Anatomy and Neuroscience - Research Publications
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ItemScreening, Diagnosis and Management of Sarcopenia and Frailty in Hospitalized Older Adults: Recommendations from the Australian and New Zealand Society for Sarcopenia and Frailty Research (ANZSSFR) Expert Working Group(SPRINGER FRANCE, 2022-05-31)Sarcopenia and frailty are highly prevalent conditions in older hospitalized patients, which are associated with a myriad of adverse clinical outcomes. This paper, prepared by a multidisciplinary expert working group from the Australian and New Zealand Society for Sarcopenia and Frailty Research (ANZSSFR), provides an up-to-date overview of current evidence and recommendations based on a narrative review of the literature for the screening, diagnosis, and management of sarcopenia and frailty in older patients within the hospital setting. It also includes suggestions on potential pathways to implement change to encourage widespread adoption of these evidence-informed recommendations within hospital settings. The expert working group concluded there was insufficient evidence to support any specific screening tool for sarcopenia and recommends an assessment of probable sarcopenia/sarcopenia using established criteria for all older (≥65 years) hospitalized patients or in younger patients with conditions (e.g., comorbidities) that may increase their risk of sarcopenia. Diagnosis of probable sarcopenia should be based on an assessment of low muscle strength (grip strength or five times sit-to-stand) with sarcopenia diagnosis including low muscle mass quantified from dual energy X-ray absorptiometry, bioelectrical impedance analysis or in the absence of diagnostic devices, calf circumference as a proxy measure. Severe sarcopenia is represented by the addition of impaired physical performance (slow gait speed). All patients with probable sarcopenia or sarcopenia should be investigated for causes (e.g., chronic/acute disease or malnutrition), and treated accordingly. For frailty, it is recommended that all hospitalized patients aged 70 years and older be screened using a validated tool [Clinical Frailty Scale (CFS), Hospital Frailty Risk Score, the FRAIL scale or the Frailty Index]. Patients screened as positive for frailty should undergo further clinical assessment using the Frailty Phenotype, Frailty Index or information collected from a Comprehensive Geriatric Assessment (CGA). All patients identified as frail should receive follow up by a health practitioner(s) for an individualized care plan. To treat older hospitalized patients with probable sarcopenia, sarcopenia, or frailty, it is recommended that a structured and supervised multi-component exercise program incorporating elements of resistance (muscle strengthening), challenging balance, and functional mobility training be prescribed as early as possible combined with nutritional support to optimize energy and protein intake and correct any deficiencies. There is insufficient evidence to recommend pharmacological agents for the treatment of sarcopenia or frailty. Finally, to facilitate integration of these recommendations into hospital settings organization-wide approaches are needed, with the Spread and Sustain framework recommended to facilitate organizational culture change, with the help of 'champions' to drive these changes. A multidisciplinary team approach incorporating awareness and education initiatives for healthcare professionals is recommended to ensure that screening, diagnosis and management approaches for sarcopenia and frailty are embedded and sustained within hospital settings. Finally, patients and caregivers' education should be integrated into the care pathway to facilitate adherence to prescribed management approaches for sarcopenia and frailty.
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ItemRenin-Angiotensin System Inhibitors in Patients With COVID-19: A Meta-Analysis of Randomized Controlled Trials Led by the International Society of Hypertension.(Ovid Technologies (Wolters Kluwer Health), 2022-09-06)Background Published randomized controlled trials are underpowered for binary clinical end points to assess the safety and efficacy of renin-angiotensin system inhibitors (RASi) in adults with COVID-19. We therefore performed a meta-analysis to assess the safety and efficacy of RASi in adults with COVID-19. Methods and Results MEDLINE, EMBASE, ClinicalTrials.gov, and the Cochrane Controlled Trial Register were searched for randomized controlled trials that randomly assigned patients with COVID-19 to RASi continuation/commencement versus no RASi therapy. The primary outcome was all-cause mortality at ≤30 days. A total of 14 randomized controlled trials met the inclusion criteria and enrolled 1838 participants (aged 59 years, 58% men, mean follow-up 26 days). Of the trials, 11 contributed data. We found no effect of RASi versus control on all-cause mortality (7.2% versus 7.5%; relative risk [RR], 0.95; [95% CI, 0.69-1.30]) either overall or in subgroups defined by COVID-19 severity or trial type. Network meta-analysis identified no difference between angiotensin-converting enzyme inhibitors versus angiotensin II receptor blockers. RASi users had a nonsignificant reduction in acute myocardial infarction (2.1% versus 3.6%; RR, 0.59; [95% CI, 0.33-1.06]), but increased risk of acute kidney injury (7.0% versus 3.6%; RR, 1.82; [95% CI, 1.05-3.16]), in trials that initiated and continued RASi. There was no increase in need for dialysis or differences in congestive cardiac failure, cerebrovascular events, venous thromboembolism, hospitalization, intensive care admission, inotropes, or mechanical ventilation. Conclusions This meta-analysis of randomized controlled trials evaluating angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers versus control in patients with COVID-19 found no difference in all-cause mortality, a borderline decrease in myocardial infarction, and an increased risk of acute kidney injury with RASi. Our findings provide strong evidence that RASi can be used safely in patients with COVID-19.
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ItemCkmt1 is Dispensable for Mitochondrial Bioenergetics Within White/Beige Adipose Tissue(Oxford University Press (OUP), 2022-01-01)Abstract Within brown adipose tissue (BAT), the brain isoform of creatine kinase (CKB) has been proposed to regulate the regeneration of ADP and phosphocreatine in a futile creatine cycle (FCC) that stimulates energy expenditure. However, the presence of FCC, and the specific creatine kinase isoforms regulating this theoretical model within white adipose tissue (WAT), remains to be fully elucidated. In the present study, creatine did not stimulate respiration in cultured adipocytes, isolated mitochondria or mouse permeabilized WAT. Additionally, while creatine kinase ubiquitous-type, mitochondrial (CKMT1) mRNA and protein were detected in human WAT, shRNA-mediated reductions in Ckmt1 did not decrease submaximal respiration in cultured adipocytes, and ablation of CKMT1 in mice did not alter energy expenditure, mitochondrial responses to pharmacological β3-adrenergic activation (CL 316, 243) or exacerbate the detrimental metabolic effects of consuming a high-fat diet. Taken together, these findings solidify CKMT1 as dispensable in the regulation of energy expenditure, and unlike in BAT, they do not support the presence of FCC within WAT.
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ItemThe L-NAME mouse model of preeclampsia and impact to long-term maternal cardiovascular health(LIFE SCIENCE ALLIANCE LLC, 2022-12-01)Preeclampsia affects ∼2-8% of pregnancies worldwide. It is associated with increased long-term maternal cardiovascular disease risk. This study assesses the effect of the vasoconstrictor N(ω)-nitro-L-arginine methyl ester (L-NAME) in modelling preeclampsia in mice, and its long-term effects on maternal cardiovascular health. In this study, we found that L-NAME administration mimicked key characteristics of preeclampsia, including elevated blood pressure, impaired fetal and placental growth, and increased circulating endothelin-1 (vasoconstrictor), soluble fms-like tyrosine kinase-1 (anti-angiogenic factor), and C-reactive protein (inflammatory marker). Post-delivery, mice that received L-NAME in pregnancy recovered, with no discernible changes in measured cardiovascular indices at 1-, 2-, and 4-wk post-delivery, compared with matched controls. At 10-wk post-delivery, arteries collected from the L-NAME mice constricted significantly more to phenylephrine than controls. In addition, these mice had increased kidney Mmp9:Timp1 and heart Tnf mRNA expression, indicating increased inflammation. These findings suggest that though administration of L-NAME in mice certainly models key characteristics of preeclampsia during pregnancy, it does not appear to model the adverse increase in cardiovascular disease risk seen in individuals after preeclampsia.
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ItemAnalysis of the distribution of vagal afferent projections from different peripheral organs to the nucleus of the solitary tract in rats(WILEY, 2022-08-21)Anatomical tracing studies examining the vagal system can conflate details of sensory afferent and motor efferent neurons. Here, we used a serotype of adeno-associated virus that transports retrogradely and exhibits selective tropism for vagal afferents, to map their soma location and central termination sites within the nucleus of the solitary tract (NTS). We examined the vagal sensory afferents innervating the trachea, duodenum, stomach, or heart, and in some animals, from two organs concurrently. We observed no obvious somatotopy in the somata distribution within the nodose ganglion. The central termination patterns of afferents from different organs within the NTS overlap substantially. Convergence of vagal afferent inputs from different organs onto single NTS neurons is observed. Abdominal and thoracic afferents terminate throughout the NTS, including in the rostral NTS, where the 7th cranial nerve inputs are known to synapse. To address whether the axonal labeling produced by viral transduction is so widespread because it fills axons traveling to their targets, and not just terminal fields, we labeled pre and postsynaptic elements of vagal afferents in the NTS . Vagal afferents form multiple putative synapses as they course through the NTS, with each vagal afferent neuron distributing sensory signals to multiple second-order NTS neurons. We observe little selectivity between vagal afferents from different visceral targets and NTS neurons with common neurochemical phenotypes, with afferents from different organs making close appositions with the same NTS neuron. We conclude that specific viscerosensory information is distributed widely within the NTS and that the coding of this input is probably determined by the intrinsic properties and projections of the second-order neuron.
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ItemEnteric glial cells favor accumulation of anti-inflammatory macrophages during the resolution of muscularis inflammation.(Springer Science and Business Media LLC, 2022-09-07)Monocyte-derived macrophages (Mφs) are crucial regulators during muscularis inflammation. However, it is unclear which micro-environmental factors are responsible for monocyte recruitment and anti-inflammatory Mφ differentiation in this paradigm. Here, we investigate Mφ heterogeneity at different stages of muscularis inflammation and determine how environmental cues can attract and activate tissue-protective Mφs. Results showed that muscularis inflammation induced marked alterations in mononuclear phagocyte populations associated with a rapid infiltration of Ly6c+ monocytes that locally acquired unique transcriptional states. Trajectory inference analysis revealed two main pro-resolving Mφ subpopulations during the resolution of muscularis inflammation, i.e. Cd206+ MhcIIhi and Timp2+ MhcIIlo Mφs. Interestingly, we found that damage to the micro-environment upon muscularis inflammation resulted in EGC activation, which in turn stimulated monocyte infiltration and the consequent differentiation in anti-inflammatory CD206+ Mφs via CCL2 and CSF1, respectively. In addition, CSF1-CSF1R signaling was shown to be essential for the differentiation of monocytes into CD206+ Mφs and EGC proliferation during muscularis inflammation. Our study provides a comprehensive insight into pro-resolving Mφ differentiation and their regulators during muscularis inflammation. We deepened our understanding in the interaction between EGCs and Mφs, thereby highlighting pro-resolving Mφ differentiation as a potential novel therapeutic strategy for the treatment of intestinal inflammation.
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ItemPreclinical and randomized clinical evaluation of the p38α kinase inhibitor neflamapimod for basal forebrain cholinergic degeneration.(Springer Science and Business Media LLC, 2022-09-21)The endosome-associated GTPase Rab5 is a central player in the molecular mechanisms leading to degeneration of basal forebrain cholinergic neurons (BFCN), a long-standing target for drug development. As p38α is a Rab5 activator, we hypothesized that inhibition of this kinase holds potential as an approach to treat diseases associated with BFCN loss. Herein, we report that neflamapimod (oral small molecule p38α inhibitor) reduces Rab5 activity, reverses endosomal pathology, and restores the numbers and morphology of BFCNs in a mouse model that develops BFCN degeneration. We also report on the results of an exploratory (hypothesis-generating) phase 2a randomized double-blind 16-week placebo-controlled clinical trial (Clinical trial registration: NCT04001517/EudraCT #2019-001566-15) of neflamapimod in mild-to-moderate dementia with Lewy bodies (DLB), a disease in which BFCN degeneration is an important driver of disease expression. A total of 91 participants, all receiving background cholinesterase inhibitor therapy, were randomized 1:1 between neflamapimod 40 mg or matching placebo capsules (taken orally twice-daily if weight <80 kg or thrice-daily if weight >80 kg). Neflamapimod does not show an effect in the clinical study on the primary endpoint, a cognitive-test battery. On two secondary endpoints, a measure of functional mobility and a dementia rating-scale, improvements were seen that are consistent with an effect on BFCN function. Neflamapimod treatment is well-tolerated with no study drug associated treatment discontinuations. The combined preclinical and clinical observations inform on the validity of the Rab5-based pathogenic model of cholinergic degeneration and provide a foundation for confirmatory (hypothesis-testing) clinical evaluation of neflamapimod in DLB.
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ItemImprinting fidelity in mouse iPSCs depends on sex of donor cell and medium formulation(NATURE PORTFOLIO, 2022-09-16)Reprogramming of somatic cells into induced Pluripotent Stem Cells (iPSCs) is a major leap towards personalised approaches to disease modelling and cell-replacement therapies. However, we still lack the ability to fully control the epigenetic status of iPSCs, which is a major hurdle for their downstream applications. Epigenetic fidelity can be tracked by genomic imprinting, a phenomenon dependent on DNA methylation, which is frequently perturbed in iPSCs by yet unknown reasons. To try to understand the causes underlying these defects, we conducted a thorough imprinting analysis using IMPLICON, a high-throughput method measuring DNA methylation levels, in multiple female and male murine iPSC lines generated under different experimental conditions. Our results show that imprinting defects are remarkably common in iPSCs, but their nature depends on the sex of donor cells and their response to culture conditions. Imprints in female iPSCs resist the initial genome-wide DNA demethylation wave during reprogramming, but ultimately cells accumulate hypomethylation defects irrespective of culture medium formulations. In contrast, imprinting defects on male iPSCs depends on the experimental conditions and arise during reprogramming, being mitigated by the addition of vitamin C (VitC). Our findings are fundamental to further optimise reprogramming strategies and generate iPSCs with a stable epigenome.
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ItemSystematic endoscopic staging of mediastinum to determine impact on radiotherapy for locally advanced lung cancer (SEISMIC): protocol for a prospective single arm multicentre interventional study(BMC, 2022-09-24)BACKGROUND: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is established as the preferred method of mediastinal lymph node (LN) staging in non-small cell lung cancer (NSCLC). Selective (targeted) LN sampling is most commonly performed however studies in early stage NSCLC and locally advanced NSCLC confirm systematic EBUS-TBNA evaluation improves accuracy of mediastinal staging. This study aims to establish the rate of detection of positron emission tomography (PET)-occult LN metastases following systematic LN staging by EBUS-TBNA, and to determine the utility of systematic mediastinal staging for accurate delineation of radiation treatment fields in patients with locally advanced NSCLC. METHODS: Consecutive patients undergoing EBUS-TBNA for diagnosis/staging of locally advanced NSCLC will be enrolled in this international multi-centre single arm study. Systematic mediastinal LN evaluation will be performed, with all LN exceeding 6 mm to be sampled by TBNA. Where feasible, endoscopic ultrasound staging (EUS-B) may also be performed. Results of minimally invasive staging will be compared to FDG-PET. The primary end-point is proportion of patients in whom systematic LN staging identified PET-occult NSCLC metastases. Secondary outcome measures include (i) rate of nodal upstaging, (ii) false positive rate of PET for mediastinal LN assessment, (iii) analysis of clinicoradiologic risk factors for presence of PET-occult LN metastases, (iv) impact of systematic LN staging in patients with discrepant findings on PET and EBUS-TBNA on target coverage and dose to organs at risk (OAR) in patients undergoing radiotherapy. DISCUSSION: With specificity of PET of 90%, guidelines recommend tissue confirmation of positive mediastinal LN to ensure potentially early stage patients are not erroneously denied potentially curative resection. However, while confirmation of pathologic LN is routinely sought, the exact extent of mediastinal LN involvement in NSCLC in patient with Stage III NSCLC is rarely established. Studies examining systematic LN staging in early stage NSCLC report a significant discordance between PET and EBUS-TBNA. In patients with locally advanced disease this has significant implications for radiation field planning, with risk of geographic miss in the event of PET-occult mediastinal LN metastases. The SEISMIC study will examine both diagnostic outcomes following systematic LN staging with EBUS-TBNA, and impact on radiation treatment planning. TRIAL REGISTRATION: ACTRN12617000333314, ANZCTR, Registered on 3 March 2017.
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ItemShift workers' perceptions and experiences of adhering to a nutrition intervention at night whilst working: a qualitative study(NATURE PORTFOLIO, 2022-09-15)This study explored the feasibility of implementing a meal timing intervention during night shift work. Data were collected via semi-structured interviews. Interviews were coded inductively by two researchers independently, then three major themes were collaboratively developed. Subthemes from each major theme were mapped to the theoretical domains framework and the Capability Opportunity Motivation model of behaviour change. Seventeen night shift workers (rotating or permanent) aged between 25 and 65 years were interviewed. Participants predominately worked as health professionals. The feasibility of a simple meal timing intervention to avoid eating between 1 and 6 am on night shift is largely affected by three major influences (1) physical and emotional burden of shift work which drives food temptations; (2) the workplace context including the meal break environment, social and cultural context at work, and break scheduling; and (3) motivation of the individual. Facilitators to avoiding eating at night were, keeping busy, having co-worker support, management support, education of health benefits and/or belief that the intervention was health promoting. The barriers to avoiding eating at night were the emotional and physical toll of working at night leading to comfort eating and not having rest areas away from food environments. To support night shift workers with changing timing of meals, interventions at work should target both individual and organisational level behaviour change.