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Morphogenesis requires embryonic cells to generate forces and perform mechanical work to shape their tissues. Incorrect functioning of these force fields can lead to congenital malformations. Understanding these dynamic processes requires the quantification and profiling of three-dimensional mechanics during evolving vertebrate morphogenesis. Here we describe elastic spring-like force sensors with micrometre-level resolution, fabricated by intravital three-dimensional bioprinting directly in the closing neural tubes of growing chicken embryos. Integration of calibrated sensor read-outs with computational mechanical modelling allows direct quantification of the forces and work performed by the embryonic tissues. As they displace towards the embryonic midline, the two halves of the closing neural tube reach a compression of over a hundred nano-newtons during neural fold apposition. Pharmacological inhibition of Rho-associated kinase to decrease the pro-closure force shows the existence of active anti-closure forces, which progressively widen the neural tube and must be overcome to achieve neural tube closure. Overall, our approach and findings highlight the intricate interplay between mechanical forces and tissue morphogenesis.

IMPORTANCE: Adjuvant ovarian function suppression (OFS) with oral endocrine therapy improves outcomes for premenopausal patients with hormone receptor–positive (HR+) breast cancer but adds adverse effects. A genomic biomarker for selecting patients most likely to benefit from OFS-based treatment is lacking. OBJECTIVE: To assess the predictive and prognostic performance of the Breast Cancer Index (BCI) for OFS benefit in premenopausal women with HR+ breast cancer. DESIGN, SETTING, AND PARTICIPANTS: This prospective-retrospective translational study used all available tumor tissue samples from female patients from the Suppression of Ovarian Function Trial (SOFT). These individuals were randomized to receive 5 years of adjuvant tamoxifen alone, tamoxifen plus OFS, or exemestane plus OFS. BCI testing was performed blinded to clinical data and outcome. The a priori hypothesis was that BCI HOXB13/IL17BR ratio (BCI[H/I])–high tumors would benefit more from OFS and high BCI portended poorer prognosis in this population. Settings spanned multiple centers internationally. Participants included premenopausal female patients with HR+ early breast cancer with specimens in the International Breast Cancer Study Group tumor repository available for RNA extraction. Data were collected from December 2003 to April 2021 and were analyzed from May 2022 to October 2022. MAIN OUTCOMES AND MEASURES: Primary end points were breast cancer–free interval (BCFI) for the predictive analysis and distant recurrence-free interval (DRFI) for the prognostic analyses. RESULTS: Tumor specimens were available for 1718 of the 3047 female patients in the SOFT intention-to-treat population. The 1687 patients (98.2%) who had specimens that yielded sufficient RNA for BCI testing represented the parent trial population. The median (IQR) follow-up time was 12 (10.5-13.4) years, and 512 patients (30.3%) were younger than 40 years. Tumors were BCI(H/I)-low for 972 patients (57.6%) and BCI(H/I)-high for 715 patients (42.4%). Patients with tumors classified as BCI(H/I)-low exhibited a 12-year absolute benefit in BCFI of 11.6% from exemestane plus OFS (hazard ratio [HR], 0.48 [95% CI, 0.33-0.71]) and an absolute benefit of 7.3% from tamoxifen plus OFS (HR, 0.69 [95% CI, 0.48-0.97]) relative to tamoxifen alone. In contrast, patients with BCI(H/I)-high tumors did not benefit from either exemestane plus OFS (absolute benefit, −0.4%; HR, 1.03 [95% CI, 0.70-1.53]; P for interaction = .006) or tamoxifen plus OFS (absolute benefit, −1.2%; HR, 1.05 [95% CI, 0.72-1.54]; P for interaction = .11) compared with tamoxifen alone. BCI continuous index was significantly prognostic in the N0 subgroup for DRFI (n = 1110; P = .004), with 12-year DRFI of 95.9%, 90.8%, and 86.3% in BCI low-risk, intermediate-risk, and high-risk N0 cancers, respectively. CONCLUSIONS AND RELEVANCE: In this prospective-retrospective translational study of patients enrolled in SOFT, BCI was confirmed as prognostic in premenopausal women with HR+ breast cancer. The benefit from OFS-containing adjuvant endocrine therapy was greater for patients with BCI(H/I)-low tumors than BCI(H/I)-high tumors. BCI(H/I)-low status may identify premenopausal patients who are likely to benefit from this more intensive endocrine therapy.

Overusing medication for primary headaches or other medical conditions can lead to dependency and medication-overuse headache (MOH) as an adverse drug reaction (ADR).

Trigger warnings, content warnings, or content notes are alerts about upcoming content that may contain themes related to past negative experiences. Advocates claim that warnings help people to emotionally prepare for or completely avoid distressing material. Critics argue that warnings both contribute to a culture of avoidance at odds with evidence-based treatment practices and instill fear about upcoming content. A body of psychological research has recently begun to empirically investigate these claims. We present the results of a meta-analysis of all empirical studies on the effects of these warnings. Overall, we found that warnings had no effect on affective responses to negative material or on educational outcomes. However, warnings reliably increased anticipatory affect. Findings on avoidance were mixed, suggesting either that warnings have no effect on engagement with material or that they increased engagement with negative material under specific circumstances. Limitations and implications for policy and therapeutic practice are discussed.

We study the origin of bimodal emission in AlGaN/AlN QD superlattices displaying a high internal quantum efficiency (around 50%) in the 230–300 nm spectral range. The secondary emission at longer wavelengths is linked to the presence of cone-like domains with deformed QD layers, which originate at the first AlN buffer/superlattice interface and propagate vertically. The cones originate at a 30°-faceted shallow pit in the AlN, which appears to be associated with a threading dislocation that produces strong shear strain. The cone-like structures present Ga enrichment at the boundaring facets and larger QDs within the conic domain. The bimodality of the luminescence is attributed to the differing dot size and composition within the cones and at the faceted boundaries, which is confirmed by the correlation of microscopy results and Schro¨dinger–Poisson calculations.

We present a dual-adatom diffusion-limited model to investigate the growth mechanisms of compound semiconductor nanowires, specifically via the vapor–liquid–solid or vapor–solid–solid routes. The experimental validation of the model is achieved through the growth of InAs nanowires catalyzed by a gold nanoparticle in a molecular beam epitaxy reactor. Initially, we derive essential parameters, diffusion lengths, flux to the seed, and Kelvin effect that characterize nanowire growth under an excess of one of the two beams, e.g., group III or group V atoms. We then calculate the instantaneous growth rate set by the minority current among the two types of atoms. Our model is applied to analyze the length–radius dependence of InAs nanowires, as measured by scanning electron microscopy, covering experimental growth conditions ranging from the As-limited to the In-limited regime. We find that the model successfully describes intricate transitions between the minority currents during elongation of the nanowires. This demonstrates that the notion of excess of flux, commonly applied to the growth of compound semiconductors, cannot be universally used on nano-objects like nanowires. Importantly, our approach is generic and can be broadly applied to study the growth of various compound semiconductor nanowires.

Crystal morphologies of different binary and ternary “model mixtures” were investigated using different cooling conditions (with cooling rates from 0.1 to more than 300 °C min–1). Needle-like crystals tend to form in binary mixtures under fast cooling, while uncommon spherulitic crystals were observed in ternary mixtures under slow cooling. These differences in crystal morphology lead to distinct mechanical behavior of the “model mixtures”. As shown by cone penetration tests, mixtures with spherulitic crystals exhibit a lower mechanical strength than those with densely arranged needle-like crystals. In addition, nanoindentation tests demonstrated that Young’s modulus and plasticity limit of mixtures are higher upon faster cooling. Lipstick-shaped cast samples were studied, in which cooling rates are much higher at the surface than at the center. A gradual change in crystal morphology was observed from surface to center, correlating to the hard surface and the soft center as revealed by nanoindentation tests. This work illustrates the relationship between process thermal control, microstructure morphology, and mechanical properties for wax–oil mixtures, paving the way to the monitoring of sensorial properties by control of mixture composition and process control.

In an attempt to mitigate the negative impact of graphic online imagery, Instagram has introduced sensitive-content screens—graphic images are obfuscated with a blur and accompanied by a warning. Sensitive-content screens purportedly allow “vulnerable people” with mental-health concerns to avoid potentially distressing content. However, no research has assessed whether sensitive-content screens operate as intended. Here we examined whether people, including vulnerable users (operationalized as people with more severe psychopathological symptoms, e.g., depression), use the sensitive-content screens as a tool for avoidance. In two studies, we found that the majority of participants (80%–85%) indicated a desire (Study 1) or made a choice (Study 2) to uncover a screened image. Furthermore, we found no evidence that vulnerable users were any more likely to use the screens to avoid sensitive content. Therefore, warning screens appear to be an ineffective way to deter vulnerable users from viewing negative content.

In this article, we propose an approach based on Gaussian processes (GPs) for large-scale land cover pixel-based classification with Sentinel-2 satellite image time series (SITS). We used a sparse approximation of the posterior combined with variational inference to learn the GP’s parameters. We applied stochastic gradient descent and GPU computing to optimize our GP models on massive datasets. The proposed GP model can be trained with hundreds of thousands of samples, compared to a few thousands for traditional GP methods. Moreover, we included the spatial information by adding the geographic coordinates into the GP’s covariance function to efficiently exploit the spatio-spectro-temporal structure of the SITS. We ran experiments with Sentinel-2 SITS of the full year 2018 over an area of 200000 km2 (about 2 billion pixels) in the south of France, which is representative of an operational setting. Adding the spatial information significantly improved the results in terms of classification accuracy. With spatial information, GP models have an overall accuracy of 79.8. They are more than three points above random forest (the method used for current operational systems) and more than one point above a multilayer perceptron. Compared to a transformer-based model (which provides state-of-the-art results in the literature, but is not applied in operational systems), GP models are only one point below.

Resistant hypertension is associated with increased cardiovascular risk. The endothelin pathway has been implicated in the pathogenesis of hypertension, but it is currently not targeted therapeutically, thereby leaving this relevant pathophysiological pathway unopposed with currently available drugs. The aim of the study was to assess the blood pressure lowering efficacy of the dual endothelin antagonist aprocitentan in patients with resistant hypertension.

IMPORTANCE: Patient-submitted images vary considerably in quality and usefulness. Studies that characterize patient-submitted images in a real-life setting are lacking. OBJECTIVE: To evaluate the quality and perceived usefulness of patient-submitted images as determined by dermatologists and characterize agreement of their responses. DESIGN, SETTING, AND PARTICIPANTS: This survey study included patient images submitted to the Department of Dermatology at Duke University (Durham, North Carolina) between August 1, 2018, and December 31, 2019. From a total pool of 1200 images, 10 dermatologists evaluated 200 or 400 images each, with every image being evaluated by 3 dermatologists. Data analysis occurred during the year leading up to the article being written. MAIN OUTCOMES AND MEASURES: The primary outcomes were the responses to 2 questions and were analyzed using frequency counts and interrater agreement (Fleiss κ) to assess image quality and perceived usefulness. We performed a random-effects logistic regression model to investigate factors associated with evaluators’ decision-making comfort. We hypothesized that most images would be of low quality and perceived usefulness, and that interrater agreement would be poor. RESULTS: A total of 259 of 2915 patient-submitted images (8.9%) did not depict a skin condition at all. The final analysis comprised 3600 unique image evaluations. Dermatologist evaluators indicated that 1985 images (55.1%) were useful for medical decision-making and 2239 (62.2%) were of sufficient quality. Interrater agreement for a given image’s diagnostic categorization was fair to substantial (κ range, 0.36-0.64), while agreement on image quality (κ range, 0.35-0.47) and perceived usefulness (κ range, 0.29-0.38) were fair to moderate. Senior faculty had higher odds of feeling comfortable with medical decision-making than junior faculty (odds ratio [OR], 3.68; 95% CI, 2.9-4.66; P < .001) and residents (OR, 5.55; 95% CI, 4.38-7.04; P < .001). Images depicting wounds (OR, 1.75; 95% CI, 1.18-2.58; P = .01) compared with inflammatory skin conditions and that were in focus (OR, 5.56; 95% CI, 4.63-6.67; P < .001) had higher odds of being considered useful for decision-making. CONCLUSIONS AND RELEVANCE: In this survey study including 10 dermatologists, a slight majority of patient-submitted images were judged to be of adequate quality and perceived usefulness. Fair agreement between dermatologists was found regarding image quality and perceived usefulness, suggesting that store-and-forward teledermatology initiatives should consider a physician’s individual experiences and comfort level. The study results suggest that images are most likely to be useful when they are in focus and reviewed by experienced attending physicians for wound surveillance, but dermatologists may be burdened by irrelevant or unsuitable images.

Quantifying the impact of parametric and model-form uncertainty on the predictions of stochastic models is a key challenge in many applications. Previous work has shown that the relative entropy rate is an effective tool for deriving path-space uncertainty quantification (UQ) bounds on ergodic averages. In this work we identify appropriate information-theoretic objects for a wider range of quantities of interest on path-space, such as hitting times and exponentially discounted observables, and develop the corresponding UQ bounds. In addition, our method yields tighter UQ bounds, even in cases where previous relative-entropy-based methods also apply, e.g., for ergodic averages. We illustrate these results with examples from option pricing, non-reversible diffusion processes, stochastic control, semi-Markov queueing models, and expectations and distributions of hitting times.

Compositionally graded Fe–Pt thin films were prepared on stationary 100 mm Si substrates by magnetron sputtering a base target of Fe on which a piece of Pt is asymmetrically positioned. Energy dispersive X-ray analysis was used to map the variation in film composition across the substrate, as a function of the size of the Pt piece. A scanning polar Magneto-Optical-Kerr-Effect system was used to probe the influence of composition and post-deposition annealing conditions (temperature and time) on coercivity. In this way, the maximum coercivity achievable for the sputtering system used could be established in a high throughput fashion. The evolution in coercivity with composition was correlated with the formation of L10FePt and changes in its lattice parameters, as determined by scanning X-ray diffraction. High throughput coercivity mapping was then carried out on homogeneous Fe–Pt thin films of different compositions treated to different annealing conditions. This study serves as a step towards the integration of coercive FePt films into collectively fabricated devices.

The growth of ZnTe nanowires and ZnTe–CdTe nanowire heterostructures is studied by in situ transmission electron microscopy. We describe the shape and the change of shape of the solid gold nanoparticle during vapor–solid–solid growth. We show the balance between one monolayer and two monolayer steps, which characterizes the vapor–liquid–solid and vapor–solid–solid growth modes of ZnTe. We discuss the likely role of the mismatch strain and lattice coincidence between gold and ZnTe on the predominance of two monolayer steps during vapor–solid–solid growth and on the subsequent self-regulation of the step dynamics. Finally, the formation of an interface between CdTe and ZnTe is described.

Intermittent (on 4 days per week) antiretroviral therapy (ART) for patients with HIV-1 might be more convenient, better tolerated, and cheaper than continuous treatment. We aimed to establish the efficacy and safety of a 4-days-on and 3-days-off (intermittent) maintenance regimen versus a standard 7 day (continuous) maintenance regimen.

We study the scenario where individuals (speakers) contribute to the publication of an anonymized speech corpus. Data users leverage this public corpus for downstream tasks, e.g., training an automatic speech recognition (ASR) system, while attackers may attempt to de-anonymize it using auxiliary knowledge. Motivated by this scenario, speaker anonymization aims to conceal speaker identity while preserving the quality and usefulness of speech data. In this article, we study x-vector based speaker anonymization, the leading approach in the VoicePrivacy Challenge, which converts the speaker's voice into that of a random pseudo-speaker. We show that the strength of anonymization varies significantly depending on how the pseudo-speaker is chosen. We explore four design choices for this step: the distance metric between speakers, the region of speaker space where the pseudo-speaker is picked, its gender, and whether to assign it to one or all utterances of the original speaker. We assess the quality of anonymization from the perspective of the three actors involved in our threat model, namely the speaker, the user and the attacker. To measure privacy and utility, we use respectively the linkability score achieved by the attackers and the decoding word error rate achieved by an ASR model trained on the anonymized data. Experiments on LibriSpeech show that the best combination of design choices yields state-of-the-art performance in terms of both privacy and utility. Experiments on Mozilla Common Voice further show that it guarantees the same anonymization level against re-identification attacks among 50 speakers as original speech among 20,000 speakers.

When exposed to sensory sequences, do macaque monkeys spontaneously form abstract internal models that generalize to novel experiences? Here, we show that neuronal populations in macaque ventrolateral prefrontal cortex jointly encode visual sequences by separate codes for the specific pictures presented and for their abstract sequential structure. We recorded prefrontal neurons while macaque monkeys passively viewed visual sequences and sequence mismatches in the local-global paradigm. Even without any overt task or response requirements, prefrontal populations spontaneously form representations of sequence structure, serial order, and image identity within distinct but superimposed neuronal subspaces. Representations of sequence structure rapidly update following single exposure to a mismatch sequence, while distinct populations represent mismatches for sequences of different complexity. Finally, those representations generalize across sequences following the same repetition structure but comprising different images. These results suggest that prefrontal populations spontaneously encode rich internal models of visual sequences reflecting both content-specific and abstract information.

IMPORTANCE: The cyclin-dependent kinase 4 and 6 inhibitor palbociclib in combination with letrozole has become a standard first-line treatment for patients with endocrine-sensitive, hormone receptor–positive, ERBB2-negative advanced breast cancer. Meanwhile, the antiestrogen fulvestrant was shown to be superior to anastrozole in the absence of cyclin-dependent kinase 4 and 6 inhibition for this patient population. OBJECTIVE: To assess whether fulvestrant is superior to letrozole when combined with palbociclib in the first-line scenario. DESIGN, SETTING, AND PARTICIPANTS: In this international, randomized, open-label, phase 2 clinical study conducted from July 30, 2015, to January 8, 2018, patients with hormone receptor–positive, ERBB2-negative advanced breast cancer with no prior therapy in the metastatic setting and endocrine-sensitive criteria were recruited from 47 centers in 7 countries. Data were analyzed from February 11 to May 15, 2020. INTERVENTIONS: Patients were randomly assigned (1:1 ratio) to receive palbociclib with either fulvestrant or letrozole. Stratification factors were type of disease presentation (de novo vs recurrent) and the presence of visceral involvement (yes vs no). MAIN OUTCOMES AND MEASURES: The primary end point was investigator-assessed progression-free survival determined by Response Evaluation Criteria in Solid Tumors, version 1.1. RESULTS: A total of 486 women (median age, 63 years [range, 25-90 years]; 3 Asian women [0.6%]; 4 Black women [0.8%]; 461 White women [94.9%]; 18 women of unknown race [3.7%]) were randomized (243 to fulvestrant-palbociclib and 243 to letrozole-palbociclib). Median investigator-assessed progression-free survival was 27.9 months (95% CI, 24.2-33.1 months) in the fulvestrant-palbociclib group vs 32.8 months (95% CI, 25.8-35.9 months) in the letrozole-palbociclib group (hazard ratio, 1.13; 95% CI, 0.89-1.45; P = .32). This result was consistent across the stratification factors. No significant differences were observed in objective response rate (46.5% vs 50.2%) and 3-year overall survival rate (79.4% vs 77.1%) for fulvestrant-palbociclib and letrozole-palbociclib, respectively. Grade 3-4 adverse events were comparable among treatment groups, and no new safety signals were identified. No treatment-related deaths were reported. CONCLUSIONS AND RELEVANCE: Although fulvestrant-palbociclib demonstrated significant antitumor activity, this randomized clinical trial failed to identify an improvement in progression-free survival with this regimen over letrozole-palbociclib in patients with endocrine-sensitive, hormone receptor–positive, ERBB2-negative advanced breast cancer. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02491983

La pratique du Bilan de Médication (BM), centrale dans le modèle de Pharmacie Clinique, publié par la Société française de pharmacie clinique, est maintenant actée dans la loi sous conditions d’inclusion. L’enjeu devient d’accompagner le déploiement de cette pratique à l’officine, notamment en évaluant le processus et l’impact. L’objectif de notre étude était d’analyser la faisabilité de la démarche. Quarante et une officines situées en région Auvergne Rhône-Alpes ont participé. L’intervention a été déployée par les étudiants de 6eannée du Parcours Officine. Les résultats principaux sont les suivants : un tiers des BM a été effectué au domicile du patient, le reste à l’Officine. La courbe d’apprentissage du BM permet de passer d’un temps de 2 heures au démarrage à un peu plus d’une heure en routine. La quasi-totalité des BM a été développée sur rendez-vous. Les sources de données utilisées ont été le logiciel de la pharmacie (45,8 % des lignes analysées), l’entretien avec les patients (44,2 % des lignes) et le dossier pharmaceutique (9,9 % des lignes). Au vu du nombre de refus exprimés par les patients (1/5), il reste important de travailler sur la posture de l’offre pharmaceutique par l’équipe officinale.

Attaining low-resistivity AlxGa1–xN layers is one keystone to improve the efficiency of light-emitting devices in the ultraviolet spectral range. Here, we present a microstructural analysis of AlxGa1–xN/Ge samples with 0 ≤ x≤ 1, and a nominal doping level in the range of 1020cm–3, together with the measurement of Ge concentration and its spatial distribution down to the nanometer scale. AlxGa1–xN/Ge samples with x≤ 0.2 do not present any sign of inhomogeneity. However, samples with x> 0.4 display μm-size Ge crystallites at the surface. Ge segregation is not restricted to the surface: Ge-rich regions with a size of tens of nanometers are observed inside the AlxGa1–xN/Ge layers, generally associated with Ga-rich regions around structural defects. With these local exceptions, the AlxGa1–xN/Ge matrix presents a homogeneous Ge composition which can be significantly lower than the nominal doping level. Precise measurements of Ge in the matrix provide a view of the solubility diagram of Ge in AlxGa1–xN as a function of the Al mole fraction. The solubility of Ge in AlN is extremely low. Between AlN and GaN, the solubility increases linearly with the Ga mole fraction in the ternary alloy, which suggests that the Ge incorporation takes place by substitution of Ga atoms only. The maximum percentage of Ga sites occupied by Ge saturates around 1%. The solubility issues and Ge segregation phenomena at different length scales likely play a role in the efficiency of Ge as an n-type AlGaN dopant, even at Al concentrations where Ge DX centers are not expected to manifest. Therefore, this information can have direct impact on the performance of Ge-doped AlGaN light-emitting diodes, particularly in the spectral range for disinfection (≈260 nm), which requires heavily doped alloys with a high Al mole fraction.

La Pharmacie clinique s’inscrit progressivement en officine depuis 2009 par le biais du développement des services pharmaceutiques afin de répondre à un souci d’efficience des soins, de vieillissement de la population, d’augmentation de la prévalence des pathologies chroniques et de polymédication. Alors que la Société Française de Pharmacie Clinique a récemment revisité la définition de la Pharmacie Clinique, quelles sont les perceptions des pharmaciens d’officine ? Onze entretiens semi-dirigés ont été conduits auprès de pharmaciens d’officine. Les entretiens ont été entièrement enregistrés, puis retranscrits. L’analyse thématique des verbatims a dégagé 3 axes : l’identité professionnelle, la posture de travail et l’évolution de l’organisation de l’officine et des institutions l’impactant. Outre une résistance au changement de la part des officinaux et une étonnante dissociation de la dispensation et de la Pharmacie Clinique, cette dernière est définie par les participants par une posture associée à l’écoute des patients ainsi que par des actes. Les représentations des pharmaciens d’officine, différant des définitions établies par des institutions, nous amènent à penser que celles-ci doivent être réexpliquées selon leur propre perspective.

Tamoxifen is the most prescribed selective estrogen receptor (ER) modulator in patients with ER-positive breast cancers. Tamoxifen requires the transcription factor paired box 2 protein (PAX2) to repress the transcription of ERBB2/HER2. Now, we identified that PAX2 inhibits cell growth of ER+/HER2− tumor cells in a dose-dependent manner. Moreover, we have identified that cell growth inhibition can be achieved by expressing moderate levels of PAX2 in combination with tamoxifen treatment. Global run-on sequencing of cells overexpressing PAX2, when coupled with PAX2 ChIP-seq, identified common targets regulated by both PAX2 and tamoxifen. The data revealed that PAX2 can inhibit estrogen-induced gene transcription and this effect is enhanced by tamoxifen, suggesting that they converge on repression of the same targets. Moreover, PAX2 and tamoxifen have an additive effect and both induce coding genes and enhancer RNAs (eRNAs). PAX2–tamoxifen upregulated genes are also enriched with PAX2 eRNAs. The enrichment of eRNAs is associated with the highest expression of genes that positivity regulate apoptotic processes. In luminal tumors, the expression of a subset of these proapoptotic genes predicts good outcome and their expression are significantly reduced in tumors of patients with relapse to tamoxifen treatment. Mechanistically, PAX2 and tamoxifen coexert an antitumoral effect by maintaining high levels of transcription of tumor suppressors that promote cell death. The apoptotic effect is mediated in large part by the gene interferon regulatory factor 1. Altogether, we conclude that PAX2 contributes to better clinical outcome in tamoxifen treated ER-positive breast cancer patients by repressing estrogen signaling and inducing cell death related pathways.

Several clusters of encephalopathy occurred after the market change from Holoxan® (ifosfamide lyophilized powder) to Ifosfamide EG® (liquid formulation) and justified a formal survey in 2015. In June 2016, the regulatory authority decided to apply a precautionary measure in reducing the shelf life of Ifosfamide EG® at 7 months. One-year study from spontaneous reports lead to suspect a potential residual risk. Due to the many limitations associated with spontaneous notifications, we performed a multicentric observational study, aiming to better explore this pharmacovigilance signal.

Invasive fungal infections are a major cause of disease and death in immunocompromised hosts, including patients undergoing allogeneic hematopoietic stem cell transplant (HSCT). Recovery of adaptive immunity after HSCT correlates strongly with recovery from fungal infection. Using initial selection of lymphocytes expressing the activation marker CD137 after fungal stimulation, we rapidly expanded a population of mainly CD4+ T cells with potent antifungal characteristics, including production of tumor necrosis factor α, interferon γ, interleukin-17, and granulocyte-macrophage colony stimulating factor. Cells were manufactured using a fully good manufacturing practice–compliant process. In vitro, the T cells responded to fungal antigens presented on fully and partially HLA-DRB1 antigen–matched presenting cells, including when the single common DRB1 antigen was allelically mismatched. Administration of antifungal T cells lead to reduction in the severity of pulmonary and cerebral infection in an experimental mouse model of Aspergillus. These data support the establishment of a bank of cryopreserved fungus-specific T cells using normal donors with common HLA DRB1 molecules and testing of partially HLA-matched third-party donor fungus-specific T cells as a potential therapeutic in patients with invasive fungal infection after HSCT.

Invasive fungal infections are a major cause of disease and death in immunocompromised hosts, including patients undergoing allogeneic hematopoietic stem cell transplant (HSCT). Recovery of adaptive immunity after HSCT correlates strongly with recovery from fungal infection. Using initial selection of lymphocytes expressing the activation marker CD137 after fungal stimulation, we rapidly expanded a population of mainly CD4+T cells with potent antifungal characteristics, including production of tumor necrosis factor α, interferon γ, interleukin-17, and granulocyte-macrophage colony stimulating factor. Cells were manufactured using a fully good manufacturing practice–compliant process. In vitro, the T cells responded to fungal antigens presented on fully and partially HLA-DRB1 antigen–matched presenting cells, including when the single common DRB1 antigen was allelically mismatched. Administration of antifungal T cells lead to reduction in the severity of pulmonary and cerebral infection in an experimental mouse model of Aspergillus. These data support the establishment of a bank of cryopreserved fungus-specific T cells using normal donors with common HLA DRB1 molecules and testing of partially HLA-matched third-party donor fungus-specific T cells as a potential therapeutic in patients with invasive fungal infection after HSCT.

•All Ivorian Cryptococcus deuterogattiiisolates were identified as ST173 by MLST.•64.3% (18/28) of isolates had a fluconazole (FCZ) MIC of ≥16μg/mL.•FCZ exposure increased AFR1mRNA expression, especially in isolates with high FCZ MICs.•Resistance mechanisms described in Cryptococcus neoformanswere not involved in C. deuterogattiiST173 isolates.

In vitro, Drosophila melanogasterDicer-2 (Dcr-2) uses its helicase domain to initiate processing of dsRNA with blunt (BLT) termini, and its Platform•PAZ domain to initiate processing of dsRNA with 3′ overhangs (ovrs). To understand the relationship of these in vitro observations to roles of Dcr-2 in vivo, we compared in vitro effects of two helicase mutations to their impact on production of endogenous and viral siRNAs in flies. Consistent with the importance of the helicase domain in processing BLT dsRNA, both point mutations eliminated processing of BLT, but not 3′ovr, dsRNA in vitro. However, the mutations had different effects in vivo. A point mutation in the Walker A motif of the Hel1 subdomain, G31R, largely eliminated production of siRNAs in vivo, while F225G, located in the Hel2 subdomain, showed reduced levels of endogenous siRNAs, but did not significantly affect virus-derived siRNAs. In vitro assays monitoring dsRNA cleavage, dsRNA binding, ATP hydrolysis, and binding of the accessory factor Loquacious-PD provided insight into the different effects of the mutations on processing of different sources of dsRNA in flies. Our in vitro studies suggest effects of the mutations in vivo relate to their effects on ATPase activity, dsRNA binding, and interactions with Loquacious-PD. Our studies emphasize the importance of future studies to characterize dsRNA termini as they exist in Drosophilaand other animals.

As widely employed in dye-sensitized, perovskite, and quantum-dot solar cells, the interface between F-doped SnO2(FTO) and blocking TiO2(b-TiO2) is essential in understanding the working principles of these types of solar cells. In this work, we have deposited b-TiO2layers using a simple sol–gel method. While the b-TiO2layers deposited on Si (100) wafers form pure anatase polymorph, we have found that the rutile structure of the FTO substrates consistently induces the b-TiO2layers to crystallize into mixed anatase and rutile polymorphs; the same is observed on rutile RuO2substrates. This indicates that the rutile structural similarity favors the formation of rutile polymorph in b-TiO2layers; due to the coexistence of both anatase and rutile polymorphs, the interface of FTO/b-TiO2is essentially inhomogeneous. We also show that the amount of rutile polymorph present in the b-TiO2layer is a function of layer thickness, with rutile polymorph dominating in thin b-TiO2layers. As a result, the energetic alignment at the FTO/b-TiO2interface in general still favors the charge transport. This is confirmed by directly probing an ultrathin (<10 nm) b-TiO2layer using X-ray photoelectron spectroscopy (XPS). We emphasize that the rutile structure of FTO substrate plays a significant role in determining the polymorph of successively deposited b-TiO2layer, which in turn affects the energetic alignment with FTO electrodes and mesoporous nanocrystalline TiO2, and ultimately the performance of solar devices.

The development of electrochromic systems, known for the modulation of their optical properties under an applied voltage, depends on the replacement of the state-of-the-art ITO (In2O3:Sn) transparent electrode (TE) as well as the improvement of electrochromic films. This study presents an innovative ITO-free electrochromic film architecture utilizing oxide-coated silver nanowire (AgNW) networks as a TE and V2O5as an electrochromic oxide layer. The TE was prepared by simple spray deposition of AgNWs that allowed for tuning different densities of the network and hence the resistance and transparency of the film. The conformal oxide coating (SnO2or ZnO) on AgNWs was deposited by atmospheric-pressure spatial atomic layer deposition, an open-air fast and scalable process yielding a highly stable electrode. V2O5thin films were then deposited by radio frequency magnetron sputtering on the AgNW-based TE. Independent of the oxide’s nature, a 20 nm protective layer thickness was insufficient to prevent the deterioration of the AgNW network during V2O5deposition. On the contrary, crystalline V2O5films were grown on 30 nm thick ZnO or SnO2-coated AgNWs, exhibiting a typical orange color. Electrochromic characterization demonstrated that only V2O5films deposited on 30 nm thick SnO2-coated AgNW showed characteristic oxidation–reduction peaks in the Li+-based liquid electrolyte associated with a reversible orange-to-blue color switch for at least 500 cycles. The electrochromic key properties of AgNW/SnO2(30 nm)/V2O5films are discussed in terms of structural and morphological changes due to the AgNW network and the nature and thickness of the two protective oxide coatings.

This paper reports on the development of a mesoscale multiphysics numerical model for predicting the dimensions of melt pool zones in Laser Powder Bed Fusion process, in a multilayer and multitrack application dedicated to the manufacturing of lattice metal features. In such context, a clear need emerges to study laser-matter interaction regarding the persisting questions surrounding the comprehension of melt pool. An experimental campaign involving thin pillars made of the nickel-based superalloy IN718 is presented, highlighting the complexity introduced by the thin tracks superposition. Then, a continuous mesoscale numerical model, considering heat transfer, melt pool flow, and vaporization phenomena, and its extension to multilayer-multitrack simulation is detailed. Some discussions about the numerical approach and its ability to predict the global morphology and dimensions of melt pool zones and resulting tracks after solidification are proposed. Finally, comparisons between the experiments and the numerical model show good agreement, with a maximum relative error of 8% observed for remelted zone depth. This study demonstrates the capability of the present approach to help in understanding the influence of process parameters on melt pool shape and, thereafter, to determine process parameters to optimize for lattice features building.

ABSTRACTBacterial colonization in the gut plays a pivotal role in neonatal necrotizing enterocolitis (NEC) development, but the relationship between bacteria and NEC remains unclear. In this study, we aimed to elucidate whether bacterial butyrate end-fermentation metabolites participate in the development of NEC lesions and confirm the enteropathogenicity of Clostridium butyricumand Clostridium neonatalein NEC. First, we produced C.butyricumand C.neonatalestrains impaired in butyrate production by genetically inactivating the hbdgene encoding β-hydroxybutyryl-CoA dehydrogenase that produces end-fermentation metabolites. Second, we evaluated the enteropathogenicty of the hbd-knockout strains in a gnotobiotic quail model of NEC. The analyses showed that animals harboring these strains had significantly fewer and less intense intestinal lesions than those harboring the respective wild-type strains. In the absence of specific biological markers of NEC, the data provide original and new mechanistic insights into the disease pathophysiology, a necessary step for developing potential novel therapies.

Abstract:This poem attempts to capture the sudden change in perception brought about by loss, or the anticipation of loss. Rather than providing a specific answer to the question of how such a change happens or how it might be dealt with, it attempts to capture the experience of the change itself.

Les auteurs présentent un cas de schizophrénie paranoïde avec antécédent de matricide. L’étude de ce patient, tant au travers de ses propos, de ses comportements que par ses productions picturales remarquables, vient nous signaler l’importance primordiale que tient le corps propre dans toutes les manifestations de sa psychose. Mais cette référence au corps n’en demeure pas moins une des coordonnées normales du désir. C’est ce que nous rappelle Lacan en faisant valoir que les dimensions du grand Autre, du phallus et du corps sont étroitement articulées dans la clinique et constituent finalement bien les coordonnées du désir pour tout un chacun selon qu’il est névrosé, pervers ou psychotique. Aussi, Lacan réinscrit-il la psychose dans la structure normale du sujet : « Le psychotique est normal dans sa psychose et ailleurs, parce que le psychotique, dans le désir, a affaire au corps ». (Séminaire « L’identification ») et ainsi de rappeler que, pour la psychanalyse, « Le désir humain se doit d’inclure la folie ».

Severe acute malnutrition (SAM) is one of the leading causes of morbidity and mortality in Chad. The reasons behind persistently high prevalence of SAM in the Kanem region are still poorly understood, leaving national and international partners without clearly identified drivers to address. Current knowledge of SAM determinants in this context is largely based on very limited data. The aim of this study was thus to investigate individual and household-level risk factors for SAM among under-five children in Mao health district. A matched case-control study was conducted on 411 (137 cases and 274 controls) children aged 6–59 months with their caretakers from mid-February to August 2017. Data were collected by using a structured interviewer administered questionnaire, anthropometric measurements and through direct observations of household environment. Controls were matched to their cases on place of residence and on age (± 3 months). Data were double-entered, processed and analysed using Epi Info 7.2.0.1. Conditional logistic regression was used to analyse the association of independent variables with SAM. For multivariable analysis, two models were constructed to investigate risk factors for SAM, at individual and household level. A stepwise backwards elimination approach with a significance level of p= 0.05 was used to build the final models. At the individual level, SAM was significantly associated with diarrhoea [AOR (95% CI) = 10.7 (4.2–27.3)], fever [AOR (95% CI) = 8.4 (3.1–22.8)], vomiting [AOR (95% CI) = 7.6 (3.0–19.7)], being stunted [AOR (95% CI) = 5.3 (1.7–16.3)], and type of complementary meal [AOR (95% CI) = 4.4 (1.0–19.6)]. At the household level, SAM was significantly associated with undernourished caretaker [AOR (95% CI) = 2.6 (1.2–5.5)], caretaker’s hand washing habits [AOR (95% CI) = 1.9 (1.2–3.1)], absence of toilet [AOR (95% CI) = 1.9 (1.1–3.6)], caretaker’s marriage status [AOR (95% CI) = 7.7 (2.0–30.1)], and low household food diversity [AOR (95% CI) = 1.8 (1.0–3.1)]. The present study identified the need to address both treatment and prevention of infections in children through an integrated approach. Well-organized efforts to improve child feeding practices, household hygiene and sanitation conditions, women’s nutritional status, along with increasing household food diversity are likely to lead to improved nutritional status of children in this setting.

Bereavement can lead to negative outcomes such as complicated grief (CG), but some mourners with symptoms of CG often experience positive sequelae of loss such as posttraumatic growth (PTG) as well. We propose that grief and growth co-occur and change one another because they alternately reinforce and weaken each other at the level of their respective constituent elements. We investigated the structure of a network of CG and PTG elements to elucidate how grief and growth can co-occur within a potentially causal system in bereaved young adults. Challenges to control and identity disturbance ranked as the most highly central symptoms in the CG network; the discovery of a new life path and greater personal strength were similarly central elements of PTG. Finally, the degree of disruption and change in mourners’ worldviews emerged as the element that most strongly bridged the two domains, suggesting a pivotal connection between grief and growth.

ABSTRACTBackground: Social media are currently considered as a potential complementary source of knowledge for drug safety surveillance. Our primary objective was to estimate the frequency of adverse drug reactions (ADRs) experienced by Twitter users. Our secondary objective was to determine whether tweets constitute a valuable and informative source of data for pharmacovigilance purposes, despite limitations on character number per tweet.Research design and methods: We selected a list of 33 drugs subject to careful monitoring due to safety concern in France and Europe, and extracted tweets using the streaming API from 30 September 2014 to 5 April 2015. Two pharmacovigilance centers classified these tweets manually as potential ADR case reports.Results: Among 10,534 tweets, 848 (8.05%) implied or mentioned an ADR without meeting the four FDA criteria required for reporting an ADR, and 289 (2.74%) tweets were classified as ‘case reports.’ Among them 20 (7.27%) tweets mentioned an unexpected ADR and 33 (11.42%) tweets mentioned a serious ADR.Conclusions: With the use of dedicated tools, Twitter could become a complementary source of information for pharmacovigilance, despite a major limitation regarding causality assessment of ADRs in individual tweets, which may improve with the new limitation to 280 characters per tweet.

Les Inhibiteurs Sélectifs de la Recapture de la Sérotonine (ISRS) et les Inhibiteurs de la Recapture de la Sérotonine et de la Noradrénaline (IRSNA) peuvent induire des hyponatrémies par le syndrome SIADH. Les objectifs de cette étude étaient de comparer le taux d’incidence des notifications d’hyponatrémie en fonction des différents ISRS/IRSNA de manière à identifier l'existence de molécules plus à risque, et de caractériser un profil de patient à risque.

ABSTRACTIntroduction: Thymosin alpha 1 (Tα1) is a naturally occurring polypeptide of 28 amino acids, whose mechanism of action is thought to be related to its ability to signal through innate immune receptors. Tα1 (ZADAXIN®) is used worldwide for treating viral infections, immunodeficiencies, and malignancies. Owing to its ability to activate the tolerogenic pathway of tryptophan catabolism – via the immunoregulatory enzyme indoleamine 2,3-dioxygenase – Tα1 potentiates immune tolerance mechanisms, breaking the vicious circle that perpetuates chronic inflammation in response to a variety of infectious noxae.Areas covered: Tα1 has never been studied in Cystic fibrosis (CF) in which the hyperinflammatory state is associated with early and nonresolving activation of innate immunity, which impairs microbial clearance and promotes a self-sustaining condition of progressive lung damage. Optimal CF treatments should, indeed, not only rescue CF transmembrane conductance regulator protein localization and functionality but also alleviate the associated hyperinflammatory pathology. Because of the inherent complexity of the pathogenetic mechanisms, a multidrug approach is required.Expert opinion: By providing a multipronged attack against CF, i.e. restraining inflammation and correcting the basic defect, Tα1 favorably opposed CF symptomatology in preclinical relevant disease settings, thus suggesting its possible exploitation for ‘real-life’ clinical efficacy in CF. This could represent a major conceptual advance in the CF field, namely the proposal of a drug with the unique activity to correct CFTR defects through regulation of inflammation.

Electrical stability and homogeneity of silver nanowire (AgNW) networks are critical assets for increasing their robustness and reliability when integrated as transparent electrodes in devices. Our ability to distinguish defects, inhomogeneities, or inactive areas at the scale of the entire network is therefore a critical issue. We propose one-probe electrical mapping (1P-mapping) as a specific simple tool to study the electrical distribution in these discrete structures. 1P-mapping has allowed us to show that the tortuosity of the voltage equipotential lines of AgNW networks under bias decreases with increasing network density, leading to a better electrical homogeneity. The impact of the network fabrication technique on the electrical homogeneity of the resulting electrode has also been investigated. Then, by combining 1P-mapping with electrical resistance measurements and IR thermography, we propose a comprehensive analysis of the evolution of the electrical distribution in AgNW networks when subjected to increasing voltage stresses. We show that AgNW networks experience three distinctive stages: optimization, degradation, and breakdown. We also demonstrate that the failure dynamics of AgNW networks at high voltages occurs through a highly correlated and spatially localized mechanism. In particular the in situformation of cracks could be clearly visualized. It consists of two steps: creation of a crack followed by propagation nearly parallel to the equipotential lines. Finally, we show that current can dynamically redistribute during failure, by following partially damaged secondary pathways through the crack.

Silver nanowire (AgNW) networks offer excellent electrical and optical properties and have emerged as one of the most attractive alternatives to transparent conductive oxides to be used in flexible optoelectronic applications. However, AgNW networks still suffer from chemical, thermal, and electrical instabilities, which in some cases can hinder their efficient integration as transparent electrodes in devices such as solar cells, transparent heaters, touch screens, and organic light emitting diodes. We have used atmospheric pressure spatial atomic layer deposition (AP-SALD) to fabricate hybrid transparent electrode materials in which the AgNW network is protected by a conformal thin layer of zinc oxide. The choice of AP-SALD allows us to maintain the low-cost and scalable processing of AgNW-based transparent electrodes. The effects of the ZnO coating thickness on the physical properties of AgNW networks are presented. The composite electrodes show a drastic enhancement of both thermal and electrical stabilities. We found that bare AgNWs were stable only up to 300 °C when subjected to thermal ramps, whereas the ZnO coating improved the stability up to 500 °C. Similarly, ZnO-coated AgNWs exhibited an increase of 100% in electrical stability with respect to bare networks, withstanding up to 18 V. A simple physical model shows that the origin of the stability improvement is the result of hindered silver atomic diffusion thanks to the presence of the thin oxide layer and the quality of the interfaces of hybrid electrodes. The effects of ZnO coating on both the network adhesion and optical transparency are also discussed. Finally, we show that the AP-SALD ZnO-coated AgNW networks can be effectively used as very stable transparent heaters.

•A 3D finite element modelling of the SLM process at the track scale is considered.•Heat transfer and fluid flow are simulated for different material and process conditions.•The influence of energy input and Marangoni effect is tested.•Scan speed, laser interaction and Marangoni effect have a clear impact on track shape.