De novo missense variants in FBXO11 alter its protein expression and subcellular localization

Recently, others and we identified de novo FBXO11 (F-Box only protein 11) variants as causative for a variable neurodevelopmental disorder (NDD). We now assembled clinical and mutational information on 23 additional individuals. The phenotypic spectrum remains highly variable, with developmental delay and/or intellectual disability as the core feature and behavioral anomalies, hypotonia and various facial dysmorphism as frequent aspects. The mutational spectrum includes intragenic deletions, likely gene disrupting and missense variants distributed across the protein. To further characterize the functional consequences of FBXO11 missense variants, we analyzed their effects on protein expression and localization by overexpression of 17 different mutant constructs in HEK293 and HeLa cells. We found that the majority of missense variants resulted in subcellular mislocalization and/or reduced FBXO11 protein expression levels. For instance, variants located in the nuclear localization signal and the N-terminal F-Box domain lead to altered subcellular localization with exclusion from the nucleus or the formation of cytoplasmic aggregates and to reduced protein levels in western blot. In contrast, variants localized in the C-terminal Zn-finger UBR domain lead to an accumulation in the cytoplasm without alteration of protein levels. Together with the mutational data, our functional results suggest that most missense variants likely lead to a loss of the original FBXO11 function and thereby highlight haploinsufficiency as the most likely disease mechanism for FBXO11-associated NDDs

Effects of omega-3 polyunsaturated fatty acid supplementation on cognitive functioning in youth at ultra-high risk for psychosis: secondary analysis of the NEURAPRO randomised controlled trial

BACKGROUND: Cognitive impairments are well-established features of psychotic disorders and are present when individuals are at ultra-high risk for psychosis. However, few interventions target cognitive functioning in this population. AIMS: To investigate whether omega-3 polyunsaturated fatty acid (n-3 PUFA) supplementation improves cognitive functioning among individuals at ultra-high risk for psychosis. METHOD: Data (N = 225) from an international, multi-site, randomised controlled trial (NEURAPRO) were analysed. Participants were given omega-3 supplementation (eicosapentaenoic acid and docosahexaenoic acid) or placebo over 6 months. Cognitive functioning was assessed with the Brief Assessment of Cognition in Schizophrenia (BACS). Mixed two-way analyses of variance were computed to compare the change in cognitive performance between omega-3 supplementation and placebo over 6 months. An additional biomarker analysis explored whether change in erythrocyte n-3 PUFA levels predicted change in cognitive performance. RESULTS: The placebo group showed a modest greater improvement over time than the omega-3 supplementation group for motor speed (η$_{p}$$^{2}$ = 0.09) and BACS composite score (η$_{p}$$^{2}$ = 0.21). After repeating the analyses without individuals who transitioned, motor speed was no longer significant (η$_{p}$$^{2}$ = 0.02), but the composite score remained significant (η$_{p}$$^{2}$ = 0.02). Change in erythrocyte n-3 PUFA levels did not predict change in cognitive performance over 6 months. CONCLUSIONS: We found no evidence to support the use of omega-3 supplementation to improve cognitive functioning in ultra-high risk individuals. The biomarker analysis suggests that this finding is unlikely to be attributed to poor adherence or consumption of non-trial n-3 PUFAs

Evidence that complement and coagulation proteins are mediating the clinical response to omega-3 fatty acids: A mass spectrometry-based investigation in subjects at clinical high-risk for psychosis

Preliminary evidence indicates beneficial effects of omega-3 polyunsaturated fatty acids (PUFAs) in early psychosis. The present study investigates the molecular mechanism of omega-3 PUFA-associated therapeutic effects in clinical high-risk (CHR) participants. Plasma samples of 126 CHR psychosis participants at baseline and 6-months follow-up were included. Plasma protein levels were quantified using mass spectrometry and erythrocyte omega-3 PUFA levels were quantified using gas chromatography. We examined the relationship between change in polyunsaturated PUFAs (between baseline and 6-month follow-up) and follow-up plasma proteins. Using mediation analysis, we investigated whether plasma proteins mediated the relationship between change in omega-3 PUFAs and clinical outcomes. A 6-months change in omega-3 PUFAs was associated with 24 plasma proteins at follow-up. Pathway analysis revealed the complement and coagulation pathway as the main biological pathway to be associated with change in omega-3 PUFAs. Moreover, complement and coagulation pathway proteins significantly mediated the relationship between change in omega-3 PUFAs and clinical outcome at follow-up. The inflammatory protein complement C5 and protein S100A9 negatively mediated the relationship between change in omega-3 PUFAs and positive symptom severity, while C5 positively mediated the relationship between change in omega-3 and functional outcome. The relationship between change in omega-3 PUFAs and cognition was positively mediated through coagulation factor V and complement protein C1QB. Our findings provide evidence for a longitudinal association of omega-3 PUFAs with complement and coagulation protein changes in the blood. Further, the results suggest that an increase in omega-3 PUFAs decreases symptom severity and improves cognition in the CHR state through modulating effects of complement and coagulation proteins

Characterization and prediction of clinical pathways of vulnerability to psychosis through graph signal processing

Causal interactions between specific psychiatric symptoms could contribute to the heterogenous clinical trajectories observed in early psychopathology. Current diagnostic approaches merge clinical manifestations that co-occur across subjects and could significantly hinder our understanding of clinical pathways connecting individual symptoms. Network analysis techniques have emerged as alternative approaches that could help shed light on the complex dynamics of early psychopathology. The present study attempts to address the two main limitations that have in our opinion hindered the application of network approaches in the clinical setting. Firstly, we show that a multi-layer network analysis approach, can move beyond a static view of psychopathology, by providing an intuitive characterization of the role of specific symptoms in contributing to clinical trajectories over time. Secondly, we show that a Graph-Signal-Processing approach, can exploit knowledge of longitudinal interactions between symptoms, to predict clinical trajectories at the level of the individual. We test our approaches in two independent samples of individuals with genetic and clinical vulnerability for developing psychosis. Novel network approaches can allow to embrace the dynamic complexity of early psychopathology and help pave the way towards a more a personalized approach to clinical care

Cladribine tablets in people with relapsing multiple sclerosis : A real-world multicentric study from southeast European MS centers

Cladribine is an oral disease-modifying drug authorized by the European Medicine Agency for the treatment of highly active relapsing multiple sclerosis (MS).To provide real-world evidence of cladribine's effectiveness and safety in people with MS (pwMS).A retrospective observational multi-center, multi-national study of pwMS who were started on cladribine tablets in ten centers from five European countries.We identified 320 pwMS treated with cladribine tablets. The most common comorbidities were arterial hypertension and depression. Three patients had resolved hepatitis B infection, while eight had positive Quantiferon test prior to cladribine commencement. There were six pwMS who had malignant diseases, but all were non-active. During year 1, 91.6% pwMS did not have EDSS worsening, 86.9% were relapse-free and 72.9% did not have MRI activity. During the second year, 90.2% did not experience EDSS worsening, 86.5% were relapse-free and 75.5% did not have MRI activity. NEDA-3 was present in 58.0% pwMS in year 1 and in 54.2% in year 2. In a multivariable logistic regression model age positively predicted NEDA-3 in year 1. The most common adverse events were infections and skin-related adverse events. Lymphopenia was noted in 54.7% of pwMS at month 2 and in 35.0% at month 6. Two pwMS had a newly discovered malignant disease, one breast cancer, and one melanoma, during the first year of treatment.Our real-world data on the effectiveness and safety of cladribine tablets are comparable to the pivotal study and other real-world data with no new safety signals

Iron status in Swiss adolescents with paediatric major depressive disorder and healthy controls: a matched case–control study

Purpose: Depression is associated with low-grade systemic inflammation and impaired intestinal function, both of which may reduce dietary iron absorption. Low iron status has been associated with depression in adults and adolescents. In Swiss adolescents, we determined the associations between paediatric major depressive disorder (pMDD), inflammation, intestinal permeability and iron status. Methods: This is a matched case-control study in 95 adolescents with diagnosed pMDD and 95 healthy controls aged 13-17 years. We assessed depression severity using the Children's Depression Rating Scale-Revised. We measured iron status (serum ferritin (SF) and soluble transferrin receptor (sTfR)), inflammation (C-reactive protein (CRP) and alpha-1-acid-glycoprotein (AGP)), and intestinal permeability (intestinal fatty acid binding protein (I-FABP)). We assessed history of ID diagnosis and treatment with a self-reported questionnaire. Results: SF concentrations did not differ between adolescents with pMDD (median (IQR) SF: 31.2 (20.2, 57.0) μg/L) and controls (32.5 (22.6, 48.3) μg/L, p = 0.4). sTfR was lower among cases than controls (4.50 (4.00, 5.50) mg/L vs 5.20 (4.75, 6.10) mg/L, p < 0.001). CRP, AGP and I-FABP were higher among cases than controls (CRP: 0.16 (0.03, 0.43) mg/L vs 0.04 (0.02, 0.30) mg/L, p = 0.003; AGP: 0.57 (0.44, 0.70) g/L vs 0.52 (0.41, 0.67) g/L, p = 0.024); I-FABP: 307 (17, 515) pg/mL vs 232 (163, 357) pg/mL, p = 0.047). Of cases, 44% reported having a history of ID diagnosis compared to 26% among controls (p = 0.020). Finally, 28% of cases had iron treatment at/close to study inclusion compared to 14% among controls. Conclusion: Cases had significantly higher systemic inflammation and intestinal permeability than controls but did not have lower iron status. Whether this is related to the higher rate of ID diagnosis and iron treatment in adolescents with depression is uncertain

Treatment and Outcome of Osteoporotic Thoracolumbar Vertebral Fractures With Anterior or Posterior Tension Band Failure (OF 5): Short-Term Results From the Prospective EOFTT Multicenter Study.

STUDY DESIGN Subgroup analysis of a multicenter prospective cohort study. OBJECTIVE To analyse surgical strategies applied to osteoporotic thoracolumbar osteoporotic fracture (OF) 5 injuries with anterior or posterior tension band failure and to assess related complications and clinical outcome. METHODS A multicenter prospective cohort study (EOFTT) was conducted at 17 spine centers including 518 consecutive patients who were treated for an osteoporotic vertebral fracture (OVF). For the present study, only patients with OF 5 fractures were analysed. Outcome parameters were complications, Visual Analogue Scale (VAS), Oswestry Disability Questionnaire (ODI), Timed Up & Go test (TUG), EQ-5D 5L, and Barthel Index. RESULTS In total, 19 patients (78 ± 7 years, 13 female) were analysed. Operative treatment consisted of long-segment posterior instrumentation in 9 cases and short-segment posterior instrumentation in 10 cases. Pedicle screws were augmented in 68 %, augmentation of the fractured vertebra was performed in 42%, and additional anterior reconstruction was done in 21 %. Two patients (11 %) received short-segment posterior instrumentation without either anterior reconstruction or cement-augmentation of the fractured vertebra. No surgical or major complications occurred, but general postoperative complications were observed in 45%. At a follow-up of mean 20 ± 10 weeks (range, 12 to 48 weeks), patients showed significant improvements in all functional outcome parameters. CONCLUSIONS In this analysis of patients with type OF 5 fractures, surgical stabilization was the treatment of choice and lead to significant short-term improvement in terms of functional outcome and quality of life despite a high general complication rate

Treatment and Outcome of Osteoporotic Thoracolumbar Vertebral Body Fractures With Deformation of Both Endplates With or Without Posterior Wall Involvement (OF 4): Short-Term Results from the Prospective EOFTT Multicenter Study.

STUDY DESIGN: Multicenter prospective cohort study. OBJECTIVE: To analyse therapeutical strategies applied to osteoporotic thoracolumbar OF 4 injuries, to assess related complications and clinical outcome. METHODS: A multicenter prospective cohort study (EOFTT) including 518 consecutive patients who were treated for an Osteoporotic vertebral compression fracture (OVCF). For the present study, only patients with OF 4 fractures were analysed. Outcome parameters were complications, Visual Analogue Scale, Oswestry Disability Questionnaire, Timed Up & Go test, EQ-5D 5L, and Barthel Index after a minimum follow-up of 6 weeks. RESULTS: A total of 152 (29%) patients presented with OF 4 fractures with a mean age of 76 years (range 41-97). The most common treatment was short-segment posterior stabilization (51%; hybrid stabilization in 36%). Mean follow up was 208 days (±131 days), mean ODI was 30 ± 21. Dorsoventral stabilized patients were younger compared to the other groups (P .602, Barthel: P > .252, EQ-5D 5L index value: P > .610, VAS-EQ-5D 5L: P = 1.000). The inpatient complication rate was 8% after conservative and 16% after surgical treatment. During follow-up period 14% of conservatively treated patients and 3% of surgical treated patients experienced neurological deficits. CONCLUSIONS: Conservative therapy of OF 4 injuries seems to be viable option in patients with only moderate symptoms. Hybrid stabilization was the dominant treatment strategy leading to promising clinical short-term results. Stand-alone cement augmentation seems to be a valid alternative in selected cases

Clinical Evaluation of the Osteoporotic Fracture Treatment Score (OF-Score): Results of the Evaluation of the Osteoporotic Fracture Classification, Treatment Score and Therapy Recommendations (EOFTT) Study.

STUDY DESIGN Multicenter prospective cohort study. OBJECTIVE The study aims to validate the recently developed OF score for treatment decisions in patients with osteoporotic vertebral compression fractures (OVCF). METHODS This is a prospective multicenter cohort study (EOFTT) in 17 spine centers. All consecutive patients with OVCF were included. The decision for conservative or surgical therapy was made by the treating physician independent of the OF score recommendation. Final decisions were compared to the recommendations given by the OF score. Outcome parameters were complications, Visual Analogue Scale, Oswestry Disability Questionnaire, Timed Up & Go test, EQ-5D 5 L, and Barthel Index. RESULTS In total, 518 patients (75.3% female, age 75 ± 10) years were included. 344 (66%) patients received surgical treatment. 71% of patients were treated following the score recommendations. For an OF score cut-off value of 6.5, the sensitivity and specificity to predict actual treatment were 60% and 68% (AUC .684, P < .001). During hospitalization overall 76 (14.7%) complications occurred. The mean follow-up rate and time were 92% and 5 ± 3.5 months, respectively. While all patients in the study cohort improved in clinical outcome parameters, the effect size was significantly less in the patients not treated in line with the OF score's recommendation. Eight (3%) patients needed revision surgery. CONCLUSIONS Patients treated according to the OF score's recommendations showed favorable short-term clinical results. Noncompliance with the score resulted in more pain and impaired functional outcome and quality of life. The OF score is a reliable and save tool to aid treatment decision in OVCF

A conceptual model for action and design research

Organizational research has a pattern of special characteristics which make a clear distinction from other research paradigms. When using these approaches – based on Action and Design – the Interpretivist, Constructivist, and Participatory perspectives dominate. They have already proven to have strong foundations, which turn these paradigmatic approaches into effective ways for getting knowledge, doing things, and promoting change within organizational settings. It combines the traditional scientific, engineering, and organization development approaches, depicting how an organization can, simultaneously, solve multidimensional problems and produce actionable knowledge, effective change and useful artifacts. It has been developed using a Design Science Research approach, tested in a major organizational change program (Henriques, 2015; Henriques & ONeill, 2014), and successfully used to teach research methods essentials to Master and DBA students.info:eu-repo/semantics/publishedVersio