The experience of diagnosis announcement in rare endocrine diseases: A survey of the French FIRENDO network.

CONTEXT: Diagnosis announcement of a chronic disease is a crucial moment for patients as well as for their families and an important step in the management of severe conditions such as rare endocrine diseases. Little is known of how diagnosis is communicated to patients and families. The FIRENDO network was created by the third French Plan for Rare Diseases, to promote autonomy, care and research on rare endocrine diseases. OBJECTIVES: The aim of this study was to characterize, for the first time, the experience and needs of patients and/or their parents around the announcement of diagnosis to ensure optimal quality of care. METHODS: A quantitative self-administered survey on diagnosis announcement procedures in rare endocrine diseases was launched in April 2017 by the ad hoc FIRENDO thematic working group in collaboration with its 11 partnering patient associations and support groups. The questionnaire was designed and revised by patient support group representatives, adult and pediatric endocrinologists, psychologists and biologists, all expert in rare endocrine diseases. It was made available on the FIRENDO network website and distributed mainly by email with electronic links on their respective websites to members of all affiliated patient support groups. RESULTS: Questionnaires were filled out by 391 patients and 223 parents (median age of patients: 39 years). The following conditions were associated with at least 30 answers: Addison's disease, classical forms of congenital adrenal hyperplasia (CAH), Russell-Silver syndrome, Cushing's syndrome, acromegaly and craniopharyngioma. Overall, some announcement modalities were judged favorably by patients: physician's empathy, availability and use of clear terms, and presence of family at the time of announcement. However, a lack of psychological care and information documents was reported, as well as some inadequate procedures such as postal mail announcements. CONCLUSION: This work suggests that better knowledge of the patient's experience is useful for improving the diagnosis announcement of rare endocrine disorders. The main recommendations derived from the survey were the need for several announcement visits, information on patient support groups and reference centers, imperatively avoiding impersonal announcement, and the usefulness of a written accompanying document.

Post-traumatic stress among COVID-19 survivors: A descriptive study of hospitalized first-wave survivors.

Introduction: The coronavirus Severe Acute Respiratory Syndrome Coronavirus Type 1 induces a severe respiratory disease, coronavirus disease 2019 (COVID-19). After Severe Acute Respiratory Syndrome Coronavirus Type 1 and Middle East Respiratory Syndrome infection, increased post-traumatic stress disorder (PTSD) rates were described. Methods: This single-centred, prospective study aimed to evaluate the rates of PTSD in patients who were hospitalized for COVID-19. Inclusion criteria were COVID-19 patients hospitalized in the intensive care unit (ICU) or in a standard unit with at least 2 L/min oxygen. Six months post-hospitalization, subjects were assessed for PTSD using a validated screening tool, the Post-Traumatic Stress Checklist-5 (PCL-5). Results: A total of 40 patients were included. No demographic differences between the ICU and non-ICU groups were found. The mean PCL-5 score for the population was 8.85±10. The mean PCL-5 score was 6.7±8 in the ICU group and 10.5±11 in the non-ICU group (P=0.27). We screened one patient with a positive PCL-5 score and one with a possible PCL-5 cluster score. Nine patients had a PCL-5 score of up to 15. Seven patients reported no symptoms. Seven patients accepted a psychological follow-up: one for PTSD, three for possible PTSD and three for other psychological problems. Discussion: The PCL-5 tool can be used by lung physicians during consultations to identify patients for whom follow-up mental health assessment and treatment for PTSD are warranted. Conclusion: Lung physicians should be aware of the risk of PTSD in patients hospitalized for COVID-19 and ensure appropriate screening and follow-up care.

Clinicopathologic Features and Response to Therapy of NRG1 Fusion-Driven Lung Cancers: The eNRGy1 Global Multicenter Registry.

PURPOSE: Although NRG1 fusions are oncogenic drivers across multiple tumor types including lung cancers, these are difficult to study because of their rarity. The global eNRGy1 registry was thus established to characterize NRG1 fusion-positive lung cancers in the largest and most diverse series to date. METHODS: From June 2018 to February 2020, a consortium of 22 centers from nine countries in Europe, Asia, and the United States contributed data from patients with pathologically confirmed NRG1 fusion-positive lung cancers. Profiling included DNA-based and/or RNA-based next-generation sequencing and fluorescence in situ hybridization. Anonymized clinical, pathologic, molecular, and response (RECIST v1.1) data were centrally curated and analyzed. RESULTS: Although the typified never smoking (57%), mucinous adenocarcinoma (57%), and nonmetastatic (71%) phenotype predominated in 110 patients with NRG1 fusion-positive lung cancer, further diversity, including in smoking history (43%) and histology (43% nonmucinous and 6% nonadenocarcinoma), was elucidated. RNA-based testing identified most fusions (74%). Molecularly, six (of 18) novel 5' partners, 20 unique epidermal growth factor domain-inclusive chimeric events, and heterogeneous 5'/3' breakpoints were found. Platinum-doublet and taxane-based (post-platinum-doublet) chemotherapy achieved low objective response rates (ORRs 13% and 14%, respectively) and modest progression-free survival medians (PFS 5.8 and 4.0 months, respectively). Consistent with a low programmed death ligand-1 expressing (28%) and low tumor mutational burden (median: 0.9 mutations/megabase) immunophenotype, the activity of chemoimmunotherapy and single-agent immunotherapy was poor (ORR 0%/PFS 3.3 months and ORR 20%/PFS 3.6 months, respectively). Afatinib achieved an ORR of 25%, not contingent on fusion type, and a 2.8-month median PFS. CONCLUSION: NRG1 fusion-positive lung cancers were molecularly, pathologically, and clinically more heterogeneous than previously recognized. The activity of cytotoxic, immune, and targeted therapies was disappointing. Further research examining NRG1-rearranged tumor biology is needed to develop new therapeutic strategies.

Compliance to regional recommendations for molecular analyses and management of advanced lung cancer patients.

Aim: We performed a clinical audit of the management of patients with EGFR mutations, 1 year after the introduction of EGFR tyrosine kinase inhibitor (EGFR-TKI) in first-line treatment. Methods: Compliance was defined by tumor molecular profiling for stage IIIB and IV non-small-cell lung cancer and first-line treatment as recommended by the French guidelines. Results: Among the 169 EGFR-mutated patients, compliance was 76.4%. The most common noncompliance criterion was chemotherapy given in first-line treatment instead of EGFR-TKI. No dedicated multidisciplinary meeting and type of institutions were independent unfavorable predictors for compliance. Compliance to guidelines was significantly correlated with time-to-first subsequent treatment improvement (2.5 vs 9.1 months; p < 0.0001). Conclusion: Implementation of new standards of care is challenging. Our results reinforce the role of multidisciplinary meetings to provide a better access to innovating therapeutics.

Longitudinal MRI monitoring of brain damage in the neonatal ventral hippocampal lesion rat model of schizophrenia.

Rat with excitotoxic neonatal ventral hippocampal lesions (NVHL rats) is considered as a heuristic neurodevelopmental model for studying schizophrenia. Extensive study of this model is limited by the lack of clear validity criteria of such lesions and because ascertaining of the lesions is realized postmortem with histological examination after completing experiments. Here, in a first experiment, by assessing the locomotor response to amphetamine in adult NVHL rats, we further specify that the lesions must be bilateral and confined to the ventral hippocampus to obtain the validated behavioral phenotype. We then show a longitudinal magnetic resonance imaging (MRI) protocol suitable for the detection of brain structural changes in NVHL rats. The T(2)-weighted images acquired in adult NVHL rats reveal the same structural changes as those appraised with histological protocol. Moreover, we demonstrate that the lesion status in adulthood can be accurately predicted from the T(2)-weighted images acquired in the juvenile period. As technical advantages, our MRI protocol makes possible to select animals according to lesion criteria as soon as in the juvenile period before long-lasting experiments and gives access in vivo to a quantitative parameter indicative of the lesion extent. Finally, we show that the lesion size increases only slightly between juvenile and adult periods. These latter results are discussed in the context of the specific postpubertal emergence of the behavioral deficits in NVHL rats.

Post-pubertal emergence of alterations in locomotor activity in stop null mice.

Overt schizophrenia is preceded by a prodromal phase during which juvenile patients display attenuated schizophrenia-related symptoms. Here, we have looked for evidence of a prodromal phase in juvenile STOP null mice, which, during adulthood, imitate features of schizophrenia. We have principally examined locomotor activity, which is abnormal in adult STOP null mice, and its apparent relationship with perturbed glutamatergic and dopaminergic transmission. When compared to corresponding wild-type mice, juvenile STOP null mice did not exhibit the basal hyperlocomotion or locomotor hypersensitivity to mild stress observed in adult mice. Juvenile STOP null mice also lacked disturbed locomotor sensitivity to MK-801, which was evident in adult mice. In contrast, juvenile STOP null mice exhibited a similar hypersensitivity to amphetamine as that found in adult mice. Thus, STOP null mice exhibited both a progression of locomotor activity defects over time and subtle alterations in the prepubertal period. We suggest that the pattern of locomotor disturbances observed in this study is related to altered dopaminergic reactivity in juvenile mice without major disturbance in glutamatergic transmission, whereas both neurotransmitter systems are impaired in adult mice.

Impaired verbal source monitoring in schizophrenia: an intermediate trait vulnerability marker?

Patients with schizophrenia, particularly those with positive symptoms show impaired verbal source monitoring. Specific cognitive deficits have been observed during both active and remission phases of the illness as well as in groups of unaffected first degree relatives of patients with schizophrenia. This type of schizophrenia vulnerability marker may precede the onset of frank psychotic symptoms and contribute to their developments. The aim of this study was first to determine if unaffected siblings were impaired in discriminate internal vs. external generated events when compared to their remitted schizophrenics relatives and healthy subjects. Performances of healthy subjects were then compared with results from previous studies with acute hallucinating patients, acute non-hallucinating patients and patients with resistant auditory verbal hallucinations. Compared with healthy subjects, unaffected siblings are impaired (effect size, ES=0.7), remitted or acute non-hallucinating patients are more impaired than siblings (ES=1.4); patients with verbal auditory hallucinations (acute or resistant) are even more impaired than non-hallucinating patients (ES=2.1). Our results suggest that a source monitoring deficit could be considered as an intermediate vulnerability marker of schizophrenia.

Microtubule stabilizer ameliorates synaptic function and behavior in a mouse model for schizophrenia.

BACKGROUND: Recent data suggest that cytoskeletal defects may play a role in schizophrenia. We previously imitated features of schizophrenia in an animal model by disrupting gene coding for a microtubule-associated protein called STOP. STOP-null mice display synaptic defects in glutamatergic neurons, hyper-dopaminergy, and severe behavioral disorders. Synaptic and behavioral deficits are amended by neuroleptic treatment in STOP-null mice, providing an attractive model to test new antipsychotic agents. We examined the effects of a taxol-related microtubule stabilizer, epothilone D. METHODS: Mice were treated either with vehicle alone or with epothilone D. Treatment effects on synaptic function were assessed using electron-microscopy quantification of synaptic vesicle pools and electrophysiology in the CA1 region of the hippocampus. Dopamine transmission was investigated using electrochemical assays. Behavior was principally assessed using tests of maternal skills. RESULTS: In STOP-null mice, treatment with epothilone D increased synaptic vesicle pools, ameliorated both short- and long-term forms of synaptic plasticity in glutamatergic neurons, and had a dramatic beneficial effect on mouse behavior. CONCLUSIONS: A microtubule stabilizer can have a beneficial effect on synaptic function and behavior, suggesting new possibilities for treatment of schizophrenia.

Experimental validation of coincidence summing corrections computed by the ETNA software.

The ETNA software has been developed to compute efficiency transfer and coincidence summing corrections. Different experiments are combined to test the validity of this last facility. Point sources with multi-gamma emitters are measured at several source-to-detector distances. Experimental correction factors are determined from the variation in the peaks' relative intensities versus the geometrical conditions. The ETNA code is used to compute the corrections due to coincidence summing for the same geometries. The calculated values are compared to the experimental ones.

Dopaminergic transmission in STOP null mice.

Neuroleptics are thought to exert their anti-psychotic effects by counteracting a hyper-dopaminergic transmission. Here, we have examined the dopaminergic status of STOP (stable tubule only polypeptide) null mice, which lack a microtubule-stabilizing protein and which display neuroleptic-sensitive behavioural disorders. Dopamine transmission was investigated using both behavioural analysis and measurements of dopamine efflux in different conditions. Compared to wild-type mice in basal conditions or following mild stress, STOP null mice showed a hyper-locomotor activity, which was erased by neuroleptic treatment, and an increased locomotor reactivity to amphetamine. Such a behavioural profile is indicative of an increased dopaminergic transmission. In STOP null mice, the basal dopamine concentrations, measured by quantitative microdialysis, were normal in both the nucleus accumbens and the striatum. When measured by electrochemical techniques, the dopamine efflux evoked by electrical stimulations mimicking physiological stimuli was dramatically increased in the nucleus accumbens of STOP null mice, apparently due to an increased dopamine release, whereas dopaminergic uptake and auto-inhibition mechanisms were normal. In contrast, dopamine effluxes were slightly diminished in the striatum. Together with previous results, the present study indicates the association in STOP null mice of hippocampal hypo-glutamatergy and of limbic hyper-dopaminergy. Such neurotransmission defects are thought to be central to mental diseases such as schizophrenia.

Specific involvement of neurotensin type 1 receptor in the neurotensin-mediated in vivo dopamine efflux using knock-out mice.

Abstract Neurotensin is a tridecapeptide neurotransmitter known to be involved in psychiatric disorders, various physiological processes and several different neurobiological mechanisms, including modulation of accumbal dopamine release. Two neurotensin extracellular binding sites, namely NT1- and NT2-receptor (NT1R and NT2R), have been cloned from the rat brain. These receptors are distinguishable by their different in vitro pharmacological properties but the available pharmacological tools have weak in vivo potency and specificity. The use of genetically engineered knock-out mice has provided a powerful alternative to the classical pharmacological approach to investigate their respective roles. In this study, using in vivo differential pulse amperometry, we show that, in wild-type mice, neurotensin application into the ventral tegmental area dose-dependently evokes dopamine efflux in the nucleus accumbens. This neurotensin-mediated efflux is dramatically decreased in mice lacking NT1R while it is unaffected in NT2R-deleted mice. This finding indicates that a large part of the dopamine efflux evoked by neurotensin in the nucleus accumbens of wild-type mice is mediated via NT1R present in the ventral tegmental area.

SSR181507, a dopamine D(2) receptor antagonist and 5-HT(1A) receptor agonist. I: Neurochemical and electrophysiological profile.

SSR181507 ((3-exo)-8-benzoyl-N-[[(2S)7-chloro-2,3-dihydro-1,4-benzodioxin-1-yl]methyl]-8-azabicyclo[3.2.1]octane-3-methanamine monohydrochloride) is a novel tropanemethanamine benzodioxane derivative that possesses high and selective affinities for D2-like and 5-HT(1A) receptors (K(I)=0.8, 0.2, and 0.2 nM for human D(2), D(3), and 5-HT(1A), respectively). In vivo, SSR181507 inhibited [(3)H]raclopride binding to D(2) receptors in the rat (ID(50)=0.9 and 1 mg/kg, i.p. in limbic system and striatum, respectively). It displayed D(2) antagonist and 5-HT(1A) agonist properties in the same concentration range in vitro (IC(50)=5.3 nM and EC(50)=2.3 nM, respectively, in the GTPgammaS model) and in the same dose range in vivo (ED(50)=1.6 and 0.7 mg/kg, i.p. on striatal DA and 5-HT synthesis, respectively, and 0.03-0.3 mg/kg, i.v. on dorsal raphe nucleus firing rate). It selectively enhanced Fos immunoreactivity in mesocorticolimbic areas as compared to the striatum. This regional selectivity was confirmed in electrophysiological studies where SSR181507, given acutely (0.1-3 mg/kg, i.p.) or chronically (3 mg/kg, i.p., o.d., 22 days), increased or decreased, respectively, the number of spontaneous active DA cells in the ventral tegmental area, but not in the substantia nigra. Moreover, SSR181507 increased both basal and phasic DA efflux (as assessed by microdialysis and electrochemistry) in the medial prefrontal cortex and nucleus accumbens, but not in the striatum. This study shows that the combination of D(2) receptor antagonism and 5-HT(1A) agonism, in the same dose range, confers on SSR181507 a unique neurochemical and electrophysiological profile and suggests the potential of this compound for the treatment of the main dimensions of schizophrenia.

The neurotensin receptor antagonist SR 142948A blocks the efflux of dopamine evoked in nucleus accumbens by neurotensin ejection into the ventral tegmental area.

The neuropeptide neurotensin (NT) exerts a wide range of central and peripheral effects. In particular, ejection of NT (10(-7) M, 65 nl) into the ventral tegmental area (VTA) in anaesthetised rats pre-treated with pargyline increases the dopamine (DA) efflux within the nucleus accumbens (NAcc) as measured by differential pulse amperometry (DPA) combined with carbon fibre electrodes. However, this effect is not blocked by systemic pre-treatment with the potent and selective non-peptide NT receptor antagonists SR 48692 and SR 142948A, at any dose studied. The present study was designed to determine the ability of these NT receptor antagonists to block the increase in DA efflux evoked within the NAcc when they are locally applied with the peptide into the VTA. The competitive N-methyl- D-aspartate (NMDA) receptor antagonist, 2-amino-5-phosphonopentanoic acid (AP-5), applied into the VTA 1 min before NMDA, blocked the effect of NMDA on DA efflux concentration and volume dependently, thus demonstrating the suitability of our experimental procedure for characterizing both an agonist and an antagonist specific for receptors present on mesencephalic dopaminergic neurons and involved in the regulation of DA efflux within the NAcc. Intra-VTA application of SR 142948A blocked the NT-evoked increase in DA efflux within the NAcc dose dependently whereas SR 48692, at the concentration used, was inactive. These results suggest that NT regulates mesencephalic dopaminergic activity through NT receptors sensitive to SR 142948A, but possibly not to SR 48692.