"Delabeling" by direct provocation testing in children and adolescents with a suspected history of a delayed reaction to ß-lactam antibiotics: Consensus paper of Gesellschaft für pädiatrische Allergologie und Umweltmedizin (GPAU), Deutsche Gesellschaft für Allergologie und klinische Immunologie (DGAKI), and Ärzteverband deutscher Allergologen (ÄDA).

BACKGROUND: Approximately 10% of European children are classified as allergic to drugs. In the majority of these children, no allergy to ß-lactam antibiotics (BLA) can be found. In most cases, the exanthema is caused by the infection. MATERIALS AND METHODS: The objective of this paper is to describe the causes and consequences of a misdiagnosis of drug allergy. We propose a method for establishing a correct diagnosis in the case of a history of a delayed reaction during treatment with a BLA. For this purpose, a proposal was discussed via e-mail communication, and consensus was reached among the members of the drug allergy working groups of the participating medical societies. RESULTS: The suspicion of a BLA allergy based on the medical history alone can have a negative impact on future antibiotic treatment. Exanthema associated with febrile infections not related to drug administration is a frequent finding in children. This makes it all the more important to be able to recommend a standardized procedure for clarification in children and adolescents with suspected hypersensitivity reactions. The medical history should be the basis on which to diagnose either a drug allergy or another possible differential diagnosis. A mild maculopapular exanthema (MPE) can be an expression of a drug allergy or a nonspecific viral exanthema. Uncomplicated MPE is not associated with significant systemic involvement, and there is no involvement of the mucous membranes or cutaneous blistering. Only a small number of children with uncomplicated MPE show positive skin tests and only ~ 7 - 16% of suspected BLA diagnoses can be confirmed by provocation tests. Thus, in children with uncomplicated MPE, drug provocation can be performed in an outpatient setting even without prior skin testing. This paper presents a 3-day outpatient direct provocation scheme for BLA delabeling in children with uncomplicated MPE. CONCLUSION: Many children and adolescents are unnecessarily denied treatment with BLA after an uncomplicated MPE while being treated with a BLA.

Insular giant leporid matured later than predicted by scaling.

The island syndrome describes morphological, behavioral, and life history traits that evolve in parallel in endemic insular organisms. A basic axiom of the island syndrome is that insular endemics slow down their pace of life. Although this is already confirmed for insular dwarfs, a slow life history in giants may not be adaptive, but merely a consequence of increasing body size. We tested this question in the fossil insular giant leporid Nuralagus rex. Using bone histology, we constructed both a continental extant taxon model derived from experimentally fluorochrome-labeled Lepus europaeus to calibrate life history events, and a growth model for the insular taxon. N. rex grew extremely slowly and delayed maturity well beyond predictions from continental phylogenetically corrected scaling models. Our results support the life history axiom of the island syndrome as generality for insular mammals, regardless of whether they have evolved into dwarfs or giants.

Alveolar macrophages in early stage COPD show functional deviations with properties of impaired immune activation.

Despite its high prevalence, the cellular and molecular mechanisms of chronic obstructive pulmonary disease (COPD) are far from being understood. Here, we determine disease-related changes in cellular and molecular compositions within the alveolar space and peripheral blood of a cohort of COPD patients and controls. Myeloid cells were the largest cellular compartment in the alveolar space with invading monocytes and proliferating macrophages elevated in COPD. Modeling cell-to-cell communication, signaling pathway usage, and transcription factor binding predicts TGF-ß1 to be a major upstream regulator of transcriptional changes in alveolar macrophages of COPD patients. Functionally, macrophages in COPD showed reduced antigen presentation capacity, accumulation of cholesteryl ester, reduced cellular chemotaxis, and mitochondrial dysfunction, reminiscent of impaired immune activation.

Palaeohistology reveals a slow pace of life for the dwarfed Sicilian elephant.

The 1-m-tall dwarf elephant Palaeoloxodon falconeri from the Pleistocene of Sicily (Italy) is an extreme example of insular dwarfism and epitomizes the Island Rule. Based on scaling of life-history (LH) traits with body mass, P. falconeri is widely considered to be 'r-selected' by truncation of the growth period, associated with an early onset of reproduction and an abbreviated lifespan. These conjectures are, however, at odds with predictions from LH models for adaptive shifts in body size on islands. To settle the LH strategy of P. falconeri, we used bone, molar, and tusk histology to infer growth rates, age at first reproduction, and longevity. Our results from all approaches are congruent and provide evidence that the insular dwarf elephant grew at very slow rates over an extended period; attained maturity at the age of 15 years; and had a minimum lifespan of 68 years. This surpasses not only the values predicted from body mass but even those of both its giant sister taxon (P. antiquus) and its large mainland cousin (L. africana). The suite of LH traits of P. falconeri is consistent with the LH data hitherto inferred for other dwarfed insular mammals. P. falconeri, thus, not only epitomizes the Island Rule but it can also be viewed as a paradigm of evolutionary change towards a slow LH that accompanies the process of dwarfing in insular mammals.

Labelling experiments in red deer provide a general model for early bone growth dynamics in ruminants.

Growth rates importantly determine developmental time and are, therefore, a key variable of a species' life history. A widely used method to reconstruct growth rates and to estimate age at death in extant and particularly in fossil vertebrates is the analysis of bone tissue apposition rates. Lines of arrested growth (LAGs) are of special interest here, as they indicate a halt in bone growth. However, although of great importance, the time intervals between, and particularly the reason of growth arrests remains unknown. Therefore, experiments are increasingly called for to calibrate growth rates with tissue types and life history events, and to provide reliable measurements of the time involved in the formation of LAGs. Based on in vivo bone labelling, we calibrated periods of bone tissue apposition, growth arrest, drift and resorption over the period from birth to post-weaning in a large mammal, the red deer. We found that bone growth rates tightly matched the daily weight gain curve, i.e. decreased with age, with two discrete periods of growth rate disruption that coincided with the life history events birth and weaning, that were visually recognisable in bone tissue as either partial LAGs or annuli. Our study identified for the first time in a large mammal a general pattern for juvenile bone growth rates, including periods of growth arrest. The tight correlation between daily weight gain and bone tissue apposition suggests that the red deer bone growth model is valid for ruminants in general where the daily weight gain curve is comparable.

Prospective evaluation of hydroxychloroquine in pediatric interstitial lung diseases: Study protocol for an investigator-initiated, randomized controlled, parallel-group clinical trial.

BACKGROUND: Interstitial lung diseases in children (chILD) are rare and consist of many different entities that affect the parenchyma of the lungs, leading to a chronic lung disease. The natural course of many of these diseases is connected with a high morbidity and significant mortality. Symptomatic treatment consists of oxygen supplementation, adequate nutrition adapted to the high energy demand generated by the disease due to the increased breathing effort required, as well as immunization against respiratory pathogens to prevent exacerbations through respiratory infections. No proven pharmacological treatments are available to date. This placebo-controlled study aims to evaluate the efficacy and safety of the mid-term use of hydroxychloroquine in chILD. METHODS AND DESIGN: The study is an explorative, prospective, randomized, double-blind, placebo-controlled investigation of hydroxychloroquine (HCQ) in chILD. Patients can be included into the trial when diagnosed with a chronic (≥ 3 weeks' duration) diffuse parenchymal lung disease (chILD) (1) genetically defined, (2) histologically defined or (3) diagnosed with idiopathic pulmonary hemorrhage (hemosiderosis). The study contains of two different study blocks, a START and a STOP block, which can be initiated in any sequence. Each patient can participate in each block only once. In the START block subjects are randomized to parallel groups for 4 weeks treatment, then the placebo group is switched to the active drug. In the STOP block, subjects taking HCQ are randomized into parallel groups treated with placebo or HCQ. DISCUSSION: This study is the first international, investigator-initiated, prospective and controlled investigation of a pharmacological treatment in chILD. The block design was selected as it has the advantage of accommodating patients who are initiating or withdrawing from HCQ therapy, thus allowing the participation of those who were previously started on off-label HCQ. The cross-over design and selected outcome parameters enables us to include appropriate numbers of patients of all age groups from neonates to adults suffering from these rare diseases. TRIAL REGISTRATION: This is an exploratory, Phase 2a, randomized, double-blind, placebo-controlled, parallel-group, multinational study investigating the initiation or withdrawal of hydroxychloroquine in subjects with chILD. Study title: Hydroxychloroquine in pediatric ILD: START randomized controlled in parallel groups, then switch placebo to the active drug, and STOP randomized controlled in parallel groups to evaluate the efficacy and safety of hydroxychloroquine (HCQ). Short title: HCQ in pediatric ILD, particularly 4surfdefect. EudraCT, ID: 2013-003714-40. Registered on 2 July 2013. ClinicalTrials.gov, ID: NCT02615938. Registered on 8 November 2015. IZKS trial code: 2013-006; Sponsor: University Hospital, Ludwig-Maximilians University of Munich. Responsible Party: Prof. Dr. med. Matthias Griese, University Hospital, Ludwig-Maximilians University of Munich, Germany.

Publisher Correction: Bone histology provides insights into the life history mechanisms underlying dwarfing in hipparionins.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Calibration of life history traits with epiphyseal closure, dental eruption and bone histology in captive and wild red deer.

The study of skeletochronology and bone tissue as a record of information on ontogenetic stages and events is widely used for improving the knowledge about life histories (LHs) of extinct and extant vertebrates. Compared with dinosaurs and extant reptiles, mammalian bone histology has received little attention. Here, we calibrate for the first time bone and dental age with histological bone characteristics and LH stages in ontogenetic series of red deer. We rely on known LHs of different aged individuals of captive Cervus elaphus hippelaphus from Austria to correlate epiphyseal closure, dental eruption pattern, bone growth marks and bone tissue patterns in femora and tibiae, and of wild Cervus elaphus hispanicus from Spain. Our data show that females (of both subspecies) attain skeletal maturity earlier than males. At this moment, epiphyseal closure (in femora and tibiae) and dental eruption are complete and long bones start to deposit an external fundamental system. The results also show that the attainment of reproductive maturity in red deer occurs slightly before skeletal maturity.

Bone histology provides insights into the life history mechanisms underlying dwarfing in hipparionins.

Size shifts may be a by-product of alterations in life history traits driven by natural selection. Although this approach has been proposed for islands, it has not yet been explored in continental faunas. The trends towards size decrease experienced by some hipparionins constitute a good case study for the application of a life history framework to understand the size shifts on the continent. Here, we analysed bone microstructure to reconstruct the growth of some different-sized hipparionins from Greece and Spain. The two dwarfed lineages studied show different growth strategies. The Greek hipparions ceased growth early at a small size thus advancing maturity, whilst the slower-growing Spanish hipparion matured later at a small size. Based on predictive life history models, we suggest that high adult mortality was the likely selective force behind early maturity and associated size decrease in the Greek lineage. Conversely, we infer that resource limitation accompanied by high juvenile mortality triggered decrease in growth rate and a relative late maturity in the Spanish lineage. Our results provide evidence that different selective pressures can precipitate different changes in life history that lead to similar size shifts.

Ontogeny and taxonomy of the hadrosaur (Dinosauria, Ornithopoda) remains from Basturs Poble bonebed (late early Maastrichtian, Tremp Syncline, Spain).

The lower Maastrichtian site of Basturs Poble (southern Pyrenees, Spain) is the first hadrosaur bonebed reported from Europe. It is an accumulation of disarticulated lambeosaurine skeletal elements, possibly belonging to Pararhabdodon isonensis. The sample shows high intraspecific morphological variability among many skeletal elements, suggesting the need for caution in choosing characters for phylogenetic analyses. Juvenile to adult individuals are represented in the sample, while hatchling remains are absent. Bone histology reveals that juveniles are over-represented and that the youngest individuals represented by tibia specimens were two years old. Adult individuals, with tibiae 550-600 mm long, were 14-15 years old when they died. However, individual variation in tibia length at skeletal maturity occurs within the sample, so individual maturity cannot be assumed on the basis of bone size alone. The Basturs Poble bonebed occurs within the upper part of the C31r magnetochron. Thus, lambeosaurine hadrosaurids were already present and abundant in the Ibero-Armorica Island at the end of the early Maastrichtian and P. isonensis spans the upper part of the lower Maastrichtian to the upper part of the upper Maastrichtian (upper part of C31r-lower part of C29r).

Nonlinear association structures in flexible Bayesian additive joint models.

Joint models of longitudinal and survival data have become an important tool for modeling associations between longitudinal biomarkers and event processes. The association between marker and log hazard is assumed to be linear in existing shared random effects models, with this assumption usually remaining unchecked. We present an extended framework of flexible additive joint models that allows the estimation of nonlinear covariate specific associations by making use of Bayesian P-splines. Our joint models are estimated in a Bayesian framework using structured additive predictors for all model components, allowing for great flexibility in the specification of smooth nonlinear, time-varying, and random effects terms for longitudinal submodel, survival submodel, and their association. The ability to capture truly linear and nonlinear associations is assessed in simulations and illustrated on the widely studied biomedical data on the rare fatal liver disease primary biliary cirrhosis. All methods are implemented in the R package bamlss to facilitate the application of this flexible joint model in practice.

Limb bone histology records birth in mammals.

The annual cyclicality of cortical bone growth marks (BGMs) allows reconstruction of some important life history traits, such as longevity, growth rate or age at maturity. Little attention has been paid, however, to non-cyclical BGMs, though some record key life history events such as hatching (egg-laying vertebrates), metamorphosis (amphibians), or weaning (suggested for Microcebus and the hedgehog). Here, we investigate the relationship between non-cyclical BGMs and a stressful biological event in mammals: the moment of birth. In the present study, we histologically examine ontogenetic series of femora, tibiae and metapodia in several extant representatives of the genus Equus (E. hemionus, E. quagga and E. grevyi). Our analysis reveals the presence of a non-cyclical growth mark that is deposited around the moment of birth, analogous to the neonatal line described for teeth. We therefore refer to it as neonatal line. The presence of this feature within the bone cross-section agrees with a period of growth arrest in newborn foals regulated by the endocrine system. The neonatal line is accompanied by modifications in bone tissue type and vascularization, and has been identified in all bones studied and at different ontogenetic ages. Our discovery of a non-cyclical BGM related to the moment of birth in mammals is an important step towards the histological reconstruction of life histories in extant and fossil equids.

Reconstructing molar growth from enamel histology in extant and extinct Equus.

The way teeth grow is recorded in dental enamel as incremental marks. Detailed analysis of tooth growth is known to provide valuable insights into the growth and the pace of life of vertebrates. Here, we study the growth pattern of the first lower molar in several extant and extinct species of Equus and explore its relationship with life history events. Our histological analysis shows that enamel extends beyond the molar's cervix in these mammals. We identified three different crown developmental stages (CDS) in the first lower molars of equids characterised by different growth rates and likely to be related to structural and ontogenetic modifications of the tooth. Enamel extension rate, which ranges from ≈400 µm/d at the beginning of crown development to rates of ≈30 µm/d near the root, and daily secretion rate (≈17 µm/d) have been shown to be very conservative within the genus. From our results, we also inferred data of molar wear rate for these equids that suggest higher wear rates at early ontogenetic stages (13 mm/y) than commonly assumed. The results obtained here provide a basis for future studies of equid dentition in different scientific areas, involving isotope, demographic and dietary studies.

Joint modeling of longitudinal autoantibody patterns and progression to type 1 diabetes: results from the TEDDY study.

AIMS: The onset of clinical type 1 diabetes (T1D) is preceded by the occurrence of disease-specific autoantibodies. The level of autoantibody titers is known to be associated with progression time from the first emergence of autoantibodies to the onset of clinical symptoms, but detailed analyses of this complex relationship are lacking. We aimed to fill this gap by applying advanced statistical models. METHODS: We investigated data of 613 children from the prospective TEDDY study who were persistent positive for IAA, GADA and/or IA2A autoantibodies. We used a novel approach of Bayesian joint modeling of longitudinal and survival data to assess the potentially time- and covariate-dependent association between the longitudinal autoantibody titers and progression time to T1D. RESULTS: For all autoantibodies we observed a positive association between the titers and the T1D progression risk. This association was estimated as time-constant for IA2A, but decreased over time for IAA and GADA. For example the hazard ratio [95% credibility interval] for IAA (per transformed unit) was 3.38 [2.66, 4.38] at 6 months after seroconversion, and 2.02 [1.55, 2.68] at 36 months after seroconversion. CONCLUSIONS: These findings indicate that T1D progression risk stratification based on autoantibody titers should focus on time points early after seroconversion. Joint modeling techniques allow for new insights into these associations.

Flexible Bayesian additive joint models with an application to type 1 diabetes research.

The joint modeling of longitudinal and time-to-event data is an important tool of growing popularity to gain insights into the association between a biomarker and an event process. We develop a general framework of flexible additive joint models that allows the specification of a variety of effects, such as smooth nonlinear, time-varying and random effects, in the longitudinal and survival parts of the models. Our extensions are motivated by the investigation of the relationship between fluctuating disease-specific markers, in this case autoantibodies, and the progression to the autoimmune disease type 1 diabetes. Using Bayesian P-splines, we are in particular able to capture highly nonlinear subject-specific marker trajectories as well as a time-varying association between the marker and event process allowing new insights into disease progression. The model is estimated within a Bayesian framework and implemented in the R-package bamlss.

The difficulty with correlations: Energy expenditure and brain mass in bats.

Brain mass has been suggested to determine a mammal's energy expenditure. This potential dependence is examined in 48 species of bats. A correlation between characters may be direct or derived from shared correlations with intervening factors without a direct interaction. Basal rate of metabolism in these bats increases with brain mass: large brains are more expensive than small brains, and both brain mass and basal rate increase with body mass. Basal rate and brain mass also correlate with food habits in bats. Mass-independent basal rate weakly correlates with mass-independent brain mass, the correlation only accounting for 12% of the variation in basal rate, which disappears when the combined effects of body mass and food habits are deleted. The correlation between basal rate and brain mass seen in this and other studies usually accounts for <10% of the variation in basal rate and often <4%, even when statistically significant, a minimalist explanation for the level the basal rate. This correlation probably reflects the intermediacy of secondary factors, as occurred with food habits in bats. Most biological correlations are complicated and must be examined in detail before assurance can be given as to their bases.

Histological variability in the limb bones of the Asiatic wild ass and its significance for life history inferences.

The study of bone growth marks (BGMs) and other histological traits of bone tissue provides insights into the life history of present and past organisms. Important life history traits like longevity or age at maturity, which could be inferred from the analysis of these features, form the basis for estimations of demographic parameters that are essential in ecological and evolutionary studies of vertebrates. Here, we study the intraskeletal histological variability in an ontogenetic series of Asiatic wild ass (Equus hemionus) in order to assess the suitability of several skeletal elements to reconstruct the life history strategy of the species. Bone tissue types, vascular canal orientation and BGMs have been analyzed in 35 cross-sections of femur, tibia and metapodial bones of 9 individuals of different sexes, ages and habitats. Our results show that the number of BGMs recorded by the different limb bones varies within the same specimen. Our study supports that the femur is the most reliable bone for skeletochronology, as already suggested. Our findings also challenge traditional beliefs with regard to the meaning of deposition of the external fundamental system (EFS). In the Asiatic wild ass, this bone tissue is deposited some time after skeletal maturity and, in the case of the femora, coinciding with the reproductive maturity of the species. The results obtained from this research are not only relevant for future studies in fossil Equus, but could also contribute to improve the conservation strategies of threatened equid species.

Longitudinal Frequencies of Blood Leukocyte Subpopulations Differ between NOD and NOR Mice but Do Not Predict Diabetes in NOD Mice.

Immune phenotyping provides insight into disease pathogenesis and prognostic markers. Trajectories from age of 4 to 36 weeks were modeled for insulin autoantibodies and for leukocyte subpopulations in peripheral blood from female NOD (n = 58) and NOR (n = 22) mice. NOD mice had higher trajectories of insulin autoantibodies, CD4(+) and CD8(+) T lymphocytes, B lymphocytes, IgD(+)IgM(-) B lymphocytes, and NK cells and lower trajectories of CD4(+)CD25(+) T lymphocytes, IgM(+) B lymphocytes, granulocytes, and monocytes than NOR mice (all p < 0.001). Of these, only the increased IAA trajectory was observed in NOD mice that developed diabetes as compared to NOD mice that remained diabetes-free. Therefore, the profound differences in peripheral blood leukocyte proportions observed between the diabetes-prone NOD mice and the diabetes-resistant mice do not explain the variation in diabetes development within NOD mice and do not provide markers for diabetes prediction in this model.

How large are the extinct giant insular rodents? New body mass estimations from teeth and bones.

The island rule entails a modification of the body size of insular mammals, a character related with numerous biological and ecological variables. From the Miocene to human colonization (Holocene), Mediterranean and Canary Islands were unaltered natural ecosystems, with paleofaunas formed with endemic giant rodents among other mammals. Our aim is to create methods to estimate the body masses of fossil island rodents and address the nature of ecological pressures driving the island rule. We created regression equations based on extant rodent data and used these to estimate the body masses of the extinct species. Our results show strong correlations between teeth, cranial and postcranial measurements and body mass, except for the length of the long bones, the transversal diameter of the distal tibia and the anteroposterior diameter of the proximal tibia, where the equations were less reliable. The use of equations obtained from a more homogeneous group (suborder and family) is preferable when analyzing the area of the first molar. The new regressions were applied to estimate the body masses of some Mediterranean and Canarian fossil rodents (Canariomys, C. bravoi 1.5 kg and C. tamarani 1 kg; Hypnomys, H. morpheus 230 g and H. onicensis 200 g; and Muscardinus cyclopeus 100 g). Our results indicate that under absence of predation, resource availability (island area) is the key factor that determines the size of the Canariomys sp. However, under presence of specialized predators (birds of prey), body size evolution is less pronounced (Hypnomys sp.).