INTRODUCTION: Amyloid precursor protein (APP) undergoes striking changes following traumatic brain injury (TBI). Considering its role in the control of gene expression, we investigated whether APP regulates transcription and translation following TBI. METHODS: We assessed brain morphology (n = 4-9 mice/group), transcriptome (n = 3 mice/group), proteome (n = 3 mice/group), and behavior (n = 17-27 mice/group) of wild-type (WT) and APP knock-out (KO) mice either untreated or 10-weeks following TBI. RESULTS: After TBI, WT mice displayed transcriptional programs consistent with late stages of brain repair, hub genes were predicted to impact translation and brain proteome showed subtle changes. APP KO mice largely replicated this transcriptional repertoire, but showed no transcriptional nor translational response to TBI. DISCUSSION: The similarities between WT mice following TBI and APP KO mice suggest that developmental APP deficiency induces a condition reminiscent of late stages of brain repair, hampering the control of gene expression in response to injury. HIGHLIGHTS: 10-weeks after TBI, brains exhibit transcriptional profiles consistent with late stage of brain repair. Developmental APP deficiency maintains brains perpetually in an immature state akin to late stages of brain repair. APP responds to TBI by changes in gene expression at a transcriptional and translational level. APP deficiency precludes molecular brain changes in response to TBI.

• MeSH
• Amyloid beta-Protein Precursor * genetics   MeSH
• Disease Models, Animal MeSH
• Brain * metabolism   pathology   MeSH
• Mice, Inbred C57BL MeSH
• Mice, Knockout MeSH
• Mice MeSH
• Brain Injuries * metabolism   genetics   pathology   MeSH
• Proteome * metabolism   MeSH
• Proteomics MeSH
• Transcriptome * MeSH
• Brain Injuries, Traumatic * metabolism   genetics   pathology   MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

OBJECTIVE: The clinical diversity of schizophrenia is reflected by structural brain variability. It remains unclear how this variability manifests across different gray and white matter features. In this meta- and mega-analysis, the authors investigated how brain heterogeneity in schizophrenia is distributed across multimodal structural indicators. METHODS: The authors used the ENIGMA dataset of MRI-based brain measures from 22 international sites with up to 6,037 individuals for a given brain measure. Variability and mean values of cortical thickness, cortical surface area, cortical folding index, subcortical volume, and fractional anisotropy were examined in individuals with schizophrenia and healthy control subjects. RESULTS: Individuals with schizophrenia showed greater variability in cortical thickness, cortical surface area, subcortical volume, and fractional anisotropy within the frontotemporal and subcortical network. This increased structural variability was mainly associated with psychopathological symptom domains, and the schizophrenia group frequently displayed lower mean values in the respective structural measures. Unexpectedly, folding patterns were more uniform in individuals with schizophrenia, particularly in the right caudal anterior cingulate region. The mean folding values of the right caudal anterior cingulate region did not differ between the schizophrenia and healthy control groups, and folding patterns in this region were not associated with disease-related parameters. CONCLUSIONS: In patients with schizophrenia, uniform folding patterns in the right caudal anterior cingulate region contrasted with the multimodal variability in the frontotemporal and subcortical network. While variability in the frontotemporal and subcortical network was associated with disease-related diversity, uniform folding may indicate a less flexible interplay between genetic and environmental factors during neurodevelopment.

• MeSH
• Anisotropy MeSH
• White Matter pathology   diagnostic imaging   MeSH
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Magnetic Resonance Imaging MeSH
• Brain * pathology   diagnostic imaging   MeSH
• Schizophrenia * pathology   diagnostic imaging   MeSH
• Gray Matter pathology   diagnostic imaging   MeSH
• Diffusion Tensor Imaging MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Meta-Analysis MeSH

BACKGROUND AND OBJECTIVES: Patients with multiple sclerosis (MS) may demonstrate better disease control when treatment is initiated on high-efficacy disease-modifying therapies (DMTs) from onset. This subgroup analysis assessed the long-term efficacy and safety profile of the high-efficacy DMT ocrelizumab (OCR) as first-line therapy for early-stage relapsing MS (RMS). METHODS: Post hoc exploratory analyses of efficacy and safety were performed in a subgroup of treatment-naive patients with RMS who received ≥1 dose of OCR in the multicenter OPERA I/II (NCT01247324/NCT01412333) studies. Patients were randomized to OCR or interferon β-1a for 96 weeks (double-blind controlled treatment period [DBP]), before switching to OCR in the open-label extension (OLE). Efficacy assessments included no evidence of disease activity (NEDA-3), 24-week confirmed disability progression (CDP), MRI lesion activity, change in whole-brain volume; with safety outcomes assessed over a 9-year treatment period. RESULTS: Overall, 757 patients were included (interferon-treated n = 382, mean age 36.3 years, 65.7% female; OCR-treated n = 375, mean age 35.5 years, 64.0% female); 505 of 757 (66.7%) completed 9 years of follow-up. The difference in NEDA status between OCR-treated and interferon-treated patients achieved during the DBP (72.5% and 43.8%, respectively, odds ratio 3.48, 95% CI 2.52-4.81) was maintained throughout the 7-year OLE (48.2% vs 25.7%; odds ratio 2.72, 95% CI 1.94-3.82). No 24-week CDP was observed in 78.7% of OCR-treated patients over 9 years. Brain volume loss over the entire study period remained numerically higher among patients starting OCR later (p = 0.09 at OLE at week 336). During the DBP, safety profiles in both groups were similar; no new safety signals were observed during the OLE. Over >9 years of continuous OCR treatment, the rate of infections remained low and stable over time. DISCUSSION: A higher proportion of OCR-treated patients achieved NEDA status compared with interferon-treated patients during the DBP, which was maintained throughout the OLE. After switching to OCR, disability accrual and brain volume loss among interferon-treated patients became similar to the OCR-OCR group, but disability and brain volume loss accrued during interferon treatment were not recovered. Possible study limitations include assessment bias due to unmaintained blinding during the OLE. These data support OCR as first-line therapy for these patients. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that OCR delays disease progression in treatment-naïve patients with early-stage RMS.

• MeSH
• Adult MeSH
• Double-Blind Method MeSH
• Antibodies, Monoclonal, Humanized * adverse effects   therapeutic use   administration & dosage   MeSH
• Immunologic Factors * adverse effects   administration & dosage   therapeutic use   MeSH
• Interferon beta-1a therapeutic use   administration & dosage   MeSH
• Middle Aged MeSH
• Humans MeSH
• Magnetic Resonance Imaging MeSH
• Disease Progression MeSH
• Multiple Sclerosis, Relapsing-Remitting * drug therapy   diagnostic imaging   MeSH
• Treatment Outcome MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH
• Randomized Controlled Trial MeSH

The EN ISO 15189:2022 standard, titled "Medical laboratories - Requirements for quality and competence," is a significant update to the regulations for medical laboratories. The revised standard was published on December 6, 2022, replacing both EN ISO 15189:2012 and EN ISO 22870:2016. Key objectives of the revision include: 1. Alignment with ISO/IEC 17025:2017, 2. Removal of unintended prescription, 3. Focus on patient interest and safety, 4. Minimization of new requirements, and 5. Improved clarity of text. Dedicating to harmonizing accreditation processes across Europe the EFLM Committee on Accreditation and ISO/CEN standards (C: A/ISO) has produced this guidance document to assist the laboratory medicine community in understanding and implementing the criteria of the EN ISO 15189 revision. Two main objectives of the guidance in educating both laboratories and accreditation bodies with their assessors as well as other stakeholders in laboratory medicine were agreed on. Firstly, to clarify the relevant changes covering all paragraphs of the standard and secondly to make an impact analysis on previous C: A/ISO guidance documents.

• MeSH
• Accreditation * standards   MeSH
• Laboratories, Clinical * standards   MeSH
• Laboratories standards   MeSH
• Humans MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Geographicals
• Europe MeSH

BACKGROUND AND OBJECTIVES: Early treatment of multiple sclerosis (MS) reduces disease activity and the risk of long-term disease progression. Effectiveness of ocrelizumab is established in relapsing MS (RMS); however, data in early RMS are lacking. We evaluated the 4-year effectiveness and safety of ocrelizumab as a first-line therapy in treatment-naive patients with recently diagnosed relapsing-remitting MS (RRMS). METHODS: ENSEMBLE was a prospective, 4-year, international, multicenter, single-arm, open-label, phase IIIb study. Patients were treatment naive, aged 18-55 years, had early-stage RRMS with a disease duration ≤3 years, Expanded Disability Status Scale (EDSS) score ≤3.5, and ≥1 clinically reported relapse(s) or ≥1 signs of brain inflammatory activity on MRI in the prior 12 months. Patients received IV ocrelizumab 600 mg every 24 weeks. Effectiveness endpoints over 192 weeks were proportion of patients with no evidence of disease activity (NEDA-3; defined as absence of relapses, 24-week confirmed disability progression [CDP], and MRI measures, with prespecified MRI rebaselining at week 8), 24-week/48-week CDP and 24-week confirmed disability improvement, annualized relapse rate (ARR), mean change in EDSS score from baseline, and safety. Cognitive status, patient-reported outcomes, and serum neurofilament light chain (NfL) were assessed. Descriptive analysis was performed on the intention-to-treat population. RESULTS: Baseline characteristics (N = 678) were consistent with early-stage RRMS (n = 539 patients, 64.6% female, age 40 years and younger; median age: 31.0 years; duration since: MS symptom onset 0.78 years, RRMS diagnosis 0.24 years; mean baseline EDSS score [SD] 1.71 [0.95]). At week 192, most of the patients had NEDA-3 (n = 394/593, 66.4%), 85.0% had no MRI activity, 90.9% had no relapses, and 81.8% had no 24-week CDP over the study duration. Adjusted ARR at week 192 was low (0.020, 95% CI 0.015-0.027). NfL levels were reduced to and remained within the healthy donor range, by week 48 and week 192, respectively. No new or unexpected safety signals were observed. DISCUSSION: Disease activity based on clinical and MRI measures was absent in most of the patients treated with ocrelizumab over 4 years in the ENSEMBLE study. Safety was consistent with the known profile of ocrelizumab. Although this single-arm study was limited by lack of a parallel group for comparison of outcome measures, the positive benefit-risk profile observed may provide confidence to adopt ocrelizumab as a first-line treatment in newly diagnosed patients with early RMS. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that adult patients with early-stage MS who were treatment naive maintained low disease activity (NEDA-3) over 4 years with ocrelizumab treatment; no new safety signals were detected. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier NCT03085810; first submitted March 16, 2017; first patient enrolled: March 27, 2017; available at clinicaltrials.gov/ct2/show/NCT03085810.

• MeSH
• Adult MeSH
• Antibodies, Monoclonal, Humanized * therapeutic use   adverse effects   administration & dosage   MeSH
• Immunologic Factors * therapeutic use   adverse effects   administration & dosage   MeSH
• Middle Aged MeSH
• Humans MeSH
• Magnetic Resonance Imaging MeSH
• Adolescent MeSH
• Young Adult MeSH
• Disability Evaluation MeSH
• Disease Progression MeSH
• Prospective Studies MeSH
• Multiple Sclerosis, Relapsing-Remitting * drug therapy   diagnostic imaging   MeSH
• Treatment Outcome MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase III MeSH
• Multicenter Study MeSH

Posttraumatic stress disorder (PTSD) is associated with lower cortical thickness (CT) in prefrontal, cingulate, and insular cortices in diverse trauma-affected samples. However, some studies have failed to detect differences between PTSD patients and healthy controls or reported that PTSD is associated with greater CT. Using data-driven dimensionality reduction, we sought to conduct a well-powered study to identify vulnerable networks without regard to neuroanatomic boundaries. Moreover, this approach enabled us to avoid the excessive burden of multiple comparison correction that plagues vertex-wise methods. We derived structural covariance networks (SCNs) by applying non-negative matrix factorization (NMF) to CT data from 961 PTSD patients and 1124 trauma-exposed controls without PTSD. We used regression analyses to investigate associations between CT within SCNs and PTSD diagnosis (with and without accounting for the potential confounding effect of trauma type) and symptom severity in the full sample. We performed additional regression analyses in subsets of the data to examine associations between SCNs and comorbid depression, childhood trauma severity, and alcohol abuse. NMF identified 20 unbiased SCNs, which aligned closely with functionally defined brain networks. PTSD diagnosis was most strongly associated with diminished CT in SCNs that encompassed the bilateral superior frontal cortex, motor cortex, insular cortex, orbitofrontal cortex, medial occipital cortex, anterior cingulate cortex, and posterior cingulate cortex. CT in these networks was significantly negatively correlated with PTSD symptom severity. Collectively, these findings suggest that PTSD diagnosis is associated with widespread reductions in CT, particularly within prefrontal regulatory regions and broader emotion and sensory processing cortical regions.

• MeSH
• Emotions MeSH
• Humans MeSH
• Magnetic Resonance Imaging MeSH
• Brain MeSH
• Stress Disorders, Post-Traumatic * psychology   MeSH
• Prefrontal Cortex MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

OBJECTIVE: The objective of this qualitative systematic review is to understand the experiences of mental health practitioners after clients' suicide. INTRODUCTION: Mental health practitioners inevitably encounter client suicide during their careers, which can significantly affect their personal lives and professional outcomes. A deeper understanding of mental health practitioners' experiences in the aftermath of clients' suicide is necessary to provide effective support and assist with adaptation to this situation. INCLUSION CRITERIA: This systematic review will consider qualitative studies that explore the experiences of mental health practitioners, including psychotherapists, psychiatrists, psychological counselors, clinical psychologists, psychiatric mental health nurse practitioners, and social workers following clients' suicide. Experiences may include emotional responses, coping strategies, changes in social relationships, and reflections on practice. METHODS: This review will follow the JBI methodology for qualitative systematic reviews. The databases to be searched will include PubMed, CINAHL (EBSCOhost), Embase, PsycINFO (EBSCOhost), SocINDEX (EBSCOhost), Web of Science, CNKI, Wanfang, VIP, Bibliographia Medica Čechoslovaca, and Bibliographia Medica Slovaca. Gray literature sources will include Google Scholar and ProQuest Dissertations and Theses. Studies in English, Czech, Slovak, and Chinese will be assessed for inclusion regardless of publication date. Studies that are initially selected will be assessed for methodological quality using the JBI critical appraisal tool for qualitative studies. Then, findings with illustrations will be extracted for subsequent meta-aggregation and ConQual assessment. All the above steps will be conducted by 2 independent reviewers. REVIEW REGISTRATION: PROSPERO CRD42023410523.

• MeSH
• Adaptation, Psychological MeSH
• Qualitative Research * MeSH
• Humans MeSH
• Suicide * psychology   MeSH
• Systematic Reviews as Topic * MeSH
• Health Personnel psychology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

BACKGROUND: Ublituximab is a novel anti-CD20 monoclonal antibody glycoengineered for enhanced antibody-dependent cellular cytotoxicity. The phase 3 ULTIMATE I and II studies showed significant improvements in annualized relapse rate, total number of gadolinium-enhancing (Gd+) T1 lesions, and total number of new or enlarging T2 at Week 96, as well as improvement in the proportion of participants with no evidence of disease activity (NEDA) from Weeks 24-96 with ublituximab vs. teriflunomide. METHODS: In ULTIMATE I (NCT03277261; www.clinicaltrials.gov) (N = 549) and II (NCT03277248; www.clinicaltrials.gov) (N = 545), participants with relapsing multiple sclerosis received ublituximab 450 mg intravenous infusion every 24 weeks (following Day 1 infusion of 150 mg and Day 15 infusion of 450 mg) or teriflunomide 14 mg oral once daily for 96 weeks. Pooled post hoc analyses evaluated NEDA by treatment epoch and participant subtype: age ( ≤ 38 or >38 years), early or later disease (<3 or ≥3 years following diagnosis), treatment history (treatment naïve or previously treated), 0 or ≥1 Gd+ T1 lesions at baseline, and Expanded Disability Status Scale score ≤ 3.5 or >3.5 at baseline. NEDA was defined as no confirmed relapses, no Gd+ T1 lesions, no new or enlarging T2 lesions, and no disability progression confirmed for ≥12 weeks. RESULTS: NEDA rates in the ublituximab vs. teriflunomide cohorts by treatment epoch were: Weeks 0-96, 44.6% vs. 12.4% (3.6 × improvement); Weeks 24-96 (re-baselined), 82.1% vs. 22.5% (3.6 × improvement); and Weeks 48-96 (re-baselined), 88.2% vs. 30.4% (2.9 × improvement) (all p < 0.0001). The primary driver of disease activity in ublituximab-treated participants was new or enlarging T2 lesions during Weeks 0-24. 41.8% of ublituximab-treated participants who had evidence of disease activity in the first year (Weeks 0-48) experienced NEDA in the second year of treatment (Weeks 48-96) compared with 17.3% of teriflunomide-treated participants. At Weeks 24-96 (re-baselined), rates of NEDA were significantly higher with ublituximab than teriflunomide in all participant subtypes (all p < 0.0001). CONCLUSIONS: ULTIMATE I and II pooled post hoc analyses demonstrated a consistent NEDA benefit among ublituximab-treated participants across treatment epochs and key participant subpopulations.

• Publication type
• Journal Article MeSH

Velikán české novinařiny v polistopadových textech; Velikán české novinařiny v polistopadových textech Milan Kundera o něm tvrdil, že by byl nejlepším ministrem zahraničí v polistopadové éře. Antonín J. Liehm proslul zejména svou novinářskou činností během šedesátých let u nás a následný exil z něj učinil mimořádnou postavu evropské kultury. Patřil k těm několika silným hlasům, které zvládaly kriticky komentovat českou kulturu, umění, společnost i politiku za každé konstelace. A nepřestal ani po pádu železné opony a návratu Československa k demokracii. Výbor z jeho polistopadových textů ukazuje, že ať už jeho tématy byly nové české filmy, kulturní politika, nebo reflexe novinářské práce, vždy o nich psal s vědomím širšího celku a souvislostí, které společenský a kulturní život propojují s dějinami a perspektivou do budoucna. I proto je Liehmova publicistika i po letech často velmi aktuální a má co říct ke stavu nejen české společnosti a kultury.