'Sink or swim': An evaluation of the clinical characteristics of individuals with high bone mass

Summary High bone mineral density on routine dual energy X-ray absorptiometry (DXA) may indicate an underlying skeletal dysplasia. Two hundred fifty-eight individuals with unexplained high bone mass (HBM), 236 relatives (41% with HBM) and 58 spouses were studied. Cases could not float, had mandible enlargement, extra bone, broad frames, larger shoe sizes and increased body mass index (BMI). HBM cases may harbour an underlying genetic disorder. Introduction High bone mineral density is a sporadic incidental finding on routine DXA scanning of apparently asymptomatic individuals. Such individuals may have an underlying skeletal dysplasia, as seen in LRP5 mutations. We aimed to characterize unexplained HBM and determine the potential for an underlying skeletal dysplasia. Methods Two hundred fifty-eight individuals with unexplained HBM (defined as L1 Z-score ≥ +3.2 plus total hip Z-score ≥ +1.2, or total hip Z-score ≥ +3.2) were recruited from 15 UK centres, by screening 335,115 DXA scans. Unexplained HBM affected 0.181% of DXA scans. Next 236 relatives were recruited of whom 94 (41%) had HBM (defined as L1 Z-score + total hip Z-score ≥ +3.2). Fifty-eight spouses were also recruited together with the unaffected relatives as controls. Phenotypes of cases and controls, obtained from clinical assessment, were compared using random-effects linear and logistic regression models, clustered by family, adjusted for confounders, including age and sex. Results Individuals with unexplained HBM had an excess of sinking when swimming (7.11 [3.65, 13.84], p < 0.001; adjusted odds ratio with 95% confidence interval shown), mandible enlargement (4.16 [2.34, 7.39], p < 0.001), extra bone at tendon/ligament insertions (2.07 [1.13, 3.78], p = 0.018) and broad frame (3.55 [2.12, 5.95], p < 0.001). HBM cases also had a larger shoe size (mean difference 0.4 [0.1, 0.7] UK sizes, p = 0.009) and increased BMI (mean difference 2.2 [1.3, 3.1] kg/m 2, p < 0.001). Conclusion Individuals with unexplained HBM have an excess of clinical characteristics associated with skeletal dysplasia and their relatives are commonly affected, suggesting many may harbour an underlying genetic disorder affecting bone mass.

Adjusting body cell mass for size in women of differing nutritional status

Background: Body cell mass (BCM) may be estimated in clinical practice to assess functional nutritional status, eg, in patients with anorexia nervosa. Interpretation of the data, especially in younger patients who are still growing, requires appropriate adjustment for size. Previous investigations of this general issue have addressed chemical rather than functional components of body composition and have not considered patients at the extremes of nutritional status, in whom the ability to make longitudinal comparisons is of particular importance. Objective: Our objective was to determine the power by which height should be raised to adjust BCM for height in women of differing nutritional status. Design: BCM was estimated by K-40 counting in 58 healthy women, 33 healthy female adolescents, and 75 female adolescents with anorexia nervosa. The relation between BCM and height was explored in each group by using log-log regression analysis. Results: The powers by which height should be raised to adjust BCM,A,ere 1.73. 1.73, and 2.07 in the women, healthy female adolescents, and anorexic female adolescents, respectively. A simplified version of the index, BCM/height(2), was appropriate for all 3 categories and was negligibly correlated with height. Conclusions: In normal-weight women, the relation between height and BCM is consistent with that reported previously between height and fat-free mass. Although the consistency of the relation between BCM and fat-free mass decreases with increasing weight loss, the relation between height and BCM is not significantly different between normal-weight and underweight women. The index BCM/height(2) is easy to calculate and applicable to both healthy and underweight women. This information may be helpful in interpreting body-composition data in clinical practice.

Comparison of the Cosmed K4 b2 and the Deltatrac II™ metabolic cart in measuring resting energy expenditure in adults

Background and Aims: The objective of the study was to compare data obtained from the Cosmed K4 b2 and the Deltatrac II™ metabolic cart for the purpose of determining the validity of the Cosmed K4 b2 in measuring resting energy expenditure. Methods: Nine adult subjects (four male, five female) were measured. Resting energy expenditure was measured in consecutive sessions using the Cosmed K4 b2, the Deltatrac II™ metabolic cart separately and the Cosmed K4 b2 and Deltatrac II™ metabolic cart simultaneously, performed in random order. Resting energy expenditure (REE) data from both devices were then compared with values obtained from predictive equations. Results: Bland and Altman analysis revealed a mean bias for the four variables, REE, respiratory quotient (RQ), VCO2, VO2 between data obtained from Cosmed K4 b2 and Deltatrac II™ metabolic cart of 268 ± 702 kcal/day, -0.0±0.2, 26.4±118.2 and 51.6±126.5 ml/min, respectively. Corresponding limits of agreement for the same four variables were all large. Also, Bland and Altman analysis revealed a larger mean bias between predicted REE and measured REE using Cosmed K4 b2 data (-194±603 kcal/day) than using Deltatrac™ metabolic cart data (73±197 kcal/day). Conclusions: Variability between the two devices was very high and a degree of measurement error was detected. Data from the Cosmed K4 b2 provided variable results on comparison with predicted values, thus, would seem an invalid device for measuring adults. © 2002 Elsevier Science Ltd. All rights reserved.

Predictors of clinical improvement in children with recurrent abdominal pain

Forty-three children with recurrent abdominal pain who had received treatment from a paediatric gastroenterology clinic were reassessed 6 and 12 months after initial presentation. Measures of children's pain included a pain diary (PD) which measured pain intensity, a parent observation record (POR) which assessed pain behaviour and a structured interview to assess the degree to which pain interferes with the child's activities. Pretreatment measures of the child's history of pain, coping strategies in dealing with pain, and their mother's caregiving strategies were examined as predictors of two indices of clinical improvement: the extent of change in pain on the child's pain diary from pre-test to 6 months follow-up, and the degree of interference to the child's activities. All children had shown significant improvement in the level of pain at follow up, with 74.4% being pain free at 12 month follow-up on the PD and 83.7% being pain free on the POR. The amount of change they showed varied, with some showing residual impairment even though they were significantly improved. Regression analyses showed that children with greatest reductions on the child's pain diary at the 6 month follow-up were those with a stress-related mode of onset, whose mothers used more adaptive caregiving strategies, and who received cognitive behavioural family intervention. There was also a non significant trend for younger children to fare better. These data suggest the importance of early diagnosis and routinely assessing parental caregiving behaviour and beliefs about the origins of pain in planning treatment for children with RAP.

Benefits of blended learning for the first year medical imaging students in preparation for clinical placement

Although there is a plethora of definitions of blended learning, the underlying distinguishing feature is the combination of traditional content delivery and the utilisation of technology. Within Medical Imaging undergraduate education there is evidence of advantages and increased student engagement when utilising a blended learning approach. Although the embedding of technology has been proven to be a useful teaching tool, “Educators should tailor their teaching media to learner’s needs rather than assume that web based learning is intrinsically superior”. This study aims to determine which clinical learning tools are perceived to be the most useful to the student in preparing them for placements.

Validation of processing maps for 304L stainless steel using hot forging, rolling and extrusion

The development of a microstructure in 304L stainless steel during industrial hot-forming operations, including press forging (mean strain rate of 0.15 s(-1)), rolling/extrusion (2-5 s(-1)), and hammer forging (100 s(-1)) at different temperatures in the range 600-1200 degrees C, was studied with a view to validating the predictions of the processing map. The results have shown that excellent correlation exists between the regimes exhibited by the map and the product microstructures. 304L stainless steel exhibits instability bands when hammer forged at temperatures below 1100 degrees C, rolled/extruded below 1000 degrees C, or press forged below 800 degrees C. All of these conditions must be avoided in mechanical processing of the material. On the other hand, ideally, the material may be rolled, extruded, or press forged at 1200 degrees C to obtain a defect-free microstructure.

targetTB: A target identification pipeline for Mycobacterium tuberculosis through an interactome, reactome and genome-scale structural analysis

Background: Tuberculosis still remains one of the largest killer infectious diseases, warranting the identification of newer targets and drugs. Identification and validation of appropriate targets for designing drugs are critical steps in drug discovery, which are at present major bottle-necks. A majority of drugs in current clinical use for many diseases have been designed without the knowledge of the targets, perhaps because standard methodologies to identify such targets in a high-throughput fashion do not really exist. With different kinds of 'omics' data that are now available, computational approaches can be powerful means of obtaining short-lists of possible targets for further experimental validation. Results: We report a comprehensive in silico target identification pipeline, targetTB, for Mycobacterium tuberculosis. The pipeline incorporates a network analysis of the protein-protein interactome, a flux balance analysis of the reactome, experimentally derived phenotype essentiality data, sequence analyses and a structural assessment of targetability, using novel algorithms recently developed by us. Using flux balance analysis and network analysis, proteins critical for survival of M. tuberculosis are first identified, followed by comparative genomics with the host, finally incorporating a novel structural analysis of the binding sites to assess the feasibility of a protein as a target. Further analyses include correlation with expression data and non-similarity to gut flora proteins as well as 'anti-targets' in the host, leading to the identification of 451 high-confidence targets. Through phylogenetic profiling against 228 pathogen genomes, shortlisted targets have been further explored to identify broad-spectrum antibiotic targets, while also identifying those specific to tuberculosis. Targets that address mycobacterial persistence and drug resistance mechanisms are also analysed. Conclusion: The pipeline developed provides rational schema for drug target identification that are likely to have high rates of success, which is expected to save enormous amounts of money, resources and time in the drug discovery process. A thorough comparison with previously suggested targets in the literature demonstrates the usefulness of the integrated approach used in our study, highlighting the importance of systems-level analyses in particular. The method has the potential to be used as a general strategy for target identification and validation and hence significantly impact most drug discovery programmes.

Malnutrition in children with chronic liver disease accepted for liver transplantation : clinical profile and effect on outcome

The nutritional profiles of 37 children (aged 0.5-14.0 years) with chronic liver disease at the time of acceptance for orthotopic liver transplantation (OLTP) have been evaluated using clinical, biochemical and body composition methods. Nutritional progress while waiting for a donor has been related to outcome, whether transplanted or not. At the time of acceptance, most children were underweight (mean standard deviation (s.d.) weight = -1.4 ± 0.2) and stunted (mean s.d. height = - 2.2 ± 0.4), had low serum albumin (27/35) and had reduced body fat and depleted body cell mass (measured by total body potassium - mean % expected for age = 58 ± 5%, n = 15). Mean ad libitum nutrient intake was 63 ± 5% of recommended daily intake (RDI). Those who died while waiting (n = 8) had significantly lower mean initial s.d. weight compared with those transplanted. The overall actuarial 1 year survival of those who were transplanted (mean waiting time = 75 days) was 81% but those who were initially well nourished (s.d. weight >-1.0) had an actuarial 1 year survival of 100%. There were no significant differences in actuarial survival in relationship to age, type of transplant (whole liver or segmental), liver biochemistry or the presence or absence of ascites. Of the total group accepted for OLTP, whether transplanted or not, the overall 1 year survival for those who were relatively well nourished was 88% and for those undernourished (initial s.d. weight <-1.0) was 38% (P<0.003). Declining nutritional status during the waiting period also adversely affected outcome. We conclude that malnutrition and/or declining nutritional status is a major factor adversely affecting survival in children awaiting OLTP. In transplant units where waiting time is greater than 40 days, earlier referral, prioritization of cases and the use of adult donor livers may reduce this risk and efforts to maintain or improve nutritional status deserve further study.

Cardiovascular diseases and vulnerable plaques: data, modeling, predictions and clinical applications PREFACE

Introduction Two symposia on “cardiovascular diseases and vulnerable plaques” Cardiovascular disease (CVD) is the leading cause of death worldwide. Huge effort has been made in many disciplines including medical imaging, computational modeling, bio- mechanics, bioengineering, medical devices, animal and clinical studies, population studies as well as genomic, molecular, cellular and organ-level studies seeking improved methods for early detection, diagnosis, prevention and treatment of these diseases [1-14]. However, the mechanisms governing the initiation, progression and the occurrence of final acute clinical CVD events are still poorly understood. A large number of victims of these dis- eases who are apparently healthy die suddenly without prior symptoms. Available screening and diagnostic methods are insufficient to identify the victims before the event occurs [8,9]. Most cardiovascular diseases are associated with vulnerable plaques. A grand challenge here is to develop new imaging techniques, predictive methods and patient screening tools to identify vulnerable plaques and patients who are more vulnerable to plaque rupture and associated clinical events such as stroke and heart attack, and recommend proper treatment plans to prevent those clinical events from happening. Articles in this special issue came from two symposia held recently focusing on “Cardio-vascular Diseases and Vulnerable Plaques: Data, Modeling, Predictions and Clinical Applications.” One was held at Worcester Polytechnic Institute (WPI), Worcester, MA, USA, July 13-14, 2014, right after the 7th World Congress of Biomechanics. This symposium was endorsed by the World Council of Biomechanics, and partially supported by a grant from NIH-National Institute of Biomedical Image and Bioengineering. The other was held at Southeast University (SEU), Nanjing, China, April 18-20, 2014.

A new method for the in vivo identification of mechanical properties in arteries from cine MRI images: Theoretical framework and validation

Quantifying the stiffness properties of soft tissues is essential for the diagnosis of many cardiovascular diseases such as atherosclerosis. In these pathologies it is widely agreed that the arterial wall stiffness is an indicator of vulnerability. The present paper focuses on the carotid artery and proposes a new inversion methodology for deriving the stiffness properties of the wall from cine-MRI (magnetic resonance imaging) data. We address this problem by setting-up a cost function defined as the distance between the modeled pixel signals and the measured ones. Minimizing this cost function yields the unknown stiffness properties of both the arterial wall and the surrounding tissues. The sensitivity of the identified properties to various sources of uncertainty is studied. Validation of the method is performed on a rubber phantom. The elastic modulus identified using the developed methodology lies within a mean error of 9.6%. It is then applied to two young healthy subjects as a proof of practical feasibility, with identified values of 625 kPa and 587 kPa for one of the carotid of each subject.

Analysis of word embeddings and sequence features for clinical information extraction

This study investigates the use of unsupervised features derived from word embedding approaches and novel sequence representation approaches for improving clinical information extraction systems. Our results corroborate previous findings that indicate that the use of word embeddings significantly improve the effectiveness of concept extraction models; however, we further determine the influence that the corpora used to generate such features have. We also demonstrate the promise of sequence-based unsupervised features for further improving concept extraction.

Designs for phase I clinical trials with multiple courses of subjects at different doses

The goal of this article is to provide a new design framework and its corresponding estimation for phase I trials. Existing phase I designs assign each subject to one dose level based on responses from previous subjects. Yet it is possible that subjects with neither toxicity nor efficacy responses can be treated at higher dose levels, and their subsequent responses to higher doses will provide more information. In addition, for some trials, it might be possible to obtain multiple responses (repeated measures) from a subject at different dose levels. In this article, a nonparametric estimation method is developed for such studies. We also explore how the designs of multiple doses per subject can be implemented to improve design efficiency. The gain of efficiency from "single dose per subject" to "multiple doses per subject" is evaluated for several scenarios. Our numerical study shows that using "multiple doses per subject" and the proposed estimation method together increases the efficiency substantially.

Decision-theoretic designs for dose-finding clinical trials with multiple outcomes

A decision-theoretic framework is proposed for designing sequential dose-finding trials with multiple outcomes. The optimal strategy is solvable theoretically via backward induction. However, for dose-finding studies involving k doses, the computational complexity is the same as the bandit problem with k-dependent arms, which is computationally prohibitive. We therefore provide two computationally compromised strategies, which is of practical interest as the computational complexity is greatly reduced: one is closely related to the continual reassessment method (CRM), and the other improves CRM and approximates to the optimal strategy better. In particular, we present the framework for phase I/II trials with multiple outcomes. Applications to a pediatric HIV trial and a cancer chemotherapy trial are given to illustrate the proposed approach. Simulation results for the two trials show that the computationally compromised strategy can perform well and appear to be ethical for allocating patients. The proposed framework can provide better approximation to the optimal strategy if more extensive computing is available.

Kallikrein-related peptidases in prostate cancer: From molecular function to clinical application

Prostate cancer is a leading contributor to male cancer-related deaths worldwide. Kallikrein-related peptidases (KLKs) are serine proteases that exhibit deregulated expression in prostate cancer, with KLK3, or prostate specific antigen (PSA), being the widely-employed clinical biomarker for prostate cancer. Other KLKs, such as KLK2, show promise as prostate cancer biomarkers and, additionally, their altered expression has been utilised for the design of KLK-targeted therapies. There is also a large body of in vitro and in vivo evidence supporting their role in cancer-related processes. Here, we review the literature on studies to date investigating the potential of other KLKs, in addition to PSA, as biomarkers and in therapeutic options, as well as their current known functional roles in cancer progression. Increased knowledge of these KLK-mediated functions, including degradation of the extracellular matrix, local invasion, cancer cell proliferation, interactions with fibroblasts, angiogenesis, migration, bone metastasis and tumour growth in vivo, may help define new roles as prognostic biomarkers and novel therapeutic targets for this cancer.

Analysis of human immunodeficiency virus type 1 drug resistance in children receiving nucleoside analogue reverse-transcriptase inhibitors plus nevirapine, nelfinavir, or ritonavir (Pediatric AIDS Clinical Trials Group 377)

In Pediatric AIDS Clinical Trials Group 377, antiretroviral therapy-experienced children were randomized to 4 treatment arms that included different combinations of stavudine, lamivudine (3TC), nevirapine (Nvp), nelfinavir (Nfv), and ritonavir (Rtv). Previous treatment with zidovudine (Zdv), didanosine (ddI), or zalcitabine (ddC) was acceptable. Drug resistance ((R)) mutations were assessed before study treatment (baseline) and at virologic failure. Zdv(R), ddI(R), and ddC(R) mutations were detected frequently at baseline but were not associated with virologic failure. Children with drug resistance mutations at baseline had greater reductions in virus load over time than did children who did not. Nvp(R) and 3TC(R) mutations were detected frequently at virologic failure, and Nvp(R) mutations were more common among children receiving 3-drug versus 4-drug Nvp-containing regimens. Children who were maintained on their study regimen after virologic failure accumulated additional Nvp(R) and 3TC(R) mutations plus Rtv(R) and Nfv(R) mutations. However, Rtv(R) and Nfv(R) mutations were detected at unexpectedly low rates.