Recent genome-wide studies have reported novel associations between common polymorphisms and susceptibility to many major infectious diseases in humans. In parallel, an increasing number of rare ...mutations underlying susceptibility to specific phenotypes of infectious disease have been described. Together, these developments have highlighted a key role for host genetic variation in determining the susceptibility to infectious disease. They have also provided insights into the genetic architecture of infectious disease susceptibility and identified immune molecules and pathways that are directly relevant to the human host defence.
Vaccines against malaria Hill, Adrian V. S.
Philosophical transactions of the Royal Society of London. Series B. Biological sciences,
10/2011, Letnik:
366, Številka:
1579
Journal Article
Recenzirano
Odprti dostop
There is no licenced vaccine against any human parasitic disease and Plasmodium falciparum malaria, a major cause of infectious mortality, presents a great challenge to vaccine developers. This has ...led to the assessment of a wide variety of approaches to malaria vaccine design and development, assisted by the availability of a safe challenge model for small-scale efficacy testing of vaccine candidates. Malaria vaccine development has been at the forefront of assessing many new vaccine technologies including novel adjuvants, vectored prime-boost regimes and the concept of community vaccination to block malaria transmission. Most current vaccine candidates target a single stage of the parasite's life cycle and vaccines against the early pre-erythrocytic stages have shown most success. A protein in adjuvant vaccine, working through antibodies against sporozoites, and viral vector vaccines targeting the intracellular liver-stage parasite with cellular immunity show partial efficacy in humans, and the anti-sporozoite vaccine is currently in phase III trials. However, a more effective malaria vaccine suitable for widespread cost-effective deployment is likely to require a multi-component vaccine targeting more than one life cycle stage. The most attractive near-term approach to develop such a product is to combine existing partially effective pre-erythrocytic vaccine candidates.
Recombinant adenoviruses are among the most promising tools for vaccine antigen delivery. Recently, the development of new vectors has focused on serotypes to which the human population is less ...exposed in order to circumvent pre-existing anti vector immunity. This study describes the derivation of a new vaccine vector based on a chimpanzee adenovirus, Y25, together with a comparative assessment of its potential to elicit transgene product specific immune responses in mice. The vector was constructed in a bacterial artificial chromosome to facilitate genetic manipulation of genomic clones. In order to conduct a fair head-to-head immunological comparison of multiple adenoviral vectors, we optimised a method for accurate determination of infectious titre, since this parameter exhibits profound natural variability and can confound immunogenicity studies when doses are based on viral particle estimation. Cellular immunogenicity of recombinant E1 E3-deleted vector ChAdY25 was comparable to that of other species E derived chimpanzee adenovirus vectors including ChAd63, the first simian adenovirus vector to enter clinical trials in humans. Furthermore, the prevalence of virus neutralizing antibodies (titre >1:200) against ChAdY25 in serum samples collected from two human populations in the UK and Gambia was particularly low compared to published data for other chimpanzee adenoviruses. These findings support the continued development of new chimpanzee adenovirus vectors, including ChAdY25, for clinical use.
From ESO VLT/FLAMES/GIRAFFE spectra, abundance measurements of Zn have been made in ≈100 individual red giant branch (RGB) stars in the Sculptor dwarf spheroidal galaxy. This is the largest sample of ...individual Zn abundance measurements within a stellar system beyond the Milky Way. In the observed metallicity range, −2.7 ≤ Fe/H ≤ −0.9, the general trend of Zn abundances in Sculptor is similar to that of α-elements. That is, super-solar abundance ratios of Zn/Fe at low metallicities, which decrease with increasing Fe/H, eventually reaching subsolar values. However, at the higher metallicities in Sculptor, Fe/H ≳ −1.8, we find a significant scatter, −0.8 ≲ Zn/Fe ≲ +0.4, which is not seen in any α-element. Our results are consistent with previous observations of a limited number of stars in Sculptor and in other dwarf galaxies. These results suggest that zinc has a complex nucleosynthetic origin, behaving neither completely like an α- nor an iron-peak element.
Differentiating pseudoprogression, a radiation-induced treatment effect, from tumor progression on imaging is a substantial challenge in glioblastoma management. Unfortunately, guidelines set by the ...Response Assessment in Neuro-Oncology criteria are based solely on bidirectional diametric measurements of enhancement observed on T1WI and T2WI/FLAIR scans. We hypothesized that quantitative 3D shape features of the enhancing lesion on T1WI, and T2WI/FLAIR hyperintensities (together called the lesion habitat) can more comprehensively capture pathophysiologic differences across pseudoprogression and tumor recurrence, not appreciable on diametric measurements alone.
A total of 105 glioblastoma studies from 2 institutions were analyzed, consisting of a training (
= 59) and an independent test (
= 46) cohort. For every study, expert delineation of the lesion habitat (T1WI enhancing lesion and T2WI/FLAIR hyperintense perilesional region) was obtained, followed by extraction of 30 shape features capturing 14 "global" contour characteristics and 16 "local" curvature measures for every habitat region. Feature selection was used to identify most discriminative features on the training cohort, which were evaluated on the test cohort using a support vector machine classifier.
The top 2 most discriminative features were identified as local features capturing total curvature of the enhancing lesion and curvedness of the T2WI/FLAIR hyperintense perilesional region. Using top features from the training cohort (training accuracy = 91.5%), we obtained an accuracy of 90.2% on the test set in distinguishing pseudoprogression from tumor progression.
Our preliminary results suggest that 3D shape attributes from the lesion habitat can differentially express across pseudoprogression and tumor progression and could be used to distinguish these radiographically similar pathologies.
Highlights • Inserting tPA leader sequence enhanced humoral responses of ChAdOx1 MERS. • ChAdOx1 MERS elicited cellular immunity and neutralising antibodies. • ChAdOx1 MERS responses were boosted by ...MVA MERS. • Immunogenicity of a single dose of ChAdOx1 MERS was equivalent to 2 doses of MVA MERS. • In MVA, F11 promoter enhanced cellular, but not humoral, immunogenicity, comparing to mH5 promoter.
To examine opioid prescribing patterns after general surgery procedures and to estimate an ideal number of pills to prescribe.
Diversion of prescription opioids is a major contributor to the rising ...mortality from opioid overdoses. Data to inform surgeons on the optimal dose of opioids to prescribe after common general surgical procedures is lacking.
We evaluated 642 patients undergoing 5 outpatient procedures: partial mastectomy (PM), partial mastectomy with sentinel lymph node biopsy (PM SLNB), laparoscopic cholecystectomy (LC), laparoscopic inguinal hernia repair (LIH), and open inguinal hernia repair (IH). Postoperative opioid prescriptions and refill data were tabulated. A phone survey was conducted to determine the number of opioid pills taken.
There was a wide variation in the number of opioid pills prescribed to patients undergoing the same operation. The median number (and range) prescribed were: PM 20 (0-50), PM SLNB 20 (0-60), LC 30 (0-100), LIH 30 (15-70), and IH 30 (15-120). Only 28% of the prescribed pills were taken. This percentage varied by operation: PM 15%, PM SLNB 25%, LC 33%, LIH 15%, and IH 31%. Less than 2% of patients obtained refills.We identified the number of pills that would fully supply the opioid needs of 80% of patients undergoing each operation: PM 5, PM SLNB 10, LC 15, LIH 15, and IH 15. If this number were prescribed, the number of opioid initially prescribed would be 43% of the actual number prescribed.
There is wide variability in opioid prescriptions for common general surgery procedures. In many cases excess pills are prescribed. Using our ideal number, surgeons can adequately treat postoperative pain and markedly decrease the number of opioids prescribed.
Protection against liver-stage malaria relies on the induction of high frequencies of antigen-specific CD8⁺ T cells. We have previously reported high protective levels against mouse malaria, albeit ...short-lived, by a single vaccination with adenoviral vectors coding for a liver-stage antigen (ME.TRAP). Here, we report that prime-boost regimens using modified vaccinia virus Ankara (MVA) and adenoviral vectors encoding ME.TRAP can enhance both short- and long-term sterile protection against malaria. Protection persisted for at least 6 months when simian adenoviruses AdCh63 and AdC9 were used as priming vectors. Kinetic analysis showed that the MVA boost made the adenoviral-primed T cells markedly more polyfunctional, with the number of gamma interferon (INF-γ), tumor necrosis factor alpha (TNF-α), and interleukin-2 (IL-2) triple-positive and INF-γ and TNF-α double-positive cells increasing over time, while INF-γ single-positive cells declined with time. However, IFN-γ production prevailed as the main immune correlate of protection, while neither an increase of polyfunctionality nor a high integrated mean fluorescence intensity (iMFI) correlated with protection. These data highlight the ability of optimized viral vector prime-boost regimens to generate more protective and sustained CD8⁺ T-cell responses, and our results encourage a more nuanced assessment of the importance of inducing polyfunctional CD8⁺ T cells by vaccination.
Combining nitrate, nitrite and phosphate data from several sources with additional quality control produced a database that eliminates many questionable values. This database, in turn, facilitated ...estimation of net community production (NCP) in the Arctic Marine System (AMS). In some regions, the new database enabled quantitative calculation of NCP over the vegetative season from changes in nutrient concentrations. In others, useful inferences were possible based on nutrient concentration patterns. This analysis demonstrates that it is possible to estimate NCP from seasonal changes in nutrients in many parts of the Arctic, however, the data were so sparse that most of our estimates for 14 sub-regions of the AMS are attended by uncertainties >50%. Nevertheless, the wide regional variation of NCP within the AMS (∼two orders of magnitude) may make the results useful. NCP for the entire AMS was estimated as 345±72TgC over the vegetative season. Converting this value to annual primary production (PP) as determined by typical ¹⁴C incubations suggests an annual primary production rate for the AMS of ∼1000TgC. We divided the AMS and its marginal seas into the same 13 sub-regions employed in the companion studies of Matrai et al. (2012) and Hill et al. (2013) and estimated NCP for each. We also made separate estimates for the Eurasian and Amerasian portions of the Arctic Basin. Significant findings include:
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