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Dystonia is one of the most prevalent movement disorders, characterized by significant clinical and etiological heterogeneity. Despite considerable heritability (~25%) and the identification of several disease-linked genes, the etiology in most patients remains elusive. Moreover, understanding the correlations between clinical manifestation and genetic variants has become increasingly complex. To comprehensively unravel dystonia's genetic spectrum, we performed exome sequencing on 1,924 dystonia patients [40.3% male, 92.9% White, 93.2% isolated dystonia, median age at onset (AAO) 33 years], including 1,895 index patients, who were previously genetically unsolved. The sample was mainly based on two dystonia registries (DysTract and the Dystonia Coalition). Further, 72 additional patients of Asian ethnicity, mainly from Malaysia, were also included. We prioritized patients with negative genetic prescreening, early AAO, positive family history, and multisite involvement of dystonia. Rare variants in genes previously linked to dystonia ( n =405) were examined. Variants were confirmed via Sanger sequencing, and segregation analysis was performed when possible. We identified 137 distinct likely pathogenic or pathogenic variants (according to ACMG criteria) across 51 genes in 163/1,924 patients [42.9% male, 85.9% White, 68.7% isolated dystonia, median AAO 19 years]. This included 153/1,895 index patients, resulting in a diagnostic yield of 8.1%. Notably, 77/137 (56.2%) of these variants were novel, with recurrent variants in EIF2AK2 , VPS16 , KCNMA1 , and SLC2A1 , and novel variant types such as two splice site variants in KMT2B , supported by functional evidence. Additionally, 321 index patients (16.9%) harbored variants of uncertain significance in 102 genes. The most frequently implicated genes included VPS16 , THAP1 , GCH1 , SGCE , GNAL , and KMT2B. Presumably pathogenic variants in less well-established dystonia genes were also found, including KCNMA1 , KIF1A , and ZMYND11. At least six variants (in ADCY5 , GNB1 , IR2BPL, KCNN2 , KMT2B , and VPS16 ) occurred de novo, supporting pathogenicity. ROC curve analysis indicated that AAO and the presence of generalized dystonia were the strongest predictors of a genetic diagnosis, with diagnostic yields of 28.6% in patients with generalized dystonia and 20.4% in those with AAO < 30 years. This study provides a comprehensive examination of the genetic landscape of dystonia, revealing valuable insights into the frequency of dystonia-linked genes and their associated phenotypes. It underscores the utility of exome sequencing in establishing diagnoses within this heterogeneous condition. Despite prescreening, presumably pathogenic variants were identified in almost 10% of patients. Our findings reaffirm several dystonia candidate genes and expand the phenotypic spectrum of some of these genes to include prominent, sometimes isolated dystonia., Competing Interests: K.E.Z. has received research support from Strathmann and the German Research Council. She reports speaker’s honoraria from Bayer Vital GmbH, BIAL, AbbVie, Alexion, Allergan and Merz outside the submitted work. She has served as a consultant and received fees from Merz, Ipsen, Alexion, Bial and the German Federal Institute for Drugs and Medical Devices (BfArM). J.S.P. has research support RF1NS075321, RO1NS134586, RO1NS103957, NS107281, NS097437, U54NS116025, U19 NS110456, NS097799, R33 AT010753, RO1NS118146, NS124738, R01AG065214, NS124789, R21 NS133875, R21TR004422, R21TR005231. Foundation support: Michael J Fox Foundation, Barnes-Jewish Hospital Foundation (Elliot Stein Family Fund and Parkinson disease research fund), American Parkinson Disease Association (APDA) Advanced Research Center at Washington University, Missouri Chapter of the APDA, Paula and Rodger Riney Fund, Jo Oertli Fund, Huntington Disease Society of America, Murphy Fund, Fixel Foundation, N. Grant Williams Fund, Pohlman Fund, CHDI and Prilenia. He is also co-director for the Dystonia Coalition, which has received the majority of its support through the NIH (grants NS116025, NS065701 from the National Institutes of Neurological Disorders and Stroke TR 001456 from the Office of Rare Diseases Research at the National Center for Advancing Translational Sciences). R.L.B. performs botulinum toxin injections at the University of Rochester (50% effort); serves/has served on scientific advisory board for Allergan, Ipsen, Merz and Revance; receives research support Fox Foundation; NIH (NINDS, ORDR): Dystonia Coalition Projects, Site PI; Consultant and research study rater for Abbvie/Allergan; holds stock options in VisualDx; and serves/has served as an expert witness in legal proceedings including malpractice, not involving commercial entities. J.V. has received consultancies from Medtronic, Boston Scientific, Ceregate, and Newronika. He has served on advisory boards for Medtronic and Boston Scientific. He reports speaker’s honoraria from Medtronic, Boston Scientific, Abbott, AbbVie, Bial, and Zambon outside the submitted work. H.A.J. has active or recent grant support (recent, active, or pending) from the US government (NIH), private philanthropic organizations (Cure Dystonia Now, Lesch-Nyhan Syndrome Children’s Research Foundation), and industry (Abbvie, Addex, Aeon, Sage, Ipsen, Jazz). H.A.J. has also served on advisory boards or as a consultant for the NIH (CREATE Bio DSMB) and industry (Abbvie, Addex, Ipsen, Merz, and Vima). He has received stipends for administrative work from the International Parkinson’s Disease and Movement Disorders Society. H.A.J. has also served on the Scientific Advisory Boards for several private foundations (Benign Essential Blepharospasm Research Foundation, Dystonia Medical Research Foundation). He also is principle investigator for the Dystonia Coalition, which has received the majority of its support through the NIH (NS116025, NS065701 from the National Institutes of Neurological Disorders and Stroke TR001456 from the Office of Rare Diseases Research at the National Center for Advancing Translational Sciences). C.Kl. has served as medical advisor to Centogene, Retromer Therapeutics, Takeda, and Lundbeck and has received speakers’ honoraria from Bial and Desitin. C.Ka. reports serving on advisory boards for Biogen and Roche outside of the submitted work. The other authors report no competing interests.

Background: Elevated lipoprotein(a) (Lp(a)) is an established risk factor for cardiovascular disease (CVD). To date, the only approved treatment to lower Lp(a) is lipoprotein apheresis (LA). Previous studies have demonstrated that LA is effective in reducing cardiovascular (CV) risk in patients with elevated low-density lipoprotein cholesterol (LDL-C) and/or Lp(a). Here we report our long-term experience with LA and its effectiveness in reducing CVD events in patients with elevated Lp(a)., Methods: This retrospective open-label, single-center study included 25 individuals with Lp(a) elevation >60 mg/dL and LDL-C < 2.59 mmol/L who had indication for LA. The primary endpoint of this study was the incidence of any CV event (determined by medical records) after initiation of LA., Results: Mean LA treatment duration was 7.1 years (min-max: 1-19 years). Median Lp(a) was reduced from 95.0 to 31.1 mg/dL after LA (-67.3%, p < 0.0001). Mean LDL-C was reduced from 1.85 to 0.76 mmol/L after LA (-58.9%, p < 0.0001). Prior to LA, 81 CV events occurred in total (0.87 events/patient/year). During LA, 49 CV events occurred in total (0.24 events/patient/year; -0.63, p = 0.001). Yearly major adverse cardiac event (MACE) rate was reduced from 0.34 to 0.006 (-0.33, p = 0.0002). Similar results were obtained when considering only individuals with baseline LDL-C below 1.42 mmol/L., Conclusion: In this observational study of a heterogeneous CV high-risk cohort with elevated Lp(a), LA reduced Lp(a) levels and was paralleled by a decrease in CV events and MACE. We recommend LA for patients with high Lp(a) who still have CV events despite optimal lipid-lowering medication and lifestyle changes., Competing Interests: Conflict of interest None., (Copyright © 2024 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

High resistance to environmental factors as well as the ability to form biofilms allow Listeria monocytogenes to persist for a long time in difficult-to-reach places in food-producing plants. L. monocytogenes enters final products from contaminated surfaces in different areas of plants and poses a health risk to consumer. Modified surfaces are already used in the food industry to prevent cross-contamination. In this study, stainless-steel surfaces were coated with nanoscale silicon dioxide and the effects on attachment, bacterial growth and detachment of L. monocytogenes were evaluated. Attachment was considered for three different ways of application to simulate different scenarios of contamination. Bacterial growth of L. monocytogenes on the surface was recorded over a period of up to 8 h. Detachment was tested after cleaning inoculated stainless-steel surfaces with heated distilled water or detergent. Coating stainless-steel surfaces with nanoscale silica tends to reduce adherence and increased detachment and does not influence the bacterial growth of L. monocytogenes. Further modifications of the coating are necessary for a targeted use in the reduction of L. monocytogenes in food-processing plants., (© 2023. The Author(s).)

We argue that many of the crises currently afflicting science can be associated with a present failure of science to sufficiently embody its own values. Here, we propose a response beyond mere crisis resolution based on the observation that an ethical framework of flourishing derived from the Buddhist tradition aligns surprisingly well with the values of science itself. This alignment, we argue, suggests a recasting of science from a competitively managed activity of knowledge production to a collaboratively organized moral practice that puts kindness and sharing at its core. We end by examining how Flourishing Science could be embodied in academic practice, from individual to organizational levels, and how that could help to arrive at a flourishing of scientists and science alike., Competing Interests: We declare we have no competing interests., (© 2023 The Authors.)

Background and Aims: Low-density lipoprotein cholesterol (LDL-C) is the main therapeutic target in the treatment of hypercholesterolemia. Small interfering RNA (siRNA) inclisiran is a new drug, which targets PCSK9 mRNA in the liver, reducing concentrations of circulating LDL-C. In randomized trials, inclisiran demonstrated a substantial reduction in LDL-C. The German Inclisiran Network (GIN) aims to evaluate LDL-C reductions in a real-world cohort of patients treated with inclisiran in Germany., Methods: Patients who received inclisiran in 14 lipid clinics in Germany for elevated LDL-C levels between February 2021 and July 2022 were included in this analysis. We described baseline characteristics, individual LDL-C changes (%) and side effects in 153 patients 3 months (n = 153) and 9 months (n = 79) after inclisiran administration., Results: Since all patients were referred to specialized lipid clinics, only one-third were on statin therapy due to statin intolerance. The median LDL-C reduction was 35.5% at 3 months and 26.5% at 9 months. In patients previously treated with PCSK9 antibody (PCSK9-mAb), LDL-C reductions were less effective than in PCSK9-mAb-naïve patients (23.6% vs. 41.1% at 3 months). Concomitant statin treatment was associated with more effective LDL-C lowering. There was a high interindividual variability in LDL-C changes from baseline. Altogether, inclisiran was well-tolerated, and side effects were rare (5.9%)., Conclusion: In this real-world patient population referred to German lipid clinics for elevated LDL-C levels, inclisiran demonstrated a high interindividual variability in LDL-C reductions. Further research is warranted to elucidate reasons for the interindividual variability in drug efficacy., (© 2023. The Author(s).)

Here we present a systematic plan to the experimental study of test-retest reliability in the multitasking domain, adopting the multitrait-multimethod (MTMM) approach to evaluate the psychometric properties of performance in Düker-type speeded multiple-act mental arithmetic. These form of tasks capacitate the experimental analysis of integrated multi-step processing by combining multiple mental operations in flexible ways in the service of the overarching goal of completing the task. A particular focus was on scoring methodology, particularly measures of response speed variability. To this end, we present data of two experiments with regard to (a) test-retest reliability, (b) between-measures correlational structure, (c) and stability (test-retest practice effects). Finally, we compared participants with high versus low performance variability to assess ability-related differences in measurement precision (typically used as proxy to "simulate" patient populations), which is especially relevant in the applied fields of clinical neuropsychology. The participants performed two classic integrated multi-act arithmetic tasks, combining addition and verification (Exp. 1) and addition and comparison (Exp. 2). The results revealed excellent test-retest reliability for the standard and the variability measures. The analysis of between-measures correlational structure revealed the typical pattern of convergent and discriminant relationships, and also, that absolute response speed variability was highly correlated with average speed ( r > 0.85), indicating that these measures mainly deliver redundant information. In contrast, speed-adjusted (relativized) variability revealed discriminant validity being correlated to a much lesser degree with average speed, indicating that this measure delivers additional information not already provided by the speed measure. Furthermore, speed-adjusted variability was virtually unaffected by test-retest practice, which makes this measure interesting in situations with repeated testing., 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., (Copyright © 2022 Schumann, Steinborn, Flehmig, Kürten, Langner and Huestegge.)

Aims: Lipoprotein (a) [Lp(a)] is a lipoprotein species causatively associated with atherosclerosis. Unlike statins, PCSK9 inhibitors (PCSK9i) reduce Lp(a), but this reduction is highly variable. Levels of Lp(a) are chiefly governed by the size of its signature protein, apolipoprotein (a) [apo(a)]. Whether this parameter determines some of the reduction in Lp(a) induced by PCSK9i remains unknown. We aimed to investigate if the Lp(a) lowering efficacy of PCSK9i is modulated by the size of apo(a), which is genetically determined by the variable number of KIV domains present on that protein., Methods and Results: The levels of Lp(a) and the size of apo(a) were assessed in plasma samples from 268 patients before and after treatment with PCSK9i. Patients were recruited at the Outpatient Lipid Clinic of the Charité Hospital (Berlin) between 2015 and 2020. They were hypercholesterolaemic at very high cardiovascular disease risk with low-density lipoprotein (LDL)-cholesterol levels above therapeutic targets despite maximally tolerated lipid-lowering therapy. Patients received either Alirocumab (75 or 150 mg) or Evolocumab (140 mg) every 2 weeks. Apo(a), apoB100, and apoE concentrations as well as apoE major isoforms were determined by liquid chromatography high-resolution mass spectrometry. Apo(a) isoforms sizes were determined by western blot. PCSK9i sharply reduced LDL-cholesterol (-57%), apoB100 (-47%), and Lp(a) (-36%). There was a positive correlation between the size of apo(a) and the relative reduction in Lp(a) induced by PCSK9i (r = 0.363, P = 0.0001). The strength of this association remained unaltered after adjustment for baseline Lp(a) levels and all other potential confounding factors. In patients with two detectable apo(a) isoforms, there was also a positive correlation between the size of apo(a) and the reduction in Lp(a), separately for the smaller (r = 0.350, P = 0.0001) and larger (r = 0.324, P = 0.0003) isoforms. The relative contribution of the larger isoform to the total concentration of apo(a) was reduced from 29% to 15% (P < 0.0001)., Conclusions: The size of apo(a) is an independent determinant of the response to PCSK9i. Each additional kringle domain is associated with a 3% additional reduction in Lp(a). This explains in part the variable efficacy of PCSK9i and allows to identify patients who will benefit most from these therapies in terms of Lp(a) lowering., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Statins are among the best studied drugs. Due to the extensive evidence regarding efficacy and safety, they are the cornerstone of lipid-lowering therapy. While the tolerability of statins in large blinded studies is at the placebo level, so-called statin intolerance (SI) is a frequent and complex problem in everyday clinical practice. Statin-associated muscular pain (SAMS) is most commonly reported. In many cases SI is associated with inadequate lowering of low-density lipoprotein (LDL) cholesterol (LDL-C), thereby increasing the cardiovascular risk. The diagnosis of SAMS is based on the exclusion of possible alternative causes of muscular symptoms and the exclusion of nocebo effects through a diagnostic strategy of discontinuation of statin treatment, observation and assessment of symptoms, followed by renewed administration of a different statin initially at a low dose with subsequent dose increase. A large proportion of patients with SI and SAMS can take statins permanently and without discomfort by this approach. If LDL‑C lowering is insufficient, combination therapies are used. It is an important task of the prescribing physicians and all those involved in the treatment to increase the adherence to statins through appropriate communication. Numerous questions on SI remain open and are being addressed by an ongoing register., (© 2022. The Author(s).)

Most research in psychiatry on extremism focuses on the question whether there is a connection between extremism and psychiatric diagnoses. In addition, practitioners are increasingly asked to take part in programs aimed at preventing and countering violent extremism by assessing risk for radicalization. However, an issue that remains largely unaddressed is that the rise of the far right in many countries during the last years poses a challenge for psychiatric services as working with right-wing patients can be a source of conflict for practitioners and patients alike. In this article, we assert that the narrow conceptual scope on psychological vulnerabilities and the practical focus on risk assessment contribute to processes of psychiatrization and limit the scope of research on right-wing extremism in psychiatry. By giving a brief overview of social research into right-wing extremism, the article argues that right wing beliefs should not be conceptualized as an expression of psychological vulnerabilities but rather as attempts to deal with conflict-laden social reality. Thus, a shift of perspective in psychiatric research on extremism is needed. On a conceptional level, the scope needs to be broadened to grasp the interplay of individual and social factors in radicalization with sufficient complexity. On a practical level, it is necessary to further investigate challenges for practitioners and institutions working with right-wing extremist patients., 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., (Copyright © 2022 Schumann, Brook and Heinze.)