalation was 20% (95% CrI:-9 to 42%). The posterior probability that the true % reduction in VT > 0% was 93%. GSK3008348 was well tolerated with no reports of serious adverse events or clinically significant abnormalities that were attributable to study treatment. PK was successfully characterised showing rapid absorption followed by a multiphasic elimination. Conclusions: This study demonstrated engagement of the αvβ6 integrin target in the lung following nebulised dosing with GSK3008348 to participants with IPF. To the best of our knowledge this is the first time a target-specific PET radioligand has been used to assess target engagement in the lung, not least for an inhaled drug. Trial registration: Clinicaltrials.gov: NCT03069989; date of registration: 3 March 2017

Evidence of a recent magma dike intrusion at the slow spreading Lucky Strike segment, Mid-Atlantic Ridge

Author Posting. © American Geophysical Union, 2004. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Journal of Geophysical Research 109 (2004): B12102, doi:10.1029/2004JB003141.Mid-ocean ridge volcanic activity is the fundamental process for creation of ocean crust, yet the dynamics of magma emplacement along the slow spreading Mid-Atlantic Ridge (MAR) are largely unknown. We present acoustical, seismological, and biological evidence of a magmatic dike intrusion at the Lucky Strike segment, the first detected from the deeper sections (>1500 m) of the MAR. The dike caused the largest teleseismic earthquake swarm recorded at Lucky Strike in >20 years of seismic monitoring, and one of the largest ever recorded on the northern MAR. Hydrophone records indicate that the rate of earthquake activity decays in a nontectonic manner and that the onset of the swarm was accompanied by 30 min of broadband (>3 Hz) intrusion tremor, suggesting a volcanic origin. Two submersible investigations of high-temperature vents located at the summit of Lucky Strike Seamount 3 months and 1 year after the swarm showed a significant increase in microbial activity and diffuse venting. This magmatic episode may represent one form of volcanism along the MAR, where highly focused pockets of magma are intruded sporadically into the shallow ocean crust beneath long-lived, discrete volcanic structures recharging preexisting seafloor hydrothermal vents and ecosystems.This study was made possible through the support of the U.S. National Science Foundation (grants OCE-9811575, OCE- 0137164, and OCE-0201692) and the NOAA Vents Program

Impaired Spleen Formation Perturbs Morphogenesis of the Gastric Lobe of the Pancreas

Despite the extensive use of the mouse as a model for studies of pancreas development and disease, the development of the gastric pancreatic lobe has been largely overlooked. In this study we use optical projection tomography to provide a detailed three-dimensional and quantitative description of pancreatic growth dynamics in the mouse. Hereby, we describe the epithelial and mesenchymal events leading to the formation of the gastric lobe of the pancreas. We show that this structure forms by perpendicular growth from the dorsal pancreatic epithelium into a distinct lateral domain of the dorsal pancreatic mesenchyme. Our data support a role for spleen organogenesis in the establishment of this mesenchymal domain and in mice displaying perturbed spleen development, including Dh +/−, Bapx1−/− and Sox11−/−, gastric lobe development is disturbed. We further show that the expression profile of markers for multipotent progenitors is delayed in the gastric lobe as compared to the splenic and duodenal pancreatic lobes. Altogether, this study provides new information regarding the developmental dynamics underlying the formation of the gastric lobe of the pancreas and recognizes lobular heterogeneities regarding the time course of pancreatic cellular differentiation. Collectively, these data are likely to constitute important elements in future interpretations of the developing and/or diseased pancreas

Translational pharmacology of an inhaled small molecule αvβ6 integrin inhibitor for idiopathic pulmonary fibrosis

The αvβ6 integrin plays a key role in the activation of transforming growth factor-β (TGFβ), a pro-fibrotic mediator that is pivotal to the development of idiopathic pulmonary fibrosis (IPF). We identified a selective small molecule αvβ6 RGD-mimetic, GSK3008348, and profiled it in a range of disease relevant pre-clinical systems. To understand the relationship between target engagement and inhibition of fibrosis, we measured pharmacodynamic and diseaserelated end points. Here we report, GSK3008348 binds to αvβ6 with high affinity in human IPF lung and reduces downstream pro-fibrotic TGFβ signaling to normal levels. In human lung epithelial cells, GSK3008348 induces rapid internalization and lysosomal degradation of the αvβ6 integrin. In the murine bleomycin-induced lung fibrosis model, GSK3008348 engages αvβ6, induces prolonged inhibition of TGFβ signaling and reduces lung collagen deposition and serum C3M, a marker of IPF disease progression. These studies highlight the potential of inhaled GSK3008348 as an anti-fibrotic therapy