Respiratory syncytial virus disease morbidity in Australian infants aged 0 to 6 months: a systematic review with narrative synthesis.

BACKGROUND: A significant proportion of the global respiratory syncytial virus (RSV) associated morbidity is accounted for by infants aged 0 to 6 months, who are particularly vulnerable to severe disease. In 2015, 44% of global hospitalisations in infants in this age group were secondary to RSV. The objective of this systematic review is to appraise and synthesise the local evidence of RSV infection morbidity among Australian infants aged 0 to 6 months and to assess the implications for future immunisation strategies. METHODS: Electronic databases (Medline, Embase, Pubmed and Global Health) were searched for full-text articles published between 2000 and 2023 in English language. Studies that examined markers of RSV disease morbidity in infants aged 0 to 6 months in Australia who had laboratory confirmed RSV infection were eligible for inclusion. The outcomes of interest were incidence, prevalence, testing rate, positivity rate, mortality, emergency department visits, community health visits, hospitalisation, intensive care unit admission, supplementary oxygen use, mechanical ventilation, risk factors for disease severity and monoclonal antibody use. RESULTS: The database search identified 469 studies. After removal of duplicates and full-text review, 17 articles were eligible for inclusion. This review was reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and Synthesis without meta-analysis guidelines. CONCLUSIONS: Qualitative analysis of the included studies showed that Australian infants aged 0 to 6 months have higher rates of RSV testing, positivity and incidence; and more likely to develop severe disease that requires hospitalisation, intensive care unit admission or respiratory support, compared to children and adults of all ages. Aboriginal and Torres Strait Islander infants aged 0 to 6 months demonstrated higher rates of RSV infection and hospitalisation, compared to non-Indigenous infants. Age-related trends persisted in geographic areas with varying seasonal transmission of RSV, and during the SARS-CoV-2 pandemic. Passive immunisation strategies targeting infants in their first 6 months of life, either via vaccination of pregnant women or administration of long-acting monoclonal antibody during infancy, could effectively reduce RSV disease burden in Australia.

Efficacy of epothilones in central nervous system trauma treatment: what has age got to do with it?

Central nervous system injury, specifically traumatic brain and spinal cord injury, can have significant long lasting effects. There are no comprehensive treatments to combat the injury and sequalae of events that occurring following a central nervous system trauma. Herein we discuss the potential for the epothilone family of microtubule stabilizing agents to improve outcomes following experimentally induced trauma. These drugs, which are able to cross the blood-brain barrier, may hold great promise for the treatment of central nervous system trauma and the current literature presents the extensive range of beneficial effects these drugs may have following trauma in animal models. Importantly, the effect of the epothilones can vary and our most recent contributions to this field indicate that the efficacy of epothilones following traumatic brain injury is dependent upon the age of the animals. Therefore, we present a case for a greater emphasis to be placed upon age when using an intervention aimed at neural regeneration and highlight the importance of tailoring the therapeutic regime in the clinic to the age of the patient to promote improved patient outcomes.

A Case for Microtubule Vulnerability in Amyotrophic Lateral Sclerosis: Altered Dynamics During Disease.

Amyotrophic lateral sclerosis (ALS) is an aggressive multifactorial disease converging on a common pathology: the degeneration of motor neurons (MNs), their axons and neuromuscular synapses. This vulnerability and dysfunction of MNs highlights the dependency of these large cells on their intracellular machinery. Neuronal microtubules (MTs) are intracellular structures that facilitate a myriad of vital neuronal functions, including activity dependent axonal transport. In ALS, it is becoming increasingly apparent that MTs are likely to be a critical component of this disease. Not only are disruptions in this intracellular machinery present in the vast majority of seemingly sporadic cases, recent research has revealed that mutation to a microtubule protein, the tubulin isoform TUBA4A, is sufficient to cause a familial, albeit rare, form of disease. In both sporadic and familial disease, studies have provided evidence that microtubule mediated deficits in axonal transport are the tipping point for MN survivability. Axonal transport deficits would lead to abnormal mitochondrial recycling, decreased vesicle and mRNA transport and limited signaling of key survival factors from the neurons peripheral synapses, causing the characteristic peripheral "die back". This disruption to microtubule dependant transport in ALS has been shown to result from alterations in the phenomenon of microtubule dynamic instability: the rapid growth and shrinkage of microtubule polymers. This is accomplished primarily due to aberrant alterations to microtubule associated proteins (MAPs) that regulate microtubule stability. Indeed, the current literature would argue that microtubule stability, particularly alterations in their dynamics, may be the initial driving force behind many familial and sporadic insults in ALS. Pharmacological stabilization of the microtubule network offers an attractive therapeutic strategy in ALS; indeed it has shown promise in many neurological disorders, ALS included. However, the pathophysiological involvement of MTs and their functions is still poorly understood in ALS. Future investigations will hopefully uncover further therapeutic targets that may aid in combating this awful disease.

Axonal degeneration, distal collateral branching and neuromuscular junction architecture alterations occur prior to symptom onset in the SOD1(G93A) mouse model of amyotrophic lateral sclerosis.

Degeneration of the distal axon and neuromuscular junction (NMJ) is considered a key and early feature of the pathology that accompanies motor neuron loss in people with amyotrophic lateral sclerosis (ALS). The mutant SOD1(G93A) mouse replicates many features of the disease, however the sequence of events resulting in degeneration of the neuromuscular circuitry remains unknown. Furthermore, despite widespread degenerative neuronal pathology throughout the spinal cord in this model, hindlimb motor function is lost before forelimb function. We investigated axons and NMJs in the hindlimb (gastrocnemius) and forelimb (extensor) muscles in the high copy number mutant SOD1(G93A)xYFP (yellow fluorescent protein) mouse. We found that distal axonal and NMJ alterations were present prior to previously reported functional symptom onset in this strain. Indeed, increased branch complexity as well as colocalisation between pre- and post-synaptic markers indicated widespread early axonal and NMJ alterations in the hindlimb. Immunohistochemical analysis demonstrated that the colocalisation of the scaffolding proteins nestin, LRP-4, dystrophin and rapsyn were diminished before post-synaptic receptors in the gastrocnemius, and the degree of loss differed between proteins. Analysis of the forelimb muscle revealed axonal and NMJ degeneration at a late, post symptomatic stage, as well as novel differences in NMJ morphology, with reduced complexity. Furthermore, post-synaptic scaffolding proteins were preserved in the forelimb compared with the hindlimb. Analysis of protein levels indicated an increase in LRP-4, dystrophin and rapsyn in post symptomatic skeletal muscle that may suggest ongoing attempts at repair. This study indicates that axonal and NMJ degeneration in the SOD1 model of ALS is a complex and evolving sequence of events. We provide evidence that YFP can detect morphological and plastic alterations in the SOD1(G93A) mouse, and that the pre- and post-synaptic integrity of the NMJ plays an important role in the pathogenic mechanisms of ALS.

Identifying the primary site of pathogenesis in amyotrophic lateral sclerosis - vulnerability of lower motor neurons to proximal excitotoxicity.

There is a desperate need for targeted therapeutic interventions that slow the progression of amyotrophic lateral sclerosis (ALS). ALS is a disorder with heterogeneous onset, which then leads to common final pathways involving multiple neuronal compartments that span both the central and peripheral nervous system. It is believed that excitotoxic mechanisms might play an important role in motor neuron death in ALS. However, little is known about the mechanisms by which excitotoxicity might lead to the neuromuscular junction degeneration that characterizes ALS, or about the site at which this excitotoxic cascade is initiated. Using a novel compartmentalised model of site-specific excitotoxin exposure in lower motor neurons in vitro, we found that spinal motor neurons are vulnerable to somatodendritic, but not axonal, excitotoxin exposure. Thus, we developed a model of somatodendritic excitotoxicity in vivo using osmotic mini pumps in Thy-1-YFP mice. We demonstrated that in vivo cell body excitotoxin exposure leads to significant motor neuron death and neuromuscular junction (NMJ) retraction. Using confocal real-time live imaging of the gastrocnemius muscle, we found that NMJ remodelling preceded excitotoxin-induced NMJ degeneration. These findings suggest that excitotoxicity in the spinal cord of individuals with ALS might result in a die-forward mechanism of motor neuron death from the cell body outward, leading to initial distal plasticity, followed by subsequent pathology and degeneration.