A combined active shape and mean appearance model for the reconstruction of segmental bone loss.

This study investigates the novel combination of an active shape and mean appearance model to estimate missing bone geometry and density distribution from sparse inputs simulating segmental bone loss of the femoral diaphysis. An active shape Gaussian Process Morphable model was trained on healthy right femurs of South African males to model shape. The density distribution was approximated based on the mean appearance of computed tomography images from the training set. Estimations of diaphyseal resections were obtained by probabilistic fitting of the active shape model to sparse inputs consisting of proximal and distal femoral data on computed tomography images. The resulting shape estimates of the diaphyseal resections were then used to map the mean appearance model to the patients' missing bone geometry, constructing density estimations. In this way, resected bone surfaces were estimated with an average error of 2.24 (0.5) mm. Density distributions were approximated within 87 (0.7) % of the intensity of the original target images before the simulated segmental bone loss. These results fall within the acceptable tolerances required for surgical planning and reconstruction of long bone defects.

Increase in temperature enriches heat tolerant taxa in Aedes aegypti midguts.

Insect midgut microbial symbionts have been considered as an integral component in thermal adaptation due to their differential thermal sensitivity. Altered midgut microbial communities can influence both insect physiology and competence for important vector-borne pathogens. This study sought to gain insights into how Aedes aegypti midgut microbes and life history traits are affected by increase in baseline diurnal temperature. Increase in temperature resulted in the enrichment of specific taxa with Bacillus being the most enriched. Bacillus is known to be heat tolerant. It also resulted in a dissimilar microbial assemblage (Bray-Curtis Index, PERMANOVA, F = 2.2063; R2 = 0.16706; P = 0.002) and reduced survivorship (Log-rank [Mantel-Cox] test, Chi-square = 35.66 df = 5, P < 0.0001). Blood meal intake resulted in proliferation of pathogenic bacteria such as Elizabethkingia in the midgut of the mosquitoes. These results suggest that alteration of temperature within realistic parameters such as 2 °C for Ae. aegypti in nature may impact the midgut microbiome favoring specific taxa that could alter mosquito fitness, adaptation and vector-pathogen interactions.

10th European immunogenicity platform open symposium on immunogenicity of biopharmaceuticals.

Therapeutic proteins and emerging gene and cell-based therapies are attractive therapeutic tools for addressing unmet medical needs or when earlier conventional treatment approaches failed. However, the development of an immune response directed against therapeutic agents is a significant concern as it occurs in a substantial number of cases across products and indications. The specific anti-drug antibodies that develop can lead to safety adverse events as well as inhibition of drug activity or accelerated clearance, both phenomena resulting in loss of treatment efficacy. The European Immunogenicity Platform (EIP) is a meeting place for experts and newcomers to the immunogenicity field, designed to stimulate discussion amongst scientists across industry and academia, encourage interactions with regulatory agencies and share knowledge and the state-of-the-art of immunogenicity sciences with the broader scientific community. Here we report on the main topics covered during the EIP 10th Open Symposium on Immunogenicity of Biopharmaceuticals held in Lisbon, 26-27 February 2019, and the 1-d training course on practical and regulatory aspects of immunogenicity held ahead of the conference. These main topics included immunogenicity testing, clinical relevance of immunogenicity, immunogenicity prediction, regulatory aspects, tolerance induction as a mean to mitigate immunogenicity and immunogenicity in the context of gene therapy.

Evolution of femtosecond laser damage in a hafnia-silica multi-layer dielectric coating.

To optimize optical coating materials, designs, and technologies for high damage resistance, understanding the growth of laser damage is of paramount importance. In this Letter, we show the evolution of femtosecond laser damage in a hafnia-silica (HfO2/SiO2) multilayer dielectric mirror coating. Depending on various spatial features of damaged sites, we identified several regimes of the laser-material interaction with varying laser fluence and incident number of pulses. A change in surface roughness has been observed only for a small number of pulses, and interestingly, a threshold number of pulses is found for nanocrack formation. We report the polarization-dependent orientation of nanocracks and their growth with an increasing number of pulses. The presented results demonstrate that the laser damage originates from the nanobumps and surface roughening, which then leads to the formation of nanocracks. The presented experimental results acknowledge the existing theoretical models in bulk dielectrics to explain the formation of nanostructures by interference of the incident laser with the scattering radiation from laser-induced inhomogeneities and growth of the field enhancement due to nanoplasma.

Who cares? The impact on caregivers of suspected mining-related lung cancer.

Background: In the present study, we investigated the emotional, physical, financial, occupational, practical, and quality-of-life impacts on caregivers of patients with mining-related lung cancer. Methods: This concurrent, embedded, mixed-methods study used individual in-depth qualitative interviews and the 36-item Short Form Health Survey (version 2: RAND Corporation, Santa Monica, CA, U.S.A.) quality-of-life measure with 8 caregivers of patients with suspected mining-related lung cancer who had worked in Sudbury or Elliot Lake (or both), and sometimes elsewhere. Individuals who assist workers in filing compensation claims were also interviewed in Sudbury and Elliot Lake. Interviews (n = 11) were transcribed and analyzed thematically. Results: Caregiver themes focused on the long time to, and the shock of, diagnosis and dealing with lung cancer; not much of a life for caregivers; strong views about potential cancer causes; concerns about financial impacts; compensation experiences and long time to compensation; and suggestions for additional support. Quality-of-life scores were below the norm for most measures. Individuals who assist workers in preparing claims were passionate about challenges in the compensation journey; the requirement for more and better family support; the need to focus on compensation compared with cost control; the need for better exposure monitoring, controls, resources, and research; and job challenges, barriers, and satisfaction. Conclusions: Caregivers expressed a need for more education about the compensation process and for greater support. Worker representatives required persistence, additional workplace monitoring and controls, additional research, and a focus on compensation compared with cost control. They also emphasized the need for more family support.

Reduced fetal growth velocities and the association with neonatal outcomes in appropriate-for-gestational-age neonates: a retrospective cohort study.

BACKGROUND: Fetal growth restriction is, despite advances in neonatal care and uptake of antenatal ultrasound scanning, still a major cause of perinatal morbidity. Neonates with birth weight > 10th percentile are assumed to be appropriate-for-gestational-age (AGA), although many are at increased risk of perinatal morbidity, because of undetected mild restriction of growth potential. We hypothesized that within AGA neonates, reduced fetal growth velocities are associated with adverse neonatal outcome. METHODS: A retrospective cohort study of singleton pregnancies, in the Maastricht University Medical Centre (MUMC) between 2010 and 2016. Women had two fetal biometry scans (18-22 weeks and 30-34 weeks of gestational age) and delivered a newborn with a birth weight between the 10th-80th percentile. Differences in growth velocities of the abdominal circumference (AC), biparietal diameter (BPD), head circumference (HC) and femur length (FL) were compared between the suboptimal AGA (sAGA) (birth weight centiles 10-50) and optimal AGA (oAGA) (birth weight centiles 50-80) group. We assessed the association between velocities and neonatal outcomes. RESULTS: We included 934 singleton pregnancies. In the suboptimal AGA group, fetal growth velocities were lower (in mm/week): AC 10.72 ± 1.00 vs 11.23 ± 1.00 (p < .001), HC 10.50 ± 0.80 vs 10.68 ± 0.77 (p = 0.001), BPD 3.01 ± 0.28 vs 3.08 ± 0.27 (p < .0001) and FL 2.47 ± 0.21 vs 2.50 ± 0.22 (p = 0.014), compared to the optimal AGA group. Neonates with an adverse neonatal outcome had significantly lower growth velocities (in mm/week) of: AC 10.57 vs 10.94 (p = 0.034), HC 10.28 vs 10.59 (p = 0.003) and BPD 2.97 vs 3.04 (p = 0.043) compared to those with normal outcome. An inverse association was observed between the AC velocity and a composite adverse neonatal outcome (OR) = 0.667 (95%CI 0.507-0.879, p = 0.004), and between the AC velocity and neonates with NICU stay (OR) = 0.733 (95%CI 0.570-0.942, p = 0.015). Neonates with a birthweight lower than expected (based on the abdominal circumference at 20 weeks) had significantly more composite adverse neonatal outcomes 8.5% vs 5.0% (p = 0.047), NICU stays 9.6% vs 3.8% (p < .0001) and hospital stays 44.4% vs 35.6% (p = 0.006). CONCLUSIONS: Appropriate-for-gestational-age neonates are a heterogeneous group with some showing suboptimal fetal growth. Abnormal fetal growth velocities, especially abdominal circumference velocity, are associated with adverse neonatal outcome and can potentially improve the detection of mild growth restriction when used in multivariate models.

DNMT3A mutant transcript levels persist in remission and do not predict outcome in patients with acute myeloid leukemia.

We investigated the prognostic impact of minimal residual disease (MRD) monitoring in acute myeloid leukemia patients harboring DNA methyltransferase 3A-R882H/-R882C mutations (DNMT3Amut). MRD was determined by real-time quantitative PCR (RQ-PCR) in 1494 samples of 181 DNMT3Amut patients. At the time of diagnosis, DNMT3Amut transcript levels did not correlate with presenting clinical characteristics and concurrent gene mutations as well as the survival end points. In Cox regression analyses, bone marrow (BM) DNMT3Amut transcript levels (log10-transformed continuous variable) were not associated with the rate of relapse or death. DNMT3Amut transcript levels were significantly higher in BM than in blood after induction I (P=0.01), induction II (P=0.05), consolidation I (P=0.004) and consolidation II (P=0.008). With regard to the clinically relevant MRD time points, after two cycles of induction and at the end of therapy, DNMT3Amut transcript levels had no impact on the end point remission duration and overall survival. Of note, only a minority of the patients achieved RQ-PCR negativity, whereas most had constantly high DNMT3Amut transcript levels, a finding which is consistent with the persistence of clonal hematopoiesis in hematological remission.

Syndesmosis injuries in the pediatric and adolescent athlete: an analysis of risk factors related to operative intervention.

PURPOSE: To review all paediatric ankle syndesmotic injuries occurring at our institution and identify risk factors associated with operative intervention. METHODS: Among 22 873 evaluations for ankle trauma, we found 220 children suffering from syndesmotic injuries (incidence: 0.96%). We recorded demographic data, details of the injury, features on examination and treatment variables. Univariable and multivariable logistic regression modelling was performed to identify risk factors associated with operative intervention. RESULTS: The mean age at injury was 15.8 years (8.9 to 19.0) with a median follow-up of 13 weeks (IQR 5 to 30 weeks). A sports-related injury was most common (168/220, 76%). A total of 82 of 220 (37%) patients underwent operative fixation, of which 76 (93%) had an associated fibular fracture. Patients undergoing surgery had a higher incidence of swelling and inability to weight bear (p < 0.001). Statistically significant differences were recorded in tibiofibular (TF) clear space, TF overlap and medial clear space (MCS) between the operative and non-operative cohorts (6.0 vs 4.6 mm (p = 0.002), 5.4 vs 6.9 mm (p = 0.004) and 6.4 vs 3.5 mm (p < 0.001)). Multivariable analysis revealed patients with a fracture of the ankle had 44 times the odds of surgical intervention, patients with a closed physis had over five times the odds of surgical intervention and patients with a medial clear space greater than 5 mm had nearly eight times the odds of requiring surgical intervention. CONCLUSIONS: Operative ankle syndesmotic injuries in the paediatric population are often associated with a closed distal tibial physis and concomitant fibular fracture.

En Bloc Liver Kidney Transplantation Using Donor Splenic Artery as Inflow to the Kidney: Report of Two Cases.

The number of simultaneous liver-kidney transplants has been increasing. This surgery is associated with an increased risk of complications, longer duration of surgery and longer ischemia time for the renal allograft. Two patients listed for liver-kidney transplant at our center underwent en bloc combined liver-kidney transplantation using donor splenic artery as inflow. Patient 1 previously underwent cardiac catheterization that was complicated by a bleeding pseudoaneurysm of the right external iliac artery that required endovascular stenting of the external iliac artery and embolization of the inferior epigastric artery. Patient 2 was on vasopressor support and continuous renal replacement therapy at the time of transplant. In this paper, we described a novel technique of en bloc liver-kidney transplant with simultaneous reperfusion of both allografts using the donor splenic artery for renal inflow. This technique is useful for decreasing cold ischemia time and total operative time by simultaneous reperfusion of both allografts. It is a useful technical variant that can be used in patients with severe disease of the iliac arteries.

Standardizing terms, definitions and concepts for describing and interpreting unwanted immunogenicity of biopharmaceuticals: recommendations of the Innovative Medicines Initiative ABIRISK consortium.

Biopharmaceuticals (BPs) represent a rapidly growing class of approved and investigational drug therapies that is contributing significantly to advancing treatment in multiple disease areas, including inflammatory and autoimmune diseases, genetic deficiencies and cancer. Unfortunately, unwanted immunogenic responses to BPs, in particular those affecting clinical safety or efficacy, remain among the most common negative effects associated with this important class of drugs. To manage and reduce risk of unwanted immunogenicity, diverse communities of clinicians, pharmaceutical industry and academic scientists are involved in: interpretation and management of clinical and biological outcomes of BP immunogenicity, improvement of methods for describing, predicting and mitigating immunogenicity risk and elucidation of underlying causes. Collaboration and alignment of efforts across these communities is made difficult due to lack of agreement on concepts, practices and standardized terms and definitions related to immunogenicity. The Innovative Medicines Initiative (IMI; www.imi-europe.org), ABIRISK consortium [Anti-Biopharmaceutical (BP) Immunization Prediction and Clinical Relevance to Reduce the Risk; www.abirisk.eu] was formed by leading clinicians, academic scientists and EFPIA (European Federation of Pharmaceutical Industries and Associations) members to elucidate underlying causes, improve methods for immunogenicity prediction and mitigation and establish common definitions around terms and concepts related to immunogenicity. These efforts are expected to facilitate broader collaborations and lead to new guidelines for managing immunogenicity. To support alignment, an overview of concepts behind the set of key terms and definitions adopted to date by ABIRISK is provided herein along with a link to access and download the ABIRISK terms and definitions and provide comments (http://www.abirisk.eu/index_t_and_d.asp).

A pro-apoptotic function of iASPP by stabilizing p300 and CBP through inhibition of BRMS1 E3 ubiquitin ligase activity.

The p53 family and its cofactors are potent inducers of apoptosis and form a barrier to cancer. Here, we investigated the impact of the supposedly inhibitory member of the apoptosis-stimulating protein of p53, iASPP, on the activity of the p53 homolog TAp73, and its cofactors p300 and CBP. We found that iASPP interacted with and stabilized the histone acetyltransferase p300 and its homolog CBP upon cisplatin treatment. Vice versa, iASPP depletion by shRNA resulted in decreased amounts of p300 and CBP, impaired binding of p300 and TAp73 to target site promoters, reduced induction of pro-apoptotic TAp73 target genes, and impaired apoptosis. Mechanistically, we observed that the p300-regulatory E3 ubiquitin ligase BRMS1 could rescue the degradation of p300 and CBP in cisplatin-treated, iASPP-depleted cells. This argues that iASPP stabilizes p300 and CBP by interfering with their BRMS1-mediated ubiquitination, thereby contributing to apoptotic susceptibility. In line, iASPP overexpression partially abolished the interaction of BRMS1 and CBP upon DNA damage. Reduced levels of iASPP mRNA and protein as well as CBP protein were observed in human melanoma compared with normal skin tissue and benign melanocytic nevi. In line with our findings, iASPP overexpression or knockdown of BRMS1 each augmented p300/CBP levels in melanoma cell lines, thereby enhancing apoptosis upon DNA damage. Taken together, destabilization of p300/CBP by downregulation of iASPP expression levels appears to represent a molecular mechanism that contributes to chemoresistance in melanoma cells.

Social neighborhood environment and sports participation among Dutch adults: does sports location matter?

Studies on the relation between the social neighborhood environment and sports participation have produced inconsistent results. Use of generic sports outcomes may have obscured associations only apparent for sports at certain locations. This study aims to assess the association between the social neighborhood environment and three location-specific sports outcomes. Repeated cross-sectional data on sports participation (any type of sports, sports at indoor sports clubs, sports at outdoor sports clubs, sports on streets) were obtained from 20 600 adults using the Dutch national health survey 2006-2009. Data on neighborhood social safety and social capital were obtained using the Dutch Housing Research 2006. Over 40% of Dutch adults participated in any type of sports. Indoor sports clubs were most popular. Multilevel logistic regression analyses revealed that neighborhood social safety was positively associated with sports at indoor sports clubs [odds ratio (OR) = 1.25, 95% confidence interval (CI) = 1.06-1.48), but not with the other sports outcomes. Contrary, neighborhood social capital was positively associated with sports on streets only (OR = 1.69, 95% CI = 1.17-2.44). The results suggest that a positive social neighborhood environment enhances sports participation, but that this impact depends on the location of the sports activity. This study highlights the importance of using location-specific sports outcomes when assessing environmental determinants.

New developments for the investigation of hard X-rays emitted by peeling adhesive tapes.

We realized an advanced apparatus for the investigation of emitted X-rays produced by peeling adhesive tape rolls under vacuum conditions. Two stepper motors can unwind and rewind a tape roll, and an additional roller with an optical encoder provides measurement and control of the tape speed. This way reproducible and consecutive experiments are feasible without having to change the tape or break the vacuum. The dependence of the X-ray emission on tape speed, gas pressure, type of adhesive tape, and detector angle has been investigated. The resulting spectra are continuous and span an X-ray energy range of typically 2-60 keV with high intensity. Furthermore, the new apparatus allows the in situ metalization of adhesive tape rolls by a gold sputter source. A significantly increased X-ray emission was observed for adhesive tapes with a metal coating. Thin metal foils have been placed between the tape and the detector, different K- and L-absorption edges could be measured. A considerable enhancement of the emission was achieved under the influence of the magnetic field of an NdFeB permanent magnet.

[The new preschool examination in Baden-Wuerttemberg: what determinants influence the school medical evaluation special need for language promotion in childhood development?]. / Die neue Einschulungsuntersuchung in Baden-Württemberg: Welche Determinanten beeinflussen die schulärztliche Gesamtbewertung Intensiver pädagogischer Förderbedarf im kindlichen Entwicklungsfeld Sprache?

BACKGROUND AND AIMS: The new examination before primary school enrollment in Baden-Wuerttemberg aims at detecting problems in infant development with regard to later school success in time to initiate supporting measures, especially to improve the language skills of children with other native languages. By a 2-level process composed of a screening of language skills (HASE and KVS) and an additional test (SETK 3-5) of children who did not pass the screening, the school physicians attested special needs for language promotion in the kindergarten. This study looked for associated risks of children with special needs for language promotion. The degree of test quality of the 2-level process for identifying special needs for language promotion was determined. METHODS AND RESULTS: This cross-sectional analysis explored findings of n=80,781 children in the new examination before primary school enrollment of the data-set of Baden-Wuerttemberg (children with school enrollment 2011). 56,352 children (69.8%) were speaking German, 24,429 children (30.2%) had other family languages. 20,461 children (25.3%) had special needs for language promotion in the kindergarten. A logistic regression model to determine main risks of special needs for language promotion was developed. Main effects were other native languages (OR 5.1 [4.8; 5.2]), problems in subitising (OR 2.8 [2.7; 3.0]) and language development lags in the questionnaire of the nursery school teachers (OR 3.5 [3.3; 3.7]). Protective effects were an elevated graduation of the mother (OR 0.7 [0.7; 0.7]) or the father (OR 0.8 [0.7; 0.8]). Risk scores of the effects were defined. The corresponding predictive probability to different levels of risk scores was calculated. The true positive rate of the screening of language skills (HASE/KVS) in regard to special needs for language promotion was 0.95, the true negative rate was 0.72 and the -positive predictive value was 0.53. The school physician's findings of special needs for language promotion acted as gold standard. With the additional test (SETK 3-5) the positive predictive value improved to 0.9, if at least one of the subtests of the SETK 3-5 was not passed. The risk score-level corresponded with the pretest-probability and the consecutive positive predictive value of the screening of language skills. CONCLUSIONS: This study showed an adequate degree of test quality of the 2-level process in the new examination before primary school enrollment in Baden-Wuerttemberg (screening of language skills and additional test, if the screening is not passed). In addition children with special needs for language promotion had associated risks. Risk scores, that have been defined, offer an information tool to the school physicians concerning the positive predictive value of the screening of language skills without additional testing.

Laboratory diagnosis of paraneoplastic pemphigus.

BACKGROUND: Paraneoplastic pemphigus (PNP) is a multiorgan disease characterized by antibodies against plakins, desmogleins and the α2-macroglobulin-like-1 (A2ML1) protein, in association with an underlying neoplasm. Accurate diagnosis relies on the demonstration of these autoantibodies in serum. OBJECTIVES: To evaluate the value of different laboratory techniques in the serological diagnosis of PNP. METHODS: We performed immunoblotting, envoplakin (EP) enzyme-linked immunosorbent assay (ELISA), indirect immunofluorescence (IIF) on rat bladder, radioactive immunoprecipitation and a nonradioactive combined immunoprecipitation-immunoblot assay. Additional assays included BP180 ELISA and BP230 ELISA. We included the sera of 19 patients with PNP and 40 control subjects. RESULTS: The sensitivities were 63% for anti-EP ELISA, 74% for rat bladder IIF, 89% for immunoblotting, 95% for radioactive immunoprecipitation and 100% for nonradioactive immunoprecipitation. Specificities ranged from 86% to 100%. The BP180 and BP230 ELISAs had low sensitivity and specificity for PNP. The combination of rat bladder IIF and immunoblot showed 100% sensitivity and specificity. The analysis of sequential PNP sera showed that antibody titres may decrease over time, possibly resulting in negative outcomes for EP ELISA and rat bladder IIF studies. CONCLUSIONS: The detection of autoantibodies against EP and periplakin, or A2ML1 by immunoprecipitation is most sensitive for PNP. The combination of rat bladder IIF and immunoblotting is equally sensitive and highly specific, and represents an alternative valuable and relatively easy approach for the serological diagnosis of PNP.

[Normalisation of screening HASE for 4- to 4½-year-old children]. / Normierung des Screening HASE für 4- bis 4 ½-jährige Kinder.

For reasons of prevention medical examinations of school beginners are brought forward up to 2 years before school enrollment. In Baden-Württemberg HASE is used as screening for risks in the acquisition of language and in learning to read and write. Up to now norms were insufficient for the age-group of 4;0-4;5 years. Based on the results of 3 354 children the norms for this age-group could be recalculated and are now available as percentile ranks, T-scores, and C-scores.

Influence of anthropometric features on graft diameter in ACL reconstruction.

BACKGROUND: There is a paucity of literature regarding the influence of anthropometric features on the hamstring graft obtained in ACL reconstruction. This study was undertaken to assess the influence of anthropometric measurements on the graft diameter obtained at ACL reconstruction surgery within the European population. We hypothesise that anthropometric features do influence graft thickness in ACL reconstruction. MATERIALS AND METHODS: Data from 121 consecutive patients who had undergone ACL reconstruction by the same surgeon using quadruple hamstring grafts were analysed. The body mass index (BMI), height and weight of these patients were correlated with the graft diameter obtained during surgery. Regression analysis was undertaken to assess the influence of individual anthropometric variables on the graft diameter. RESULTS: There were 121 patients with mean age of 32 years (14-55). There was a statistically significant positive correlation individually between the height and graft diameter (r = 0.38, p < 0.01) as well as between the body weight and graft diameter (r = 0.29, p < 0.01). However, when the body mass index was calculated, the correlation was not statistically significant (r = 0.08, p > 0.1). Regression analysis confirmed that BMI was not statistically significant as a predictor of hamstring graft diameter whereas height was statistically the most important predictor (F = 20.1; p < 0.01).This yielded the predictive equation, graft diameter = 4.5 + 0.02 x Ht (in cm). CONCLUSION: Although body mass index did not significantly correlate, body height may be a predictive variable in predicting the graft diameter in ACL reconstruction and provide useful pre operative information.