Interaction between handgrip strength and vitamin D deficiency on all-cause mortality in community-dwelling older adults: a prospective cohort study.

OBJECTIVE: Muscle strength decline and vitamin D deficiency are coexisting conditions associated with multiple adverse health outcomes. This prospective study aimed to investigate the multiplicative and additive interactions between handgrip strength (HS) and serum 25-hydroxyvitamin D [25(OH)D] on all-cause mortality in Chinese community-dwelling older adults. STUDY DESIGN: This is a population-based cohort study. METHODS: 2635 older adults (85.15 ± 12.01 years) were recruited from the Chinese Longitudinal Healthy Longevity Survey (2012-2018). Low HS was defined according to the Asian Working Group for Sarcopenia 2019 updated consensus (<28 kg for men and <18 kg for women). Serum 25(OH)D < 50 nmol/L were defined as vitamin D deficiency. Cox proportional hazard models were used to examine the association of HS and 25(OH)D with all-cause mortality. Socio-demographics, health status, and clinical characteristics were included as covariates. RESULTS: 1715 (65.09 %) and 1885 (71.54 %) participants had low HS and vitamin D deficiency, respectively. During a median follow-up of 3.52 years, 1107 older people died. After multivariable adjustment, both HS and 25(OH)D levels were inversely associated with all-cause mortality risk (Ps < 0.001). The hazard ratios (HRs) of low HS and vitamin D deficiency for all-cause mortality were 1.73 (95 % CI: 1.41-2.13) and 1.61 (95 % CI: 1.32-1.93), respectively. Although significant multiplicative interactions were not found, the association between low HS and all-cause mortality was attenuated in the higher 25(OH)D subgroup than in the lower 25(OH)D subgroup (stratified by 50 nmol/L). The multiple-adjusted HR of mortality for combined low HS and vitamin D deficiency was 2.18 (95 % CI: 1.73-2.56), which was higher than that for these two conditions alone. Significant additive interactions between low HS and vitamin D deficiency on mortality were observed (relative excess risk due to interaction: 0.71, 95 % CI: 0.37-1.05). CONCLUSIONS: Low HS and low 25(OH)D levels synergistically increased the risk of all-cause mortality. Our results added new insights to the priority of early detection for older adults with comorbid muscle strength decline and vitamin D deficiency.

Priorities for research in multiple conditions in later life (multi-morbidity): findings from a James Lind Alliance Priority Setting Partnership.

INTRODUCTION: multiple conditions in later life (multi-morbidity) is a major challenge for health and care systems worldwide, is of particular relevance for older people, but has not (until recently) received high priority as a topic for research. We have identified the top 10 research priorities from the perspective of older people, their carers, and health and social care professionals using the methods of a James Lind Alliance Priority Setting Partnership. METHODS: in total, 354 participants (162 older people and carers, 192 health professionals) completed a survey and 15 older people and carers were interviewed to produce 96 'unanswered questions'. These were further refined by survey and interviews to a shortlist of 21 topics, and a mix of people aged 80+ living with three or more conditions, carers and health and social care providers to prioritised the top 10. RESULTS: the key priorities were about the prevention of social isolation, the promotion of independence and physical and emotional well-being. In addition to these broad topics, the process also identified detailed priorities including the role of exercise therapy, the importance of falls (particularly fear of falling), the recognition and management of frailty and Comprehensive Geriatric Assessment. CONCLUSION: these topics provide a unique perspective on research priorities on multiple conditions in later life and complement existing UK and International recommendations about the optimisation of health and social care systems to deliver essential holistic models of care and the prevention and treatment of multiple co-existing conditions.

Excitation and Control of Plasma Wakefields by Multiple Laser Pulses.

We demonstrate experimentally the resonant excitation of plasma waves by trains of laser pulses. We also take an important first step to achieving an energy recovery plasma accelerator by showing that a plasma wave can be damped by an out-of-resonance trailing laser pulse. The measured laser wakefields are found to be in excellent agreement with analytical and numerical models of wakefield excitation in the linear regime. Our results indicate a promising direction for achieving highly controlled, GeV-scale laser-plasma accelerators operating at multikilohertz repetition rates.

Secondary wavelength stabilization of unbalanced Michelson interferometers for the generation of low-jitter pulse trains.

We present a double unbalanced Michelson interferometer producing up to four output pulses from a single input pulse. The interferometer is stabilized with the Hänsch-Couillaud method using an auxiliary low power continuous wave laser injected into the interferometer, allowing the stabilization of the temporal jitter of the output pulses to 0.02 fs. Such stabilized pulse trains would be suitable for driving multi-pulse laser wakefield accelerators, and the technique could be extended to include amplification in the arms of the interferometer.

Experimental validation of a novel compact focusing scheme for future energy-frontier linear lepton colliders.

A novel scheme for the focusing of high-energy leptons in future linear colliders was proposed in 2001 [P. Raimondi and A. Seryi, Phys. Rev. Lett. 86, 3779 (2001)]. This scheme has many advantageous properties over previously studied focusing schemes, including being significantly shorter for a given energy and having a significantly better energy bandwidth. Experimental results from the ATF2 accelerator at KEK are presented that validate the operating principle of such a scheme by demonstrating the demagnification of a 1.3 GeV electron beam down to below 65 nm in height using an energy-scaled version of the compact focusing optics designed for the ILC collider.

Measurement of the decay of laser-driven linear plasma wakefields.

We present measurements of the temporal decay rate of one-dimensional (1D), linear Langmuir waves excited by an ultrashort laser pulse. Langmuir waves with relative amplitudes of approximately 6% were driven by 1.7J, 50fs laser pulses in hydrogen and deuterium plasmas of density n_{e0}=8.4×10^{17}cm^{-3}. The wakefield lifetimes were measured to be τ_{wf}^{H_{2}}=(9±2) ps and τ_{wf}^{D_{2}}=(16±8) ps, respectively, for hydrogen and deuterium. The experimental results were found to be in good agreement with 2D particle-in-cell simulations. In addition to being of fundamental interest, these results are particularly relevant to the development of laser wakefield accelerators and wakefield acceleration schemes using multiple pulses, such as multipulse laser wakefield accelerators.

Meter-scale conditioned hydrodynamic optical-field-ionized plasma channels.

We demonstrate through experiments and numerical simulations that low-density, low-loss, meter-scale plasma channels can be generated by employing a conditioning laser pulse to ionize the neutral gas collar surrounding a hydrodynamic optical-field-ionized (HOFI) plasma channel. We use particle-in-cell simulations to show that the leading edge of the conditioning pulse ionizes the neutral gas collar to generate a deep, low-loss plasma channel which guides the bulk of the conditioning pulse itself as well as any subsequently injected pulses. In proof-of-principle experiments, we generate conditioned HOFI (CHOFI) waveguides with axial electron densities of n_{e0}≈1×10^{17}cm^{-3} and a matched spot size of 26µm. The power attenuation length of these CHOFI channels was calculated to be L_{att}=(21±3)m, more than two orders of magnitude longer than achieved by HOFI channels. Hydrodynamic and particle-in-cell simulations demonstrate that meter-scale CHOFI waveguides with attenuation lengths exceeding 1 m could be generated with a total laser pulse energy of only 1.2 J per meter of channel. The properties of CHOFI channels are ideally suited to many applications in high-intensity light-matter interactions, including multi-GeV plasma accelerator stages operating at high pulse repetition rates.

Adverse reactions to Mycobacterium bovis bacille Calmette-Guérin (BCG) vaccination against tuberculosis in humans, veterinary animals and wildlife species.

The Mycobacterium bovis strain, bacille Calmette-Guérin (BCG) is one of the most widely used human vaccines and remains one of the safest vaccines available. It has been used in human populations for over 80 years and 100 million children receive the vaccine annually. It has also been employed extensively for vaccine studies in laboratory animal hosts and is currently being developed for use in a variety of livestock and wild animals. Despite the large number of doses delivered since is first usage in 1921, reports of adverse reactions arising from the use of the BCG vaccine are relatively uncommon and where serious reactions do occur they are often the result of vaccination of immuno-compromised individuals. Factors that may influence the development of adverse reactions to BCG include the potency and dose of the vaccine strain, the route of delivery, the age and immune status of the host, and the skill levels of the operator administering the vaccine. Circumstances affecting the notification of adverse reactions include the lack of clear case definitions of abnormal vaccine reactions, and a scarcity of systematic surveillance and functioning reporting systems. With continued use of the BCG and the development of a new generation of prophylactic and therapeutic vaccines against tuberculosis in different host species, the risk factors associated with adverse reactions may need to be reappraised.

Experimental tuberculosis in the European badger (Meles meles) after endobronchial inoculation with Mycobacterium bovis: II. Progression of infection.

The aim of the study was to describe, over a period of 24 weeks, the pathological and bacteriological changes in badgers experimentally infected with Mycobacterium bovis. The badgers were infected by endobronchial instillation of 2.5 x10(4) colony forming units (cfu) M. bovis. After infection, the badgers were examined at 3 weekly intervals when blood and tracheal aspirates were collected. At 6, 12, 18 and 24 weeks post-infection (pi) three animals were euthanized and a detailed pathological and bacteriological examination was performed to assess the nature of the experimental disease. During the course of the study only one badger developed clinical signs of disease: a subcutaneous swelling on its head, first observed at 18 weeks pi. At post-mortem examination gross and histological lesions of tuberculosis were observed and M. bovis was recovered from all, except one badger. In the majority of badgers the endobronchial route of inoculation resulted in the establishment of infection that over 24 weeks was non-progressive with limited dissemination of infection from the thoracic cavity, mainly to the hepatic and mesenteric lymph nodes. However, in one of the badgers examined at 18 weeks pi and one at 24 weeks pi, infection was widely disseminated. The disease induced by the endobronchial inoculation displayed the characteristics of disease observed in naturally infected badgers.

The effect of varying levels of population control on the prevalence of tuberculosis in badgers in Ireland.

We examined the effect of varying levels of badger population control on the prevalence of Mycobacterium bovis infection in badgers in four counties of Ireland. In the 'Removal' and 'Buffer' areas, proactive culling was conducted to substantially reduce and subsequently maintain badger populations at a low level for five years. In the 'Reference' areas, localised reactive culling was conducted in association with herd breakdowns. The infection status of badgers was determined using bacteriology. A total of 2696 badgers were recruited into the study, and 19.0% were found to be infected with M. bovis. The two population control strategies had differing effects on the subsequent prevalence of tuberculosis in badger populations. Proactive culling led to a long term decrease in the prevalence of tuberculosis in the re-emergent populations. Although there was an overall decline in the disease prevalence, no consistent trend in disease prevalence as a result of reactive culling was observed.

Hydrodynamic optical-field-ionized plasma channels.

We present experiments and numerical simulations which demonstrate that fully ionized, low-density plasma channels could be formed by hydrodynamic expansion of plasma columns produced by optical field ionization. Simulations of the hydrodynamic expansion of plasma columns formed in hydrogen by an axicon lens show the generation of 200 mm long plasma channels with axial densities of order n_{e}(0)=1×10^{17}cm^{-3} and lowest-order modes of spot size W_{M}≈40µm. These simulations show that the laser energy required to generate the channels is modest: of order 1 mJ per centimeter of channel. The simulations are confirmed by experiments with a spherical lens which show the formation of short plasma channels with 1.5×10^{17}cm^{-3}≲n_{e}(0)≲1×10^{18}cm^{-3} and 61µm≳W_{M}≳33µm. Low-density plasma channels of this type would appear to be well suited as multi-GeV laser-plasma accelerator stages capable of long-term operation at high pulse repetition rates.

Experimental tuberculosis in the European badger (Meles meles) after endobronchial inoculation of Mycobacterium bovis: I. Pathology and bacteriology.

The aim was to develop an endobronchial infection procedure for the study of Mycobacterium bovis infection in badgers. The badgers were anaesthetised and a cannula was passed per os to the tracheal bifurcation. When in place 1 ml of M. bovis suspension was inoculated. Three concentrations of M. bovis suspension were used; <10 colony forming units (cfu), approximately 10(2) cfu and approximately 3 x 10(3) cfu. The badgers were examined at three weekly intervals for clinical signs of disease and a tracheal aspirate was collected at each examination. The badgers were euthanased 17 weeks post infection (pi) and at the post mortem examination a wide range of tissues were examined for gross and histopathological lesions of tuberculosis and cultured for M. bovis. A sample of bronchial alveolar lavage (BAL) fluid was collected at post mortem for culture. At post mortem examination 17 weeks after infection, gross and histopathological lesions of tuberculosis were observed in all badgers inoculated with the high and medium dose and 1/3 inoculated with the low dose. M. bovis was recovered from all inoculated badgers. Infection in the high dose group was more widely disseminated than in the other groups. The number of sites with gross and histopathological lesions increased with increasing dose of M. bovis. All tracheal aspirates were negative on culture and only one BAL, collected from a badger of the high dose group, was positive on culture. No clinical signs due to the experimental infection were observed. The endobronchial route of inoculation is an effective route for establishing experimental infection, and could be used for studies of tuberculosis pathogenesis, immunology of M. bovis infection in badgers and for challenging badgers in vaccine protection studies. Badgers appeared to be very susceptible to infection by this procedure even with a dose of < 10 cfu but appear to control and limit the resulting infection.

Does reactive badger culling lead to an increase in tuberculosis in cattle?

The conclusion from the randomised badger culling trial was that localised badger culling not only fails to control but can actually increase the incidence of bovine tuberculosis in cattle. Professor Simon More and colleagues from University College Dublin question that conclusion, arguing that the data do not provide sufficient evidence to rule out alternative hypotheses.

A systematic literature review of the effectiveness of non-pharmacological interventions to prevent wandering in dementia and evaluation of the ethical implications and acceptability of their use.

OBJECTIVES: To determine the effectiveness and cost-effectiveness of non-pharmacological interventions (excluding subjective barriers) in the prevention of wandering in people with dementia, in comparison with usual care, and to evaluate through the review and a qualitative study the acceptability to stakeholders of such interventions and identify ethical issues associated with their use. DATA SOURCES: Major electronic databases were searched up until 31 March 2005. Specialists in the field. REVIEW METHODS: Selected studies were assessed and analysed. The results of two of the efficacy studies that used similar interventions, designs and outcome measures were pooled in a meta-analysis; results for other studies which reported standard deviations were presented in a forest plot. Owing to a lack of cost-effectiveness data, a modelling exercise could not be performed. Four focus groups were carried out with relevant stakeholders (n = 19) including people with dementia and formal and lay carers to explore ethical and acceptability issues in greater depth. Transcripts were coded independently by two reviewers to develop a coding frame. Analysis was via a thematic framework approach. RESULTS: Ten studies met the inclusion criteria (multi-sensory environment, three; music therapy, one; exercise, one; special care units, two; aromatherapy, two; behavioural intervention, one). There was no robust evidence to recommend any non-pharmacological intervention to reduce wandering in dementia. There was some evidence, albeit of poor quality, for the effectiveness of exercise and multi-sensory environment. There were no relevant studies to determine the cost-effectiveness of the interventions. Findings from the narrative review and focus groups on acceptability and ethical issues were comparable. Exercise and distraction therapies were the most acceptable interventions and raised no ethical concerns. All other interventions were considered acceptable except for physical restraints, which were considered unacceptable. Considerable ethical concerns exist with the use of electronic tagging and tracking devices and physical barriers. Existing literature ignores the perspectives of people with dementia. The small number of participants with dementia expressed caution regarding the use of unfamiliar technology. Balancing risk and risk assessment was an important theme for all carers in the management of wandering. CONCLUSIONS: There is no robust evidence so far to recommend the use of any non-pharmacological intervention to reduce or prevent wandering in people with dementia. High-quality studies, preferably randomised controlled trials, are needed to determine the clinical and cost-effectiveness of non-pharmacological interventions that allow safe wandering and are considered practically and ethically acceptable by carers and people with dementia. Large-scale, long-term cohort studies are needed to evaluate the morbidity and mortality associated with wandering in dementia for people both in the community and in residential care. Such data would inform future long-term cost-effectiveness studies.

The role of wild animal populations in the epidemiology of tuberculosis in domestic animals: how to assess the risk.

Tuberculosis is present in wild animal populations in North America, Europe, Africa and New Zealand. Some wild animal populations are a source of infection for domestic livestock and humans. An understanding of the potential of each wild animal population as a reservoir of infection for domestic animals is reached by determining the nature of the disease in each wild animal species, the routes of infection for domestic species and the risk of domestic animals encountering an infectious dose. The mere presence of infection in a wild animal population does not of itself provide evidence of a significant wildlife reservoir. Although at times counterintuitive, wildlife populations with high disease prevalence may not necessarily have a role in the epidemiology of disease in domestic livestock. The key concepts used in deciding whether an infected wild animal population is involved in the epidemiology of tuberculosis in domestic livestock is illustrated by reference to six well-researched cases: the feral pig (Suis scrofa) and feral Asian water buffalo (Bubalus bubalis) in Australia, white tailed deer (Odocoileus virginianus) in Michigan, and the brushtail possum (Trichosurus vulpecula) and other species, such as the ferret (Mustela furo), in New Zealand. A detailed analysis of Mycobacterium bovis infection in the Eurasian badger (Meles meles) in Ireland and their role as a reservoir of infection for cattle is also presented.

Restriction fragment length polymorphism analysis of Fusobacterium necrophorum using a novel repeat DNA sequence and a 16S rRNA gene probe.

A repeated DNA sequence was isolated from Fusobacterium necrophorum biotype AB, strain FnS1. The repeated sequence shared considerable homology with the transposase gene from the Pseudomonas syringiae insertion sequence IS801. The repeat sequence was used together with a 16S ribosomal RNA gene probe to type F. necrophorum isolates using restriction fragment length polymorphisms. The probes revealed differences between several clinical isolates and will be useful tools to study the epidemiology of ovine foot abscess and other diseases caused by F. necrophorum.

Post mortem diagnosis of Mycobacterium bovis infection in cattle.

A tentative diagnosis of bovine tuberculosis can be made following the macroscopic detection at necropsy of typical lesions. Histo-pathological examination of the lesion may increase the confidence of the diagnosis but bacteriological isolation of Mycobacterium bovis from the lesion is the only way to make a definitive diagnosis. The sensitivity of gross post mortem examination is affected by the method employed and the anatomical sites examined. Careful examination of as few as 6 pairs of lymph nodes, the lungs and the mesenteric lymph nodes can result in 95% of cattle with macroscopic lesions being identified. Although during post mortem inspection of carcases at abattoir all the principle sites where lesions are to be found were examined, this procedure was found to be insensitive for the detection of lesions. To determine the significance of cattle that give a positive reaction in diagnostic tests but do not have visible lesions (NVL), a bacteriological examination is necessary. NVLs may be due to early infection, poor necropsy technique or infection with mycobacteria other than M. bovis. M. bovis was found to survive best in frozen tissue and the tissue preservative, sodium tetraborate, was found to have adverse effects on viability. It was found desirable to use two different culture media for the primary isolation of M. bovis; agar media for rapid growth and egg media for control of contamination. Additional control of contamination was achieved without adversely affecting the viability by treating the specimen before culture with 0.075% hexadecylpyridinium chloride. The addition of CO2 to the incubation atmosphere did not enhance the recovery of M. bovis. Conventional identification of isolates of M. bovis is by biochemical tests and cultural characteristics, but methods employing monoclonal antibodies and DNA probes may be used to obtain a rapid identification.

An evaluation of 1-hexadecylpyridinium chloride as a decontaminant in the primary isolation of Mycobacterium bovis from bovine lesions.

For the primary isolation of Mycobacterium bovis from bovine lesions, 1-hexadecylpyridinium chloride (HPC) at a concentration of 0.75% was as effective as 2% NaOH in controlling the growth of contamination. The advantages of using HPC over NaOH are that it is a rapid one-step procedure not requiring neutralisation with acid, it is less toxic to M. bovis thus increasing isolation rates, and it promotes the earlier appearance of colonies.

Serological reactivity to Mycobacterium bovis protein antigens in cattle.

The serological response to 12 purified Mycobacterium bovis antigens were examined in an ELISA assay. These antigens included the majority of M. bovis protein antigens described to date and in most cases they were very similar to the M. tuberculosis antigens of the same molecular mass. The purified antigens were tested against sera from M. bovis infected cattle, M. bovis culture-negative cattle from infected herds and animals infected with related microorganisms, mainly other mycobacterial species. All the antigens gave strong reactions with at least some sera from the M. bovis infected group and showed cross-reactivity with some of the sera from the other two groups. The antigen with the highest specificity reacted strongly with only 60% of the M. bovis infected sera. Antigens that reacted with most or all of the M. bovis infected sera also gave the highest cross-reactivity with sera from the other two groups. These results indicate that a serological test based on any one or a combination of these antigens, without removal of the cross-reacting epitopes, would be unsatisfactory.

Identification of Mycobacterium bovis isolates using a monoclonal antibody.

A rapid immunoperoxidase slide assay for the identification of Mycobacterium bovis culture isolates is described. The monoclonal antibody used in this assay is specific for the M. tuberculosis complex of organisms. All M. bovis isolates tested, including 151 separate field isolates of M. bovis were positive as were 11 out of 12 M. tuberculosis strains and 4 out of 6 Bacillus Calmette Guerin (BCG) strains. One strain each of M. africanum and M. microti was negative. This assay provides a considerable improvement in both time and expense over the conventional methods of biochemical typing of M. bovis.