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The MHC class I region contains crucial genes for the innate and adaptive immune response, playing a key role in susceptibility to many autoimmune and infectious diseases. Genome‐wide association studies have identified numerous disease‐associated SNPs within this region. However, these associations do not fully capture the immune‐biological relevance of specific HLA alleles. HLA imputation techniques may leverage available SNP arrays by predicting allele genotypes based on the linkage disequilibrium between SNPs and specific HLA alleles. Successful imputation requires diverse and large reference panels, especially for admixed populations. This study employed a bioinformatics approach to call SNPs and HLA alleles in multi‐ethnic samples from the 1000 genomes (1KG) dataset and admixed individuals from Brazil (SABE), utilising 30X whole‐genome sequencing data. Using HIBAG, we created three reference panels: 1KG (n = 2504), SABE (n = 1171), and the full model (n = 3675) encompassing all samples. In extensive cross‐validation of these reference panels, the multi‐ethnic 1KG reference exhibited overall superior performance than the reference with only Brazilian samples. However, the best results were achieved with the full model. Additionally, we expanded the scope of imputation by developing reference panels for non‐classical, MICA, MICB and HLA‐H genes, previously unavailable for multi‐ethnic populations. Validation in an independent Brazilian dataset showcased the superiority of our reference panels over the Michigan Imputation Server, particularly in predicting HLA‐B alleles among Brazilians. Our investigations underscored the need to enhance or adapt reference panels to encompass the target population's genetic diversity, emphasising the significance of multiethnic references for accurate imputation across different populations. [ABSTRACT FROM AUTHOR]

The terahertz (THz) plasmonic instability in the lateral graphene structure (LGS) with the n+‐i‐n‐i‐n+ junction in its graphene channel (GC) is analyzed. The i‐regions in the LGS n+‐i‐n‐i‐n+ GC plays the role of the transit spaces of the electrons emitted from the n+‐regions (the emitters) and collected by the gated n‐region (collector) and the side contact to the latter. The interband Zener–Klein tunneling (ZKT) in the i‐regions also contributes to the currents received by the n‐region. Simultaneously, the n‐region constitutes the transverse resonant plasmonic cavity, in which the plasmons with the wave vector directed perpendicular to the electron propagation direction are excited. The plasmonic instability in the LGSs is associated with the transit‐time negative dynamic conductance of the i‐regions supported by the plasmonic resonances in the n‐region. The self‐excitation of plasmonic oscillations associated with the instability in the LGS with sub‐micrometer i‐regions and supplied with a proper antenna can lead to the emission of THz radiation. The LGS can form periodic arrays, which can serve as an active distributed antenna. [ABSTRACT FROM AUTHOR]

Human genomics has quickly evolved, powering genome‐wide association studies (GWASs). SNP‐based GWASs cannot capture the intense polymorphism of HLA genes, highly associated with disease susceptibility. There are methods to statistically impute HLA genotypes from SNP‐genotypes data, but lack of diversity in reference panels hinders their performance. We evaluated the accuracy of the 1000 Genomes data as a reference panel for imputing HLA from admixed individuals of African and European ancestries, focusing on (a) the full dataset, (b) 10 replications from 6 populations, and (c) 19 conditions for the custom reference panels. The full dataset outperformed smaller models, with a good F1‐score of 0.66 for HLA‐B. However, custom models outperformed the multiethnic or population models of similar size (F1‐scores up to 0.53, against up to 0.42). We demonstrated the importance of using genetically specific models for imputing populations, which are currently underrepresented in public datasets, opening the door to HLA imputation for every genetic population. [ABSTRACT FROM AUTHOR]

Field hockey players are exposed to high biomechanical loads. These loads often cannot be adequately estimated with global navigational satellite systems (GNSS) since on-field displacements during these movements are often small. Therefore, this study aims to explore the potential of different proxies of biomechanical load in field hockey with use of a simple inertial measurement unit (IMU) system. Sixteen field hockey players performed a range of field hockey specific exercises, including running with stick on the ground, running upright, and different types of shots and passes. All exercises were performed at two different frequencies (i.e. number of actions per minute). A variety of proxies of biomechanical load (time spent with forward tilted pelvis, time spent in lunge position, time spent with flexed thighs, and Hip Load) were obtained using wearable IMUs. In addition, total distance was quantified using a GNSS system. Linear mixed models were constructed to determine the effects of the different exercises and action frequency on all quantified metrics. All metrics increased approximately proportional to the increase in action frequency. Total distance and Hip Load were greatest for the running exercises, but the different types of shots and passes had greater effects on specific on the times spent in the demanding body postures. This shows that these proxies of biomechanical load can be used to estimate field hockey-specific biomechanical loads. The use of these metrics may provide coaches and medical staff with a more complete view of the training load that field hockey players experience. Highlights New proxies of biomechanical load derived with inertial measurement units were used to quantify field hockey specific biomechanical loads. These new biomechanical metrics are complementary to metrics obtained with global navigation satellite systems and increased proportionally to a doubling of the exercise intensity. The presented biomechanical load metrics can help field hockey coaches to achieve a better balance between load and recovery for their players. [ABSTRACT FROM AUTHOR]

Systems Modeling Language (SysML) has been applied in the past years to a variety of software and systems engineering projects, by hundreds of researchers, engineers, and other systems and software professionals. Thus, it is expected that all this experience has been described in research articles. Therefore, we propose a survey describing what practitioners and researchers think about this modeling language, the actual use of SysML, and how SysML is used in the software and system engineering life cycle. This article describes a survey on SysML, answering questions such as the most used diagrams for each phase of the development of a system, the most common domains, and other data about the participants. The survey was answered by 343 participants from 38 countries, mostly systems engineers, software and systems architects, and researchers. Industry and academia can use our results (i) for assisting researchers and engineers to select appropriate diagrams for each software and systems development phase, (ii) for a better understanding of which industry domains SysML is most commonly applied, (iii) as a reference for identifying which types of systems are modeled with SysML, (iv) for knowing which software tools are most used, and (v) which other modeling languages are most commonly integrated with SysML for software and systems development. [ABSTRACT FROM AUTHOR]

The rating of perceived exertion method (RPE) allows to describe training intensity in a single value. To better understand the underlying components, the separate rating of perceived breathlessness (RPE-B) and leg-muscle exertion (RPE-L) has been proposed. Here we hypothesised that the separation between the two components may (partly) be determined by the impacts on the lower extremities. In this study, we aimed to experimentally evaluate the differential effect of high versus low impact running and jumping on RPE-B and RPE-L in team sport activities by manipulating the movement strategy (heel strike and passive landing pattern versus forefoot strike and active landing pattern). Eighteen recreational team sport players participated in two submaximal tests consisting of a sequence of running and jumping bouts, whilst ground reaction forces (GRF) were collected. RPE-B and RPE-L data were collected after each bout using the CR100 scale. Paired-samples t-tests were used to analyse between-session differences in these variables. GRF analysis showed that absorption mechanics differed considerably between the two sessions. RPE-L was on average 6.50 AU higher in the low impact session (p = 0.006). However, RPE-B was also increased by 4.96 AU with low impact (p = 0.009). We conclude that the extent to which the lower extremities are being exposed to high or low impacts does not explain a possible separation between the two RPE types. Highlights The separate rating of the different underlying components of RPE (e.g. variables related to the cardiorespiratory and the muscular system) may provide more insight in the relationship between training load and training outcomes, which likely differs between these components. The findings of this study do not support the idea that the separation in rating between perceived breathlessness (RPE-B, cardiorespiratory) and leg-muscle exertion (RPE-L, muscular) is also rooted in the extent to which musculoskeletal structures in the lower extremities are being exposed to high or low impacts. [ABSTRACT FROM AUTHOR]

Summary: Introduction: This systematic review and meta‐analysis investigate the long‐term effects of primary school‐based obesity prevention interventions on body‐mass index (and z‐scores), waist circumference (and z‐scores) and weight status. Methods: Four databases were searched for studies from date of inception until June 8th, 2021. We included randomized controlled trials (RCT) and non‐RCTs investigating effects ≥12 months post‐intervention of primary school‐based interventions with intervention duration ≥6 months and containing a diet and/or physical activity component on outcomes of interest. Articles were assessed on risk of bias and methodological quality by RoB2 and ROBINS‐I. Meta‐analysis was performed and results were narratively summarized. Evidence quality was assessed with GRADE. Results: Nineteen studies were included, 9 were pooled in a meta‐analysis. No long‐term effects were found on body‐mass index (+0.06 kg/m2; CI95% = −0.38, 0.50; I2 = 66%), body‐mass index z‐scores (−0.08; CI95% = −0.20, 0.04; I2 = 36%), and waist circumference (+0.57 cm; CI95% = −0.62, 1.75; I2 = 13%). Non‐pooled studies reported mixed findings regarding long‐term effects on body‐mass index, body‐mass index z‐scores and weight status, and no effects on waist circumference and waist circumference z‐scores. Evidence certainty was moderate to very low. Discussion: No clear evidence regarding long‐term effects of primary school‐based interventions on obesity‐related outcomes was found. Recommendations for further research and policy are discussed. Prospero registration ID: CRD42021240446. [ABSTRACT FROM AUTHOR]

El Niño Southern Oscillation (ENSO) events yield precipitation deficits and ensuing droughts, often damaging regional forests, in many parts of the world. The relative roles of ENSO, other natural climate changes, and anthropogenic factors on the forest clearing of Easter Island over the last millennium are still debated. Here, we analyze Easter Island precipitation changes using in situ, satellite‐derived and reanalysis products spanning the last 4–7 decades, and 46 monthly 156‐year‐long (1850–2014) simulations derived from 25 CMIP5 and 21 CMIP6 (Coupled Model Intercomparison Project phases 5 and 6) General Circulation Models. Our analysis shows that La Niña events, the cold phases of ENSO, cause precipitation deficits of −0.2 to −0.3 standard deviation (relative to long‐term mean) in all analyzed data types. ENSO‐like events are further examined over the last millennium (850–1981). A new multiproxy reconstruction of the NINO3.4 index based on proxy records from the Past Global Changes 2k database and Random Forest method is produced. Our reconstruction reveals unusual high recurrences of La Niña‐like situations during the fifteenth to seventeenth centuries, which likely induced significant precipitation deficits on the island. These situations are compared to published vegetation reconstructions based on pollen analyses derived from sedimentary cores collected in three island sites. We conclude the environmental consequences of cumulative precipitation deficits over long‐lasting La Niña‐like situations reconstructed here over the fifteenth to seventeenth centuries were likely favoring drought and forest flammability. La Niña events should be better accounted for among the causes of forest clearing on Easter Island. Plain Language Summary: Easter Island is a small remote island located in the south‐eastern Pacific Ocean. It is home of several scientific enigmas: the origin of early settlements, the construction of the giant moai statues, and causes of the forest clearing. Was the forest clearing abrupt, gradual, homogenous in time and space, human‐induced (in line with the ecocide hypothesis), or related to natural climate variability? The question we address in this paper is related to the natural climate variability hypothesis, focusing on the El Niño Southern Oscillation (ENSO) phenomenon. We analyze ENSO effects on Easter Island precipitation from three instrumental (1950–2021) and 42‐simulation data sets (1850–2014). Our analysis shows the cold phases of ENSO, also known as La Niña, cause significant precipitation deficits over the island in all analyzed data types. Then, we provide a new up‐to‐date reconstruction of ENSO over 850–1981. We found a large number of La Niña‐like situations during the fifteenth‐seventeenth centuries. These situations are compared to vegetation reconstructions derived from sedimentary cores collected in three island sites. We conclude that the environmental consequences of cumulative precipitation deficits during long‐lasting La Niña‐like situations could be an additional cause of the forest clearing of Easter Island. Key Points: Analysis of independent data sets shows precipitation deficits over Eastern Island during La Niña events over the period 1850–2021A new reconstruction of El Niño Southern Oscillation episodes reveals a large number of La Niña‐like situations during the fifteenth to seventeenth centuriesHigh repetitions of La Niña events, favoring drought, likely played a role in the forest clearing of the island, on top of other stressors [ABSTRACT FROM AUTHOR]

Background: Dementia affects more Black individuals, likely due to a combination of environmental and biological factors1,2,3. APOE ε4 allele risk of dementia is different between individuals with European (EUR) and African (AFR) ancestries4,5,6. It is unclear what drives these differences in Alzheimer's disease (AD) neuropathology among patients with cognitive decline, both outcomes influenced by different sets of biological and environmental factors. We studied the interaction between global and local APOE African ancestry, e4 allele, burden of neuritic plaques (NP) and neurofibrillary tangles (NFT), and cognition in a postmortem sample of admixed individuals with AD pathology. Method: Community‐dwelling autopsied brains (n=400) without neuropathological changes or with NP scored using CERAD and NFT scored by Braak stage but lacking others comorbid neuropathologies. Subject's cognitive function prior to death as assessed using Clinical Dementia Rating sum of boxes (CDR‐SOB). APOE genotypes were assessed with allele‐specific amplification. Global ancestry was inferred using Admixture and local ancestry using RFMix, derived from panels of variants interrogated by microarray. Result: When dichotomously ascertained at 2% of AFR, and adjusting for age, sex, educational attainment and APOE ε4 carrier status, the admixed group is significantly protected of neuritic plaques (NP, beta=‐0.21, p=0.04) but not neurofibrillary tangles (NFT, beta=0.137, p=0.39). However, CDR‐SOB was associated with continuously distributed AFR (Table 1) only among individuals with severe levels of NFT (beta=7.04, p<0.001) and NP (beta=3.9, p<0.001). Stratifying the same analysis between APOE status, only APOE ε4 noncarriers presented significant associations between AFR and CDR‐SOB, but APOE ε4 carriers lost significance. APOE local ancestry inference of showed that non‐European admixed APOE ε4 noncarriers had lower NP burden outcomes (Table 2, beta=‐0.28, p=0.032 and beta=‐0.27, p=0.015 with and without adjusting for AFR, respectively), but worst cognitive decline compared to European APOE of the same genotype group when adjusting by NP levels (beta=1.01, p=0.041, without adjusting for AFR). Lastly, APOE ε has a significant effect on neuropathology, but not cognition, only within European local ancestry contexts (Table 3, beta=0.61, p<0.001). Conclusion: Our results demonstrate a complex relation between APOE genotypes and local ancestry, AFR global ancestry and AD‐related neuropathology and cognition outcomes. [ABSTRACT FROM AUTHOR]

The 700‐km‐long Chaman fault (CF) marks the western edge of the plate boundary between India and Eurasia. Although global plate models predict 2.3–3.6 cm/yr left‐lateral motion between both plates, the fault is known to have hosted few earthquakes in historical times. Recent geodetic measurements attested the presence of aseismic slip locally. To detail the interplay between fast and slow slip along the CF, we build three Interferometric Synthetic‐Aperture Radar time series of ground deformation covering the whole fault length over 5 years (2014–2019). We find that most of the active fault trace slips aseismically and continuously. From south to north, we identify three creeping fault portions: the Nushki, Central, and Qalat segments of lengths between 80 and 130 km. The loading rate is 1.2 ± 0.3 cm/yr for the two southernmost portions, while it is about 0.7 ± 0.2 cm/yr for the Qalat segment. The Central segment and the nearby locked segments have hosted the largest known historical earthquakes on the CF, and three moderate magnitude earthquakes in our observation period. We image these earthquakes for which modeled slip at depth (Mw 5–5.6), time series of surface slip and deformation patterns argue toward large triggered aseismic slip. The June 2018 event displays postseismic moment 3–15 times greater than coseismic moment. Over the two decades covered by geodetic observations, continuous or triggered aseismic slip dominates along most of the fault and co‐locates with earthquakes. We observe that fault geometrical complexities delimit active segments and may be responsible for the kilometer‐scale intertwining between seismic and aseismic events. Plain Language Summary: The Chaman fault (CF) separates Indian and Eurasian tectonic plates moving at about 3 cm/yr with respect to each other. This fault is known to have hosted very few earthquakes (sudden and rapid slip) in historical times, and appears to slip slowly. We measure slip on the CF with radar satellite images covering 2014–2019, and assess the average amount of slip attributed to earthquakes over the past century. We identify three 80–130‐km‐long portions of the 700‐km‐long fault that slip silently, without radiating seismic waves, at rates reaching 1.2 ± 0.3 cm/year along the southern half, and 0.7 ± 0.2 cm/year in the north. The largest historical earthquakes and three earthquakes of moderate size in our observation period occurred on the central part of the CF. We image the surface deformation induced by these three earthquakes and find that they were followed by significant slow slip on the fault, especially the third event in June 2018. Since the 2000s space‐based measurements indicate that the slow mode of slip dominates on the CF plane and co‐locates with earthquakes. Changes of fault orientation may delimit portions of the fault which either slip slowly or break into fast earthquakes. Key Points: Aseismic slip along the Chaman fault (CF) reaches 12 mm/yr with three large distinct aseismic sections, despite marked elastic strain increaseThree earthquakes are imaged along the central CF and two exhibit large post‐seismic afterslipAlong‐strike distribution of slip is compared with historical seismicity and fault geometry [ABSTRACT FROM AUTHOR]

Summary: Design flaws and vulnerabilities inherent to network protocols, devices, and services make Distributed Denial of Service (DDoS) a persisting threat in the cyberspace, despite decades of research efforts in the area. The historical vertical integration of traditional IP networks limited the solution space, forcing researchers to tweak network protocols while maintaining global compatibility and proper service to legitimate flows. The advent of Software‐Defined Networking (SDN) and advances in Programmable Data Planes (PDP) changed the state of affairs and brought novel possibilities to deal with such attacks. In summary, the ability of bringing together network intelligence to a control plane, and offloading flow processing tasks to the forwarding plane, opened up interesting opportunities for network security researchers unlike ever. In this article, we dive into recent research that relies on SDN and PDP to detect, mitigate, and prevent DDoS attacks. Our literature review takes into account the SDN layered view as defined in RFC7426 and focuses on the data, control, and application planes. We follow a systematic methodology to capture related articles and organize them into a taxonomy of DDoS defense mechanisms focusing on three facets: activity level, deployment location, and cooperation degree. From the analysis of existing work, we also highlight key research gaps that may foster future research in the field. [ABSTRACT FROM AUTHOR]

We study the drivers behind the global atmospheric methane (CH4) increase observed after 2006. Candidate emission and sink scenarios are constructed based on proposed hypotheses in the literature. These scenarios are simulated in the TM5 tracer transport model for 1984–2016 to produce three‐dimensional fields of CH4 and δ13C‐CH4, which are compared with observations to test the competing hypotheses in the literature in one common model framework. We find that the fossil fuel (FF) CH4 emission trend from the Emissions Database for Global Atmospheric Research 4.3.2 inventory does not agree with observed δ13C‐CH4. Increased FF CH4 emissions are unlikely to be the dominant driver for the post‐2006 global CH4 increase despite the possibility for a small FF emission increase. We also find that a significant decrease in the abundance of hydroxyl radicals (OH) cannot explain the post‐2006 global CH4 increase since it does not track the observed decrease in global mean δ13C‐CH4. Different CH4 sinks have different fractionation factors for δ13C‐CH4, thus we can investigate the uncertainty introduced by the reaction of CH4 with tropospheric chlorine (Cl), a CH4 sink whose abundance, spatial distribution, and temporal changes remain uncertain. Our results show that including or excluding tropospheric Cl as a 13 Tg/year CH4 sink in our model changes the magnitude of estimated fossil emissions by ∼20%. We also found that by using different wetland emissions based on a static versus a dynamic wetland area map, the partitioning between FF and microbial sources differs by 20 Tg/year, ∼12% of estimated fossil emissions. Key Points: Increased fossil fuel emissions are unlikely the dominant driver for post‐2006 global CH4 increaseA significant decrease in the abundance of hydroxyl radicals (OH) cannot explain the post‐2006 global CH4 increaseCH4 emission attributions are sensitive to the uncertainties in OH fractionation, tropospheric Cl sink, and wetland areas [ABSTRACT FROM AUTHOR]

Background: Apolipoprotein E ε4 allele (APOE‐ε4) is the main genetic risk factor for dementia. APOE‐ε4 is also associated with Alzheimer's disease (AD) pathology, cerebrovascular disease, and non‐AD neurodegenerative pathologies. Although APOE‐ε4 may influence cognitive impairment through these pathways, less evidence is available from diverse populations, considering that APOE genotype associations seem to vary by race. Therefore, we aimed to evaluate the pathways linking APOE‐ε4 to cognition through AD and non‐AD neuropathology in an autopsy study with an admixed sample. Method: We used data from the Biobank for Aging Studies of the University of Sao Paulo Medical School. Participants were classified into APOE‐ε4 carriers (at least one ε4 allele) and non‐carriers. Cognitive function was evaluated by the Clinical Dementia Rating Scale sum of boxes. Mediation analyses were conducted to assess the APOE‐ε4 association with cognition through direct and indirect pathways. Indirect pathways included the following mediators: AD‐type pathology, lacunar infarcts, hyaline arteriosclerosis, cerebral amyloid angiopathy (CAA), Lewy body disease (LBD), and TAR DNA‐binding protein 43 (TDP‐43). We used immunohistochemistry to detect AD pathology, CAA, LBD, and TDP‐43. AD pathology was scored using the Braak staging for neurofibrillary tangles and the Consortium to Establish a Registry for AD criteria for β‐amyloid plaque. Lacunar infarcts and hyaline arteriosclerosis were evaluated microscopically using hematoxylin and eosin‐stained. All analyses were adjusted for demographic and clinical cofounders. Result: We included 648 participants (mean age 75±12 y, 52% women, 69% white, and 28% APOE‐ε4 carriers). The association between APOE‐ε4 and cognitive abilities was mediated by the burden of neurofibrillary tangles (β = 0.78, 95% CI = 0.39; 1.22, p<0.001) and β‐amyloid plaques (β = 0.87, 95% CI = 0.39; 1.40, p<0.001). Lacunar infarcts, hyaline arteriosclerosis, CAA, LBD, and TDP‐43 were not mediators in the pathway from APOE‐ε4 to cognitive function. Direct pathways remained significant in the presence of all mediators except TDP‐43 (p = 0.09) and β‐amyloid plaques (p = 0.07). Conclusion: The influence of APOE‐ε4 on cognitive abilities was partially mediated by AD pathology. However, cerebrovascular lesions and non‐AD pathologies were not mediators in the pathway linking APOE‐ε4 to cognition. [ABSTRACT FROM AUTHOR]

Background: The APOE gene is identified as a major risk factor for late onset Alzheimer's disease and has three alleles, ε2, ε3 and ε4, related to two non‐synonymous substitutions. The presence of the ε4 allele confers an increased risk for the disease in a dose dependent manner (odds ratio 12.9 for homozygous individuals and between 3.2 and 4.2 for heterozygous individuals). The most prevalent form of Alzheimer's disease has a multifactorial etiology, where several genetic and environmental factors influence its pathology. Factors such as age and sex are relevant in determining the risk for APOE, recent studies point out that the ancestry around the APOE gene is also relevant to the risk for the disease. Individuals of African‐American ancestry have a reduced risk of developing the disease compared to European and Asian whites. These regions may act in a cis‐regulatory manner in modulating gene expression. The Brazilian population results from miscegenation between indigenous, African and European populations, offering an opportunity to study the effects of different ancestries on the risk of Alzheimer's disease, fill the lack of genetic information about admixed groups and characterize the differential patterns of APOE's expression in Brazilian population. Method: This project aims to quantitatively characterize the role of different local ancestry in the different APOE genotypes using 36 post‐mortem brain tissue, with distinct genotypes and local ancestries combinations (33,34,44, European‐European, African‐African, European‐African, African‐European) and associating them with the expression of this gene through molecular marker genotyping and RT‐qPCR techniques. It is expected that the mRNA expression is differentially increased when European local ancestry is shown to be present, compared to non‐European ancestry and may explain, in part, the difference in risks observed in populations of different ancestries. Result: ongoing research Conclusion: ongoing research [ABSTRACT FROM AUTHOR]

Objective: The objectives of the present study were to: (1) evaluate the effect of an educational course on competence (knowledge and clinical reasoning) of primary care physical therapists (PTs) in treating patients with knee osteoarthritis (KOA) and comorbidity according to the developed strategy; and (2) identify facilitators and barriers for usage. Method: The present research was an observational study with a pretest‐posttest design using mixed methods. PTs were offered a postgraduate course consisting of e‐learning and two workshops (blended education) on the application of a strategy for exercise prescription in patients with KOA and comorbidity. Competences were measured by questionnaire on knowledge (administered before and 2 weeks after the course), and a patient vignette to measure clinical reasoning (administered before the course and after a 6 month period of treating patients). Facilitators and barriers for using the strategy were assessed by a questionnaire and semi‐structured interviews. Results: Thirty‐four PTs were included. Competence (knowledge and clinical reasoning) improved significantly (p < 0.01). Fourteen out of 34 PTs had actually treated patients with KOA and comorbidity, during a 6‐month period. The strategy was found to be feasible in daily practice. The main barriers included the limited number of (self‐) referrals of patients, limited number of reimbursed treatment sessions by insurance companies and a suboptimal collaboration with (referring) physicians. Conclusion: A blended course on exercise therapy for patients with KOA and comorbidity seems to improve PTs' competence through increasing knowledge and clinical reasoning skills. Identified barriers should be solved before large‐scale implementation of exercise therapy can take place in these complex patients. [ABSTRACT FROM AUTHOR]

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Talented athletes use metacognitive skills to improve their performance. Also, it is known that these skills are important for managing one's health. The goal of this study was to identify the relationship between metacognitive skills and overuse injuries in talented tennis players. Metacognitive skills were measured in 73 talented tennis players (45 boys and 28 girls, age 11‐14) at the start of the season, using the Self‐Regulation of Learning Self‐Report Scale. Overuse injuries were monitored for one season using the Oslo Sports Trauma Research Centre Questionnaire on Health Problems. Ordinal regression indicated that moderate or low selfmonitoring skills (compared to high selfmonitoring) (OR 4.555, CI 1.096‐18.927, P = 0.037) and exposure time (OR 1.380, CI 1.106‐1.721, P = 0.004) were associated with more time loss overuse injuries. A second analysis showed that this was the case in girls (OR 10.757, CI 1.845‐62.714, P = 0.008), but not in boys. Linear regression revealed that higher reflection scores and exposure time predicted overuse severity (F(5,58) = 2.921, P = 0.020, R2 = 0.201). Possibly, selfmonitoring can help players to prevent themselves from time loss overuse injuries. Coaches should be aware that players can differ in selfmonitoring ability and thus in the ability to prevent overuse injuries. The role of reflection needs more research. [ABSTRACT FROM AUTHOR]

The purpose of this study was to investigate the relation between external and internal load and the response of the patellar tendon structure assessed with ultrasound tissue characterization (UTC) in elite male volleyball players during preseason. Eighteen players were followed over 7 weeks, measuring four load parameters during every training and match: volume (minutes played), rating of perceived exertion (RPE) (ranging from 6 to 20), weekly load (RPE*volume), and jump frequency (number of jumps). Patellar tendon structure was measured biweekly using UTC, which quantifies tendon matrix stability resulting in four different echo types (I‐IV). On average, players spent 615 min/wk on training and matches with an RPE of 13.9 and a jump frequency of 269. Load evaluation shows significant changes over the 7 weeks: Volume and weekly load parameters were significantly higher in week 3 than week 7 and in week 4 than week 2. Weekly load performed in week 4 was significantly higher than week 7. No significant changes were observed in tendon structure. On the non‐dominant side, no significant correlations were found between changes in load parameters and echo types. At the dominant side, a higher weekly volume and weekly load resulted in a decrease of echo type I and a higher mean RPE in an increase of echo type II. The results of this study show that both external and internal load influence changes in patellar tendon structure of elite male volleyball players. Monitoring load and the effect on patellar tendon structure may play an important role in injury prevention. [ABSTRACT FROM AUTHOR]

Background: Although the Nordic Hamstring Exercise (NHE) prevents hamstring injury in soccer players effectively, the annual incidence of these injuries still increases. This may be because of poor long‐term compliance with the program. Furthermore, the timing and amplitude of gluteal and core muscle activation seem to play an important role in hamstring injury prevention, the NHE program was not designed to improve activation of these muscles. Therefore, we propose plyometric training as an alternative to reduce hamstring injuries in soccer players. Purpose: To determine the preventive effect of the Bounding Exercise Program (BEP) on hamstring injury incidence and severity in adult male amateur soccer players. Study design: A cluster‐Randomized Controlled Trial. Methods: Thirty‐two soccer teams competing in the first‐class amateur league were cluster‐randomized into the intervention or control group. Both groups were instructed to perform their regular training program, and the intervention group additionally performed BEP. Information about player characteristics was gathered at baseline and exposure, hamstring injuries and BEP compliance were weekly registered during one season (2016‐2017). Results: The data of 400 players were analyzed. In total, 57 players sustained 65 hamstring injuries. The injury incidence was 1.12/1000 hours in the intervention group and 1.39/1000 hours in the control group. There were no statistically significant differences in hamstring injury incidence (OR = 0.89, 95% CI 0.46‐1.75) or severity between the groups (P > 0.48). Conclusion: In this large cluster‐randomized controlled trial, no evidence was found for plyometric training in its current form to reduce hamstring injuries in amateur soccer players. [ABSTRACT FROM AUTHOR]

Atmospheric methane grew very rapidly in 2014 (12.7 ± 0.5 ppb/year), 2015 (10.1 ± 0.7 ppb/year), 2016 (7.0 ± 0.7 ppb/year), and 2017 (7.7 ± 0.7 ppb/year), at rates not observed since the 1980s. The increase in the methane burden began in 2007, with the mean global mole fraction in remote surface background air rising from about 1,775 ppb in 2006 to 1,850 ppb in 2017. Simultaneously the 13C/12C isotopic ratio (expressed as δ13CCH4) has shifted, has shifted, now trending negative for more than a decade. The causes of methane's recent mole fraction increase are therefore either a change in the relative proportions (and totals) of emissions from biogenic and thermogenic and pyrogenic sources, especially in the tropics and subtropics, or a decline in the atmospheric sink of methane, or both. Unfortunately, with limited measurement data sets, it is not currently possible to be more definitive. The climate warming impact of the observed methane increase over the past decade, if continued at >5 ppb/year in the coming decades, is sufficient to challenge the Paris Agreement, which requires sharp cuts in the atmospheric methane burden. However, anthropogenic methane emissions are relatively very large and thus offer attractive targets for rapid reduction, which are essential if the Paris Agreement aims are to be attained. Plain Language Summary: The rise in atmospheric methane (CH4), which began in 2007, accelerated in the past 4 years. The growth has been worldwide, especially in the tropics and northern midlatitudes. With the rise has come a shift in the carbon isotope ratio of the methane. The causes of the rise are not fully understood, and may include increased emissions and perhaps a decline in the destruction of methane in the air. Methane's increase since 2007 was not expected in future greenhouse gas scenarios compliant with the targets of the Paris Agreement, and if the increase continues at the same rates it may become very difficult to meet the Paris goals. There is now urgent need to reduce methane emissions, especially from the fossil fuel industry. Key Points: Atmospheric methane is rising; its carbon isotopic ratio has become more depleted in C‐13The possible causes of the change include an increase in emissions, with changing relative proportions of source inputs, or a decline in methane destruction, or bothIf this rise continues, there are significant consequences for the UN Paris Agreement [ABSTRACT FROM AUTHOR]

From 2007 to 2013, the globally averaged mole fraction of methane in the atmosphere increased by 5.7 ± 1.2 ppb yr−1. Simultaneously, δ13CCH4 (a measure of the 13C/12C isotope ratio in methane) has shifted to significantly more negative values since 2007. Growth was extreme in 2014, at 12.5 ± 0.4 ppb, with a further shift to more negative values being observed at most latitudes. The isotopic evidence presented here suggests that the methane rise was dominated by significant increases in biogenic methane emissions, particularly in the tropics, for example, from expansion of tropical wetlands in years with strongly positive rainfall anomalies or emissions from increased agricultural sources such as ruminants and rice paddies. Changes in the removal rate of methane by the OH radical have not been seen in other tracers of atmospheric chemistry and do not appear to explain short-term variations in methane. Fossil fuel emissions may also have grown, but the sustained shift to more 13C-depleted values and its significant interannual variability, and the tropical and Southern Hemisphere loci of post-2007 growth, both indicate that fossil fuel emissions have not been the dominant factor driving the increase. A major cause of increased tropical wetland and tropical agricultural methane emissions, the likely major contributors to growth, may be their responses to meteorological change. [ABSTRACT FROM AUTHOR]

Objective: To compare the natural history of familial transthyretin amyloid polyneuropathies (FAP) due to the Val30Met, Ser77Tyr, and Ile107Val mutations in France with the classical Portuguese Val30Met FAP.Methods: We compared 84 French patients with a control group of 110 Portuguese patients carrying the Val30Met mutation also living in France, all referred to and followed at the French National FAP Reference Center from 1988 to 2010. Clinical examination, functional and walking disability scores, nerve conduction studies, and muscle biopsies are reported. We also conducted a comprehensive literature review to further determine the range of phenotypic expression.Results: By comparison with Portuguese Val30Met FAP, French Ile107Val, Ser77Tyr, and LateVal30Met FAP showed more rapid and severe disease progression; onset of gait disorders was 3 times more rapid (p < 0.0001) and the rate of modified Norris test decline was up to 40 times faster in Ile107Val patients (p < 0.0001). Median survival was much shorter in Ile107Val and in Val30Met mutation with late onset (>50 years; LateMet30) FAP (p = 0.0005). Other distinctive features relative to the Portuguese patients included atypical clinical presentations, demyelination on nerve conduction studies (p = 0.0005), and difficult identification of amyloid deposits in nerve and muscle biopsies.Interpretation: Ile107Val and LateMet30 mutations are associated with the most debilitating and severe FAP ever described, with rapid onset of tetraparesis and shorter median survival. It could be explained by frequent large-fiber involvement and associated demyelination and more severe axonal loss. These findings have major implications for genetic counseling and patient management as new therapeutic options are being assessed in clinical trials (TTR gene silencing). [ABSTRACT FROM AUTHOR]

Background Genomewide association studies identified ORMDL3 as a plausible asthma candidate gene. ORMDL proteins regulate sphingolipid metabolism and ceramide homeostasis and participate in lymphocyte activation and eosinophil recruitment. Strong sequence homology between the three ORMDL genes and ORMDL protein conservation among different species suggest that they may have shared functions. We hypothesized that if single nucleotide polymorphisms ( SNPs) in ORMDL3 alter its gene expression and play a role in asthma, variants in ORMDL1 and ORMDL2 might also be associated with asthma. Methods Asthma associations of 44 genotyped SNPs were determined in at least 1303 subjects (651 asthmatics). ORMDL expression was evaluated in peripheral blood mononuclear cells ( PBMC) from 55 subjects (eight asthmatics) before and after allergen stimulation, and in blood ( n = 60, 5 asthmatics). Allele-specific cis-effects on ORMDL expression were assessed. Interactions between human ORMDL proteins were determined in living cells. Results Sixteen SNPs in all three ORMDLs were associated with asthma (14 in ORMDL3). Baseline expression of ORMDL1 ( P = 1.7 × 10−6) and ORMDL2 ( P = 4.9 × 10−5) was significantly higher in PBMC from asthmatics, while induction of ORMDLs upon stimulation was stronger in nonasthmatics. Disease-associated alleles (rs8079416, rs4795405, rs3902920) alter ORMDL3 expression. ORMDL proteins formed homo- and heterooligomers and displayed similar patterns of interaction with SERCA2 and SPT1. Conclusions Polymorphisms in ORMDL genes are associated with asthma. Asthmatics exhibit increased ORMDL levels, suggesting that ORMDLs contribute to asthma. Formation of heterooligomers and similar interaction patterns with proteins involved in calcium homeostasis and sphingolipid metabolism could indicate shared biological roles of ORMDLs, influencing airway remodeling and hyperresponsiveness. [ABSTRACT FROM AUTHOR]

The increased prevalence of metabolic disorders and obesity in modern society, together with the widespread use of artificial light at night, have led researchers to investigate whether altered patterns of light exposure contribute to metabolic disorders. This article discusses the experimental evidence that perturbed environmental cycles induce rhythm disorders in the circadian system, thus leading to metabolic disorders. This notion is generally supported by animal studies. Distorted environmental cycles, including continuous exposure to light, affect the neuronal organization of the central circadian pacemaker in the suprachiasmatic nucleus (SCN), its waveform and amplitude of the rhythm in electrical activity. Moreover, repeated exposure to a shifted light cycle or the application of dim light at night are environmental cues that cause a change in SCN function. The effects on the SCN waveform are the result of changes in synchronization among the SCN's neuronal cell population, which lead consistently to metabolic disturbances. Furthermore, we discuss the effects of sleep deprivation and the time of feeding on metabolism, as these factors are associated with exposure to disturbed environmental cycles. Finally, we suggest that these experimental studies reveal a causal relationship between the rhythm disorders and the metabolic disorders observed in epidemiological studies performed in humans. [ABSTRACT FROM AUTHOR]

We established a flow cytometric lymphocyte proliferation test (LPT) for the detection of nickel (Ni) and palladium (Pd) sensitization. Eighty-one consecutive patients with an indication for patch test (PT) were tested by LPT with Ni (NiSO4) and Pd (Na2PdCl4 and PdCl2) salts. The imprecision of the LPT was low (coefficient of variation 7.2%). Using PT as a diagnostic reference, the sensitivity and specificity of LPT were 74.4% and 80% for NiSO4, 74.4% and 78.3% for Na2PdCl4, and 57.2% and 85.4% for PdCl2, respectively. For both Ni and Pd, the likelihood ratio for a positive PT markedly increased with increasing LPT value. With medical history as a reference, the sensitivity and specificity were 40.6% and 82.1% for LPT and 59.4% and 89.7% for PT, respectively. Combination of LPT and PT resulted in a higher specificity of 95%, albeit lower sensitivity of 34.4%. In conclusion, flow cytometric LPT represents a reliable and useful method for the detection of Ni and Pd sensitization. LPT values correlate with PT results and, when used in combination with PT, increase test specificity. [ABSTRACT FROM AUTHOR]

Background Genomewide association and epigenetic studies found a region within the RAD50 gene on chromosome 5q31 to be associated with total serum IgE levels and asthma. In mice, this region harbors a locus control region for nearby TH2 cytokines, which is characterized by four Rad50 DNase I hypersensitive sites ( RHS4-7). Among these, RHS7 seems to have the strongest impact on TH2 differentiation. We investigated whether within the human homolog of RHS7, functional polymorphisms exist, which could affect DNA methylation or gene expression in the 5q31 locus and might have an influence on asthma status or IgE regulation. Methods The human RHS7 region was fine mapped using 1000 genomes database information. In silico analysis and electrophoretic mobility shift assays were used to assess SNP function. Allele-specific effects on DNA methylation were evaluated in cord blood ( n = 73) and at age of 4.5 years ( n = 61) by pyrosequencing. Allele-specific effects on RAD50, IL4, and IL13 expression were analyzed in 100 subjects. Associations with asthma and IgE levels were investigated in the MAGICS/ ISAAC II population ( n = 1145). Results Polymorphism rs2240032 in the RHS7 region is suggestive of allele-specific transcription factor binding, affects methylation of the IL13 promoter region and influences RAD50 and IL4 expression (lowest P = 0.0027). It is also associated with total serum IgE levels ( P = 0.0227). Conclusion A functional relevant polymorphism in the TH2 locus control region, equivalent to RHS7 in mice, affects DNA methylation and gene expression within 5q31 and influences total serum IgE on the population level. [ABSTRACT FROM AUTHOR]

Background Genome-wide association studies ( GWAS) repeatedly identified 1q23 ( FCER1A), 5q31 ( RAD50- IL13 and IL4), and 12q13 ( STAT6) as major susceptibility loci influencing the regulation of total serum IgE levels. As GWAS may be insufficient to capture causal variants, we performed fine-mapping and re-genotyping of the three loci using 1000 Genomes Project datasets. Methods Linkage disequilibrium tagging polymorphisms and polymorphisms of putative functional relevance were genotyped by chip technology (24 polymorphisms) or MALDI- TOF- MS (40 polymorphisms) in at least 1303 German children (651 asthmatics). The effect of polymorphisms on total serum IgE, IgE percentiles, and atopic diseases was assessed, and a risk score model was applied for gene-by-gene interaction analyses. Functional effects of putative causal variants from these three loci were studied in silico. Results Associations from GWAS were confirmed and extended. For 1q23 and 5q31, the majority of associations were found with mild to moderately elevated IgE levels, while in the 12q13 locus, single-nucleotide polymorphisms ( SNPs) were associated with strongly elevated IgE levels. Gene-by-gene interaction analyses suggested that the presence of mutations in all three loci increases the risk for elevated IgE up to fourfold. Conclusion This fine-mapping study confirmed previous associations and identified novel associations of SNPs in 1q23, 5q31, and 12q13 with different levels of serum IgE and their concomitant contribution to IgE regulation. [ABSTRACT FROM AUTHOR]

Background Both FCER2 and FCER1A encode subunits of IgE receptors. Variants in FCER1A were previously identified as major determinants of IgE levels in genome-wide association studies. Methods Here we investigated in detail whether FCER2 polymorphisms affect IgE levels alone and/or by interaction with FCER1A polymorphisms. To cover the genetic information of FCER2, 21 single-nucleotide polymorphisms ( SNPs) were genotyped by Illumina HumanHap300 BeadChip (5 SNPs) and the matrix-assisted laser desorption/ionization time-of-flight mass spectrometry ( MALDI- TOF MS; 14 SNPs) in at least 1303 Caucasian children (651 asthmatics) ( ISAAC II/ MAGICS population); genotypes of two SNPs were imputed. Results SNP rs3760687 showed the most consistent effect on total serum IgE levels (b [ SE] = −0.38 [0.16]; P = 0.016), while FCER2 polymorphisms in general were predominantly associated with mildly-to-moderately increased IgE levels (50th and 66th percentiles). Gene-by-gene interaction analysis suggests that FCER2 polymorphism rs3760687 influences IgE levels mainly in individuals not homozygous for the risk allele of FCER1A polymorphism rs2427837, which belongs to the major IgE-determining tagging bin in the population. Conclusion FCER2 polymorphism rs3760687 affects moderately elevated total serum IgE levels, especially in the absence of homozygosity for the risk allele of FCER1A SNP rs2427837. [ABSTRACT FROM AUTHOR]

Background Interferon-regulatory factors ( IRFs) play a crucial role in immunity, not only influencing interferon expression but also T cell differentiation. IRF-4 was only recently recognized as a further major player in T cell differentiation. Objective As IRF-1 polymorphisms were shown to be associated with atopy and allergy, we comprehensively investigated effects of IRF-4 variants on allergy, asthma and related phenotypes in German children. Methods Fifteen tagging single nucleotide polymorphisms (SNPs) in the IRF-4 gene were genotyped by MALDI- TOF MS in the cross-sectional ISAAC phase II study population from Munich and Dresden (age 9-11; N = 3099). Replication was performed in our previously established genome-wide association study ( GWAS) data set ( N = 1303) consisting of asthma cases from the Multicenter Asthma Genetic in Childhood ( MAGIC) study and reference children from the ISAAC II study. Results SNPs were not significantly associated with asthma but with bronchial hyperresponsiveness, atopy and, most interestingly, with recurrent bronchitis in the first data set. The IRF-4 variant rs9378805 was associated with recurrent bronchitis in the ISAAC population and replicated in the GWAS data set where further SNPs showed associations with recurrent bronchitis and asthma. Conclusions We found genetic associations in IRF-4 to be associated with recurrent bronchitis in our two study populations. Associated polymorphisms are localized in a putative regulatory element in the 3′ UTR region of IRF-4. These findings suggest a putative role of IRF-4 in the development of bronchitis. [ABSTRACT FROM AUTHOR]

Background Both asthma and obesity are complex disorders that are influenced by environmental and genetic factors. Shared genetic factors between asthma and obesity have been proposed to partly explain epidemiological findings of co-morbidity between these conditions. Objective To identify genetic variants that are associated with body mass index ( BMI) in asthmatic children and adults, and to evaluate if there are differences between the genetics of BMI in asthmatics and healthy individuals. Methods In total, 19 studies contributed with genome-wide analysis study ( GWAS) data from more than 23 000 individuals with predominantly European descent, of whom 8165 are asthmatics. In total, 19 studies contributed with genome-wide analysis study ( GWAS) data from more than 23 000 individuals with predominantly European descent, of whom 8165 are asthmatics. In total, 19 studies contributed with genome-wide analysis study ( GWAS) data from more than 23 000 individuals with predominantly European descent, of whom 8165 are asthmatics. In total, 19 studies contributed with genome-wide analysis study ( GWAS) data from more than 23 000 individuals with predominantly European descent, of whom 8165 are asthmatics. In total, 19 studies contributed with genome-wide analysis study ( GWAS) data from more than 23 000 individuals with predominantly European descent, of whom 8165 are asthmatics. In total, 19 studies contributed with genome-wide analysis study ( GWAS) data from more than 23 000 individuals with predominantly European descent, of whom 8165 are asthmatics. In total, 19 studies contributed with genome-wide analysis study ( GWAS) data from more than 23 000 individuals with predominantly European descent, of whom 8165 are asthmatics. In total, 19 studies contributed with genome-wide analysis study ( GWAS) data from more than 23 000 individuals with predominantly European descent, of whom 8165 are asthmatics. In total, 19 studies contributed with genome-wide analysis study ( GWAS) data from more than 23 000 individuals with predominantly European descent, of whom 8165 are asthmatics. Results We report associations between several DENND1B variants ( P = 2.2 × 10−7 for rs4915551) on chromosome 1q31 and BMI from a meta-analysis of GWAS data using 2691 asthmatic children (screening data). The top DENND1B single nucleotide polymorphisms ( SNPs) were next evaluated in seven independent replication data sets comprising 2014 asthmatics, and rs4915551 was nominally replicated ( P < 0.05) in two of the seven studies and of borderline significance in one ( P = 0.059). However, strong evidence of effect heterogeneity was observed and overall, the association between rs4915551 and BMI was not significant in the total replication data set, P = 0.71. Using a random effects model, BMI was overall estimated to increase by 0.30 kg/m2 ( P = 0.01 for combined screening and replication data sets, N = 4705) per additional G allele of this DENND1B SNP. FTO was confirmed as an important gene for adult and childhood BMI regardless of asthma status. Conclusions and Clinical Relevance DENND1B was recently identified as an asthma susceptibility gene in a GWAS on children, and here, we find evidence that DENND1B variants may also be associated with BMI in asthmatic children. However, the association was overall not replicated in the independent data sets and the heterogeneous effect of DENND1B points to complex associations with the studied diseases that deserve further study. [ABSTRACT FROM AUTHOR]

Background Genetic susceptibility and environmental influences are important contributors to the development of asthma and atopic diseases. Epigenetic mechanisms may facilitate gene by environment interactions in these diseases. Methods We studied the rural birth cohort PASTURE (Protection against allergy: study in rural environments) to investigate (a) whether epigenetic patterns in asthma candidate genes are influenced by farm exposure in general, (b) change over the first years of life, and (c) whether these changes may contribute to the development of asthma. DNA was extracted from cord blood and whole blood collected at the age of 4.5 years in 46 samples per time point. DNA methylation in 23 regions in ten candidate genes ( ORMDL1, ORMDL2, ORMDL3, CHI3L1, RAD50, IL13, IL4, STAT6, FOXP3, and RUNX3) was assessed by pyrosequencing, and differences between strata were analyzed by nonparametric Wilcoxon-Mann-Whitney tests. Results In cord blood, regions in ORMDL1 and STAT6 were hypomethylated in DNA from farmers' as compared to nonfarmers' children, while regions in RAD50 and IL13 were hypermethylated (lowest P-value ( STAT6) = 0.001). Changes in methylation over time occurred in 15 gene regions (lowest P-value ( IL13) = 1.57*10−8). Interestingly, these differences clustered in the genes highly associated with asthma ( ORMDL family) and IgE regulation ( RAD50, IL13, and IL4), but not in the T-regulatory genes ( FOXP3, RUNX3). Conclusions In this first pilot study, DNA methylation patterns change significantly in early childhood in specific asthma- and allergy-related genes in peripheral blood cells, and early exposure to farm environment seems to influence methylation patterns in distinct genes. [ABSTRACT FROM AUTHOR]

Reasons for performing study: There are no detailed studies describing the resistance of equine tibiae and radii to side impact loads, such as a horse kick and a better understanding of the general long bone impact behavioural model is required. Objectives: To quantify the typical impact energy required to fracture or fissure an equine long bone, as well as to determine the range and time course of the impact force under conditions similar to that of a horse kick. Methods: Seventy-two equine tibiae and radii were investigated using a drop impact tester. The prepared bones were preloaded with an axial force of 2.5 kN and were then hit in the middle of the medial side. The impact velocity of the metal impactor, weighting 2 kg, was varied within the range of 6-11 m/s. The impact process was captured with a high-speed camera from the craniomedial side of the bone. The videos were used both for slow-motion observation of the process and for quantifying physical parameters, such as peak force via offline video tracking and subsequent numerical derivation of the 'position vs. time' function for the impactor. Results: The macroscopic appearance of the resultant bone injuries was found to be similar to those produced by authentic horse kicks, indicating a successful simulation of the real load case. The impact behaviours of tibiae and radii do not differ considerably in terms of the investigated general characteristics. Peak force occurred between 0.15-0.30 ms after the start of the impact. The maximum contact force correlated with the 1.45-power of the impact velocity if no fracture occurred ( Fmax≅ 0.926 ·vi1.45). Peak force scatter was considerably larger within the fractured sub-group compared with fissured bones. The peak force for fracture tended to lie below the aforementioned function, within the range of Fmax= 11-23 kN ('fracture load'). The impact energy required to fracture a bone varied from 40-90 J. Conclusions: The video-based measuring method allowed quantifying of the most relevant physical parameters, such as contact force and energy balance. Potential relevance: The results obtained should help with the development of bone implants and guards, supporting theoretical studies, and in the evaluation of bone injuries. [ABSTRACT FROM AUTHOR]

Background We aimed to validate the lymph node ratio (LNR) as an independent prognostic factor in oral squamous cell carcinoma (OSCC) and compare its utility with the current nodal staging system. Methods We conducted a retrospective analysis of 313 patients with OSCC undergoing neck dissection. The LNR was adjusted by relevant covariates in a multivariable Cox regression model. Results LNR displaced conventional nodal staging and was shown to be an independent predictor of regional failure ( p = .020), disease-specific ( p = .003) and overall survival ( p = .001). Patients with an LNR of 2.5% to 7.5%, 7.5% to 20%, and >20% had 2.6, 3.7, and 4.4 times the risk of death from OSCC, respectively, when compared with patients with an LNR <2.5%. Conclusions The LNR is an independent prognostic factor in OSCC and may be used in conjunction with the current TNM staging to enable better risk stratification and selection for adjuvant therapy. © 2010 Wiley Periodicals, Inc. Head Neck, 2010 [ABSTRACT FROM AUTHOR]

Purpose: The accuracy of the system model that governs the transformation from the image space to the projection space in positron emission tomography (PET) greatly affects the quality of reconstructed images. For efficient computation in iterative reconstructions, the system model in PET can be factored into a product of geometric projection and sinogram blurring function. To further speed up reconstruction, fully 3D PET data can be rebinned into a stack of 2D sinograms and then be reconstructed using 2D iterative algorithms. The purpose of this work is to develop a method to estimate the sinogram blurring function to be used in reconstruction of Fourier-rebinned data. Methods: In a previous work, the authors developed an approach to estimating the sinogram blurring function of nonrebinned PET data from experimental scans of point sources. In this study, the authors extend this method to the estimation of sinogram blurring function for Fourier-rebinned PET data. A point source was scanned at a set of sampled positions in the microPET II scanner. The sinogram blurring function is considered to be separable between the transaxial and axial directions. A radially and angularly variant 2D blurring function is estimated from Fourier-rebinned point source scans to model the transaxial blurring with consideration of the detector block structure of the scanner; a space-variant 1D blurring kernel along the axial direction is estimated separately to model the correlation between neighboring planes due to detector intrinsic blurring and Fourier rebinning. The estimated sinogram blurring function is incorporated in a 2D maximum a posteriori (MAP) reconstruction algorithm for image reconstruction. Results: Physical phantom experiments were performed on the microPET II scanner to validate the proposed method. The authors compared the proposed method to 2D MAP reconstruction without sinogram blurring model and 2D MAP reconstruction with a Monte Carlo based blurring model. The results show that the proposed method produces images with improved contrast and spatial resolution. The reconstruction time is unaffected by the new method since the blurring component takes a relatively negligible part of the overall reconstruction time. Conclusions: The proposed method can estimate sinogram blurring matrix for Fourier-rebinned PET data and can be used to improve contrast and spatial resolution of reconstructed images. The method can be applied to other human and animal scanners. [ABSTRACT FROM AUTHOR]

The treatment of thoracic aortic disease has changed radically with the advances made in endovascular therapy since the concept of thoracic endovascular aortic repair was first described 15 years ago. Currently, there is a diverse array of endografts that are commercially available to treat the thoracic aorta. Multiple studies, including industry-sponsored and single-institution reports, have demonstrated excellent outcomes of thoracic endovascular aortic repair for the treatment of thoracic aortic aneurysms, with less reported perioperative morbidity and mortality in comparison with conventional open repair. Additionally, similar outcomes have been demonstrated for the treatment of type B dissections. However, the technology remains relatively novel, and larger studies with longer term outcomes are necessary to more fully evaluate the role of endovascular therapy for the treatment of thoracic aortic disease. This review examines the currently available thoracic endografts, preoperative planning for thoracic endovascular aortic repair, and outcomes of thoracic endovascular aortic repair for the treatment of both thoracic aortic aneurysms and type B aortic dissections. Mt Sinai J Med 77:256–269, 2010. © 2010 Mount Sinai School of Medicine [ABSTRACT FROM AUTHOR]

OBJECTIVE: Mammalian circadian rhythms are driven by the circadian pacemaker of the suprachiasmatic nucleus (SCN) and are synchronized to the external 24-hour light/dark cycle. After advance time zone transitions (eastbound jet lag), overt circadian rhythms require several days to adjust. The retarded adaptation may protect against acute imbalance of different brain systems. Abrupt circadian rhythm changes may trigger migraine attacks, possibly because migraineurs have an inadequate adaptation mechanism. The novel R192Q knock-in migraine mouse model carries mutated Ca(v)2.1 calcium channels, causing increased presynaptic calcium influx and neurotransmitter release. We investigated whether these mice have an abnormal adjustment to phase advance shifts. METHODS: We examined phase resetting to 6-hour advance shifts of the light/dark cycle with behavioral and electroencephalographic recordings in R192Q and wild-type mice. We recorded excitatory postsynaptic currents in the SCN, and electrical impulse frequency in vitro and in vivo. RESULTS: R192Q mice showed a more than twofold enhanced adjustment of behavioral wheel-running activity and electroencephalographic patterns, as well as enhanced shifts of electrical activity of SCN neurons in vivo. No differences were found for in vitro recordings of the electrical impulse frequency in SCN slices. INTERPRETATION: R192Q migraine mice lack the physiological retardation in circadian adaptation to phase advance shifts. The opposite findings in vivo and in vitro exclude involvement of the retinal input pathway or the phase-shifting capacity of the SCN. Thus, the physiological inhibitory process appears to be mediated by Ca(v)2.1 channel-dependent afferent signaling from extra-SCN brain areas to the SCN. [ABSTRACT FROM AUTHOR]

Light information reaches the suprachiasmatic nucleus (SCN) through a subpopulation of retinal ganglion cells that utilize glutamate as a neurotransmitter. A variety of evidence suggests that the release of glutamate then activates N-methyl-d-aspartate (NMDA) receptors within the SCN and triggers a signaling cascade that ultimately leads to phase shifts in the circadian system. In this study, we first sought to explore the role of the NR2B subunit in mediating the effects of light on the circadian system of hamsters and mice. We found that localized microinjection of the NR2B subunit antagonist ifenprodil into the SCN region reduces the magnitude of light-induced phase shifts of the circadian rhythm in wheel-running activity. Next, we found that the NR2B message and levels of phospho-NR2B vary with time of day in SCN tissue using semiquantitative real-time polymerase chain reaction and western blot analysis, respectively. Functionally, we found that blocking the NR2B subunit with ifenprodil significantly reduced the magnitude of NMDA currents recorded in SCN neurons. Ifenprodil also significantly reduced the magnitude of NMDA-induced Ca2+ changes in SCN cells. Together, these results demonstrate that the NR2B subunit is an important component of NMDA receptor-mediated responses within SCN neurons and that this subunit contributes to light-induced phase shifts of the mammalian circadian system. [ABSTRACT FROM AUTHOR]

We assessed the contributions of target site- and non-target site-based resistance to herbicides inhibiting acetyl-coenzyme A carboxylase (ACC) in Alopecurus myosuroides (black grass). A total of 243 A. myosuroides populations collected across France were analysed using herbicide sensitivity bioassay (24 300 seedlings analysed) and ACC genotyping (13 188 seedlings analysed). Seedlings resistant to at least one ACC-inhibiting herbicide were detected in 99.2% of the populations. Mutant, resistant ACC allele(s) were detected in 56.8% of the populations. Among the five resistant ACC alleles known in A. myosuroides, alleles containing an isoleucine-to-leucine substitution at codon 1781 were predominant (59.5% of the plants containing resistant ACC alleles). Comparison of the results from herbicide sensitivity bioassays with genotyping indicated that more than 75% of the plants resistant to ACC-inhibiting herbicides in France would be resistant via increased herbicide metabolism. Analysis of herbicide application records suggested that in 15.9% of the populations studied, metabolism-based resistance to ACC-inhibiting herbicides was mostly selected for by herbicides with other modes of action. Our study revealed the importance of non-target site-based resistance in A. myosuroides. Using herbicides with alternative modes of action to control populations resistant to ACC-inhibiting herbicides, the recommended management approach, may thus be jeopardised by the widespread occurrence of metabolism-based resistance mechanisms conferring broad-spectrum cross-resistance. [ABSTRACT FROM AUTHOR]

Abdominal aortic aneurysms (AAAs) can typically remain stable until the strength of the aortic wall is unable to withstand the forces acting on it as a result of the luminal blood pressure, resulting in AAA rupture. The clinical treatment of AAA patients presents a dilemma for the surgeon: surgery should only be recommended when the risk of rupture of the AAA outweighs the risks associated with the interventional procedure. Since AAA rupture occurs when the stress acting on the wall exceeds its strength, the assessment of AAA rupture should include estimates of both wall stress and wall strength distributions. The present work details a method for noninvasively assessing the rupture potential of AAAs using patient-specific estimations the rupture potential index (RPI) of the AAA, calculated as the ratio of locally acting wall stress to strength. The RPI was calculated for thirteen AAAs, which were broken up into ruptured ( n= 8 and nonruptured ( n= 5) groups. Differences in peak wall stress, minimum strength and maximum RPI were compared across groups. There were no statistical differences in the maximum transverse diameters (6.8 ± 0.3 cm vs. 6.1 ± 0.5 cm, p= 0.26) or peak wall stress (46.0 ± 4.3 vs. 49.9 ± 4.0 N/cm2, p= 0.62) between groups. There was a significant decrease in minimum wall strength for ruptured AAA (81.2 ± 3.9 and 108.3 ± 10.2 N/cm2, p= 0.045). While the differences in RPI values (ruptured = 0.48 ± 0.05 vs. nonruptured = 0.36 ± 0.03, respectively; p= 0.10) did not reach statistical significance, the p-value for the peak RPI comparison was lower than that for both the maximum diameter ( p= 0.26) and peak wall stress ( p= 0.62) comparisons. This result suggests that the peak RPI may be better able to identify those AAAs at high risk of rupture than maximum diameter or peak wall stress alone. The clinical relevance of this method for rupture assessment has yet to be validated, however, its success could aid clinicians in decision making and AAA patient management. [ABSTRACT FROM AUTHOR]

Light information reaches the suprachiasmatic nucleus (SCN) through a subpopulation of retinal ganglion cells. Previous work raised the possibility that brain-derived neurotrophic factor (BDNF) and its high-affinity tropomyosin-related receptor kinase may be important as modulators of this excitatory input into the SCN. In order to test this possibility, we used whole-cell patch-clamp methods to measure spontaneous excitatory currents in mouse SCN neurons. We found that the amplitude and frequency of these currents were increased by BDNF and decreased by the neurotrophin receptor inhibitor K252a. The neurotrophin also increased the magnitude of currents evoked by application of N-methyl-d-aspartate and amino-methyl proprionic acid. Next, we measured the rhythms in action potential discharge from the SCN brain slice preparation. We found that application of K252a dramatically reduced the magnitude of phase shifts of the electrical activity rhythm generated by the application of glutamate. By itself, BDNF caused phase shifts that resembled those produced by glutamate and were blocked by K252a. The results demonstrate that BDNF and neurotrophin receptors can enhance glutamatergic synaptic transmission within a subset of SCN neurons and potentiate glutamate-induced phase shifts of the circadian rhythm of neural activity in the SCN. [ABSTRACT FROM AUTHOR]