Association of computed tomography measures of muscle and adipose tissue and progressive changes throughout treatment with clinical endpoints in patients with advanced lung cancer treated with immune checkpoint inhibitors

To investigate the association between skeletal muscle mass and adiposity measures with disease-free progression (DFS) and overall survival (OS) in patients with advanced lung cancer receiving immunotherapy, we retrospectively analysed 97 patients (age: 67.5 ± 10.2 years) with lung cancer who were treated with immunotherapy between March 2014 and June 2019. From computed tomography scans, we assessed the radiological measures of skeletal muscle mass, and intramuscular, subcutaneous and visceral adipose tissue at the third lumbar vertebra. Patients were divided into two groups based on specific or median values at baseline and changes throughout treatment. A total number of 96 patients (99.0 %) had disease progression (median of 11.3 months) and died (median of 15.4 months) during follow-up. Increases of 10 % in intramuscular adipose tissue were significantly associated with DFS (HR: 0.60, 95 % CI: 0.38 to 0.95) and OS (HR: 0.60, 95 % CI: 0.37 to 0.95), while increases of 10 % in subcutaneous adipose tissue were associated with DFS (HR: 0.59, 95 % CI: 0.36 to 0.95). These results indicate that, although muscle mass and visceral adipose tissue were not associated with DFS or OS, changes in intramuscular and subcutaneous adipose tissue can predict immunotherapy clinical outcomes in patients with advanced lung cancer

Utilising routine non-invasive faecal samples for the detection of oestrus and early gestation in okapi (Okapi johnstoni)

Zoos play a vital role in conservation with an overall aim of preserving species, such as the okapi (Okapi johnstoni), from extinction. To ensure species survival, sustainable ex-situ populations are required, and therefore understanding the reproductive status of individuals is important for population management. In this study, the oestrous cycles and gestations of four okapi (n = 7 pregnancies) were monitored through non-invasive faecal sampling methods to quantify progestagen and oestrogen metabolites. Baseline criteria for determining oestrous cycles was developed using approximately 20 months of sampling from each of two non-pregnant females, before being applied to pre- and early conception data. Pre-conception oestrous cycles were characterised in two females with luteal phase (mean ± SD) was 8.47 ± 1.41 days (n = 59) with an inter-luteal phase of 7.38 ± 1.67 days (n = 58), and overall average cycle length of 15.83 ± 2.02 days (n = 54 full cycles only). Observed in all four females, oestrogen metabolite peaks occurred at the beginning of the inter-luteal phase as progestagen metabolites were decreasing. Gestation was confirmed when progestagen metabolite concentrations remained at luteal phase concentrations for at least 20 days, with concentrations remaining at this level for the first 120 days of gestation without return to baseline values. A secondary increase at around 150 days lasted until parturition. These data demonstrate that okapi exhibit similar oestrous cycles to other members of the giraffidae family, with faecal oestrogens for the first time indicating that ovulation occurs at the beginning of the inter-luteal phase while progestagens are still elevated. Furthermore, we have shown that through routine sample collection and hormone monitoring, gestation can be confirmed within the first trimester, which can benefit the management of the species in ex-situ populations

The association between different trajectories of low back pain and degenerative imaging findings in young adult participants within the Raine Study

Abstract Study design: Case-control study. Objective: Investigate the association between lumbar spine magnetic resonance imaging (MRI) findings and 5-year trajectories of low back pain (LBP) in young Australian adults. Summary of Background Data: The association between lumbar spine imaging findings and LBP remains unclear due to important limitations of previous research, such as a lack of clearly defined LBP phenotypes and inadequate controlling for age, which may substantially affect the association. Methods: Seventy-eight “case” participants with a previously identified “consistent high disabling LBP” trajectory from age 17 to 22 years and 78 “control” participants from a trajectory with consistently low LBP over the same time period, matched for sex, body mass index, physical activity levels, and work physical demands, were identified from Gen2 Raine Study participants. At age 27, participants underwent a standardized lumbar MRI scan, from which 14 specific MRI phenotypes were identified. Primary analyses used unconditional logistic regression, adjusting for covariates used in the matching process, to investigate the relationship between presence of each imaging finding and being a case or control. Secondary analyses explored those relationships based on the number of spinal levels with each MRI finding. Results: The odds for being a case compared with a control were higher in those with disc degeneration (Pfirrmann grade ≥ 3; OR = 3.21, 95% CI: 1.60‐6.44; P = 0.001) or those with a herniation (OR = 1.90, 95% CI: 0.96‐3.74; P - 0.065). We also found that the association became substantially stronger when either disc degeneration or herniation was present at two or more spinal levels (OR = 5.56, 95% CI: 1.97‐15.70; P = 0.001, and OR = 5.85, 95% CI: 1.54‐22.25; P = 0.009, respectively). The other investigated MRI findings were not associated with greater odds of being a case. Conclusions: Lumbar disc degeneration and herniation may be important contributors to disabling LBP in young adults. Further investigation of their potential prognostic and causal roles is indicated

Eculizumab prevents anti-ganglioside antibody-mediated neuropathy in a murine model

Anti-GQ1b ganglioside antibodies are the serological hallmark of the Miller Fisher syndrome (MFS) variant of the paralytic neuropathy, Guillain–Barré syndrome, and are believed to be the principal pathogenic mediators of the disease. In support of this, we previously showed in an in vitro mouse model of MFS that anti-GQ1b antibodies were able to bind and disrupt presynaptic motor nerve terminals at the neuromuscular junction (NMJ) as one of their target sites, thereby causing muscle paralysis. This injury only occurred through activation of complement, culminating in the formation and deposition of membrane attack complex (MAC, C5b-9) in nerve membranes. Since this step is crucial to the neuropathic process and an important convergence point for antibody and complement mediated membrane injury in general, it forms an attractive pharmacotherapeutic target. Here, we assessed the efficacy of the humanized monoclonal antibody eculizumab, which blocks the formation of human C5a and C5b-9, in preventing the immune-mediated motor neuropathy exemplified in this model. Eculizumab completely prevented electrophysiological and structural lesions at anti-GQ1b antibody pre-incubated NMJs in vitro when using normal human serum (NHS) as a complement source. In a novel in vivo mouse model of MFS generated through intraperitoneal injection of anti-GQ1b antibody and NHS, mice developed respiratory paralysis due to transmission block at diaphragm NMJs, resulting from anti-GQ1b antibody binding and complement activation. Intravenous injection of eculizumab effectively prevented respiratory paralysis and associated functional and morphological hallmarks of terminal motor neuropathy. We show that eculizumab protects against complement-mediated damage in murine MFS, providing the rationale for undertaking clinical trials in this disease and other antibody-mediated neuropathies in which complement activation is believed to be involved

The incidence and associations of malignancy in a large cohort of patients with biopsy-determined idiopathic inflammatory myositis

The South Australian (SA) myositis database has registered all patients with biopsy-proven inflammatory myositis in SA from 1980 to 2009. We determined the incidence and associations of malignancy in myositis by linking this database with the SA cancer registry. Standardized incidence ratios (SIR) for malignancy were determined using the total SA population over the same time period, stratified by age and gender. The SIR for cancer in the myositis population (n = 373) was 1.39, p = 0.047. There was a trend towards an increased SIR in dermatomyositis but no increased risk of malignancy in polymyositis or inclusion body myositis. Malignancies of the lung and prostate were the commonest and 28 % of malignancies occurred within one year of IIM diagnosis. The odds of developing cancer were significantly raised in the presence of a shawl sign, male gender, and in patients with overlap syndrome or rheumatoid arthritis whilst myalgia was a significant protective factor. HLA-A28 allele was overrepresented in patients with malignancy (11 vs 2 %, p = 0.006). Patients in SA with myositis are at modestly increased risk for malignancy. We report clinical and genetic risk factors allowing the identification of patients at greatest risk for malignancy.Vidya Limaye, Colin Luke, Graeme Tucker, Catherine Hill, Susan Lester, Peter Blumbergs, Peter Roberts-Thomso