[Which contribution of wastewater treatment plants in the fight against antimicrobial resistance?] / La filière d'assainissement, quel rôle dans la lutte contre l'antibiorésistance ?

Due to the massive use of antibiotics, antimicrobial resistance (AMR) continues to spread, endangering global disease control and environmental quality. The sources of bacteria or antimicrobial resistance genes are linked to human activities: urban, hospital and industrial discharges, livestock farms). The role of sanitation systems-sewerage, wastewater treatment and sludge treatment (WWTP)-in the problem of AMR has not yet been clearly established by the scientific community. The data available to date show that they eliminate part of the bacteria, genes and antibiotics, although this is not their primary vocation. WWTPs thus play an important filtering role to limit dissemination in the environment. On the other hand, some authors warn against their potential involvement in the selection of new resistant germs, given the conditions conducive to the exchange of genetic material between microbial strains of various types and exposed to selective agents. Today, knowledge of the mechanisms involved in the selection of antibiotic resistance and the fate of bacteria and resistance genes within sanitation systems remains limited. Research is needed to better characterize the contribution of wastewater systems and the performance of wastewater, recycled water, stormwater and sludge treatment processes.

Du fait de l'utilisation massive des antibiotiques, l'antibiorésistance (ABR) ne cesse de se répandre, mettant en danger le contrôle des maladies dans le monde et la qualité de l'environnement. Les sources d'émissions de bactéries ou de gènes de résistance aux antimicrobiens sont liées aux activités humaines : rejets urbains, hospitaliers, industriels, élevages. Le rôle que jouent les systèmes d'assainissement ­ réseau, filières de traitement des eaux usées (STEU) et traitement des boues ­ dans la problématique de l'ABR n'a pas encore été clairement établi par la communauté scientifique. Les données disponibles à ce jour montrent que les STEU éliminent une partie des bactéries, gènes et antibiotiques, bien que ce ne soit pas leur vocation première. Elles jouent ainsi un rôle de filtre important pour limiter la dissémination dans l'environnement. Mais à l'inverse, certains auteurs mettent en garde contre leur implication potentielle dans la sélection de nouveaux germes résistants, compte tenu des conditions propices aux échanges de matériel génétique entre souches microbiennes de natures diverses et exposées à des agents sélectifs. Aujourd'hui, les connaissances sur les mécanismes impliqués dans la sélection de l'ABR et le devenir des bactéries et gènes de résistance au sein des systèmes d'assainissement restent limitées. Des travaux de recherche sont nécessaires pour mieux caractériser leur contribution et évaluer les performances des procédés de traitement des eaux usées, recyclées, pluviales et des boues.

[Practical management during maintenance therapy of pediatric acute lymphoblastic leukemia: Recommendations of the French Society for Childhood and Adolescent Cancer and Leukemia (SFCE)]. / Modalités pratiques de prise en charge en cours de traitement d'entretien des leucémies aiguës lymphoblastiques pédiatriques : recommandations du Comité leucémies de la Société française de lutte contre les cancers et les leucémies de l'enfant et de l'adolescent (SFCE).

Maintenance therapy is the last phase of treatment for acute lymphoblastic leukemia in children and adolescents. Although maintenance therapy is associated with toxicities and specific management issues, it is an essential phase of treatment that reduces the risk of relapse. The objective of this work is to propose a guide for the initiation, administration, and monitoring of maintenance therapy, and for the management of food, schooling, leisure, community life, risk of infection and links with family medicine.

Lack of renoprotective effects of targeting the endothelin A receptor and (or) sodium glucose transporter 2 in a mouse model of Type 2 diabetic kidney disease.

Two recent clinical trials, using sodium glucose cotransporter (SGLT2) or endothelin-A receptor (ET-A) blocker, reported the first efficacious treatments in 18 years to slow progression of diabetic kidney disease (DKD). We hypothesized that combined inhibition of SGLT2 and ET-A receptor may confer greater protection against renal injury than either agent alone. Uninephrectomized male db/db mice were randomized to four groups: vehicle, SGLT2 inhibitor (dapagliflozin (dapa), 1 mg/kg/day), ET-A blocker (atrasentan (atra), 5 mg/kg/day), or dual treatment from 10 weeks until 22 weeks of age. At 10 weeks of age, no differences were observed in body weight, blood glucose or urinary albumin excretion among the four groups. At 16 and 22 weeks of age, body weight was lower and blood glucose levels higher in the vehicle and atra groups compared with dapa- and dual-treated groups. No notable differences were observed among the four groups in urinary albumin excretion at weeks 16 and 22. Histological analysis showed mild glomerulosclerosis and tubular injury (<5%) in all four groups with reduced glomerulosclerosis in the dual treatment group compared with vehicle. Individual or combined treatment with an SGLT2 inhibitor and (or) an ET-A antagonist did not confer renoprotective effects in this model.

[Factors associated with non-conversion of the direct smear after the initial phase of anti-tuberculous treatment. A study undertaken in three tuberculosis management centres in South Benin]. / Facteurs associés à la non-conversion de la bacilloscopie après la phase d'attaque du traitement antituberculeux. Étude réalisée dans trois centres de prise en charge de la tuberculose au Sud Bénin.

The objective of this work was to describe the profile of routinely managed tuberculosis patients whose sputum smear did not become negative after the initial phase of anti-tuberculous treatment and to analyze the factors associated with this. With this aim a cross-sectional, retrospective, descriptive and analytical study was carried out in a population of adults with pulmonary tuberculosis (PTB) between 2013 and 2014 in three cities in southern Benin (Cotonou, Porto-Novo and Abomey). The data of the patients who did not convert (PTB +) were compared with those who did (PTB-). A multivariate logistic regression analysis was performed. In 1989 (94%) of the cases, 305 (15.3%) were TPB+ with significant differences between the cities. The mean age was 38±13 years vs 34±12 years, respectively, for PTB+and PTB -, P=0.091. At the end of the multivariate analysis, the factors associated with non-conversion were: high bacillary load (≥10 AFB/microscopic field) at diagnosis, HIV+status, and adverse outcome at the end of anti-tuberculous treatment. These patients should be monitored carefully.

[Expectation about maintenance therapy among the GINECO French ovarian cancer cohort from the European NOGGO/ENGOT-ov22 Expression IV survey]. / Attentes des patientes suivies pour un cancer de l'ovaire concernant les traitements d'entretien : résultats de la cohorte française GINECO de l'enquête européenne NOGGO/ENGOT-ov22 (Expression IV).

BACKGROUND: Expression IV survey evaluated the patients' expectations to a maintenance therapy. METHODS: From January 2015 to March 2016, 401 French patients, in first line or recurrent disease, answered a 24-items anonymous questionnaire. The results were specifically analyzed according to the demographic characteristics and treatment lines. RESULTS: Among the patients, 62% had already been informed about maintenance therapy. Thirty-seven percent of patients received a maintenance treatment: 111 patients during first line and 39 patients in relapse. Expectations of patients were: 1) the chance of cure (73%), 2) the tumor shrinkage (36%), 3) quality of life improvement (35%) and 4) tumor growth reduction (27%). Among the responders, 42% were willing to take the treatment for 6-24 months, 20% for 24-60 months and 38% until tumor progression. 64% of patients expected more than a 6 months progression-free survival. Patients older than 70 years were less informed than their younger counterparts (48% vs 66%) and had lesser hope for cure with maintenance treatment (60% vs 77%). Patients in relapse had more expectation than patients in remission (tumor shrinkage: 47% vs 22%, slowing of tumor growth: 37% vs 15%, improving the progression-free survival of more than 6 months: 71% vs 53%, respectively). Among patients, 48% in relapse consented to take a treatment until progression vs 24% of patients in remission. CONCLUSION: This sub-analysis in French patients demonstrate a gap between the efficacy of maintenance therapy and the patients' expectations in ovarian cancer, particularly in relapsing disease justifying better information and explanations.

[Metastatic colorectal cancer: To stop or not to stop?] / Cancer colorectal métastatique : place du traitement d'entretien et de la pause thérapeutique.

The introduction of new regimens and targeted therapies has prolonged survival in metastatic colorectal cancer from 1 year during the fluoropyrimidines-only era to more than 30 months today. Avoiding the cumulative toxicity of oxaliplatin, but also the physical or psychological asthenia of prolonged chemotherapy, is currently a worthwhile management goal. Data from randomized controlled trials indicate that a formalized stop-and-go approach to the delivery of oxaliplatin does not compromise efficacy. This paper presents also a critical review of the randomized trials evaluating the place of bevacizumab and cetuximab as maintenance therapy. To conclude we recommend chemotherapy holidays only after 4 to 6 months of chemotherapy and only in the population of very good responders to the induction treatment.

TOP-DOWN AND BOTTOM-UP: THE ROLE OF SOCIAL INFORMATION PROCESSING AND MINDFULNESS AS PREDICTORS IN MATERNAL-INFANT INTERACTION.

The cross-generational transmission of attachment appears to reflect a complex interplay of factors, which have been challenging to identify. The current longitudinal study explored the maternal cognitive model of relationships through language use, maternal mindfulness, and attachment style assessed prenatally, as predictors of maternal response to distress and infant behavior at 6 months' postpartum. Infant behavior to the mother also was examined to provide an understanding of the evolving relationship. Thirty-two females were interviewed prenatally regarding social and family experiences. At 6 months' postpartum, each mother participated in a video-recorded session where she was asked to teach her infant a developmentally appropriate task. Videos were analyzed using the NCAST Teaching Protocol. Language use prenatally as well as the mindfulness facets (acting with awareness and describing) predicted the mothers' ability to respond to infant distress, indicating greater attunement. Infant's response to mother and clarity of cues also were predicted by maternal pronoun use. The study highlights the role of internal working models reflective of interpersonal beliefs, cognitive models, and current-moment awareness in maternal behavior. The effect of maternal language on infant behavior arguably indicates the infant's integration of maternal internal working models.

[Allergic bronchopulmonary aspergillosis: Evaluation of a maintenance therapy with nebulized Ambisome®]. / Aspergillose bronchopulmonaire allergique : évaluation d'un traitement d'entretien par Ambisome® nébulisé.

BACKGROUND: Allergic bronchopulmonary aspergillosis (ABPA) affects 3-13% of patients with asthma. Its natural history includes possibly life-threatening exacerbations and evolution towards fixed obstructive ventilatory disorders or even irreversible lung fibrosis lesions. ABPA prognosis is directly associated with exacerbation control and the main objective of the treatment is to decrease their frequency and duration. Recommendations regarding dosage and duration of treatment are not very precise. The currently used combination of itraconazole and corticosteroid therapy has many limitations. The interests of a therapeutic strategy using nebulized liposomal amphotericin B (LAmB) are to heighten antifungal lung tissue concentration, to circumvent drug interactions and decrease the potential toxicity of systemic antifungal treatments. Finally, this association leads to improved eradication of Aspergillus, thereby limiting the risk of side effects and the emergence of treatment-resistant Aspergillus strains. METHODS: This is a phase II, multicentre, randomized, single blind, controlled therapeutic study, with the objective of comparing the potential benefit on exacerbation control of a maintenance therapy by LAmB nebulization. The main objective of the study is to compare the incidence of severe clinical exacerbations in ABPA treatment, between a maintenance treatment strategy with nebulized LAmB and a conventional strategy without antifungal maintenance therapy. EXPECTED RESULTS: The results will guide practitioners in the management of ABPA treatments and help to define the place of aerosols of LAmB on "evidence base medicine" criteria.

The novel combination of theophylline and bambuterol as a potential treatment of hypoxemia in humans.

Hypoxemia can be life-threatening, both acutely and chronically. Because hypoxemia causes vascular dysregulation that further restricts oxygen availability to tissue, it can be pharmacologically addressed. We hypothesized that theophylline can be safely combined with the ß2-adrenergic vasodilator bambuterol to improve oxygen availability in hypoxemic patients. Ergogenicity and hemodynamic effects of bambuterol and theophylline were measured in rats under hypobaric and normobaric hypoxia (12% O2). Feasibility in humans was assessed using randomized, double-blind testing of the influence of combined slow-release theophylline (300 mg) and bambuterol (20 mg) on adverse events (AEs), plasma K+, pulse, blood pressure, and drug interaction. Both drugs and their combination significantly improved hypoxic endurance in rats. In humans, common AEs were low K+ (<3.5 mmol/L; bambuterol: 12, theophylline: 4, combination: 13 episodes) and tremors (10, 0, 14 episodes). No exacerbation or serious AE occurred when drugs were combined. A drop in plasma K+ coincided with peak bambuterol plasma concentrations. Bambuterol increased heart rate by approximately 13 bpm. Drug interaction was present but small. We report promise, feasibility, and relative safety of combined theophylline and bambuterol as a treatment of hypoxemia in humans. Cardiac safety and blood K+ will be important safety endpoints when testing these drugs in hypoxemic subjects.

Lucas: un fin de análisis / Lucas: end of analysis

En este trabajo se trata de dar cuenta de un final de análisis, en el caso de un niño diagnosticado como “autista”. El mismo considera la labor de la terapeuta tanto en las indicaciones sobre la frecuencia del tratamiento respecto del niño, como con la de los padres, conteniendo así al grupo familiar. También, queda destacada la transferencia establecida entre la terapeuta y el niño y la actitud de los padres a través de la aceptación de las propuestas planteadas. Del mismo modo describe la finalización del tratamiento teniendo en cuenta sus particularidades, considerando los efectos tanto en el niño y sus padres como en la terapeuta.

This paper is to account for the end of an analysis, in the case of a childdiagnosed as “autistic”. It considers the work of the therapist in bothdirections on the frequency of treatment for the child, as with that of parentsto contain the family group. Transfer established between the therapist andthe child and parental attitudes through acceptance of the proposals alsoremains outstanding. Similarly describes the completion of treatment takinginto account their particularities, considering the effects on both the childand parents and the therapist.

Ce document est de rendre compte de la fin du traitement, dans le casd’un enfant diagnostiqué comme “autiste”. Il estime que le travail duthérapeute dans les deux sens sur la fréquence du traitement de l’enfant,comme celui de parents et contenant le groupe de la famille. Transfert établientre le thérapeute et l’enfant et l’attitude des parents par l’acceptation despropositions reste également remarquable. Décrit même la fin du traitementen tenant compte de leurs particularités, en tenant compte des effets surl’enfant et les parents et le thérapeute.

[Anti-angiogenic treatments in metastatic colorectal cancer: Does a continuous angiogenic blockade make sense?]. / Traitements anti-angiogéniques dans le cancer colorectal métastatique : peut-on envisager un blocage continu de l'angiogenèse ?

Ten years after the approval of bevacizumab in colorectal cancer patients, results from ML18147 and CORRECT studies have recently demonstrated the possibility to target angiogenesis in patients previously exposed to anti-VEGF. An increasing number of anti-angiogenic treatments are now available, however, no biomarker has yet succeeded in rationalizing our therapeutic strategies. Nevertheless, several lessons have been learned from preclinical and pivotal clinical studies. The first clinical trials demonstrated a survival benefit, adding VEGFA targeting monoclonal antibodies to chemotherapy in metastatic colorectal cancer patients (AVF2107, ECOG 3200). Many phase III clinical trials confirmed the interest of this strategy, in combination with chemotherapies containing irinotecan, oxaliplatin, or with 5-fluorouracil in monotherapy. To date, such results have not been reproduced with tyrosine kinase inhibitors targeting the angiogenesis pathways, with an increasing rate of chemotherapy related toxicities. Clinical trials performed in the adjuvant setting (AVANT, NSABPC08) failed to demonstrate any efficacy of the anti-VEGFA treatments on the micrometastatic disease, encouraging its prescription in the unresectable cases. On the other hand, a continuous inhibition of angiogenesis during the course of the metastatic disease was shown to be feasible and to extend colon cancer patient's survival in two recent randomized trials. For these patients, the continuation of bevacizumab beyond progression in first line improves overall survival. Lastly, results achieved by the CORRECT and CONCUR studies demonstrated that anti-angiogenics might be effective in colorectal cancers resistant to chemotherapy. This review presents the main results of preclinical and clinical studies sustaining the prescription of anti-angiogenics in metastatic colorectal cancers. The future challenge is to promote the development of biomarkers to enable the stratification of the different therapeutic strategies.

Atorvastatin reduces T-cell activation and exhaustion among HIV-infected cART-treated suboptimal immune responders in Uganda: a randomised crossover placebo-controlled trial.

OBJECTIVE: T-cell activation independently predicts mortality, poor immune recovery and non-AIDS illnesses during combination antiretroviral therapy (cART). Atorvastatin showed anti-immune activation effects among HIV-infected cART-naïve individuals. We investigated whether adjunct atorvastatin therapy reduces T-cell activation among cART-treated adults with suboptimal immune recovery. METHODS: A randomised double-blind placebo-controlled crossover trial, of atorvastatin 80 mg daily vs. placebo for 12 weeks, was conducted among individuals with CD4 increase <295 cells/µl after seven years of suppressive cART. Change in T-cell activation (CD3 + CD4 + /CD8 + CD38 + HLADR+) and in T-cell exhaustion (CD3 + CD4 + /CD8 + PD1 + ) was measured using flow cytometry. RESULTS: Thirty patients were randomised, 15 to each arm. Atorvastatin resulted in a 28% greater reduction in CD4 T-cell activation (60% reduction) than placebo (32% reduction); P = 0.001. Atorvastatin also resulted in a 35% greater reduction in CD8-T-cell activation than placebo (49% vs. 14%, P = 0.0009), CD4 T-cell exhaustion (27% vs. 17% in placebo), P = 0.001 and CD8 T-cell exhaustion (27% vs. 16%), P = 0.004. There was no carry-over/period effect. Expected adverse events were comparable in both groups, and no serious adverse events were reported. CONCLUSION: Atorvastatin reduced T-cell immune activation and exhaustion among cART-treated adults in a Ugandan cohort. Atorvastatin adjunct therapy should be explored as a strategy to improve HIV treatment outcomes among people living with HIV in sub-Saharan Africa.

[Proliferative lupus nephritis treatment: practice survey in nephrology and internal medicine in France]. / Prise en charge des glomérulonéphrites lupiques prolifératives: enquête de pratique du Groupe Coopératif sur le Lupus Rénal auprès des néphrologues et internistes Français.

European and American recommendations have recently been published for the treatment of proliferative lupus nephritis (LN). This study aimed to describe current practice in France. An electronic survey was sent to French nephrologists and internists via their scientific society between March and December 2012. One hundred and nine specialists (60 internists, 48 nephrologists and 1 rheumatologist), mostly from hospitals, completed the survey. Low-dose cyclophosphamide (Euro-Lupus) was the first induction immunosuppressive therapy used (67%), followed by mycophenolate mofetil (MMF) (20%) and high dose CYC (NIH, 9%). Maintenance immunosuppressive therapy after an induction with CYC was preferentially MMF (58%), versus 14% for azathioprine (AZA) and 25% using either MMF or AZA without preference. After an induction with MMF, maintenance treatment was mainly MMF (77%). Antimalarial drugs were prescribed systematically by 86% of specialists. In patients in stable remission, maintenance treatment was withdrawn after 2 years (40%), 3 years (25%) or more (34%). Low-dose corticosteroids were continued in the long-term by 54% of specialists. No difference was observed between nephrologists and internists, even in the prescription of antimalarials. Treatment of proliferative LN in France is homogenous enough and is consistent with recent international recommendations.

[Natalizumab as induction therapy in multiple sclerosis]. / Traitement d'induction dans la sclérose en plaques: place du natalizumab.

BACKGROUND: Current treatment options for first-line immunotherapy in relapsing-remitting multiple sclerosis (MS) are recombinant interferon-ß and glatiramer acetate. However, these therapies are only partially effective and certain patients may fail to respond. For this reason, it is important to elaborate alternative treatment strategies. Induction therapy represents a more aggressive approach in which powerful drugs are used right from the beginning to tackle the disease process hard and early. Natalizumab is a powerful monoclonal antibody approved for the treatment of relapsing-remitting MS and is known to silence disease activity. METHODS: We describe here the early outcome at 1 month and at 6 months of three patients treated with natalizumab for relapsing-remitting MS. RESULTS: All three patients had a high disease activity before the initiation of natalizumab, with 4, 8 and 5 gadolinium-enhancing lesions on brain MRI respectively. On the MRI scans made at 1 month after the first infusion, and at 6 months, there was no more gadolinium-enhancement and no new T2-lesion. Clinically, they did not experience any relapse. DISCUSSION: In these three cases, natalizumab showed a dramatic efficacy: the patients became "disease activity free" right from the first infusion. To our knowledge, natalizumab is not classically used as an induction therapy, unlike mitoxantrone. However, this treatment has potential hematological and cardiac toxicity and its use can be limited. Thus, in JC virus negative patients, natalizumab could be an interesting alternative treatment. CONCLUSION: Our report suggests that induction strategy with natalizumab may be applicable in patients with aggressive multiple sclerosis. A study of more similar cases may be interesting to confirm these preliminary results.