Thoracolumbar injury classification and severity score: a new paradigm for the treatment of thoracolumbar spine trauma

BACKGROUND: Contemporary understanding of the biomechanics, natural history, and methods of treating thoracolumbar spine injuries continues to evolve. Current classification schemes of these injuries, however, can be either too simplified or overly complex for clinical use. METHODS: The Spine Trauma Group was given a survey to identify similarities in treatment algorithms for common thoracolumbar injuries, as well as to identify characteristics of injury that played a key role in the decision-making process. RESULTS: Based on the survey, the Spine Trauma Group has developed a classification system and an injury severity score (thoracolumbar injury classification and severity score, or TLICS), which may facilitate communication between physicians and serve as a guideline for treating these injuries. The classification system is based on the morphology of the injury, integrity of the posterior ligamentous complex, and neurological status of the patient. Points are assigned for each category, and the final total points suggest a possible treatment option. CONCLUSIONS: The usefulness of this new system will have to be proven in future studies investigating inter- and intraobserver reliability, as well as long-term outcome studies for operative and nonoperative treatment methods

Simultaneous Analysis of All SNPs in Genome-Wide and Re-Sequencing Association Studies

Testing one SNP at a time does not fully realise the potential of genome-wide association studies to identify multiple causal variants, which is a plausible scenario for many complex diseases. We show that simultaneous analysis of the entire set of SNPs from a genome-wide study to identify the subset that best predicts disease outcome is now feasible, thanks to developments in stochastic search methods. We used a Bayesian-inspired penalised maximum likelihood approach in which every SNP can be considered for additive, dominant, and recessive contributions to disease risk. Posterior mode estimates were obtained for regression coefficients that were each assigned a prior with a sharp mode at zero. A non-zero coefficient estimate was interpreted as corresponding to a significant SNP. We investigated two prior distributions and show that the normal-exponential-gamma prior leads to improved SNP selection in comparison with single-SNP tests. We also derived an explicit approximation for type-I error that avoids the need to use permutation procedures. As well as genome-wide analyses, our method is well-suited to fine mapping with very dense SNP sets obtained from re-sequencing and/or imputation. It can accommodate quantitative as well as case-control phenotypes, covariate adjustment, and can be extended to search for interactions. Here, we demonstrate the power and empirical type-I error of our approach using simulated case-control data sets of up to 500 K SNPs, a real genome-wide data set of 300 K SNPs, and a sequence-based dataset, each of which can be analysed in a few hours on a desktop workstation

Missed opportunities for tobacco use screening and brief cessation advice in South African primary health care: a cross-sectional study

BACKGROUND: Primary health care (PHC) settings offer opportunities for tobacco use screening and brief cessation advice, but data on such activities in South Africa are limited. The aim of this study was to determine the extent to which participants were screened for and advised against tobacco use during consultations. METHODS: This cross-sectional study involved 500 participants, 18 years and older, attended by doctors or PHC nurses. Using an exit-interview questionnaire, information was obtained on participants' tobacco use status, reason(s) for seeking medical care, whether participants had been screened for and advised about their tobacco use and patients' level of comfort about being asked about and advised to quit tobacco use. Main outcome measures included patients' self-reports on having been screened and advised about tobacco use during their current clinic visit and/or any other visit within the last year. Data analysis included the use of chi-square statistics, t-tests and multiple logistic regression analysis. RESULTS: Of the 500 participants, 14.9% were current smokers and 12.1% were smokeless tobacco users. Only 12.9% of the participants were screened for tobacco use during their current visit, indicating the vast majority were not screened. Among the 134 tobacco users, 11.9% reported being advised against tobacco use during the current visit and 35.1% during any other visit within the last year. Of the participants not screened, 88% indicated they would be 'very comfortable' with being screened. A pregnancy-related clinic visit was the single most significant predictor for being screened during the current clinic visit (OR = 4.59; 95%CI = 2.13-9.88). CONCLUSION: Opportunities for tobacco use screening and brief cessation advice were largely missed by clinicians. Incorporating tobacco use status into the clinical vital signs as is done for pregnant patients during antenatal care visits in South Africa has the potential to improve tobacco use screening rates and subsequent cessation

The Childhood Acute Illness and Nutrition (CHAIN) network nested case-cohort study protocol: a multi-omics approach to understanding mortality among children in sub-Saharan Africa and South Asia

Introduction: Many acutely ill children in low- and middle-income settings have a high risk of mortality both during and after hospitalisation despite guideline-based care. Understanding the biological mechanisms underpinning mortality may suggest optimal pathways to target for interventions to further reduce mortality. The Childhood Acute Illness and Nutrition (CHAIN) Network ( www.chainnnetwork.org) Nested Case-Cohort Study (CNCC) aims to investigate biological mechanisms leading to inpatient and post-discharge mortality through an integrated multi-omic approach. Methods and analysis; The CNCC comprises a subset of participants from the CHAIN cohort (1278/3101 hospitalised participants, including 350 children who died and 658 survivors, and 270/1140 well community children of similar age and household location) from nine sites in six countries across sub-Saharan Africa and South Asia. Systemic proteome, metabolome, lipidome, lipopolysaccharides, haemoglobin variants, toxins, pathogens, intestinal microbiome and biomarkers of enteropathy will be determined. Computational systems biology analysis will include machine learning and multivariate predictive modelling with stacked generalization approaches accounting for the different characteristics of each biological modality. This systems approach is anticipated to yield mechanistic insights, show interactions and behaviours of the components of biological entities, and help develop interventions to reduce mortality among acutely ill children. Ethics and dissemination. The CHAIN Network cohort and CNCC was approved by institutional review boards of all partner sites. Results will be published in open access, peer reviewed scientific journals and presented to academic and policy stakeholders. Data will be made publicly available, including uploading to recognised omics databases. Trial registration NCT03208725

Sustained antiproliferative mechanisms by RB24, a targeted precursor of multiple inhibitors of epidermal growth factor receptor and a DNA alkylating agent in the A431 epidermal carcinoma of the vulva cell line

Recently, with the purpose of enhancing the potency of epidermal growth factor receptor (EGFR)-based therapies, we designed a novel strategy termed ‘Cascade-release targeting’ that seeks to develop molecules capable of degrading to multiple tyrosine kinase (TK) inhibitors and highly reactive electrophiles, in a stepwise fashion. Here we report on the first prototype of this model, RB24, a masked methyltriazene, that in addition to being an inhibitor on its own was designed to degrade to RB14, ZR08, RB10+a DNA alkylating methyldiazonium species. The cascade degradation of RB24 requires the generation of two reactive electrophiles: (a) an iminium ion and (b) a methyldiazonium ion. Thus, we surmise that these species could alkylate the active site of EGFR, thereby irreversibly blocking its action and that DNA damage could be induced by the methyldiazonium. Using the EGFR-overexpressing human epidermoid carcinoma of the vulva cell line, A431, we demonstrate herein that (a) RB24 and its derived species (e.g. RB14, ZR08) irreversibly inhibit EGFR autophosphorylation, (b) RB24 induced significant levels of DNA strand breaks, (c) sustained inhibition of EGFR by RB24 was associated with blockade of MAPK activation and c-fos gene expression, (d) RB24 induced irreversible cell growth inhibition with a 100-fold greater potency than Temodal™, a clinical methyltriazene. The pronounced growth inhibitory potency of RB24 was attributed to its ability to simultaneously damage DNA and irreversibly block EGFR TK activity