Targeting intracellular nontuberculous mycobacteria and M. tuberculosis with a bactericidal enzymatic cocktail.

To address intracellular mycobacterial infections, we developed a cocktail of four enzymes that catalytically attack three layers of the mycobacterial envelope. This cocktail is delivered to macrophages, through a targeted liposome presented here as ENTX_001. Endolytix Cocktail 1 (EC1) leverages mycobacteriophage lysin enzymes LysA and LysB, while also including α-amylase and isoamylase for degradation of the mycobacterial envelope from outside of the cell. The LysA family of proteins from mycobacteriophages has been shown to cleave the peptidoglycan layer, whereas LysB is an esterase that hydrolyzes the linkage between arabinogalactan and mycolic acids of the mycomembrane. The challenge of gaining access to the substrates of LysA and LysB provided exogenously was addressed by adding amylase enzymes that degrade the extracellular capsule shown to be present in Mycobacterium tuberculosis. This enzybiotic approach avoids antimicrobial resistance, specific receptor-mediated binding, and intracellular DNA surveillance pathways that limit many bacteriophage applications. We show this cocktail of enzymes is bactericidal in vitro against both rapid- and slow-growing nontuberculous mycobacteria (NTM) as well as M. tuberculosis strains. The EC1 cocktail shows superior killing activity when compared to previously characterized LysB alone. EC1 is also powerfully synergistic with standard-of-care antibiotics. In addition to in vitro killing of NTM, ENTX_001 demonstrates the rescue of infected macrophages from necrotic death by Mycobacteroides abscessus and Mycobacterium avium. Here, we demonstrate shredding of mycobacterial cells by EC1 into cellular debris as a mechanism of bactericide.IMPORTANCEThe world needs entirely new forms of antibiotics as resistance to chemical antibiotics is a critical problem facing society. We addressed this need by developing a targeted enzyme therapy for a broad range of species and strains within mycobacteria and highly related genera including nontuberculous mycobacteria such as Mycobacteroides abscessus, Mycobacterium avium, Mycobacterium intracellulare, as well as Mycobacterium tuberculosis. One advantage of this approach is the ability to drive our lytic enzymes through encapsulation into macrophage-targeted liposomes resulting in attack of mycobacteria in the cells that harbor them where they hide from the adaptive immune system and grow. Furthermore, this approach shreds mycobacteria independent of cell physiology as the drug targets the mycobacterial envelope while sidestepping the host range limitations observed with phage therapy and resistance to chemical antibiotics.

Silver Memories: implementation and evaluation of a unique radio program for older people.

OBJECTIVES: A unique radio program, Silver Memories, specifically designed to address social isolation and loneliness in older people by broadcasting music (primarily), serials and other programs relevant to the period when older people grew up--the 1920-1950s--first aired in Brisbane, Australia, in April 2008. The impact of the program upon older listeners' mood, quality of life (QOL) and self-reported loneliness was independently evaluated. METHOD: One hundred and thirteen community-dwelling persons and residents of residential care facilities, aged 60 years and older participated in a three month evaluation of Silver Memories. They were asked to listen to the program daily and baseline and follow-up measures of depression, QOL and loneliness were obtained. Participants were also asked for their opinions regarding the program's quality and appeal. RESULTS: The results showed a statistically significant improvement in measures of depression and QOL from baseline to follow-up but there was no change on the measure of loneliness. The results did not vary by living situation (community vs. residential care), whether the participant was lonely or not lonely, socially isolated or not isolated, or whether there had been any important changes in the participant's health or social circumstances throughout the evaluation. CONCLUSION: It was concluded that listening to Silver Memories appears to improve the QOL and mood of older people and is an inexpensive intervention that is flexible and readily implemented.

Reflexivity and minimization of the impact of age-cohort differences between researcher and research participants.

Reflexivity in research can be defined as (a) the acknowledgment and identification of one's place and presence in the research, and (b) the process of using these insights to critically examine the entire research process. Many authors implore qualitative researchers to be reflexive. Very few, however, specify how to do this in practice. Furthermore, in discussions of the presence and place of the researcher, the tendency has been to focus on such factors as gender and race or ethnicity with very little attention being given to age or cohort. In this article we seek to redress this deficiency by examining how reflexivity was practiced in a context in which there was a marked difference in age and cohort membership between researcher and research participants. Specifically, we describe the methodological challenges faced by a younger researcher conducting research with older study participants on the lived experience of the body, and how reflexivity was used to adapt the methodology employed so it became more appropriate and productive within this context.

Community perceptions on the significant extension of life: an exploratory study among urban adults in Brisbane, Australia.

Some researchers in the field of ageing claim that significant extension of the human lifespan will be possible in the near future. While many of these researchers have assumed that the community will welcome this technology, there has been very little research on community attitudes to life extension. This paper presents the results of an in-depth qualitative study of community attitudes to life extension across age groups and religious boundaries. There were 57 individual interviews, and 8 focus groups (totalling 72 focus group participants) conducted with community members in Brisbane, Australia. Community attitudes to life extension were more varied and complex than have been assumed by some biogerontologists and bioethicists. While some participants would welcome the opportunity to extend their lives others would not even entertain the possibility. This paper details these differences of opinion and reveals contrasting positions that reflect individualism or social concern among community members. The findings also highlight the relationship between Christianity, in particular belief in an afterlife, and attitudes to life extension technology. Overall, the study raises questions about the relationship between interest in life extension, the medicalisation of ageing and the increasing acceptability of enhancement technologies that need to be addressed in more representative samples of the community.

Professional and personal attitudes of researchers in ageing towards life extension.

It is often assumed that there is broad public support for strong life extension research (i.e. research aimed at the dramatic extension of human life beyond the current maximum), and that there would be a near universal interest in using any life extending technologies that this research may produce. In this paper we report the opinions of researchers in ageing on the controversial promise of life extension, and compare these views. This paper describes the professional attitudes, personal interest and concerns expressed by Australian and international researchers in ageing (n = 14) as expressed during semi-structured, in-depth interviews. Researchers held varying opinions about the possibility of significantly extending human life. Some saw a limit to the extension of human life, while others did not. Some felt that research into the fundamental ageing process was a priority; others did not. Researchers tended to weigh up the potential risks and benefits of life extension with most expressing a personal interest in life extension that was contingent on the technology providing a good quality of life. Some participants were not interested in the prospect of life extension for personal reasons, because they felt the potential risks outweighed the potential benefits, or because life extension raised issues of justice and equity.

Transition care: will it deliver?

Transition care is a new program to Australia that is designed to facilitate transitions of frail older people between the hospital and aged care systems. This program is designed to deliver potentially important improvements to the Australian health care system--but will it deliver? The current evidence base regarding the efficacy of this type of program is mixed, and there is little evidence to indicate improved patient outcomes. An average transition care episode is expensive (about $11 000). Therefore, careful consideration of the relative cost-effectiveness compared with other interface programs such as inpatient subacute services is essential. Transition care services should be established within the context of overall regional plans for aged care, incorporating hospital acute and subacute inpatient services, and long-term community and residential care programs.

Measuring the impact of increased exercise on quality of life in older adults: the UQQoL, a new instrument.

The University of Queensland Quality of Life instrument (UQQoL) was developed to provide a quantitative measure sensitive to the impact of increased exercise on the quality of life (QoL) of older individuals. This paper describes the development and testing of the UQQoL including an exploratory study of focus group interviews with 18 participants aged 65 and over, item development and selection, and instrument piloting with groups of older adults undergoing high-intensity training. The SF-36, another established QoL tool, was also administered at the same time points for comparative purposes. The UQQoL displayed good convergent validity with selected SF-36 domains. A significant change in QoL following training was found, complementing functional improvements. This change was not detected by the SF-36. While broader testing is required, the UQQoL appears to be a reliable instrument sensitive to the change in QoL experienced by healthy community-dwelling older adults following resistance exercise.

Behavioral determinants of healthy aging.

With global trends in population aging, many nations are developing and implementing healthy aging policies to promote quality as well as years of healthy life. To broaden the evidence base for such policy development, a review of the literature was conducted to summarize the existing evidence regarding the behavioral determinants of healthy aging. Such research is needed so that the efficacy of modes of intervention can be better understood. The outcome of "healthy" or "successful" aging was selected for this review since this nomenclature dominates the literature describing a global measure of multidimensional functioning at the positive end of the health continuum in older age. Studies published between 1985 and 2003 that reported statistical associations between baseline determinants and healthy aging outcome were identified from a systematic search of medical, psychological, sociological, and gerontological databases. Eight studies satisfied the search criteria. Modifiable risk factors among the behavioral determinants included smoking status, physical activity level, body mass index, diet, alcohol use, and health practices. On the basis of these findings, effective healthy aging policies need to enhance opportunities across the life span for modification of lifestyle risk factors. Efforts to standardize concepts and terminology will facilitate further research activity in this important area.

Primary health care for older people: progress towards an integrated strategy?

The importance of providing integrated, holistic and cohesive primary care for older people has been increasingly emphasized in recent policy initiatives and directives in the UK. These have sometimes proved to be elusive goals, however, as an ageing population and rapidly changing health care environment have increased the pressures on the primary care team to keep pace with the growing level of need. As primary care faces a new set of challenges presented by the development of Primary Care Groups (PCGs), opportunities may be found to address older people's health needs in a more coordinated way. In South Buckinghamshire, a multi-agency group, Health for All (HFA), has been keen to develop collaborative and inter-agency working in older peoples' services and commissioned an evaluation to inform their work. This paper focuses on some of the key findings from the evaluation with reference to primary care. The purpose of the evaluation was to provide a snapshot of service provision for older people, identifying the level of access, availability of services and areas of unmet need. Twelve user groups were consulted and interviews held with 58 service representatives from health and social services agencies in the statutory and voluntary sectors. Primary care was considered in the wider context of service provision and key issues from the perspectives of providers and users were identified. A number of problems specific to primary care were identified which echo experiences in other parts of the country. However, also identified were common issues across a wide range of service provision, suggesting the need for coordinated strategies and more effective user participation. The HFA group is using the recommendations of the evaluation to assist in a priority setting exercise, which will inform the development of a strategy for older people in South Buckinghamshire.