Automatic determination of Greulich and Pyle bone age in healthy Dutch children

Background: Bone age (BA) assessment is a routine procedure in paediatric radiology, for which the Greulich and Pyle (GP) atlas is mostly used. There is rater variability, but the advent of automatic BA determination eliminates this. Objective: To validate the BoneXpert method for automatic determination of skeletal maturity of healthy children against manual GP BA ratings. Materials and methods: Two observers determined GP BA with knowledge of the chronological age (CA). A total of 226 boys with a BA of 3-17 years and 179 girls with a BA of 3-15 years were included in the study. BoneXpert's estimate of GP BA was calibrated to agree on average with the manual ratings based on several studies, including the present study. Results: Seven subjects showed a deviation between manual and automatic BA in excess of 1.9 years. They were re-rated blindly by two raters. After correcting these seven ratings, the root mean square error between manual and automatic rating in the 405 subjects was 0.71 years (range 0.66-0.76 years, 95% CI). BoneXpert's GP BA is on average 0.28 and 0.20 years behind the CA for boys and girls, respectively. Conclusion: BoneXpert is a robust method for automatic determination of BA

Naturally-acquired protection against upper respiratory symptoms involving group A Streptococcus in a longitudinal cohort study

Background Pharyngitis due to group A Streptococcus (GAS) represents a major cause of outpatient visits and antibiotic use in the United States. A leading vaccine candidate targets 30 of the >200 emm types of GAS. We aimed to assess natural protection conferred by GAS against respiratory symptoms. Methods In a 5-year study among school-aged children in Pittsburgh, Pennsylvania, pharyngeal cultures were obtained from children at 2-week intervals, and active surveillance was conducted for respiratory illnesses. We assessed protection via the relative odds of previous detection of homologous strains (defined by field-inversion gel electrophoresis banding pattern), emm types, and emm clusters at visits where GAS was detected with symptoms, versus visits where GAS was detected without symptoms. We used a cluster bootstrap of children to adjust estimates for repeated sampling. Results At visits where previously-detected GAS emm types were identified, we estimated 81.8% (95%CI: 67.1-91.7%) protection against typical pharyngitis symptoms among children re-acquiring the same strain, and 94.5% (83.5-98.6%) protection among children acquiring a distinct strain. We estimated 77.1% (33.7-96.3%) protection against typical symptoms among children acquiring partially-heterologous emm types belonging to a previously-detected emm cluster. Protection was evident after both symptomatic and asymptomatic detections of GAS. We did not identify strong evidence of protection against atypical respiratory symptoms. Conclusions Within a 5-year longitudinal study, previous detection of GAS emm types was associated with protection against typical symptoms when homologous strains were subsequently detected. Naturally-acquired protection against partially-heterologous types suggests emm type-based vaccines may have broader strain coverage than what has been previously assumed

Promising development from translational or perhaps anti-translational research in breast cancer

Background: A great deal of the public’s money has been spent on cancer research but demonstrable benefits to patients have not been proportionate. We are a group of scientists and physicians who several decades ago were confronted with bimodal relapse patterns among early stage breast cancer patients who were treated by mastectomy. Since the bimodal pattern was not explainable with the then well-accepted continuous growth model, we proposed that metastatic disease was mostly inactive before surgery but was driven into growth somehow by surgery. Most relapses in breast cancer would fall into the surgery-induced growth category thus it was highly important to understand the ramifications of this process and how it may be curtailed. With this hypothesis, we have been able to explain a wide variety of clinical observations including why mammography is less effective for women age 40–49 than it is for women age 50–59, why adjuvant chemotherapy is most effective for premenopausal women with positive lymph nodes, and why there is a racial disparity in outcome. Methods: We have been diligently looking for new clinical or laboratory information that could provide a connection or correlation between the bimodal relapse pattern and some clinical factor or interventional action and perhaps lead us towards methods to prevent surgery-initiated tumor activity. Results: A recent development occurred when a retrospective study appeared in an anesthesiology journal that suggested the perioperative NSAID analgesic ketorolac seems to reduce early relapses following mastectomy. Collaborating with these anesthesiologists to understand this effect, we independently re-examined and updated their data and, in search of a mechanism, focused in on the transient systemic inflammation that follows surgery to remove a primary tumor. We have arrived at several possible explanations ranging from mechanical to biological that suggest the relapses avoided in the early years do not show up later. Conclusions: We present the possibility that a nontoxic and low cost intervention could prevent early relapses. It may be that preventing systemic inflammation post surgery will prevent early relapses. This could be controlled by the surgical anesthesiologist’s choice of analgesic drugs. This development needs to be confirmed in a randomized controlled clinical trial and we have identified triple negative breast cancer as the ideal subset with which to test this. If successful, this would be relatively easy to implement in developing as well as developed countries and would be an important translational result

Specific MRI Abnormalities Reveal Severe Perrault Syndrome due to CLPP Defects

In establishing a genetic diagnosis in heterogeneous neurological disease, clinical characterization and whole exome sequencing (WES) go hand-in-hand. Clinical data are essential, not only to guide WES variant selection and define the clinical severity of a genetic defect but also to identify other patients with defects in the same gene. In an infant patient with sensorineural hearing loss, psychomotor retardation, and epilepsy, WES resulted in identification of a novel homozygous CLPP frameshift mutation (c.21delA). Based on the gene defect and clinical symptoms, the diagnosis Perrault syndrome type 3 (PRLTS3) was established. The patient's brain-MRI revealed specific abnormalities of the subcortical and deep cerebral white matter and the middle blade of the corpus callosum, which was used to identify similar patients in the Amsterdam brain-MRI database, containing over 3000 unclassified leukoencephalopathy cases. In three unrelated patients with similar MRI abnormalities the CLPP gene was sequenced, and in two of them novel missense mutations were identified together with a large deletion that covered part of the CLPP gene on the other allele. The severe neurological and MRI abnormalities in these young patients were due to the drastic impact of the CLPP mutations, correlating with the variation in clinical manifestations among previously reported patients. Our data show that similarity in brain-MRI patterns can be used to identify novel PRLTS3 patients, especially during early disease stages, when only part of the disease manifestations are present. This seems especially applicable to the severely affected cases in which CLPP function is drastically affected and MRI abnormalities are pronounce

Leveraging population admixture to characterize the heritability of complex traits.

Despite recent progress on estimating the heritability explained by genotyped SNPs (h(2)g), a large gap between h(2)g and estimates of total narrow-sense heritability (h(2)) remains. Explanations for this gap include rare variants or upward bias in family-based estimates of h(2) due to shared environment or epistasis. We estimate h(2) from unrelated individuals in admixed populations by first estimating the heritability explained by local ancestry (h(2)γ). We show that h(2)γ = 2FSTCθ(1 - θ)h(2), where FSTC measures frequency differences between populations at causal loci and θ is the genome-wide ancestry proportion. Our approach is not susceptible to biases caused by epistasis or shared environment. We applied this approach to the analysis of 13 phenotypes in 21,497 African-American individuals from 3 cohorts. For height and body mass index (BMI), we obtained h(2) estimates of 0.55 ± 0.09 and 0.23 ± 0.06, respectively, which are larger than estimates of h(2)g in these and other data but smaller than family-based estimates of h(2)

Coring, profiling, and trenching: Archaeological field strategies for investigating the Pleistocene-Holocene-Anthropocene continuum

Archaeologists have long emphasized the importance of large-scale excavations and multi-year or even decades-long projects at a single site or site complex. Here, we highlight archaeological field strategies, termed coring, profiling, and trenching (CPT), that rely on relatively small-scale excavations or the collection of new samples from intact deposits in previously excavated trenches (aka test units or pits). Examples from multiple sites in Africa, Asia, and North America demonstrate that CPT is highly effective for obtaining high-resolution archaeobiological and geoarchaeological samples (e.g., faunal and botanical remains, sediments) and artefacts from areas that have seen limited or no archaeological research, little systematic application of archaeological science methods, or research only on a relatively narrow time period or geographic scale. Designed to complement large-scale excavations at single sites, CPT is ideal for multi-scalar research that works in tandem with remote sensing techniques, providing samples for detailed laboratory analyses and offering a bridge between surface surveys and large-scale excavation. Given the threats facing archaeological sites around the world from climate change and human development, as well as financial, training and infrastructure constraints, and concerns from many Indigenous communities about large excavations, we argue that CPT is an important method for addressing 21st century human-environmental research questions

The diminishing role of hubs in dynamical processes on complex networks

It is notoriously difficult to predict the behaviour of a complex self-organizing system, where the interactions among dynamical units form a heterogeneous topology. Even if the dynamics of each microscopic unit is known, a real understanding of their contributions to the macroscopic system behaviour is still lacking. Here we develop information-theoretical methods to distinguish the contribution of each individual unit to the collective out-of-equilibrium dynamics. We show that for a system of units connected by a network of interaction potentials with an arbitrary degree distribution, highly connected units have less impact on the system dynamics as compared to intermediately connected units. In an equilibrium setting, the hubs are often found to dictate the long-term behaviour. However, we find both analytically and experimentally that the instantaneous states of these units have a short-lasting effect on the state trajectory of the entire system. We present qualitative evidence of this phenomenon from empirical findings about a social network of product recommendations, a protein-protein interaction network, and a neural network, suggesting that it might indeed be a widespread property in nature.Comment: Published versio