Does specificity of electrodiagnostic test referrals predict test outcome in children?

INTRODUCTION/AIMS: Electrodiagnostic testing (EDX) is important in evaluation of pediatric neuromuscular disease. Non-specific referrals have emerged as a leading reason for EDX in recent years. We examine whether referral-specificity is predictive of test outcomes in children. METHODS: EDX referrals and outcomes were audited over a 7-year period from 2013 to 2020 at CHI-Crumlin. Pre-test details were coded and compared to EDX outcomes using multinomial logistic regression. RESULTS: EDX studies were performed in 702 children (median age 10.2 years). In 36% of patients, EDX-referrals did not specify any pre-test diagnosis. Mononeuropathy (24%) and polyneuropathy (15%) were the leading pre-specified diagnoses as well as the most common test outcomes. Neurology and orthopedics/plastic surgery contributed the majority of referrals. Metabolic medicine and hematology/oncology were most likely to pre-specify a working diagnosis and were the specialties with both the highest proportion of abnormal outcomes and referral accuracy. EDX abnormality was present in 42% of patients and was predicted by specificity of referral and the absence of pain as a leading symptom. The accuracy of specified pre-test diagnoses was highest for suspected anterior horn cell disorders (67%). Accuracy of referrals, as well as abnormal test outcomes, were negatively predicted by the presence of pain as a leading symptom. DISCUSSION: EDX is informative in children but the likelihood of abnormal test-outcomes is diminished when a pre-specified working diagnosis is lacking or when the primary reason for referral is pain.

Measuring the effects of pre-test probability on out-patient first EEG investigation in children - A guide to evidence-based EEG triage in a pandemic.

INTRODUCTION: The yield of epileptiform EEG abnormalities is lower in unselected Paediatric populations than in prospective studies of incident seizures or prevalent epilepsy studies. At a time of limited capacity, it is important to match available EEG resources to children who are most likely to benefit. In this study we evaluated a prospective triage tool for estimating the likelihood of epileptiform abnormality in children's first out-patient EEG. METHODS: We prospectively triaged 1865 out-patient referrals to the largest Paediatric EEG laboratory in Ireland. Based on a structured algorithm, we dichotomized first EEG referrals into priority and non-priority groups and assigned one of 5 sub-levels based on anticipated EEG yield. EEGs were reported by a single Consultant in Clinical Neurophysiology. RESULTS: Triage designated 757 (41 %) EEG referrals as non-priority. Priority exceeded non-priority referrals for all age groups except children between 18 months and 3.5 years. EEGs showed a two-fold higher incidence of interictal epileptiform abnormalities for priority referrals (36 % vs 18 %, p < 0.001). Rates of interictal epileptiform abnormality correlated with the 5 sub-levels of triage (p < 0.01). Epileptiform yield was highest (39 %) for children over 5 years vs 17 % for those under 5 years (p < 0.00001); these rates increased to 49 % and 20 % respectively for priority referrals. CONCLUSION: Structured pre-test triage of EEG referrals can identify children who have the greatest likelihood of epileptiform abnormality. In a mixed population of Paediatric referrals, the epileptiform yield of first time EEG is 49 % for children over 5 years who are referred with an appropriate EEG indication. This is subject to much variability with epileptiform yields as low as 13 % in younger children with non-priority referrals. The use of a structured triage algorithm can help to optimise utility of EEG in situations of limited laboratory capacity.

RHAPSODY, Biomarkers and Novel Clinical Trial design in type 2 diabetes (T2D) and prediabetes.

Developing a novel therapeutic product for the treatment of type 2 diabetes (T2D) is a long, resource-intensive process. Novel biomarkers could potentially aid clinical trial design by shortening clinical trials or enabling better prediction of at-risk populations and/or disease progression. Novel clinical trial designs could lead to reduced costs of development and less burden to patients, due to shorter trial duration, and/or less burdensome assessments.

An investigation of causal relationships between prediabetes and vascular complications.

Prediabetes is a state of glycaemic dysregulation below the diagnostic threshold of type 2 diabetes (T2D). Globally, ~352 million people have prediabetes, of which 35-50% develop full-blown diabetes within five years. T2D and its complications are costly to treat, causing considerable morbidity and early mortality. Whether prediabetes is causally related to diabetes complications is unclear. Here we report a causal inference analysis investigating the effects of prediabetes in coronary artery disease, stroke and chronic kidney disease, complemented by a systematic review of relevant observational studies. Although the observational studies suggest that prediabetes is broadly associated with diabetes complications, the causal inference analysis revealed that prediabetes is only causally related with coronary artery disease, with no evidence of causal effects on other diabetes complications. In conclusion, prediabetes likely causes coronary artery disease and its prevention is likely to be most effective if initiated prior to the onset of diabetes.

Brain 5-HT Deficiency Prevents Antidepressant-Like Effects of High-Fat-Diet and Blocks High-Fat-Diet-Induced GSK3ß Phosphorylation in the Hippocampus.

Obesity is associated with an increased risk of depression and anxiety disorders, but the nature of the relationship(s) between obesity and mental illness remains highly controversial. Some argue that depression and anxiety lead to increased consumption of "comfort foods," the intake of which reduces negative affect and promotes obesity. In contrast, others have theorized that negative affect results from chronic excessive consumption of highly palatable foods. The brain serotonin (5-HT) system has long been implicated in both the development and treatment of mental illness. Preclinical studies have shown that low brain 5-HT exacerbates depression- and anxiety-like behaviors induced by stress and blocks reductions in depression-like behavior induced by antidepressants, but the effects of brain 5-HT deficiency on responses to high-fat diet (HFD) have not been explored. The current work used genetically modified mice to evaluate the effects of low 5-HT on behavioral and molecular alterations induced by chronic exposure to HFD. Our results reveal that HFD decreases depression-like behavior and increases some anxiety-like behaviors in wild-type (WT) mice. However, genetic brain 5-HT deficiency blocks HFD-induced reductions in forced swim immobility and prevents HFD-induced increases in hippocampal GSK3ß phosphorylation despite having no significant effects on HFD-induced changes in body weight or anxiety-like behavior. Together, our results suggest that brain 5-HT deficiency significantly impacts a subset of behavioral and molecular responses to HFD, a finding that could help explain the complex relationships between obesity and mental illness.

Deregulation of RNA polymerase III transcription in cervical epithelium in response to high-risk human papillomavirus.

RNA polymerase (pol) III transcription is a major determinant of biosynthetic capacity, providing essential products such as tRNA and 5S rRNA. It is controlled directly by the tumour suppressors RB and p53. High-risk types of human papillomavirus (HPV), such as HPV16, express the oncoproteins E6 and E7 that can inactivate p53 and RB, respectively. Accordingly, both E6 and E7 stimulate pol III transcription in cultured cells. HPV16-positive cervical biopsies express elevated levels of tRNA and 5S rRNA when compared to biopsies that test negative for HPV or are infected with the lower risk HPV11. Integration of viral DNA into the host cell genome stimulates expression of E6 and E7 and correlates with induction of tRNA and 5S rRNA. Expression of mRNA encoding the pol III-specific transcription factor Brf1 also correlates with the presence of integrated HPV16. Brf1 levels are limiting for tRNA and 5S rRNA synthesis in cervical cells. Furthermore, pol III-transcribed genes that do not use Brf1 are not induced in HPV16-positive biopsies. Three complementary mechanisms may therefore allow high-risk HPV to stimulate production of tRNA and 5S rRNA: E6-mediated removal of p53; E7-mediated neutralization of RB; and induction of Brf1. The resultant increase in biosynthetic capacity may contribute to deregulated cell growth.

Direct regulation of RNA polymerase III transcription by RB, p53 and c-Myc.

The synthesis of tRNA and 5S rRNA by RNA polymerase (pol) III is cell cycle regulated in higher organisms. Overexpression of pol III products is a general feature of transformed cells. These observations may be explained by the fact that a pol III-specific transcription factor, TFIIIB, is strongly regulated by the tumor suppressors RB and p53, as well as the proto-oncogene product c-Myc. RB and p53 repress TFIIIB, but this restraint can be lost in tumors through a variety of mechanisms. In contrast, c-Myc binds and activates TFIIIB, causing potent induction of pol III transcription. Using chromatin immunoprecipitation and RNA interference, we show that c-Myc interacts with tRNA and 5S rRNA genes in transformed cervical cells, stimulating their expression. Availability of pol III products may be an important determinant of a cell's capacity to grow. The ability to regulate pol III output may therefore be integral to the growth control functions of RB, p53 and c-Myc.