Validation of two multiplex platforms to quantify circulating markers of inflammation and endothelial injury in severe infection

Biomarkers can prognosticate outcome and enable risk-stratification. In severe infection, focusing on multiple markers reflecting pathophysiological mechanisms of organ injury could enhance management and pathway-directed therapeutics. Limited data exist on the performance of multiplex biomarker platforms. Our goal was to compare endothelial and immune activation biomarkers in severe pediatric infections using two multiplex platforms. Frozen plasma from 410 children presenting to the Jinja Regional Hospital in Uganda with suspected infection was used to measure biomarkers of endothelial (Angiopoietin-2, sFlt-1, sVCAM-1, sICAM-1) and immune (IL-6, IP-10, sTNFR-1, CHI3L1) activation. Two multiplex platforms (Luminex®, EllaTM) based on monoclonal antibody sandwich immunoassays using biotin-streptavidin conjugate chemistry were selected with reagents from R&D Systems. The two platforms differed in ease and time of completion, number of samples per assay, and dynamic concentration range. Intra-assay variability assessed using a coefficient of variation (CV%) was 2.2-3.4 for Luminex® and 1.2-2.9 for EllaTM. Correlations for biomarker concentrations within dynamic range of both platforms were best for IL-6 (ρ = 0.96, p<0.0001), IP-10 (ρ = 0.94, p<0.0001) and sFlt-1 (ρ = 0.94, p<0.0001). Agreement between concentrations obtained by both methods assessed by the Bland-Altman test varied, with best agreement for CHI3L1. Our data suggest that biomarkers of endothelial and immune activation can be readily measured with multiplex platforms. Luminex® and EllaTM produced reliable results with excellent CV% values. The EllaTM platform was more automated and completed in 75 minutes, potentially compatible with near-patient use. Trends in concentrations obtained by these methods were highly correlated, although absolute values varied, suggesting caution is required when comparing data from different multiplex platforms

Paediatric reference values for total psoas muscle area

Background: Sarcopenia, the unintentional loss of skeletal muscle mass, is associated with poor outcomes in adult patient populations. In adults, sarcopenia is often ascertained by cross-sectional imaging of the psoas muscle area (PMA). Although children with chronic medical illnesses may be at increased risk for muscle loss because of nutritional deficiencies, physical deconditioning, endocrine anomalies, and systemic inflammation, consistent quantitative definitions for sarcopenia in children are lacking. We aimed to generate paediatric reference values for PMA at two intervertebral lumbar levels, L3–4 and L4–5. Methods: In this cross-sectional study, we analysed abdominal computed tomography scans of consecutive children presenting to the emergency department. Participants were children 1–16 years who required abdominal cross-sectional imaging after paediatric trauma between January 1, 2005 and December 31, 2015 in a large Canadian quaternary care centre. Children with a documented chronic medical illness or an acute spinal trauma at presentation were excluded. Total PMA (tPMA) at levels L3–4 and L4–5 were measured in square millimetres (mm2) as the sum of left and right PMA. Age-specific and sex-specific tPMA percentile curves were modelled using quantile regression. Results: Computed tomography images from 779 children were included. Values of tPMA at L4–5 were significantly larger than at L3–4 at all ages, but their correlation was high for both girls (r = 0.95) and boys (r = 0.98). Amongst girls, tPMA 50th percentile values ranged from 365 to 2336 mm2 at L3–4 and from 447 to 2704 mm2 for L4–5. Amongst boys, 50th percentile values for tPMA ranged between 394 and 3050 mm2 at L3–4 and from 498 to 3513 mm2 at L4–5. Intraclass correlation coefficients were excellent at L3–4 (0.97, 95% CI 0.94 to 0.981) and L4–5 (0.99, 95% CI 0.986 to 0.995). Weight and tPMA were correlated, stratified by sex for boys (L3–4 r = 0.90; L4–5 r = 0.90) and for girls (L3–4 r = 0.87; L4–5 r = 0.87). An online application was subsequently developed to easily calculate age-specific and sex-specific z-scores and percentiles. Conclusions: We provide novel paediatric age-specific and sex-specific growth curves for tPMA at intervertebral L3–4 and L4–5 levels for children between the ages of 1-16 years. Together with an online tool (https://ahrc-apps.shinyapps.io/sarcopenia/), these tPMA curves should serve as a reference enabling earlier identification and targeted intervention of sarcopenia in children with chronic medical conditions

Estimating Non-homogeneous Intensity Matrices in Continuous Time Multi-state Markov Models

Multi-State-Markov (MSM) models can be used to characterize the behaviour of categorical outcomes measured repeatedly over time. Kalbfleisch and Lawless (1985) and Gentleman et al. (1994) examine the MSM model under the assumption of time-homogeneous transition intensities. In the context of non-homogeneous intensities, current methods use piecewise constant approximations which are less than ideal. We propose a local likelihood method, based on Tibshirani and Hastie (1987) and Loader (1996), to estimate the transition intensities as continuous functions of time. In particular the local EM algorithm suggested by Betensky et al. (1999) is employed to estimate the in-homogeneous intensities in the presence of missing data. A simulation comparing the piecewise constant method with the local EM method is examined using two different sets of underlying intensities. In addition, model assessment tools such as bandwidth selection, grid size selection, and bootstrapped percentile intervals are examined. Lastly, the method is applied to an HIV data set to examine the intensities with regard to depression scores. Although computationally intensive, it appears that this method is viable for estimating non-homogeneous intensities and outperforms existing methods.Ph

Lateral damage and point of impact in intersection crashes: Implications for injury

Crashes in intersections may result in damage to vehicles and injury to occupants in many different ways. One vehicle hitting the side of another (T-type) is the classic side impact; however, we have argued in the past that other crash configurations (e.g., L-type) may subject occupants to similar risks because both vehicles may sustain lateral damage. To test this assumption, we examined crash data from police reports of 4032 intersection right-angle crashes (IRC), collected by the Insurance Corporation of British Columbia for 2002. We compared the risk and types of injury in target and bullet vehicles for T-type crashes, L-type crashes by front and rear fender involvement and for all other IRC crashes. There were 787 T-type crashes (impact into either side of target vehicle), compared to 798 L-type crashes (impact into front fender) and 350 L-type (impact into rear fender). Overall, injury risk was 23.5%. Proportions injured were very similar for occupants of target and bullet vehicles in T-type crashes (OR = 0.996; 95% ci 0.80 to 1.24.); for L-type crashes, the proportions were 23.2% for front and/or front fender involvement and 15.0% for crashes involving the rear fender of one vehicle and the front or front fender of the other (OR =1.71; 95% ci 1.40 - 2.10). Apart from rear fender crashes, proportions injured were very similar (P > 0.05). Other factors, notably weather, lighting, land use and vehicle damage differed significantly by crash type, and were strongly associated with injury risk. Since rear-fender crashes are a small proportion of IRC crashes, this suggests that it is not necessary to subdivide crashes by configuration in IRC crashes.Cet article traite des accidents d’automobile au niveau des intersections routières et susceptible de causer diverses blessures aux occupants ou divers dommages aux véhicules. L’impact classique est le fait d’un véhicule de frapper le côté d’un autre véhicule (Type T). Cependant, les auteurs ont démontré par le passé qu’il existe d’autres formes d’accident, tel, Type L) susceptibles de causer aux occupants des risques similaires car les deux véhicules peuvent subir des dommages latéraux. Pour tester cette hypothèse, ils ont examiné les données d’accident de constats établis par la police, soit 4 032 accidents aux angles droits des intersections (IRC), compilées en 2002 par Insurance Corporation of British Columbia (ICBC). Ils ont aussi comparé le risque et les types de blessures lorsque les véhicules sont à la fois la cible et le projectile dans les accidents dits Type T, les accidents frontaux ou de pare-chocs arrière dits Type L et dans les autres accidents aux angles droits des intersections (IRC). Nous avons dénombré 787 accidents dits Type T (impact latéraux de véhicules), comparativement à 798 accidents dits Type L au niveau des pare-choc avant et 350 accidents dits Type L au niveau des pare-choc arrière. Globalement le risque de blessure corporelle se situait à 23,5 %. Les proportions de blessure étaient similaires en ce qui concerne les occupants de véhicules cibles ou de véhicules projectiles dans les accidents dits Type T (OR = 0,996; 95 % ci 0,80 à 1,24) ; pour les accidents dits Type L, les proportions de blessure s’établissaient à 23,2 % pour les accidents frontaux ou impliquant les pare-chocs avant et à 15 % pour les accidents impliquant les pare-chocs arrière d’un véhicule et autres accidents frontaux ou impliquant les parechocs avant (OR = 1,71; 95 % ci 1,40 à 2,10). Sauf en ce qui concerne les accidents impliquant les pare-chocs arrières, on en arrive aux mêmes proportions de blessures (P > 0,05). D’autres facteurs, principalement les conditions du temps, les éclairs, le terrain et les dommages matériels diffèrent de façon significative selon le type d’accident et sont fortement reliés au risque de blessures corporelles. Vu que les accidents impliquant les pare-chocs arrière ne sont qu’une faible proportion des accidents aux angles droits des intersections (IRC), ceci semble indiquer qu’il n’est pas nécessaire de subdiviser la forme des accidents lorsqu’ils se produisent aux angles droits des intersections (IRC)

Association between noncow milk beverage consumption and childhood height

Background: Cow milk consumption in childhood has been associated with increased height, which is an important measure of children's growth and development. Many parents are choosing noncow milk beverages such as soy and almond milk because of perceived health benefits. However, noncow milk contains less protein and fat than cow milk and may not have the same effect on height.Objective: We sought to determine whether there is an association between noncow milk consumption and lower height in childhood and assess whether cow milk consumption mediates the relation between noncow milk consumption and height.Design: This was a cross-sectional study of 5034 healthy Canadian children aged 24-72 mo enrolled in the Applied Research Group for Kids cohort. The primary exposure was the volume of noncow milk consumption (number of 250-mL cups per day). The primary outcome was height, which was measured as height-for-age z score. Multivariable linear regression was used to determine the association between noncow milk consumption and height. A mediation analysis was conducted to explore whether cow milk consumption mediated the association between noncow milk consumption and height.Results: There was a dose-dependent association between higher noncow milk consumption and lower height (P < 0.0001). For each daily cup of noncow milk consumed, children were 0.4 cm (95% CI: 0.2, 0.8 cm) shorter. In the mediation analysis, lower cow milk consumption only partially mediated the association between noncow milk consumption and lower height. The height difference for a child aged 3 y consuming 3 cups noncow milk/d relative to 3 cups cow milk/d was 1.5 cm (95% CI: 0.8, 2.0 cm).Conclusions: Noncow milk consumption was associated with lower childhood height. Future research is needed to understand the causal relations between noncow milk consumption and height.Supported by the Canadian Institutes of Health Research Institute of Human Development, Child and Youth Health, and the Institute of Nutrition, Metabolism, and Diabetes and St. Michael’s Hospital Foundation

Designing and evaluating a web-based self-management site for patients with type 2 diabetes - systematic website development and study protocol

Abstract Background Given that patients provide the majority of their own diabetes care, patient self-management training has increasingly become recognized as an important strategy with which to improve quality of care. However, participation in self management programs is low. In addition, the efficacy of current behavioural interventions wanes over time, reducing the impact of self-management interventions on patient health. Web-based interventions have the potential to bridge the gaps in diabetes care and self-management. Methods Our objective is to improve self-efficacy, quality of life, self-care, blood pressure, cholesterol and glycemic control and promote exercise in people with type 2 diabetes through the rigorous development and use of a web-based patient self-management intervention. This study consists of five phases: (1) intervention development; (2) feasibility testing; (3) usability testing; (4) intervention refinement; and (5) intervention evaluation using mixed methods. We will employ evidence-based strategies and tools, using a theoretical framework of self-efficacy, then elicit user feedback through focus groups and individual user testing sessions. Using iterative redesign the intervention will be refined. Once finalized, the impact of the website on patient self-efficacy, quality of life, self-care, HbA1c, LDL-cholesterol, blood pressure and weight will be assessed through a non-randomized observational cohort study using repeated measures modeling and individual interviews. Discussion Increasing use of the World Wide Web by consumers for health information and ongoing revolutions in social media are strong indicators that users are primed to welcome a new era of technology in health care. However, their full potential is hindered by limited knowledge regarding their effectiveness, poor usability, and high attrition rates. Our development and research agenda aims to address these limitations by improving usability, identifying characteristics associated with website use and attrition, and developing strategies to sustain patient use in order to maximize clinical outcomes

Designing and evaluating a web-based self-management site for patients with type 2 diabetes - systematic website development and study protocol

Abstract Background Given that patients provide the majority of their own diabetes care, patient self-management training has increasingly become recognized as an important strategy with which to improve quality of care. However, participation in self management programs is low. In addition, the efficacy of current behavioural interventions wanes over time, reducing the impact of self-management interventions on patient health. Web-based interventions have the potential to bridge the gaps in diabetes care and self-management. Methods Our objective is to improve self-efficacy, quality of life, self-care, blood pressure, cholesterol and glycemic control and promote exercise in people with type 2 diabetes through the rigorous development and use of a web-based patient self-management intervention. This study consists of five phases: (1) intervention development; (2) feasibility testing; (3) usability testing; (4) intervention refinement; and (5) intervention evaluation using mixed methods. We will employ evidence-based strategies and tools, using a theoretical framework of self-efficacy, then elicit user feedback through focus groups and individual user testing sessions. Using iterative redesign the intervention will be refined. Once finalized, the impact of the website on patient self-efficacy, quality of life, self-care, HbA1c, LDL-cholesterol, blood pressure and weight will be assessed through a non-randomized observational cohort study using repeated measures modeling and individual interviews. Discussion Increasing use of the World Wide Web by consumers for health information and ongoing revolutions in social media are strong indicators that users are primed to welcome a new era of technology in health care. However, their full potential is hindered by limited knowledge regarding their effectiveness, poor usability, and high attrition rates. Our development and research agenda aims to address these limitations by improving usability, identifying characteristics associated with website use and attrition, and developing strategies to sustain patient use in order to maximize clinical outcomes.</p

Misclassification of child body mass index from cut-points defined by rounded percentiles instead of Z-scores

Abstract Objective To evaluate the misclassification resulting from the use of body mass index (BMI) cut-points defined by rounded percentiles instead of Z-scores in early childhood. Using data from the TARGet Kids primary care network we conducted a cross-sectional study among 5836 children  1.0, > 2.0, > 3.0 are recommended to define wasted, at risk of overweight, overweight and obese. However, rounded percentiles of the 3rd, 85th, 97th, and 99.9th are commonly used. Misclassification was calculated comparing the frequency distributions for BMI categories defined by rounded percentiles and Z-score cut-points. Results Using rounded percentiles, the proportion of children who were wasted, at risk of overweight, overweight, and obese was 4.2, 12.5, 4.3 and 0.8%, whereas the distribution using Z-scores was: 3.6, 13.8, 3.4 and 1.0%, respectively. Overall, 117 (2%) children were misclassified when using percentiles instead of Z-scores; however, 13% (33/245) of children who were wasted and 14% (8/57) of children who were obese were misclassified. Misclassification of child growth results from the use of cut-points defined by rounded percentiles instead of Z-scores and limits comparability between studies. Trial registration Clinicaltrials.gov NCT01869530 June 5, 201

The Guyana Diabetes and Foot Care Project: Improved Diabetic Foot Evaluation Reduces Amputation Rates by Two-Thirds in a Lower Middle Income Country

Background. Type 2 diabetes is the fourth leading cause of death in Guyana, South America. A complex, interprofessional, quality improvement intervention to improve foot and diabetes care was rolled out in two phases. Methods & Findings. Phase 1: Establishment of an Interprofessional Diabetic Foot Center (DFC) of Excellence to improve foot care and reduce diabetes-related amputations at the national referral hospital. Phase 2: Regionalization to cover 90% of the Guyanese population and expansion to include improved management of diabetes and hypertension. Fourteen key opinion leaders were educated and 340 health care professionals from 97 facilities trained. Eight centers for the evaluation and treatment of foot ulcers were established and 7567 people with diabetes evaluated. 3452 participants had foot screening and 48% were deemed high risk; 10% of these had undocumented foot ulcers. There was a 68% reduction in rate of major amputations (P<0.0001); below knee amputations were decreased by 80%, while above knee amputations were unchanged. An increased association of diabetes with women (F/M = 2.09) and increased risk of major amputation in men [odds ratio 2.16 (95% CI 1.83, 2.56)] were documented. Conclusions. This intervention improved foot care with reduction in major amputations sustained over 5 years