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Myasthenia gravis (MG) is a rare autoantibody-mediated disease affecting the neuromuscular junction. We performed a genome-wide association study of 5708 MG cases and 432,028 controls of European ancestry and a replication study in 3989 cases and 226,643 controls provided by 23andMe Inc. We identified 12 independent genome-wide significant hits (P

The InsectAI COST action will support insect monitoring and conservation at the national and continental scale in order to understand and counteract widespread insect declines. The Action will bring together a critical mass of researchers and stakeholders in image-based insect AI technologies to direct and drive the research agenda, build research capacity across Europe and support innovation and application.There is mounting evidence that populations of insects around the world are in sharp decline. Understanding trends in species and their drivers is key to knowing the size of the challenge, its causes and how to address it. To identify solutions that lead to sustainable biodiversity alongside economic prosperity, insect monitoring should be efficient and provide standardised and frequently updated status indicators to guide conservation actions.The EU Biodiversity Strategy 2030 identifies the critical challenge of delivering standardised information about the state of nature and image-based insect AI can contribute to this. Specifically, the EU Nature Restoration Law will likely set binding targets for the high resolution data that cameras can provide. Thus, outputs of the Action will contribute directly to EU policies implementation, where biodiversity monitoring is considered a key component.The InsectAI COST Action will organise workshops, conferences, short-term scientific missions, hackathons, design-sprints and much more, across four Working Groups. These groups will address how image-based insect AI technologies can best address Societal Needs, support innovation in Image Collection hardware, create standardised approaches for Image Processing and develop novel Data Analysis and Integration methods for turning data into actionable insights.

Abstract The scaffold protein PEAK1 acts downstream of integrin adhesion complexes and the epidermal growth factor receptor, orchestrating signaling events that control cell proliferation and cytoskeletal remodeling. In this study we investigated the role of PEAK1 in colorectal carcinoma (CRC) progression using various in vitro and in vivo models to replicate the stepwise pathogenesis of CRC. While we observed a cell-type specific role for PEAK1 in the proliferation and in human CRC cell lines in vitro, our in vivo experiments using different CRC mouse models driven by loss of Apc, with or without oncogenic Kras or Pten loss suggest that PEAK1 does not significantly contribute to tumor formation in vivo. However, the survival time of Peak1 −/− mice in the Apc fl/+ model appeared to be slightly increased. Furthermore, PEAK1 promotes EGF-induced Caco-2 cell proliferation and regulates spheroid polarization and lumenization. Given that the Caco-2 cells harbor mutations in the tumor suppressors APC and β-CATENIN, but not in other tumor suppressors or in proto-oncogenes, we conclude that the PEAK1’s impact on colon carcinogenesis is limited, potentially playing a role in the initial stage of the adenoma to carcinoma progression.

Abstract Myasthenia gravis (MG) is a rare autoantibody-mediated disease affecting the neuromuscular junction. We performed a genome-wide association study of 5708 MG cases and 432,028 controls of European ancestry and a replication study in 3989 cases and 226,643 controls provided by 23andMe Inc. We identified 12 independent genome-wide significant hits (P

Summary: Muscle-specific kinase (MuSK) orchestrates the establishment and maintenance of neuromuscular synapses. Autoantibodies targeting MuSK cause myasthenia gravis (MG), a disease characterized by skeletal muscle weakness. MuSK autoantibodies are predominantly IgG4 which are bispecific, functionally monovalent antibodies that are antagonists of MuSK signaling. We hypothesized that bivalent MuSK agonist antibodies can rescue MuSK MG. Here, we investigated whether ARGX-119, a MuSK frizzled-like domain agonist antibody, can ameliorate disease in passive transfer models induced by polyclonal patient IgG4. ARGX-119 improved survival and muscle weakness in a mouse model induced by one patient material, but not by three others. Patient-specific efficacy could not be explained by titer or competition for ARGX-119 binding, but rather correlated with the presence of MuSK activating antibodies in some patients. This first proof of concept of a MuSK agonist in a clinically relevant MuSK MG model forms a starting point for therapeutic studies toward ARGX-119 efficacy in neuromuscular diseases.

We evaluated a digital cognitive assessment platform, Philips IntelliSpace Cognition, in a case-control study of patients diagnosed with mild cognitive impairment (MCI) and cognitively normal (CN) older adults. Performance on individual neuropsychological tests, cognitive z-scores, and Alzheimer's disease (AD)-specific composite scores was compared between the CN and MCI groups. These groups were matched for age, sex, and education. Performance on all but two neuropsychological tests was worse in the MCI group. After ranking the cognitive scores by effect size, we found that the memory score was the most impaired, followed by executive functioning. The Early AD/MCI Alzheimer's Cognitive Composite (EMACC) and Preclinical Alzheimer's Cognitive Composite (PACC) scores were constructed from the digital tests on Philips IntelliSpace Cognition. Both AD-specific composite scores showed greater sensitivity and specificity than the Mini-Mental State Examination or individual cognitive z-scores. Together, these results demonstrate the diagnostic value of Philips IntelliSpace Cognition in patients with MCI.

Abstract Objective Aim of this study was to assess the cost‐effectiveness and cost‐utility of mindfulness‐based cognitive therapy (MBCT) and treatment as usual (TAU) compared to TAU alone in adults with Bipolar disorder (BD). Methods An economic evaluation with a time horizon of 15 months was conducted from a societal perspective. Outcomes were expressed in costs per quality adjusted life years (QALYs) and costs per responder using the inventory of depressive symptomatology clinician rating score. Results People with BD (N = 144) were included in this study. From a societal perspective, the difference of total costs between MBCT + TAU and TAU was €615, with lower costs in the MBCT + TAU group. Only healthcare costs differed significantly between the two groups. A small difference in QALYs in favor of MBCT + TAU was found combined with lower costs (−€836; baseline adjusted) for MBCT + TAU compared to TAU, resulting in a dominant incremental cost‐utility ratio. The probability that the MBCT + TAU was cost‐effective was 65%. All sensitivity analyses attested to the robustness of the base case analyses. Conclusion Concludingly, MBCT + TAU seems to be cost‐effective compared to TAU alone, indicated by a small or neglectable difference in effect, in favor of MBCT + TAU, while resulting in lower costs.

The mammalian carboxylesterase 1 (Ces1/CES1) family comprises several enzymes that hydrolyze many xenobiotic chemicals and endogenous lipids. To investigate the pharmacological and physiological roles of Ces1/CES1, we generated Ces1 cluster knockout (Ces1–/–) mice, and a hepatic human CES1 transgenic model in the Ces1–/– background (TgCES1). Ces1–/– mice displayed profoundly decreased conversion of the anticancer prodrug irinotecan to SN-38 in plasma and tissues. TgCES1 mice exhibited enhanced metabolism of irinotecan to SN-38 in liver and kidney. Ces1 and hCES1 activity increased irinotecan toxicity, likely by enhancing the formation of pharmacodynamically active SN-38. Ces1–/– mice also showed markedly increased capecitabine plasma exposure, which was moderately decreased in TgCES1 mice. Ces1–/– mice were overweight with increased adipose tissue, white adipose tissue inflammation (in males), a higher lipid load in brown adipose tissue, and impaired blood glucose tolerance (in males). These phenotypes were mostly reversed in TgCES1 mice. TgCES1 mice displayed increased triglyceride secretion from liver to plasma, together with higher triglyceride levels in the male liver. These results indicate that the carboxylesterase 1 family plays essential roles in drug and lipid metabolism and detoxification. Ces1–/– and TgCES1 mice will provide excellent tools for further study of the in vivo functions of Ces1/CES1 enzymes.

Background Studies have found statin treatment to be associated with improved 1-year survival after transcatheter aortic valve implantation (TAVI), suggesting pleiotropic effects of statins on preventing perioperative complications. Statin treatment is not associated with postoperative cardiovascular complications or mortality; however, other postoperative complications have not been investigated.Aim To explore whether preoperative statin treatment is associated with a lower short-term risk of mortality, readmission and major postoperative complications in older patients undergoing TAVI.Methods A retrospective cohort study including patients aged 65 years and older who had undergone a comprehensive geriatric assessment prior to TAVI between January 2014 and January 2021. The primary outcomes were 90-day mortality, 90-day readmissions and major postoperative complications according to the Clavien-Dindo classification. Multivariable logistic regression was performed with adjustment for potential confounders, namely age, gender, comorbidity, body mass index, smoking, diminished renal function, alcohol use and falls .Results This study included 584 patients, of whom 324 (55.5%) were treated with a statin. In the statin treated group, 15 (4.6%) patients died within 90 days of TAVI compared with 10 (3.8%) patients in the non statin group (adjusted OR 1.17; 95% CI 0.51 to 2.70). The number of 90-day readmissions was 39 (12.0%) and 34 (13.1%) (adjusted OR 0.91; 95% CI 0.54 to 1.52), respectively. In the statin treated group, 115 (35.5%) patients experienced a major complication compared with 98 (37.7%) in the non-statin group (adjusted OR 0.95; 95% CI 0.67 to 1.37).Conclusion Preoperative statin treatment is not associated with improved short-term outcomes after TAVI. A randomised controlled trial with different statin doses may be warranted to investigate whether initiating statin treatment before TAVI improves both postoperative outcomes and long-term survival.

This essay responds briefly to contributions by Éloïse Adde-Michel Margue, Étienne Doublier and Giovanni Francesco Contel discussing the volume Emperors and imperial discourse in Italy.

Abstract Introduction Both elevated cortisol and hippocampal volume have been linked to an increased risk for the development of Alzheimer's disease (AD). This longitudinal study assessed the effects of plasma cortisol on hippocampal atrophy and clinical progression rates in patients with mild cognitive impairment (MCI). Methods Patients with amnestic MCI (n = 304) were selected from the Alzheimer's Disease Neuroimaging Initiative (ADNI) based on availability of baseline plasma cortisol and hippocampal volume measures, assessed at baseline and during follow‐ups. We investigated associations between plasma cortisol, hippocampal volume, and risk of clinical progression to AD over a study period of up to 100 months (mean follow‐up time 36.8 months) using linear mixed models, Cox proportional hazards models, and Kaplan‐Meier estimators. Results Plasma cortisol predicted greater hippocampal atrophy, such that participants with higher cortisol showed faster decline in hippocampal volume over time (interaction: β = ‐0.15, p = 0.004). Small hippocampal volume predicted a higher risk of clinical progression to AD (haard ratio [HR] = 2.15; confidence in terval [CI], 1.64–2.80; p

Abstract Background Preliminary evidence suggests that Mindfulness-Based Cognitive Therapy (MBCT) is a promising treatment for bipolar disorder (BD). A proposed working mechanism of MBCT in attenuating depressive symptoms is reducing depressive rumination. The primary aim of this study was to investigate the effect of MBCT on self-reported trait depressive rumination and an experimental state measure of negative intrusive thoughts in BD patients. Exploratively, we investigated the effect of MBCT on positive rumination and positive intrusive thoughts. Methods The study population consisted of a subsample of bipolar type I or II patients participating in a multicenter randomized controlled trial comparing MBCT + treatment as usual (TAU) (N = 25) to TAU alone (N = 24). Trait depressive rumination (RRS brooding subscale) and intrusive thoughts (breathing focus task (BFT)) were assessed at baseline (full subsample) and post-treatment (MBCT + TAU; n = 15, TAU; n = 15). During the BFT, participants were asked to report negative, positive and neutral intrusive thoughts while focusing on their breathing. Results Compared to TAU alone, MBCT + TAU resulted in a significant pre- to post-treatment reduction of trait depressive rumination (R 2 = .16, F(1, 27) = 5.15, p = 0.031; medium effect size (f 2 = 0.19)) and negative intrusive thoughts on the BFT (R 2 = .15, F(1, 28) = 4.88, p = 0.036; medium effect size (f 2 = 0.17)). MBCT did not significantly change positive rumination or positive intrusive thoughts. Conclusions MBCT might be a helpful additional intervention to reduce depressive rumination in BD which might reduce risk of depressive relapse or recurrence. Considering the preliminary nature of our findings, future research should replicate our findings and explore whether this reduction in rumination following MBCT indeed mediates a reduction in depressive symptoms and relapse or recurrence in BD.

We evaluated a digital cognitive assessment platform, Philips IntelliSpace Cognition, in a case-control study of patients diagnosed with mild cognitive impairment (MCI) and cognitively normal (CN) older adults. Performance on individual neuropsychological tests, cognitive z -scores, and Alzheimer's disease (AD)-specific composite scores was compared between the CN and MCI groups. These groups were matched for age, sex, and education. Performance on all but two neuropsychological tests was worse in the MCI group. After ranking the cognitive scores by effect size, we found that the memory score was the most impaired, followed by executive functioning. The Early AD/MCI Alzheimer's Cognitive Composite (EMACC) and Preclinical Alzheimer's Cognitive Composite (PACC) scores were constructed from the digital tests on Philips IntelliSpace Cognition. Both AD-specific composite scores showed greater sensitivity and specificity than the Mini-Mental State Examination or individual cognitive z -scores. Together, these results demonstrate the diagnostic value of Philips IntelliSpace Cognition in patients with MCI. [ABSTRACT FROM AUTHOR]

Abstract Promiscuous activity of the Streptococcus pyogenes DNA nuclease CRISPR-Cas9 can result in destruction of a successfully modified sequence obtained by templated repair of a Cas9-induced DNA double-strand break. To avoid re-cutting, additional target-site-disruptions (TSDs) are often introduced on top of the desired base-pair alteration in order to suppress target recognition. These TSDs may lower the efficiency of introducing the intended mutation and can cause unexpected phenotypes. Alternatively, successfully edited sites can be protected against Cas9 re-cutting activity. This method exploits the finding that Cas9 complexed to trimmed guideRNAs can still tightly bind specific genomic sequences but lacks nuclease activity. We show here that the presence of a guideRNA plus a trimmed guideRNA that matches the successfully mutated sequence, which we call hideRNA, can enhance the recovery of precise single base-pair substitution events tenfold. The benefit of hideRNAs in generating a single point mutation was demonstrated in cell lines using plasmid-based delivery of CRISPR-Cas9 components and in mouse zygotes injected with Cas9/guideRNA plus Cas9/hideRNA ribonucleoprotein complexes. However, hRNA protection sometimes failed, which likely reflects an unfavorable affinity of hRNA/Cas9 versus gRNA/Cas9 for the DNA target site. HideRNAs can easily be implemented into current gene editing protocols and facilitate the recovery of single base-pair substitution. As such, hideRNAs are of great value in gene editing experiments demanding high accuracy.

The pro-tumorigenic effects of vimentin have been attributed to intracellular functions in tumour cells so far. Here, the authors show that tumour endothelial cells can secrete vimentin as a pro-angiogenic factor and that targeting of vimentin can be used as an immunotherapeutic strategy.

Discontinuing antidepressant medication (ADM) can be challenging for patients and clinicians. In the current study we investigated if Mindfulness-Based Cognitive Therapy (MBCT) added to supported protocolized discontinuation (SPD) is more effective than SPD alone to help patients discontinue ADM. This study describes a prospective, cluster-randomized controlled trial (completed). From 151 invited primary care practices in the Netherlands, 36 (24%) were willing to participate and randomly allocated to SPD+MBCT (k = 20) or SPD (k = 16). Adults using ADM > 9 months were invited by GPs to discuss tapering, followed by either MBCT+SPD, or SPD alone. Exclusion criteria included current psychiatric treatment; substance use disorder; non-psychiatric indication for ADM; attended MBCT within past 5 years; cognitive barriers. From the approximately 3000 invited patients, 276 responded, 119 participated in the interventions and 92 completed all assessments. All patients were offered a decision aid and a personalized tapering schedule (with GP). MBCT consisted of eight group sessions of 2.5 hours and one full day of practice. SPD was optional and consisted of consultations with a mental health assistant. Patients were assessed at baseline and 6, 9 and 12 months follow-up, non-blinded. In line with our protocol, primary outcome was full discontinuation of ADM within 6 months. Secondary outcomes were depression, anxiety, withdrawal symptoms, rumination, well-being, mindfulness skills, and self-compassion. Patients allocated to SPD + MBCT (n = 73) were not significantly more successful in discontinuing (44%) than those allocated to SPD (n = 46; 33%), OR 1.60, 95% CI 0.73 to 3.49, p = .24, number needed to treat = 9. Only 20/73 allocated to MBCT (27%) completed MBCT. No serious adverse events were reported. In conclusion, we were unable to demonstrate a significant benefit of adding MBCT to SPD to support discontinuation in general practice. Actual participation in patient-tailored interventions was low, both for practices and for patients. (Trial registration: ClinicalTrials.gov PRS ID: NCT03361514 registered December 2017)