Esophageal cancer presenting with atrial fibrillation: A case report

<p>Abstract</p> <p>Introduction</p> <p>Atrial fibrillation was previously reported in patients with esophageal cancer as a complication of total esophagectomy or photodynamic therapy. Here, we propose that atrial fibrillation may also be caused by external compression of the left atrium by esophageal cancer.</p> <p>Case presentation</p> <p>We present a 58-year-old man who developed atrial fibrillation with rapid ventricular rate in the emergency room while being evaluated for dysphagia and weight loss. Atrial fibrillation lasted less than 12 hours and did not recur. Echocardiogram did not reveal any structural heart disease. A 10-cm, ulcerated mid-esophageal mass was seen during esophagogastroscopy. Microscopic examination showed squamous cell carcinoma. Computed tomography of the chest revealed esophageal thickening compressing the left atrium.</p> <p>Conclusion</p> <p>External compression of the left atrium was previously reported to provoke atrial fibrillation. Similarly, esophageal cancer may precipitate atrial fibrillation by mechanical compression of the left atrium or pulmonary veins, triggering ectopic beats in susceptible patients.</p

A bacterial artificial chromosome mouse model of amyotrophic lateral sclerosis manifests ‘space cadet syndrome’ on two FVB backgrounds

C9orf72-related amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD) has proven difficult to model in mice. Liu et al. (2016) reported a bacterial artificial chromosome (BAC) transgenic mouse displaying behavioural, motor and pathological abnormalities. This was followed by multiple laboratories independently refuting and confirming phenotypes. A proposed explanation centred on the use of different FVB background lines (from The Jackson Laboratory and Janvier Labs). We studied C9orf72 BAC mice on both backgrounds and found significantly elevated levels of dipeptide repeat proteins, but no evidence of a transgene-associated phenotype. We observed seizures and a gradual decline in functional performance in transgenic and non-transgenic mice, irrespective of genetic background. The phenotype was in keeping with the so-called ‘space cadet syndrome’. Our findings indicate that the differences previously reported are not due to C9orf72 status and highlight the importance of using genetic backgrounds that do not confound interpretation of neurodegenerative phenotypes

Novel strategies to assess cytokine release mediated by chimeric antigen receptor T cells based on the adverse outcome pathway concept

The success of cellular immunotherapies such as chimeric antigen receptor (CAR) T cell therapy has led to their implementation as a revolutionary treatment option for cancer patients. However, the safe translation of such novel immunotherapies, from non-clinical assessment to first-in-human studies is still hampered by the lack of suitable in vitro and in vivo models recapitulating the complexity of the human immune system. Additionally, using cells derived from human healthy volunteers in such test systems may not adequately reflect the altered state of the patient's immune system thus potentially underestimating the risk of life-threatening conditions, such as cytokine release syndrome (CRS) following CAR T cell therapy. The IMI2/EU project imSAVAR (immune safety avatar: non-clinical mimicking of the immune system effects of immunomodulatory therapies) aims at creating a platform for novel tools and models for enhanced non-clinical prediction of possible adverse events associated with immunomodulatory therapies. This platform shall in the future guide early non-clinical safety assessment of novel immune therapeutics thereby also reducing the costs of their development. Therefore, we review current opportunities and challenges associated with non-clinical in vitro and in vivo models for the safety assessment of CAR T cell therapy ranging from organ-on-chip models up to advanced biomarker screening.</p

Simultaneous ALS and SCA2 associated with an intermediate-length ATXN2 CAG-repeat expansion

Spinocerebellar ataxia type 2 (SCA2) and amyotrophic lateral sclerosis (ALS) share a common molecular basis: both are associated with CAG-repeat expansion of ATXN2 and TDP-43-positive neuronal cytoplasmic inclusions. To date, the two disorders are viewed as clinically distinct with ALS resulting from 30-33 CAG-repeats and SCA2 from >34 CAG-repeats. We describe a 67-year old with a 32 CAG-repeat expansion of ATXN2 who presented with simultaneous symptoms of ALS and SCA2. Our case demonstrates that the clinical dichotomy between SCA2 and ATXN2-ALS is false. We suggest instead that CAG-repeat expansion length determines the timing of SCA2 clinical symptoms relative to onset of ALS; consistent with this age of onset of SCA2 but not ATXN2-ALS, is dependent upon expansion length. Review of the literature and our local cohort provides evidence for occurrence of ALS in late stage SCA2, which may be under-recognised by clinicians who think of the two diseases as distinct

Integrated Measure of PRogram Element SuStainability in Childcare Settings (IMPRESS-C): development and psychometric evaluation of a measure of sustainability determinants in the early childhood education and care setting

Background There is a need for valid and reliable measures of determinants of sustainability of public health interventions in early childhood education and care (ECEC) settings. This study aimed to develop and evaluate the psychometric and pragmatic properties of such a measure – the Integrated Measure of PRogram Element SuStainability in Childcare Settings (IMPRESS-C). Methods We undertook a two-phase process guided by the COnsensus-based Standards for the selection of health status Measurement INstruments checklist (COSMIN) and Psychometric and Pragmatic Evidence Rating Scale (PAPERS). Phase 1 involved measure development; i.e., determining items and scales through an iterative process and assessment of face and content validity. Phase 2 involved the evaluation of psychometric and pragmatic properties. The 29-item measure completed by service executives (directors and nominated supervisors) was embedded in a larger survey from a national sample of Australian ECEC services assessing their implementation of nutrition and physical activity programs. Structural validity, concurrent validity, known groups validity, internal consistency, floor and ceiling effects, norms, and pragmatic qualities of the measure were assessed according to the PAPERS criteria. Results The final measure contained 26 items, with respondents reporting how strongly they agreed or disagreed on a five-point Likert scale. Phase 1 assessments confirmed the relevance, and face and content validity of the scale. In Phase 2, we obtained 482 completed surveys, of which 84% (n = 405) completed the entire measure across 405 ECEC settings (one executive per service). Three of the four fit indices for the confirmatory factor analysis met the pre-specified criteria (SRMR = 0.056, CFI = 0.993, RMSEA = 0.067) indicating ‘good’ structural validity. The IMPRESS-C illustrated: ‘good’ internal consistency, with Cronbach’s alpha values from 0.53 to 0.92; ‘emerging’ concurrent validity; ‘poor’ known groups validity; ‘good’ norms; and ‘good’ overall pragmatic qualities (cost, readability, length, and assessor burden). Conclusions The IMPRESS-C possesses strong psychometric and pragmatic qualities for assessing service executive-level perceptions of determinants influencing sustainment of public health interventions within ECEC settings. To achieve a full range of perspectives in this setting, future work should be directed to also develop and test measures of sustainability determinants at the implementer level (e.g., among individual educators and staff)

Optimised machine learning for time-to-event prediction in healthcare applied to timing of gastrostomy in ALS:a multi-centre, retrospective model development and validation study

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is invariably fatal but there are large variations in the rate of progression. The lack of predictability can make it difficult to plan clinical interventions. This includes the requirement for gastrostomy where early or late placement can adversely impact quality of life and survival.METHODS: We designed a model to predict the timing of gastrostomy requirement in ALS as indicated by 5% weight loss from diagnosis. We considered &gt;5000 different prediction model configurations including spline models and a set of deep learning (DL) models designed for time-to-event prediction. The optimal prediction model was chosen via a Bayesian framework to avoid overfitting. Model covariates were measurements routinely collected at diagnosis; a separate longitudinal model also incorporated weight at six months. We employed a training dataset of 3000 patients from Europe, and two external validation cohorts spanning distinct populations and clinical contexts (United States, n = 299; and Sweden, n = 215). Missing data was imputed using a random forest model.FINDINGS: The optimal model configuration was a logistic hazard DL model. The optimal model achieved a median absolute error (MAE) between predicted and measured time of 3.7 months, with AUROC 0.75 for gastrostomy requirement at 12 months. To increase accuracy we updated predictions for those who had not received gastrostomy at six months after diagnosis: here MAE was 2.6 months (AUROC 0.86). Combining both models achieved MAE of 1.2 months for the modal group of patients. Prediction performance is stable across both validation cohorts. Missing data was imputed without degrading model performance.INTERPRETATION: To enter routine clinical practice a prospective study will be required, but we have demonstrated stable performance across multiple populations and clinical contexts suggesting that our prediction model can be used to guide individualised gastrostomy decision making for patients with ALS.FUNDING: Research Ireland (RI) and Biogen have supported the PRECISION ALS programme.</p

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency–Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research