Sara Vogrin

Clinical, EEG, and quantitative MRI differences in pediatric frontal and temporal lobe epilepsy

ObjectiveTo examine the clinical, electrographic, and quantitative MRI differences between frontal lobe (FLE) and mesial temporal lobe epilepsy (MTLE) in children. MethodsThe population included children who underwent video-EEG monitoring between 1995 and 2000 who were classified as either FLE (n = 39) or MTLE (n = 17) according to the criteria of the International League Against Epilepsy. Clinical, EEG, and quantitative MRI data (including frontal cortical volumes) were compared between the two syndromes and a control group (n = 42). ResultsIn FLE, seizures were significantly briefer, more frequent, and predominantly from sleep, and had differing motor characteristics. The rates of bilateral epileptiform interictal and ictal EEG abnormalities were significantly higher in FLE. A nonlesional MRI was significantly more common in FLE. Mean frontal cortical volume in FLE was significantly lower than MTLE and controls. Seizure freedom after surgery was lower in FLE. ConclusionsThe clinical syndrome of FLE is clearly distinct from MTLE. The etiology of this disorder is unknown in the majority of cases despite extensive investigation. Because of a lack of a clearly defined etiology and frequent nonlateralizing EEG changes, few of these children are considered optimal surgical candidates. The demonstration of bilateral frontal cortical volume loss and bilateral EEG abnormalities suggests that FLE is a bilateral disease in a high proportion of patients. The outcome in those patients who were deemed surgical candidates was significantly worse than the MTLE cases.

Amygdala volumetry in “imaging-negative” temporal lobe epilepsy

Objective: Although amygdala abnormalities are sometimes suspected in “imaging-negative” patients with video EEG confirmed unilateral focal epilepsy suggestive of temporal lobe epilepsy (TLE), amygdala asymmetry is difficult to assess visually. This study examined a group of “imaging-negative” TLE patients, estimating amygdala volumes, to determine whether cryptic amygdala lesions might be detected. Methods: Review of video EEG monitoring data yielded 11 patients with EEG lateralised TLE and normal structural imaging. Amygdala volumes were estimated in this group, in 77 patients with pathologically verified hippocampal sclerosis (HS), and in 77 controls. Results: Seven of 11 “imaging-negative” cases had both significant amygdala asymmetry and amygdala enlargement, concordant with seizure lateralisation. Although significant amygdala asymmetry occurred in 35 of 77 HS patients, it was never attributable to an abnormally large ipsilateral amygdala. Compared with patients with HS, patients with amygdala enlargement were less likely to have suffered secondarily generalised seizures (p<0.05), and had an older age of seizure onset (p<0.01). Conclusion: Abnormal amygdala enlargement is reported in seven cases of “imaging-negative” TLE. Such abnormalities are not observed in patients with HS. It is postulated that amygdala enlargement may be attributable to a developmental abnormality or low grade tumour. It is suggested that amygdala volumetry is indicated in the investigation and diagnosis of “imaging-negative” TLE.

Evaluation of SPECT in the assessment and treatment of intractable childhood epilepsy

Article abstract The authors retrospectively examined the role of SPECT in 65 children undergoing video-EEG telemetry. SPECT was concordant in most children whose lesions were already localized by MRI and epilepsy syndrome and provided localizing data in more than half not localized by these modalities. Ictal SPECT provided no additional prognostic benefit in patients undergoing epilepsy surgery (n = 23) who have a localized MRI lesion. In patients without lesions, however, ictal SPECT provides useful additional localization that may be used as a guide to intracranial implantation.

Clinical utility of distributed source modelling of interictal scalp EEG in focal epilepsy

OBJECTIVEnAssess the clinical utility of non-invasive distributed EEG source modelling in focal epilepsy.nnnMETHODSnInterictal epileptiform discharges were recorded from eight patients - benign focal epilepsy of childhood (BFEC), four; mesial temporal lobe epilepsy (MTLE), four. EEG source localization (ESL) applied 48 forward-inverse-subspace set-ups: forward - standardized, leadfield-interpolated boundary element methods (BEMs, BEMi), finite element method (FEMi); inverse - minimum norm (MNLS), L1 norm (L1), low resolution electromagnetic tomography (LORETA), standardized LORETA (sLORETA); subspace- whole volume (3D), cortex with rotating sources (CxR), cortex with fixed sources (CxN), cortex with fixed extended sources (patch). Current density reconstruction (CDR) maxima defined best-fit.nnnRESULTSnFrom 19,200 CDR parameter results and 2304 CDR maps, the dominant variables on best-fit were inverse model and subspace constraint. The most clinically meaningful and statistically robust results came with sLORETA-CxR/patch (lower Rolandic in BFEC, basal temporal lobe in MTLE). Computation time was inverse model dependent: sub-second (MNLS, sLORETA), seconds (L1), minutes (LORETA).nnnCONCLUSIONSnFrom the largest number of distributed ESL approaches compared in a clinical setting, an optimum modelling set-up for BFEC and MTLE incorporated sLORETA (inverse), CxR or patch (subspace), and either BEM or FEMi (forward). Computation is efficient and CDR results are reproducible.nnnSIGNIFICANCEnDistributed source modelling demonstrates clinical utility for the routine work-up of unilateral BFEC of the typical Rolandic variety, and unilateral MTLE secondary to hippocampal sclerosis.

Volumetric analysis of a specific language region – the planum temporale

Planum temporale volumes were determined for 42 control children (ages 4.2-15.7 years) using magnetic resonance imaging. The mean left planum temporale volume was 2729 mm3 (SD = 567) and the mean right planum temporale volume was 2758 mm3 (SD = 546). No significant hemispheric asymmetry was demonstrated. Analysis of co-variance (ANCOVA) showed that the absolute and proportional planum temporale volumes were not significantly associated with age or gender. We also demonstrated a reproducible method for planum temporale volume measurement by acquiring images in the coronal plane and then visualising the sagittal plane to improve accuracy for the posterior border.

Age, gender, and percentage of circulating osteoprogenitor (COP) cells: The COP Study

Abstract Circulating osteoprogenitor (COP) cells are blood‐borne cells which express a variety of osteoblastic markers and are able to form bone nodules in vivo. Whereas a high percentage of COP cells (%COP) is associated with vascular calcification, low %COP has been associated with disability and frailty. However, the reference range of %COP in age‐ and gender‐matching populations, and the age‐related changes in %COP remain unknown. A cross‐sectional study was undertaken in 144 healthy volunteers in Western Sydney (20–90 year‐old, 10 male and 10 female subjects per decade). %COP was quantified by flow cytometry. A high inter‐and intra‐rater reliability was found. In average, in this healthy population average of %COP was 0.42. There was no significant difference in %COP among the age groups. Similarly, no significant difference was found in %COP with gender, weight, height or BMI. In addition, we identified a normal reference range of %COP of 0.1–3.8%. In conclusion, in addition to the identification of steady levels of COP cells with age, we also identified a normal reference range of %COP, which could be used in future studies looking at musculoskeletal diseases in older populations. HighlightsPercentage of circulating osteoprogenitor (COP) cells is not affected by age.The normal reference range of %COP in the blood of a normal population is 0.1–3.8%.Age‐related changes in osteogenic differentiation of COP cells remain to be elucidated.

Comparative Effectiveness of Routine Invasive Coronary Angiography for Managing Unstable Angina

Acute coronary syndromes consist of ST-segment elevation myocardial infarction (MI), nonST-segment elevation MI, and unstable angina. The latter 2 conditions, collectively termed nonST-segment elevation acute coronary syndromes, are differentiated primarily by whether the patients troponin level is elevated (nonST-segment elevation MI) or not (unstable angina). Reported rates of unstable angina have declined with the introduction of high-sensitivity troponin testing, which identifies patients with nonST-segment elevation MI (1). However, patients with unstable angina still account for one quarter to one half of all those with acute coronary syndromes who present to the hospital (2, 3). In general, current guidelines recommend routine invasive coronary angiography for patients with nonST-segment elevation MI but not for those with unstable angina (46). European guidelines recommend a selective rather than routine invasive strategy for patients with a negative troponin test, no further chest pain, no evidence of heart failure, and a normal electrocardiogram; however, they do not give explicit advice regarding the timing of angiography in all patients with unstable angina and negative biomarkers (6). The U.S. guidelines advise against a routine, early, invasive strategy in patients (particularly women) with troponin-negative chest pain and a low likelihood of acute coronary syndromes (4). Five trials have included patients with unstable angina; the 3 largestthe FRISC II (Fragmin and Fast Revascularization During Instability in Coronary Artery Disease [1996 to 1998]) trial (n= 2456, 45% with negative biomarkers) (7), the TACTICS TIMI 18 (Treat Angina With Aggrastat and Determine Cost of Therapy With an Invasive or Conservative StrategyThrombolysis in Myocardial Infarction 18 [1997 to 1999]) trial (n= 2220, 46% with negative biomarkers) (8), and RITA-3 (Randomized Intervention Trial of Unstable Angina 3 [1997 to 2001]) (n= 1810, 25% with negative biomarkers) (9)were done in the era of dual-antiplatelet therapy and stenting. Several meta-analyses of these trials have been conducted (1012), 2 of which commented on patients with biomarker-negative unstable angina. Mehta and colleagues (12) found that among patients with negative results on troponin testing, the odds of death or acute MI within the average follow-up of 17.3 months were 11% lower in those who received invasive management; however, this finding was not statistically significant (odds ratio [OR], 0.89 [95% CI, 0.67 to 1.18]). Manfrini and colleagues (11), using a different meta-analytic approach, reported a statistically significant decrease in odds of 21% (OR, 0.79 [CI, 0.70 to 0.90]) for studies including patients with unstable angina. Of note, all included trials had high crossover rates, with nearly 50% of the control group having revascularization within 2 years, predominantly to manage refractory symptoms or recurrent acute coronary syndromes (13). To add to the evidence in this area, we sought to examine the effect of a routine invasive management strategy, beginning with invasive coronary angiography and followed by revascularization as indicated, on the cumulative risk for death at 12 months in patients with unstable angina by using clinically coded hospital discharge data from Victoria, Australia, between 2001 and 2011. Moreover, we used an analytic approach that accounted for additional angiograms, revascularizations, and acute coronary syndromes during this 12-month period. Methods Setting and Data Sources Victoria is Australias second largest state; during the study, its multiethnic population ranged from 4.8 million to 5.6 million. The states age and sex distribution is similar to that of the United States. Public hospitals are freely accessible to all permanent residents of Australia and are funded by state and federal governments through a prospective payment system with capped funding. Approximately 45% of Australians have private health insurance. In each hospital and emergency department in Victoria (131 public and 179 private hospitals), routinely collected data are coded by qualified coders (hospitals) or attending doctors (emergency departments) using the International Statistical Classification of Diseases and Related Health Problems, 10th Revision, Australian Modification (ICD-10AM), and the Australian Classification of Health Interventions, 7th edition. A statewide independent audit program maintains hospital coding quality, and a series of internal logic checks combined with manual reviews of randomly selected case groups ensures high-quality data linkage. Linked death data released for this project were rounded to the nearest month of death after hospital discharge. Study Population The sampling frame included all patients admitted to the hospital from 1 July 2001 to 30 June 2011 who had a discharge diagnosis of unstable angina (ICD-10AM 4-digit code I200 as a primary diagnosis) but no history of acute coronary syndromes, invasive coronary angiography, percutaneous coronary intervention, or coronary artery bypass grafting in the year before this index hospitalization. The University of Melbourne ethics committee approved the study (approval number 1033080). Statistical Analysis Data are presented as frequencies and percentages for categorical variables and as means and SDs for continuous variables. To quantify the treatment effect of angiography (henceforth referred to as the treatment effect) on the cumulative incidence of death at 12 months in patients with unstable angina, we obtained 3 treatment effect estimates: the average treatment effect, the average treatment effect in treated patients, and the average treatment effect in untreated patients. The average treatment effect provides a whole-population perspective, as if the entire sample of observed patients with unstable angina were moved from the untreated to the treated group (14). The average treatment effect in treated patients demonstrates the effect of angiography in the sample who originally were chosen for treatment; this subsample may be younger, with fewer comorbid conditions. The average effect of treatment in untreated patients estimates the effect of angiography if patients who did not receive this treatment had received it. This group likely is older and frailer, with more comorbid conditions. To account for the observational nature of the data, a propensity score was developed from which weights were calculated for each treatment effect. These weights were used in separate discrete-time survival models to estimate each treatment effect (14, 15). To determine the association between angiography and mortality given the time variability of further angiograms, revascularizations, and acute coronary episodes, these events were included as time-varying covariates (16). The model also included further adjustments for age, sex, and comorbidity burden based on Charlson comorbidity score. Sensitivity analysis was conducted to determine whether the presence of an unmeasured confounder (such as receipt of optimal medical therapy) altered the observed treatment effect. The prevalence in the exposed versus unexposed group (the prevalence gap) and the effect size of the putative unmeasured confounder used in the sensitivity analysis were based on the basis of previous studies. The sensitivity analysis was performed by using the user-written Stata (StataCorp) command episensrri (17). All analyses were performed by using Stata 13.1 (18). Further details on the statistical methods are presented in the Appendix. Role of the Funding Source Grants from the National Health and Medical Research Council, the Victorian Department of Health and Human Services, and the BUPA Health Foundation funded the study; none of the funders had any role in study design, conduct, or reporting. Results Our study included 33901 patients with a primary diagnosis of unstable angina (Figure 1); their baseline characteristics are presented in Table 1. Figure 1. Flowchart of sample selection. Table 1. Baseline Characteristics of Overall and Propensity ScoreWeighted Samples* In the overall sample, 43% of patients received angiography at the index admission and an additional 9% received it within 12 months (mostly within 3 months of the index admission). The proportion of patients receiving revascularization at index admission was similar to that of patients who received it later: 41.1% versus 42.5% (Table 2). Of patients who had 2 or more angiograms during the 12-month period, nearly 100% had revascularization after the second angiogram. At the index hospitalization, percutaneous coronary intervention was performed twice as often as coronary artery bypass grafting; this ratio decreased to 1.7:1 when angiography and revascularization were delayed. Table 2. Receipt of ICA and Revascularization in Overall Sample* During the 12 months after the index admission, approximately 3.1% of patients who received angiography and 5.2% of those who did not (P < 0.001) had at least 1 readmission for acute MI (Table 3). Readmission was more than 3 times likelier during the first month after the index admission than in the subsequent 11 months. Table 3. Hospital Readmissions After Index Hospitalization for Unstable Angina in Overall Sample, Stratified by the Receipt of ICA at Index Admission* Characteristics of weighted samples used to evaluate the average treatment effect represent those of all patients with unstable angina, characteristics of those used to evaluate the effect in treated patients represent those of patients who received angiography, and characteristics of those used to evaluate the effect in untreated patients represent those of patients who did not receive angiography. Patients who received angiography were younger, mostly male, and from rural areas; a larger proportion arrived by ambulance and used private health insurance. The comorbidity burden and cardiac sequelae were fairly similar, whereas car

Effect of 6 months of hybrid closed-loop insulin delivery in adults with type 1 diabetes: a randomised controlled trial protocol

Introduction Manual determination of insulin dosing largely fails to optimise glucose control in type 1 diabetes. Automated insulin delivery via closed-loop systems has improved glucose control in short-term studies. The objective of the present study is to determine the effectiveness of 6 months’ closed-loop compared with manually determined insulin dosing on time-in-target glucose range in adults with type 1 diabetes. Methods and analysis This open-label, seven-centre, randomised controlled parallel group clinical trial will compare home-based hybrid closed-loop versus standard diabetes therapy in Australia. Adults aged ≥25 years with type 1 diabetes using intensive insulin therapy (via multiple daily injections or insulin pump, total enrolment target n=120) will undertake a run-in period including diabetes and carbohydrate-counting education, clinical optimisation and baseline data collection. Participants will then be randomised 1:1 either to 26 weeks of MiniMed 670G hybrid closed-loop system therapy (Medtronic, Northridge, CA, USA) or continuation of their current diabetes therapy. The hybrid closed-loop system delivers insulin automatically to address basal requirements and correct to target glucose level, while bolus doses for meals require user initiation and carbohydrate estimation. Analysis will be intention to treat, with the primary outcome time in continuous glucose monitoring (CGM) target range (3.9–10.0u2009mmol/L) during the final 3 weeks of intervention. Secondary outcomes include: other CGM parameters, HbA1c, severe hypoglycaemia, psychosocial well-being, sleep, cognition, electrocardiography, costs, quality of life, biomarkers of vascular health and hybrid closed-loop system performance. Semistructured interviews will assess the expectations and experiences of a subgroup of hybrid closed-loop users. Ethics and dissemination The study has Human Research Ethics Committee approval. The study will be conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice. Results will be disseminated at scientific conferences and via peer-reviewed publications. Trial registration number ACTRN12617000520336; Pre-results.

Can neutral dietary cation-anion difference (DCAD) decrease occurrence of clinical periparturient hypocalcaemia in dairy cattle?

BACKGROUNDnAdjusting the dietary cation-anion difference (DCAD) is one of the most efficient ways to stimulate calcium homeostasis in periparturient dairy cattle. However, adjusting DCAD to the recommended negative values (-100 to -150 mEq/kg) is associated with decreased food intake and metabolic acidosis. The critical conditions of the animals at peripartum (i.e. drastic hormonal changes, decreased appetite and negative energy balance) can be detrimental to the health, productivity and welfare of the animals if combined with decreased feed intake caused by unpalatable acidogenic salts.nnnMETHODSnIn a cross-sectional study, we analysed the ration of eight small to large dairy herds with intensive husbandry systems, including 6949 dry cows. Sodium, potassium, chlorine and sulfur concentrations in the feed were determined and DCAD was calculated. The DCAD of the ration of the farms ranged from -33.5 to +24.7u2009mEq/kg. Parturient paresis (PP, or milk fever) prevalence was investigated and correlated to DCAD values.nnnRESULTSnClinical PP occurrence in the dairies of this investigation on average declined by 87% (ranging from a 97% decline to 5% increase). This indicates that adjusting DCAD at neutral values (0 ± 30u2009mEq/kg range) may both lower the PP prevalence and increase ration palatability by lowering acidogenic salts in the ration.nnnCONCLUSIONSnFurther research is recommended to investigate the effects of neutral DCAD on subclinical hypocalcaemia and food intake of the cattle.

Fractures in indigenous compared to non-indigenous populations: A systematic review of rates and aetiology

Background Compared to non-indigenous populations, indigenous populations experience disproportionately greater morbidity, and a reduced life expectancy; however, conflicting data exist regarding whether a higher risk of fracture is experienced by either population. We systematically evaluate evidence for whether differences in fracture rates at any skeletal site exist between indigenous and non-indigenous populations of any age, and to identify potential risk factors that might explain these differences. Methods On 31 August 2016 we conducted a comprehensive computer-aided search of peer-reviewed literature without date limits. We searched PubMed, OVID, MEDLINE, CINAHL, EMBASE, and reference lists of relevant publications. The protocol for this systematic review is registered in PROSPERO, the International Prospective Register of systematic reviews (CRD42016043215). Using the World Health Organization reference population as standard, hip fracture incidence rates were re-standardized for comparability between countries. Results Our search yielded 3227 articles; 283 potentially eligible articles were cross-referenced against predetermined criteria, leaving 27 articles for final inclusion. Differences in hip fracture rates appeared as continent-specific, with lower rates observed for indigenous persons in all countries except for Canada and Australia where the opposite was observed. Indigenous persons consistently had higher rates of trauma-related fractures; the highest were observed in Australia where craniofacial fracture rates were 22-times greater for indigenous compared to non-indigenous women. After adjustment for socio-demographic and clinical risk factors, approximately a three-fold greater risk of osteoporotic fracture and five-fold greater risk of craniofacial fractures was observed for indigenous compared to non-indigenous persons; diabetes, substance abuse, comorbidity, lower income, locality, and fracture history were independently associated with an increased risk of fracture. Conclusions The observed paucity of data and suggestion of continent-specific differences indicate an urgent need for further research regarding indigenous status and fracture epidemiology and aetiology. Our findings also have implications for communities, governments and healthcare professionals to enhance the prevention of trauma-related fractures in indigenous persons, and an increased focus on modifiable lifestyle behaviours to prevent osteoporotic fractures in all populations.