Levels of pneumococcal conjugate vaccine coverage and indirect protection against invasive pneumococcal disease and pneumonia hospitalisations in Australia: An observational study

BackgroundThere is limited empiric evidence on the coverage of pneumococcal conjugate vaccines (PCVs) required to generate substantial indirect protection. We investigate the association between population PCV coverage and indirect protection against invasive pneumococcal disease (IPD) and pneumonia hospitalisations among undervaccinated Australian children.Methods and findingsBirth and vaccination records, IPD notifications, and hospitalisations were individually linked for children aged <5 years, born between 2001 and 2012 in 2 Australian states (New South Wales and Western Australia; 1.37 million children). Using Poisson regression models, we examined the association between PCV coverage, in small geographical units, and the incidence of (1) 7-valent PCV (PCV7)-type IPD; (2) all-cause pneumonia; and (3) pneumococcal and lobar pneumonia hospitalisation in undervaccinated children. Undervaccinated children received <2 doses of PCV at <12 months of age and no doses at ≥12 months of age. Potential confounding variables were selected for adjustment a priori with the assistance of a directed acyclic graph.There were strong inverse associations between PCV coverage and the incidence of PCV7-type IPD (adjusted incidence rate ratio [aIRR] 0.967, 95% confidence interval [CI] 0.958 to 0.975, p-value < 0.001), and pneumonia hospitalisations (all-cause pneumonia: aIRR 0.991 95% CI 0.990 to 0.994, p-value < 0.001) among undervaccinated children. Subgroup analyses for children <4 months old, urban, rural, and Indigenous populations showed similar trends, although effects were smaller for rural and Indigenous populations. Approximately 50% coverage of PCV7 among children <5 years of age was estimated to prevent up to 72.5% (95% CI 51.6 to 84.4) of PCV7-type IPD among undervaccinated children, while 90% coverage was estimated to prevent 95.2% (95% CI 89.4 to 97.8). The main limitations of this study include the potential for differential loss to follow-up, geographical misclassification of children (based on residential address at birth only), and unmeasured confounders.ConclusionsIn this study, we observed substantial indirect protection at lower levels of PCV coverage than previously described—challenging assumptions that high levels of PCV coverage (i.e., greater than 90%) are required. Understanding the association between PCV coverage and indirect protection is a priority since the control of vaccine-type pneumococcal disease is a prerequisite for reducing the number of PCV doses (from 3 to 2). Reduced dose schedules have the potential to substantially reduce program costs while maintaining vaccine impact.

In an observational study, Jocelyn Chan and colleagues investigate associations between pneumococcal conjugate vaccine coverage and incidence of invasive pneumococcal disease and pneumonia among children under 5 years in Australia.     

Design and synthesis of novel furoquinoline based inhibitors of multiple targets in the PI3K/Akt-mTOR pathway

We herein report the design and synthesis of furoquinoline based novel molecules (16-36) and their in vitro multiple targeted inhibitory potency against PI3K/Akt phosphorylation and mTOR using cell based and cell-free kinase assay. In particular, compound 23 in addition to PI3K-mTOR inhibitory potency, it has shown potent inhibition of hypoxia-induced accumulation of HIF-1alpha protein in U251-HRE cell line. The inhibitory activities of compound 23 were confirmed by Western blot analysis, using human non-small cell lung carcinoma H-460 cell line and glioblastoma U251 cell lines.     

Iron dictates the virulence of <Emphasis Type="Italic">Pseudomonas aeruginosa</Emphasis> in urinary tract infections

Iron-limiting conditions have been reported to be prevalent in the milieu of urinary tract. In the present investigation, effect of iron on virulence of uropathogenic Pseudomonas aeruginosa in planktonic and biofilm cell mode was studied. Significant enhancement in elaboration of all the virulence traits along with increased adherence to uroepithelial cells and decreased phagocytosis of P. aeruginosa was observed following growth in iron-deplete medium. On the contrary, decrease in all these parameters except phagocytosis was observed when P. aeruginosa was grown in iron-rich medium. In vivo, P. aeruginosa grown in iron-deplete medium showed increased renal bacterial load and tissue pathology in a mouse model of ascending urinary tract infection compared with organisms grown in iron-replete medium. The results of the present study may help in understanding host–parasite interaction and in developing alternative preventive approach against P. aeruginosa induced urinary tract infections.     

Disruption of c-Jun reduces cellular migration and invasion through inhibition of c-Src and hyperactivation of ROCK II kinase

The spread of metastatic tumors to different organs is associated with poor prognosis. The metastatic process requires migration and cellular invasion. The protooncogene c-jun encodes the founding member of the activator protein-1 family and is required for cellular proliferation and DNA synthesis in response to oncogenic signals and plays an essential role in chemical carcinogenesis. The role of c-Jun in cellular invasion remains to be defined. Genetic deletion of c-Jun in transgenic mice is embryonic lethal; therefore, transgenic mice encoding a c-Jun gene flanked by LoxP sites (c-jun^f/f) were used. c-jun gene deletion reduced c-Src expression, hyperactivated ROCK II signaling, and reduced cellular polarity, migration, and invasiveness. c-Jun increased c-Src mRNA abundance and c-Src promoter activity involving an AP-1 site in the c-Src promoter. Transduction of c-jun^−/− cells with either c-Jun or c-Src retroviral expression systems restored the defective cellular migration of c-jun^−/− cells. As c-Src is a critical component of pathways regulating proliferation, survival, and metastasis, the induction of c-Src abundance, by c-Jun, provides a novel mechanism of cooperative signaling in cellular invasion.     

The tyrosine kinase activity of c-Src regulates actin dynamics and organization of podosomes in osteoclasts

Podosomes are dynamic actin-rich structures composed of a dense F-actin core surrounded by a cloud of more diffuse F-actin. Src performs one or more unique functions in osteoclasts (OCLs), and podosome belts and bone resorption are impaired in the absence of Src. Using Src^−/− OCLs, we investigated the specific functions of Src in the organization and dynamics of podosomes. We found that podosome number and the podosome-associated actin cloud were decreased in Src^−/− OCLs. Videomicroscopy and fluorescence recovery after photobleaching analysis revealed that the life span of Src^−/− podosomes was increased fourfold and that the rate of actin flux in the core was decreased by 40%. Thus, Src regulates the formation, structure, life span, and rate of actin polymerization in podosomes and in the actin cloud. Rescue of Src^−/− OCLs with Src mutants showed that both the kinase activity and either the SH2 or the SH3 binding domain are required for Src to restore normal podosome organization and dynamics. Moreover, inhibition of Src family kinase activities in Src^−/− OCLs by Src inhibitors or by expressing dominant-negative Src^K295M induced the formation of abnormal podosomes. Thus, Src is an essential regulator of podosome structure, dynamics and organization.     

Operating conditions of a 200l staged vertical reactor for bioconversion of wheat straw by Phanerochaete chrysosporium

Bioconversion of wheat straw using Phanerochaete chrysosporium was carried out in a 200l staged vertical reactor. The bioconversion process was characterized by measuring the percentage degradation of lignin and cellulose, and increment in crude protein content. The effect of airflow rate, inoculum amount and wheat straw loading on bioconversion was investigated using a statistical experimental design. An analysis of variance was performed to determine response surfaces. The quality of bioconversion indicated by an optimization index called the desirability coefficient had the highest value of 0.75 for the fifth day of cultivation. This corresponded to an operating condition of 1.5kg wheat straw per stage using an inoculum amount of 0.38g (100g dry wheat straw)(-1) and an airflow rate of 15lmin(-1). The lignin and cellulose degradation achieved at this operating condition was 27% and 29%, respectively. A ratio of 3 for the weight of wheat straw to inoculum amount gave the highest crude protein of 5.9% on dry weight basis. Among the variables investigated, the airflow rate exhibited a significant effect on the quality of bioconversion. Our results indicate that the quality of bioconversion may be controlled by implementing a predetermined airflow rate schedule.     

Analysis of cytokine gene polymorphisms in recipient’s matched with living donors on acute rejection after renal transplantation

Despite advances in immunosuppressive therapy in last few years, allograft rejection still remains the concern for kidney graft failure. Cytokines are key mediators in the induction and effector phases of all immune and inflammatory responses. They are not allospecific so both recipient as well as donor cells may be subjected to cytokine changes. We sought to ascertain whether IL-1B −511, IL-1B +3954, TNF-A −308, TGF-B Codon 10 and 25, IL-2 −330, IL-6 −174, IL-10 −1082, IL-10 −819 (SNPs), IL-1RN, IL-4 (VNTR) and TGF-B C-del (deletion) genes in two hundred subjects including recipients and their live matched donors influence renal allograft outcome. Screening was performed using PCR-RFLP and amplification refractory mutation system (ARMS-PCR). The risk for rejection appeared significant amongst recipients for pro-inflammatory cytokines IL-1B + 3954 (P = 0.045) and TNF-A −308 (0.031). No association of cytokine gene variants with rejection was observed in donors group. Further evaluating combinational effect of TNF-A (−308), IL-4 and IL-10 (−819) genes with the risk of allograft rejection showed no additive influence. Haplotype analysis between IL-1 gene cluster, TGF-B Codon 10 and 25 and IL-10 −1082 and −819 revealed that haplotypes of IL-1 gene 240-T–C, 410-T–C and 410-T–T showed very high risk among the recipients (>16, >5 and >12 folds risk respectively) when compared to donors. Interestingly, all these three haplotypes contained the variant allele T* of IL-B −511. In conclusion, our results suggest that high producing genotypes of pro-inflammatory cytokine genes in recipients have risk for allograft rejection. Lack of association in donors may be suggestive of having no conspicuous role in allograft outcome. Further analysis of diversity in haplotype variations in large populations could conceivably provide the basis for defined approaches to limit the rejections.