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.

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.

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.

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.

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.

Bacteriological diagnosis and molecular strain typing of Mycobacterium bovis and Mycobacterium caprae.

The primary isolation of a Mycobacterium sp. of the Mycobacterium tuberculosis complex from an infected animal provides a definitive diagnosis of tuberculosis. However, as Mycobacterium bovis and Mycobacterium caprae are difficult to isolate, particularly for animals in the early stages of disease, success is dependent on the optimal performance of all aspects of the bacteriological process, from the initial choice of tissue samples at post-mortem examination or clinical samples, to the type of media and conditions used to cultivate the microorganism. Each step has its own performance characteristics, which can contribute to sensitivity and specificity of the procedure, and may need to be optimized in order to achieve the gold standard diagnosis. Having isolated the slow-growing mycobacteria, species identification and fine resolution strain typing are keys to understanding the epidemiology of the disease and to devise strategies to limit transmission of infection. New technologies have emerged that can now even discriminate different isolates from the same animal. In this review we highlight the key factors that contribute to the accuracy of bacteriological diagnosis of M. bovis and M. caprae, and describe the development of advanced genotyping techniques that are increasingly used in diagnostic laboratories for the purpose of supporting detailed epidemiological investigations.

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.

Control strategies for wildlife tuberculosis in Ireland.

The principal domestic maintenance host for Mycobacterium bovis is infected cattle. In countries where comprehensive surveillance schemes have been applied, tuberculosis rarely affects an animal to the extent that it presents with clinical disease. In the latter stages of an eradication campaign, the aim is to maintain the disease-free status of clear herds and eliminate foci of infection in herds as well as restricting movement of infected animals from these herds, other than to slaughter. However, the eradication of tuberculosis from cattle herds may be compromised if infected wildlife species, such as Eurasian badgers (Meles meles), share the same environment and contribute to transmission of infection. The options for dealing with tuberculosis in the wildlife reservoir hosts are limited to segregation of domestic animals from the wildlife, culling of the wildlife host or vaccination. Options are further limited by conservation and social reasons, particularly where culling is concerned. In Ireland and the UK, vaccination of badgers against M. bovis, if successfully employed, could directly facilitate the completion of bovine tuberculosis eradication. Programmes of research into vaccination of badgers are being undertaken in both countries, and there is clear evidence that vaccination induces protection. Vaccine trials in captive badgers have established that the M. bovis bacille Calmette-Guérin (BCG) vaccine can induce a protective response that limits the distribution and severity of tuberculosis disease following experimental challenge. In Ireland, a large-scale field trial of oral BCG vaccination is being conducted to measure the protection generated in wild badgers subjected to natural transmission of infection and to estimate vaccine efficacy. The results will provide a framework for the development and implementation of a national strategy to address the disease in badger populations and if successful will remove this major impediment to tuberculosis eradication from cattle.

Primary isolation of Mycobacterium bovis from bovine tissues: conditions for maximising the number of positive cultures.

In studies of Mycobacterium bovis infection in animals a definitive diagnosis requires the isolation of the organism. However, the optimum conditions for the primary isolation of M. bovis have not been determined. The aim of this study was to determine for primary isolation of M. bovis, (a) the incubation time required to achieve maximum sensitivity (i.e., the number of positive samples identified), (b) the effect of decontaminants on bacterial growth rates, and (c) the influence of media and the number of slopes of media on the number of positive samples detected. Two agar-based media, modified Middlebrook 7H11 (7H11) and tuberculosis blood agar (B83), and an egg-based medium, Stonebrink's (SB) were compared. Three decontaminants, 2% (w/v) sodium hydroxide (NaOH), 0.75% (w/v) and 0.075% (w/v) cetylpyridinium chloride (CPC, also called hexadecylpyridinium chloride, HPC) and 0.5% (w/v) benzalkonium chloride (BC) were evaluated against treatment with sterile distilled water. The inoculated media slopes were incubated for up to 15 weeks. Colonies first appeared after 2 weeks on all media types and 75% of positive slopes were identified by 8 weeks. An incubation time of 15 weeks was required to identify all positive samples. The slowest growth was associated with inocula that contained the fewest viable bacilli. The time to the appearance of colonies was influenced by medium type: the median time to detection of colonies was 28 days on 7H11 and B83, and 36 days on SB. However, SB returned the greatest number of positive samples. Decontamination procedures increased the minimum incubation time required to detect positive cultures, probably due to the toxic effect of the decontaminants. Increasing the number of inoculated slopes resulted in an increased number of positive samples and a decreased time to the detection of colonies. Overall, the detection of M. bovis was significantly influenced by the choice of media, the decontaminant and the duration of incubation of cultures.

Tuberculosis in cattle herds are sentinels for Mycobacterium bovis infection in European badgers (Meles meles): the Irish Greenfield Study.

In Ireland badgers are removed in response to tuberculosis (TB) breakdowns in cattle herds (focal culling). Prevalence studies, conducted using a detailed post mortem and bacteriological examination, showed that 36-50% of badgers were infected with Mycobacterium bovis. Focal culling forms part of the medium term national strategy for the control of bovine TB in cattle and is based on the premise that badgers in areas with herd breakdowns have a higher prevalence of infection than the badger population at large. However, the hypothesis that cattle can be used as sentinels for infection in the badger population has never been formally tested. In this study we tested the hypothesis by determining the infection prevalence in badgers in areas where there had been historically, a consistently low prevalence of infection in cattle. Low cattle TB prevalence areas were defined as those herds with ≤ 2 standard reactors in the annual round of skin testing over the preceding 5 years (Greenfield sites). Using GIS, and adjusting for variation in land use, previous culling and cattle density, 198 Greenfield sites were identified and surveyed, and 138 areas with badger setts or signs of badger activity were identified. A single badger was removed from 87 sites and all were examined using detailed post mortem and bacteriological procedures. A prevalence of M. bovis infection of 14.9% was found in the Greenfield site badgers. This prevalence was significantly lower (P<0.001) than in badgers removed during focal culling (36.6%). The results validate the use of cattle as sentinels for TB in badgers and support the medium term national strategy for the control of bovine TB. The geographic variation in M. bovis infection prevalence in the Irish badger populations will be used when devising strategies for the incorporation of badger vaccination into the long term bovine TB control programme.

Mycobacterium bovis infection in the Eurasian badger (Meles meles): the disease, pathogenesis, epidemiology and control.

Eurasian badgers (Meles meles) are an important wildlife reservoir of tuberculosis (Mycobacterium bovis) infection in Ireland and the United Kingdom. As part of national programmes to control tuberculosis in livestock, considerable effort has been devoted to studying the disease in badgers and this has lead to a rapid increase in our knowledge of tuberculosis in this host. Tuberculosis in badgers is a chronic infection and in a naturally-infected population the severity of disease can vary widely, from latent infection (infection without clinical signs and no visible lesions) to severe disease with generalized pathology. The high prevalence of pulmonary infection strongly supports the lungs as the principal site of primary infection and that inhalation of infectious aerosol particles is the principal mode of transmission. However, other routes, including transmission via infected bite wounds, are known to occur. The ante-mortem diagnosis of infection is difficult to achieve, as clinical examination and immunological and bacteriological examination of clinical samples are insensitive diagnostic procedures. Because infection in the majority of badgers is latent, the gross post-mortem diagnosis is also insensitive. A definitive diagnosis can only be made by the isolation of M. bovis. However, to gain a high level of sensitivity in the bacteriological examination, a large number of tissues from each badger must be cultured and sensitive culture methods employed. The transmission and maintenance of M. bovis in badger populations are complex processes where many factors influence within-population prevalence and rates of transmission. Badger social structures and the longevity of infected animals make them an ideal maintenance host for M. bovis infection. Badgers are directly implicated in the transmission of infection to cattle and the inability to eradicate the disease from cattle is, in part, a consequence of the interactions between the two species. A detailed understanding and knowledge of the epidemiology and pathogenesis of the disease are recognized as fundamental for devising new strategies to control infection with a view to limiting interspecies transmission. Vaccination, in spite of formidable challenges, is seen as the best long-term strategy option and studies with captive badgers have shown that vaccination with M. bovis bacillus Calmette-Guérin (BCG) induces protection when delivered by a variety of routes. Continued research is required to develop effective technologies to control the disease both in badgers and cattle. A combination of strategies, which employ the optimal use and targeting of resources, is likely to make a significant contribution towards eradication of the disease.

The prevalence and distribution of Mycobacterium bovis infection in European badgers (Meles meles) as determined by enhanced post mortem examination and bacteriological culture.

The accurate diagnosis of Mycobacterium bovis infection in badgers is key to understanding the epidemiology of tuberculosis in this species and has significant implications for devising strategies to limit spread of the disease. In this study, badgers (n=215) in the Republic of Ireland were examined at post mortem and tissues were collected from a range of anatomical locations and pooled into groups for bacterial culture of M. bovis. By assessing confirmed gross visible lesions (VL) alone, infection was detected in 12.1% of badgers. However, by including the results of all culture positive pooled samples, the overall infection prevalence increased significantly to 36.3%. Two-thirds (66.7%) of infected animals had no visible lesions (NVL). While the thoracic cavity (lungs and pulmonary lymph nodes) was found to be the most common site of infection, in a proportion of animals infection was absent from the lungs and draining lymph nodes and was confined to the lymph nodes of the carcase or the head. This may indicate an early extrapulmonary dissemination of infection or alternatively, in the case of the head lymph nodes, a secondary pathogenic pathway involving the lymphoid tissues of the upper respiratory tract (URT).

Tuberculosis in European badgers (Meles meles) and the control of infection with bacille Calmette-Guérin vaccination.

The eradication of tuberculosis (Mycobacterium bovis infection) from cattle herds may be compromised if infected wildlife species, such as European badgers (Meles meles), share the same environment and contribute to transfer of infection. Options for dealing with tuberculosis in this wild reservoir host are limited by conservation and social concerns, despite a clear implication that infected badgers are involved with the initiation of tuberculosis in cattle herds. Vaccination of badgers against M. bovis, if successfully employed, would directly facilitate the completion of bovine tuberculosis eradication in affected areas. Vaccine trials in captive badgers have established that the M. bovis bacille Calmette-Guérin (BCG) vaccine can induce a protective response that limits the distribution and severity of tuberculosis disease following experimental challenge. The protective effect of the vaccine has been demonstrated when the vaccine was delivered by subcutaneous injection, deposited on mucous membranes, and given orally in a lipid formulation. A large-scale field trial of oral BCG vaccine has been designed to measure the protection generated in wild badgers subjected to natural transmission of infection and to estimate vaccine efficacy. These parameters will be estimated by comparing the prevalence of M. bovis infection in vaccinated and nonvaccinated badgers. The results will provide a framework for the development and implementation of a national strategy to eliminate the disease in badger populations and if successful will remove this major impediment to bovine tuberculosis eradication.

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.

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.

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.

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.