The impact of adult neurogenesis on affective functions: of mice and men.

In most mammals, new neurons are not only produced during embryogenesis but also after birth. Soon after adult neurogenesis was discovered, the influence of recruiting new neurons on cognitive functions, especially on memory, was documented. Likewise, the late process of neuronal production also contributes to affective functions, but this outcome was recognized with more difficulty. This review covers hypes and hopes of discovering the influence of newly-generated neurons on brain circuits devoted to affective functions. If the possibility of integrating new neurons into the adult brain is a commonly accepted faculty in the realm of mammals, the reluctance is strong when it comes to translating this concept to humans. Compiling data suggest now that new neurons are derived not only from stem cells, but also from a population of neuroblasts displaying a protracted maturation and ready to be engaged in adult brain circuits, under specific signals. Here, we discuss the significance of recruiting new neurons in the adult brain circuits, specifically in the context of affective outcomes. We also discuss the fact that adult neurogenesis could be the ultimate cellular process that integrates elements from both the internal and external environment to adjust brain functions. While we must be critical and beware of the unreal promises that Science could generate sometimes, it is important to continue exploring the potential of neural recruitment in adult primates. Reporting adult neurogenesis in humankind contributes to a new vision of humans as mammals whose brain continues to develop throughout life. This peculiar faculty could one day become the target of treatment for mental health, cognitive disorders, and elderly-associated diseases. The vision of an adult brain which never stops integrating new neurons is a real game changer for designing new therapeutic interventions to treat mental disorders associated with substantial morbidity, mortality, and social costs.

Rethinking surgical revisions: impact of the MonarchE trial on axillary dissection in hormone-positive HER2-negative early breast cancer patients potentially eligible for abemaciclib.

INTRODUCTION: The MonarchE trial explored the use of abemaciclib, a CDK4/6 inhibitor, as an adjuvant treatment in high-risk early-stage luminal-like breast cancer. The study's inclusion criteria, especially the N2 status, may require revisiting surgical interventions, including invasive axillary lymph node dissection (ALND)-a procedure that current guidelines generally do not recommend. METHODS: We conducted a single-centre, retrospective, observational cohort study on non-metastatic breast cancer patients managed from 2002 to 2011, at the Institut Curie. Data collection involved clinical and histological characteristics plus treatment follow-up. RESULTS: Out of 8715 treated patients, 721 met the inclusion criteria. Overall, 12% (87) were classified as N2 ( ≥ 4 positive lymph nodes), thus eligible for abemaciclib per "node criterion." Tumour size, positive sentinel lymph nodes, and lobular histology showed a significant correlation with N2 status. Approximately 1000 ALNDs would be required to identify 120 N2 cases and prevent four recurrences. CONCLUSION: The MonarchE trial may significantly affect surgical practices due to the need for invasive procedures to identify high-risk patients for adjuvant abemaciclib treatment. The prospect of unnecessary morbidity demands less invasive N2 status determination methods. Surgical decisions must consider patient health and potential treatment benefits.

Would shared decision-making be useful in breast cancer screening programmes? A qualitative study using focus group discussions to gather evidence from French women with different socioeconomic backgrounds.

BACKGROUND: To inform the development of an online tool to be potentially used in shared decision-making about breast cancer screening, French women were questioned about participation in breast cancer screening, the health professional's role, and their perceptions of the proposed tool. METHODS: We organised focus group discussions with 55 French women. Two different strategies were used to recruit women from high and low socioeconomic backgrounds. We applied both inductive and deductive approaches to conduct a thematic analysis of the discussions. We analysed the responses by using the main determinants from different health behaviour models and compared the two groups. RESULTS: Independently of socioeconomic status, the most important determinant for a woman's participation in breast cancer screening was the perceived severity of breast cancer and the perceived benefits of its early detection by screening. Cues to action reported by both groups were invitation letters; recommendations by health professionals, or group/community activities and public events were reported by women from high and low socioeconomic backgrounds, respectively. Among other positive determinants, women from high socioeconomic backgrounds reported making informed decisions and receiving peer support whereas women from low socioeconomic backgrounds reported community empowerment through group/community events. Fear of cancer was reported as a barrier in both groups. Among other barriers, language issues were reported only by women from low socioeconomic backgrounds; women from high socioeconomic backgrounds reported breast cancer screening-related risks other than overdiagnosis and/or overtreatment. Barriers to accessing the online tool to be developed were mainly reported by women from high socioeconomic backgrounds. CONCLUSION: Limitations in implementing shared decision-making for women from low socioeconomic backgrounds were highlighted. An online tool that is suitable for all women, regardless of socioeconomic status, would provide "on-demand" reliable and tailored information about breast cancer screening and improve access to health professionals and social exchanges.

Respiratory muscle metabolic activity on PET/CT correlates with obstructive ventilatory defect severity and prognosis in patients undergoing lung cancer surgery.

BACKGROUND AND OBJECTIVE: Respiratory muscle activity is increased in patients with chronic respiratory disease. 18 F-FDG-PET/CT can assess respiratory muscle activity. We hypothesized that respiratory muscles metabolism was correlated to lung function impairment and was associated to prognosis in patients undergoing lung cancer surgery based on the research question whether respiratory muscle metabolism quantitatively correlates with the severity of lung function impairment in patients? Does respiratory muscle hypermetabolism have prognostic value? METHODS: Patients undergoing 18 F-FDG-PET/CT and pulmonary function tests prior to lung cancer surgery were identified. Maximum Standardized Uptake Value (SUVm) were measured in each respiratory muscle group (sternocleidomastoid, scalene, intercostal, diaphragm), normalized against deltoid SUVm. Respiratory muscle hypermetabolism was defined as SUVm >90th centile in any respiratory muscle group. Clinical outcomes were collected from a prospective cohort. RESULTS: One hundred fifty-six patients were included, mostly male [110 (71%)], 53 (34%) with previous diagnosis of COPD. Respiratory muscle SUVm were: scalene: 1.84 [1.51-2.25], sternocleidomastoid 1.64 [1.34-1.95], intercostal 1.01 [0.84-1.16], diaphragm 1.79 [1.41-2.27]. Tracer uptake was inversely correlated to FEV1 for the scalene (r = -0.29, p < 0.001) and SCM (r = -0.17, p = 0.03) respiratory muscle groups and positively correlated to TLC for the scalene (r = 0.17, p = 0.04). Respiratory muscle hypermetabolism was found in 45 patients (28.8%), who had a lower VO2 max (15.4 [14.2-17.5] vs. 17.2 mL/kg/min [15.2-21.1], p = 0.07) and poorer overall survival when adjusting to FEV1% (p < 0.01). CONCLUSION: Our findings show respiratory muscle hypermetabolism is associated with lung function impairment and has prognostic significance. 18 F-FDG/PET-CT should be considered as a tool for assessing respiratory muscle activity and to identify high-risk patients.

Respiratory gated multistatic PET reconstructions to delineate radiotherapy target volume in patients with mobile lung tumors.

BACKGROUND: PET-CT with 18F-FDG or other radiopharmaceuticals is a recommended tool to help the delineation of lung cancers candidate to radiotherapy. The motion artifacts caused by respiratory movements are reduced by 4D acquisitions. We introduced an extended reconstruction algorithm (multiple reconstruct register and average [multi-RRA]) which requires much shorter acquisition times than standard 4D PET-CT. Our aim was to evaluate the interest on multi-RRA images as an alternative of 3D and 4D PET-CT for the delineation of lung lesion. METHODS: PET acquisitions synchronized to the respiratory signal were obtained in 18 patients with mobile lung tumors. We compared the tumor volumes delineated on Multi-RRA images to 3D and 4D PET-CT, considering the 4D CT as a reference. The tumor volumes were delineated and compared with topologic similarity indexes (Dice, Jaccard and overlap). RESULTS: Twenty tumors were delineated. The volumes delineated with multi-RRA and 4D PET were not significantly different (mean difference of 0.2±0.7 mL). Comparison by pairs (Tukey-Kramer test) showed that 3D-PET volumes were significantly smaller than 4D-PET and multi-RRA volumes (P<0.001). Topologic similarity indexes with 4D-PET were slightly statistically higher with multi-RRA than with 3D-PET (Dice and Jaccard) or 4D-CT (Dice, Jaccard and Overlap). CONCLUSIONS: The tumor volumes delineated on multi-RRA are similar to the volumes obtained with 4D PET, with shorter acquisition time.

Perceived stigma, substance use and self-medication in night-shift healthcare workers: a qualitative study.

BACKGROUND: Many risk factors related to altered circadian rhythms impact the health of night-shift hospital workers (NSHW), resulting in mental and somatic disorders. Easy access to psychoactive substances (PS) may facilitate addictive behaviors in NSHW. They are also exposed to a stressful work environment, which may further affect sleep quality. This study aimed to explore the link between sleep deprivation, work-related psychosocial stress and psychoactive substance use as a self-medication response in NSHW. METHODS: Qualitative study to verify the plausibility of the self-medication theory applied to addictive behaviors. Semi-structured interviews (N = 18 NSHW) and thematic analysis, following consolidated criteria for reporting qualitative research recommendations. RESULTS: Stigma against NSHW was a primary element of a stressful work environment. The stressful and stigmatizing environment, together with night-shift work, further affected NSHW sleep and their mental and physical health. The use of PS appeared to be for self-medication, encouraged by social and professional environments, source(s) of stress, discrimination, and isolation. The work environment, through aggravated sleep disorders, led NSHW to use non-prescribed sleeping pills. Alcohol after work and smoking were used as a social break but also as a means to reduce stress. CONCLUSION: Anti-stigma interventions in the healthcare setting and screening of mental/somatic disorders in NSHW can help reduce harmful self-medication behaviors and improve hospital care in the COVID-19 era.

Factors associated with fear of COVID-19 infection in people living with HIV / Facteurs associés à la crainte de l'infection par la COVID-19 chez des personnes vivant avec le VIH

INTRODUCTION: People living with HIV (PLHIV) who may have experienced biographical disruptions in their life trajectory may have a vulnerability to risk that differs from the general population, particularly in the context of an infectious health crisis. This study aimed to understand the factors associated with concerns about being infected with COVID-19 among PLHIV during the first period of the health crisis. METHODS: This was an online cross-sectional study using an online self-administered questionnaire in the context of the COVID-19 epidemic in France among a population of PLHIV. The recruitment was done via social networks and through various actors in the fight against HIV. The self-questionnaire was available from July 2020 to September 2020. RESULTS: The ACOVIH study collected 249 responses, 202 men and 47 women, with a mean age of 46.6 ± 12.9 years. The most represented socio-professional categories were employees (n=73.29%), followed by managers, professionals and artists (n=59.24%). The PLHIV most worried about being infected by COVID-19 had a level of education lower than or equal to the baccalaureate, family difficulties related to HIV and a deterioration in the relationship of trust with the HIV medical team. CONCLUSION: Feelings of anxiety can have a health and psychosocial impact on PLHIV. It is necessary to consider these negative factors by proposing adapted support and by carrying out preventive actions aiming in particular at improving the literacy of the PLHIV.

Introduction: Les personnes vivant avec le VIH (PVVIH) ayant déjà vécu des perturbations biographiques dans leur trajectoire de vie peuvent avoir une vulnérabilité accrue aux risques, particulièrement dans le cadre d'une crise sanitaire infectieuse. La présente étude (« Adaptations à la COVID-19 lorsque l'on vit avec le VIH ¼ [ACOVIH]) vise à appréhender les facteurs associés à l'inquiétude d'être infecté par la COVID-19 chez les PVVIH durant la première période de la crise sanitaire. Méthodes: Il s'agissait d'une étude transversale en ligne par questionnaire autoadministré conduite dans le contexte épidémique de la COVID-19 sur le territoire français auprès d'une population de PVVIH. Les participants ont été recrutés via les réseaux sociaux et par le biais de divers acteur·trice·s de la lutte contre le VIH. L'autoquestionnaire était disponible de juillet 2020 à septembre 2020. Résultats: L'étude ACOVIH a recueilli 249 réponses, 202 hommes et 47 femmes, d'un âge moyen de 46,6 ± 12,9 ans. Les catégories socioprofessionnelles les plus représentées étaient les employés (n = 73, 29 %), suivis des cadres et des professions intellectuelles et artistiques (n = 59, 24 %). Les PVVIH les plus inquiètes à l'idée d'être infectées par la COVID-19 ont un niveau d'études inférieur ou égal au baccalauréat, des difficultés familiales en lien avec le VIH et une dégradation de la relation de confiance vis-à-vis de l'équipe médicale VIH. Conclusion: Le sentiment d'inquiétude peut avoir un impact sanitaire et psychosocial chez les PVVIH. Il est nécessaire de considérer ces facteurs négatifs en proposant un accompagnement adapté et en menant des actions préventives visant notamment à améliorer la littératie des PVVIH.

Analysis of flavonoids with unified chromatography-electrospray ionization mass spectrometry-method development and application to compounds of pharmaceutical and cosmetic interest.

In this project, we aimed at analysing flavonoid-type compounds with unified chromatography (joining supercritical fluid chromatography and enhanced fluidity liquid chromatography with carbon dioxide-methanol mobile phases covering a wide range of compositions) and diode-array and electrospray ionization mass spectrometric detection (UC-DAD-ESI-MS). First, the chromatographic method was developed for 9 standard flavonoid molecules from three different families (flavanols, flavanones and flavonols, glycosylated or not), with a strong focus on mobile phase composition to achieve the elution of a wide range of flavonoids with good chromatographic quality (efficiency and resolution). For this purpose, two stationary phases were selected (ACQUITY UPC2 DEA and Diol), and five different additives (formic acid, citric acid, phosphoric acid, methanesulfonic acid and ammonium hydroxide) were successively introduced in the methanol co-solvent. The composition containing 0.1% methanesulfonic acid in methanol was retained as it provided the best chromatographic quality together with the possibility of hyphenating the chromatography to mass spectrometry. The DEA column appeared to provide the best efficiency and was retained for further method development. The gradient method was then optimized to achieve a fast analysis, which involved elution with a wide range of mobile phase composition (from 20 to 100% co-solvent in methanol) together with reversed flow rate and reversed pressure gradients at fixed temperature. The final gradient lasted 10 min, followed by 2.5 min of re-equilibration. Then, ESI-MS detection was optimized. Because the single-quadrupole mass spectrometer employed (ACQUITY UPC2 QDa) allowed the variation of only a few parameters, a design of experiments was used to define the best compromise for three parameters (probe temperature, cone voltage and capillary voltage). The make-up fluid introduced before entering the MS was also varied: different compositions of methanol-water containing either formic acid, ammonium hydroxide or sodium chloride were tested. The best results in terms of signal-to-noise ratio were obtained with methanol containing 20 mM ammonium hydroxide and 2% water. The optimal UC-DAD-ESI-MS method was then applied to two different flavonoid formulation ingredients. The first one, hidrosmin (5-O-(ß-hydroxyethyl)diosmin), is known for its vasoprotective properties and therefore employed in pharmaceutical formulations. The second one, α-glucosyl-hesperidin (sometimes referred to as vitamin P), is employed in cosmetic formulations. Identification of the major compounds in each sample was achieved with the help of MS detection. Graphical abstract.

The next psychoactive drugs: From imipramine to ketamine.

Since the 1950s, the therapeutic arsenal against depression has grown considerably. From the discovery of mono-amine oxidase inhibitors (MAOIs) to the antidepressant effect of ketamine, several pharmacological breakthroughs made the history of psychiatry. These discoveries oriented the research about the pathophysiology of depression, which is one of the most disabling diseases worldwide affecting 10 to 20% of general population. In this article, we offer a short historical review of the various therapeutic options developed over the past century and the consequences of these innovations. We then review the discovery of the antidepressant effects of ketamine (and its S-enantiomer, esketamine), the lastest development in depression treatment. Ketamine's effects are spectacular both in terms of their very short onset time, and because they are observed even in treatment-resistant depression. Just as MAOIs and tricyclic antidepressants allowed the "monoaminergic hypothesis of depression" to emerge, unravelling the mechanisms of ketamine's antidepressant effects should highlight the role of glutamatergic system and neuro-inflammation in the neurobiology of depression. Ketamine might also help to refine our understanding of the cognitive pathophysiology of depression and to deeply transform the clinical representations of depressive disorder.

Depuis les années 1950, l'arsenal thérapeutique permettant de lutter contre la dépression s'est considérablement enrichi. De la découverte des inhibiteurs de la mono-amine oxydase (IMAO) à celle de la kétamine, ces percées pharmacologiques ont marqué l'histoire de la psychiatrie et guidé la recherche sur la physiopathologie de la dépression, cette pathologie dévastatrice affectant entre 10 et 20 % de la population mondiale. Nous proposons dans cet article une courte revue historique des différentes options thérapeutiques développées au cours du siècle passé et des conséquences qu'ont eues ces innovations. Nous réalisons ensuite un état des lieux de la plus récente de ces découvertes, celle des effets antidépresseurs de la kétamine (et de son énantiomère S, l'eskétamine), spectaculaires de par leur délai d'action et leur efficacité même dans les formes les plus résistantes de dépression. De même que la découverte des IMAO et des tricycliques a permis de concevoir une théorie monoaminergique de la dépression, l'étude des mécanismes d'actions de la kétamine pourrait permettre de comprendre le rôle de la transmission glutamatergique ou de la neuro-inflammation dans la neurobiologie de cette pathologie, d'affiner nos connaissances sur sa physiopathologie cognitive, ou encore de transformer en profondeur les représentations des cliniciens sur cette maladie.

Background mortality drivers of European tree species: climate change matters.

Increases in tree mortality rates have been highlighted in different biomes over the past decades. However, disentangling the effects of climate change on the temporal increase in tree mortality from those of management and forest dynamics remains a challenge. Using a modelling approach taking tree and stand characteristics into account, we sought to evaluate the impact of climate change on background mortality for the most common European tree species. We focused on background mortality, which is the mortality observed in a stand in the absence of abrupt disturbances, to avoid confusion with mortality events unrelated to long-term changes in temperature and rainfall. We studied 372 974 trees including 7312 dead trees from forest inventory data surveyed across France between 2009 and 2015. Factors related to competition, stand characteristics, management intensity, and site conditions were the expected preponderant drivers of mortality. Taking these main drivers into account, we detected a climate change signal on 45% of the 43 studied species, explaining an average 6% of the total modelled mortality. For 18 out of the 19 species sensitive to climate change, we evidenced greater mortality with increasing temperature or decreasing rainfall. By quantifying the mortality excess linked to the current climate change for European temperate forest tree species, we provide new insights into forest vulnerability that will prove useful for adapting forest management to future conditions.

Microglial production of quinolinic acid as a target and a biomarker of the antidepressant effect of ketamine.

Major depressive disorder is a complex multifactorial condition with a so far poorly characterized underlying pathophysiology. Consequently, the available treatments are far from satisfactory as it is estimated that up to 30% of patients are resistant to conventional treatment. Recent comprehensive evidence has been accumulated which suggests that inflammation may be implied in the etiology of this disease. Here we investigated ketamine as an innovative treatment strategy due to its immune-modulating capacities. In a murine model of LPS-induced depressive-like behavior we demonstrated that a single dose of ketamine restores the LPS-induced depressive-like alterations. These behavioral effects are associated with i/ a reversal of anxiety and reduced self-care, ii/ a decrease in parenchymal cytokine production, iii/ a modulation of the microglial reactivity and iv/ a decrease in microglial quinolinic acid production that is correlated with plasmatic peripheral production. In a translational approach, we show that kynurenic acid to quinolinic acid ratio is a predictor of ketamine response in treatment-resistant depressed patients and that the reduction in quinolinic acid after a ketamine infusion is a predictor of the reduction in MADRS score. Our results suggest that microglia is a key therapeutic target and that quinolinic acid is a biomarker of ketamine response in major depressive disorder.

The stochastic system approach for estimating dynamic treatments effect.

The problem of assessing the effect of a treatment on a marker in observational studies raises the difficulty that attribution of the treatment may depend on the observed marker values. As an example, we focus on the analysis of the effect of a HAART on CD4 counts, where attribution of the treatment may depend on the observed marker values. This problem has been treated using marginal structural models relying on the counterfactual/potential response formalism. Another approach to causality is based on dynamical models, and causal influence has been formalized in the framework of the Doob-Meyer decomposition of stochastic processes. Causal inference however needs assumptions that we detail in this paper and we call this approach to causality the "stochastic system" approach. First we treat this problem in discrete time, then in continuous time. This approach allows incorporating biological knowledge naturally. When working in continuous time, the mechanistic approach involves distinguishing the model for the system and the model for the observations. Indeed, biological systems live in continuous time, and mechanisms can be expressed in the form of a system of differential equations, while observations are taken at discrete times. Inference in mechanistic models is challenging, particularly from a numerical point of view, but these models can yield much richer and reliable results.

[Smoking and smoking cessation among migrants in France: A qualitative study]. / « Un bien pour un mal ¼. Consommation et arrêt du tabac chez les migrants en France : une étude qualitative (TATAMI).

INTRODUCTION: The aim of this study is to identify factors related to smoking and smoking cessation as well as preferences for cessation methods reported by migrants in France. METHODS: Qualitative study using semi-directive interviews with migrants in the Parisian area thematically analyzed using an inductive approach. RESULTS: Sixteen interviews conducted. The stress and isolation induced by migration favor the increase of tobacco consumption. These two factors, as well as the lack of information on the resources available for quitting smoking, were identified as obstacles to cessation. The main motivations for quitting are the identified or experienced effects of smoking on their health and pressure from family members, especially children. Quitting is essentially a personal strategy centered on the true will to quit. The most popular method identified by the participants as the most effective in helping them to quit, is follow-up or therapy by a health professional combining listening and psychological support. DISCUSSION: For migrants, smoking is a resource to combat stress that increases during the migration process and upon arrival in the host country and presents a psychosocial dimension for the most isolated individuals. Smoking cessation must be accompanied and must take into account the specificities of this population as well as the expressed need for psychosocial support, as suggested by our results, to be most effective.

Early effects predict trajectories of response to esketamine in treatment-resistant depression.

BACKGROUND: The efficacy of esketamine in treatment-resistant depression (TRD) has been confirmed. However, its administration is expensive and restrictive, with limited knowledge on how long the treatment should be continued. Predicting the treatment outcome would benefit patients and alleviate the global treatment cost. We aimed to define distinct trajectories of treatment response and assess their predictability. METHODS: In this longitudinal study, two independent samples of patients with unipolar or bipolar TRD were treated with esketamine in real-world settings. Depression severity was assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS) before each esketamine administration. Latent class analyses were used to define trajectories of response. RESULTS: In the original sample (N = 50), we identified two classes whose trajectories depicted response and non-response, respectively. The model was validated in the confirmatory sample (N = 55). Class membership was influenced by a few baseline characteristics such as concomitant benzodiazepine medication, number of depressive episodes or polarity. On the other hand, after only two esketamine administrations, the MADRS score predicted the 90-day trajectory of response with an accuracy of 80 %. LIMITATIONS: This observational study is not placebo-controlled. Therefore, its results and their generalizability need to be confirmed in experimental settings. CONCLUSIONS: After the first administrations of esketamine, the MADRS score has a good capacity to predict the most plausible trajectory of response. While thresholds and their predictive values need to be confirmed, this finding suggests that clinicians could base on MADRS scores their decision to discontinue treatment because of poor remaining chances of treatment response.

Seroprevalence and SARS-CoV-2 invasion in general populations: A scoping review over the first year of the pandemic.

Since the beginning of the COVID-19 pandemic, counting infected people has underestimated asymptomatic cases. This literature scoping review assessed the seroprevalence progression in general populations worldwide over the first year of the pandemic. Seroprevalence studies were searched in PubMed, Web of Science and medRxiv databases up to early April 2021. Inclusion criteria were a general population of all ages or blood donors as a proxy. All articles were screened for the title and abstract by two readers, and data were extracted from selected articles. Discrepancies were resolved with a third reader. From 139 articles (including 6 reviews), the seroprevalence estimated in 41 countries ranged from 0 to 69%, with a heterogenous increase over time and continents, unevenly distributed among countries (differences up to 69%) and sometimes among regions within a country (up to 10%). The seroprevalence of asymptomatic cases ranged from 0% to 31.5%. Seropositivity risk factors included low income, low education, low smoking frequency, deprived area residency, high number of children, densely populated centres, and presence of a case in a household. This review of seroprevalence studies over the first year of the pandemic documented the progression of this virus across the world in time and space and the risk factors that influenced its spread.

Association of body mass index with clinicopathological features and survival in patients with primary invasive lobular breast cancer.

PURPOSE: Invasive lobular carcinoma (ILC) represents up to 15% of all breast carcinomas. While the proportion of women with overweight and obesity increases globally, the impact of body mass index (BMI) at primary diagnosis on clinicopathological features of ILC and the prognosis of the patients has not been investigated yet. PATIENTS AND METHODS: We performed a multicentric retrospective study including patients diagnosed with non-metastatic pure ILC. The association of BMI at diagnosis with clinicopathological variables was assessed using linear or multinomial logistic regression. Univariable and multivariable survival analyses were performed to evaluate the association of BMI with disease-free survival (DFS), distant recurrence-free survival (DRFS), and overall survival (OS). RESULTS: The data of 2856 patients with ILC and available BMI at diagnosis were collected, of which 2570/2856 (90.0%) had oestrogen receptor (ER)-positive and human epidermal growth factor receptor (HER2) not amplified/overexpressed (ER+/HER2-) ILC. Of these 2570 patients, 80 were underweight (3.1%), 1410 were lean (54.9%), 712 were overweight (27.7%), and 368 were obese (14.3%). Older age at diagnosis, a higher tumour grade, a larger tumour size, a nodal involvement, and multifocality were associated with a higher BMI. In univariable models, higher BMI was associated with worse outcomes for all end-points (DFS: hazard ratio (HR) 1.21, 95CI 1.12-1.31, p value<0.01; DRFS: HR 1.25, 95CI 1.12-1.40, p value<0.01; OS: HR 1.25, 95CI 1.13-1.37, p value<0.01). This association was not statistically significant in multivariable analyses (DFS: HR 1.09, 95CI 0.99-1.20, p value 0.08; DRFS: HR 1.03, 95CI 0.89-1.20, p value 0.67; OS: HR 1.11, 95CI 0.99-1.24, p value 0.08), whereas grade, tumour size, and nodal involvement were still prognostic for all end-points. CONCLUSION: Worse prognostic factors such as higher grade, larger tumour size, and nodal involvement are associated with higher BMI in ER+/HER2- ILC, while there was no statistical evidence for an independent prognostic role for BMI. Therefore, we hypothesise that the effect of BMI on survival could be mediated through its association with these clinicopathological variables.

Fungicide impacts on photosynthesis in crop plants.

Fungicides are widely used to control pests in crop plants. However, it has been reported that these pesticides may have negative effects on crop physiology, especially on photosynthesis. An alteration in photosynthesis might lead to a reduction in photoassimilate production, resulting in a decrease in both growth and yield of crop plants. For example, a contact fungicide such as copper inhibits photosynthesis by destroying chloroplasts, affecting photosystem II activity and chlorophyll biosynthesis. Systemic fungicides such as benzimidazoles, anilides, and pyrimidine are also phytotoxic, whereas azoles stimulate photosynthesis. This article focuses on the available information about toxic effects of fungicides on photosynthesis in crop plants, highlighting the mechanisms of perturbation, interaction, and the target sites of different classes of fungicides.

Activation of the ancestral polarity regulator protein kinase C zeta at the immunological synapse drives polarization of Th cell secretory machinery toward APCs.

A key feature in T lymphocyte biology is that Th cells rapidly polarize their secretory machinery toward cognate APCs. The molecular mechanisms of these dynamic Th cell responses and their impact on APC biology remain to be elucidated. In this study, we demonstrate that protein kinase Czeta (PKCzeta) is rapidly activated at the immunological synapse (IS) in human Th cells interacting with cognate dendritic cells (DCs) and that a functional PKCzeta is required for the polarization of Th cell secretory machinery toward DCs. We also show that PKCzeta-dependent Th cell polarization allows dedicated delivery of IFN-gamma and CD40L at the IS and is required for the activation of cognate DCs to IL-12 production. PKCzeta synaptic activation is a low-threshold phenomenon and, in Th cells interacting with multiple DCs, selectively occurs at the IS formed with the DCs offering the strongest stimulus leading to dedicated Th cell polarization. Our results identify the PKCzeta signaling pathway as a key component of the Th cell polarization machinery and provide a molecular basis for T cell-dedicated activation of cognate DCs.

Myasthenia gravis in the elderly: a rare cause of undernutrition.

Myasthenia gravis is not a frequent disease in the elderly. The diagnosis of this neuromuscular junction disease in the elderly is difficult because of comorbidities and the broad differential diagnosis. We report here the case of a 86-year-old woman referred to hospital for loss of weight and difficulties in feeding. She was cachectic and had been suffering from dysphagia for several weeks. One week later, her clinical state worsened with the appearance of ptosis and oropharyngeal dysfunction, disturbing eating and talking. Myasthenia gravis was suspected and confirmed by a positive acetylcholine receptor antibody titer. The clinical state of the patient unfortunately worsened, with acute respiratory insufficiency, causing death. Myasthenia gravis must be suspected in a context of dysphagia, swallowing difficulties and loss of weight. This diagnosis leads to specific and symptomatic treatment and allows neuromuscular blockade-inducing drugs to be avoided.