Insulin/IGF-1 Drives PERIOD Synthesis to Entrain Circadian Rhythms with Feeding Time.

In mammals, endogenous circadian clocks sense and respond to daily feeding and lighting cues, adjusting internal ∼24 h rhythms to resonate with, and anticipate, external cycles of day and night. The mechanism underlying circadian entrainment to feeding time is critical for understanding why mistimed feeding, as occurs during shift work, disrupts circadian physiology, a state that is associated with increased incidence of chronic diseases such as type 2 (T2) diabetes. We show that feeding-regulated hormones insulin and insulin-like growth factor 1 (IGF-1) reset circadian clocks in vivo and in vitro by induction of PERIOD proteins, and mistimed insulin signaling disrupts circadian organization of mouse behavior and clock gene expression. Insulin and IGF-1 receptor signaling is sufficient to determine essential circadian parameters, principally via increased PERIOD protein synthesis. This requires coincident mechanistic target of rapamycin (mTOR) activation, increased phosphoinositide signaling, and microRNA downregulation. Besides its well-known homeostatic functions, we propose insulin and IGF-1 are primary signals of feeding time to cellular clocks throughout the body.

CRYPTOCHROMES promote daily protein homeostasis.

The daily organisation of most mammalian cellular functions is attributed to circadian regulation of clock-controlled protein expression, driven by daily cycles of CRYPTOCHROME-dependent transcriptional feedback repression. To test this, we used quantitative mass spectrometry to compare wild-type and CRY-deficient fibroblasts under constant conditions. In CRY-deficient cells, we found that temporal variation in protein, phosphopeptide, and K+ abundance was at least as great as wild-type controls. Most strikingly, the extent of temporal variation within either genotype was much smaller than overall differences in proteome composition between WT and CRY-deficient cells. This proteome imbalance in CRY-deficient cells and tissues was associated with increased susceptibility to proteotoxic stress, which impairs circadian robustness, and may contribute to the wide-ranging phenotypes of CRY-deficient mice. Rather than generating large-scale daily variation in proteome composition, we suggest it is plausible that the various transcriptional and post-translational functions of CRY proteins ultimately act to maintain protein and osmotic homeostasis against daily perturbation.

Hybrid Blockchain for IoT-Energy Analysis and Reward Plan.

Blockchain technology has brought significant advantages for security and trustworthiness, in particular for Internet of Things (IoT) applications where there are multiple organisations that need to verify data and ensure security of shared smart contracts. Blockchain technology offers security features by means of consensus mechanisms; two key consensus mechanisms are, Proof of Work (PoW) and Practical Byzantine Fault Tolerance (PBFT). While the PoW based mechanism is computationally intensive, due to the puzzle solving, the PBFT consensus mechanism is communication intensive due to the all-to-all messages; thereby, both may result in high energy consumption and, hence, there is a trade-off between the computation and the communication energy costs. In this paper, we propose a hybrid-blockchain (H-chain) framework appropriate for scenarios where multiple organizations exist and where the framework enables private transaction verification and public transaction sharing and audit, according to application needs. In particular, we study the energy consumption of the hybrid consensus mechanisms in H-chain. Moreover, this paper proposes a reward plan to incentivize the blockchain agents so that they make contributions to the H-chain while also considering the energy consumption. While the work is generally applicable to IoT applications, the paper illustrates the framework in a scenario which secures an IoT application connected using a software defined network (SDN). The evaluation results first provide a method to balance the public and private parts of the H-chain deployment according to network conditions, computation capability, verification complexity, among other parameters. The simulation results demonstrate that the reward plan can incentivize the blockchain agents to contribute to the H-chain considering the energy consumption of the hybrid consensus mechanism, this enables the proposed H-chain to achieve optimal social welfare.

Caffeine is a risk factor for osteopenia of prematurity in preterm infants: a cohort study.

BACKGROUND: Caffeine, the most commonly used medication in Neonatal Intensive Care Units, has calciuric and osteoclastogenic effects. METHODS: To examine the association between the cumulative dose and duration of therapy of caffeine and osteopenia of prematurity, a retrospective cohort study was conducted including premature infants less than 31 weeks and birth weight less than 1500 g. Osteopenia of prematurity was evaluated using chest X-rays on a biweekly basis over 12 weeks of hospitalization. RESULTS: The cohort included 109 infants. 51% had osteopenia of prematurity and 8% had spontaneous rib fractures. Using the generalized linear mixed model, caffeine dose and duration of caffeine therapy showed a strong association with osteopenia of prematurity. Steroids and vitamin D were also significantly correlated with osteopenia of prematurity while diuretic use did not show a statistically significant effect. CONCLUSION: The cumulative dose and duration of therapy of caffeine, as well as steroid are associated with osteopenia of prematurity in this cohort. Future studies are needed to confirm these findings and determine the lowest dose of caffeine needed to treat effectively apnea of prematurity.

Intracellular antibody receptor TRIM21 prevents fatal viral infection.

Host species have evolved mechanisms that can inhibit pathogen replication even after a cell has been successfully invaded. Here we show that tripartite-motif protein 21 (TRIM21), a ubiquitously expressed E3 ubiquitin ligase that targets viruses inside the cytosol, protects mice against fatal viral infection. Upon infection with mouse adenovirus-1, naive mice lacking TRIM21 succumb to encephalomyelitis within 7 d. In contrast, wild-type mice rapidly up-regulate TRIM21 and control viremia. Trim21 heterozygous mice have a haploinsufficiency phenotype in which reduced TRIM21 expression leads to a viral load that is higher than wild types but lower than knockouts. TRIM21 is a high-affinity antibody receptor that allows antibodies to operate inside an infected cell. In passive transfer experiments at high viral dose, antisera that fully protects wild-type mice fails to protect most Trim21 knockout animals. These results demonstrate that TRIM21 provides potent antiviral protection and forms an important part of the humoral immune response.

Common normal variants of pediatric vertebral development that mimic fractures: a pictorial review from a national longitudinal bone health study.

Children with glucocorticoid-treated illnesses are at risk for osteoporotic vertebral fractures, and growing awareness of this has led to increased monitoring for these fractures. However scant literature describes developmental changes in vertebral morphology that can mimic fractures. The goal of this paper is to aid in distinguishing between normal variants and fractures. We illustrate differences using lateral spine radiographs obtained annually from children recruited to the Canada-wide STeroid-Associated Osteoporosis in the Pediatric Population (STOPP) observational study, in which 400 children with glucocorticoid-treated leukemia, rheumatic disorders, and nephrotic syndrome were enrolled near glucocorticoid initiation and followed prospectively for 6 years. Normal variants mimicking fractures exist in all regions of the spine and fall into two groups. The first group comprises variants mimicking pathological vertebral height loss, including not-yet-ossified vertebral apophyses superiorly and inferiorly, which can lead to a vertebral shape easily over-interpreted as anterior wedge fracture, physiological beaking, or spondylolisthesis associated with shortened posterior vertebral height. The second group includes variants mimicking other radiologic signs of fractures: anterior vertebral artery groove resembling an anterior buckle fracture, Cupid's bow balloon disk morphology, Schmorl nodes mimicking concave endplate fractures, and parallax artifact resembling endplate interruption or biconcavity. If an unexpected vertebral body contour is detected, careful attention to its location, detailed morphology, and (if available) serial changes over time may clarify whether it is a fracture requiring change in management or simply a normal variant. Awareness of the variants described in this paper can improve accuracy in the diagnosis of pediatric vertebral fractures.

Variability of physicians' thresholds for neuroimaging in children with recurrent headache.

BACKGROUND: We sought to determine the extent to which physicians agree about the appropriate decision threshold for recommending magnetic resonance imaging in a clinical practice guideline for children with recurrent headache. METHODS: We surveyed attending physicians in Canada practicing in community pediatrics, child neurology, pediatric radiology, and pediatric neurosurgery. For children in each of six risk categories, physicians were asked to determine whether they would recommend for or against routine magnetic resonance imaging of the brain in a clinical practice guideline for children with recurrent headache. RESULTS: Completed surveys were returned by 114 physicians. The proportion recommending routine neuroimaging for each risk group was 100% (50% risk), 99% (10% risk), 93% (4% risk), 54% (1% risk), 25% (0.4% risk), 4% (0.01% risk). Community pediatricians, physicians in practice >15 years, and physicians who believed they ordered neuroimaging less often than peers were less likely to recommend neuroimaging for the 1% risk group (all p < 0.05). CONCLUSIONS: There is no consensus among pediatric specialists regarding the appropriate decision threshold for neuroimaging in a clinical practice guideline for children with recurrent headache. Because of the impact that individual threshold preferences may have on guidelines, these findings support the need for careful composition of guideline committees and consideration of the role of patient and family preferences. Our findings also support the need for transparency in guidelines regarding how evidence was translated into recommendations and how conflicts were resolved.

Spine surgeons' requirements for imaging at the time of referral: a survey of Canadian spine surgeons.

BACKGROUND: Routine imaging of patients with spine-related complaints referred for surgical assessment may represent an inefficient use of technological resources. Our objective was to explore Canadian spine surgeons' requirements with respect to imaging studies accompanying spine-related referrals. METHODS: We administered an 8-item survey to all 100 actively practising surgeon members of the Canadian Spine Society that inquired about demographic variables and imaging requirements for patients referred with spine-related complaints. RESULTS: Fifty-five spine surgeons completed our survey, for a response rate of 55%. Most respondents (43; 78%) required imaging studies to accompany all spine-related referrals. The type of imaging required was highly variable, with respondents endorsing 7 different combinations. Half (47%) required magnetic resonance imaging and 38% required plain radiographs either alone or in combination with other forms of imaging. Half of the respondents refused to see 20% or more of all patients referred for spine-related complaints. CONCLUSION: Most Canadian spine surgeons require imaging studies to accompany spine-related referrals; however, the type and combination of studies is highly variable, and many patients who are referred are never seen (for a consultation). Standardization and optimization of imaging practices for patients with spine-related complaints referred for surgical assessment may be an important area for cost savings.

CONTEXTE: Le recours systématique aux épreuves d'imagerie chez les patients qui se plaignent de maux de dos et qui sont référés pour consultation en chirurgie pourrait constituer une utilisation inefficace des ressources technologiques. Notre objectif était d'analyser les épreuves d'imagerie demandées par les chirurgiens canadiens spécialistes de la colonne vertébrale, suite aux demandes de consultation qui leur sont adressées pour des patients qui ont des problèmes de colonne vertébrale. MÉTHODES: Nous avons administré un sondage en 8 questions aux 100 chirurgiens en pratique active qui forment la Canadian Spine Society; le questionnaire portait sur des variables démographiques et sur les demandes d'épreuves d'imagerie pour les patients qui leur sont référés pour des maux de dos. RÉSULTATS: Cinquante-cinq chirurgiens de la colonne ont répondu à notre sondage, pour un taux de réponse de 55 %. La plupart des répondants (43; 78 %) ont dit demander des épreuves d'imagerie pour toutes les références qui leur sont adressées pour des problèmes de colonne vertébrale. Les types d'épreuves d'imagerie demandés variaient considérablement et les répondants ont mentionné 7 combinaisons d'épreuves différentes. La moitié d'entre eux (47 %) demandaient une imagerie par résonnance magnétique et 38 % demandaient des radiographies ordinaires, seules ou combinées à d'autres modalités d'imagerie. La moitié des répondants ont dit refuser de voir 20 % ou plus de tous les patients qui leur étaient référés pour des maux de dos. CONCLUSION: La plupart des chirurgiens spécialistes de la colonne vertébrale au Canada demandent des épreuves d'imagerie pour tous les patients qui leur sont référés pour des problèmes de colonne vertébrale; toutefois, les types d'épreuves et leurs combinaisons sont très variables et de nombreux patients qui sont référés en consultation ne réussissent jamais à voir les spécialistes. La standardisation et l'optimisation des pratiques au chapitre de l'imagerie pour les patients qui souffrent de maux de dos et qui sont référés à un chirurgien représentent un poste budgétaire important où des économies pourraient être réalisées.

Management of childhood intussusception after reduction by enema.

OBJECTIVE: The objective of the study was to describe the utility of emergency department (ED)/outpatient management after enema reduction for childhood intussusception. METHODS: A retrospective medical record review of children aged 2 months to 6 years with confirmed intussusception who underwent enema reduction in a tertiary care academic children's hospital was performed. Subjects were analyzed with respect to location of care after reduction (ED/outpatient vs inpatient) and number, timing, and outcome of recurrences. RESULTS: One hundred seventeen patients were diagnosed with intussusception by contrast or air enema during the 15-year study period, and 56 fulfilled our inclusion criteria. Ten patients (18%) were admitted to hospital after enema reduction. Mean length of stay was 33.7 hours in the hospitalized group and 7 hours in the ED group. Seven of the 56 patients had recurrences (12.5% recurrence rate). Two recurred while being observed in the ED (at 30 minutes and at 2 hours after reduction), 2 recurred at home (at 10 and 28 hours after reduction), and the other 3 recurred several months later. The early recurrence rate (recurring within 24 hours) was 5.3%. No patient had an adverse event (perforation, sepsis, bowel resection). CONCLUSIONS: Outpatient management is used for the majority of patients with intussusception at our institution after enema reduction. The early recurrence rate is low, and patients with recurrence after discharge do well without adverse outcomes. Emergency department observation of patients after enema reduction appears to be safe and should be routine for uncomplicated cases of intussusception.

Antiscatter grid use in pediatric digital tomosynthesis imaging.

The objective of this study was to assess the effect of antiscatter grid use on tomosynthesis image quality. We performed an observer study that rated the image quality of digital tomosynthesis scout radiographs and slice images of a Leeds TO.20 contrast-detail test object embedded in acrylic with and without a grid. We considered 10, 15, 20 and 25 cm of acrylic to represent the wide range of patient thicknesses encountered in pediatric imaging. We also acquired and rated images without a grid at an increased patient dose. The readers counted the total number of visible details in each image as a measure of relative image quality. We observed that the antiscatter grid improves tomosynthesis image quality compared to the grid-out case, which received image quality scores similar to grid-in radiography. Our results suggest that, in order to achieve the best image quality in exchange for the increase in patient dose, it may often be appropriate to include an antiscatter grid for pediatric tomosynthesis imaging, particularly if the patient thickness is greater than 10 cm.

The developmental spectrum of proximal radioulnar synostosis.

OBJECTIVE: Proximal radioulnar synostosis is a rare upper limb malformation. The elbow is first identifiable at 35 days (after conception), at which stage the cartilaginous anlagen of the humerus, radius and ulna are continuous. Subsequently, longitudinal segmentation produces separation of the distal radius and ulna. However, temporarily, the proximal ends are united and continue to share a common perichondrium. We investigated the hypothesis that posterior congenital dislocation of the radial head and proximal radioulnar fusion are different clinical manifestations of the same primary developmental abnormality. MATERIALS AND METHODS: Records were searched for "proximal radioulnar fusion/posterior radial head dislocation" in patients followed at the local Children's Hospital and Rehabilitation Centre for Children. Relevant radiographic, demographic and clinical data were recorded. Ethics approval was obtained through the University Research Ethics Board. RESULTS: In total, 28 patients met the inclusion criteria. The majority of patients (16) had bilateral involvement; eight with posterior dislocation of the radial head only; five had posterior radial head dislocation with radioulnar fusion and two had radioulnar fusion without dislocation. One patient had bilateral proximal radioulnar fusion and posterior dislocation of the left radial head. Nine patients had only left-sided involvement, and three had only right-sided involvement.The degree of proximal fusion varied, with some patients showing 'complete' proximal fusion and others showing fusion that occurred slightly distal to the radial head: 'partially separated.' Associated disorders in our cohort included Poland syndrome (two patients), Cornelia de Lange syndrome, chromosome anomalies (including tetrasomy X) and Cenani Lenz syndactyly. CONCLUSION: The suggestion of a developmental relationship between posterior dislocation of the radial head and proximal radioulnar fusion is supported by the fact that both anomalies can occur in the same patient. Furthermore, both anomalies can be seen in different patients with the same genetic diagnosis, further supporting the notion that these defects are developmentally related. Posterior dislocation of the radial head and radioulnar fusion are considered to be related primary developmental anomalies of radioulnar differentiation/segmentation. We speculate that the eventual specific defect of this spectrum is influenced by very subtle differences in developmental timing. This is in contrast to patients with transverse forearm defects who can also display radial head dislocation but in an anterior or lateral direction. This direction of dislocation is seen when an abnormal force is exerted on a normally formed radial head later in development or postnatally in disorders such as multiple osteochondromatosis and various mesomelic dysplasias, or as a result of trauma.

The carpal bones in Poland syndrome.

OBJECTIVE: Classical Poland syndrome is represented by unilateral aplasia of the sternocostal head of the pectoralis major muscle and ipsilateral simple syndactyly and brachydactyly. Various classifications of the severity of hand involvement have been proposed. Since its initial description, numerous studies have been made of the bony, soft tissue, organ, and hematological disturbances. However, carpal bone involvement has been largely overlooked. The purpose of this study was to evaluate the carpal bones in patients with Poland syndrome from a local (Manitoba) cohort as well as those from the literature. MATERIALS AND METHODS: Hand radiographs from local patients and cases identified from the literature with confirmed Poland syndrome were examined for evidence of carpal bone involvement. Only cases with radiographs of adequate quality were included in the analysis. Clinical information (including gender and age) was necessary for evaluation of bone maturation. In total, seven local patients and 23 patients from the literature were evaluated. Ethics approval for study of the local patients was obtained by the Research Ethics Board of the University of Manitoba. RESULTS: Of the 23 literature patients, 12 patients (52%) had abnormal findings. Of the abnormal patients, four of 12 (33%) had carpal fusions, eight of 12 (67%) showed disharmonious ossification between the carpal and tubular bones and seven of 12 (58%) showed delay of carpal ossification. Of the local cohort, three patients were too young to characterize carpal involvement. Of the four remaining patients, two (50%) had abnormal carpal morphology, three out of four had disharmonious ossification and all four had delay of ossification of carpal bones. Carpal fusions, particularly of the scaphoid and trapezium, were common in both groups. CONCLUSION: Carpal bone anomalies (delay, disharmony, and/or fusions) are frequent in Poland syndrome and can occur in patients with either mild or severe hand involvement. Imaging of the unaffected hand is helpful in determining the extent of carpal findings.

A new closed reduction technique for the treatment of radial neck fractures in children.

Displaced radial neck fractures in the skeletally immature patient are uncommon and can be difficult to reduce. We describe a new technique for the closed reduction of radial neck fractures in children. One of the authors (R.M.) has used this technique in treating 6 children with displaced radial neck fractures. This was a retrospective review carried out at a tertiary care hospital in Winnipeg, Manitoba, Canada. All charts and radiographs were reviewed. One patient underwent an ultrasound assessment to assist reduction (case 4). Average age of the patients was 9 years and 6 months. Average follow-up was 4.3 months. Closed reduction was successful in all patients. No patient went on to an open reduction. The results in this series using a newly described technique are encouraging, and there is consideration for its continued use.