The healthcare and societal burden associated with influenza in vaccinated and unvaccinated European and Israeli children.

Few data exist regarding the healthcare and societal burden of culture-confirmed influenza illness in European and Israeli children. The current analysis describes this burden in vaccinated and unvaccinated children 2-17 years of age. Healthcare and societal burden outcomes were prospectively collected for culture-confirmed influenza illness in three previous randomized studies: a study of live attenuated influenza vaccine (LAIV) versus placebo in children aged <48 months attending day care (N = 846-973), and studies of LAIV versus inactivated influenza vaccine (IIV) in children aged <72 months with recurrent respiratory infections (N = 1,609) and in children aged 6-17 years with asthma (N = 2,211). The incidence of each endpoint among enrolled subjects and subjects with influenza was determined by treatment group and by country. Among subjects with influenza, 57-91% missed school or day care, 45-90% used non-antibiotic medications, 29-55% of parents missed work, 17-55% used antibiotics, 11-62% had additional provider visits, and 9-20% had acute otitis media. Where evaluated, rates of outcomes were generally similar between countries. Among all children enrolled, LAIV recipients missed 324-902 and 150 fewer days of day care per 1,000 children than those of placebo and IIV recipients, respectively; parents of LAIV recipients missed 197-340 and 76 fewer days of work per 1,000 children than those of placebo and IIV recipients, respectively. Influenza illness in European and Israeli children 2-17 years of age resulted in a considerable absenteeism and healthcare utilization that was similar across the countries studied. These data underscore the potential benefits of annual vaccination of children against influenza.

Epidemiological investigation of a Legionnaires' disease outbreak in Christchurch, New Zealand: the value of spatial methods for practical public health.

Between April and August 2005 Christchurch, New Zealand experienced an outbreak of Legionnaires' disease. There were 19 laboratory-confirmed case including three deaths. Legionella pneumophila serogroup 1 (Lpsg1) was identified as the causative agent for all cases. A case-control study indicated a geographical association between the cases but no specific common exposures. Rapid spatial epidemiological investigation confirmed the association and identified seven spatially significant case clusters. The clusters were all sourced in the same area and exhibited a clear anisotropic process (noticeable direction) revealing a plume effect consistent with aerosol dispersion from a prevailing southwesterly wind. Four out of five cases tested had indistinguishable allele profiles that also matched environmental isolates from a water cooling tower within the centre of the clusters. This tower was considered the most probable source for these clusters. The conclusion would suggest a maximum dispersal distance in this outbreak of 11·6 km. This work illustrated the value of geostatistical techniques for infectious disease epidemiology and for providing timely information during outbreak investigations.

The test-negative design: validity, accuracy and precision of vaccine efficacy estimates compared to the gold standard of randomised placebo-controlled clinical trials.

The test-negative design (TND) is an efficient form of case-control study commonly applied to influenza vaccine effectiveness (VE) estimation. TND validity is predicated on the core assumption that the intervention (vaccine) has no effect on other non-targeted aetiologies resulting in similar illness/disease. Here we verify this core assumption and compare efficacy estimates derived by the TND versus classical per-protocol analysis of four datasets obtained from randomised placebo-controlled clinical trials (RCT) of the live attenuated influenza vaccine (LAIV) in children ≤7 years-old and the elderly ≥60 years-old. We further assess generalisability of the TND approach in two other RCT datasets to evaluate monoclonal antibody in the prevention of respiratory syncytial virus (RSV) hospitalisation. Efficacy estimates and their confidence intervals were virtually identical for per-protocol RCT versus TND analyses of LAIV and also for RSV monoclonal antibody. Neither LAIV nor monoclonal antibodies affected the risk of disease aetiologies that were not specifically targeted by the respective interventions (e.g. other respiratory viruses). This study validates the core assumption of the TND approach for influenza vaccine efficacy estimation and confirms the accuracy and precision of its estimates compared to the gold standard of classic per-protocol RCT analysis of the same data sets. The TND approach is generalisable for other conditions such as RSV for which the core assumption is also met. However, when used in observational studies, the TND, like all designs, still requires assessment for bias and confounding that may exist in the absence of randomised participation and blinded follow-up.

Trinucleotide repeat length instability and age of onset in Huntington's disease.

The initial observation of an expanded and unstable trinucleotide repeat in the Huntington's disease gene has now been confirmed and extended in 150 independent Huntington's disease families. HD chromosomes contained 37-86 repeat units, whereas normal chromosomes displayed 11-34 repeats. The HD repeat length was inversely correlated with the age of onset of the disorder. The HD repeat was unstable in more than 80% of meiotic transmissions showing both increases and decreases in size with the largest increases occurring in paternal transmissions. The targeting of spermatogenesis as a particular source of repeat instability is reflected in the repeat distribution of HD sperm DNA. The analysis of the length and instability of individual repeats in members of these families has profound implications for presymptomatic diagnosis.

Cloning of the alpha-adducin gene from the Huntington's disease candidate region of chromosome 4 by exon amplification.

We have applied the technique of exon amplification to the isolation of genes from the chromosome 4p16.3 Huntington's disease (HD) candidate region. Exons recovered from cosmid Y24 identified cDNA clones corresponding to the alpha-subunit of adducin, a calmodulin-binding protein that is thought to promote assembly of spectrin-actin complexes in the formation of the membrane cytoskeleton, alpha-adducin is widely expressed and, at least in brain, is encoded by alternatively spliced mRNAs. The alpha-adducin gene maps immediately telomeric to D4S95, in a region likely to contain the HD defect, and must be scrutinized to establish whether it is the site of the HD mutation.

De novo expansion of a (CAG)n repeat in sporadic Huntington's disease.

Huntington's disease (HD) chromosomes contain an expanded unstable (CAG)n repeat in chromosome 4p16.3. We have examined nine families with potential de novo expression of the disease. With one exception, all of the affected individuals had 42 or more repeat units, well above the normal range. In four families, elderly unaffected relatives inherited the same chromosome as that containing the expanded repeat in the proband, but had repeat lengths of 34-38 units, spanning the gap between the normal and HD distributions. Thus, mutation to HD is usually associated with an expansion from an already large repeat.

Autophagy Plays a Crucial Role in Ameloblast Differentiation.

Tooth enamel is generated by ameloblasts. Any failure in amelogenesis results in defects in the enamel, a condition known as amelogenesis imperfecta. Here, we report that mice with deficient autophagy in epithelial-derived tissues (K14-Cre;Atg7F/F and K14-Cre;Atg3F/F conditional knockout mice) exhibit amelogenesis imperfecta. Micro-computed tomography imaging confirmed that enamel density and thickness were significantly reduced in the teeth of these mice. At the molecular level, ameloblast differentiation was compromised through ectopic accumulation and activation of NRF2, a specific substrate of autophagy. Through bioinformatic analyses, we identified Bcl11b, Dlx3, Klk4, Ltbp3, Nectin1, and Pax9 as candidate genes related to amelogenesis imperfecta and the NRF2-mediated pathway. To investigate the effects of the ectopic NRF2 pathway activation caused by the autophagy deficiency, we analyzed target gene expression and NRF2 binding to the promoter region of candidate target genes and found suppressed gene expression of Bcl11b, Dlx3, Klk4, and Nectin1 but not of Ltbp3 and Pax9. Taken together, our findings indicate that autophagy plays a crucial role in ameloblast differentiation and that its failure results in amelogenesis imperfecta through ectopic NRF2 activation.

Fracture and mechanical properties of an impact toughened polypropylene composite: modification for automotive dashboard-airbag application.

Thermoplastic olefin (TPO) is the principal material for automotive instrument panels and is prone to fracture especially under heavy airbag deployment, which can prevent the airbag deploying properly. Thus, polyolefin elastomer (POE) was introduced to improve impact properties and fracture resistance. Fundamental methods to characterise TPO with the addition of POE are proposed. The influence of POE content on the mechanical properties was examined. With increasing POE content, the storage modulus and glass transition temperature values decreased, and the damping increased due to the POE increasing the polymer chain mobility. The tensile modulus, ultimate tensile strength and yield stress decreased with increasing POE content, while the ductility of the blends significantly increased. Furthermore, the POE reduced hardness and increased energy absorption during impact. In the fracture analysis, the addition of POE content increased the fracture resistance by increasing the crack energy and decreasing the resistance to crack initiation. Fractographic analysis showed how stretched microfibrils in the blends increase the fracture resistance. These results gave a significant indication of the utility of the elastomer in improving some mechanical properties and impact toughness of the interior automotive material to resist an undesired failure or over-fracture in airbag deployment.

Sensing-triggered stiffness-tunable smart adhesives.

Artificial dry adhesives have exhibited great potential in the field of robotics. However, there is still a wide gap between bioinspired adhesives and living tissues, especially regarding the surface adaptability and switching ability of attachment/detachment. Here, we propose a sensing-triggered stiffness-tunable smart adhesive material, combining the functions of muscle tissues and sensing nerves rather than traditional biomimetic adhesive strategy that only focuses on structural geometry. Authorized by real-time perception of the interface contact state, conformal contact, shape locking, and active releasing are achieved by adjusting the stiffness based on the magnetorheological effect. Because of the fast switching of the magnetic field, a millisecond-level attachment/detachment response is successfully achieved, breaking the bottleneck of adhesive materials for high-speed manipulation. The innovative design can be applied to any toe's surface structure, opening up a previously unknown avenue for the development of adhesive materials.

The safety and efficacy of live attenuated influenza vaccine in young children with asthma or prior wheezing.

In the European Union and Canada, an Ann Arbor strain live attenuated influenza vaccine (LAIV) is approved for use in children aged 2-17 years, including those with mild to moderate asthma or prior wheezing. The safety and efficacy of LAIV versus trivalent inactivated influenza vaccine (TIV) in children with asthma aged 6-17 years have been demonstrated. However, few data are available for children younger than 6 years of age with asthma or prior wheezing. Safety and efficacy data were collected for children aged 2-5 years with asthma or prior wheezing from two randomized, multinational trials of LAIV and TIV (N = 1,940). Wheezing, lower respiratory illness, and hospitalization were not significantly increased among children receiving LAIV compared with TIV. Increased upper respiratory symptoms and irritability were observed among LAIV recipients (p < 0.05). Relative efficacies were consistent with the results observed in the overall study populations, which demonstrated fewer cases of culture-confirmed influenza illness in LAIV compared with TIV recipients. Study results support the safety and efficacy of LAIV among children aged 2-17 years with mild to moderate asthma or a history of wheezing. Data regarding LAIV use are limited among individuals with severe asthma or active wheezing within the 7 days before vaccination.

Long-term hearing results and otological complications of nasopharyngeal carcinoma patients: comparison between treatment with conventional two-dimensional radiotherapy and intensity-modulated radiotherapy.

OBJECTIVE: To assess the long-term audiological outcome and otological complications of nasopharyngeal carcinoma patients who have received intensity-modulated radiotherapy (IMRT) versus conventional two-dimensional radiotherapy (2 DRT). STUDY DESIGN: Prospective study on the audiological outcome and otological complications 5-9 years after radiotherapy. METHODOLOGY: Patients had pure-tone audiogram before radiotherapy and 5 years after radiotherapy. Otological examination was performed 5-9 years after radiotherapy by an otolaryngologist. RESULTS: There is a significant deterioration of the hearing threshold 5 years after radiotherapy but there is no statistically significant difference in the deterioration of hearing between IMRT and 2 DRT. Six patients in the 2 DRT group and 1 patient in the IMRT group had osteoradionecrosis of the external auditory canal (p = 0.042). CONCLUSION: There are fewer incidences of osteoradionecrosis of the external auditory canal in patients treated with IMRT. There is no difference in bone conduction threshold in patients treated with IMRT or 2 DRT.

Prevalence and clinical characteristics of perinatal chronic lung disease by infant gestational age.

BACKGROUND: Children with perinatal chronic lung disease (CLD) are at elevated risk for severe respiratory syncytial virus (RSV) disease in the first two years of life. The American Academy of Pediatrics policy does not recommend RSV immunoprophylaxis for infants with CLD born at ≥32 weeks' gestational age (wGA). The objective of this study was to describe the number and clinical characteristics of US infants in this population. METHODS: Birth hospitalization data from the Kids' Inpatient Database were utilized to estimate the prevalence of CLD (International Classification of Diseases, Ninth Revision [ICD-9] = 770.7) in 2003-2012 overall and by gestational age (ICD-9 = 765.21-765.29). CLD birth hospitalizations were evaluated by length of stay, costs, ventilatory support, and inpatient mortality. RESULTS: A total of 33,537 infants were diagnosed with CLD, representing 0.2% of US births; 79% had wGA coded in the database. Among infants with CLD with wGA, 3.5% were born at >32 wGA, representing 7 of every 100,000 US births, or approximately 300 infants annually. Across all wGA categories, birth hospitalization length of stay and costs were elevated, and mechanical ventilation use ranged from 73% to 97%. All-cause inpatient mortality was highest among those <27 wGA and >32 wGA. CONCLUSIONS: Approximately 300 infants born at >32 wGA are diagnosed with CLD annually in the United States. The all-cause perinatal mortality rate is high in this population. The rationale for excluding this small but high-risk group of infants from the recommendations for RSV immunoprophylaxis is unclear.

Inhibition of the secondary antibody response in vitro by salicylate and gentisate.

Salicylate inhibition of the secondary antibody response initiated in vitro on day 0 has been studied in cultures of rabbit lymph node fragments. Levels of 1.25 to 1.5 mM (0.20 to 0.24 mg/ml) sodium salicylate present in serum-free medium throughout an 18- or 21-day culture period completely inhibit the secondary response. This inhibition is largely accomplished by the drug's action during the first 9 days, which corresponds to the inductive phase for this culture system. Relatively little inhibition is produced by adding the drug only after day 9, although over 90% of the antibody produced during a 21-day experiment is synthesized after day 9. Studies with media of different pH's show that this inhibition is more correctly a function of the nonionized salicylic acid concentration in the medium than of the total salicylate concentration. Arguments are presented against the possibility that salicylate at the levels used here inhibits antibody synthesis by uncoupling oxidative phosphorylation. Acetylsalicylic acid (aspirin) produces the same degree of inhibition in vitro as do equimolar concentrations of sodium salicylate. Gentisate (5-hydroxysalicylate) is 15-fold more effective in producing 50% inhibition than salicylate; its temporal pattern of inhibition is similar to that of salicylate.

Regulation of the secondary antibody response in vitro. Enhancement by actinomycin D and inhibition by a macromolecular product of stimulated lymph node cultures.

Two opposite effects of actinomycin D on antibody synthesis have been studied in organ cultures of rabbit lymph node fragments. These cultures were prepared from previously primed rabbits and stimulated with antigen(s) on day 0 to yield a secondary response, whose inductive phase extended to about day 9 and whose productive phase may last for several months in the serum-free medium described here. Concentrations of actinomycin D above 0.01 microM (0.012 microg/ml) produce inhibition of antibody synthesis during both phases of the response. However, antibody synthesis is about 10 times more sensitive to inhibition by this drug when it is added during the inductive phase than during the productive phase. During the latter phase, synthesis is more rapidly terminated as the drug level approaches 10 /microM (12.5 microg/ml). At this level the 50% synthesis time is about 2.8 hr, which is identical with that found when 5-10 microM puromycin is added to the medium of parallel cultures. Transient enhancement of antibody synthesis is frequently produced by a brief exposure to low levels of actinomycin D (generally less than 0.01 microM). Enhancement appears in precise temporal association with actinomycin pulses added for 2 days or less only between days 6 and 16. This apparent enhancement of antibody synthesis resembles the increased enzyme synthesis described by Garren et al. (6) and led to a search for an antibody-inhibitory material (AIM) whose synthesis might be stopped preferentially by low levels of the drug. Stimulated lymph node cultures produce between days 6 and 15 a nondialyzable material which inhibits antibody synthesis during the productive phase of heterologous antigen-antibody culture systems. Just as enhancement with low levels of actinomycin D appears within 2 hr after the drug has been added to cultures, so inhibition occurs within 4 hr of adding AIM to cultures during their productive phase. These observations suggest that AIM is analogous to the translational "repressor" postulated by Garren et al. (6). AIM has relevance in two areas of immunology: (a) it may be the explanation for many examples of antigenic competition, and (b) it may represent a normal control mechanism for the productive phase.

Regulation of the secondary antibody response in vitro. II. Chemical properties of an antibody inhibitory material (AIM) produced in antigen-stimulated rabbit lymph node organ culture.

A material inhibiting antibody synthesis in vitro is produced during the productive phase by rabbit lymph node organ cultures undergoing a secondary response. This antibody inhibitory material (AIM) has been isolated from serum-free medium taken from the cultures and also extracted from lymph node fragments as late as their 4th wk in vitro. AIM inhibits most strikingly the early productive phase of the secondary response in vitro (i.e, during the 2nd wk). AIM isolated from cultures undergoing a given immune response inhibits the same as well as different responses, thus indicating an immunologically nonspecific effect. Ultrafiltration and related studies reveal that the molecular size of AIM is 10,000-50,000 daltons and that it is not antibody. AIM can readily be separated from 7S globulin by use of CM-cellulose. The inhibitory activity of AIM is lost by digestion with ribonuclease. Thus the avoidance of serum with its high levels of ribonucleases may be crucial in the study of this material. The presence in eukaryotic cells of metabolic regulators, governors, etc. has been postulated largely by analogy with microbial systems (27). There is little direct evidence about the chemical nature of these presumed regulators. Our data on the RNase sensitivity of AIM raises the possibility in this lymphoid system of regulation by a species of RNA.

Mice transgenic for BAFF develop lymphocytic disorders along with autoimmune manifestations.

The cause of many autoimmune and inflammatory diseases is unresolved, although dysregulated production of tumor necrosis factor (TNF) family members appears to be important in many cases. BAFF, a new member of the TNF family, binds to B cells and costimulates their growth in vitro. Mice transgenic for BAFF have vastly increased numbers of mature B and effector T cells, and develop autoimmune-like manifestations such as the presence of high levels of rheumatoid factors, circulating immune complexes, anti-DNA autoantibodies, and immunoglobulin deposition in the kidneys. This phenotype is reminiscent of certain human autoimmune disorders and suggests that dysregulation of BAFF expression may be a critical element in the chain of events leading to autoimmunity.

A soluble form of B cell maturation antigen, a receptor for the tumor necrosis factor family member APRIL, inhibits tumor cell growth.

A proliferation-inducing ligand (APRIL) is a ligand of the tumor necrosis factor (TNF) family that stimulates tumor cell growth in vitro and in vivo. Expression of APRIL is highly upregulated in many tumors including colon and prostate carcinomas. Here we identify B cell maturation antigen (BCMA) and transmembrane activator and calcium modulator and cyclophilin ligand (CAML) interactor (TACI), two predicted members of the TNF receptor family, as receptors for APRIL. APRIL binds BCMA with higher affinity than TACI. A soluble form of BCMA, which inhibits the proliferative activity of APRIL in vitro, decreases tumor cell proliferation in nude mice. Growth of HT29 colon carcinoma cells is blocked when mice are treated once per week with the soluble receptor. These results suggest an important role for APRIL in tumorigenesis and point towards a novel anticancer strategy.

BAFF, a novel ligand of the tumor necrosis factor family, stimulates B cell growth.

Members of the tumor necrosis factor (TNF) family induce pleiotropic biological responses, including cell growth, differentiation, and even death. Here we describe a novel member of the TNF family, designated BAFF (for B cell activating factor belonging to the TNF family), which is expressed by T cells and dendritic cells. Human BAFF was mapped to chromosome 13q32-34. Membrane-bound BAFF was processed and secreted through the action of a protease whose specificity matches that of the furin family of proprotein convertases. The expression of BAFF receptor appeared to be restricted to B cells. Both membrane-bound and soluble BAFF induced proliferation of anti-immunoglobulin M-stimulated peripheral blood B lymphocytes. Moreover, increased amounts of immunoglobulins were found in supernatants of germinal center-like B cells costimulated with BAFF. These results suggest that BAFF plays an important role as costimulator of B cell proliferation and function.

BAFF binds to the tumor necrosis factor receptor-like molecule B cell maturation antigen and is important for maintaining the peripheral B cell population.

The tumor necrosis factor (TNF) family member B cell activating factor (BAFF) binds B cells and enhances B cell receptor-triggered proliferation. We find that B cell maturation antigen (BCMA), a predicted member of the TNF receptor family expressed primarily in mature B cells, is a receptor for BAFF. Although BCMA was previously localized to the Golgi apparatus, BCMA was found to be expressed on the surface of transfected cells and tonsillar B cells. A soluble form of BCMA, which inhibited the binding of BAFF to a B cell line, induced a dramatic decrease in the number of peripheral B cells when administered in vivo. Moreover, culturing splenic cells in the presence of BAFF increased survival of a percentage of the B cells. These results are consistent with a role for BAFF in maintaining homeostasis of the B cell population.

BAFF-R, a newly identified TNF receptor that specifically interacts with BAFF.

B cell homeostasis has been shown to critically depend on BAFF, the B cell activation factor from the tumor necrosis factor (TNF) family. Although BAFF is already known to bind two receptors, BCMA and TACI, we have identified a third receptor for BAFF that we have termed BAFF-R. BAFF-R binding appears to be highly specific for BAFF, suggesting a unique role for this ligand-receptor interaction. Consistent with this, the BAFF-R locus is disrupted in A/WySnJ mice, which display a B cell phenotype qualitatively similar to that of the BAFF-deficient mice. Thus, BAFF-R appears to be the principal receptor for BAFF-mediated mature B cell survival.