Highly Pathogenic Avian Influenza A(H5N8) Virus Spread by Short- and Long-Range Transmission,France, 2016–17

We detected 3 genotypes of highly pathogenic avian influenza A(H5N8) virus in France during winter 2016–17. Genotype A viruses caused dramatic economic losses in the domestic duck farm industry in southwestern France. Our phylogenetic analysis suggests that genotype A viruses formed 5 distinct geographic clusters in southwestern France. In some clusters, local secondary transmission might have been started by a single introduction. The intensity of the viral spread seems to correspond to the density of duck holdings in each production area. To avoid the introduction of disease into an unaffected area, it is crucial that authorities limit the movements of potentially infected birds.     

Development of Hip Bone Geometry During Gender-Affirming Hormone Therapy in Transgender Adolescents Resembles That of the Experienced Gender When Pubertal Suspension Is Started in Early Puberty

Bone geometry can be described in terms of periosteal and endocortical growth and is partly determined by sex steroids. Periosteal and endocortical apposition are thought to be regulated by testosterone and estrogen, respectively. Gender-affirming hormone (GAH) treatment with sex steroids in transgender people might affect bone geometry. However, in adult transgender people, no change in bone geometry during GAH was observed. In this study, we investigated changes in bone geometry among transgender adolescents using a gonadotropin-releasing hormone agonist (GnRHa) and GAH before achieving peak bone mass. Transgender adolescents treated with GnRHa and subsequent GAH before the age of 18 years were eligible for inclusion. Participants were grouped based on their Tanner stage at the start of GnRHa treatment and divided into early, mid, and late puberty groups. Hip structure analysis software calculating subperiosteal width (SPW) and endocortical diameter (ED) was applied to dual-energy X-ray absorptiometry scans performed at the start of GnRHa and GAH treatments, and after ≥2 years of GAH treatment. Mixed-model analyses were performed to study differences over time. Data were visually compared with reference values of the general population. A total of 322 participants were included, of whom 106 were trans women and 216 trans men. In both trans women and trans men, participants resembled the reference curve for SPW and ED of the experienced gender but only when GnRHa was started during early puberty. Those who started during mid and late puberty remained within the reference curve of the gender assigned at birth. A possible explanation might be sought in the phenomenon of programming, which conceptualizes that stimuli during critical windows of development can have major consequences throughout one's life span. Therefore, this study adds insights into sex-specific bone geometry development during puberty of transgender adolescents treated with GnRHa, as well as the general population. © 2021 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.     

1p36 deletion syndrome: Review and mapping with further characterization of the phenotype,a new cohort of 86 patients

Chromosome 1p36 deletion syndrome (1p36DS) is one of the most common terminal deletion syndromes (incidence between 1/5000 and 1/10,000 live births in the American population), due to a heterozygous deletion of part of the short arm of chromosome 1. The 1p36DS is characterized by typical craniofacial features, developmental delay/intellectual disability, hypotonia, epilepsy, cardiomyopathy/congenital heart defect, brain abnormalities, hearing loss, eyes/vision problem, and short stature. The aim of our study was to (1) evaluate the incidence of the 1p36DS in the French population compared to 22q11.2 deletion syndrome and trisomy 21; (2) review the postnatal phenotype related to microarray data, compared to previously publish prenatal data. Thanks to a collaboration with the ACLF (Association des Cytogénéticiens de Langue Française), we have collected data of 86 patients constituting, to the best of our knowledge, the second-largest cohort of 1p36DS patients in the literature. We estimated an average of at least 10 cases per year in France. 1p36DS seems to be much less frequent than 22q11.2 deletion syndrome and trisomy 21. Patients presented mainly dysmorphism, microcephaly, developmental delay/intellectual disability, hypotonia, epilepsy, brain malformations, behavioral disorders, cardiomyopathy, or cardiovascular malformations and, pre and/or postnatal growth retardation. Cardiac abnormalities, brain malformations, and epilepsy were more frequent in distal deletions, whereas microcephaly was more common in proximal deletions. Mapping and genotype–phenotype correlation allowed us to identify four critical regions responsible for intellectual disability. This study highlights some phenotypic variability, according to the deletion position, and helps to refine the phenotype of 1p36DS, allowing improved management and follow-up of patients.     

Vinflunine (20′,20′-difluoro- 3′,4′-dihydrovinorelbine), a novel Vinca alkaloid, which participates in P-glycoprotein (Pgp)-mediated multidrug resistance in vivo and in vitro

Vinflunine (VFL) is a novel derivative of vinorelbine (NVB, Navelbine®), which has shown markedly superior antitumor activity to NVB, in various experimental animal models. To establish whether this new Vinca alkaloid participates in P-glycoprotein (Pgp)-mediated multidrug resistance (MDR), VFL-resistant murine P388 cells (P388/VFL) were established in vivo and used in conjunction with the well established MDR P388/ADR subline, to define the in vivo resistance profile for VFL. P388/VFL cells proved cross-resistant to drugs implicated in MDR (other Vinca alkaloids, doxorubicin, etoposide), but not to campothecin or cisplatin and showed an increased expression of Pgp, without any detectable alterations in topoisomerase II or in glutathione metabolism. The P388/ADR cells proved cross-resistant to VFL both in vivo and in vitro, and this VFL resistance was efficiently modulated by verapamil in vitro. Cellular transport experiments with tritiated-VFL revealed differential uptake by P388 sensitive and P388/ADR resistant cells, comparable with data obtained using tritiated-NVB. In various in vitro models of human MDR tumor cells, whilst full sensitivity was retained in cells expressing alternative non-Pgp-mediated MDR mechanisms, cross resistance was identified in Pgp-overexpressing cells. Differences were, however, noted in terms of the drug resistance profiles relative to the other Vincas, with tumor cell lines proving generally least cross-resistant to VFL. Overall, these results suggest that VFL, like other Vinca alkaloids, participates in Pgp-mediated MDR, with tumor cells selected for resistance to VFL overexpressing Pgp, yet MDR tumor cell lines proved generally less cross resistant to VFL relative to the other Vinca alkaloids.     

C-Jun NH(2)-terminal kinase mediates proliferation and tumor growth of human prostate carcinoma.

PURPOSE: C-Jun NH(2)-terminal kinase (JNK) has been implicated in numerous functions including stress responses, apoptosis,and transformation. The role in transformation is based largely on studies of isolated cell types with little indication of whether JNK plays a general role in a specific human tumor type or whether this occurs in vivo. EXPERIMENTAL DESIGN: We examined 9 human prostate carcinoma cell lines in vitro and a representative line in vivo. RESULTS: For all of the cell lines proliferation is highly correlated with serum-supported JNK activity (r(Pearson) = 0.91; P = 0.004), whereas no relationship was observed for 10 human breast cancer cell lines (r(Pearson) = -0.32). Treatment with characterized antisense oligonucleotides complementary to sequences common to either the JNK1 or JNK2 family of isoforms showed that, whereas antisense JNK1 inhibited growth by a maximum of 57%, antisense JNK2 inhibited proliferation up to 80%. Sense and scrambled control oligonucleotides had little effect (average 3.7 +/- 1.5%). Moreover, systemic treatment of mice bearing established xenografts of PC3 prostate carcinoma cells with antisense JNK1 and JNK2 led to inhibition tumor growth by 57% (P < 0.002) and 80% (P < 0.001), respectively. The difference is significant (P < 0.012). Combined antisense treatment led to a significant increase in frequency of tumor regression (P = 0.022). CONCLUSION: These results indicate that JNK is required for growth of prostate carcinoma cells in vitro and in vivo, and additionally indicate that JNK2 plays a dominant role. The JNK pathway is a novel target in the treatment of prostate carcinoma.     

Adaptation and optimization of the emulsification-diffusion technique to prepare lipidic nanospheres.

In this study, the emulsification-diffusion method traditionally used to prepare polymeric nanoparticles was adapted to obtain lipidic nanospheres (LN) using four model lipids. The method consists of dissolving the lipid in a partially water-miscible solvent (previously saturated with water) at room temperature or at controlled temperature depending on lipid solubility. This organic phase is emulsified in an aqueous solution of a stabilizing agent (saturated with solvent) by conventional stirring at the same temperature used to dissolve the lipid. This oil-in-water emulsion is then diluted with an excess of water at controlled temperature in order to provoke the diffusion from the internal phase into the external phase thereby causing lipid aggregation in the form of LN. This new approach for the preparation of LN has clear advantages over the existing methods, namely: (i) it is efficient and versatile; (ii) easy implementation and scaling up (with no need of high energy sources); (iii) high reproducibility and narrow size distribution; (iv) less physical stress (i.e., long exposure to high temperatures and to mechanical dispersion); (v) it is not necessary to dissolve the drug in the melted lipid. The selection of the water-miscible solvent and the stabilizers are critical parameters to obtain lipidic particles in the nanometric range. In general, solvents with high water miscibility and stabilizers able to form stable emulsions are preferred. The results demonstrated that it was possible to reduce the particle size by increasing the process temperature, the stirring rate, the amount of stabilizer, and by lowering the amount of lipid. Control of the preparative variables allowed to obtain LN with diameters under 100 nm. It was found that the influence of preparative parameters was associated with a mechanism based on a physicochemical instability. In this sense, it is suggested that the rapid solvent diffusion produces regions of local supersaturation near the interface, and LN are formed due to the ensuing interfacial phase transformations and lipid aggregation that occur in these interfacial domains. In terms of stability, only poly(vinyl alcohol) (PVAL) was able to preserve the physical stability of the dispersion for long periods after preparation. This effect was attributed to the ability of PVAL chains to form a strongly attached layer on the nanoparticle surface with an excellent repulsion effect.     

Resistance to tyrosine kinase inhibitors: calling on extra forces.

Over the past 5 years, small molecule tyrosine kinase inhibitors have been successfully introduced as new cancer therapeutics. The pioneering work with the ABL inhibitor imatinib (Glivec, Gleevec) was rapidly extended to other types of leukemias as well as solid tumors, which stimulated the development of a variety of new tyrosine kinase inhibitors. Unfortunately, oncogenic tyrosine kinases seem to have little problem to develop resistance to these inhibitors, and there is good evidence that this is not limited to imatinib, but also occurs with other inhibitors, such as FLT3 and EGFR inhibitors. Based on studies with imatinib, mutation and amplification of the target kinase seem to be the most important mechanisms for the development of resistance, but these mechanisms alone cannot explain all cases of resistance. A better understanding of the resistance mechanisms will be required to design improved treatment strategies in the future. In this review, we summarize the current insights in the different mechanisms of resistance to small molecule tyrosine kinase inhibitors, and discuss future improvements that might limit or even overcome resistance.     

Early variations of circulating interleukin-6 and interleukin-10 levels during thoracic radiotherapy are predictive for radiation pneumonitis.

PURPOSE: To investigate variations of circulating serum levels of interleukin-6 (IL-6), tumor necrosis factor alpha (TNFalpha), and interleukin-10 (IL-10) during three-dimensional conformal radiation therapy (3D-CRT) in patients with non-small-cell lung cancer and correlate these variations with the occurrence of radiation pneumonitis. PATIENTS AND METHODS: Ninety-six patients receiving 3D-CRT for stage I to III disease were evaluated prospectively. Circulating cytokine levels were determined before, every 2 weeks during, and at the end of treatment. Radiation pneumonitis was evaluated prospectively between 6 and 8 weeks after 3D-CRT. The predictive value of clinical, dosimetric, and biologic (cytokine levels) factors was evaluated both in univariate and multivariate analyses. RESULTS: Forty patients (44%) experienced score 1 or more radiation pneumonitis. No association was found between baseline cytokine levels and the risk of radiation pneumonitis. In the whole population, mean levels of TNFalpha, IL-6, and IL-10 remained stable during radiotherapy. IL-6 levels were significantly higher (P = .047) during 3D-CRT in patients with radiation pneumonitis. In the multivariate analysis, covariations of IL-6 and IL-10 levels during the first 2 weeks of 3D-CRT were evidenced as independently predictive of radiation pneumonitis in this series (P = .011). CONCLUSION: Early variations of circulating IL-6 and IL-10 levels during 3D-CRT are significantly associated with the risk of radiation pneumonitis. Variations of circulating IL-6 and IL-10 levels during 3D-CRT may serve as independent predictive factors for this complication.     

Severe Maternal Morbidity in Canada: Temporal Trends and Regional Variations, 2003-2016

ObjectiveThis study sought to quantify temporal trends and provincial and territorial variations in severe maternal morbidity (SMM) in Canada.MethodsThe study used data on all hospital deliveries in Canada (excluding Québec) from 2003 to 2016 to examine temporal trends and from 2012 to 2016 to study regional variations. SMM was identified using diagnosis and intervention codes. Contrasts among periods and regions were quantified using rate ratios (RRs) and 95% confidence intervals (CIs). Temporal changes were also assessed using chi-square tests for trend (Canadian Task Force Classification II-1).ResultsThe study population included 3 882 790 deliveries between 2003 and 2016 and 1 418 545 deliveries between 2012 and 2016. Severe hemorrhage rates increased from 44.8 in 2003 to 62.4 per 10 000 deliveries in 2012 (P for trend <0.0001) and then declined to 41.8 per 10 000 deliveries in 2016 (P for trend <0.0001). Maternal intensive care unit admission and sepsis rates decreased between 2003 and 2016, whereas rates of stroke, severe uterine rupture, hysterectomy, obstetric embolism, shock, and assisted ventilation increased. Rates of composite SMM in 2012-2016 were higher in Newfoundland and Labrador (RR 1.15; 95% CI 1.04–1.26), Nova Scotia (RR 1.11; 95% CI 1.03–1.19), New Brunswick (RR1.22; 95% CI 1.13–1.32), Manitoba (RR 1.09; 95% CI 1.03–1.15), Saskatchewan (RR 1.15; 95% CI 1.09–1.22), the Yukon (RR 1.74; 95% CI 1.35–2.25), and Nunavut (RR 1.76; 95% CI 1.46–2.11) compared with the rest of Canada, whereas rates were lower in Alberta and British Columbia.ConclusionThis surveillance report helps inform clinical practice and public health policy for improving maternal health in Canada.     

Nutri-Score: Awareness,Perception and Self-Reported Impact on Food Choices among French Adolescents

To date, no studies have evaluated the appropriation of the front-of-pack Nutri-Score labeling among adolescents, although they are both consumers and buyers of food products. Therefore, the objectives of the present study were (1) to assess Nutri-Score awareness, perception and self-reported impact on food choices in French adolescents and (2) to identify the determinants associated with higher Nutri-Score awareness and self-reported impact on food choices. A web-based survey was conducted in November 2021 among 1201 adolescents. Multivariate logistic models were used to evaluate the relationships between individual factors and Nutri-Score awareness and self-reported impact on food choices. Almost all the adolescents reported to know the Nutri-Score (97.0%) and more than 9 out of 10 considered this logo easy to understand and easy to identify on food packages. Finally, 54% self-reported that the label had already impacted their food choices. Girls (2.28 (1.09–4.77), p = 0.028) and the 15–17-year-olds (3.12 (1.32–7.35), p = 0.0094) were more likely to be aware of the label compared with their respective counterparts (i.e., boys and the 11–14-year-olds). Regarding the impact of food choices, the use of the Nutri-Score by the parents was the most determinant criterion (7.74 (5.74–10.42), p < 0.0001). Thus, promotion campaigns should target both adolescents and parents.