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Etripamil, a fast‐acting nondihydropyridine L‐type calcium channel blocker, is under investigation for potential self‐administration for the acute treatment of supraventricular tachyarrhythmias in a medically unsupervised setting. We report detailed pharmacokinetics and pharmacodynamics of intranasally administered etripamil in healthy adults from 2 Phase 1, randomized, double‐blind studies: Study MSP‐2017‐1096 (sequential dose‐escalation, crossover study design, n = 64) and NODE‐102 (single dose, 4‐way crossover study, n = 24). Validated bioanalytical assays determined plasma concentrations of etripamil and its inactive metabolite. Noncompartmental pharmacokinetic parameters were calculated. Pharmacodynamic parameters were determined for PR interval, blood pressure, and heart rate. Etripamil was rapidly absorbed intranasally, with time to maximal plasma concentration of 5‐8.5 minutes, corresponding to a rapid greater than 10% increase in mean maximum PR interval from baseline within 4‐7 minutes of doses of 60 mg or greater. Following peak plasma concentrations, systemic etripamil levels declined rapidly within the first 15 minutes following dosing and decreased more gradually thereafter. PR interval prolongation greater than 10% from baseline was generally sustained for about 45 minutes at doses of 60 mg or greater. The mean terminal half‐life ranged from about 1.5 hours with 60 mg to about 2.5‐3 hours for the 70‐ and 105‐mg doses. Etripamil was generally well tolerated without symptomatic hypotension. Adverse events were primarily mild to moderate and related to the administration site; no serious adverse events or episodes of atrioventricular block occurred. Intranasal etripamil administration, at doses of 60 mg or greater, produced rapidly occurring slowing of atrioventricular nodal conduction with a limited duration of effect without hemodynamic or electrocardiographic safety signals in healthy volunteers. [ABSTRACT FROM AUTHOR]

Background and Objective: Dynamic hyperinflation (DH) is a major marker of exertional dyspnoea in severe emphysema. We hypothesized that bronchoscopic lung volume reduction (BLVR) using endobronchial valves (EBVs) decreases DH. Methods: In this prospective bi‐centre study from both Toulouse and Limoges Hospitals, we assessed DH during an incremental cycle ergometry before and 3 months after EBVs treatment. The primary objective was to observe the change in inspiratory capacity (IC) at isotime. Target lobe volume reduction (TLVR) and changes in residual volume (RV), forced expiratory volume in one‐second (FEV1), mMRC, 6 minutes walking distance (6MWD), BODE and other dynamic measures like tele‐expiratory volume (EELV) were also analysed. Results: Thirty‐nine patients were included, of whom thirty‐eight presented DH. IC and EELV at isotime significantly improved (+214 mL, p = 0.004; −713 mL, p ˂ 0.001, respectively). Mean changes were +177 mL for FEV1 (+19%, p < 0.001), −600 mL for RV (p < 0.0001), +33 m for 6MWD (p < 0.0001), respectively. Patients who responded on RV (>430 mL decrease) and FEV1 (>12% gain) had better improvements compared to non‐responders (+368 mL vs. +2 mL; +398 mL vs. −40 mL IC isotime, respectively). On the opposite, in patients who responded on DH (>200 mL IC isotime increase), changes in TLV (−1216 mL vs. −576 mL), FEV1 (+261 mL vs. +101 mL), FVC (+496 mL vs. +128 mL) and RV (−805 mL vs. −418 mL) were greater compared to non‐responders. Conclusions: DH decreases after EBVs treatment, and this improvement is correlated with static changes. Bronchoscopic lung volume reduction using endobronchial valves leads to a decrease in dynamic hyperinflation; and these changes correlate with improvements in static parameters changes (target lobe volume reduction, residual volume, forced expiratory volume in 1 second, forced vital capacity). Dynamic hyperinflation decrease is deeper in most severe patients. See relatedEditorial [ABSTRACT FROM AUTHOR]

Background: Childhood cancer confront the whole family with a traumatic event. Because brothers and sisters may encounter emotional problems that can remain for a long time and that only few studies have assessed their long‐term outcome, our present objectives were to describe the long‐term quality of life (QoL) of childhood leukemia survivors' siblings and to explore its determinant. Methods: Brothers and sisters (from 8‐year‐old) of survivors included in the French LEA Cohort completed a QoL questionnaire (according to their age). Scores were compared with those reported by age‐ and gender‐matched French general population and by survivors. Using a clustering method, siblings were categorized into 3 groups depending on their level of QoL's scores and factors likely to be linked with these clusters were explored with multivariate analyses. Results: We included 689 brothers and sisters (313 minors, 376 adults) and the mean time from diagnosis was 13.2 ± 6.6 years. Minor siblings reported higher QoL scores than general population (p < 0.001), but a lower score for relationship with family than survivors (p < 0.001). In adult siblings, Mental Component Summary score was lower than general population (p < 0.001). Level of siblings' QoL was linked with female gender, but no association was found with cancer‐related factors. Conclusion: Brothers and sisters expressed a divergent perception of their long‐term QoL depending on their age. To minimize the impact from childhood to adulthood, long‐term attention should also be paid to siblings, often referred as "forgotten children". [ABSTRACT FROM AUTHOR]

Objective: Complement C3 and other components of the alternative pathway are higher in individuals with obesity. Moreover, C3 has been identified as a risk factor for cardiovascular disease. This study investigated whether, and how, a weight-loss intervention reduced plasma C3, activated C3 (C3a), and factor D and explored potential biological effects of such a reduction.Methods: The study measured plasma C3, C3a, and factor D by ELISA and measured visceral adipose tissue, subcutaneous adipose tissue, and intrahepatic lipid by magnetic resonance imaging in lean men (n = 25) and men with abdominal obesity (n = 52). The men with obesity were randomized to habitual diet or an 8-week dietary weight-loss intervention.Results: The intervention significantly reduced C3 (-0.15 g/L [95% CI: -0.23 to -0.07]), but not C3a or factor D. The C3 reduction was mainly explained by reduction in visceral adipose tissue but not subcutaneous adipose tissue or intrahepatic lipid. This reduction in C3 explained a part of the weight-loss-induced improvement of markers of endothelial dysfunction, particularly the reduction in soluble endothelial selectin and soluble intercellular adhesion molecule.Conclusions: Diet-induced weight loss in men with abdominal obesity could be a way to lower plasma C3 and thereby improve endothelial dysfunction. C3 reduction may be part of the mechanism via which diet-induced weight loss could ameliorate the risk of cardiovascular disease in men with abdominal obesity. [ABSTRACT FROM AUTHOR]

Background: Testicular tissue freezing is proposed for fertility preservation to (pre)pubertal boys with cancer before highly gonadotoxic treatment. Studies accurately comparing human (pre)pubertal testicular tissue quality before freezing and after thawing are exceptional. No study has reported this approach in a systematic manner and routine care. Objectives: To assess the impact of a control slow freezing protocol on testicular tissue architecture and integrity of (pre)pubertal boys after thawing. Materials and methods: (Pre)pubertal boys (n = 87) with cancer from 8 Reproductive Biology Laboratories of the French CECOS network benefited from testicular tissue freezing before hematopoietic stem cell transplantation. Seminiferous tubule cryodamage was determined histologically by scoring morphological alterations and by quantifying intratubular spermatogonia and the expression of DNA replication and repair marker in frozen‐thawed testicular fragments. Results: A significant increase in nuclear and epithelial score alterations was observed after thawing (p < 0.0001). The global lesional score remained lower than 1.5 and comparable to fresh testicular tissue. The number of intratubular spermatogonia and the expression of DNA replication and repair marker in spermatogonia and Sertoli cells did not vary significantly after thawing. These data showed the good preservation of the seminiferous tubule integrity and architecture after thawing, as previously reported in our studies performed in prepubertal mice and rats. Discussion: The current study reports, for the first time, the development of a semi‐quantitative analysis of cryodamage in human (pre)pubertal testicular tissue, using a rapid and useful tool that can be proposed in routine care to develop an internal and external quality control for testicular tissue freezing. This tool can also be used when changing one or several parameters of the freezing‐thawing procedure. Conclusion: Control slow freezing protocol without seeding maintains the seminiferous tubule architecture and integrity, the concentration of spermatogonia and the expression of DNA replication and repair marker in spermatogonia and Sertoli cells after thawing. [ABSTRACT FROM AUTHOR]

Summary: Among 143 patients with elastase, neutrophil‐expressed (ELANE)‐related neutropenia enrolled in the French Severe Chronic Neutropenia Registry, 94 were classified as having severe chronic neutropenia (SCN) and 49 with cyclic neutropenia (CyN). Their infectious episodes were classified as severe, mild or oral, and analysed according to their natural occurrence without granulocyte‐colony stimulating factor (G‐CSF), on G‐CSF, after myelodysplasia/acute leukaemia or after haematopoietic stem‐cell transplantation. During the disease's natural history period (without G‐CSF; 1913 person‐years), 302, 957 and 754 severe, mild and oral infectious events, respectively, occurred. Among severe infections, cellulitis (48%) and pneumonia (38%) were the most common. Only 38% of episodes were microbiologically documented. The most frequent pathogens were Staphylococcus aureus (37·4%), Escherichia coli (20%) and Pseudomonas aeruginosa (16%), while fungal infections accounted for 1%. Profound neutropenia (<200/mm3), high lymphocyte count (>3000/mm3) and neutropenia subtype were associated with high risk of infection. Only the p.Gly214Arg variant (5% of the patients) was associated with infections but not the overall genotype. The first year of life was associated with the highest infection risk throughout life. G‐CSF therapy achieved lower ratios of serious or oral infectious event numbers per period but was less protective for patients requiring >10 µg/kg/day. Infections had permanent consequences in 33% of patients, most frequently edentulism. [ABSTRACT FROM AUTHOR]

Summary: BRAF inhibitors are an effective treatment for BRAFV600E‐mutated, risk‐organ‐positive Langerhans cell histiocytosis (RO+ LCH). However, cell‐free BRAFV600E DNA often persists during therapy and recurrence frequently occurs after therapy discontinuation. To identify a pathological reservoir of BRAFV600E‐mutated cells, we studied peripheral blood cells obtained from six infants with RO+ multisystem (MS) LCH that received targeted therapy. After cell sorting, the BRAFV600E mutation was detected in monocytes (n = 5), B lymphocytes (n = 3), T lymphocytes (n = 2), and myeloid and plasmacytoid dendritic cells (n = 2 each). This biomarker may offer an interesting tool for monitoring the effectiveness of new therapeutic approaches for weaning children with RO+ LCH from targeted therapy. [ABSTRACT FROM AUTHOR]

DNA‐sensing receptor Cyclic GMP–AMP Synthase (cGAS) and its downstream signaling effector STimulator of INterferon Genes (STING) have gained significant interest in the field of tumor immunology, as a dysfunctional cGAS‐STING pathway is associated with poor prognosis and worse response to immunotherapy. However, studies so far have not taken into account the polymorphic nature of the STING‐encoding STING1 gene. We hypothesized that the presence of allelic variance in STING1 would cause variation between individuals as to their susceptibility to cancer development, cancer progression, and potential response to (immuno)therapy. To start to address this, we defined the genetic landscapes of STING1 in cervical scrapings and investigated their corresponding clinical characteristics across a unique cohort of cervical cancer patients and compared them with independent control cohorts. Although we did not observe an enrichment of particular STING1 allelic variants in cervical cancer patients, we did find that the occurrence of homozygous variants HAQ/HAQ and R232H/R232H of STING1 were associated with both younger age of diagnosis and higher recurrence rate. These findings were accompanied by worse survival, despite comparable mRNA and protein levels of STING and numbers of infiltrated CD8+ T cells. Our findings suggest that patients with HAQ/HAQ and R232H/R232H genotypes may have a dysfunctional cGAS‐STING pathway that fails to promote efficient anticancer immunity. Interestingly, the occurrence of these genotypes coincided with homozygous presence of the V48V variant, which was found to be individually associated with worse outcome. Therefore, we propose V48V to be further evaluated as a novel prognostic marker for cervical cancer. [ABSTRACT FROM AUTHOR]

Summary: The nucleoside analogue, 2‐chlorodeoxyadenosine (2CDA), was reported to be an active treatment for childhood Langerhans cell histiocytosis (LCH) without risk organ (RO−) involvement. However, we lack data on long‐term effects of 2CDA treatment, including the disease reactivation rate, permanent sequelae and long‐term tolerance. This study included 44 children from the French LCH registry, treated for a RO− LCH with 2CDA monotherapy (median number of six courses). The median age at the beginning of 2CDA was 3·6 years (range, 0·3–19·7 years) and the median follow‐up after was 5·4 years (range, 0·6–15·1 years). Objective response to 2CDA was observed in 25 patients (56·8%), while six patients (13·6%) had stable disease and 13 patients (29·5%) exhibited progressive disease. Among patients without progression, only two experienced disease reactivation after 2CDA discontinuation. The five‐year cumulative incidence of disease progression or reactivation after 2CDA therapy initiation was 34·3%. The lymphopenia reported in all cases [72% below absolute lymphocyte count (ALC) of 0·5 G/l], was addressed with appropriate prophylactic measures. Other toxicities above grade 2 were uncommon, and no second malignant neoplasm or neuropathy was reported. The five‐year overall survival was 97·7%. In conclusion, we could confirm that 2CDA monotherapy was a beneficial long‐term therapy for treating patients with RO− LCH. Appropriate management of induced immune deficiency is mandatory. [ABSTRACT FROM AUTHOR]

Over the years, the prognosis of adolescents treated for acute lymphoblastic leukemia (ALL) has improved. However, this age group still represents a challenge with an overall survival (OS) of 60% compared to 85% in younger children. Herein, we report the outcome of adolescents treated in the European Organisation for Research and Treatment of Cancer (EORTC) 58951 clinical trial. EORTC 58951 clinical trial included patients with de novo ALL between 1998 and 2008. For this study, we analyzed data of all adolescents between 15 and under 18. Data from 97 adolescents were analyzed, 70 had B‐lineage and 27 had T‐lineage ALL. The 8‐year event‐free survival (EFS) and OS for the B‐cell precursor ALL cases were 72.3% (59.4%–81.7%) and 80.8% (67.4%–89.1%), respectively. For the T‐lineage, the 8‐year EFS and OS were 57.4% (36.1%–74.0%) and 59.0% (36.1%–76.2%), respectively. "B‐other" ALL, defined as BCP‐ALL lacking any known recurrent genetic abnormalities were more frequent in our adolescent population (52.8%) than in younger children (27.1%). Outcome of adolescents in the EORTC 58951 study is supporting the findings that adolescents have better outcome in pediatric compared to adults' trials. Nevertheless, in pediatric studies, adolescents still have a worse prognosis than younger children. Despite the fact that specific unfavorable characteristics may be linked to the adolescent population, a careful study and characterization of adolescents "B‐other" genetic abnormalities in ALL is critical to improve the outcome of this population. [ABSTRACT FROM AUTHOR]

Despite the increased awareness of differences in the inflammatory response between men and women, only limited research has focused on the biological factors underlying these sex differences. The cholesterol derivative 27‐hydroxycholesterol (27HC) has been shown to have opposite inflammatory effects in independent experiments using mouse models of atherosclerosis and non‐alcoholic steatohepatitis (NASH), pathologies characterized by cholesterol‐induced inflammation. As the sex of mice in these in vivo models differed, we hypothesized that 27HC exerts opposite inflammatory effects in males compared to females. To explore whether the sex‐opposed inflammatory effects of 27HC translated to humans, plasma 27HC levels were measured and correlated with hepatic inflammatory parameters in obese individuals. To investigate whether 27HC exerts sex‐opposed effects on inflammation, we injected 27HC into female and male Niemann–Pick disease type C1 mice (Npc1nih) that were used as an extreme model of cholesterol‐induced inflammation. Finally, the involvement of estrogen signaling in this mechanism was studied in bone marrow‐derived macrophages (BMDMs) that were treated with 27HC and 17β‐estradiol (E2). Plasma 27HC levels showed opposite correlations with hepatic inflammatory indicators between female and male obese individuals. Likewise, hepatic 27HC levels oppositely correlated between female and male Npc1nih mice. Twenty‐seven hydroxycholesterol injections reduced hepatic inflammation in female Npc1nih mice in contrast to male Npc1nih mice, which showed increased hepatic inflammation after 27HC injections. Furthermore, 27HC administration also oppositely affected inflammation in female and male BMDMs cultured in E2‐enriched medium. Remarkably, female BMDMs showed higher ERα expression compared to male BMDMs. Our findings identify that the sex‐opposed inflammatory effects of 27HC are E2‐dependent and are potentially related to differences in ERα expression between females and males. Hence, the individual's sex needs to be taken into account when 27HC is employed as a therapeutic tool as well as in macrophage estrogen research in general. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

Keywords: acute lymphoblastic leukaemia; childhood leukaemia; immunotherapy EN acute lymphoblastic leukaemia childhood leukaemia immunotherapy e53 e56 4 07/01/20 20200701 NES 200701 Paediatric patients with refractory or relapsed (r/r) B-cell acute lymphoblastic leukaemia (BALL) are facing therapeutic challenges, considering their poor five year disease-free survival.[[1]] Immunotherapy could improve their survival and reduce adverse events. Lymphocyte subpopulations were studied in four patients: B-cell aplasia post InO was documented as soon as day 8 of cycle 1 and as late as day 16 after the last injection (Table SII). Loss of I CD19 i was also described with blinatumomab or CAR-T cell therapy.[[8]] InO can be effective and safe in r/r I CD22 i -positive B-ALL paediatric patients. [Extracted from the article]

Summary: We investigated the long‐term outcome, the incidence of second neoplasms (SN) and the rate of late adverse effects (LAE) in children with central nervous system (CNS) negative medium/high‐risk de novo acute lymphoblastic leukaemia (ALL), in first complete remission (CR1) at end of late intensification, randomized to receive no cranial radiotherapy (No CRT, n = 92) versus CRT (standard arm, n = 84) in the non‐inferiority EORTC 58832 study (1983–1989). Median follow‐up was 20 years (range 4–32 years). The 25‐year disease‐free survival rate (±SE) was 67·4 ± 4·9% without CRT and 70·2 ± 5·0% with CRT. The 25‐year incidence of isolated (6·5 ± 2·6% vs. 4·8 ± 2·3%) and any CNS relapse {8·7 ± 2·9% vs. 11·9 ± 3·5%; hazard ratio (HR) 0·71 [95% confidence interval (CI) 0·28–1·79]; test of non‐inferiority: P = 0·01} was not increased without CRT. The 25‐year SN incidence in CR1 was 7·9 ± 4·6% vs. 11·0 ± 4·2%. The 25‐year event‐free and overall survival rates were quite similar in both arms [59·5 ± 6·3% vs. 60·5 ± 5·9%, HR 0·94 (95% CI 0·57–1·52), and 78·1 ± 4·3% vs. 78·5 ± 4·5%, HR 1·00 (95% CI 0·53–1·88)]. Omission of CRT was associated with dramatic decrease in CNS and endocrine LAE rates. In conclusion, our data suggest that, with proper systemic and intrathecal CNS prophylaxis, CRT could totally be omitted in CR1 without jeopardizing survival, while decreasing LAE in childhood ALL. [ABSTRACT FROM AUTHOR]

Aim: Inflammatory markers such as serum C‐reactive protein (CRP) are used as routine markers to detect anastomotic leakage following colorectal surgery. However, CRP is characterized by a relatively low predictive value, emphasizing the need for the development of novel diagnostic approaches. Volatile organic compounds (VOCs) are gaseous metabolic products deriving from all conceivable bodily excrements and reflect (alterations in) the patient's physical status. Therefore, VOCs are increasingly considered as potential non‐invasive diagnostic biomarkers. The aim of this study was to assess the diagnostic accuracy of urinary VOCs for colorectal anastomotic leakage. Methods: In this explorative multicentre study, urinary VOC profiles of 22 patients with confirmed anastomotic leakage and 27 uneventful control patients following colorectal surgery were analysed by field asymmetric ion mobility spectrometry (FAIMS). Results: Urinary VOCs of patients with anastomotic leakage could be distinguished from those of control patients with high accuracy: area under the receiver operating characteristics curve 0.91 (95% CI 0.81–1.00, P < 0.001), sensitivity 86% and specificity 93%. Serum CRP was significantly increased in patients with a confirmed anastomotic leak but with lower diagnostic accuracy compared to VOC analysis (area under the receiver operating characteristics curve 0.82, 95% CI 0.68–0.95, P < 0.001). Combining VOCs and CRP did not result in a significant improvement of the diagnostic performance compared to VOCs alone. Conclusion: Analysis by FAIMS allowed for discrimination between urinary VOC profiles of patients with a confirmed anastomotic leak and control patients following colorectal surgery. A superior accuracy compared to CRP and apparently high specificity was observed, underlining the potential as a non‐invasive biomarker for the detection of colorectal anastomotic leakage. [ABSTRACT FROM AUTHOR]

Although increasing apolipoprotein A‐I (apoA‐I) might lower the cardiovascular disease risk, knowledge on natural compounds that elevate apoA‐I transcription is limited. Therefore, the aim of this study was to discover natural compounds that increase apoA‐I transcription in HepG2 cells. Since BRD4 inhibition is known to elevate apoA‐I transcription, we focused on natural BRD4 inhibitors. For this, the literature was screened for compounds that might increase apoA‐I and or inhibit BRD4. This resulted in list A, (apoA‐I increasers with unknown BRD4 inhibitor capacity), list B (known BRD4 inhibitors that increase apoA‐I), and list C (BRD4 inhibitors with unknown effect on apoA‐I). These compounds were compared with the compounds in two natural compound databases. This resulted in (1) a common substructure (ethyl‐benzene) in 60% of selected BRD4‐inhibitors, and (2) four compounds that increased ApoA‐I: hesperetin, equilenin, 9(S)‐HOTrE, and cymarin. Whether these increases are regulated via BRD4 inhibition and the ethyl‐benzene structure inhibits BRD4 requires further study. [ABSTRACT FROM AUTHOR]

Summary: Outcomes in childhood T‐cell acute lymphoblastic leukaemia (T‐ALL) are steadily improving due to intensive therapy. Between 1989 and 2008, 599 children with newly diagnosed T‐ALL were enrolled in two successive European Organization for Research and Treatment of Cancer ‐ Children's Leukaemia Group trials (58881 and 58951), both based on the Berlin‐Frankfurt‐Munster protocol and without cranial irradiation. In the latter trial induction chemotherapy was intensified. The most important randomizations were Medac Escherichia coli asparaginase versus Erwinia asparaginase in trial 58881, and dexamethasone (6 mg/m2/day) versus prednisolone (60 mg/m2/day) and prolonged versus conventional asparaginase duration in trial 58951. 8‐year event‐free survival (EFS) increased from 65·1% to 74·0% in trial 58951. Improvement was most profound for patients with white blood cell (WBC) counts <100 × 109/l and "good responders" to prephase. Medac E. coli asparaginase was associated with longer EFS [hazard ratio (HR) 0·54, P = 0·0015] and overall survival (HR 0·51, P = 0·0018). Induction therapy with dexamethasone did not improve EFS compared to prednisolone. Remarkably, intensification of central nervous system (CNS)‐directed therapy in trial 58951 resulted in fewer bone marrow relapses, while the incidence of CNS relapses remained low. In summary, we showed that adequate asparaginase therapy, intensified induction treatment and intensification of CNS‐directed chemotherapy can result in an improvement of outcome in T‐ALL patients with good prephase response and initial WBC counts <100 × 109/l, representing approximately 50% of T‐ALL patients. [ABSTRACT FROM AUTHOR]

The authors report their findings regarding lung ultrasound profiles in a population of transplant recipients. Twenty‐two patients were studied once each in multiple different ultrasound windows focusing on pleural, lung, and diaphragmatic signatures. All studies were performed in presumably otherwise healthy recipients at an outpatient follow‐up visit at least 3 months after transplantation. Those with recent pulmonary infections or decline in lung function were excluded from enrollment. The majority of scans revealed otherwise normal lungs with lung sliding, but there were more abnormalities than one would expect in a healthy control group. Lung ultrasonography will likely never replace other cross‐sectional imaging given its inherent visual limitations but adds another modality to interrogate the lung/pleural interface and diaphragmatic function. [ABSTRACT FROM AUTHOR]

Neurodegenerative (ND) complications in Langerhans cell histiocytosis (LCH) are a late‐onset but dramatic sequelae for which incidence and risk factors are not well defined. Based on a national prospective registry of paediatric LCH patients, we determined the incidence rate of clinical ND LCH (cND‐LCH) and analysed risk factors, taking into account disease extent and molecular characteristics. Among 1897 LCH patients, 36 (1·9%) were diagnosed with a cND‐LCH. The 10‐year cumulative incidence of cND‐LCH was 4·1%. cND‐LCH typically affected patients previously treated for a multisystem, risk organ–negative LCH, represented in 69·4% of cND‐LCH cases. Pituitary gland, skin and base skull/orbit bone lesions were more frequent (P < 0·001) in cND‐LCH patients compared to those without cND‐LCH (respectively 86·1% vs. 12·2%, 75·0% vs. 34·2%, and 63·9% vs. 28·4%). The 'cND susceptible patients' (n = 671) i.e., children who had experienced LCH disease with pituitary or skull base or orbit bone involvement, had a 10‐year cND risk of 7·8% vs. 0% for patients who did not meet these criteria. Finally, BRAFV600E status added important information among these cND susceptible patients, with the 10‐year cND risk of 33·1% if a BRAFV600E mutation was present compared to 2·9% if it was absent (P = 0·002). [ABSTRACT FROM AUTHOR]

In this work we present some experiments with an Iron‐Chrome‐Redox‐Flow‐Battery (RFB) which are adapted to high school students. In the experiments the students shall discover mostly on their own advantages and challenges of RFB. After we have set up and characterized the system four different experiments have been developed, in which the students will learn something about the experimental set‐up of RFB, will characterize electrically the charging/uncharging process and will attend to the different colouration of the electrolyts during charging (uncharging) the battery as well as to the crossover in RFB. Additionally concepts of internal resistance, spectral photometry and diffusion are included. The students tested the experiments appreciate the open as well as linked experiments. In an evaluation two month later we could show a remarkable improvement in understanding of the technique of RFB by the students taken part in these experiments. [ABSTRACT FROM AUTHOR]

Increasing apolipoprotein A‐I (apoA‐I), the predominant protein of high‐density lipoprotein (HDL) particles, has favorable effects on atherogenic risk factors. Here, we investigated the effects of peroxisome proliferator‐activated receptor α (PPARα) transactivating compounds on apoA‐I transcription in HepG2 cells. A transient PPARα agonist transactivation assay was used to screen 2500 natural compounds. To analyze the effects on apoA‐I transcription, human hepatocellular liver carcinoma (HepG2) were exposed to 0.1, 1, and 10 μg/mL of the natural PPARα transactivators. ApoA‐I mRNA expression was determined by quantitative polymerase chain reaction. Extensive dose–response experiments were performed using compounds that increased apoA‐I transcription by minimally 20%. Kelch‐like ECH‐associated protein 1 (KEAP) and carnitine palmitoyltransferase 1 alpha (CPT1α) expression were used respectively to confirm Bromodomain‐containing protein 4 inhibition or PPARα activation. Twenty‐eight natural compounds increased PPARα transactivation by at least twofold. Despite the increased CPT1α expression seen after the addition of most PPARα activating compounds, CPT1α expression and PPARα transactivation did not correlate. Addition of 0.05 μg/mL 9S‐hydroxy‐10E,12Z,15Z‐octadecatrienoic acid (9(S)‐HOTrE) increased apoA‐I mRNA expression by 35%, whereas 10–25 μg/mL of cymarin increased apoA‐I transcription by 37%. However, combining cymarin and 9(S)‐HOTrE did not result in a synergistic effect, in contrast this combination even decreased apoA‐I transcription. ApoA‐I transcription involves multiple regulatory players, and PPARα transactivation alone is not sufficient. A search for natural compounds resembling the molecular structure of 9(S)‐HOTrE or cymarin could aid to find additional components that increase apoA‐I transcription. [ABSTRACT FROM AUTHOR]

Abstract: Although phytosterols, plant‐derived sterol‐like components, are well known for their cholesterol‐lowering properties, their atherogenic potential is still under debate. Although they are known to share structural similarities with cholesterol, it is unclear whether their oxidized forms (oxyphytosterols) have the capacity to mediate proinflammatory responses in macrophages. In the present study, bone marrow‐derived macrophages were treated with oxidized low‐density lipoproteins, oxyphytosterols (7keto‐sito/campesterol [7keto‐sit/camp] or 7‐beta‐hydroxy‐sito/campesterol [7βOH‐sit/camp]), nonoxidized phytosterol (β‐sitosterol), or carrier‐control (cyclodextrin) in a dose‐ and time‐dependent manner. Inflammatory cytokine release, activity, and the corresponding mRNA expression levels were analyzed. 7βOH‐sit/camp, rather than 7keto‐sit/camp, induced a modest proinflammatory response in wild‐type cells derived from C57Bl/6 mice. The observed mild inflammatory effects are independent of the low‐density lipoprotein receptor and Cluster of differentiation 36/Scavenger receptor‐a. These data suggest that exogenously added oxyphytosterols do not affect macrophage‐mediated inflammatory responses, at least in vitro. [ABSTRACT FROM AUTHOR]

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The BRAF V600E mutation is reported in half of patients with Langerhans cell histiocytosis ( LCH). This study investigated the detection of the BRAF V600E allele in circulating cell-free (ccf) DNA in a paediatric LCH cohort. Children with BRAFV600E-mutated LCH were investigated to detect ccf BRAF V600E at diagnosis ( n = 48) and during follow-up ( n = 17) using a picolitre-droplet digital PCR assay. At diagnosis, ccf BRAFV600E was positive in 15/15 (100%) patients with risk-organ positive multisystem ( RO+ MS) LCH, 5/12 (42%) of patients with RO− MS LCH and 3/21 (14%) patients with single-system ( SS) LCH ( P < 0·001, Fisher's exact test). The positive BRAFV600E load was higher for RO+ patients (mean, 2·90%; range, 0·04-11·4%) than for RO− patients (mean, 0·16%; range, 0·01-0·39) ( P = 0·003, Mann-Whitney U test). After first-line vinblastine-steroid induction therapy, 7/7 (100%) of the non-responders remained positive for ccf BRAFV600E compared to 2/4 (50%) of the partial-responders and 0/4 of the complete responders ( P = 0·002, Fisher's exact test). Six children treated with vemurafenib showed a clinical response that was associated with a decrease in the ccf BRAFV600E load at day 15. Thus, ccf BRAFV600E is a promising biomarker for monitoring the response to therapy for children with RO+ MS LCH or RO− LCH resistant to first-line chemotherapy. [ABSTRACT FROM AUTHOR]

The French national cohort of children with Langerhans cell histiocytosis ( LCH) has included 1478 patients since it was established in 1983. LCH therapeutic strategies substantially changed in 1998, so we have divided the cohort into two 15-year periods. Starting in 1998, therapy duration increased from 6 to 12 months, repeated induction therapy was performed in cases showing a poor response to the first induction with vinblastine and steroids, and refractory disease in a risk organ ( RO+) was treated with cladribine and cytarabine. A total of 483 (33%) patients were enrolled before 1998, and 995 (67%) after 1998. Five-year survival was 96·6% (95% confidence interval: 95·4-97·5%) overall, improving from 92% pre-1998 to 99% post-1998 ( P < 0·001 adjusted to disease extent). This change was supported by an increase in 5-year survival from 60% to 92% in the RO+ group. Survival was particularly associated with cladribine and cytarabine among refractory RO+ patients. Disease reactivation was slightly less frequent after 1998, due to better enrolment of single-system patients, extended therapy duration, and more efficient second-line therapy. The crude rates of endocrine and neurological sequelae (the most frequent sequelae) appeared to improve over time, but this difference was not observed when the analysis was stratified by disease extent. [ABSTRACT FROM AUTHOR]

Abstract: A system of systems (SoS) relies on each constituent system contributing towards achieving some global emergent behavior. Integrating constituent systems can be particularly challenging for SoS engineering, partly because of the independence of the constituents and the difficulty of producing a realistic, scalable test environment before changes are deployed to the live environment. For this reason modeling and simulation can be important tools for regression testing within an integration scenario. We provide a worked example of an SoS integration scenario using a traffic management system as demonstrator, employing a structured, model‐based framework (the COMPASS Integration Framework) designed for integrating CSs in a variety of SoS integration scenarios. The Framework is designed to be used with architectural modelling views (we use SysML for our case study). Finally, we provide some pointers for future work and next steps. [ABSTRACT FROM AUTHOR]

The kinetics of plant stanol uptake and routing in 8-week-old C57BL/6J mice were determined after a plant stanol ester gavage. In addition, acute changes in intestinal and hepatic gene expression were investigated. Mice were fed a plant sterol/stanol poor diet from weaning. At the age of 8 weeks, they received an oral gavage consisting of 0.25 mg cholesterol + 50 mg plant stanol esters dissolved in olive oil. Animals were euthanized at different time points. In a second comparable set-up, mesenteric lymph-cannulated versus sham-operated mice received the same oral gavage, which was now deuterium labeled. Intestinal and hepatic sitostanol concentrations increased within 15 min post-gavage. This rapid hepatic appearance was absent in lymph-cannulated mice, suggesting a very fast lymph-mediated uptake. Hepatic mRNA expression of SREBP2 and its target genes rapidly decreased, whereas expression of LXR target genes increased. The intestinal SREBP2 pathway was increased, whereas the expression of LXR target genes hardly changed. The fivefold and sixfold increased expression of intestinal LDLr and PCSK9 is suggestive of TICE activation. We conclude that in C57BL/6J mice plant stanol kinetics are fast, and affect intestinal and hepatic gene expression within 15 min postprandial after lymph-mediated uptake. [ABSTRACT FROM AUTHOR]

Purpose Type 2 focal cortical dysplasia ( FCD2) is one of the main causes of refractory partial epilepsy, but often remains overlooked by MRI. This study aimed to elucidate whether 3T MRI offers better detection and characterization of FCD2 than 1.5T, using similar coils and acquisition time. Methods Two independent readers reviewed the 1.5T and 3T MR images of 25 patients with histologically proven FCD2. For both magnetic fields, the ability to detect a lesion was analyzed. We compared the identification of each of the five criteria typical of FCD2 (cortical thickening, blurring, cortical signal changes, subcortical signal changes, and 'transmantle' sign) and artifacts, using a four-point scale (0-3). Interobserver reliability for lesion detection was calculated. Key Findings Seventeen lesions (68%) were detected at 3T, two of which were overlooked at 1.5T. Interobserver reliability was better at 3T (κ = 1) than at 1.5T (κ = 0.83). The transmantle sign was more clearly identified at 3T than 1.5T (mean visualization score: 1.72 vs. 0.56; p = 0.002). Significance The use of 3T MRI in patients suspected of type 2 FCD improves the detection rate and the lesion characterization owing to the transmantle sign being more clearly seen at 3T. This point is of interest, since this feature is considered as an MR signature of FCD2. [ABSTRACT FROM AUTHOR]

Study Objectives To compare the cholesterol level goal attainment rates in patients receiving simvastatin doses recommended in clinical practice guidelines and simvastatin doses most frequently prescribed in clinical practice versus other statins at various dose levels, and to assess statin adherence rates in patients receiving all statins. Design Retrospective cohort study. Data Source PHARMO database, which contains linked prescription drug information, hospitalization records, and laboratory test results of over 1 million patients in the Netherlands. Patients A total of 7355 new statin users with available cholesterol level measurements before and 12 months after starting statin treatment between 1999 and 2006. Measurements and Main Results Simvastatin was chosen as the reference drug because policy makers in the Netherlands have promoted the use of generically available statins to reduce costs. Cholesterol level goal attainment rates were compared in patients receiving simvastatin 40 mg/day, which was the statin dose promoted in the 2006 Dutch cardiovascular risk management guidelines, or simvastatin 20 mg/day, which was the most frequently prescribed dose up to 2006, versus other statins at various dose levels. Relative risks ( RRs) were adjusted for age, sex, year of therapy initiation, cardiovascular disease, type 2 diabetes mellitus, hypertension, baseline low-density lipoprotein cholesterol level, and adherence during the 3 months before the 12-month follow-up cholesterol measurement. Compared with simvastatin 40 mg/day, cholesterol goal attainment rates were significantly higher with atorvastatin 40 mg/day ( RR 1.15, 95% confidence interval [ CI] 1.04-1.28) and rosuvastatin 10 mg/day ( RR 1.13, 95% CI 1.04-1.23), were similar with atorvastatin 20 mg/day ( RR 1.06, 95% CI 0.97-1.16) and rosuvastatin 20 mg/day ( RR 1.14, 95% CI 0.93-1.39), and were significantly lower with all other frequently used statin dose levels. Compared with simvastatin 20 mg/day, cholesterol goal attainment was significantly higher with any dose of atorvastatin and rosuvastatin, but were lower with any dose of pravastatin. Goal attainment rates were similar among patients with lower and higher cardiovascular risk. Among the 13-18% of patients who had follow-up cholesterol level measurements at 12 months in all statin groups, the proportion of adherent patients was approximately 75%; this was higher than the proportion of adherent patients in the total population (48-55%), which included patients without follow-up cholesterol levels. Conclusion A larger proportion of patients reached cholesterol lipid goals with simvastatin 40 mg/day. Cholesterol level goals were achieved by many patients using the recommended simvastatin 40 mg/day, but by fewer patients among those using the more commonly prescribed simvastatin 20 mg/day. Therefore, especially in high-risk patients, the choice of statin should be based on baseline cholesterol levels and expected reductions in these levels, and treatment should be adapted if targets are not met. Improved cholesterol level monitoring may increase adherence and cholesterol management. [ABSTRACT FROM AUTHOR]

Water channel AQP2 is the target for vasopressin (AVP) and a major determinant of urinary concentrating capacity. In mature kidneys, prostaglandins counteract the effect of AVP on AQP2 expression at functional sites. We investigated whether disturbances in water homeostasis in infants with patent ductus arteriosus (PDA) treated with prostaglandin inhibitors can be attributed to activation of AQP2. In 53 infants with symptomatic PDA (gestational age 24-33 weeks), 30 receiving ibuprofen and 23 indomethacin starting at 2-15 days of life, clinical and biochemical data were collected before treatment and after each dose of the drugs. Urinary AQP2 was determined by dot immunoblotting. Urinary AQP2 level and osmolality were decreased in both groups. Urinary osmolality was overall low and correlated inversely with fluid uptake. In ibuprofen group, there was no correlation of AQP2 level with urinary osmolality. There was no AQP2 upregulation in the infants. The low urinary osmolality and dissociation between urinary osmolality and urinary AQP2 level indicate that the fluid retention sometimes observed in PDA infants treated with prostaglandin inhibitors is not caused by increased levels of functional AQP2. Thus, knowledge about the renal physiology of the adult cannot always be transferred to the infant kidney. [ABSTRACT FROM AUTHOR]

Long-chain saturated fatty acids such as palmitic acid induce insulin resistance and NF-κB activation in skeletal muscle cells. Here we investigated the effects of long-chain fatty acid (FA) saturation and configuration on NF-κB activity and insulin sensitivity in cultured skeletal muscle cells. Of all tested unsaturated FAs, only elaidic acid (3-fold), cis9, trans11-CLA (3-fold) and trans10, cis12-CLA (13-fold) increased NF-κB transactivation in myotubes. This was not accompanied by decreased insulin sensitivity (measured as insulin-induced glucose uptake and GLUT4 translocation). We therefore conclude that FA-induced NF-κB activation is not sufficient for the induction of insulin resistance in skeletal muscle cells. [ABSTRACT FROM AUTHOR]