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Aims: DNA methylation profiling, recently endorsed by the World Health Organisation (WHO) as a pivotal diagnostic tool for brain tumours, most commonly relies on bead arrays. Despite its widespread use, limited data exist on the technical reproducibility and potential cross‐institutional differences. The LOGGIC Core BioClinical Data Bank registry conducted a prospective laboratory comparison trial with 12 international laboratories to enhance diagnostic accuracy for paediatric low‐grade gliomas, focusing on technical aspects of DNA methylation data generation and profile interpretation under clinical real‐time conditions. Methods: Four representative low‐grade gliomas of distinct histologies were centrally selected, and DNA extraction was performed. Participating laboratories received a DNA aliquot and performed the DNA methylation‐based classification and result interpretation without knowledge of tumour histology. Additionally, participants were required to interpret the copy number profile derived from DNA methylation data and conduct DNA sequencing of the BRAF hotspot p.V600 due to its relevance for low‐grade gliomas. Results had to be returned within 30 days. Results: High technical reproducibility was observed, with a median pairwise correlation of 0.99 (range 0.94–0.99) between coordinating laboratory and participants. DNA methylation‐based tumour classification and copy number profile interpretation were consistent across all centres, and BRAF mutation status was accurately reported for all cases. Eleven out of 12 centres successfully reported their analysis within the 30‐day timeframe. Conclusion: Our study demonstrates remarkable concordance in DNA methylation profiling and profile interpretation across 12 international centres. These findings underscore the potential contribution of DNA methylation analysis to the harmonisation of brain tumour diagnostics. [ABSTRACT FROM AUTHOR]

Background: Axillary disease extent according to baseline [18F]fluorodeoxyglucose PET/CT combined with pathological axillary treatment response has been proposed to guide de-escalation of axillary treatment for clinically node-positive breast cancer patients treated with neoadjuvant systemic therapy. The aim of this study was to assess whether axillary disease extent according to baseline [18F]fluorodeoxyglucose PET/CT and breast cancer molecular subtype are predictors of axillary pCR. Methods: This study included clinically node-positive patients treated with neoadjuvant systemic therapy in the prospective Radioactive Iodine Seed placement in the Axilla with Sentinel lymph node biopsy ('RISAS') trial (NCT02800317) with baseline [18F]fluorodeoxyglucose PET/CT imaging available. The predictive value of axillary disease extent according to baseline [18F]fluorodeoxyglucose PET/CT and breast cancer molecular subtype to estimate axillary pCR was evaluated using logistic regression analysis. Discriminative ability is expressed using ORs with 95% confidence intervals. Results: Overall, 185 patients were included, with an axillary pCR rate of 29.7%. The axillary pCR rate for patients with limited versus advanced baseline axillary disease according to [18F]fluorodeoxyglucose PET/CT was 31.9% versus 26.1% respectively. Axillary disease extent was not a significant predictor of axillary pCR (OR 0.75 (95% c.i. 0.38 to 1.46) (P = 0.404)). There were significant differences in axillary pCR rates between breast cancer molecular subtypes. The lowest probability (7%) was found for hormone receptor+/human epidermal growth factor receptor 2− tumours. Using this category as a reference group, significantly increased ORs of 14.82 for hormone receptor+/human epidermal growth factor receptor 2+ tumours, 40 for hormone receptor−/human epidermal growth factor receptor 2+ tumours, and 6.91 for triple-negative tumours were found (P < 0.001). Conclusion: Molecular subtype is a significant predictor of axillary pCR after neoadjuvant systemic therapy, whereas axillary disease extent according to baseline [18F]fluorodeoxyglucose PET/CT is not. Molecular subtype is a significant predictor of axillary pCR, whereas axillary disease extent according to baseline [18F]fluorodeoxyglucose PET/CT is not. Therefore, information on molecular subtype might be considered in guiding axillary treatment for clinically node-positive breast cancer patients treated with neoadjuvant systemic therapy. [ABSTRACT FROM AUTHOR]

There are ample data to suggest that early‐life dysbiosis of both the gut and/or airway microbiome can predispose a child to develop along a trajectory toward asthma. Although individual studies show clear associations between dysbiosis and asthma development, it is less clear what (collection of) bacterial species is mechanistically responsible for the observed effects. This is partly due to issues related to the asthma diagnosis and the broad spectrum of anatomical sites, sample techniques, and analysis protocols that are used in different studies. Moreover, there is limited attention for potential differences in the genetics of individuals that would affect the outcome of the interaction between the environment and that individual. Despite these challenges, the first bacterial components were identified that are able to affect the transcriptional state of human cells, ergo the immune system. Such molecules could in the future be the basis for intervention studies that are now (necessarily) restricted to a limited number of bacterial species. For this transition, it might be prudent to develop an ex vivo human model of a local mucosal immune system to better and safer explore the impact of such molecules. With this approach, we might move beyond association toward understanding of causality. [ABSTRACT FROM AUTHOR]

Background: Advances in treatment of childhood malignancies have improved overall cure rates to 80%. Nevertheless, cancer is still the most common cause of childhood mortality in Sweden. The prognosis is particularly poor for relapse of high-risk malignancies. In the international INFORM registry, tumor tissue from patients with relapsed, refractory, or progressive pediatric cancer as well as from very-high risk primary tumors is biologically characterized using next-generation sequencing to identify possible therapeutic targets. We analyzed data from Swedish children included in the INFORM registry concerning patient characteristics, survival, sequencing results and whether targeted treatment was administered to the children based on the molecular findings. Methods: A registry-based descriptive analysis of 184 patients included in the INFORM registry in Sweden during 2016-2021. Results: The most common diagnoses were soft tissue and bone sarcomas followed by high grade gliomas [including diffuse intrinsic pontine glioma (DIPG)]. Complete molecular analysis was successful for 203/212 samples originating from 184 patients. In 88% of the samples, at least one actionable target was identified. Highly prioritized targets, according to a preset scale, were identified in 48 (24%) samples from 40 patients and 24 of these patients received matched targeted treatment but only six children within a clinical trial. No statistically significant benefit in terms of overall survival or progression free survival was observed between children treated with matched targeted treatment compared to all others. Conclusion: This international collaborative study demonstrate feasibility regarding sequencing of pediatric high-risk tumors providing molecular data regarding potential actionable targets to clinicians. For a few individuals the INFORM analysis was of utmost importance and should be regarded as a new standard of care with the potential to guide targeted therapy. [ABSTRACT FROM AUTHOR]

Background: Pediatric low-grade glioma (pLGG) is essentially a single pathway disease, with most tumors driven by genomic alterations affecting the mitogen-activated protein kinase/ERK (MAPK) pathway, predominantly KIAA1549::BRAF fusions and BRAF V600E mutations. This makes pLGG an ideal candidate for MAPK pathway-targeted treatments. The type I BRAF inhibitor, dabrafenib, in combination with the MEK inhibitor, trametinib, has been approved by the United States Food and Drug Administration for the systemic treatment of BRAF V600E-mutated pLGG. However, this combination is not approved for the treatment of patients with tumors harboring BRAF fusions as type I RAF inhibitors are ineffective in this setting and may paradoxically enhance tumor growth. The type II RAF inhibitor, tovorafenib (formerly DAY101, TAK-580, MLN2480), has shown promising activity and good tolerability in patients with BRAF-altered pLGG in the phase 2 FIREFLY-1 study, with an objective response rate (ORR) per Response Assessment in Neuro-Oncology high-grade glioma (RANO-HGG) criteria of 67%. Tumor response was independent of histologic subtype, BRAF alteration type (fusion vs. mutation), number of prior lines of therapy, and prior MAPK-pathway inhibitor use. Methods: LOGGIC/FIREFLY-2 is a two-arm, randomized, open-label, multicenter, global, phase 3 trial to evaluate the efficacy, safety, and tolerability of tovorafenib monotherapy vs. current standard of care (SoC) chemotherapy in patients < 25 years of age with pLGG harboring an activating RAF alteration who require first-line systemic therapy. Patients are randomized 1:1 to either tovorafenib, administered once weekly at 420 mg/m2 (not to exceed 600 mg), or investigator's choice of prespecified SoC chemotherapy regimens. The primary objective is to compare ORR between the two treatment arms, as assessed by independent review per RANO-LGG criteria. Secondary objectives include comparisons of progression-free survival, duration of response, safety, neurologic function, and clinical benefit rate. Discussion: The promising tovorafenib activity data, CNS-penetration properties, strong scientific rationale combined with the manageable tolerability and safety profile seen in patients with pLGG led to the SIOPe-BTG-LGG working group to nominate tovorafenib for comparison with SoC chemotherapy in this first-line phase 3 trial. The efficacy, safety, and functional response data generated from the trial may define a new SoC treatment for newly diagnosed pLGG. Trial registration: ClinicalTrials.gov: NCT05566795. Registered on October 4, 2022. [ABSTRACT FROM AUTHOR]

Greater collaboration needed to realize potential of molecular profiling initiatives for pediatric cancers. [ABSTRACT FROM AUTHOR]

Extreme water-level recurrence estimates for a complex estuary using a high-resolution 2D model and a new method for estimating remotely generated sea level anomalies (SLAs) at the model boundary have been developed. The hydrodynamic model accurately resolves the dominant physical processes contributing to extreme water levels across the Washington State waters of the Salish Sea, including the relative contribution of remote SLA and other non-tidal residual processes that drive extreme water levels above the predicted tide. The model's predictions have errors of less than 15 cm (<5% of 3–4 m tidal range) at eight tide gauge locations across the model domain. The influence of remote SLAs at the seaward boundary of the model was implemented using a multivariate regression of readily available and locally relevant wind, sea surface temperature, and pressure anomaly data, combined with El Niño Index data (R2 = 0.76). The hydrodynamic model simulations using the remote SLA predictor compared well with simulations using the widely used data-assimilative global ocean model HYCOM SLA data (root mean square difference of 5.5 cm). Extreme water-level recurrence estimates with and without remote SLA show that remote forcing accounts for 50–60% of the total water level anomaly observed along Salish Sea shorelines. The resulting model simulations across decadal timescales provide estimates of extreme water level recurrence across the Salish Sea, capturing climate variability important to long-term coastal hazard planning. This approach has widespread applications for other complex estuarine systems. [ABSTRACT FROM AUTHOR]

Novel drug treatments for pediatric patients with cancer are urgently needed. Success of drug development in pediatric oncology has been promising, but many drugs still fail in translation from preclinical to clinical phases. To increase the translational potential, several improvements have been implemented, including the use of clinically achievable concentrations in the drug testing phase. Although pharmacokinetic (PK) parameters of numerous investigated drugs are published, a comprehensive PK overview of the most common drugs in pediatric oncology could guide preclinical trial design and improve the translatability into clinical trials. A review of the literature was conducted for PK parameters of 74 anticancer drugs, from the drug sensitivity profiling library of the INdividualized Therapy FOr Relapsed Malignancies in Childhood (INFORM) registry. PK data in the pediatric population were reported and complemented by adult parameters when no pediatric data were available. In addition, blood–brain barrier (BBB)‐penetration assessment of drugs was provided by using the BBB score. Maximum plasma concentration was available for 73 (97%), area under the plasma concentration‐time curve for 69 (92%), plasma protein binding for 66 (88%), plasma half‐life for 57 (76%), time to maximum concentration for 54 (72%), clearance for 52 (69%), volume of distribution for 37 (49%), lowest plasma concentration reached by the drug before the next dose administration for 21 (28%), and steady‐state concentration for 4 (5%) of drugs. Pediatric PK data were available for 48 (65%) drugs. We provide a comprehensive review of PK data for 74 drugs studied in pediatric oncology. This data set can serve as a reference to design experiments more closely mimicking drug PK conditions in patients, and may thereby increase the probability of successful clinical translation. [ABSTRACT FROM AUTHOR]

Purpose: MYC-driven Group 3 medulloblastoma (MB) (subtype II) is a highly aggressive childhood brain tumor. Sensitivity of MYC-driven MB to class I histone deacetylase inhibitors (HDACi) has been previously demonstrated in vitro and in vivo. In this study we characterize the transcriptional effects of class I HDACi in MYC-driven MB and explore beneficial drug combinations. Methods: MYC-amplified Group 3 MB cells (HD-MB03) were treated with class I HDACi entinostat. Changes in the gene expression profile were quantified on a microarray. Bioinformatic assessment led to the identification of pathways affected by entinostat treatment. Five drugs interfering with these pathways (olaparib, idasanutlin, ribociclib, selinexor, vinblastine) were tested for synergy with entinostat in WST-8 metabolic activity assays in a 5 × 5 combination matrix design. Synergy was validated in cell count and flow cytometry experiments. The effect of entinostat and olaparib on DNA damage was evaluated by γH2A.X quantification in immunoblotting, fluorescence microscopy and flow cytometry. Results: Entinostat treatment changed the expression of genes involved in 22 pathways, including downregulation of DNA damage response. The PARP1 inhibitors olaparib and pamiparib showed synergy with entinostat selectively in MYC-amplified MB cells, leading to increased cell death, decreased viability and increased formation of double strand breaks, as well as increased sensitivity to additional induction of DNA damage by doxorubicin. Non-MYC-amplified MB cells and normal human fibroblasts were not susceptible to this triple treatment. Conclusion: Our study identifies the combination of entinostat with olaparib as a new potential therapeutic approach for MYC-driven Group 3 MB. [ABSTRACT FROM AUTHOR]

Objectives: In approximately 45% of invasive breast cancer (IBC) patients treated with neoadjuvant systemic therapy (NST), ductal carcinoma in situ (DCIS) is present. Recent studies suggest response of DCIS to NST. The aim of this systematic review and meta-analysis was to summarise and examine the current literature on imaging findings for different imaging modalities evaluating DCIS response to NST. More specifically, imaging findings of DCIS pre- and post-NST, and the effect of different pathological complete response (pCR) definitions, will be evaluated on mammography, breast MRI, and contrast-enhanced mammography (CEM). Methods: PubMed and Embase databases were searched for studies investigating NST response of IBC, including information on DCIS. Imaging findings and response evaluation of DCIS were assessed for mammography, breast MRI, and CEM. A meta-analysis was conducted per imaging modality to calculate pooled sensitivity and specificity for detecting residual disease between pCR definition no residual invasive disease (ypT0/is) and no residual invasive or in situ disease (ypT0). Results: Thirty-one studies were included. Calcifications on mammography are related to DCIS, but can persist despite complete response of DCIS. In 20 breast MRI studies, an average of 57% of residual DCIS showed enhancement. A meta-analysis of 17 breast MRI studies confirmed higher pooled sensitivity (0.86 versus 0.82) and lower pooled specificity (0.61 versus 0.68) for detection of residual disease when DCIS is considered pCR (ypT0/is). Three CEM studies suggest the potential benefit of simultaneous evaluation of calcifications and enhancement. Conclusions and Clinical Relevance: Calcifications on mammography can remain despite complete response of DCIS, and residual DCIS does not always show enhancement on breast MRI and CEM. Moreover, pCR definition effects diagnostic performance of breast MRI. Given the lack of evidence on imaging findings of response of the DCIS component to NST, further research is demanded. Key Points: • Ductal carcinoma in situ has shown to be responsive to neoadjuvant systemic therapy, but imaging studies mainly focus on response of the invasive tumour. • The 31 included studies demonstrate that after neoadjuvant systemic therapy, calcifications on mammography can remain despite complete response of DCIS and residual DCIS does not always show enhancement on MRI and contrast-enhanced mammography. • The definition of pCR has impact on the diagnostic performance of MRI in detecting residual disease,and when DCIS is considered pCR, pooled sensitivity was slightly higher and pooled specificity slightly lower. [ABSTRACT FROM AUTHOR]

Introduction: The coronavirus disease 2019 (COVID-19) pandemic has led to the death of almost 7 million people, however, with a cumulative incidence of 0.76 billion, most people survive COVID-19. Several studies indicate that the acute phase of COVID-19 may be followed by persistent symptoms including fatigue, dyspnea, headache, musculoskeletal symptoms, and pulmonary functional-and radiological abnormalities. However, the impact of COVID-19 on long-term health outcomes remains to be elucidated. Aims: The Precision Medicine for more Oxygen (P4O2) consortium COVID-19 extension aims to identify long COVID patients that are at risk for developing chronic lung disease and furthermore, to identify treatable traits and innovative personalized therapeutic strategies for prevention and treatment. This study aims to describe the study design and first results of the P4O2 COVID-19 cohort. Methods: The P4O2 COVID-19 study is a prospective multicenter cohort study that includes nested personalized counseling intervention trial. Patients, aged 40–65 years, were recruited from outpatient post-COVID clinics from five hospitals in The Netherlands. During study visits at 3–6 and 12–18 months post-COVID-19, data from medical records, pulmonary function tests, chest computed tomography scans and biological samples were collected and questionnaires were administered. Furthermore, exposome data was collected at the patient's home and state-of-the-art imaging techniques as well as multi-omics analyses will be performed on collected data. Results: 95 long COVID patients were enrolled between May 2021 and September 2022. The current study showed persistence of clinical symptoms and signs of pulmonary function test/radiological abnormalities in post-COVID patients at 3–6 months post-COVID. The most commonly reported symptoms included respiratory symptoms (78.9%), neurological symptoms (68.4%) and fatigue (67.4%). Female sex and infection with the Delta, compared with the Beta, SARS-CoV-2 variant were significantly associated with more persisting symptom categories. Conclusions: The P4O2 COVID-19 study contributes to our understanding of the long-term health impacts of COVID-19. Furthermore, P4O2 COVID-19 can lead to the identification of different phenotypes of long COVID patients, for example those that are at risk for developing chronic lung disease. Understanding the mechanisms behind the different phenotypes and identifying these patients at an early stage can help to develop and optimize prevention and treatment strategies. [ABSTRACT FROM AUTHOR]

Child abuse is a dangerous situation for an infant. Professionals need to weigh the risk of failing to act when children are seriously harmed against the serious harm done by carrying out safeguarding interventions. In severe cases, foster care might be advisable. The negative effects for the child's psychosocial development requires that such placement must be based on very solid evidence. Our aim is to identify why Dutch parents whose child may have a medical condition that could mimic symptoms of child abuse have a significant chance of being erroneously convicted and losing custody of their child. As a method, we describe and analyze the following case. An Armenian-Dutch newborn (uncomplicated term vaginal delivery), starting at two weeks after birth, developed small bruises on varying body locations. At two months, a Well-Baby Clinic physician referred the girl to a university hospital, mentioning that there were no reasons to suspect child abuse and that her Armenian grandmother easily bruised as well. However, before consultation by a pediatrician of the hospital-located Expertise Center for Child Abuse, the parents were suspected of child abuse. Based on the expertise center's protocols, skeletal X-rays were made, which showed three healed, asymptomatic rib fractures, while invalid statistics suggested, incorrectly, a 10–100 times more likely non-accidental than accidental cause of the symptoms (discussed in Part II of this series). The expertise enter physician ignored any argument that could show parental innocence, including the positive parent-child relationship reported by the Well-Baby Clinic and the general practitioner. The girl and her older brother were placed in a family foster home and then in a secret home. The case radically resolved when a large bruise also developed there, and an independent tissue disease specialist diagnosed a hereditary connective tissue disorder in the mother, implying that the girl's bruises and rib fractures could well be disease-related. In conclusion, if child abuse is suspected, and foster care placement considered, the patient and the parents should be thoroughly investigated by an independent experienced pediatrician together with an experienced pediatric clinical psychologist or psychotherapist to produce an independent opinion. Children deserve this extra safeguard before being separated from their parents. [ABSTRACT FROM AUTHOR]

Purpose: We and others have demonstrated that MYC-amplified medulloblastoma (MB) cells are susceptible to class I histone deacetylase inhibitor (HDACi) treatment. However, single drug treatment with HDACi has shown limited clinical efficacy. We hypothesized that addition of a second compound acting synergistically with HDACi may enhance efficacy. Methods: We used a gene expression dataset to identify PLK1 as a second target in MB cells and validated the relevance of PLK1 in MB. We measured cell metabolic activity, viability, and cycle progression in MB cells after treatment with PLK1-specific inhibitors (PLK1i). Chou–Talalay synergy calculations were used to determine the nature of class I HDACi entinostat and PLK1i interaction which was validated. Finally, the clinical potential of the combination was assessed in the in vivo experiment. Results: MYC-amplified tumor cells are highly sensitive towards treatment with ATP-competitive PLK1i as a monotherapy. Entinostat and PLK1i in combination act synergistically in MYC-driven MB cells, exerting cytotoxic effects at clinically relevant concentrations. The downstream effect is exerted via MYC-related pathways, pointing out the potential of MYC amplification as a clinically feasible predictive biomarker for patient selection. While entinostat significantly extended survival of mice implanted with orthotopic MYC-amplified MB PDX, there was no evidence of the improvement of survival when treating the animals with the combination. Conclusion: The combination of entinostat and PLK1i showed synergistic interaction in vitro, but not in vivo. Therefore, further screening of blood–brain barrier penetrating PLK1i is warranted to determine the true potential of the combination as no on-target activity was observed after PLK1i volasertib treatment in vivo. [ABSTRACT FROM AUTHOR]

Background: To quantify the relationship between [18F]FDG uptake of the primary tumour measured by PET-imaging with immunohistochemical (IHC) expression of ER, PR, HER2, Ki-67, and clinical subtypes based on these markers in breast cancer patients. Methods: PubMed and Embase were searched for studies that compared SUVmax between breast cancer patients negative and positive for IHC expression of ER, PR, HER2, Ki-67, and clinical subtypes based on these markers. Two reviewers independently screened the studies and extracted the data. Standardized mean differences (SMD) and 95% confidence intervals (CIs) were estimated by using DerSimonian-Laird random-effects models. P values less than or equal to 5% indicated statistically significant results. Results: Fifty studies were included in the final analysis. SUVmax is significantly higher in ER-negative (31 studies, SMD 0.66, 0.56–0.77, P < 0.0001), PR-negative (30 studies, SMD 0.56; 0.40–0.71, P < 0.0001), HER2-positive (32 studies, SMD − 0.29, − 0.49 to − 0.10, P = 0.0043) or Ki-67-positive (19 studies, SMD − 0.77; − 0.93 to − 0.61, P < 0.0001) primary tumours compared to their counterparts. The majority of clinical subtypes were either luminal A (LA), luminal B (LB), HER2-positive or triple negative breast cancer (TNBC). LA is associated with significantly lower SUVmax compared to LB (11 studies, SMD − 0.49, − 0.68 to − 0.31, P = 0.0001), HER2-positive (15 studies, SMD − 0.91, − 1.21 to − 0.61, P < 0.0001) and TNBC (17 studies, SMD − 1.21, − 1.57 to − 0.85, P < 0.0001); and LB showed significantly lower uptake compared to TNBC (10 studies, SMD − 0.77, − 1.05 to − 0.49, P = 0.0002). Differences in SUVmax between LB and HER2-positive (9 studies, SMD − 0.32, − 0.88 to 0.24, P = 0.2244), and HER2-positive and TNBC (17 studies, SMD − 0.29, − 0.61 to 0.02, P = 0.0667) are not significant. Conclusion: Primary tumour SUVmax is significantly higher in ER-negative, PR-negative, HER2-positive and Ki-67-positive breast cancer patients. Luminal tumours have the lowest and TNBC tumours the highest SUVmax. HER2 overexpression has an intermediate effect. [ABSTRACT FROM AUTHOR]

Simple Summary: Neoadjuvant chemo(targeted) therapy (NCT) can downstage disease burden in breast cancer, allowing less invasive surgery. The ability of sequential hybrid [18F]FDG PET/MRI to predict the final pathologic primary tumour response to NCT in breast cancer was investigated. In addition, the value of sequential hybrid [18F]FDG PET/MRI in predicting axillary response was investigated separately in clinically node-positive breast cancer patients. In this study, final pathologic primary tumour and axillary lymph node response prediction with qualitative or quantitative [18F]FDG PET/MRI after NCT is not reliable. However, combining the relative decrease in [18F]FDG PET and MR imaging variables halfway through NCT improved diagnostic performance, especially in predicting the final pathologic axillary lymph node response. These findings suggest that sequential hybrid [18F]FDG PET/MRI could have complementary value in the early prediction of the final pathologic response to NCT in breast cancer. Background: The aim of this study was to investigate whether sequential hybrid [18F]FDG PET/MRI can predict the final pathologic response to neoadjuvant chemo(targeted) therapy (NCT) in breast cancer. Methods: Sequential [18F]FDG PET/MRI was performed before, halfway through and after NCT, followed by surgery. Qualitative response evaluation was assessed after NCT. Quantitatively, the SUVmax obtained by [18F]FDG PET and signal enhancement ratio (SER) obtained by MRI were determined sequentially on the primary tumour. For the response of axillary lymph node metastases (ALNMs), SUVmax was determined sequentially on the most [18F]FDG-avid ALN. ROC curves were generated to determine the optimal cut-off values for the absolute and percentage change in quantitative variables in predicting response. Diagnostic performance in predicting primary tumour response was assessed with AUC. Similar analyses were performed in clinically node-positive (cN+) patients for ALNM response. Results: Forty-one breast cancer patients with forty-two primary tumours and twenty-six cases of pathologically proven cN+ disease were prospectively included. Pathologic complete response (pCR) of the primary tumour occurred in 16 patients and pCR of the ALNMs in 14 cN+ patients. The AUC of the qualitative evaluation after NCT was 0.71 for primary tumours and 0.54 for ALNM responses. For primary tumour response, combining the percentage decrease in SUVmax and SER halfway through NCT achieved an AUC of 0.78. The AUC for ALNM response prediction increased to 0.92 by combining the absolute and the percentage decrease in SUVmax halfway through NCT. Conclusions: Qualitative PET/MRI after NCT can predict the final pathologic primary tumour response, but not the ALNM response. Combining quantitative variables halfway through NCT can improve the diagnostic accuracy for final pathologic ALNM response prediction. [ABSTRACT FROM AUTHOR]

Once prostate cancer cells metastasize to bone, they perceive approximately 2 kPa compression. We hypothesize that 2 kPa compression stimulates the epithelial-to-mesenchymal transition (EMT) of prostate cancer cells and alters their production of paracrine signals to affect osteoclast and osteoblast behavior. Human DU145 prostate cancer cells were subjected to 2 kPa compression for 2 days. Compression decreased expression of 2 epithelial genes, 5 out of 13 mesenchymal genes, and increased 2 mesenchymal genes by DU145 cells, as quantified by qPCR. Conditioned medium (CM) of DU145 cells was added to human monocytes that were stimulated to differentiate into osteoclasts for 21 days. CM from compressed DU145 cells decreased osteoclast resorptive activity by 38% but did not affect osteoclast size and number compared to CM from non-compressed cells. CM was also added to human adipose stromal cells, grown in osteogenic medium. CM of compressed DU145 cells increased bone nodule production (Alizarin Red) by osteoblasts from four out of six donors. Compression did not affect IL6 or TNF-α production by PC DU145 cells. Our data suggest that compression affects EMT-related gene expression in DU145 cells, and alters their production of paracrine signals to decrease osteoclast resorptive activity while increasing mineralization by osteoblasts is donor dependent. This observation gives further insight in the altered behavior of PC cells upon mechanical stimuli, which could provide novel leads for therapies, preventing bone metastases. [ABSTRACT FROM AUTHOR]

We thank all FASTX patients for their participation and the research staff at Forskningscentrum, Södersjukhuset. All participants then underwent an open peanut challenge (pOIT start), before starting peanut OIT (pOIT) in combination with continued omalizumab treatment. The x-axis shows the gene ratio of the overlapping genes of our gene list with the pathway gene set. [Extracted from the article]

Background: Neoadjuvant systemic therapy (NST) is a widely accepted initial treatment modality that can lead to pathologic downstaging of the axillary disease burden in breast cancer patients. Axillary response as well as baseline 18F-fluorodeoxyglucose (18F-FDG) uptake on positron emission tomography with computed tomography (PET/CT) differ between breast cancer subtypes. The value of baseline 18F-FDG PET/CT in predicting axillary response to NST is not yet established, possibly since breast cancer subtype was not taken into account. The purpose of this study was to investigate the value of baseline 18F-FDG PET/CT in predicting axillary response to NST with a specific emphasis on subtype. Methods: PET-parameters derived from the primary tumor as well as the most FDG-avid axillary lymph node were measured on baseline 18F-FDG PET/CT. Overall imaging findings were compared with the gold standard of histopathology of the axillary surgery specimen. Analyses for ER-positive/HER2-negative were performed separately from HER2-positive and TN patients. In addition, separate analyses for clinically node-positive patients were performed. Results: Sixty-six patients with 69 primary tumors were included in this study. Thirty-three axillae contained ER-positive/HER2-negative, 16 HER2-positive, and 20 TN breast cancer. No significant difference in PET-parameters between patients with axillary residual disease and axillary pathologic complete response were found for ER-positive/HER2-negative breast cancer. In the combined HER2-positive/TN subgroup, the SUVmax was significantly lower in patients without residual axillary disease in both the entire cohort and in patients with clinically node-positive disease. In this combined subgroup, a cut-off of 4.89 SUVmax measured on the most FDG-avid axillary lymph node could predict residual axillary disease with a sensitivity, specificity, PPV, and NPV of 90%, 69%, 53%, and 95%, respectively. Conclusions: Predicting axillary response following NST with baseline 18F-FDG PET/CT can be performed when focusing on breast cancer subtypes. The easily computed PET-parameter SUVmax can predict axillary response in HER2-positive and TN breast cancer. This study adds to the accumulating evidence that studies investigating the value of 18F-FDG PET/CT in breast cancer should always take subtypes into account. [ABSTRACT FROM AUTHOR]

The purpose of this study was to identify key deficiencies in pediatric oncology early phase clinical trial protocols in Germany and to provide guidance for efficient trial protocol development. A systematic review of the response letters of German competent authorities (CAs) and Ethics Committees to phase I/II pediatric oncology trial submissions in the period from 2014 to 2019 was performed. Documents were requested from all five Society for Paediatric Oncology and Haematology in Germany (GPOH) phase I/II trial networks plus all nine German Innovative Therapies for Children with Consortium Cancer (ITCC) centers. A blinded dataset containing aggregated data from 33 studies was analyzed for validation. All deficiencies were reviewed, listed, and weighted using a structured matrix according to frequency, category, significance, and feasibility. In total, documents of 17 trials from 6 different sites were collected. Two hundred fifty deficiencies identified by the CAs were identified and categorized into eight categories. "Toxicity and safety" was the most prominent category (27.6%), followed by "Manufacturing and Import" (18%). The majority of deficiencies were categorized as minor and potential measures as easy to address, but an important group of major and difficult to implement deficiencies was also identified. The blinded validation dataset confirmed these findings. The majority of the EC deficiencies could be resolved by changing the wording in the patient‐facing documents. In conclusion, this study was able to detect a pattern of key deficiencies. Most of the shortcomings can be anticipated by minor changes in the protocol and increased awareness can prevent time‐consuming revisions, withdrawals, or even rejections. A corresponding guideline describing key regulatory aspects is provided. [ABSTRACT FROM AUTHOR]

Long-term complications such as radiation-induced second malignancies occur in a subset of patients following radiation-therapy, particularly relevant in pediatric patients due to the long follow-up period in case of survival. Radiation-induced gliomas (RIGs) have been reported in patients after treatment with cranial irradiation for various primary malignancies such as acute lymphoblastic leukemia (ALL) and medulloblastoma (MB). We perform comprehensive (epi-) genetic and expression profiling of RIGs arising after cranial irradiation for MB (n =23) and ALL (n =9). Our study reveals a unifying molecular signature for the majority of RIGs, with recurrent PDGFRA amplification and loss of CDKN2A/B and an absence of somatic hotspot mutations in genes encoding histone 3 variants or IDH1/2, uncovering diagnostic markers and potentially actionable targets. [ABSTRACT FROM AUTHOR]

Taken together, 41 patients harbored an I NTRK i alteration (eight patients in MAPPYACTS and 33 patients in INFORM - representing 1.4% and 3.7%, respectively, of cases with RNA sequencing data available) across 20 different tumor entities. Over the last 2 years, two neurotrophic-tropomyosin receptor tyrosine kinase (NTRK) inhibitors have been approved for a tissue-agnostic indication in adults and children, namely, larotrectinib and entrectinib both in the United States and Europe. Although I NTRK i -fusion-positive malignancies are rare, patients with tumors harboring this alteration may greatly benefit from those innovative targeted therapies. [Extracted from the article]

Aims: KIAA1549‐BRAF fusions occur in certain brain tumours and provide druggable targets due to a constitutive activation of the MAP‐kinase pathway. We introduce workflows for calling the KIAA1549‐BRAF fusion from DNA methylation array‐derived copy number as well as DNA panel sequencing data. Methods: Copy number profiles were analysed by automated screening and visual verification of a tandem duplication on chromosome 7q34, indicative of the KIAA1549‐BRAF fusion. Pilocytic astrocytomas of the ICGC cohort with known fusion status were used for validation. KIAA1549‐BRAF fusions were called from DNA panel sequencing data using the fusion callers Manta, Arriba with modified filtering criteria and deFuse. We screened DNA methylation and panel sequencing data of 7790 specimens from brain tumour and sarcoma entities. Results: We identified the fusion in 337 brain tumours with both DNA methylation and panel sequencing data. Among these, we detected the fusion from copy number data in 84% and from DNA panel sequencing data in more than 90% using Arriba with modified filters. While in 74% the KIAA1549‐BRAF fusion was detected from both methylation array‐derived copy number and panel sequencing data, in 9% it was detected from copy number data only and in 16% from panel data only. The fusion was almost exclusively found in pilocytic astrocytomas, diffuse leptomeningeal glioneuronal tumours and high‐grade astrocytomas with piloid features. Conclusions: The KIAA1549‐BRAF fusion can be reliably detected from either DNA methylation array or DNA panel data. The use of both methods is recommended for the most sensitive detection of this diagnostically and therapeutically important marker. [ABSTRACT FROM AUTHOR]

Taken together, 41 patients harbored an I NTRK i alteration (eight patients in MAPPYACTS and 33 patients in INFORM - representing 1.4% and 3.7%, respectively, of cases with RNA sequencing data available) across 20 different tumor entities. Over the last 2 years, two neurotrophic-tropomyosin receptor tyrosine kinase (NTRK) inhibitors have been approved for a tissue-agnostic indication in adults and children, namely, larotrectinib and entrectinib both in the United States and Europe. Although I NTRK i -fusion-positive malignancies are rare, patients with tumors harboring this alteration may greatly benefit from those innovative targeted therapies. [Extracted from the article]

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Defiant ILC2s resist steroids: Group 2 innate lymphoid cells (ILC2s) contribute to the inflammation associated with human allergic airway diseases, including asthma and chronic rhinosinusitis. Corticosteroid drugs are used to manage type 2 respiratory diseases, but steroid resistance may arise in the course of therapy. By comparing ILC2s from inflamed nasal polyps with blood ILC2s from healthy controls, van der Ploeg et al. observed that enhanced cytokine expression by nasal polyp ILC2s and loss of steroid responsiveness were both associated with ILC2s becoming CD45RO+ rather than CD45RA+ like most resting ILC2s. Expression of the CD45RO isoform by inflammatory ILC2s in blood was increased in patients with asthma and correlated with more severe airway disease. CD45RO is a candidate biomarker for human inflammatory ILC2s that correlates with acquisition of steroid resistance. Group 2 innate lymphoid cells (ILC2s) orchestrate protective type 2 immunity and have been implicated in various immune disorders. In the mouse, circulatory inflammatory ILC2s (iILC2s) were identified as a major source of type 2 cytokines. The human equivalent of the iILC2 subset remains unknown. Here, we identify a human inflammatory ILC2 population that resides in inflamed mucosal tissue and is specifically marked by surface CD45RO expression. CD45RO+ ILC2s are derived from resting CD45RA+ ILC2s upon activation by epithelial alarmins such as IL-33 and TSLP, which is tightly linked to STAT5 activation and up-regulation of the IRF4/BATF transcription factors. Transcriptome analysis reveals marked similarities between human CD45RO+ ILC2s and mouse iILC2s. Frequencies of CD45RO+ inflammatory ILC2 are increased in inflamed mucosal tissue and in the circulation of patients with chronic rhinosinusitis or asthma, correlating with disease severity and resistance to corticosteroid therapy. CD45RA-to-CD45RO ILC2 conversion is suppressed by corticosteroids via induction of differentiation toward an immunomodulatory ILC2 phenotype characterized by low type 2 cytokine and high amphiregulin expression. Once converted, however, CD45RO+ ILC2s are resistant to corticosteroids, which is associated with metabolic reprogramming resulting in the activation of detoxification pathways. Our combined data identify CD45RO+ inflammatory ILC2s as a human analog of mouse iILC2s linked to severe type 2 inflammatory disease and therapy resistance. [ABSTRACT FROM AUTHOR]

Patient: Male, 1-year-old. Final Diagnosis: Healthy. Symptoms: None. Clinical Procedure: Foster care. Specialty: Pediatrics and Neonatology. Objective: Rare disease. Background: The commercial software for hospitals, Weight Velocity for Age Standard Deviation Score (SDSWVA), claims to document the growth and development of children, although published details are unavailable. The statisticsderived parameter SDSWVA includes the weight velocity at age t, WV(t) (weight gained between t and (t-1.23) years, divided by 1.23), and 3 standard weight velocity curves at average age AA, defined as AA=t-1.23/2 years. SDSWVA denotes the number of standard deviations that WV(t) deviates from the 0 SD weight velocity at AA. WV(t) yielded erroneous outcomes when applied to weights of a seriously underweight boy with an allergy to cows' milk who showed strong weight growth after being fed on food free of cows' milk. The SDSWVA software tacitly suggests that it is more accurate than WV(t). Case Report: The case of this boy was previously described in this Journal. Using SDSWVA(t,AA) software, his weight growth was analyzed by his third pediatrician, beginning at age 1.5 years. The diagnosis of the mother with Pediatric Condition Falsification was confirmed, adding 6 months to foster care, which totalled 8.5 months. Testing of the SDSWVA software on the boy's weight curve yielded results that were complex, nontransparent, and as erroneous as WV(t), explaining the misdiagnosis by the third pediatrician. Conclusions: SDSWVA software should not be used for children under 3 years and during variable weight behavior. Erroneous performance, unpublished details, and an error identified in their new but untested software make the Dutch Growth Research Foundation unlikely to meet the 2020 European Union regulations for in vitro medical devices. [ABSTRACT FROM AUTHOR]

Introduction: A hallmark of pediatric low-grade glioma (pLGG) is aberrant signaling of the mitogen activated protein kinase (MAPK) pathway. Hence, inhibition of MAPK signaling using small molecule inhibitors such as MEK inhibitors (MEKi) may be a promising strategy. Methods: In this multi-center retrospective centrally reviewed study, we analyzed 18 patients treated with the MEKi trametinib for progressive pLGG as an individual treatment decision between 2015 and 2019. We have investigated radiological response as per central radiology review, molecular classification and investigator observed toxicity. Results: We observed 6 partial responses (PR), 2 minor responses (MR), and 10 stable diseases (SD) as best overall responses. Disease control rate (DCR) was 100% under therapy. Responses were observed in KIAA1549:BRAF- as well as neurofibromatosis type 1 (NF1)-driven tumors. Median treatment time was 12.5 months (range: 2 to 27 months). Progressive disease was observed in three patients after cessation of trametinib treatment within a median time of 3 (2–4) months. Therapy related adverse events occurred in 16/18 patients (89%). Eight of 18 patients (44%) experienced severe adverse events (CTCAE III and/or IV; most commonly skin rash and paronychia) requiring dose reduction in 6/18 patients (33%), and discontinuation of treatment in 2/18 patients (11%). Conclusions: Trametinib was an active and feasible treatment for progressive pLGG leading to disease control in all patients. However, treatment related toxicity interfered with treatment in individual patients, and disease control after MEKi withdrawal was not sustained in a fraction of patients. Our data support in-class efficacy of MEKi in pLGGs and necessity for upfront randomized testing of trametinib against current standard chemotherapy regimens. [ABSTRACT FROM AUTHOR]

Energy poverty is a huge social problem. Academic and policy deliberations about energy poverty focus repeatedly on the same issues: the lack of a shared definition, who is responsible for the problem, and how best to measure it through indicators. We argue that debates at EU and national level do not address the daily reality of people living in energy poverty. The preliminary findings of our ESRC funded project suggest that local actors (e.g., NGOs) make a substantial contribution to bridging the gap between top-down policy and the energy poor. We argue that these actors represent an adaptive response to the inherent limitations of state and supra-national action and, therefore, play a key role in the governance of energy poverty. In presenting this argument, we suggest, as an avenue for future research, nodal governance as a lens through which to understand the role local actors play in the governing order for tackling energy poverty. The article provides an exploratory analysis of these issues, discussed through the selection of four illustrative examples in Italy, France, Catalonia, and England. [ABSTRACT FROM AUTHOR]

Background: Pediatric patients with relapsed or refractory disease represent a population with a desperate medical need. The aim of the INFORM (INdividualized Therapy FOr Relapsed Malignancies in Childhood) program is to translate next generation molecular diagnostics into a biomarker driven treatment strategy. The program consists of two major foundations: the INFORM registry providing a molecular screening platform and the INFORM2 series of biomarker driven phase I/II trials. The INFORM2 NivEnt trial aims to determine the recommended phase 2 dose (RP2D) of the combination treatment of nivolumab and entinostat (phase I) and to evaluate activity and safety (phase II).Methods: This is an exploratory non-randomized, open-label, multinational and multicenter seamless phase I/II trial in children and adolescents with relapsed / refractory or progressive high-risk solid tumors and CNS tumors. The phase I is divided in 2 age cohorts: 12-21 years and 6-11 years and follows a 3 + 3 design with two dose levels for entinostat (2 mg/m2 and 4 mg/m2 once per week) and fixed dose nivolumab (3 mg/kg every 2 weeks). Patients entering the trial on RP2D can seamlessly enter phase II which consists of a biomarker defined four group basket trial: high mutational load (group A), high PD-L1 mRNA expression (group B), focal MYC(N) amplification (group C), low mutational load and low PD-L1 mRNA expression and no MYC(N) amplification (group D). A Bayesian adaptive design will be used to early stop cohorts that fail to show evidence of activity. The maximum number of patients is 128.Discussion: This trial intends to exploit the immune enhancing effects of entinostat on nivolumab using an innovative biomarker driven approach in order to maximize the chance of detecting signs of activity. It prevents exposure to unnecessary risks by applying the Bayesian adaptive design for early stopping for futility. The adaptive biomarker driven design provides an innovative approach accelerating drug development and reducing exposure to investigational treatments in these vulnerable children at the same time.Trial Registration: ClinicalTrials.gov, NCT03838042. Registered on 12 February 2019. [ABSTRACT FROM AUTHOR]

The Scottish Women's Hospitals for Foreign Service (SWH) was a women's organization that equipped fourteen women's hospital units across Europe during the First World War. About one hundred female doctors of different backgrounds served with the SWH. The aim of this study is to investigate how the experiences of women doctors during the First World War affected their later careers. This retrospective cohort study included the 92 women doctors who survived the War, as well as another 6 volunteers who qualified in medicine shortly after the War. By studying their publications, (auto)biographies, obituaries, genealogical databases and entries in the Medical Directory, their lives and careers are reconstructed. This study argues that, even though wartime service undoubtedly had an enormous impact on this group of brave and forward-thinking women, the beneficial effects on the position of women doctors, as a whole, were negligible. [ABSTRACT FROM AUTHOR]

Background: Diagnostic reference levels (DRLs) are a crucial element of auditing radiation doses in paediatric computed tomography (CT). Currently, there are no national paediatric CT DRLs in South Africa. Objectives: The aim of this article was to establish local paediatric DRLs for CT examinations at two academic hospitals and to compare paediatric CT radiation output levels with established DRLs in the developed and developing world. Method: Computed Tomography Dose Indexvolume (CTDIvol) and dose length product (DLP) values were collected from CT examinations performed at two university hospitals for patients aged 0–15 years, during 01 November 2016–30 April 2017. The 75th percentile of the data distribution was calculated for each CT examination type and age group, further categorised into routine working hours and after-hours for both hospitals and statistically compared. Results: Of the 1031 CT examinations performed, CT brain examination was the most common (755/1031; 72.23%). DLP values were increased in the after-hours categories compared to regular working hours at both hospitals. The largest increase was in the 0–1 year age group (150.56%). With the exception of CT Chest and CT abdomen in the 0–1 year age group, the CTDIvol and DLP values compared favourably to international standards. Conclusion: Most of the calculated DRLs are acceptable and internationally comparable. This likely indicates effective reduction techniques and protocols. Computed tomography body examination protocols for 0–1 year patients should be reviewed. Strategies should be implemented to limit higher doses in after-hours examinations. [ABSTRACT FROM AUTHOR]

Background: Until today, adult and pediatric clinical trials investigating single-agent or combinatorial HDAC inhibitors including vorinostat in solid tumors have largely failed to demonstrate efficacy. These results may in part be explained by data from preclinical models showing significant activity only at higher concentrations compared to those achieved with current dosing regimens. In the current pediatric trial, we applied an intra-patient dose escalation design. The purpose of this trial was to determine a safe dose recommendation (SDR) of single-agent vorinostat for intra-patient dose escalation, pharmacokinetic analyses (PK), and activity evaluation in children (3–18 years) with relapsed or therapy-refractory malignancies. Results: A phase I intra-patient dose (de)escalation was performed until individual maximum tolerated dose (MTD). The starting dose was 180 mg/m2/day with weekly dose escalations of 50 mg/m2 until DLT/maximum dose. After MTD determination, patients seamlessly continued in phase II with disease assessments every 3 months. PK and plasma cytokine profiles were determined. Fifty of 52 patients received treatment. n = 27/50 (54%) completed the intra-patient (de)escalation and entered phase II. An SDR of 130 mg/m2/day was determined (maximum, 580 mg/m2/day). n = 46/50 (92%) patients experienced treatment-related AEs which were mostly reversible and included thrombocytopenia, fatigue, nausea, diarrhea, anemia, and vomiting. n = 6/50 (12%) had treatment-related SAEs. No treatment-related deaths occurred. Higher dose levels resulted in higher Cmax. Five patients achieved prolonged disease control (> 12 months) and showed a higher Cmax (> 270 ng/mL) and MTDs. Best overall response (combining PR and SD, no CR observed) rate in phase II was 6/27 (22%) with a median PFS and OS of 5.3 and 22.4 months. Low levels of baseline cytokine expression were significantly correlated with favorable outcome. Conclusion: An SDR of 130 mg/m2/day for individual dose escalation was determined. Higher drug exposure was associated with responses and long-term disease stabilization with manageable toxicity. Patients with low expression of plasma cytokine levels at baseline were able to tolerate higher doses of vorinostat and benefited from treatment. Baseline cytokine profile is a promising potential predictive biomarker. Trial registration: ClinicalTrials.gov, NCT01422499. Registered 24 August 2011, [ABSTRACT FROM AUTHOR]

This study compared external load variations between 5 vs 5 and 10 vs 10 sided game formats played under two conditions: (i) a ball possession game with two floaters, and (ii) a regular game with goalkeepers and small goals. Twenty-two professional soccer players participated in this study: four central defenders, four wide defenders, nine central midfielders, three wide forwards, and three strikers. Total distance (TD), running distance (RD), sprinting distance (SD), number of sprints (NS), and player's training load (PL) were recorded by GPS units. Within-format analyses revealed very likely large increases in TD (20.0%, [9.2; 31.9]; effect size (ES): 1.48, [0.71; 2.25]) and RD (130.9%, [20.2; 343.7]; ES: 1.32, [0.29; 2.35]) during the regular game when compared to the ball possession game in the 5 vs 5 format. In the 10 vs 10 format, large increases in TD (27.9%, [17.7; 39.1]; ES: 3.54, [2.34; 4.74]) and PL (27.4%, [12.6; 44.1]; ES: 2.46, [1.20; 3.72]) were observed in the regular condition when compared to the ball possession condition. Between-formats analyses revealed that, in the 10 vs 10 format, when compared to the 5 vs 5 format, RD was very likely larger (123.5%, [33.7; 273.7]), as was SD (195.8%, [20.5; 626.2]). However, very likely large decreases in PL were observed in the 10 vs 10 format (-19.6%; [-29.4; -8.3]) in the ball possession condition. Unclear differences were revealed based on variations in external load variables between formats in the regular condition. Smaller formats reduce the area available for running and sprinting and, thus, may be more adequate for increasing player's training load (based on accelerometer data). [ABSTRACT FROM AUTHOR]

The purpose of this study was to analyze the day-to-day variance of a typical weekly external training workload of two professional soccer teams from different countries. Twenty-nine players from two professional teams from Portugal and the Netherlands participated in this study. The players' external load was monitored for 7 weeks, by means of portable GPS devices (10 Hz, JOHAN, Noordwijk, Netherlands). Results revealed that match day -1 (MD-1), i.e. the training day before a match, had significantly (p = 0.001) less training volume (4584.50 m) than the other days. MD-5 (training five days before a match), MD-4 (four days before a match) and MD-3 (three days before a match) were the most intense (390.83, 176.90 and 247.32 m of sprinting distance, respectively) and with large volume (7062.66, 6077.30 and 6919.49 m, respectively). Interestingly, significant differences were found between clubs of different countries (p < 0.05) with the Portuguese team showing significantly higher intensity (sprinting distance) and volume (total distance) in all days with exception of MD-1 than the Dutch team. The results of this study possibly allow for the identification of different training workloads and tapering strategies between countries in relation to volume and intensity. It should be noted, however, that both clubs used a significant tapering phase in the last two days before the competition in an attempt to reduce residual fatigue accumulation. [ABSTRACT FROM AUTHOR]

This study compared the relative physical demands of official matches and sided games (medium and large) in professional soccer players by means of a global positioning system. Twenty-three professional male soccer players (24.632.84 years old; 180.946.49 cm; 77.196.46 kg; 52.995.01 VO2max) participated in the study. Total distance, running distance, sprinting distance, number of sprints, and acceleration sum were quantified per minute to compare the different games. Running distance in full match was greater than in 5vs5+GK (d = 2.303, moderate effect), 6vs6+GK (d = 1.719, moderate effect) and 9vs9+GK (d = 1.084, minimum effect) sided games. Greater values for sprinting distance were found in the full match compared to 5vs5+GK (d = 3.673, strong effect), 6vs6+GK (d = 2.606, moderate effect) and 9vs9+GK (d = 1.903, moderate effect) sided games. However, the load was greater in the 5vs5+GK game compared to the 6vs6+GK (d = 1.323, moderate effect) and 9vs9+GK (d = 1.030, minimum effect) games and the full match (d = 1.478, moderate effect). This study revealed that medium-sided games are not appropriate for simulating the sprinting conditions of official full matches. However, medium-sided games are more intense than full matches in that accelerations are made more often in medium-sided games. [ABSTRACT FROM AUTHOR]

Commercial software package "Growth Analyser Viewer Edition" ("GAVE") aims to document, monitor and analyze growth and development in children and adolescents. Although its clinical and scientific use is widespread, there are no published studies that describe the method and its validation. We were informed that GAVE calculates the weight velocity (kg/year) at age t from the weight difference between t and 448 days earlier or at birth, divided by the time difference. We recently discussed a case of false child abuse diagnosis (Pediatric Condition Falsification), resulting in the separation of the child from its parents, in which GAVE played a negative contributing role. To prevent such inappropriate diagnoses, we analyzed GAVE from a schematic representation of the measured clinical weight curve, with precisely defined weight velocities. In conclusion, the 448 days included for weight velocity predictions by GAVE caused the erroneous outcomes. Until the necessary changes to the software are implemented and validated, we advise against the use of GAVE in infants younger than 1.5 years, if multiple weight changes occur within 448 days, and following a long-lasting weight velocity change. Our analysis suggests to discard all medical software packages that lack public description and proof of validation. [ABSTRACT FROM AUTHOR]

Hormonal changes during lactation are associated with profound changes in bone cell biology, such as osteocytic osteolysis, resulting in larger lacunae. Larger lacuna shape theoretically enhances the transmission of mechanical signals to osteocytes. We aimed to provide experimental evidence supporting this theory by comparing the mechanoresponse of osteocytes in the bone of lactating mice, which have enlarged lacunae due to osteocytic osteolysis, with the response of osteocytes in bone from age-matched virgin mice. The osteocyte mechanoresponse was measured in excised fibulae that were cultured in hormone-free medium for 24 h and cyclically loaded for 10 min (sinusoidal compressive load, 3000 µε, 5 Hz) by quantifying loading-related changes in Sost mRNA expression (qPCR) and sclerostin and β-catenin protein expression (immunohistochemistry). Loading decreased Sost expression by ~ threefold in fibulae of lactating mice. The loading-induced decrease in sclerostin protein expression by osteocytes was larger in lactating mice (55% decrease ± 14 (± SD), n = 8) than virgin mice (33% decrease ± 15, n = 7). Mechanical loading upregulated β-catenin expression in osteocytes in lactating mice by 3.5-fold (± 0.2, n = 6) which is significantly (p < 0.01) higher than the 1.6-fold increase in β-catenin expression by osteocytes in fibulae from virgin mice (± 0.12, n = 4). These results suggest that osteocytes in fibulae from lactating mice with large lacunae may respond stronger to mechanical loading than those from virgin mice. This could indicate that osteocytes residing in larger lacuna show a stronger response to mechanical loading. [ABSTRACT FROM AUTHOR]

Making adaptive choices between solution strategies is a central element of contemporary mathematics education. However, previous studies signal that students make suboptimal choices between mental and written strategies to solve division problems. In particular, some students of a lower math ability level appear inclined to use mental strategies that lead to lower performance. The current study uses a pretest-training-posttest design to investigate the extent to which these students’ choices for written strategies and performance may be increased. Sixth graders of below-average mathematics level (n = 147) participated in one of two training conditions: an explicit-scaffolding training designed to promote writing down calculations or a practice-only training where strategy use was not explicitly targeted. Written strategy choices and performance increased considerably from pretest to posttest for students in both training conditions, but not in different amounts. Exploratory results suggest that students’ strategy choices may also be affected by their attitudes and beliefs and the sociocultural context regarding strategy use. [ABSTRACT FROM AUTHOR]

Background: Endotyping chronic rhinitis has proven hardest for the subgroup of non-allergic rhinitis (NAR) patients. While IgE-related inflammation is typical for allergic rhinitis (AR), no markers have been found that can be seen to positively identify NAR. A further complication is that AR and NAR might co-exist in patients with mixed rhinitis. As previous studies have considered only a limited number of inflammatory mediators, we wanted to explore whether a wider panel of mediators could help us refine the endotyping in chronic rhinitis patients. Objective: To endotype chronic rhinitis, and non-allergic rhinitis in particular, with help of molecular or cellular markers. Method: In this study we included 23 NAR patients without allergen sensitizations and with persistent rhinitis symptoms, 22 pollen sensitized rhinitis patients with seasonal symptoms, 21 mixed rhinitis patients with pollen-related symptoms and persistent symptoms outside of the pollen season, and 23 healthy controls without any symptoms. Nasal secretions were collected outside of pollen season and differences between the endotypes were assessed for a broad range of inflammatory mediators and growths factors using a multiplex ELISA. Results: Although we were able to identify two new nasal secretion makers (IL-12 and HGF) that were low in mixed and AR patients versus NAR and healthy controls, the most intriguing outcome is that despite investigating 29 general inflammatory mediators and growth factors no clear profile of non-allergic or mixed rhinitis could be found. Conclusion: Classical inflammatory markers are not able to differentiate between non-allergic or mixed rhinitis patients and healthy controls. [ABSTRACT FROM AUTHOR]

Objective: Rare disease. Background: Pediatric condition falsification (PCF) is a rare form of child abuse in which a caregiver fabricates or induces illness in the child. The diagnosis is difficult and controversial and can easily include false positives. Case Report: A boy, 3.18 kg birthweight (P25 curve), lost weight between age 56 to120 days. Cow milk allergy was suspected, feeding was changed to elementary formula, and he started catch-up weight growth while remaining significantly underweight. His pediatrician continuously interpreted his low weight as insufficient growth, despite prescribing 3 times the normal caloric intake, concluded that the mother purposely malnourished her son, diagnosed PCF, and the boy was separated from his family (days 502-755 of age). PCF was confirmed by 2 other pediatricians and 3 child protection physicians and was supported by 4 child protection agencies and 6 judges. However, proper analysis of the weight growth (kg/year) from the weight curve showed a normal weight gain. Beyond 120 days of age, weight gain at home was significantly above normal (during 347-489 days: 6.2 versus 3 kg/year of the P50). He reached P25 again at around 516 days. Conclusions: The question "How could so many physicians misjudge weight gain?" has scientific and sociologic aspects. Scientifically, low weight was wrongly interpreted as insufficient weight growth, requiring that physicians learn how to assess weight gain from weight curves. Sociologically, physicians seem to follow a diagnosis made by a colleague without proper evaluation. Arguments provided by the parents against this diagnosis seemed to be neglected. Confirmation bias occurs when any information against PCF is disregarded. [ABSTRACT FROM AUTHOR]

Background: Coffee is widely consumed and contains many bioactive compounds, any of which may impact pathways related to disease development.Objective: To identify individual metabolite changes in response to coffee.Methods: We profiled the metabolome of fasting serum samples collected from a previously reported single-blinded, three-stage clinical trial. Forty-seven habitual coffee consumers refrained from drinking coffee for 1 month, consumed four cups of coffee/day in the second month and eight cups/day in the third month. Samples collected after each coffee stage were subject to nontargeted metabolomic profiling using UPLC-ESI-MS/MS. A total of 733 metabolites were included for univariate and multivariate analyses.Results: A total of 115 metabolites were significantly associated with coffee intake (P < 0.05 and Q < 0.05). Eighty-two were of known identity and mapped to one of 33 predefined biological pathways. We observed a significant enrichment of metabolite members of five pathways (P < 0.05): (i) xanthine metabolism: includes caffeine metabolites, (ii) benzoate metabolism: reflects polyphenol metabolite products of gut microbiota metabolism, (iii) steroid: novel but may reflect phytosterol content of coffee, (iv) fatty acid metabolism (acylcholine): novel link to coffee and (v) endocannabinoid: novel link to coffee.Conclusions: The novel metabolites and candidate pathways we have identified may provide new insight into the mechanisms by which coffee may be exerting its health effects. [ABSTRACT FROM AUTHOR]

ABSTRACT: We aimed to develop an in vitro model for bone implant loosening, allowing analysis of biophysical and biological parameters contributing to mechanical instability‐induced osteoclast differentiation and peri‐implant bone loss. MLO‐Y4‐osteocytes were mechanically stimulated for 1 h by fluid shear stress using regimes simulating: (i) supraphysiological loading in the peri‐prosthetic interface (2.9 ± 2.9 Pa, 1 Hz, square wave); (ii) physiologic loading in the cortical bone (0.7 ± 0.7 Pa, 5 Hz, sinusoidal wave); and (iii) stress shielding. Cellular morphological parameters, membrane‐bound RANKL expression, gene expression influencing osteoclast differentiation, nitric oxide release and caspase 3/7‐activity were determined. Either Mouse bone marrow cells were cultured on top of loaded osteocytes or osteocyte‐conditioned medium was added to bone marrow cells. Osteoclast differentiation was assessed after 6 days. We found that osteocytes subjected to supraphysiological loading showed similar morphology and caspase 3/7‐activity compared to simulated physiological loading or stress shielding. Supraphysiological stimulation of osteocytes enhanced osteoclast differentiation by 1.9‐fold compared to physiological loading when cell‐to‐cell contact was permitted. In addition, it enhanced the number of osteoclasts using conditioned medium by 1.7‐fold, membrane‐bound RANKL by 3.3‐fold, and nitric oxide production by 3.2‐fold. The stimulatory effect of supraphysiological loading on membrane‐bound RANKL and nitric oxide production was higher than that achieved by stress shielding. In conclusion, the in vitro model developed recapitulated the catabolic biological situation in the peri‐prosthetic interface during instability that is associated with osteoclast differentiation and enhanced RANKL expression. The model thus provides a platform for pre‐clinical testing of pharmacological interventions with potential to stop instability‐induced bone implant loosening. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1425–1434, 2018. [ABSTRACT FROM AUTHOR]

The International Thermonuclear Experimental Reactor (ITER) magnetic system includes 18 toroidal field (TF) coils constructed using Nb3Sn cable-in-conduit superconductor. Each TF coil comprises a winding pack (WP) composed of seven double pancake modules stacked together, impregnated and inserted into a stainless steel coil case. Ten TF coils are being produced in Europe, under the responsibility of Fusion for Energy (F4E, the European Domestic Agency), while the remaining nine TF coils are being produced in Japan. F4E has implemented a strategy dividing the procurement into three packages. One is related to the construction of 70 radial plates (RP), another to the fabrication of 10 WP, and a third to the cold test and coil-case insertion of 10 WP. After 7 years of R&D and qualification activities and of industrial production, the first ITER TF coilWPhas been completed in Europe. Factory acceptance tests, including leak, dimensional, and electrical tests at room temperature, were completed in May 2017 and the series production of the remaining nine TF WPs in Europe is underway. The first package has been completed and all 70 RP have been delivered. Commissioning ofmajor tooling for the third package is to be performed at the end of 2017. In this paper, we report on the test of the first TF WP and on the status of the remaining production. [ABSTRACT FROM AUTHOR]