Multi-modal Biomarkers Quantify Recovery in Autoimmune Autonomic Ganglionopathy

Objective: To evaluate patients with ganglionic acetylcholine receptor antibody (gAChR‐Ab) positive autoimmune autonomic ganglionopathy using a multi‐modal testing protocol to characterise their full clinical phenotype and explore biomarkers to quantify immunotherapy response. Methods: Cohort study of thirteen individuals (seven female; 21–69 years) with autonomic failure and gAChR‐Ab>100pM identified between 2005–2019. From 2018, all patients were longitudinally assessed with cardiovascular, pupillary, urinary, sudomotor, lacrimal and salivary testing, and COMPASS‐31 autonomic symptom questionnaires. The orthostatic intolerance ratio was calculated by dividing change in systolic blood pressure over time tolerated on head‐up tilt. Eleven patients received immunotherapy. Results: At first assessment, all 13 patients had cardiovascular and pupillary impairments, 7/8 had post‐ganglionic sudomotor dysfunction, 9/11 had urinary retention and xeropthalmia, and 6/8 had xerostomia. After immunotherapy, there were significant improvements in orthostatic intolerance ratio (33.3[17.8–61.3] to 5.2[1.4–8.2], P = .007), heart rate response to deep breathing (1.5[0.0–3.3] to 4.5[3.0–6.3], P = .02), pupillary constriction to light (12.0[5.5–18.0] to 19.0[10.6–23.8]%, P = .02), saliva production (0.01[0.01–0.05] to 0.08[0.02–0.20]g/min, P = .03) and COMPASS‐31 scores (52 to 17, P = .03). Orthostatic intolerance ratio correlated with autonomic symptoms at baseline (r = 0.841, P = .01) and following immunotherapy (r = 0.889, P = .02). Immunofluorescence analyses of skin samples from a patient 32 years after disease onset showed loss of nerve fibres supplying the dermal autonomic adnexa and epidermis, with clear improvements following immunotherapy. Interpretation: Patients with autoimmune autonomic ganglionopathy demonstrated objective evidence of widespread sympathetic and parasympathetic autonomic failure, with significant improvements after immunotherapy. Quantitative autonomic biomarkers should be used to define initial deficits, guide therapeutic decisions, and document treatment response

Improving statistical inference on pathogen densities estimated by quantitative molecular methods: malaria gametocytaemia as a case study

BACKGROUND: Quantitative molecular methods (QMMs) such as quantitative real-time polymerase chain reaction (q-PCR), reverse-transcriptase PCR (qRT-PCR) and quantitative nucleic acid sequence-based amplification (QT-NASBA) are increasingly used to estimate pathogen density in a variety of clinical and epidemiological contexts. These methods are often classified as semi-quantitative, yet estimates of reliability or sensitivity are seldom reported. Here, a statistical framework is developed for assessing the reliability (uncertainty) of pathogen densities estimated using QMMs and the associated diagnostic sensitivity. The method is illustrated with quantification of Plasmodium falciparum gametocytaemia by QT-NASBA. RESULTS: The reliability of pathogen (e.g. gametocyte) densities, and the accompanying diagnostic sensitivity, estimated by two contrasting statistical calibration techniques, are compared; a traditional method and a mixed model Bayesian approach. The latter accounts for statistical dependence of QMM assays run under identical laboratory protocols and permits structural modelling of experimental measurements, allowing precision to vary with pathogen density. Traditional calibration cannot account for inter-assay variability arising from imperfect QMMs and generates estimates of pathogen density that have poor reliability, are variable among assays and inaccurately reflect diagnostic sensitivity. The Bayesian mixed model approach assimilates information from replica QMM assays, improving reliability and inter-assay homogeneity, providing an accurate appraisal of quantitative and diagnostic performance. CONCLUSIONS: Bayesian mixed model statistical calibration supersedes traditional techniques in the context of QMM-derived estimates of pathogen density, offering the potential to improve substantially the depth and quality of clinical and epidemiological inference for a wide variety of pathogens

Mortality within 30 days of chemotherapy: a clinical governance benchmarking issue for oncology patients

No national benchmark figures exist for early mortality due to chemotherapy unlike for surgical interventions. Deaths within 30 days of chemotherapy during a 6-month period were identified from the Royal Marsden Hospital electronic patient records. Treatment intention – curative or palliative, cause of death and number of previous treatments – were documented. Between April 2005 and September 2005, 1976 patients received chemotherapy with 161 deaths within 30 days of chemotherapy (8.1%). Of these, 124 deaths (77.0%) were due to disease progression. Of the other 37 deaths, 12 (7.5%) were related to chemotherapy, six each for solid tumours and haematological malignancies, of which seven (4.3%) were due to neutropenic sepsis. For the remaining 25 deaths (15.5%) there was insufficient information. There were more deaths after third and subsequent lines of therapy than with first and secondlines of therapy. Only 12 of the 161 deaths occurred in patients who were receiving potentially curative chemotherapy to give a mortality rate in breast and gastrointestinal malignancy of 0.5 and 1.5%, respectively. It is possible to audit mortality within 30 days of chemotherapy and this should become a benchmark for standard practice nationally. Most deaths were due to disease progression in the palliative setting. We practice this form of audit each quarter and feed back to the treating teams so that deaths are discussed and practice monitored

Morphological characteristics of motor neurons do not determine their relative susceptibility to degeneration in a mouse model of severe spinal muscular atrophy

Spinal muscular atrophy (SMA) is a leading genetic cause of infant mortality, resulting primarily from the degeneration and loss of lower motor neurons. Studies using mouse models of SMA have revealed widespread heterogeneity in the susceptibility of individual motor neurons to neurodegeneration, but the underlying reasons remain unclear. Data from related motor neuron diseases, such as amyotrophic lateral sclerosis (ALS), suggest that morphological properties of motor neurons may regulate susceptibility: in ALS larger motor units innervating fast-twitch muscles degenerate first. We therefore set out to determine whether intrinsic morphological characteristics of motor neurons influenced their relative vulnerability to SMA. Motor neuron vulnerability was mapped across 10 muscle groups in SMA mice. Neither the position of the muscle in the body, nor the fibre type of the muscle innervated, influenced susceptibility. Morphological properties of vulnerable and disease-resistant motor neurons were then determined from single motor units reconstructed in Thy.1-YFP-H mice. None of the parameters we investigated in healthy young adult mice - including motor unit size, motor unit arbor length, branching patterns, motor endplate size, developmental pruning and numbers of terminal Schwann cells at neuromuscular junctions - correlated with vulnerability. We conclude that morphological characteristics of motor neurons are not a major determinant of disease-susceptibility in SMA, in stark contrast to related forms of motor neuron disease such as ALS. This suggests that subtle molecular differences between motor neurons, or extrinsic factors arising from other cell types, are more likely to determine relative susceptibility in SMA

Challenges in developing methods for quantifying the effects of weather and climate on water-associated diseases: A systematic review

Infectious diseases attributable to unsafe water supply, sanitation and hygiene (e.g. Cholera, Leptospirosis, Giardiasis) remain an important cause of morbidity and mortality, especially in low-income countries. Climate and weather factors are known to affect the transmission and distribution of infectious diseases and statistical and mathematical modelling are continuously developing to investigate the impact of weather and climate on water-associated diseases. There have been little critical analyses of the methodological approaches. Our objective is to review and summarize statistical and modelling methods used to investigate the effects of weather and climate on infectious diseases associated with water, in order to identify limitations and knowledge gaps in developing of new methods. We conducted a systematic review of English-language papers published from 2000 to 2015. Search terms included concepts related to water-associated diseases, weather and climate, statistical, epidemiological and modelling methods. We found 102 full text papers that met our criteria and were included in the analysis. The most commonly used methods were grouped in two clusters: process-based models (PBM) and time series and spatial epidemiology (TS-SE). In general, PBM methods were employed when the bio-physical mechanism of the pathogen under study was relatively well known (e.g. Vibrio cholerae); TS-SE tended to be used when the specific environmental mechanisms were unclear (e.g. Campylobacter). Important data and methodological challenges emerged, with implications for surveillance and control of water-associated infections. The most common limitations comprised: non-inclusion of key factors (e.g. biological mechanism, demographic heterogeneity, human behavior), reporting bias, poor data quality, and collinearity in exposures. Furthermore, the methods often did not distinguish among the multiple sources of time-lags (e.g. patient physiology, reporting bias, healthcare access) between environmental drivers/exposures and disease detection. Key areas of future research include: disentangling the complex effects of weather/climate on each exposure-health outcome pathway (e.g. person-to-person vs environment-to-person), and linking weather data to individual cases longitudinally

End-stage kidney disease due to haemolytic uraemic syndrome - outcomes in 241 consecutive ANZDATA Registry cases

Extent: 11p.Background: The aim of this study was to investigate the characteristics and outcomes of patients receiving renal replacement therapy for end-stage kidney disease (ESKD) secondary to haemolytic uraemic syndrome (HUS). Methods: The study included all patients with ESKD who commenced renal replacement therapy in Australia and New Zealand between 15/5/1963 and 31/12/2010, using data from the ANZDATA Registry. HUS ESKD patients were compared with matched controls with an alternative primary renal disease using propensity scores based on age, gender and treatment era. Results: Of the 58422 patients included in the study, 241 (0.4%) had ESKD secondary to HUS. HUS ESKD was independently associated with younger age, female gender and European race. Compared with matched controls, HUS ESKD was not associated with mortality on renal replacement therapy (adjusted hazard ratio [HR] 1.14, 95% CI 0.87-1.50, p = 0.34) or dialysis (HR 1.34, 95% CI 0.93-1.93, p = 0.12), but did independently predict recovery of renal function (HR 54.01, 95% CI 1.45-11.1, p = 0.008). 130 (54%) HUS patients received 166 renal allografts. Overall renal allograft survival rates were significantly lower for patients with HUS ESKD at 1 year (73% vs 91%), 5 years (62% vs 85%) and 10 years (49% vs 73%). HUS ESKD was an independent predictor of renal allograft failure (HR 2.59, 95% CI 1.70-3.95, p < 0.001). Sixteen (12%) HUS patients experienced failure of 22 renal allografts due to recurrent HUS. HUS ESKD was not independently associated with the risk of death following renal transplantation (HR 0.92, 95% CI 0.35-2.44, p = 0.87). Conclusions: HUS is an uncommon cause of ESKD, which is associated with comparable patient survival on dialysis, an increased probability of renal function recovery, comparable patient survival post-renal transplant and a heightened risk of renal transplant graft failure compared with matched ESKD controls.Wen Tang, Janaki Mohandas, Stephen P McDonald, Carmel M Hawley, Sunil V Badve, Neil Boudville, Fiona G Brown, Philip A Clayton, Kathryn J Wiggins, Kym M Bannister, Scott B Campbell and David W Johnso