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Speciation and diversification patterns in angiosperms are frequently shaped by niche evolution. Centaurium Hill is a Mediterranean genus with ca. 25 species, of which 60% are polyploids (tetra- and hexaploids), distributed mainly in the Mediterranean Basin and in areas with temperate and arid climates of Asia, Europe, North-Central Africa and North America. The evolutionary history of this genus has been studied using morphological, biogeographical and molecular approaches, but its climatic niche characterization and its relation with genome evolution (chromosome number and ploidy level) has not been addressed yet. Thus, this study aims to identify the role of the evolution of climatic niche, ploidy level, life cycle and floral traits in the diversification of Centaurium . Climatic niche characterization involved estimating present climate preferences using quantitative data and reconstructing ancestral niches to evaluate climatic niche shifts. The evolution of climatic niche towards selective optima determined by ploidy level (three ploidy levels) and different binary traits (polyploidy, floral size, floral display, herkogamy and life cycle) was addressed under the Ornstein-Uhlenbeck model. Chromosome number evolution was inferred using the ChromoSSE model, testing if changes are clado- or anagenetic. Chromosome number evolution and its link with cladogenesis, life cycle and floral traits was modeled on the phylogeny. The reconstruction of the ancestral niches shows that Centaurium originated in a mild climate and diversified to both humid and cold as well as to dry and warmer climates. Niche conservatism was estimated in the climatic niche of the ancestors, while the climatic niche of the current taxa experienced transitions from their ancestors' niche. Besides, the evolution of climatic niche towards multiple selective optima determined by the studied traits was supported, life cycle optima receiving the highest support. The reconstruction of chromosome number transitions shows that the rate of speciation process resulting from chromosomal changes (chromosomal cladogenesis) is similar to that of non-chromosomal cladogenesis. Additionally, dependent evolution of floral size, floral display and herkogamy with chromosome number variation was supported. In conclusion, polyploidization is a crucial process in the Mediterranean region that assisted speciation and diversification into new areas with different climates, entailing niche shifts and evolution of reproductive strategies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision, (Copyright © 2024 Valdés-Florido, Valcárcel, Maguilla, Díaz-Lifante, Andrés-Camacho, Zeltner, Coca-de-la-Iglesia, Medina, Arroyo and Escudero.)

Individuals with ultrarare disorders pose a structural challenge for healthcare systems since expert clinical knowledge is required to establish diagnoses. In TRANSLATE NAMSE, a 3-year prospective study, we evaluated a novel diagnostic concept based on multidisciplinary expertise in Germany. Here we present the systematic investigation of the phenotypic and molecular genetic data of 1,577 patients who had undergone exome sequencing and were partially analyzed with next-generation phenotyping approaches. Molecular genetic diagnoses were established in 32% of the patients totaling 370 distinct molecular genetic causes, most with prevalence below 1:50,000. During the diagnostic process, 34 novel and 23 candidate genotype-phenotype associations were identified, mainly in individuals with neurodevelopmental disorders. Sequencing data of the subcohort that consented to computer-assisted analysis of their facial images with GestaltMatcher could be prioritized more efficiently compared with approaches based solely on clinical features and molecular scores. Our study demonstrates the synergy of using next-generation sequencing and phenotyping for diagnosing ultrarare diseases in routine healthcare and discovering novel etiologies by multidisciplinary teams., (© 2024. The Author(s).)

Objective: Assessment of suicidal risk is one of the most challenging tasks faced by health professionals, notably in emergency care. We compared telephone suicide risk assessment at prehospital Emergency Medical Services Dispatch Center (EMS-DC), with subsequent face-to-face evaluation at Psychiatric Emergency Service (PES), using French national Risk-Urgency-Danger standards (RUD)., Method: Data were collected for all suicidal adult patients ( N  = 80) who were addressed by EMS-DC to PES between December 2018 and August 2019 and benefited from RUD assessment at both services. Suicidal risk was given a score of 1, 2, 3 or 4, in order of severity., Results: Mean of the differences between the RUD score at EMS-DC and PES was -0.825 (SD = 1.19), and was found to be significant ( p  < 0.01). The average time between RUD assessments was 420 min (SD = 448) and was negatively correlated with the difference in the RUD score ( r  = -0.295, p  = 0.008). Associated suicide attempt increased the odds of a decrease in the RUD score (OR = 2.989; 95% CI = 1.141-8.069; p  < 0.05)., Conclusions: Telephone evaluation of suicidal risk using RUD at EMS-DC yielded moderately higher scores than those obtained by a subsequent face-to face evaluation at PES, with this difference partially explained by the time between assessments, and by clinical and contextual factors.

Background: People with complex symptomatology but unclear diagnosis presenting to a centre for rare diseases (CRD) may present with mental (co-)morbidity. We hypothesised that combining an expert in somatic medicine with a mental health specialist working in tandem will improve the diagnostic outcome., Methods: Patients aged 12 years and older who presented to one of the 11 participating German CRDs with an unknown diagnosis were recruited into this prospective cohort trial with a two-phase cohort design. From October 1, 2018 to September 30, 2019, participants were allocated to standard care (SC, N = 684), and from October 1, 2019 to January 31, 2021 to innovative care (IC, N = 695). The cohorts consisted mainly of adult participants with only a minority of children included (N = 67). IC included the involvement of a mental health specialist in all aspects of care (e.g., assessing medical records, clinic visits, telehealth care, and case conferences). Clinicaltrials.gov identifier: NCT03563677., Findings: The proportion of patients with diagnoses established within 12 months after the first visit to the CRD explaining the entire symptomatology (primary outcome) was 19% (N = 131 of 672) in the SC and 42% (N = 286 of 686) in the IC cohort (OR adjusted for centre effects 3.45 [95% CrI: 1.99-5.65]). The difference was mainly due to a higher prevalence of mental disorders and non-rare somatic diseases in the IC cohort. The median time to explaining diagnoses was one month shorter with IC (95% CrI: 1-2), and significantly more patients could be referred to local regular care in the IC (27.5%; N = 181 of 659) compared to the SC (12.3%; N = 81 of 658) cohort (OR adjusted for centre effects 2.70 [95% CrI: 2.02-3.60]). At 12-month follow-up, patient satisfaction with care was significantly higher in the IC compared to the SC cohort, while quality of life was not different between cohorts., Interpretation: Our findings suggested that including a mental health specialist in the entire evaluation process of CRDs for undiagnosed adolescents and adults should become an integral part of the assessment of individuals with a suspected rare disease., Funding: The study was funded by the Global Innovation Fund from the Joint Federal Committee in Germany (Innovationsfonds des Gemeinsamen Bundesausschusses), grant number 01NVF17031., Competing Interests: HH, MB and TM report funding from the Bavarian State Ministry of Science and the Arts paid to their institution to support projects on rare diseases unrelated to ZSE-DUO. HH also reports unrelated funding to his institution by the Federal Ministry of Education and Research, and honoraria from Springer Verlag, Takeda Pharma GmbH and Chiesi GmbH. JD reports funding to his institution from the German Research Association, German Secretary of Education and Research, and the Innovation Fund for several unrelated projects. GH's institution has received funding from the Innovation Fund for another project. OT's institution has received funding from the European Regional Development Fund, EU Horizon 2020, Leibniz Association, and the Federal Ministry of Education and Research. OT has received royalties as an author. CZ reports funding to her institution by the Federal Ministry of Education and Research and the European Union, and voluntary work for the advisory board of the severe chronic neutropenia international registry. All other authors declare no competing interests., (© 2023 The Author(s).)

Variants in MFSD8 can cause neuronal ceroid lipofuscinoses (NCLs) as well as nonsyndromic retinopathy. The mutation spectrum includes mainly missense and stop variants, but splice sites and frameshift variants have also been reported. To date, apparently synonymous substitutions have not been shown to cause MFSD8 -associated diseases. We report two closely related subjects from a consanguineous Turkish family who presented classical features of NCLs but demonstrated marked intrafamilial variability in age at the onset and severity of symptoms. In fact, the difference in the onset of first neurologic symptoms was 15 years and that of ophthalmologic symptoms was 12 years. One subject presented an intellectual disability and a considerable cerebellar ataxia syndrome, while the other subject showed no intellectual disability and only a mild atactic syndrome. The diagnostic genetic testing of both subjects based on genome sequencing prioritized a novel, apparently synonymous variant in MFSD8 , which was found in homozygosity in both subjects. The variant was not located within an integral part of the splice site consensus sequences. However, the bioinformatic analyses suggested that the mutant allele is more likely to cause exon skipping due to an altered ratio of exonic splice enhancer and silencer motifs. Exon skipping was confirmed in vitro by minigene assays and in vivo by RNA analysis from patient lymphocytes. The mutant transcript is predicted to result in a frameshift and, if translated, in a truncated protein. Synonymous variants are often given a low priority in genetic diagnostics because of their expected lack of functional impact. This study highlights the importance of investigating the impact of synonymous variants on splicing.

In current international classification systems (ICD-10, DSM5), the diagnostic criteria for psychotic disorders (e.g. schizophrenia and schizoaffective disorder) are based on symptomatic descriptions since no unambiguous biomarkers are known to date. However, when underlying causes of psychotic symptoms, like inflammation, ischemia, or tumor affecting the neural tissue can be identified, a different classification is used ("psychotic disorder with delusions due to known physiological condition" (ICD-10: F06.2) or psychosis caused by medical factors (DSM5)). While CSF analysis still is considered optional in current diagnostic guidelines for psychotic disorders, CSF biomarkers could help to identify known physiological conditions. In this retrospective, partly descriptive analysis of 144 patients with psychotic symptoms and available CSF data, we analyzed CSF examinations' significance to differentiate patients with specific etiological factors (F06.2) from patients with schizophrenia, schizotypal, delusional, and other non-mood psychotic disorders (F2). In 40.3% of all patients, at least one CSF parameter was out of the reference range. Abnormal CSF-findings were found significantly more often in patients diagnosed with F06.2 (88.2%) as compared to patients diagnosed with F2 (23.8%, p < 0.00001). A total of 17 cases were identified as probably caused by specific etiological factors (F06.2), of which ten cases fulfilled the criteria for a probable autoimmune psychosis linked to the following autoantibodies: amphiphysin, CASPR2, CV2, LGl1, NMDA, zic4, and titin. Two cases presented with anti-thyroid tissue autoantibodies. In four cases, further probable causal factors were identified: COVID-19, a frontal intracranial tumor, multiple sclerosis (n = 2), and neurosyphilis. Twenty-one cases remained with "no reliable diagnostic classification". Age at onset of psychotic symptoms differed between patients diagnosed with F2 and F06.2 (p = 0.014), with the latter group being older (median: 44 vs. 28 years). Various CSF parameters were analyzed in an exploratory analysis, identifying pleocytosis and oligoclonal bands (OCBs) as discriminators (F06.2 vs. F2) with a high specificity of > 96% each. No group differences were found for gender, characteristics of psychotic symptoms, substance dependency, or family history. This study emphasizes the great importance of a detailed diagnostic workup in diagnosing psychotic disorders, including CSF analysis, to detect possible underlying pathologies and improve treatment decisions.

X-linked Adrenoleukodystrophy (X-ALD) is caused by mutations in the ABCD1 gene resulting in the accumulation of very long chain fatty acids (VLCFA). X-ALD is the most common peroxisomal disorder with adult patients (male and female) presenting with progressive spastic paraparesis with bladder disturbance, sensory ataxia with impaired vibration sense, and leg pain. 80% of male X-ALD patients have an adrenal failure, while adrenal dysfunction is rare in women with X-ALD. The objective of this study was to define optimal serum VLCFA cutoff values in patients with X-ALD-like phenotypes for the differentiation of genetically confirmed X-ALD and Non-X-ALD individuals. Three groups were included into this study: a) X-ALD cases with confirmed ABCD1 mutations (n = 34) and two Non-X-ALD cohorts: b) Patients with abnormal serum VCLFA levels despite negative testing for ABCD1 mutations (n = 15) resulting from a total of 1,953 VLCFA tests c) Phenotypically matching patients as Non-X-ALD controls (n = 104). Receiver operating curve analysis was used to optimize VLCFA cutoff values, which differentiate patients with genetically confirmed X-ALD and Non-X-ALD individuals. The serum concentration of C26:0 was superior to C24:0 for the detection of X-ALD. The best differentiation of Non-X-ALD and X-ALD individuals was obtained with a cutoff value of < 1.0 for the C24:0/C22:0 ratio resulting in a sensitivity of 97%, a specificity of 94.1% and a positive predictive value (PPV) of 83.8% for true X-ALD. Our findings further suggested a cutoff of < 0.02 for the ratio C26:0/C22:0 leading to a sensitivity of 90.9%, a specificity of 95.0%, and a PPV of 80.6%. Pearson correlation indicated a significant positive association between total blood cholesterol and VLCFA values. Usage of serum VLCFA are economical and established biomarkers suitable for the guidance of genetic testing matching the X-ALD phenotype. We suggest using our new optimized cutoff values, especially the two ratios (C24:0/C22:0 and C26:0/C22:0), in combination with standard lipid profiles.

Background: In 2009, we identified TACO1 as a novel mitochondrial disease gene in a single family, however no second family has been described to confirm the role of TACO1 in mitochondrial disease., Objective: In this report, we describe two independent consanguineous families carrying pathogenic variants in TACO1, confirming the phenotype., Methods: Detailed clinical investigations and whole exome sequencing with haplotype analysis have been performed in several members of the two reported families., Results: Clinical phenotype of the patients confirms the originally reported phenotype of a childhood-onset progressive cerebellar and pyramidal syndrome with optic atrophy and learning difficulties. Brain MRI showed periventricular white matter lesions with multiple cystic defects, suggesting leukoencephalopathy in both patients. One patient carried the previously described homozygous TACO1 variant (p.His158ProfsTer8) and haplotype analysis suggested that this variant is a rare founder mutation. The second patient from another family carried a homozygous novel frame shift variant (p.Cys85PhefsTer15)., Conclusions: The identification of two Turkish families with similar characteristic clinical presentation and an additional homozygous nonsense mutation confirms that TACO1 is a human mitochondrial disease gene. Although most patients with this clinical presentation undergo next generation sequencing analysis, screening for selected founder mutations in the Turkish population based on the precise clinical presentation may reduce time and cost of finding the genetic diagnosis even in the era of massively parallel sequencing.

Objective: To analyze whether 1 of the 2 apheresis techniques, therapeutic plasma exchange (PE) or immunoadsorption (IA), is superior in treating neuromyelitis optica spectrum disorder (NMOSD) attacks and to identify predictive factors for complete remission (CR)., Methods: This retrospective cohort study was based on the registry of the German Neuromyelitis Optica Study Group, a nationwide network established in 2008. It recruited patients with neuromyelitis optica diagnosed according to the 2006 Wingerchuk criteria or with aquaporin-4 (AQP4-ab)-antibody-seropositive NMOSD treated at 6 regional hospitals and 16 tertiary referral centers until March 2013. Besides descriptive data analysis of patient and attack characteristics, generalized estimation equation (GEE) analyses were applied to compare the effectiveness of the 2 apheresis techniques. A GEE model was generated to assess predictors of outcome., Results: Two hundred and seven attacks in 105 patients (87% AQP4-ab-antibody seropositive) were treated with at least 1 apheresis therapy. Neither PE nor IA was proven superior in the therapy of NMOSD attacks. CR was only achieved with early apheresis therapy. Strong predictors for CR were the use of apheresis therapy as first-line therapy (OR 12.27, 95% CI: 1.04-144.91, p = 0.047), time from onset of attack to start of therapy in days (OR 0.94, 95% CI: 0.89-0.99, p = 0.014), the presence of AQP4-ab-antibodies (OR 33.34, 95% CI: 1.76-631.17, p = 0.019), and monofocal attack manifestation (OR 4.71, 95% CI: 1.03-21.62, p = 0.046)., Conclusions: Our findings suggest early use of an apheresis therapy in NMOSD attacks, particularly in AQP4-ab-seropositive patients. No superiority was shown for one of the 2 apheresis techniques., Classification of Evidence: This study provides Class IV evidence that for patients with NMOSD, neither PE nor IA is superior in the treatment of attacks.

Objective: To analyse predictors for relapses and number of attacks under different immunotherapies in patients with neuromyelitis optica spectrum disorder (NMOSD)., Design: This is a retrospective cohort study conducted in neurology departments at 21 regional and university hospitals in Germany. Eligible participants were patients with aquaporin-4-antibody-positive or aquaporin-4-antibody-negative NMOSD. Main outcome measures were HRs from Cox proportional hazard regression models adjusted for centre effects, important prognostic factors and repeated treatment episodes., Results: 265 treatment episodes with a mean duration of 442 days (total of 321 treatment years) in 144 patients (mean age at first attack: 40.9 years, 82.6% female, 86.1% aquaporin-4-antibody-positive) were analysed. 191 attacks occurred during any of the treatments (annual relapse rate=0.60). The most common treatments were rituximab (n=77, 111 patient-years), azathioprine (n=52, 68 patient-years), interferon-β (n=32, 61 patient-years), mitoxantrone (n=34, 32.1 patient-years) and glatiramer acetate (n=17, 10 patient-years). Azathioprine (HR=0.4, 95% CI 0.3 to 0.7, p=0.001) and rituximab (HR=0.6, 95% CI 0.4 to 1.0, p=0.034) reduced the attack risk compared with interferon-β, whereas mitoxantrone and glatiramer acetate did not. Patients who were aquaporin-4-antibody-positive had a higher risk of attacks (HR=2.5, 95% CI 1.3 to 5.1, p=0.009). Every decade of age was associated with a lower risk for attacks (HR=0.8, 95% CI 0.7 to 1.0, p=0.039). A previous attack under the same treatment tended to be predictive for further attacks (HR=1.5, 95% CI 1.0 to 2.4, p=0.065)., Conclusions: Age, antibody status and possibly previous attacks predict further attacks in patients treated for NMOSD. Azathioprine and rituximab are superior to interferon-β., Competing Interests: Competing interests: AB has received honoraria for consultancy or lectures and travel reimbursement from Bayer HealthCare, Biogen, Merck Serono, Mylan, Roche, Novartis and Teva, and grant support from Bayer HealthCare and Chugai. AG has received travel reimbursement from Sanofi Genzyme. BH reports grants from Chugai, grants, personal fees and non-financial support from Roche, personal fees and non-financial support from Biogen, personal fees and non-financial support from Novartis, personal fees and non-financial support from Merck, and personal fees and non-financial support from Bayer. BW has received grants from the German Ministry of Education and Research, Dietmar Hopp Foundation, Biogen, Biotest, Merck, Novartis Pharmaceuticals and Teva Pharma, personal fees from Biogen, Merck, Novartis Pharmaceuticals, Teva Pharma, Bayer HealthCare and Genzyme. CG received honoraria for lectures, travel reimbursement and grant support from Merck Serono, Teva, Novartis and CSL Behring. CT has received honoraria for consultation and expert testimony from Bayer Vital GmbH, Biogen Idec/Biogen GmbH, Genzyme GmbH and Novartis Pharmaceuticals/Pharma GmbH. FL reports travel expenses from Teva Pharma. FlP reports grants from BIH‐Charité Clinical Scientist Program funded by the Charité–Universitätsmedizin Berlin and the Berlin Institute of Health and non-financial support from ECTRIMS-Travel grant 2014. FrP reports grants and personal compensations from Alexion, Bayer, Biogen, Shire, Novartis, Medimmune, Merck and Genzyme. FTB reports grants and others from Bayer, personal fees and others from Biogen Idec, grants and personal fees from CSL Behring, grants from Fresenius, personal fees and others from Genzyme Sanofi, others from Merck Serono, grants, personal fees and others from Novartis, grants, personal fees and others from Teva, grants and others from Actelion, and grants from the German Ministry of Education and Research. HPH received, with approval of the Rector of Heinrich-Heine-University and the CEO of University of Düsseldorf Hospital, honoraria for consulting, serving on steering committees and speaking from Biogen, Geneuro, Genzyme, Medimmune, Merck, Novartis, Opexa, Receptos/Celgene, Roche, Sanofi and Teva. IK has received honoraria for consultancy or lectures and travel reimbursement from Bayer HealthCare, Biogen Idec, Chugai, Novartis, Shire and Roche, and grant support from Biogen Idec, Novartis, Chugai and Diamed. JHF received grant support and honoraria from Novartis, Bayer Vital, Merck, Biogen, Sanofi-Genzyme and Roche. JH reports personal fees and non-financial support from Sanofi Genzyme, Bayer HealthCare, Merck and Novartis Pharma. JPS received honoraria for consultancy or lectures, travel reimbursement and grant support from Biogen, Merck Serono, Novartis, Genzyme and Medimmune. KH reports grants and personal fees from Bayer HealthCare, grants and personal fees from Biogen, grants and personal fees from Teva, grants and personal fees from Merck Serono, grants and personal fees from Novartis, grants and personal fees from Almirall. KLY has nothing to disclose. KR has received research support from the German Ministry of Education and Research (BMBF/KKNMS, Competence Network Multiple Sclerosis) and Novartis, as well as speaking fees and travel grants from Guthy Jackson Charitable Foundation, Bayer HealthCare, Biogen Idec, Merck Serono, Sanofi-Aventis/Genzyme, Teva Pharmaceuticals, Roche and Novartis. LZ has nothing to disclose. MK received grant support, travelling expenses and scientific advisory board honoraria from Novartis, Novartis Foundation, Genzyme, Bayer, Roche and Biogen. MM has received grants from Biogen, Novartis; personal fees from Bayer Vital, Biogen, Genzyme, Merck Serono, Novartis, Sanofi-Aventis and Teva; and non-financial support from Biogen. MR received speaker honoraria from Novartis and Bayer Vital GmbH, and travel reimbursement from Bayer Schering and Biogen Idec. MSch has nothing to disclose. MSt reports grants and personal fees from Bayer HealthCare, personal fees from Baxter/Baxalta, grants and personal fees from Biogen, personal fees from CSL Behring, grants and personal fees from Genzyme, personal fees from Grifols, personal fees from Merck, personal fees from Roche, grants and personal fees from Novartis, personal fees from Sanofi, and grants and personal fees from Teva. NB has received grants from Alexion Pharmaceuticals, Inc. ON has nothing to disclose. RAL reports grants and personal fees from Biogen, personal fees from Bayer, grants and personal fees from Novartis, grants and personal fees from Merck, personal fees from TEVA, personal fees from Roche, personal fees from Genzyme. SJ has received a research grant from the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). MR received speaker honoraria from Novartis and Bayer Vital GmbH, and travel reimbursement from Bayer Schering and Biogen Idec. TF received honoraria for consultancies (including data monitoring committees and advisoryboards) from Novartis, Biogen, Bayer, AstraZeneca, Janssen, SGS and Pharmalog. TK reports personal fees from Biogen, grants from Novartis, personal fees from Genzyme and from Merck-Serono. UHO reports grants from Genzyme, grants from Zambon, and others from Merck Serono, Bayer, Biogen, Teva and Novartis. UZe has patents, whether planned, pending or issued, broadly relevant to the work. UZi reports personal fees from Biogen Idec GmbH, grants from Biogen Idec GmbH, personal fees from Bayer Vital GmbH, personal fees from Bristol Myers Squibb GmbH, personal fees from CorTec GmbH, personal fees from Medtronic GmbH, grants from Servier, grants from Janssen Pharmaceuticals NV and personal fees from Takeda., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Gender and age at onset are important epidemiological factors influencing prevalence, clinical presentation, and treatment response in autoimmune diseases., Objective: To evaluate the impact of female sex and fertile age on aquaporin-4-antibody (AQP4-ab) status, attack localization, and response to attack treatment in patients with neuromyelitis optica (NMO) and its spectrum disorders (neuromyelitis optica spectrum disorder (NMOSD))., Methods: Female-to-male ratios, diagnosis at last visit (NMO vs NMOSD), attack localization, attack treatment, and outcome were compared according to sex and age at disease or attack onset., Results: A total of 186 NMO/SD patients (82% female) were included. In AQP4-ab-positive patients, female predominance was most pronounced during fertile age (female-to-male ratio 23:1). Female patients were more likely to be positive for AQP4-abs (92% vs 55%; p < 0.001). Interval between onset and diagnosis of NMO/SD was longer in women than in men (mean 54 vs 27 months; p = 0.023). In women, attacks occurring ⩽40 years of age were more likely to show complete remission ( p = 0.003) and better response to high-dose intravenous steroids ( p = 0.005) compared to woman at >40 years., Conclusion: Our data suggest an influence of sex and age on susceptibility to AQP4-ab-positive NMO/SD. Genetic and hormonal factors might contribute to pathophysiology of NMO/SD.

Glatiramer acetate (GA) is an approved therapy for relapsing-remitting multiple sclerosis, but its efficacy for the prevention of attacks in neuromyelitis optica spectrum disorder (NMOSD) remains unknown. We did a multicenter retrospective analysis of GA-treated patients with NMOSD, identified through a national registry. Annualized relapse rate and expanded disability status scale (EDSS) were the main outcome measures. We identified 23 GA-treated patients (21 female, 16 aquaporin-4 antibody-positive). GA was given for <6 months in seven patients; reasons for stopping were relapses (n = 3), confirmation of NMOSD (n = 2) and side effects (n = 2). Of 16 patients treated ≥ 6 months with GA (15 female, 11 aquaporin-4 antibody-positive), 14 experienced at least one relapse. There was no reduction in the mean annualized relapse rate in the total group (1.9 ± 1.1 before vs. 1.8 ± 1.4 during GA therapy), as well as in those patients who were aquaporin-4 antibody-positive, or had a history of prior immunotherapy or not. The median EDSS increased (2.5 start vs. 3.5 finish of GA, P < 0.05). GA therapy was discontinued in 15/16 patients; reasons were therapeutic inefficacy in 13 and post-injection skin reactions in two patients. We conclude that GA is not beneficial for preventing attacks in most patients with NMOSD, particularly in aquaporin-4 antibody-positive cases.

Objective: Neuromyelitis optica (NMO) attacks often are severe, are difficult to treat, and leave residual deficits. Here, we analyzed the frequency, sequence, and efficacy of therapies used for NMO attacks., Methods: A retrospective review was made of patient records to assess demographic/diagnostic data, attack characteristics, therapies, and the short-term remission status (complete remission [CR], partial remission [PR], no remission [NR]). Inclusion criteria were NMO according to Wingerchuk's 2006 criteria or aquaporin-4 antibody-positive NMO spectrum disorder (NMOSD). Remission status was analyzed with generalized estimating equations (GEEs), a patient-based statistical approach., Results: A total of 871 attacks in 185 patients (142 NMO/43 NMOSD, 82% female) were analyzed. The 1,153 treatment courses comprised high-dose intravenous steroids (HD-S; n = 810), plasma exchange (PE; n = 192), immunoadsorption (IA; n = 38), other (n = 80), and unknown (n = 33) therapies. The first treatment course led to CR in 19.1%, PR in 64.5%, and NR in 16.4% of attacks. Second, third, fourth, and fifth treatment courses were given in 28.2%, 7.1%, 1.4%, and 0.5% of attacks, respectively. This escalation of attack therapy significantly improved outcome (p < 0.001, Bowker test). Remission rates were higher for isolated optic neuritis versus isolated myelitis (p < 0.001), and for unilateral versus bilateral optic neuritis (p = 0.020). Isolated myelitis responded better to PE/IA than to HD-S as first treatment course (p = 0.037). Predictors of CR in multivariate GEE analysis were age (odds ratio [OR] = 0.97, p = 0.011), presence of myelitis (OR = 0.38, p = 0.002), CR from previous attack (OR = 6.85, p < 0.001), and first-line PE/IA versus HD-S (OR = 4.38, p = 0.006)., Interpretation: Particularly myelitis and bilateral optic neuritis have poor remission rates. Escalation of attack therapy improves outcome. PE/IA may increase recovery in isolated myelitis., (© 2015 American Neurological Association.)

We previously reported nonlinear correlations between verbal episodic memory performance and BOLD signal in memory fMRI in healthy subjects. The purpose of the present study was to examine this observation in patients with left mesial temporal lobe epilepsy (mTLE) who often experience memory decline and need reliable prediction tools before epilepsy surgery with hippocampectomy. Fifteen patients with left mTLE (18-57years, nine females) underwent a verbal memory fMRI paradigm. Correlations between BOLD activity and neuropsychological data were calculated for the i) hippocampus (HC) as well as ii) extrahippocampal mTL structures. Memory performance was systematically associated with activations within the right HC as well as with activations within the left extrahippocampal mTL regions (amygdala and parahippocampal gyrus). As hypothesized, the analyses revealed cubic relationships, with one peak in patients with marginal memory performance and another peak in patients with very good performance. The nonlinear correlations between memory performance and activations might reflect the compensatory recruitment of neural resources to maintain memory performance in patients with ongoing memory deterioration. The present data suggest an already incipient preoperative reorganization process of verbal memory in non-amnesic patients with left mTLE by simultaneously tapping the resources of the right HC and left extrahippocampal mTL regions. Thus, in the preoperative assessment, both neuropsychological performance and memory fMRI should be considered together., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: Episodic memory processes can be investigated using different functional MRI (fMRI) paradigms. The purpose of the present study was to examine correlations between neuropsychological memory test scores and BOLD signal changes during fMRI scanning using three different memory tasks., Method: Twenty-eight right-handed healthy subjects underwent three paradigms, (a) a word pair, (b) a space-labyrinth, and (c) a face-name association paradigm. These paradigms were compared for their value in memory quantification and lateralization by calculating correlations between the BOLD signals in the mesial temporal lobe and behavioral data derived from a neuropsychological test battery., Results: As expected, group analysis showed left-sided activation for the verbal, a tendency to right-sided activation for the spatial, and bilateral activation for the face-name paradigm. No linear correlations were observed between neuropsychological data and activation in the temporo-mesial region. However, we found significant u-shaped correlations between behavioral memory performance and activation in both the verbal and the face-name paradigms, that is, BOLD signal changes were greater not only among participants who performed best on the neuropsychological tests, but also among the poorest performers. The figural learning task did not correlate with the activations in the space-labyrinth paradigm at all., Conclusions: We interpreted the u-shaped correlations to be due to compensatory hippocampal activations associated with low performance when people try unsuccessfully to remember presented items. Because activation levels did not linearly increase with memory performance, the latter cannot be quantified by fMRI alone, but only be used in conjunction with neuropsychological testing., (PsycINFO Database Record (c) 2013 APA, all rights reserved.)

Purpose: To evaluate the hypothesis that the entire hippocampus might be affected by susceptibility artifacts. Previous studies described susceptibility artifacts in the amygdala and the anterior hippocampus., Materials and Methods: We investigated 20 subjects with a verbal memory paradigm aiming at testing two different TEs (45 vs. 64 msec) at 1.5 T for hippocampal blood oxygenation level-dependent (BOLD) activity. T2* maps were calculated from the normalized mean echo-planar imaging (EPI) of the two echo times (TEs)., Results: Within the hippocampal region of interest (ROI), the amount of suprathreshold voxels was significantly higher at TE = 64 msec compared to TE = 45 msec. When corrected for multiple comparisons (family-wise error [FWE] in a small volume of interest, P < 0.05) we no longer found significant activations at TE = 45 msec, while a significant number of voxels remained after the small volume correction (P < 0.05, FWE) within the ROI at TE = 64 msec., Conclusion: Although a shorter TE demonstrates advantages, a TE of 45 msec leads to a significant loss of BOLD signal detection in memory functional magnetic resonance imaging (fMRI) studies when compared to 64 msec. We assume that the hippocampal region, even the anterior part, is not strongly affected by susceptibility gradients., (Copyright © 2012 Wiley Periodicals, Inc.)

Children are regularly faced with traumatic events, whether these are disasters (tsunami, floods, earthquakes), accidents (transport, domestic) or intentional acts (war, ill treatment). The care provided for young Haitian children following the earthquake in January 2010 offers an insight into specific intervention methods, the treatment of post-traumatic disorders and the effects of trauma on those working with them.

The goal of this survey was to evaluate the patients and their relatives' satisfaction with a home-based crisis intervention provided by a psychiatric mobile crisis team (Equipe Rapide d'Intervention de Crise, hôpital Charcot, Plaisir). We were particularly interested in measuring satisfaction with telephone response time, team mobility, patient welcome, family consultations, information given to patients and the number of caregivers. We designed a questionnaire that included 24 closed questions and 2 open-ended questions. Replies were collected over the telephone by an outside psychologist with no prior knowledge of the patients. The inclusion criteria were the following: the patient had to have received a home-based crisis intervention from the mobile crisis team and to have received at least two follow-up consultations. The response rate was 95%, from 81 relatives and 73 patients. The results show a high level of overall satisfaction, with satisfaction levels at over 90% for some of the questions. High satisfaction was due to the human and professional approach of staff - their listening skills and competence - the 24-hour availability of the telephone service, the fast intervention of the team, the team mobility, and the systematic involvement of relatives as part of the program. Low satisfaction was due to the high number of caregivers, the short length of programs, the patient referral process to outpatient services, the lack of information on medication and patients' illness and the sad appearance of the building. These results lead us to improve some aspects of our service or at least to explain our services more fully to clients. More generally, these results encourage us to listen more attentively to patients' opinions on how they experience their psychiatric care.

Chronic post-traumatic stress disorder (PTSD) is a very complex syndrome which is hard to detect because of the multiplicity of its expressions. Further more, these clinical expressions are far from the "pure" syndrome described in the DSM IV. So, the clinician faces a dilemma: how can he account for the traumatic clues without using the PTSD as a ragbag of a diagnosis? We found the way to discard this dilemma when we decided to use what M. Struber said about her experience with cancer and PTSD. She suggests not to emphasize psychopathology and to use a post-traumatic stress framework. This way to reframe some psychiatric urgencies is very useful because it gives back ability to the patient. When using a post-traumatic stress framework we tell the patient and his family that we acknowledge he has defensible reasons for not managing with an event which, we acknowledge too, was traumatic for him. In that way we begin to explore what each person is experiencing, because the traumatic experiencing is generally shared by the patient and his family. The members of the family are often angry and fed up of the patient behaviour and think themselves as victims of him. On the other part, the patient feels himself as a misunderstood person, victim of the others. The primary trauma is forgotten for a long time or nobody make any link between it and what is happening in the present. The manifestations of the PTSD initiate subsequent aftermaths and suffering for everybody. When working with psychiatric emergencies, we have to manage with acute situations in which each people is both victim and aggressor and in which clinicians run the risk of being given the role of either victim or aggressor. The trial of strength played between the patient and his family is going to be played with the clinician. These situations are described by S. Lamarre when she speaks of "victimisation" and are overloaded with control stake. Each one tries to make the other guilty and disgraced, and the clinician is at risk to feel and/or make feel in the same way the patient and his family. These situations are blocked and the temptation is to resort to a kind of coup when the clinician decides it's enough! and forces his opinion and decision. What is not a very good way to create the essential therapeutic co-operation! In this article we show how using a post-traumatic stress framework is very useful to reframe the situation of "victimisation", give the opportunity to discard its trap, open a new sight which allows to find new solutions and promote a therapeutic co-operation. It's important to stress the fact that it's not efficient to use a post-traumatic stress framework as a formula. The clinician who uses it has to feel it, otherwise he will be unable to co-create this new reality with the system he entered, when receiving the emergency.

We choose to discuss from the PTSD's point of view because this diagnostic reference is commonly used. We wish outline its restrictive sight which could prevent the professional from having a diagnosis of PTSD. We don't want to say there is a PTSD everywhere but it appears to us that a traumatic reading can be a precious advantage for the clinician to establish a real therapeutic relation with some patients. Post-traumatic syndrome differs from the majority of other diagnostic categories as it includes in its criteria the presumptive cause of the trauma (criterion A). In the case that this syndrome originates in war experiences, the presumed cause presents itself as an exceptional event overcoming the individual's resources. The notion of war traumatisation has been extended to other events such as catastrophes, physical attacks, rapes, child and wife battering, and sexual abuses. But the events which cause PTSD (Post-Traumatic Stress Disorder) are significantly more numerous. It can be seen that medical events such as giving birth, miscarriage, heart attack, cancer, or hospitalisation following resuscitation may give rise to PTSD. Further, people experiencing prolonged periods of distress may equally develop a post-traumatic syndrome without any particular event having occurred to surpass their defences. It's the case of the Prolonged Duress Stress Disorder (PDSD). The series of discontinuous stress "waste" the psychic balance and may give rise, at one moment, to posttraumatic symptoms described in DSM, without any specific stressful event. The existence of criterion A is therefore not a necessary prerequisite in establishing a diagnosis of PTSD. It is, in fact, very difficult to predict which events could cause a PTSD, and this, especially, as the subjective aspects count at least as much as the objective aspects. The clinician should have to carefully explore how the patient experienced the event or, how he apprehended the event itself and it's outcome, if he wants get the traumatic range of a life event. The feeling of deep distress, the feeling of being trapped, the loss of control, the collapse of basic beliefs, the feeling that one's life is in jeopardy, that the physical integrity is (really or in one's imagination) threatened, the feeling of helplessness, are quite as much clues for a possible PTSD which hides behind others clinical manifestations either psychological or somatic. Furthermore, the "pure" form described in the DSM and grouping together three further criteria (reliving events, avoiding stimuli associated with the trauma, hyper-reactivity) is extremely rare in the chronic form. An untreated post-traumatic syndrome evolves with time and may present, initially, with very different pathological symptoms giving rise to equally varied diagnoses. Different etiopathogenic models propose to account for the PTSD 's heterogeneous appearance and instability with time. The comorbidity concept sees the PTSD as an independent entity other independent pathologies coexist with. The typologic concept suggests that the PTSD is an independent entity which shows different clinical appearances based on symptomatic descriptions. The "cascade" concept suggests to see the PTSD as an independent entity which offers, with time, different symptomatic appearances, in evolution, because of events caused by after effects, in different areas of the PTSD itself. All of these concepts outline the transnosologic appearance of the PTSD which makes it hardly recognizable. The "chronic" syndrome is rarely diagnosed forming a real challenge to prevention. In effect, the present authors insist on the crucial nature of early detection of PTSD since the greater the time elapsed the more difficult it becomes due to the evolutionary aspect of the syndrome, which initially has more readily recognizable symptoms. The consequences of an unrecognised PTSD are serious and affect both the individual and his immediate family and friends, contributing further to the aggravation of the problems. When a PTSD is diagnosed, it can allow the clinician to further a more global care which will help the patient to get a better recovery. With patients who suffered an infarct, the treatment of PTSD which prevents their recovery will help to go back to the way they lived before the event. It has been showed how important could be the PTSD detection on the severe burned people's pain control. Thus it seems to be crucial for the clinician to keep this diagnosis in mind alongside any other.