Meningoradiculitis due to varicella zoster virus reactivation in a patient treated with ixekizumab.

INTRODUCTION: Ixekizumab is a recently developed biopharmaceutical used since 2016 in the US and Europe for the treatment of plaque psoriasis. Few adverse effects have been reported in the literature and ixekizumab is not known to increase the risk of viral reactivation. Herein we report the case of an immunocompetent female patient treated with ixekizumab who presented meningoradiculitis due to varicella zoster virus (VZV) reactivation. PATIENTS AND METHODS: A 51-year-old woman, treated with ixekizumab for psoriasis, consulted in March 2018 for left hemicrania headache associated with left facial paralysis, but without fever. Brain MRI scans revealed cerebral venous thrombosis of the superior sagittal sinus. Analysis of cerebrospinal fluid (CSF) revealed lymphocytic meningitis and positive VZV-PCR. PCR blood assay for VZV was negative. Blood concentrations of anti-VZV IgG antibody increased while Anti-VZV IgM antibodies remained negative. The final diagnosis was VZV meningoradiculitis complicated by cerebral thrombophlebitis. The absence of skin rash, the rapid increase in anti-VZV IgG antibodies, the absence of anti-VZV IgM antibodies, and the negative blood PCR assay suggested viral reactivation rather than primary infection. The patient received acyclovir and coumadin and her condition improved rapidly. After multidisciplinary discussion, ixekizumab was reintroduced together with valacyclovir prophylaxis. CONCLUSION: This case raises the question of the risk of viral reactivation during treatment with an IL-17 inhibitor and with biologics in general. Neurological and vascular complications of VZV may occur without skin lesions and their occurrence during ixekizumab therapy must be investigated by PCR testing of CSF for VZV DNA.

Cancer-related cognitive impairment: an update on state of the art, detection, and management strategies in cancer survivors.

BACKGROUND: Advances in diagnostic and therapeutic strategies in oncology have significantly increased the chance of survival of cancer patients, even those with metastatic disease. However, cancer-related cognitive impairment (CRCI) is frequently reported in patients treated for non-central nervous system cancers, particularly during and after chemotherapy. DESIGN: This review provides an update of the state of the art based on PubMed searches between 2012 and March 2019 on 'cognition', 'cancer', 'antineoplastic agents' or 'chemotherapy'. It includes the most recent clinical, imaging and pre-clinical data and reports management strategies of CRCI. RESULTS: Evidence obtained primarily from studies on breast cancer patients highlight memory, processing speed, attention and executive functions as the most cognitive domains impaired post-chemotherapy. Recent investigations established that other cancer treatments, such as hormone therapies and targeted therapies, can also induce cognitive deficits. Knowledge regarding predisposing factors, biological markers or brain functions associated with CRCI has improved. Factors such as age and genetic polymorphisms of apolipoprotein E, catechol-O-methyltransferase and BDNF may predispose individuals to a higher risk of cognitive impairment. Poor performance on neuropsychological tests were associated with volume reduction in grey matter, less connectivity and activation after chemotherapy. In animals, hippocampus-based memory and executive functions, mediated by the frontal lobes, were shown to be particularly susceptible to the effects of chemotherapy. It involves altered neurogenesis, mitochondrial dysfunction or brain cytokine response. An important next step is to identify strategies for managing cognitive difficulties, with primary studies to assess cognitive training and physical exercise regimens. CONCLUSIONS: CRCI is not limited to chemotherapy. A multidisciplinary approach has improved our knowledge of the complex mechanisms involved. Nowadays, studies evaluating cognitive rehabilitation programmes are encouraged to help patients cope with cognitive difficulties and improve quality of life during and after cancer.

Influence of Cu adatoms on the molecular assembly of 4,4'-bipyridine on Cu(111).

The formation of highly organized structures based on two ligands with pyridyl functionalities, 4,4'-bipyridine (BPY) and 1,4-di(4,4''-pyridyl) benzene (BPYB), and Cu adatoms on the Cu(111) surface has been studied with low temperature and variable temperature scanning tunneling microscopy (STM) and first-principles calculations. We show that the formation of a highly organized adlayer built from adatom-molecule and molecule-molecule units strongly depends on the number of mobile Cu atoms on the surface. While a high concentration of Cu adatoms (high adatom/BPY ratio, ≥1) leads systematically to the formation of organometallic nanolines, their absence (low adatom/BPY ratio, ≈0) gives a compact self-assembled molecular network, and more specifically hydrogen-bond networks (HBN) with BPY molecules organized in a T-shaped fashion. Alternatively, an intermediate concentration of Cu adatoms (0 < adatom/BPY < 1) allows the formation of a well-organized and compact structure where both organometallic and HBN components coexist. Although STM images cannot clearly reveal the presence of Cu adatoms within the organometallic moiety, the bonding of BPY to a single or two Cu adatoms can be clearly identified by scanning tunneling spectroscopy (STS), and is supported by Density Functional Theory (DFT) results. Additional STM simulations suggest that the relative position of the Cu adatom with respect to the organic ligands just above has a significant impact on its detection by STM. This study exemplifies the prominent role of metallic adatoms on the formation of a complex organometallic network and should open more rational practices to optimize the formation of these supramolecular networks.

Nurses' perspectives on whether medical aid in dying should be accessible to incompetent patients with dementia: findings from a survey conducted in Quebec, Canada.

We conducted a survey in a random sample of 514 Quebec nurses caring for the elderly to assess their attitudes towards extending medical aid in dying to incompetent patients and to explore associated factors. Attitudes were measured using clinical vignettes featuring a hypothetical patient with Alzheimer disease. Vignettes varied according to the stage of the disease (advanced or terminal) and the presence or absence of a written request. Of the 291 respondents, 83.5% agreed with the current legislation that allows physicians to administer aid in dying to competent patients who are at the end of life and suffer unbearably. A similar proportion (83%, p = 0.871) were in favor of extending medical aid in dying to incompetent patients who are at the terminal stage of Alzheimer disease, show signs of distress, and have made a written request before losing capacity.

Self-fertilization, long-distance flash invasion and biogeography shape the population structure of Pseudosuccinea columella at the worldwide scale.

Population genetic studies are efficient for inferring the invasion history based on a comparison of native and invasive populations, especially when conducted at species scale. An expected outcome in invasive populations is variability loss, and this is especially true in self-fertilizing species. We here focus on the self-fertilizing Pseudosuccinea columella, an invasive hermaphroditic freshwater snail that has greatly expanded its geographic distribution and that acts as intermediate host of Fasciola hepatica, the causative agent of human and veterinary fasciolosis. We evaluated the distribution of genetic diversity at the largest geographic scale analysed to date in this species by surveying 80 populations collected during 16 years from 14 countries, using eight nuclear microsatellites and two mitochondrial genes. As expected, populations from North America, the putative origin area, were strongly structured by selfing and history and harboured much more genetic variability than invasive populations. We found high selfing rates (when it was possible to infer it), none-to-low genetic variability and strong population structure in most invasive populations. Strikingly, we found a unique genotype/haplotype in populations from eight invaded regions sampled all over the world. Moreover, snail populations resistant to infection by the parasite are genetically distinct from susceptible populations. Our results are compatible with repeated introductions in South America and flash worldwide invasion by this unique genotype/haplotype. Our study illustrates the population genetic consequences of biological invasion in a highly selfing species at very large geographic scale. We discuss how such a large-scale flash invasion may affect the spread of fasciolosis.

Superior laryngeal nerve in thyroid surgery: anatomical identification and monitoring.

The aim of this study was to validate a procedure to identify and preserve the external branch of the superior laryngeal nerve (EBSLN) during thyroid surgery. The present study also aimed to analyze the EBSLN and the vagus nerve activities after stimulation and demonstrate an operative association between all the laryngeal muscles. Dissection of the cervical region was performed bilaterally in four adult cadavers. In a second step, 144 patients undergoing total thyroidectomy were included. Intraoperative stimulations of the cervical vagus nerve and the EBSLN in the sternothyroid-laryngeal triangle were performed bilaterally. Potentials in the thyroarytenoid muscle and the cricothyroid muscle were registered on each side using the NIM3 Medtronic System. EBSLN was identified according to Cernea's classification as type 1 in 62.5%, type 2a in 25%, and type 2b in 12.5% of cadaver's dissection. According to Friedman's classification, 50% of EBSLN were classified type 1, 25% type 2 and 25% type 3. The EBSLN was identified in 267 cases out of 288 peroperative dissections (92.7%). Direct stimulation (1 mA) of this branch led to a recordable contraction of the cricothyroid muscle with a mean latency of 1.42 ± 0.66 ms on the right side and 1.43 ± 0.61 ms on the left side. The stimulation of the EBSLN also led to a recordable contraction of the thyroarytenoid muscle in 211 cases (73.3%) with the same latencies. A contraction of the cricothyroid muscle was also recorded when the vagus nerve was stimulated in 219 cases (76.0%). The sole visual identification of the EBSLN during thyroid surgery is not a reliable method to prevent nerve injury. Direct stimulation of the EBSLN in the sternothyroid-laryngeal triangle is a simple and rapid procedure to detect and preserve the nerve during surgery. Functional associations between vagus nerve and EBSLN in laryngeal muscles' contractions were also identified.

How the truffle got its mate: insights from genetic structure in spontaneous and planted Mediterranean populations of Tuber melanosporum.

The life cycles and dispersal of edible fungi are still poorly known, thus limiting our understanding of their evolution and domestication. The prized Tuber melanosporum produces fruitbodies (fleshy organs where meiospores mature) gathered in natural, spontaneously inoculated forests or harvested in plantations of nursery-inoculated trees. Yet, how fruitbodies are formed remains unclear, thus limiting yields, and how current domestication attempts affect population genetic structure is overlooked. Fruitbodies result from mating between two haploid individuals: the maternal parent forms the flesh and the meiospores, while the paternal parent only contributes to the meiospores. We analyzed the genetic diversity of T. melanosporum comparatively in spontaneous forests vs. plantations, using SSR polymorphism of 950 samples from South-East France. All populations displayed strong genetic isolation by distance at the metric scale, possibly due to animal dispersal, meiospore persistence in soil, and/or exclusion of unrelated individuals by vegetative incompatibility. High inbreeding was consistently found, suggesting that parents often develop from meiospores produced by the same fruitbody. Unlike maternal genotypes, paternal mycelia contributed to few fruitbodies each, did not persist over years, and were undetectable on tree mycorrhizae. Thus, we postulate that germlings from the soil spore bank act as paternal partners. Paternal genetic diversity and outbreeding were higher in plantations than in spontaneous truffle-grounds, perhaps because truffle growers disperse fruitbodies to maintain inoculation in plantations. However, planted and spontaneous populations were not genetically isolated, so that T. melanosporum illustrates an early step of domestication where genetic structure remains little affected.

How do cumulative live birth rates and cumulative multiple live birth rates over complete courses of assisted reproductive technology treatment per woman compare among registries?

STUDY QUESTION: How do the national cumulative (multiple) live birth rates over complete assisted reproduction technology (ART) courses of treatment per woman in Belgium compare to those in other registries? SUMMARY ANSWER: Cumulative live birth rates (CLBRs) remain high with a low cumulative multiple live birth rate when compared with other registries and publications. WHAT IS KNOWN ALREADY: In ART, a reduction in the multiple live birth rate could be achieved by reducing the number of embryos transferred. It has been shown that by doing so, live birth rates per cycle were maintained, particularly when the augmentation effect of attached frozen-thawed cycles was considered. STUDY DESIGN, SIZE, DURATION: A retrospective cohort study included all patients with a Belgian national insurance number who were registered in the national ART registry (Belrap) and who started a first fresh ART cycle between 1 July 2009 until 31 December 2011 with follow up until 31 December 2012. We analysed 12 869 patients and 38 008 cycles (both fresh and attached frozen cycles). PARTICIPANTS, MATERIALS, SETTINGS, METHODS: CLBRs per patient who started a first ART cycle including fresh and consecutive frozen cycles leading to a live birth. Conservative estimates of cumulative live birth assumed that patients who did not return for treatment had no chance of achieving an ART-related live birth, whereas optimal estimates assumed that women discontinuing treatment would have the same chance of achieving a live birth as those continuing treatment. A maximum of six fresh ART cycles with corresponding frozen cycles was investigated and compared with other registries and publications. MAIN RESULTS AND ROLE OF CHANCE: The CLBR was age dependent and declined from 62.9% for women <35 years, to 51.4% for women 35-37 years, to 34.1% for women 38-40 years and 17.7% for women 41-42 years in the conservative analysis after six cycles. In the optimal estimate, the CLBR declined from 85.9% for women <35 years, to 72.0% for women 35-37 years, to 50.4% for women 38-40 years and 36.4% for women 41-42 years. The cumulative multiple live birth rates for the whole population were 5.1 and 8.6% for the conservative and optimal estimate, respectively. LIMITATIONS, REASONS FOR CAUTION: Conservative and optimal estimates use assumptions for the whole ART population and do not take the individual patient into account. WIDER IMPLICATIONS OF THE FINDINGS: These data reinforce the validity of the Belgian model of coupling reimbursement of ART costs to a restriction in the number of embryos transferred. Our data can improve decision-making in medical ART practice both on the patient level and for society at large and could provide health care takers and insurance companies with a valid model. STUDY FUNDING COMPETING INTERESTS: none.

Time-driven superoscillations with negative refraction.

The flat-lens concept based on negative refraction proposed by Veselago in 1968 has been mostly investigated in the monochromatic regime. It was recently recognized that time development of the superlensing effect discovered in 2000 by Pendry is yet to be assessed and may spring surprises: Time-dependent illumination could improve the spatial resolution of the focusing. We investigate dynamics of flexural wave focusing by a 45°-tilted square lattice of circular holes drilled in a duralumin plate. Time-resolved experiments reveal that the focused image shrinks with time below the diffraction limit, with a lateral resolution increasing from 0.8λ to 0.35λ, whereas focusing under harmonic excitation remains diffraction limited. Modal analysis reveals the role in pulse reconstruction of radiating lens resonances, which repeatedly self-synchronize at the focal spot to shape a superoscillating field.

Surgical anatomy of the ansa cervicalis nerve: which branch to use for laryngeal reinnervation in humans?

PURPOSE: The aim of this study has been to obtain some data for the selection of which branch of the ansa cervicalis nerve (AC) could be an attractive candidate for a laryngeal reinnervation using AC to recurrent laryngeal nerve (RLN) neurorrhaphy. METHODS: The AC was dissected in ten human head cadavers with an operating microscope. A vagal nerve stimulation was conducted during a bilateral thyroidectomy with normal vocal fold mobility in ten patients using a NIM Medtronic System(®) to record phasic activity within the thyroarytenoid muscle (vocal fold adduction) and one of the infrahyoid muscle (sternothyroid muscle or sternohyoid muscle). RESULTS: Despite reported variations of the roots of AC and location of its loop, the lower portion of the STM and SHM was innervated by a prominent common trunk in 80 % of cases, in a close vicinity of the RLN with an excellent size match to the RLN for a tension-free anastomosis. The STM displays slight but significant electrical activity during vocal fold adduction. CONCLUSION: The common trunk of the SHM and STM is the prime choice for laryngeal reinnervation using AC-RLN non-selective anastomosis. If the main trunk is missing, the branch to the STM can be an attractive candidate.

Descemet's membrane endothelial keratoplasty rejection after SARS-COV2 infection or vaccination: 2-year retrospective study.

PURPOSE: To assess the incidence of Descemet's membrane endothelial keratoplasty (DMEK) rejection potentially associated with coronavirus disease 2019 (COVID-19) infection or vaccination, and its association with known rejection risk factors during the first two years of the pandemic. METHODS: This retrospective study included patients with DMEK rejection between January 2020 and December 2021. Diagnostic criteria were based on symptoms, visual acuity, and other clinical assessments. Risk factors for graft rejection were considered, and a telephone survey was conducted to identify possible preceding COVID-19 infection or vaccination. RESULTS: Of 58 patients, 44 were included. Six patients (14%) reported COVID-19 infection, with one immediate endothelial graft rejection (EGR) post-infection. After vaccine availability, 13 of 36 patients had EGR at an average of 2.7 months post-vaccination. Five (38%) had immediate EGR following vaccination, four of which had concomitant risk factors for rejection. CONCLUSION: Although the risk of endothelial graft rejection (EGR) associated with COVID-19 infection or vaccination appears to be extremely low, there may be a causative relationship, especially in patients with pre-existing risk factors for EGR. A temporary increase in anti-rejection treatment following COVID-19 infection or vaccination is recommended, especially in patients with pre-existing risk factors, along with closer monitoring during the subsequent 4 to 8 weeks.

Two pathways for electrocatalytic oxidation of hydrogen by a nickel bis(diphosphine) complex with pendant amines in the second coordination sphere.

A nickel bis(diphosphine) complex containing pendant amines in the second coordination sphere, [Ni(P(Cy)2N(t-Bu)2)2](BF4)2 (P(Cy)2N(t-Bu)2 = 1,5-di(tert-butyl)-3,7-dicyclohexyl-1,5-diaza-3,7-diphosphacyclooctane), is an electrocatalyst for hydrogen oxidation. The addition of hydrogen to the Ni(II) complex gives three isomers of the doubly protonated Ni(0) complex [Ni(P(Cy)2N(t-Bu)2H)2](BF4)2. Using the pKa values and Ni(II/I) and Ni(I/0) redox potentials in a thermochemical cycle, the free energy of hydrogen addition to [Ni(P(Cy)2N(t-Bu)2)2](2+) was determined to be -7.9 kcal mol(-1). The catalytic rate observed in dry acetonitrile for the oxidation of H2 depends on base size, with larger bases (NEt3, t-BuNH2) resulting in much slower catalysis than n-BuNH2. The addition of water accelerates the rate of catalysis by facilitating deprotonation of the hydrogen addition product before oxidation, especially for the larger bases NEt3 and t-BuNH2. This catalytic pathway, where deprotonation occurs prior to oxidation, leads to an overpotential that is 0.38 V lower compared to the pathway where oxidation precedes proton movement. Under the optimal conditions of 1.0 atm H2 using n-BuNH2 as a base and with added water, a turnover frequency of 58 s(-1) is observed at 23 °C.

Impact of follicular G-CSF quantification on subsequent embryo transfer decisions: a proof of concept study.

BACKGROUND: Previous experiments have shown that granulocyte colony-stimulating factor (G-CSF), quantified in the follicular fluid (FF) of individual oocytes, correlates with the potential for an ongoing pregnancy of the corresponding fertilized oocytes among selected transferred embryos. Here we present a proof of concept study aimed at evaluating the impact of including FF G-CSF quantification in the embryo transfer decisions. METHODS: FF G-CSF was quantified with the Luminex XMap technology in 523 individual FF samples corresponding to 116 fresh transferred embryos, 275 frozen embryos and 131 destroyed embryos from 78 patients undergoing ICSI. RESULTS: Follicular G-CSF was highly predictive of subsequent implantation. The receiving operator characteristics curve methodology showed its higher discriminatory power to predict ongoing pregnancy in multivariate logistic regression analysis for FF G-CSF compared with embryo morphology [0.77 (0.69-0.83), P < 0.001 versus 0.66 (0.58-0.73), P = 0.01)]. Embryos were classified by their FF G-CSF concentration: Class I over 30 pg/ml (a highest positive predictive value for implantation), Class II from 30 to 18.4 pg/ml and Class III <18.4 pg/ml (a highest negative predictive value). Embryos derived from Class I follicles had a significantly higher implantation rate (IR) than those from Class II and III follicles (36 versus 16.6 and 6%, P < 0.001). Embryos derived from Class I follicles with an optimal morphology reached an IR of 54%. Frozen-thawed embryos transfer derived from Class I follicles had an IR of 37% significantly higher than those from Class II and III follicles, respectively, of 8 and 5% (P < 0.001). Thirty-five per cent of the frozen embryos but also 10% of the destroyed embryos were derived from G-CSF Class I follicles. Non-optimal embryos appear to have been transferred in 28% (22/78) of the women, and their pregnancy rate was significantly lower than that of women who received at least one optimal embryo (18 versus 36%, P = 0.04). CONCLUSIONS: Monitoring FF G-CSF for the selection of embryos with a better potential for pregnancy might improve the effectiveness of IVF by reducing the time and cost required for obtaining a pregnancy.

The history of Belgian assisted reproduction technology cycle registration and control: a case study in reducing the incidence of multiple pregnancy.

STUDY QUESTION: What is the effect of a legal limitation of the number of embryos that can be transferred in an assisted reproductive technology (ART) cycle on the multiple delivery rate? SUMMARY ANSWER: The Belgian national register shows that the introduction of reimbursement of ART laboratory costs in July 2003, and the imposition of a legal limitation of the number of embryos transferred in the same year, were associated with a >50% reduction of the multiple pregnancy rate from 27 to 11% between 2003 and the last assessment in 2010, without any reduction of the pregnancy rate per cycle. WHAT IS KNOWN ALREADY: Individual Belgian IVF centres have published their results since the implementation of the law, and these show a decrease in the multiple pregnancy rate on a centre by centre basis. However, the overall national picture remains unpublished. STUDY DESIGN, SIZE, DURATION: Cohort study from 1990 to 2010 of all ART cycles in Belgium (2685 cycles in 1990 evolving to 19 110 cycles in 2010), with a retrospective analysis from 1990 to 2000 and prospective online data collection since 2001. PARTICIPANTS/MATERIALS, SETTING, METHODS: Registration evolved from paper written reports per centre to a compulsory online registration of all ART cycles. From 2001 up to mid-2009, data were collected from Excel spread sheets or MS Access files into an MS Access database. Since mid-2009, data collection is done via a remote and secured web-based system (www.belrap.be) where centres can upload their data and get immediate feedback about missing data, errors and inconsistencies. MAIN RESULTS AND THE ROLE OF CHANCE: National Belgian registration data show that reimbursement of IVF laboratory costs in July 2003, coupled to a legal limitation in the number of embryos transferred in utero, were associated with a 50% reduction of the multiple pregnancy rate from 27 to 11% without reduction of the pregnancy rate per cycle, and with an increase in the number of fresh and frozen ART cycles due to improved access to treatment. LIMITATIONS, REASONS FOR CAUTION: There is potential underreporting of complications of ART treatment, pregnancy outcome and neonatal health. WIDER IMPLICATIONS OF THE FINDINGS: Over the 20 years of registration, the pregnancy rate has remained constant, despite the reduction in the number of embryos transferred, optimization of laboratory procedures and stimulation protocols, introduction of quality systems and implementation of the EU Tissue Directive over the period 2004-2010. STUDY FUNDING/COMPETING INTEREST(S): No external funding was sought for this study. None of the authors has any conflict of interest to declare.

[Short history of mixed states]. / Une approche historique des états mixtes.

The notion of mixed states is classically associated with descriptions and categories inherited from Kraepelin. However, simultaneous descriptions of depressive and manic manifestations can be traced back to ancient times. Semiology and definitions of these clinical associations have evolved across the times. We provide here a short insight on four distinct periods: Greek authors from ancient times, pre-Kraepelinian psychiatry (18th and 19th centuries), Kraepelin's conceptualization, and contemporary psychiatry (20th and 21st centuries).

[Clinical description of mixed mania]. / Clinique des manies mixtes.

DSM-IV mixed states have become the mixed mania and mixed depression in the new DSM-5. One noticeable point is the introduction of nine cations, among which the "with mixed features" specification. These non exclusive specifications may contribute to a more precise identification of mixed clinical pictures, and therefore to offer a more efficient therapeutic answer. Different dimensional approaches are widely documented. They allow the isolation of a mixed factor which is clinically associated with two other specifications: anxious distress and psychotic features. These severity markers may encourage clinicians to be alert about the risk of misdiagnosis, and cautious in the management of these clinical situations.

[Neurocognitive fuctioning in pure mania and mixed mania]. / Fonctionnement neurocognitif dans la manie pure et la manie mixte.

Neurocognitive dysfunction is increasingly recognized as a prominent feature of bipolar disorder. Cognitive function seems to be impaired across different states of bipolar illness. Nervertheless, research that studies neuropsychological functioning in acute phases is scarce. Acutely ill patients have shown dysfunctions in several cognitive areas. We reviewed the literature on neuropsychological studies of acute phases to highlight neurocognitive deficits in mixed and pure mania. The results show dysfunctions in sustained attention that are significantly more important in mixed mania rather than in pure mania. Impulsive pattern of responding seems to characterize pure manic state. We also found impairments in processing speed, verbal and spatial learning/memory and executive functions, including cognitive flexibility, inhibitory control, conceptual reasoning, planning and problem solving. Disturbance in executive functioning seems to be more important in pure mania rather than mixed mania.

[Antimanic treatments in bipolar mixed states]. / Traitements anti- maniaques dans les états mixtes.

INTRODUCTION: Mixed states present nosologic and diagnostic challenges with a relative paucity of evidence to guide treatment. Mixed bipolar states are difficult to treat and are associated with a high neuropsychiatric morbidity, a high risk of suicide and a poor outcome. In DSM- 5, the definition of mixed episode has been removed (in DSM- IV TR: "juxtaposed full manic and depressive episodes"). Mixed symptoms are captured under a broader concept called "mixed features" that is applied to mania and depression. The classification of mixed states as defined in DSM- 5 is less restrictive than in DSM- IV TR and challenges us at methodological and therapeutic levels. OBJECTIVE: The aim of this paper was to conduct an overview of the literature to ascertain the efficacy of pharmacotherapy of mixed states. METHOD: A systematic review of the literature was conducted using PubMed. RESULTS: Manic symptoms of mixed episodes seem to show a good response to second generation antipsychotics and to divalproate. There is no evidence of differential efficacy for second generation of antipsychotics (SGAs). Lithium and carbamazepine may be effective in mixed states in monotherapy and perhaps benefit in combination with SGAs as second line. Combination pharmacological treatment of SGAs and moodstabilizers are common in mixed states. This pattern has the best literature evidence. CONCLUSIONS: There is a few evidence to help us to choose the right treatment for patients with mixed state. In light with the DSM 5, more drugs specifically designed to treat mixed state are needed.

[Treatment of depressive mixed states]. / Le traitement des dépressions mixtes.

Mixed states are a frequent mood state characterized by the mixture of manic and depressive symptoms. Their clinical description has been studied for centuries but has known a renewal of interest recently. Several authors intend to redefine its diagnostic criteria to develop an appropriate therapeutic strategy. Current recommendations suggest to treat mixed depression as a mixed state whatever the dominant polarity is, and therefore according to the rules of therapeutic management of the manic state. Mood stabilizers and antipsychotic medications are indicated and have proven their effectiveness. Lithium, which was considered controversial, now appears to have some therapeutic value, especially in the prevention of suicidal behavior. The depressive component of mixed states, even pronounced, should not be an argument for a prescription of antidepressants, at the risk of aggravating clinical components such as irritability and impulsivity and increasing the danger of suicide attempt. Furthermore, electroconvulsivetherapy represents a real alternative ; psychotherapies have their place in relapse prevention and psychoeducation, but not during acute phases. Finally, an accurate assessment and appropriate management of suicide risk should be a constant concern for the clinicians.