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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.

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.

Although the UK's population is not predicted to grow very much in the future, population structure is changing and there is a shift towards a much older age distribution. The characteristics of demographic aging in the UK include a marked reduction in fertility rates, increasing rates of life expectation at birth (ELB), increasing dependency ratios and variations in mortality and social class in old age. The UK's demographic context has important implications for aged care policy planning. This paper documents the demographic trends, reviews recent major policy changes and their impact on care provision, and discusses some of the emerging implementation issues that challenge the potential of such policies to meet the needs an aging population.

Hedgehog (Hh) signaling is crucial for the generation and maintenance of both embryonic and adult stem cells, thereby regulating development and tissue homeostasis. In the developing neocortex, Sonic Hedgehog (Shh) regulates neural progenitor cell proliferation. During neurogenesis, radial glial cells of the ventricular zone (VZ) are the predominant neocortical progenitors that generate neurons through both symmetric and asymmetric divisions. Despite its importance, relatively little is known of the molecular pathways that control the switch from symmetric proliferative to differentiative/neurogenic divisions in neural progenitors. Here, we report that conditional inactivation of Patched1, a negative regulator of the Shh pathway, in Nestin positive neural progenitors of the neocortex leads to lamination defects due to improper corticogenesis and an increase in the number of symmetric proliferative divisions of the radial glial cells. Hedgehog-activated VZ progenitor cells demonstrated a concomitant upregulation of Hes1 and Blbp, downstream targets of Notch signaling. The Notch signaling pathway plays a pivotal role in the maintenance of stem/progenitor cells and the regulation of glial versus neuronal identity. To study the effect of Notch signaling on Hh-activated neural progenitors, we inactivated both Patched1 and Rbpj, a transcriptional mediator of Notch signaling, in Nestin positive cells of the neocortex. Our data indicate that by mid neurogenesis (embryonic day 14.5), attenuation of Notch signaling reverses the effect of Patched1 deletion on neurogenesis by restoring the balance between symmetric proliferative and neurogenic divisions. Hence, our results demonstrate that correct corticogenesis is an outcome of the interplay between the Hh and Notch signaling pathways.

The role of postmastectomy chest-wall irradiation in patients with breast cancer classified as pN1 (with involvement of one to three axillary nodes) or pN0 (pathologically node negative) with additional risk factors is uncertain. In this international, phase 3, randomized trial, we evaluated the omission of chest-wall irradiation in women with \"intermediate-risk\" breast cancer - defined as cancer that was stage pT1N1, pT2N1, or pT3N0 or stage pT2N0 with a histologic grade of 3, lymphovascular invasion, or both (tumor size: T1, ≤2 cm; T2, >2 cm to 5 cm; or T3, >5 cm) - that was treated with mastectomy, an axillary procedure, and systemic therapy. Patients were assigned to undergo chest-wall irradiation (40 to 50 Gy; the irradiation group) or not to undergo chest-wall irradiation (the no-irradiation group). The primary end point was overall survival, with 10 years of follow-up. Chest-wall recurrence, regional recurrence, disease-free survival, distant metastasis-free survival, causes of death, and radiation-related adverse events were also assessed. The intention-to-treat population included 808 patients in the irradiation group and 799 in the no-irradiation group. The median follow up was 9.6 years. Overall survival was 81.4% with chest-wall irradiation and 81.9% with no chest-wall irradiation according to 10-year Kaplan-Meier estimates (hazard ratio for death, 1.04; 95% confidence interval [CI], 0.82 to 1.30; P = 0.80). A total of 29 patients had a chest-wall recurrence - 9 (1.1%) in the irradiation group and 20 (2.5%) in the no-irradiation group (between-group difference, <2 percentage points; hazard ratio, 0.45; 95% CI, 0.20 to 0.99). Disease-free survival was 76.2% in the irradiation group and 75.5% in the no-irradiation group (hazard ratio for recurrence or death, 0.97; 95% CI, 0.79 to 1.18), and distant metastasis-free survival was 78.2% and 79.2%, respectively (hazard ratio for distant metastasis or death, 1.06; 95% CI, 0.86 to 1.31). In this trial, chest-wall irradiation did not result in higher overall survival than no chest-wall irradiation among patients with intermediate-risk, early breast cancer treated with mastectomy and contemporary adjuvant systemic therapy. (Funded by the Medical Research Council and others; SUPREMO ISRCTN Clinical Study Registry number, 61145589.).

Faced with a growing opioid overdose crisis, emergency departments (EDs) are increasingly hiring peers—people with lived experiences of addiction and recovery—to work with patients in the ED who have opioid use disorders (OUDs) or who have experienced an opioid overdose. Despite a clear need for more support for patients with OUD and rapid expansion in grant funding for peer programs, there are limited data on how these programs affect clinical outcomes and how they are best implemented within the ED. In this narrative review, we synthesize the existing evidence on how to develop and implement peer programs for OUD in the ED setting. We describe the key activities peers can undertake in the ED, outline requirements of the peer role and best practices for peer supervision and hiring, detail how ED administrators have built financial and political support for peer programs, and summarize the limited evidence on clinical and care linkage outcomes of peer programs. We highlight key resources that ED clinicians and administrators can use to develop peer programs and key areas where additional research is needed.

The adult mammalian central nervous system (CNS) contains a population of neural stem cells (NSCs) 1 , 2 , 3 , 4 with properties said to include the generation of non-neural progeny 5 , 6 , 7 . However, the precise identity, location and potential of the NSC in situ remain unclear. We purified NSCs from the adult mouse brain by flow cytometry, and directly examined the cells' properties. Here we show that one type of NSC, which expresses the protein nestin but only low levels of PNA-binding and HSA proteins, is found in both ependymal and subventricular zones and accounts for about 63% of the total NSC activity. Furthermore, the selective depletion of the population of this stem cell in querkopf 8 mutant mice (which are deficient in production of olfactory neurons) suggests that it acts as a major functional stem cell in vivo . Most freshly isolated NSCs, when co-cultured with a muscle cell line, rapidly differentiated in vitro into myocytes that contain myosin heavy chain (MyHC). This demonstrates that a predominant, functional type of stem cell exists in the periventricular region of the adult brain with the intrinsic ability to generate neural and non-neural cells.

The malaria genome encodes over 5,000 proteins and many of these have also been proposed to be potential vaccine candidates, although few of these have been tested clinically. RH5 is one of the leading blood-stage malaria vaccine antigens and Phase I/II clinical trials of vaccines containing this antigen are currently underway. Its likely mechanism of action is to elicit antibodies that can neutralize merozoites by blocking their invasion of red blood cells (RBC). However, many other antigens could also elicit neutralizing antibodies against the merozoite, and most of these have never been compared directly to RH5. The objective of this study was to compare a range of blood-stage antigens to RH5, to identify any antigens that outperform or synergize with anti-RH5 antibodies. We selected 55 gene products, covering 15 candidate antigens that have been described in the literature and 40 genes selected on the basis of bioinformatics functional prediction. We were able to make 20 protein-in-adjuvant vaccines from the original selection. Of these, S-antigen and CyRPA robustly elicited antibodies with neutralizing properties. Anti-CyRPA IgG generally showed additive GIA with anti-RH5 IgG, although high levels of anti-CyRPA-specific rabbit polyclonal IgG were required to achieve 50% GIA. Our data suggest that further vaccine antigen screening efforts are required to identify a second merozoite target with similar antibody-susceptibility to RH5.

There is a critical need for new pathways to develop antibacterial agents to treat life-threatening infections caused by highly resistant bacteria. Traditionally, antibacterial agents have been studied in noninferiority clinical trials that focus on one site of infection (eg, pneumonia, intra-abdominal infection). Conduct of superiority trials for infections caused by highly antibiotic-resistant bacteria represents a new, and as yet, untested paradigm for antibacterial drug development. We sought to define feasible trial designs of antibacterial agents that could enable conduct of superiority and organism-specific clinical trials. These recommendations are the results of several years of active dialogue among the white paper's drafters as well as external collaborators and regulatory officials. Our goal is to facilitate conduct of new types of antibacterial clinical trials to enable development and ultimately approval of critically needed new antibacterial agents.

Genetically distinct variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have emerged since the start of the COVID-19 pandemic. Over this period, we developed a rapid platform (R-20) for viral isolation and characterization using primary remnant diagnostic swabs. This, combined with quarantine testing and genomics surveillance, enabled the rapid isolation and characterization of all major SARS-CoV-2 variants circulating in Australia in 2021. Our platform facilitated viral variant isolation, rapid resolution of variant fitness using nasopharyngeal swabs and ranking of evasion of neutralizing antibodies. In late 2021, variant of concern Omicron (B1.1.529) emerged. Using our platform, we detected and characterized SARS-CoV-2 VOC Omicron. We show that Omicron effectively evades neutralization antibodies and has a different entry route that is TMPRSS2-independent. Our low-cost platform is available to all and can detect all variants of SARS-CoV-2 studied so far, with the main limitation being that our platform still requires appropriate biocontainment. A platform developed for rapid isolation of SARS-CoV-2 variants also facilitates the characterization of variant immune evasion and viral fitness. The platform enabled rapid detection of the Omicron variant in samples of the first cases in Australia.