Standardization of Weightage Assigned to Different Segments of the Hand X-ray for Assessment of Bone Age by the Greulich-Pyle Method.

Introduction: Bone age (BA) assessment is important in evaluating disorders of growth and puberty; the Greulich and Pyle atlas method (GP) is most used. We aimed to determine the weightage to be attributed by raters to various segments of the hand x-ray, namely, distal end of radius-ulna (RU), carpals, and short bones for rating bone age using the GP atlas method. Methods: 692 deidentified x-rays from a previous study (PUNE-dataset) and 400 from the Radiological Society of North America (RSNA-dataset) were included in the study. Mean of BA assessed by experienced raters was termed reference rating. Linear regression was used to model reference age as function of age ratings of the three segments. The root-mean-square-error (RMSE) of segmental arithmetic mean and weighted mean with respect to reference rating were computed for both datasets. Results: Short bones were assigned the highest weightage. Carpals were assigned higher weightage in pre-pubertal PUNE participants as compared to RSNA, vice-versa in RU segment of post-pubertal participants. The RMSE of weighted mean ratings was significantly lower than for the arithmetic mean in the PUNE dataset. Conclusion: We thus determined weightage to be attributed by raters to segments of the hand x-ray for assessment of bone age by the GP method.

The automated Greulich and Pyle: a coming-of-age for segmental methods?

The well-known Greulich and Pyle (GP) method of bone age assessment (BAA) relies on comparing a hand X-ray against templates of discrete maturity classes collected in an atlas. Automated methods have recently shown great success with BAA, especially using deep learning. In this perspective, we first review the success and limitations of various automated BAA methods. We then offer a novel hypothesis: When networks predict bone age that is not aligned with a GP reference class, it is not simply statistical error (although there is that as well); they are picking up nuances in the hand X-ray that lie "outside that class." In other words, trained networks predict distributions around classes. This raises a natural question: How can we further understand the reasons for a prediction to deviate from the nominal class age? We claim that segmental aging, that is, ratings based on characteristic bone groups can be used to qualify predictions. This so-called segmental GP method has excellent properties: It can not only help identify differential maturity in the hand but also provide a systematic way to extend the use of the current GP atlas to various other populations.

Safety and Efficacy of Bilateral Epiphysiodesis Surgery to Reduce Final Height in Extremely Tall Adolescents - A Follow-up Study.

INTRODUCTION: Treatment options in patients with extreme tall stature are limited. Bilateral epiphysiodesis has emerged as a possible treatment method aiming to reduce final height. However, there is still insufficient data on long-term safety and final height outcome. Therefore, the aim of this study was to assess the efficacy and safety of bilateral epiphysiodesis to reduce final adult height in tall adolescents. METHODS: The study population consisted of 72 patients with extreme tall stature who were followed at the Pediatric Endocrine Clinic at the Karolinska University Hospital, Stockholm (Sweden) and subsequently underwent bilateral epiphysiodesis around the knees (girls n=45, boys n=27). RESULTS: When compared to the final height prediction at time of surgery, the procedure significantly reduced the achieved final height by a mean of 3.6 cm ± 0.4 cm in girls (p<0.001; 26.0 ± 2.9 % reduction) and 8.6 ± 0.9 cm in boys (p<0.001; 40.5 ± 3.0 % reduction). Furthermore, a negative correlation was observed between the absolute height reduction and the bone age at time of surgery, which was stronger in boys (r=-0.63, p<0.001) than in girls (r=-0.44, p<0.001). Besides reducing final height, body proportions were affected in all patients subjected to bilateral epihyseodesis. However, as tall individuals typically have relatively long legs, body proportions were rather normalized after the surgery. There were no serious complications reported. CONCLUSION: This study suggests that bilateral epiphysiodesis is an efficient and safe method to reduce final height in extremely tall adolescent girls and boys. The achieved height reduction was higher in boys and when performed at an earlier bone age. Importantly, no serious side-effects were reported. However, a continued follow-up is still warranted to detect any potential rare complications.

Micromechanical Loading Studies in Ex Vivo Cultured Embryonic Rat Bones Enabled by a Newly Developed Portable Loading Device.

Mechanical loading has been described as having the potential to affect bone growth. In order to experimentally study the potential clinical applications of mechanical loading as a novel treatment to locally modulate bone growth, there is a need to develop a portable mechanical loading device enabling studies in small bones. Existing devices are bulky and challenging to transfer within and between laboratories and animal facilities, and they do not offer user-friendly mechanical testing across both ex vivo cultured small bones and in vivo animal models. To address this, we developed a portable loading device comprised of a linear actuator fixed within a stainless-steel frame equipped with suitable structures and interfaces. The actuator, along with the supplied control system, can achieve high-precision force control within the desired force and frequency range, allowing various load application scenarios. To validate the functionality of this new device, proof-of-concept studies were performed in ex vivo cultured rat bones of varying sizes. First, very small fetal metatarsal bones were microdissected and exposed to 0.4 N loading applied at 0.77 Hz for 30 s. When bone lengths were measured after 5 days in culture, loaded bones had grown less than unloaded controls (p < 0.05). Next, fetal rat femur bones were periodically exposed to 0.4 N loading at 0.77 Hz while being cultured ex vivo for 12 days. Interestingly, this loading regimen had the opposite effect on bone growth, i.e., loaded femur bones grew significantly more than unloaded controls (p < 0.001). These findings suggest that complex relationships between longitudinal bone growth and mechanical loading can be determined using this device. We conclude that our new portable mechanical loading device allows experimental studies in small bones of varying sizes, which may facilitate further preclinical studies exploring the potential clinical applications of mechanical loading.

Obesity-Induced Increase in Cystatin C Alleviates Tissue Inflammation.

We recently demonstrated that removal of one kidney (uninephrectomy [UniNx]) in mice reduced high-fat diet (HFD)-induced adipose tissue inflammation, thereby improving adipose tissue and hepatic insulin sensitivity. Of note, circulating cystatin C (CysC) levels were increased in UniNx compared with sham-operated mice. Importantly, CysC may have anti-inflammatory properties, and circulating CysC levels were reported to positively correlate with obesity in humans and as shown here in HFD-fed mice. However, the causal relationship of such observation remains unclear. HFD feeding of CysC-deficient (CysC knockout [KO]) mice worsened obesity-associated adipose tissue inflammation and dysfunction, as assessed by proinflammatory macrophage accumulation. In addition, mRNA expression of proinflammatory mediators was increased, whereas markers of adipocyte differentiation were decreased. Similar to findings in adipose tissue, expression of proinflammatory cytokines was increased in liver and skeletal muscle of CysC KO mice. In line, HFD-induced hepatic insulin resistance and impairment of glucose tolerance were further aggravated in KO mice. Consistently, chow-fed CysC KO mice were more susceptible to lipopolysaccharide-induced adipose tissue inflammation. In people with obesity, circulating CysC levels correlated negatively with adipose tissue Hif1α as well as IL6 mRNA expression. Moreover, healthy (i.e., insulin-sensitive) subjects with obesity had significantly higher mRNA expression of CysC in white adipose tissue. In conclusion, CysC is upregulated under obesity conditions and thereby counteracts inflammation of peripheral insulin-sensitive tissues and, thus, obesity-associated deterioration of glucose metabolism.

Glycogen storage disease type VI: clinical course and molecular background.

Glycogen storage disease type VI (GSD-VI; also known as Hers disease, liver phosphorylase deficiency) is caused by mutations in the gene coding for glycogen phosphorylase (PYGL) leading to a defect in the degradation of glycogen. Since there are only about 40 patients described in literature, our knowledge about the course of the disease is limited. In order to evaluate the long-term outcome of patients with GSD-VI, an observational retrospective case study of six patients was performed at the University Children's Hospital Zurich. The introduction of small, frequent meals as well as cornstarch has led to normal growth in all patients and to normalization of liver transaminases in most patients. After starting the dietary regimen, there were no signs of hypoglycemia. However, three of six patients showed persistent elevation of triglycerides. Further, we identified four novel pathogenic PYGL mutations and describe here their highly variable impact on phosphorylase function.Conclusions: After establishing the diagnosis, dietary treatment led to metabolic stability and to prevention of hypoglycemia. Molecular genetics added important information for the understanding of the clinical variability in this disease. While outcome was overall excellent in all patients, half of the patients showed persistent hypertriglyceridemia even after initiating treatment.What is Known:• Glycogen storage disease type VI (GSD-VI) is a metabolic disorder causing a defect in glycogen degradation. Dietary treatment normally leads to metabolic stability and prevention of hypoglycemia.• However, our knowledge about the natural course of patients with GSD-VI is limited.What is New:• While outcome was overall excellent in all patients, half of the patients showed persistent hypertriglyceridemia even after initiating treatment.• Molecular genetics added important information for the understanding of the clinical variability in this disease.

Future glycemic control of children diagnosed with type 1 diabetes mellitus at toddler and preschool/school age.

Background The main objective of this study was to compare future glycemic control in children diagnosed with type 1 diabetes mellitus (T1DM) at toddler age and preschool/school age. In addition, we aimed to examine risk factors known to be associated with future glycated hemoglobin A1c (HbA1c) levels in children diagnosed with T1DM. Methods This is a retrospective cohort study of 85 patients diagnosed with T1DM at toddler age (group 1; 0-2.9 years; n = 36) or preschool/school age (group 2; 5-6.9 years; n = 49) who were followed up at the University Children's Hospital in Zurich for at least 10 consecutive years or until the age of 15 years. Results The mean HbA1c level in the first year after diagnosis had a highly predictive value about glycemic control in the following 6 years. In addition, a longer duration of T1DM was associated with higher HbA1c values. HbA1c values did not differ significantly within 11 years after diagnosis between children in the two age groups. Neither was a difference found when comparing the two groups in respect to their chronological age, although a trend was noted (p = 0.09). This trend is very likely due to a longer duration of diabetes in group 1. Conclusions HbA1c level in the first year predicts glycemic control for the next 6 years and deterioration of HbA1c values can be noted with longer duration of T1DM. Moreover, our study demonstrated similar future glycemic control in patients diagnosed with T1DM at toddler age and preschool/school age.