Reproducibility of T1ρ and T2 quantification in a multi-vendor multi-site study.

OBJECTIVE: To evaluate the multi-vendor multi-site reproducibility of two-dimensional (2D) multi-echo spin-echo (MESE) T2 mapping (product sequences); and to evaluate the longitudinal reproducibility of three-dimensional (3D) magnetization-prepared angle-modulated partitioned k-space spoiled gradient echo snapshots (MAPSS) T1ρ and T2 mapping (research sequences), and 2D MESE T2 mapping, separated by 6 months, in a multi-vendor multi-site setting. METHODS: Phantoms and volunteers (n = 5 from each site, n = 20 in total) were scanned on four 3 T magnetic resonance (MR) systems from four sites and three vendors (Siemens, General Electric, and Phillips). Two traveling volunteers (3 knees) scanned at all 4 sites at baseline and 6-month follow-up. Data was transferred to one site for centralized processing. Coefficients of variation (CVs) were calculated to evaluate reproducibility. RESULTS: For baseline 2D MESE T2 measures, average CV were 0.37-2.45% (intra-site) and 5.96% (inter-site) for phantoms, and 3.15-8.49% (intra-site) and 14.16% (inter-site) for volunteers. For longitudinal phantom data, intra-site CVs were 1.42-3.48% for 3D MAPSS T1ρ, 1.77-3.56% for 3D MAPSS T2, and 1.02-2.54% for 2D MESE T2. For the longitudinal volunteer data, the intra-site CVs were 2.60-4.86% for 3D MAPSS T1ρ, 3.33-7.25% for 3D MAPSS T2, and 3.11-8.77% for 2D MESE T2. CONCLUSION: This study demonstrated excellent intra-site reproducibility of 2D MESE T2 imaging, while its inter-site variation was slightly higher than 3D MAPSS T2 imaging (10.06% as previously reported). This study also showed excellent reproducibility of longitudinal T1ρ and T2 cartilage quantification, in a multi-vendor multi-site setting for both product 2D MESE T2 and 3D MAPSS T1p/T2 research sequences.

Overexpression of miR-181a regulates the Warburg effect in triple-negative breast cancer.

OBJECTIVE: Triple-negative breast cancer (TNBC) is highly aggressive and leads to a poor prognosis. microRNA-181a (miR-181a) exhibits strong antineoplastic effects in many types of cancer. In this study, we examine the responses of human miR-181a-transfected TNBC cells and explore the mechanisms underlying the observed effects. METHODS: A series of cellular assays were conducted using cells from the MDA-MB-231 TNBC line to assess the impact of miR-181a overexpression. The extracellular acidification rate, lactate production and glucose uptake were evaluated as a measure of aerobic glycolysis (i.e. the Warburg effect). The expressions of glycolysis-related gene were analyzed. RESULTS: Viability, migration and survival of miR-181a-transfected MDA-MB-231 cells were all significantly reduced. miR-181a inhibited glycolysis in TNBC cells by reducing the rates of glucose uptake and lactate production and a substantial downregulation of factors known to contribute to the Warburg effect, including the serine/threonine kinase, AKT3, hypoxia-inducible factor-1α (HIF-1α) and progesterone receptor membrane component 1 (PGRMC1). CONCLUSION: Our results demonstrate that miR-181a may regulate glycolysis in MDA-MB-231 TNBC cells, potentially via interference with components of the AKT3-HIF-1α and PGRMC1 pathways. These results suggest that miR-181a might be developed as a therapeutic agent for use in antineoplastic regimens directed at TNBC and PGRMC1-overexpressing breast cancers.

[Soft tissue necrotizing infection]. / L'image du mois. Infection nécrosante des tissus mous.

Necrotizing fasciitis and gas gangrene represent a rapidly progressive and fatal tissue infection in the absence of early multidisciplinary treatment. There are multiple risk factors, but diabetes remains the main one. The presence of crackles or extensive lesions are an indication for exploration and surgical treatment. Conservative management is associated with zero survival. Iconography, biology or bacteriology can help in the diagnosis, but the latter is only made during surgery. The associated mortality is high, despite appropriate management. We report here the case of a diabetic patient requiring insulin, having presented this pathology, the starting point of which is a traumatic wound, with an extensive acute course, contra-indicating any surgical procedure.

La fasciite nécrosante et la gangrène gazeuse représentent une infection tissulaire rapidement progressive et létale en l'absence d'un traitement multidisciplinaire précoce. Il existe de multiples facteurs de risques, mais le diabète en reste le principal. La présence de crépitants ou de lésions extensives sont une indication à l'exploration et au traitement chirurgical. Une prise en charge conservatrice est associée à une survie nulle. L'iconographie, la biologie ou la bactériologie permettent d'aider au diagnostic, mais ce dernier est uniquement posé en per-opératoire. La mortalité associée est élevée, malgré une prise en charge adaptée. Nous rapportons ici le cas d'un patient diabétique de type 2 insulino-requérant, ayant présenté cette pathologie dont le point de départ est une plaie traumatique, avec une évolution aiguë extensive, contre-indiquant tout geste chirurgical.

Cost-effectiveness of mifepristone and misoprostol versus misoprostol alone for the management of missed miscarriage: an economic evaluation based on the MifeMiso trial.

OBJECTIVE: To assess the cost-effectiveness of mifepristone and misoprostol (MifeMiso) compared with misoprostol only for the medical management of a missed miscarriage. DESIGN: Within-trial economic evaluation and model-based analysis to set the findings in the context of the wider economic evidence for a range of comparators. Incremental costs and outcomes were calculated using nonparametric bootstrapping and reported using cost-effectiveness acceptability curves. Analyses were performed from the perspective of the UK's National Health Service (NHS). SETTING: Twenty-eight UK NHS early pregnancy units. SAMPLE: A cohort of 711 women aged 16-39 years with ultrasound evidence of a missed miscarriage. METHODS: Treatment with mifepristone and misoprostol or with matched placebo and misoprostol tablets. MAIN OUTCOME MEASURES: Cost per additional successfully managed miscarriage and quality-adjusted life years (QALYs). RESULTS: For the within-trial analysis, MifeMiso intervention resulted in an absolute effect difference of 6.6% (95% CI 0.7-12.5%) per successfully managed miscarriage and a QALYs difference of 0.04% (95% CI -0.01 to 0.1%). The average cost per successfully managed miscarriage was lower in the MifeMiso arm than in the placebo and misoprostol arm, with a cost saving of £182 (95% CI £26-£338). Hence, the MifeMiso intervention dominated the use of misoprostol alone. The model-based analysis showed that the MifeMiso intervention is preferable, compared with expectant management, and this is the current medical management strategy. However, the model-based evidence suggests that the intervention is a less effective but less costly strategy than surgical management. CONCLUSIONS: The within-trial analysis found that based on cost-effectiveness grounds, the MifeMiso intervention is likely to be recommended by decision makers for the medical management of women presenting with a missed miscarriage. TWEETABLE ABSTRACT: The combination of mifepristone and misoprostol is more effective and less costly than misoprostol alone for the management of missed miscarriages.

[Ambulatory laparoscopic colectomy : First experiences at the CHU of Liège]. / Colectomie cœlioscopique ambulatoire. Premières expériences au CHU de Liège.

CONTEXT: For many years, enhanced recovery programs (ERP) for colorectal surgery have been developed in many hospitals around the world. Recently, our institution took a new step forward in colonic surgery : ambulatory laparoscopic colectomies. METHODS: Our eligibility criteria for our ambulatory colectomy program were defined and our perioperative ERP protocol was adapted to the ambulatory setting. Five patients consented to inclusion in this program. RESULTS: Patients' characteristics were as follows : four women, one male, age : 48 years (range 21-67); surgical indication : cancer in two patients, diverticulitis in two patients, and Crohn disease in one patient. The surgical site was the left colon in four cases and the right colon in one case. Four out of the five patients left the hospital 5-8 h after the end of the surgery. No postoperative complication occurred, no readmission was necessary. DISCUSSION: This article discusses the benefits and risks of ambulatory colectomy. We emphasize that such outpatient management must not be pursued at the expense of the patient's safety and well-being.

Contexte : Depuis de nombreuses années, les programmes de réhabilitation améliorée après chirurgie (RAC) colorectale ont été développés dans de nombreux centres hospitaliers à travers le monde. Récemment, notre institution a franchi une nouvelle étape en chirurgie colique : la réalisation de colectomies coelioscopiques en ambulatoire. Méthodes : Après avoir déterminé nos critères d'inclusion dans le programme de colectomie ambulatoire et adapté notre protocole péri-opératoire de RAC au contexte ambulatoire, nous y avons inclus cinq patients. Résultats : Les caractéristiques des patients étaient les suivantes : quatre femmes et un homme; âge : 48 ans (range 21-67); indications chirurgicales : deux patients pour cancer, deux patients pour diverticulite et un patient pour maladie de Crohn. La colectomie concernait le côlon gauche dans quatre cas et le côlon droit dans un cas. Quatre des cinq patients ont quitté l'hôpital 5-8 h après la fin de l'intervention chirurgicale. Aucune complication postopératoire n'est survenue, aucune réadmission n'a été nécessaire. Discussion : Cet article discute les bénéfices et risques de la colectomie ambulatoire. Nous insistons sur le fait qu'une prise en charge ambulatoire ne doit pas être poursuivie au détriment du bien-être et de la sécurité du patient.

A High-Throughput Assay to Identify Allosteric Inhibitors of the PLC-γ Isozymes Operating at Membranes.

The two phospholipase C-γ (PLC-γ) isozymes are major signaling hubs and emerging therapeutic targets for various diseases, yet there are no selective inhibitors for these enzymes. We have developed a high-throughput, liposome-based assay that features XY-69, a fluorogenic, membrane-associated reporter for mammalian PLC isozymes. The assay was validated using a pilot screen of the Library of Pharmacologically Active Compounds 1280 (LOPAC1280) in 384-well format; it is highly reproducible and has the potential to capture both orthosteric and allosteric inhibitors. Selected hit compounds were confirmed with secondary assays, and further profiling led to the interesting discovery that adenosine triphosphate potently inhibits the PLC-γ isozymes through noncompetitive inhibition, raising the intriguing possibility of endogenous, nucleotide-dependent regulation of these phospholipases. These results highlight the merit of the assay platform for large scale screening of chemical libraries to identify allosteric modulators of the PLC-γ isozymes as chemical probes and for drug discovery.

Multi-vendor multi-site T1ρ and T2 quantification of knee cartilage.

OBJECTIVE: To develop 3D T1ρ and T2 imaging based on the same sequence structure on MR systems from multiple vendors, and to evaluate intra-site repeatability and inter-site inter-vendor reproducibility of T1ρ and T2 measurements of knee cartilage. METHODS: 3D magnetization-prepared angle-modulated partitioned k-space spoiled gradient echo snapshots (3D MAPSS) were implemented on MR systems from Siemens, GE and Philips. Phantom and human subject data were collected at four sites using 3T MR systems from the three vendors with harmonized protocols. Phantom data were collected by means of different positioning of the coil. Volunteers were scanned and rescanned after repositioning. Two traveling volunteers were scanned at all sites. Data were transferred to one site for centralized processing. RESULTS: Intra-site average coefficient of variations (CVs) ranged from 1.09% to 3.05% for T1ρ and 1.78-3.30% for T2 in phantoms, and 1.60-3.93% for T1ρ and 1.44-4.08% for T2 in volunteers. Inter-site average CVs were 5.23% and 6.45% for MAPSS T1ρ and T2, respectively in phantoms, and 8.14% and 10.06% for MAPSS T1ρ and T2, respectively, In volunteers. CONCLUSION: This study showed promising results of multi-site, multi-vendor reproducibility of T1ρ and T2 values in knee cartilage. These quantitative measures may be applied in large-scale multi-site, multi-vendor trials with controlled sequence structure and scan parameters and centralized data processing.

[Enhanced recovery after surgery in colorectal surgery]. / La réhabilitation améliorée après chirurgie colorectale.

Enhanced recovery after surgery (ERAS) in colorectal surgery consists of multidisciplinary, multimodal, and patient-centred care. The implementation of pre-, intra-, and post-operative measures mitigates the surgical stress, the inflammatory reaction, and their consequences. The elements of this protocol are evidence-based medicine. This allows improved and accelerated recovery. Consequently, ERAS reduces the incidence of medical complications by 50 %, including fewer infectious complications, and a possible positive impact on survival after oncologic surgery. Hospital length of stay is shortened. There is no contraindication to ERAS, which must be used for all patients undergoing colorectal surgery. Adaptation of the protocol will nevertheless be necessary in the event of urgent surgery.

La réhabilitation améliorée après chirurgie (RAC) colorectale est une prise en charge multidisciplinaire et multimodale, centrée sur le patient. La mise en place de mesures pré-, per- et postopératoires réduit la réponse au stress chirurgical, la réaction inflammatoire et leurs conséquences. Ce protocole de soins, basé sur des preuves scientifiques, permet une récupération améliorée et accélérée. L'incidence des complications médicales est, secondairement, réduite de 50 %. La réhabilitation améliorée se traduit par une diminution significative de la durée d'hospitalisation, une diminution des complications infectieuses et, probablement, par un impact positif sur la survie après chirurgie oncologique. Il n'y a pas de contre-indication à la RAC qui doit donc être proposée à tous les patients devant subir une chirurgie colorectale. Une adaptation du protocole sera néanmoins nécessaire en cas de chirurgie urgente.

[How to explore a cervical dystonia]. / Comment j'explore une dystonie cervicale.

Cervical dystonia is one of the most frequent form of focal dystonia. However, there's a great lack of awareness of this condition : a long delay to diagnosis is quite common and misdiagnosis is often seen. Nevertheless, this pathology is invalidating and improving diagnosis could have an impact on the treatment and the patient's quality of life.

Trop souvent méconnue, la dystonie cervicale (parfois appelée torticolis spasmodique) est pourtant une des formes les plus fréquentes de dystonie focale. Les errances diagnostiques sont fréquentes et le délai pour établir le bon diagnostic est souvent long. Il s'agit pourtant d'une pathologie invalidante pour laquelle un traitement est envisageable et susceptible de soulager le patient.

[Predictive factors of seclusion duration in patients hospitalized in psychiatry settings. A prospective multisite study in the DTRF Paris-Sud]. / Facteurs prédictifs de la durée d'isolement chez les patients hospitalisés en psychiatrie. Une étude prospective multicentrique au sein du DTRF Paris-Sud.

INTRODUCTION: In psychiatric inpatient settings seclusion is a last resort to ensure the safety of the patient, other patients, and staff from disturbed behaviors. Despite its major interest for patients, seclusion could negatively impact treatment adherence and patient/staff relationships. Indeed, some secluded patients report a feeling of guilt during the measure and do not consider seclusion to be a healthcare intervention. To be more beneficial and to reduce the feeling by patients of being forced, seclusions should be as short and rare as possible. In other words, measures to reduce seclusion are available and have been clearly identified. Such measures could be applied, in the first instance, in patients with longer duration. In this way, the aim of this study was to investigate predictive factors of a seclusion of long duration. METHODS: Our study was based on the dataset of the EPIC study, an observational prospective French multicenter study of seclusion and restraint. The EPIC study occurred in seven French psychiatric hospitals in the southern region of Paris. Inclusions were realized for 73days and allowed a data collection of 302 seclusion measures. Of these measures 236 were effectively a seclusion in a standardized room. Because the median duration was 7days, we defined two groups of patients: duration<7days and duration ≥ 7 days. Our variable to be explicated was duration ≥ 7 days. Explicative variables available in EPIC study were age, sex, forced hospitalization, autoagressivity, heteroagressivity, use of sedative treatment (oral or intramuscular), history of seclusion and patient diagnoses. We used bivariate and multivariate analyses to explore the association between a seclusion duration ≥ 7 days and explicative variables. Diagnoses were classified as psychotic disorders, mood disorders and others diagnoses. To be included in multivariate logistic regressions, diagnoses were treated as dummy variables (mood disorder vs psychotic disorders; psychotic disorders vs others; mood disorders vs others). Statistical analyses were performed using SPSS software 20.0 and R 3.4.0. RESULTS: Of the 236 measures of seclusion the mean age was 38.2 (±12.8), 196 (83%) patients were forcibly hospitalized prior to their seclusion, 147 (62%) had a diagnosis of psychotic disorder, 43 (18%) a diagnosis of mood disorder and 33 (14%) an "other diagnosis". Mean duration was 10.2 (1.5) days and median was 7.1 days. One hundred and thirty-five (47%) patients were in the group of duration ≥ 7 days. In bivariate analyses, variables associated with a duration ≥ 7 days were: being in forced hospitalization prior to the seclusion (P=0.04), administration of a sedative treatment (P=0.01) and against the group of others diagnoses the diagnosis of mood disorders (P<0.0005) and psychotic disorders (P=0.001). Multivariate analyses showed that, against the group of other diagnoses, the group of psychotic disorders [OR=3.3, CI 95% (1.3-8.4), P=0.01], the group of mood disorder [OR=2.7, CI 95% (1.4-4.9), P=0.002] and administration of sedative treatment [OR=8.1, CI 95% (2.0-32.5), P=0.003] were significantly associated with a duration ≥ 7 days. These results were independent from other confusion variables. Considering the hospitalization status, psychotic disorders was the only diagnosis which showed an association between duration ≥ 7 days and forced hospitalization [OR=2.9 CI 95% (1.1-7.8), P=0.03]. CONCLUSION: Our study highlighted two profiles of higher risk to remain ≥ 7days in seclusion. The first one is patients with a diagnosis of mood disorder who needed sedative treatment. The second one is patients with a diagnosis of psychotic disorder who needed sedative treatment and forced hospitalized before seclusion. Thus, these two profiles could be a good target to practice, in the first instance, measures to reduce seclusion duration in psychiatry settings.

[Acute pulmonary edema and tocolytic therapy in pregnant women : clinical case and review of literature.] / Le cas clinique du mois. Œdème aigu du poumon et traitement par tocolytiques chez la femme enceinte.

We report the case of a pregnant woman, treated by nifedipine and next by atosiban for premature labour, who develop an acute pulmonary edema. The severity of symptoms and hypoxemia lead the patient to a cesarean and next to the intensive care hospitalization. This clinical case allow us to make a review of literature and reminds us the differential diagnosis to look for during an acute dyspnea in a pregnant woman and the treatment of acute pulmonary edema in these circumstances. The pathophysiological mechanisms which are at the origins of this condition and the implication of the tocolytic treatment will also be discussed.

Nous rapportons le cas d'une patiente traitée par nifédipine puis par atosiban pour une menace d'accouchement prématuré qui développe un œdème aigu du poumon non cardiogénique. La gravité des symptômes et de l'hypoxémie ont mené à une césarienne en urgence et une hospitalisation aux soins intensifs. Ce cas clinique nous permet de faire une revue de littérature et d'aborder les différents diagnostics différentiels à évoquer et rechercher face à une dyspnée aiguë survenant chez une femme enceinte et la prise en charge d'un œdème pulmonaire aigu dans de telles circonstances. Les mécanismes physiopathologiques qui sont à l'origine de cette affection et l'implication du traitement tocolytique seront également discutés.

Caesarean section surgical techniques: 3 year follow-up of the CORONIS fractional, factorial, unmasked, randomised controlled trial.

BACKGROUND: The CORONIS trial reported differences in short-term maternal morbidity when comparing five pairs of alternative surgical techniques for caesarean section. Here we report outcomes at 3 years follow-up. METHODS: The CORONIS trial was a pragmatic international 2 × 2 × 2 × 2× 2 non-regular fractional, factorial, unmasked, randomised controlled trial done at 19 sites in Argentina, Chile, Ghana, India, Kenya, Pakistan, and Sudan. Pregnant women were eligible if they were to undergo their first or second caesarean section through a planned transverse abdominal incision. Women were randomly assigned by a secure web-based allocation system to one intervention from each of the three assigned pairs. All investigators, surgeons, and participants were unmasked to treatment allocation. In this follow-up study, we compared outcomes at 3 years following blunt versus sharp abdominal entry, exteriorisation of the uterus for repair versus intra-abdominal repair, single versus double layer closure of the uterus, closure versus non-closure of the peritoneum, and chromic catgut versus polyglactin-910 for uterine repair. Outcomes included pelvic pain; deep dyspareunia; hysterectomy and outcomes of subsequent pregnancies. Outcomes were assessed masked to the original trial allocation. This trial is registered with the Current Controlled Trials registry, number ISRCTN31089967. FINDINGS: Between Sept 1, 2011, and Sept 30, 2014, 13,153 (84%) women were followed-up for a mean duration of 3·8 years (SD 0·86). For blunt versus sharp abdominal entry there was no evidence of a difference in risk of abdominal hernias (adjusted RR 0·66; 95% CI 0·39-1·11). We also recorded no evidence of a difference in risk of death or serious morbidity of the children born at the time of trial entry (0·99, 0·83-1·17). For exteriorisation of the uterus versus intra-abdominal repair there was no evidence of a difference in risk of infertility (0·91, 0·71-1·18) or of ectopic pregnancy (0·50, 0·15-1·66). For single versus double layer closure of the uterus there was no evidence of a difference in maternal death (0·78, 0·46-1·32) or a composite of pregnancy complications (1·20, 0·75-1·90). For closure versus non-closure of the peritoneum there was no evidence of a difference in any outcomes relating to symptoms associated with pelvic adhesions such as infertility (0·80, 0·61-1·06). For chromic catgut versus polyglactin-910 sutures there was no evidence of a difference in the main comparisons for adverse pregnancy outcomes in a subsequent pregnancy, such as uterine rupture (3·05, 0·32-29·29). Overall, severe adverse outcomes were uncommon in these settings. INTERPRETATION: Although our study was not powered to detect modest differences in rare but serious events, there was no evidence to favour one technique over another. Other considerations will probably affect clinical practice, such as the time and cost saving of different approaches. FUNDING: UK Medical Research Council and the Department for International Development.

PPAR-γ Agonists for the Treatment of Major Depression: A Review.

Introduction: Selective agonists of the nuclear transcription factor peroxisome proliferator-activated receptor-gamma (PPAR-γ) are used for the treatment of type 2 diabetes. We reviewed their efficacy and safety for the treatment of major depression and the association of their potential antidepressant effects with changes in biomarkers of metabolism and inflammation. Methods: From 8 studies, 4 open-label trials, and 4 randomized controlled trials (RCT) (3 vs. placebo and 1 vs. metformin), 448 patients with major depression were included, of which 209 patients received PPAR-γ agonists (pioglitazone or rosiglitazone) for 6-12 weeks, either alone or in add-on therapy to conventional treatments. Results: PPAR-γ agonists have antidepressant effects in the 4 open-label studies and in 3 out of 4 RCT. No major adverse event was reported. Improvement in depression scores was associated with improvement in 3 biomarkers of insulin resistance (homeostatic model assessment [HOMA-IR], oral glucose tolerance test, and fasting plasma glucose) and 1 biomarker of inflammation (interleukin-6) among 21 biomarkers studied. Conclusion: PPAR-γ agonists may have antidepressant properties, which need to be assessed in further studies of major depressive episodes.

[Follow-up interventions after suicide attempt. What tools, what effects and how to assess them?] / La veille sanitaire dans la prise en charge des suicidants. Quels outils, quels effets, comment les évaluer ?

After attempting suicide, 60 to 70% of patients are discharged from emergency departments and referred to outpatient treatment which entails psychosocial strategies, pharmacological strategies or a combination. The main objective of outpatient care consists in preventing recurrent suicidal behavior. Yet suicide attempters have been found to be very difficult to engage in treatment. Between 11% and 50% of attempters refuse outpatient treatment or drop out of outpatient therapy very quickly. In order to address this extremely serious issue, for the past 20 years monitoring or follow up interventions has been presented as a promising approach. Follow-up intervention is defined as a service that aims at both increased access to and engagement in care as well as to prevent suicide and related behaviors. This approach consists in "stay in contact" or "connectedness" protocols using phone calls or tele-assistance, sending letters, email or mobile phone messages and medical visits or nursing at home. From one study to another these tools have been used separately, associated to one another or reinforced by motivational interviewing or brief psychotherapy. To our knowledge, since 1993 16 controlled and randomized controlled studies assessed the effectiveness of diverse follow-up. Four studies assessing telephone follow up reported a significant decrease in suicide reattempt while one study evaluating a sending letters strategy reported positive results. Among five studies assessing engagement in healthcare, only two (one using phone follow up and the other sending letters reported significantly positive results. The refusal rate of monitoring strategies has not exceeded 11% attesting to the high applicability of these methods. Despite several positive results, we cannot draw firm conclusions on replicability of these results. This is largely due to methodological issues: lack of standardization of interventions, lack of consensus on definition of the main measured variables (recurrent suicidal behavior, engagement in healthcare) but also to the confounding effect of other care approaches frequently associated with follow up intervention services. Further studies and research should be conducted as follow-up intervention services are increasingly used in suicide prevention because of their good acceptability and usefulness.

Post-partum depressive symptoms and medically assisted conception: a systematic review and meta-analysis.

STUDY QUESTION: Does medically assisted conception increase the risk of post-partum depressive symptoms? SUMMARY ANSWER: Our literature review and meta-analysis showed no increased risk of post-partum depressive symptoms in women after medically assisted conception. WHAT IS KNOWN ALREADY: Women who conceive with medically assisted conception, which can be considered as a stressful life event, could face an increased risk of depressive symptoms. However, no previous meta-analysis has been performed on the association between medically assisted conception and post-partum depressive symptoms. STUDY DESIGN, SIZE, DURATION: A systematic review with electronic searches of PubMed, ISI Web of Knowledge and PsycINFO databases up to December 2014 was conducted to identify articles evaluating post-partum depressive symptoms in women who had benefited from medically assisted conception compared with those with a spontaneous pregnancy. Meta-analyses were also performed on clinically significant post-partum depressive symptoms according to PRISMA guidelines. PARTICIPANTS/MATERIALS, SETTING, METHODS: From 569 references, 492 were excluded on title, 42 on abstract and 17 others on full-text. Therefore, 18 studies were included in the review and 8 in the meta-analysis (2451 women) on clinically significant post-partum depressive symptoms after medically assisted conception compared with a spontaneous pregnancy. A sensitivity meta-analysis on assisted reproductive technologies and spontaneous pregnancy (6 studies, 1773 women) was also performed. The quality of the studies included in the meta-analyses was evaluated using the Strengthening the Reporting of Observational Studies in Epidemiology Statement for observational research. The data were pooled using RevMan software by the Cochrane Collaboration. Heterogeneity between studies was assessed from the results of the χ(2) and I(2) statistics. Biases were assessed with funnel plots and Egger's test. A fixed effects model was used for the meta-analyses because of the low level of heterogeneity between the studies. MAIN RESULTS AND THE ROLE OF CHANCE: The systematic review of studies examining post-partum depressive symptoms after medically assisted conception compared with spontaneous pregnancy is not in favor of an association. Our meta-analysis on clinically significant post-partum depressive symptoms showed no significant difference between women who used medically assisted conception and those with spontaneous pregnancy: odds ratio (OR) = 0.93 (0.67-1.31), Z = 0.40, P = 0.69. The sensitivity meta-analysis reported no significant difference either: OR = 1.04 (0.71-1.52), Z = 0.18, P = 0.86. LIMITATIONS, REASONS FOR CAUTION: The literature on post-partum depressive symptoms and medically assisted conception is sparse. Only eight studies were available for our meta-analysis taking into account the rates of clinically significant post-partum depressive symptoms after medically assisted conception. However, the quality of the studies was high and the heterogeneity between trials was not significant. Whilst post-partum anxiety is more prevalent than depressive states and they can co-occur, it was not considered in these review and meta-analyses. In addition, other risk factors, such as maternal age, socio-demographic data or obstetric factors, are important for the assessment of post-partum depressive symptoms. Our review reported that several of these confounding risk factors were, however, analyzed and controlled for in the studies. WIDER IMPLICATIONS OF THE FINDINGS: Our literature review and meta-analyses showed no increased risk of post-partum depressive symptoms in women after medically assisted conception. Even if the rates of depressive symptoms are the same in the medically assisted conception population as among controls, the risk factors could be different. Though medically assisted conception can be considered as a stressful life event, these women have also lower prevalence of the usual risks. Professionals should also be careful to screen for prenatal and post-partum depressive symptoms, as with all pregnant women. Further studies are needed to clarify the specific features of post-partum depressive symptoms in this population.

Response to CYP2D6 substrate antidepressants is predicted by a CYP2D6 composite phenotype based on genotype and comedications with CYP2D6 inhibitors.

The cytochrome P450 2D6 (CYP2D6) is involved in the metabolism of most antidepressants. Comedication with a potent CYP2D6 inhibitor can convert patients with extensive metabolizer (EM) or ultra-rapid metabolizer (UM) genotypes into poor metabolizer (PM) phenotypes. Since comedication is frequent in depressed patients treated with antidepressants, we investigated the effect of the CYP2D6 composite phenotype on antidepressant efficacy, taking into account both the CYP2D6 genotype and comedication with CYP2D6 inhibitors. 87 Caucasian in patients with a major depressive episode were prospectively treated with flexible doses of antidepressant monotherapy as well as comedications and genotyped for the major CYP2D6 alleles (CYP2D6*3 rs35742686, *4 rs3892097, *5 del, *6 rs5030655, and *2xN). They were classified for CYP2D6 composite phenotype and assessed for antidepressant response after 4 weeks. In terms of genotypes (g), 6 subjects were UMg, 6 PMg, and 75 EMg. Ten patients were coprescribed a CYP2D6 inhibitor, resulting in the following composite phenotypes (cp): 5 UMcp, 16 PMcp, and 66 EMcp. Whereas none of the CYP2D6 genotypes were significantly associated with antidepressant response, UMcp had a lower antidepressant response than PMcp or EMcp (respectively: 39.0 ± 17.9, 50.0 ± 26.0, and 61.6 ± 23.4, p = 0.02). Despite small sample size, this study suggests that a CYP2D6 composite phenotype, taking into account both genotype and comedications with CYP2D6 inhibitors, could predict CYP2D6 substrate antidepressants response. Thus, to optimize antidepressant response, CYP2D6 genotype could be performed and comedications with CYP2D6 inhibitors should be avoided, when prescribing CYP2D6 substrate antidepressants.

[Security of the medicinal therapy: Cartography of risks a priori within service of orthopaedic surgery]. / Sécurisation de la prise en charge médicamenteuse : cartographie des risques a priori au sein du service de chirurgie orthopédique.

INTRODUCTION: Security and quality of the Medicinal Therapy are one of the most important objectives of the April 6th, 2011 order. The objective is to realize this study of the risks incurred by patients related to management and security of medicinal therapy in order to establish a plan to reduce the risks of drug's dispensation. MATERIALS AND METHOD: The method of the Preliminary Risk Analysis (PRA) has been implemented by a multidisciplinary group in a hospital service of orthopaedic surgery. The study focused on the dispensation phase of medicinal circuit. RESULTS: This analysis revealed 148 scenarii, 35 were criticality unacceptable. Fifty-four initial risk control actions were proposed and their stress levels to put them in place were evaluated. DISCUSSION: The main measures of risk management are: training, information, communication, computerization, automation, dual control, updating the documentation system, drug reconciliation and respect for Best Practices Hospitallers (BPH). CONCLUSIONS: Risk management requires a significant human and financial investment as well as, material resources and multidisciplinary expertise in order to offer the best solutions.

Caesarean section surgical techniques (CORONIS): a fractional, factorial, unmasked, randomised controlled trial.

BACKGROUND: Variations exist in the surgical techniques used for caesarean section and many have not been rigorously assessed in randomised controlled trials. We aimed to assess whether any surgical techniques were associated with improved outcomes for women and babies. METHODS: CORONIS was a pragmatic international 2×2×2×2×2 non-regular fractional, factorial, unmasked, randomised controlled trial that examined five elements of the caesarean section technique in intervention pairs. CORONIS was undertaken at 19 sites in Argentina, Chile, Ghana, India, Kenya, Pakistan, and Sudan. Each site was assigned to three of the five intervention pairs: blunt versus sharp abdominal entry; exteriorisation of the uterus for repair versus intra-abdominal repair; single-layer versus double-layer closure of the uterus; closure versus non-closure of the peritoneum (pelvic and parietal); and chromic catgut versus polyglactin-910 for uterine repair. Pregnant women were eligible if they were to undergo their first or second caesarean section through a planned transverse abdominal incision. Women were randomly assigned by a secure web-based number allocation system to one intervention from each of the three assigned pairs. All investigators, surgeons, and participants were unmasked to treatment allocation. The primary outcome was the composite of death, maternal infectious morbidity, further operative procedures, or blood transfusion (>1 unit) up to the 6-week follow-up visit. Women were analysed in the groups into which they were allocated. The CORONIS Trial is registered with Current Controlled Trials: ISRCTN31089967. FINDINGS: Between May 20, 2007, and Dec 31, 2010, 15 935 women were recruited. There were no statistically significant differences within any of the intervention pairs for the primary outcome: blunt versus sharp entry risk ratio 1·03 (95% CI 0·91-1·17), exterior versus intra-abdominal repair 0·96 (0·84-1·08), single-layer versus double-layer closure 0·96 (0·85-1·08), closure versus non-closure 1·06 (0·94-1·20), and chromic catgut versus polyglactin-910 0·90 (0·78-1·04). 144 serious adverse events were reported, of which 26 were possibly related to the intervention. Most of the reported serious adverse events were known complications of surgery or complications of the reasons for the caesarean section. INTERPRETATION: These findings suggest that any of these surgical techniques is acceptable. However, longer-term follow-up is needed to assess whether the absence of evidence of short-term effects will translate into an absence of long-term effects. FUNDING: UK Medical Research Council and WHO.

Transformative and therapeutic benefits of digital storytelling: a phenomenological lifeworlds study of Patient Voices participant experiences.

BACKGROUND: References to transformative and therapeutic benefits of digital storytelling are often made, yet this remains an under-explored area, which we foreground in this study. METHODS: A phenomenological research design was adopted to explore through interview how a purposive sample of Patient Voices storytellers experienced participation in more than one digital storytelling workshop. Analysis was through thematic coding, linguistic analysis and use of van Manen's lifeworld existentials framework. RESULTS: We find that for this particular group, the therapeutic and transformative experiences that re-centre and re-frame personal meaning do so through inter-personal connections and can be understood as a process of social learning. The lifeworld existentials analysis demonstrates that a pluralist and relational conception of wellbeing holds and there is a close relationship between this and Yalom's 11 therapeutic factors. CONCLUSIONS: Drawing on group analytic literature, we suggest the concept of a social learning methodology as useful in grounding further research that seeks to understand the beneficial impacts of digital storytelling methodologies in healthcare and in contributing evidence in this field with fidelity to the lived experience as central.

In silico fragment-based discovery of CIB1-directed anti-tumor agents by FRASE-bot.

Chemical probes are an indispensable tool for translating biological discoveries into new therapies, though are increasingly difficult to identify since novel therapeutic targets are often hard-to-drug proteins. We introduce FRASE-based hit-finding robot (FRASE-bot), to expedite drug discovery for unconventional therapeutic targets. FRASE-bot mines available 3D structures of ligand-protein complexes to create a database of FRAgments in Structural Environments (FRASE). The FRASE database can be screened to identify structural environments similar to those in the target protein and seed the target structure with relevant ligand fragments. A neural network model is used to retain fragments with the highest likelihood of being native binders. The seeded fragments then inform ultra-large-scale virtual screening of commercially available compounds. We apply FRASE-bot to identify ligands for Calcium and Integrin Binding protein 1 (CIB1), a promising drug target implicated in triple negative breast cancer. FRASE-based virtual screening identifies a small-molecule CIB1 ligand (with binding confirmed in a TR-FRET assay) showing specific cell-killing activity in CIB1-dependent cancer cells, but not in CIB1-depletion-insensitive cells.