Characteristics of a widespread community cluster of H275Y oseltamivir-resistant A(H1N1)pdm09 influenza in Australia.

BACKGROUND: Oseltamivir resistance in A(H1N1)pdm09 influenza is rare, particularly in untreated community cases. Sustained community transmission has not previously been reported. METHODS: Influenza specimens from the Asia-Pacific region were collected through sentinel surveillance, hospital, and general practitioner networks. Clinical and epidemiological information was collected on patients infected with oseltamivir-resistant viruses. RESULTS: Twenty-nine (15%) of 191 A(H1N1)pdm09 viruses collected between May and September 2011 from Hunter New England (HNE), Australia, contained the H275Y neuraminidase substitution responsible for oseltamivir resistance. Only 1 patient had received oseltamivir before specimen collection. The resistant strains were genetically very closely related, suggesting the spread of a single variant. Ninety percent of cases lived within 50 kilometers. Three genetically similar oseltamivir-resistant variants were detected outside of HNE, including 1 strain from Perth, approximately 4000 kilometers away. Computational analysis predicted that neuraminidase substitutions V241I, N369K, and N386S in these viruses may offset the destabilizing effect of the H275Y substitution. CONCLUSIONS: This cluster represents the first widespread community transmission of H275Y oseltamivir-resistant A(H1N1)pdm09 influenza. These cases and data on potential permissive mutations suggest that currently circulating A(H1N1)pdm09 viruses retain viral fitness in the presence of the H275Y mutation and that widespread emergence of oseltamivir-resistant strains may now be more likely.

Increased detection in Australia and Singapore of a novel influenza A(H1N1)2009 variant with reduced oseltamivir and zanamivir sensitivity due to a S247N neuraminidase mutation.

A novel influenza A(H1N1)2009 variant with mildly reduced oseltamivir and zanamivir sensitivity has been detected in more than 10% of community specimens in Singapore and more than 30% of samples from northern Australia during the early months of 2011. The variant, which has also been detected in other regions of the Asia-Pacific, contains a S247N neuraminidase mutation. When combined with the H275Y mutation, as detected in an oseltamivir-treated patient, the dual S247N+H275Y mutant had extremely high oseltamivir resistance.

Oseltamivir-resistant influenza viruses circulating during the first year of the influenza A(H1N1) 2009 pandemic in the Asia-Pacific region, March 2009 to March 2010.

During the first year of the influenza A(H1N1) 2009 pandemic, unprecedented amounts of the neuraminidase inhibitors, predominantly oseltamivir, were used in economically developed countries for the treatment and prophylaxis of patients prior to the availability of a pandemic vaccine. Due to concerns about the development of resistance, over 1,400 influenza A(H1N1) 2009 viruses isolated from the Asia-Pacific region during the first year of the pandemic (March 2009 to March 2010) were analysed by phenotypic and genotypic assays to determine their susceptibility to the neuraminidase inhibitors. Amongst viruses submitted to the World Health Organization Collaborating Centre for Reference and Research in Melbourne, Australia,oseltamivir resistance was detected in 1.3% of influenza A(H1N1) 2009 strains from Australia and 3.1% of strains from Singapore, but none was detected in specimens received from other countries in Oceania or south-east Asia, or in east Asia. The overall frequency of oseltamivir resistance in the Asia-Pacific region was 16 of 1,488 (1.1%). No zanamivir-resistant viruses were detected. Of the 16 oseltamivir-resistant isolates detected, nine were from immunocompromised individuals undergoing oseltamivir treatment and three were from immunocompetent individuals undergoing oseltamivir treatment. Importantly, four oseltamivir-resistant strains were from immunocompetent individuals who had not been treated with oseltamivir, demonstrating limited low-level community transmission of oseltamivir-resistant strains. Even with increased use of oseltamivir during the pandemic, the frequency of resistance has been low, with little evidence of community-wide spread of the resistant strains. Nevertheless, prudent use of the neuraminidase inhibitors remains necessary, as does continued monitoring for drug-resistant influenza viruses.

A new pandemic influenza A(H1N1) genetic variant predominated in the winter 2010 influenza season in Australia, New Zealand and Singapore.

Pandemic H1N1 influenza virus is of global health concern and is currently the predominant influenza virus subtype circulating in the southern hemisphere 2010 winter. The virus has changed little since it emerged in 2009, however, in this report we describe several genetically distinct changes in the pandemic H1N1 influenza virus. These variants were first detected in Singapore in early 2010 and have subsequently spread through Australia and New Zealand. At this stage, these signature changes in the haemagglutinin and neuraminidase proteins have not resulted in significant antigenic changes which might make the current vaccine less effective, but such adaptive mutations should be carefully monitored as the northern hemisphere approaches its winter influenza season.

Once-daily tobramycin in the treatment of adult patients with cystic fibrosis.

The aim of this study was to test the equivalence of once- and thrice-daily dosing with tobramycin by comparing efficacy and safety in adult patients with cystic fibrosis. Sixty adult patients with an acute respiratory exacerbation were randomized to receive either 10 mg x kg(-1) tobramycin once-daily or 3.3 mg x kg(-1) tobramycin thrice-daily. Primary efficacy and safety endpoints were defined as changes in respiratory function and changes in renal function and hearing. Both groups showed a significant increase in respiratory function without a clinically significant change in renal function. For changes in forced vital capacity % predicted and serum potassium and magnesium levels, equivalence was demonstrated. For the variables forced expiratory volume in one second and forced mid-expiratory flow % pred and serum creatinine levels, there was insufficient power to demonstrate equivalence. One patient in each group showed bilateral impairment in pure tone audiogram after treatment. This study demonstrated significant clinical improvement with both once- and thrice-daily tobramycin dosing. Equivalence between the two regimens was shown for some, but not all primary endpoints. Once-daily dosing should be used with careful monitoring of safety and efficacy until large multicentre studies confirm these encouraging results.

Mechanical stimulation induces pp125(FAK) and pp60(src) activity in an in vivo model of trabecular bone formation.

Utilizing an in vivo model of trabecular bone formation, we demonstrated the temporal and spatial activation of pp125(FAK) in response to specific mechanical load stimuli. Bone chambers equipped with hydraulic actuators were aseptically inserted into each proximal tibial metaphysis of adult, male dogs under general anesthesia. The load stimulus consisted of a trapezoidal waveform, with a maximum compressive load of 17.8 N, loading rate of 89 N/s, at 1 Hz frequency. One chamber was loaded for 2 (120 cycles), 15 (900 cycles), or 30 min (1,800 cycles), whereas the contralateral chamber served as unloaded control. Bone chambers were biopsied at postload time points of 0, 15, and 45 min. Load-induced activation of FAK was rapid, and the duration of activation was dependent on the number of applied load cycles. Mechanical stimulation increased the association of FAK with Src and the time course of complex formation paralleled the temporal activation of FAK. Evaluation of cryosections revealed prominent FAK immunoreactivity among marrow fibroblasts and stromal cells.

Ensuring seamless care at hospital discharge: a national survey.

AIM: To identify the services that hospital pharmacies were providing in 1999 to facilitate seamless care upon patient discharge. DESIGN: Postal questionnaire containing closed and open questions. SUBJECTS AND SETTING: U.K. Trust hospitals. Questionnaire addressed to Chief Pharmacists to be completed by themselves or most appropriate deputy, then returned anonymously in prepaid envelope. RESULTS: The response rate was 73.4% (163/222). 71.2% of responses came from general hospitals and 23.3% from teaching hospitals. Junior medical staff members were responsible for preparing virtually all discharge prescriptions, which were checked against the ward prescription chart by pharmacists in three-quarters of U.K. Trusts. Hospitals used a wide variety of methods to communicate information about medicine regimens to GPs. There was also wide variation in the provision of discharge counselling, telephone 'help-lines' and clear medication records to patients. Few hospitals involved community pharmacies routinely in the discharge process. CONCLUSION: There is still wide variation within hospital pharmacy practice in meeting the medicines-related needs of patients at discharge.

An in vivo model for investigations of mechanical signal transduction in trabecular bone.

The premise that bone cells are able to perceive and respond to mechanical forces is well accepted. This article describes the use of an in vivo hydraulic bone chamber for investigations of mechanical signal transduction. The servohydraulic loading mechanism was activated to apply a controlled compressive load to the woven trabecular bone that formed in one chamber, while the contralateral chamber served as an unloaded control. Specimens were harvested at a series of postload time points, and the cellular response to loading was evaluated by cytochemical, histomorphometric, and Northern blot analysis. A repetitive daily load stimulus elicited osteoblast biosynthetic activity characterized by an initial increase in type I procollagen by day 3 and a subsequent rise in alkaline phosphatase (ALP) activity after the sixth daily load episode. Application of a single load episode induced a biphasic pattern of c-fos and zif-268 gene expression with up-regulation at 30 minutes, down-regulation at 12 h, and up-regulation 24 h after the mechanical stimulus. The results show that a synchronized pattern of bone cell activity and gene expression occurs in response to controlled mechanical stimulation and that candidate load-responsive molecular mediators can be evaluated easily by this model.

Spectral Variations in Early-Type Galaxies as a Function of Mass.

We report on the strengths of three spectral indicators-Mg(2), Hbeta, and Hn/Fe-in the integrated light of a sample of 100 field and cluster E/S0 galaxies. The measured indices are sensitive to age and/or metallicity variations within the galaxy sample. Using linear regression analysis for data with nonuniform errors, we determine the intrinsic scatter present among the spectral indices of our galaxy sample as a function of internal velocity dispersion. Our analysis demonstrates that there is significantly more intrinsic scatter in the two Balmer line indices than in the Mg(2) index, indicating that the Balmer indices provide more dynamic range in determining the age of a stellar population than does the Mg(2) index. Furthermore, the scatter is much larger for the low velocity dispersion galaxies, indicating that star formation has occurred more recently in the lower mass galaxies.

Why ruminators are poor problem solvers: clues from the phenomenology of dysphoric rumination.

The phenomenology of dysphoric rumination and its consequences for problem solving were explored in 3 studies. In Study 1, self-focused rumination, compared with distraction, led dysphoric participants to rate their own biggest problems as severe and unsolvable and to report a reduced likelihood of actually implementing their solutions. Clues into the mechanisms behind these findings were explored in Study 2. The results showed that dysphoric ruminative thought is characterized by a focus on personal problems combined with a negative tone, self-criticism, and self-blame for problems as well as reduced self-confidence, optimism, and perceived control. Finally, Study 3 revealed a direct relationship between the negatively biased content of ruminative thoughts and reduced willingness to solve one's problems. Implications of these findings for the consequences of self-focused rumination are discussed.

Effects of ruminative and distracting responses to depressed mood on retrieval of autobiographical memories.

Four studies explored the effects of self-focused rumination vs. distraction on dysphoric and nondysphoric students' retrieval of autobiographical memories. Dysphorics induced to ruminate subsequently recalled more negatively biased autobiographical memories in free recall (Study 1) and in response to prompts for memories (Study 2) than either dysphorics who first distracted themselves from their mood or nondysphoric controls. In Study 3, dysphoric rumination led students to recall negative events as occurring relatively frequently in their lives and positive events as occurring relatively infrequently. In Study 4, judges scored transcripts of participants' thoughts as expressed aloud while engaging in rumination or distraction. Codings revealed that dysphoric ruminators spontaneously generated memories that were more negative than those of the other three groups. Implications of a ruminative response style for progress in therapy, as well as for enhancing dysphoria and negatively biased cognitive processes, are discussed.

Modelling the regional dynamics and management of bovine tuberculosis in New Zealand cattle herds.

A previous model addressed the within-herd transmission of bovine Tb (Mycobacterium bovis) in New Zealand cattle herds. This complementary model considers transmission between herds, in an area of New Zealand's North Island (the Waikato) largely free from wildlife reservoirs. The model is used to account for the observed pattern of Tb breakdowns and to assess the likely impact of changes in management on the percentage of herds on movement control between 1988 and 1993 (an average of 0.76% in the Waikato region). It partitions the region into two sub-areas: one small, with significant infection from wildlife; the other much larger and lacking external sources of infection. The observed pattern of herd breakdowns (in different parts of the Waikato and in the region as a whole) could be accounted for in the model by infection from wildlife reservoirs in the southern sub-area (Waitomo) and infection due to movement of cattle from infected but undiagnosed herds to uninfected herds throughout the whole region. During the above period, the model suggests that about 0.8% of herds became infected each year, that most new infections (81% of the total) occurred between herds in the larger sub-area, and that about 13% of the total occurred through infection from wildlife in the smaller sub-area. The whole situation appears to be in a state of near-neutral balance (even without input of new infection), with removal through testing of new infections almost exactly balancing the rate of infection by between-herd movement. Therefore, if the external input is removed, the number of infected herds and of herds of movement control in the whole region declines so slowly that the decline is almost undetectable. Other management changes had a more dramatic effect--particularly, reducing the testing interval to a maximum of 1 year in the whole district. This also appeared to be a necessary condition for achieving < or = 0.2% herds on movement control within 10 years (whatever other strategies were employed). The greatest reduction in the percentage of herds on movement control came from yearly testing plus a 50% reduction in infection from wildlife. A further but smaller additional improvement was gained by reducing cattle movements throughout the region by 50%.

Mechanical stimulation of tissue repair in the hydraulic bone chamber.

A hydraulically activated bone chamber model was utilized to investigate cellular and microstructural mechanisms of mechanical adaptation during bone repair. Woven trabecular bone and fibrotic granulation tissue filled the initially empty chambers by 8 weeks postimplantation into canine tibial and femoral metaphyses. Without mechanical stimulation, active bone remodeling to lamellar trabecular bone and reconstitution of marrow elements were observed between 8 and 24 weeks. In subsequent loading studies, the hydraulic mechanism was activated on one randomly chosen side of 10 dogs following 8 weeks of undisturbed bone repair. The loading treatment applied an intermittent compressive force (18 N, 1.0 Hz, 1800 cycles/day) for durations of a few days up to 12 weeks. Stereological analysis of three-dimensional microcomputed tomography images revealed an increase in trabecular plate thickness and connectivity associated with the loaded repair tissue microstructure relative to unloaded contralateral controls. These microstructural alterations corresponded to an over 600% increase in the apparent modulus of the loaded bone tissue. A significant increase in the percentage of trabecular surfaces lined by osteoblasts immunopositive for type I procollagen after a few days of loading provided further evidence for mechanical stimulation of bone matrix synthesis. The local principal tissue strains associated with these adaptive changes were estimated to range from approximately -2000 to +3000 mustrain using digital image-based finite element methods. This study demonstrates the sensitivity of bone tissue and cells to a controlled in vivo mechanical stimulus and identifies microstructural mechanisms of mechanical adaptation during bone repair. The hydraulic bone chamber is introduced as an efficient experimental model to study the effects of mechanical and biological factors on bone repair and regeneration.

Trabecular bone adaptation to variations in porous-coated implant topology.

Trabecular bone adaptation adjacent to porous-coated platen implants embedded within canine distal femoral metaphyses was evaluated following 24 weeks of daily compressive loading. The in vivo experimental model delivered controlled loads to five different platen implant topologies with variations in platen shape and porous coating distribution. Adaptive changes were evaluated based on three-dimensional stereological analyses of trabecular bone architecture underneath each platen and non-destructive mechanical tests of platen construct stiffness. Fully coated cylindrical platen designs possessed the highest construct stiffness in both tension and compression. Changes in local trabecular bone morphology were also found to be significantly influenced by platen implant topology. Cylindrical platens with fully coated bottom surfaces were associated with greater decreases in trabecular bone volume and connectivity than cylindrical platens with smooth bottom surfaces or fully coated conical platens. Comparisons to site-matched contralateral control bone volumes across all platen designs indicated significant decreases in the average bone volume fraction, trabecular plate number, and connectivity within experimental samples, but no change in trabecular plate thickness. In addition, analyses of microstructural anisotropy revealed a 20 degrees or 20.2 degrees trabecular reorientation towards the axis of loading in experimental tissue. This study demonstrates that trabecular bone adaptation near porous-coated surfaces is influenced by variations in local implant topology and provides insight into specific mechanisms of implant-mediated microstructural adaptation.

Relative effects of wound healing and mechanical stimulus on early bone response to porous-coated implants.

We hypothesized that early bone adaptation to well fixed porous-coated implants is influenced more by wound healing than by mechanical loading. To test this hypothesis, two groups of dogs with identical, hydraulically controlled porous-coated implants interference fit within distal femoral trabecular bone were used. One group had no load: the other had 35 N of load applied to the implants. At 5 weeks after surgery, the resulting adaptation of bone around the implants was quantified on a cellular basis by cytochemical analysis of type-I procollagen synthesis and on a structural basis using three-dimensional micro-computed tomography imaging. The percentage of trabecular surfaces covered by osteoblasts expressing type-I procollagen was significantly increased in bone surrounding the implant in both groups compared with contralateral control bone tissue. There was no difference between the groups with no load or 35 N of load. In addition, measures of trabecular bone structure did not differ significantly between the load and no-load groups. Taken together, these results suggest that wound healing plays a much greater role in the early response of bone to well fixed porous-coated implants than does mechanical stimulus.

Peer modeling of response chains: observational learning by students with disabilities.

Peer models (classmates without disabilities) who were proficient in performing a task completed one response chain each day and described the steps they performed while their classmates with disabilities observed. Three students with disabilities participated, and their performance of the response chains was assessed immediately prior to and following the peer modeling each day. A multiple probe design across response chains, replicated across children with disabilities, was used. In addition, participation and social interactions of children with disabilities and their peer models were assessed in classroom activities after daily modeling sessions. The results indicate that the peer models performed the response chains accurately and quickly, and students with disabilities acquired the response chains. Across the study, participation in classroom activities was high, social interactions were low, and neither was affected by the peer modeling intervention.