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Study Design: Biomechanical study by using a multibody simulation approach., Objective: Objectification of spinal biomechanics after vertebral body tethering with and without apical fusion., Summary of Background Data: Vertebral body tethering, a motion-preserving surgical technique for correction of adolescent idiopathic scoliosis, is increasingly being used for thoracolumbar curves. However, tether breakage remains a common problem with breakage rates up to 60% for TL curves. Therefore, surgeons have begun to adapt their surgical technique by fusing the apex. The short-term clinical studies show a significant reduction of the tether breakage rate to 10%, but little is known about the biomechanical reasons. Therefore, this study analyzes the intervertebral compression and tether force in a tethered spine without apical fusion and in a tethered spine with apical fusion between L1/2., Methods: A multibody simulation approach was chosen to analyze the biomechanical effects of two surgical techniques during different physiological movements. The tether and intervertebral compression forces in the different instrumented segments are once analyzed for a T10 to L3 tethered spine and once for a T10 to L3 tethered with additional L1/2 fusion using an intervertebral cage., Results: VBT with apical fusion reduces the prevailing tether forces not only at the fused level by nearly 861 N but also at the adjacent spinal segments by around 100 N. However, a significant increase in intervertebral compression force of ~706 N can be observed, especially at the adjacent spinal segments., Conclusion: L1/2 fusion in a tethered spine reduces tether forces in adjacent segments and thus might decrease the rate of tether breakage. However, fusion results in increased intervertebral compression forces by up to 31% compared with an unfused spine. Long-term clinical studies are needed to further analyze and evaluate the biomechanical consequences., Competing Interests: The authors report no conflicts of interest., (Copyright © 2025 Wolters Kluwer Health, Inc. All rights reserved.)

Examination of all publicly available Oryctolagus cuniculus (rabbit) ribosome cryo-EM structures reveals numerous confusing inconsistencies. First, there are a plethora of single nucleotide differences among the various rabbit 28S and 18S rRNA structures. Second, two nucleotides are absent from the NCBI Reference Sequence for the 18S rRNA gene. Moving forward, we propose using the Broad Institute's rabbit whole genome shotgun sequence and numbering to reduce modeling ambiguity and improve consistency between ribosome models., (Published by Cold Spring Harbor Laboratory Press for the RNA Society.)

Background: Digital phenotyping and monitoring tools are the most promising approaches to automatically detect upcoming depressive episodes. Especially, linguistic style has been seen as a potential behavioral marker of depression, as cross-sectional studies showed, for example, less frequent use of positive emotion words, intensified use of negative emotion words, and more self-references in patients with depression compared to healthy controls. However, longitudinal studies are sparse and therefore it remains unclear whether within-person fluctuations in depression severity are associated with individuals' linguistic style., Methods: To capture affective states and concomitant speech samples longitudinally, we used an ambulatory assessment approach sampling multiple times a day via smartphones in patients diagnosed with depressive disorder undergoing sleep deprivation therapy. This intervention promises a rapid change of affective symptoms within a short period of time, assuring sufficient variability in depressive symptoms. We extracted word categories from the transcribed speech samples using the Linguistic Inquiry and Word Count., Results: Our analyses revealed that more pleasant affective momentary states (lower reported depression severity, lower negative affective state, higher positive affective state, (positive) valence, energetic arousal and calmness) are mirrored in the use of less negative emotion words and more positive emotion words., Conclusion: We conclude that a patient's linguistic style, especially the use of positive and negative emotion words, is associated with self-reported affective states and thus is a promising feature for speech-based automated monitoring and prediction of upcoming episodes, ultimately leading to better patient care., (© 2024 The Author(s). Acta Psychiatrica Scandinavica published by John Wiley & Sons Ltd.)

Objective: To examine the association between preventive drug lists (PDLs) and changes in medication costs among patients with diabetes insured in commercial health plans over 2 follow-up years., Research Design and Methods: We conducted a quasiexperimental study using the Optum deidentified Clinformatics Data Mart Database (January 2003 to December 2017). The intervention group included 5,582 patients with diabetes age 12-64 years switched by employers to PDL coverage; the control group included 5,582 matched patients whose employers offered no PDL. Outcomes included out-of-pocket costs, standardized costs, and 30-day fills for all medications because PDL-associated savings could be used to pay for medicines in other classes and for five therapeutic classes covered by the PDLs (oral diabetes medications, insulins, test strips, antihypertensive drugs, and lipid-lowering drugs)., Results: Pre- to post-out-of-pocket spending for all medications declined by 29.7% in follow-up year 2 (95% CI -36.0, -23.4%) among PDL members relative to control individuals. Higher-income and lower-income PDL members experienced significant reductions in out-of-pocket spending for all medications in year 2 (30%) and for key therapeutic classes (range -23 to -67%). We found significant increases in use of key therapeutic classes in the overall population (range 8-15%) and in higher-income and lower-income PDL members (range 9-50%)., Conclusions: PDLs offer an effective strategy for employers and insurers to lower member cost sharing and encourage increased use of important medications to prevent or manage chronic illnesses. For patients with diabetes, especially those with lower incomes, PDL coverage resulted in substantial and persistent reductions in out-of-pocket medication costs, medication use increases, and some increased use of more expensive products., (© 2024 by the American Diabetes Association.)

Phosphorylation is an important modification to modulate functional and digestive properties of starches. We systematically investigated starch phosphorylation process parameters by using two different preparation methods (slurry and semi-dry conditions) and four commonly used phosphorylating agents, namely sodium tripolyphosphate (STPP), sodium trimetaphosphate (STMP), STMP/STPP (99: 1), and sodium phytate (SP). The effects of phosphorylation on physicochemical characteristics, techno-functionalities, digestive properties and structural features of corn starch were analyzed. Phosphorylation with the semi-dry method resulted in higher phosphorus content, degree of double helix, and degree of starch aggregation and lower amylose content and relative crystallinity than with the slurry method. Phosphorylation using semi-dry conditions, irrespective of the used phosphorylating agent, furthermore decreased the gelatinization temperature, enthalpy, the temperature corresponding to the maximum starch mass loss rate and estimated glycemic index of corn starch, and increased solubility, swelling power, peak viscosity, transmittance, and resistant starch content. Of the phosphorylating agents, independent of the used preparation method, STMP and STMP/STPP resulted in the highest degrees of starch phosphorylation and therefore modulated the physiochemical, functional and digestive properties of corn starch more than STPP and SP. The findings of this systematic comparison provide important information to tailor phosphorylated corn starches to meet specific food requirements., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The authors declare no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Chronic kidney disease (CKD) has a high prevalence in patients with heart failure (HF) and is associated with prolonged hospitalization, increased need for intensive care and mortality. There is an urgent need to identify factors that influence the interaction between heart and kidney disorders, often described as cardiorenal syndrome (CRS). We investigated the epidemiology and risk factors of renal insufficiency in patients with HF., Methods: We conducted a retrospective cohort study including 281 consecutive patients with HF that are examined at regular intervals at our outpatient clinic for HF. CKD was defined as the presence of an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m 2 and worsening renal function (WRF) was defined as a decrease of eGFR > 15% within a year. We assessed the patient's medical history, laboratory and echocardiographic parameters at baseline and after 12 months., Results: Right ventricular dysfunction was associated with CKD and WRF. In particular, echocardiographic parameters 'tricuspid annular plane systolic excursion (TAPSE) < 15 mm' (P < 0.001; OR 2.932), 'tricuspid regurgitation (TR) > I°' [P < 0.001; odds ratio (OR) 5.958] and dilatation of inferior vena cava (IVC) (P < 0.001; OR 3.670) were significantly correlated with renal failure. N-terminal pro-B-type natriuretic peptide levels were significantly associated with CKD (P < 0.001; OR 6.109) and correlated with pressure and volume load of the right heart., Conclusions: The results of this work support the theory of right-sided cardiac backward failure, often accompanied by hypervolaemia, as a leading cause of HF-related renal failure. Right heart parameters, especially TR, TAPSE and IVC, are obtained easily by transthoracic echocardiography and can predict renal failure., (© 2025 The Author(s). ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Context: Long-standing gaps in public health capacity exist due to extensive workforce shortages, particularly in governmental public health (GPH); these gaps were worsened during and after the COVID-19 pandemic. In response, the federal government established Public Health AmeriCorps (PHA), which supported the integration of AmeriCorps members in public health systems. Minnesota Public Health Corps (MNPHC) prioritized placing members in GPH agencies to increase GPH capacity. Initial evaluation results (2022-2023) suggest that program members were well-integrated into agencies. This article reports on the contextual information offered by MNPHC members throughout their service, including the specific programs and activities members implemented, to better explain how members were successful at extending agencies' capacity., Objectives: Activities, challenges, and successes of members during their service are described to better explain how members were successful at extending their sites' capacity., Design: Descriptive qualitative methods using data reported each month by 60 members., Setting: GPH agencies with at least one AmeriCorps member., Participants: MNPHC members and GPH agencies., Intervention: MNPHC members at GPH agencies across Minnesota who implemented service plans., Main Outcome Measure: Outcomes of interest included salient themes within MNPHC members' (1) activities, (2) encountered challenges and barriers, (3) successes., Results: MNPHC members implemented public health activities that helped bolster the capacity at host sites. The most common activities were related to public health communications, community engagement, and data analysis. Reported successes were largely concerned with progress made on the different activities being implemented by members. Members also reported few challenges; however, most reported challenges related to common issues encountered in public health, such as difficulty working with community partners or finding available data., Conclusions: MNPHC offers a compelling model that provides support to the GPH workforce while also offering those considering a career in GPH an opportunity to experience a range of public health activities., (Copyright © 2025 Wolters Kluwer Health, Inc. All rights reserved.)

Epigenome, transcriptome, and proteome analyses of postmortem brains have revealed initial molecular insights into cocaine use disorder (CUD). However, the inter-relationship between these omics and the contribution of individual cell types remains largely unknown. We present an in-depth analysis of molecular changes in the ventral striatum in CUD at multi-omics and single-cell resolution. Integrative multi-omics analyses of microRNA sequencing (microRNA-seq), RNA sequencing (RNA-seq), and proteomics datasets in 41 individuals and single-nuclei RNA-seq in a subset of 16 individuals revealed conserved deregulation of metabolic pathways, oxidative phosphorylation, and glutamatergic signaling. Cell type-specific analyses identified inverse metabolic pathway deregulation patterns in glial and neuronal cells, notably in astrocytes and medium-spiny neurons (MSNs). Characterizing astrocyte-neuron crosstalk revealed altered glutamatergic and cell-cell adhesion signaling in CUD. By applying a comprehensive multi-omics analytical framework, our study provides novel insights into CUD-associated molecular changes in the ventral striatum highlighting the perturbation of astrocytes, MSNs, and their crosstalk in CUD., Competing Interests: Declaration of interests The authors declare that there are no competing interests., (Copyright © 2025 The Author(s). Published by Elsevier Inc. All rights reserved.)

Research addressing the link between victimization experiences and fear of crime finds that intimate partner violence (IPV) victimization is also of consequence, with victims of IPV being more fearful than non-IPV victims. Though research on the IPV-fear link is plentiful, there is an absence of focusing exclusively on crime victims. The focus of this research is on the potential differential effects of IPV and other types of victimization on victims' fear and if it delineates to gender differences in victimization type and victim fear. This study uses the National Crime Victimization Survey data to examine whether IPV victims display higher levels of fear compared to victims of other relationship types and whether these relationships hold for males and females. Results indicate that IPV victimization does have a positive relationship with fear and that the effect is evident among females but not males., (© 2024 Springer Publishing Company.)

Time-resolved cryo-EM (TRCEM) makes it possible to provide structural and kinetic information on a reaction of biomolecules before the equilibrium is reached. Several TRCEM methods have been developed in the past to obtain key insights into the mechanism of action of molecules and molecular machines on the time scale of tens to hundreds of milliseconds, which is unattainable by the normal blotting method. Here, we present our TRCEM setup utilizing a polydimethylsiloxane (PDMS)-based microfluidics chip assembly, comprising three components: a PDMS-based, internally SiO 2 -coated micromixer, a glass-capillary microreactor, and a PDMS-based microsprayer for depositing the reaction product onto the EM grid. As we have demonstrated in recent experiments, this setup is capable of addressing problems of severe sample adsorption and ineffective mixing of fluids and leads to highly reproducible results in applications to the study of translation. As an example, we used our TRCEM sample preparation method to investigate the molecular mechanism of ribosome recycling mediated by High frequency of lysogenization X (HflX), which demonstrated the efficacy of the TRCEM device and its capability to yield biologically significant, reproducible information. This protocol has the promise to provide structural and kinetic information on pre-equilibrium intermediates in the 10-1,000 ms time range in applications to many other biological systems. Key features • Design and fabrication of high-performance splitting-and-recombination-based micromixer and planar microsprayer. • Protocol for SiO 2 coating on the PDMS surface and fabrication of the microfluidic chip assembly. • Preparation of time-resolved cryo-EM sample in the time range of 10-1,000 ms. • Data collection on EM grid covered with droplets from the microsprayer., Competing Interests: Competing interestsColumbia University has filed a patent application related to this work for which X.F. and J.F. are inventors., (©Copyright : © 2025 The Authors; This is an open access article under the CC BY-NC license.)

The phototoxicological effects of furocoumarins have been extensively studied. In association with UVA, some of these natural constituents of botanical isolates used in cosmetics, can be photoirritant, photogenotoxic and/or photocarcinogenic. Importantly, not all furocoumarins share the same degree of potency and some are inactive. The more potent furocoumarins, 8-methoxypsoralen and 5-methoxypsoralen, have been subject to extensive mechanistic studies. The formation of adducts with DNA has been widely studied but other contributary mechanisms have also been proposed. The phototoxicological effects, ranging from photoirritation to photocarcinogenicity, are dependent on the dermal dose of furocoumarin and the fluence (dose) of filtered, artificial UVA light. This is particularly evident from photocarcinogenicity studies in animals and from the effect of sequential irradiation sessions in patients receiving Psoralen-UVA (PUVA) therapy. A currently enforced limit of 1 ppm for sun bronzing and sunscreen products for which prolonged intentional exposure to UVA is likely, and 5ppm total furocoumarin concentration in other cosmetic products, e.g., facial cosmetics, that are likely to be only exposed to adventitious and intermittent UVA irradiation, provides a suitably protective threshold when compared to the UV exposure that has been used in studies on animals and in treating PUVA patients., Competing Interests: Declaration of Competing Interest ☒ The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Amaia Irizar reports financial support was provided by International Fragrance Association. Amaia Irizar reports a relationship with International Fragrance Association that includes: consulting or advisory. Fanny Boisleve reports a relationship with Chanel that includes: employment. Francoise Gautier reports a relationship with L’Oréal SA that includes: employment. J Frank Nash reports a relationship with The Procter & Gamble Company that includes: employment. Stefan Pfuhler reports a relationship with The Procter & Gamble Company that includes: employment. Gretchen Ritacco reports a relationship with Research Institute for Fragrance Materials that includes: employment. Matthias Vey reports a relationship with International Fragrance Association that includes: employment. Nicolas Wolf reports a relationship with LVMH Recherche that includes: employment. Peter A. Cadby reports a relationship with International Fragrance Association that includes: consulting or advisory. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025. Published by Elsevier Ltd.)

Background: Diversity competence, diversity itself, and a corresponding awareness of possible (intersectional) discrimination mechanisms have not been anchored in the German National Competence based Learning Objectives Catalogue for Medicine 2.0 (Nationaler Kompetenzbasierter Lernzielkatalog 2.0., NKLM) yet, highlighting a systemic gap in national competency frameworks. We present our first experience with a prospective diversity-specific intervention in medical students to assess its short-term impact on students' diversity acceptance (DA) and to develop actionable recommendations for integrating diversity into medical education., Methods: We designed a prospective cohort study using a control group (CG) and intervention group (IG) design. The IG absolved a five-day diversity-specific intervention (50 h; field trip; seminar). Quantitative data were collected using the validated DWD-O5 scale at baseline (T0), three months (T3), and six months (T6), complemented by qualitative responses (diversity issues in the medical curriculum; perceptions and criticisms) categorized using Mayring's content analysis. Descriptive and non-parametric statistics were performed., Results: Thirty-one medical students (n = 10, IG vs n = 21, CG) were enrolled. The IG demonstrated a short-term improvement in diversity competence (+ 9.72%) across all DWD-O5 factors during the intervention. While scores slightly declined at T6, they remained above baseline levels. 35% (CG) vs. 56% (IG) have experienced discrimination in context of medical studies on their own. Participants in both groups stressed the importance of integrating diversity criteria into curricula at an early stage (100% agreement). Findings revealed three key themes: perceived inadequacies in current curricula, self-reported discrimination experiences, and a strong desire for practical diversity training, such as simulation-based learning., Conclusion: The intervention shows promise as an initial step toward addressing diversity gaps in medical education. By combining historical, cultural, and experiential learning approaches, the program fosters essential competencies such as empathy, self-reflection, and bias recognition. More broadly, sustained improvements in diversity competence require longitudinal integration of diversity training across curricula and systemic reforms to national frameworks like the NKLM. Future research should explore the long-term impact of such interventions and strategies for institutionalizing equity-focused medical education., Competing Interests: Declarations. Ethics approval and consent to participate: Informed consent was obtained from all individual participants included in the study. All procedures performed in studies involving human participants were in accordance with the ethical standards of the Institutional Research Committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. This analysis has been approved by the independent Ethics Commission of the Faculty of Medicine of the University of Cologne (no reference number). Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Anastasis is a phenomenon observed in cancer cells, where cells that have initiated apoptosis are able to recover and survive. This molecular event is increasingly recognized as a potential contributor to cancer metastasis, facilitating the survival and migration of tumor cells. Nevertheless, the identification of a specific surface marker for detecting cancer cells in anastasis remained elusive. Here we report our observation that the cell surface expression of CD24 is preferentially enriched in a non-adherent FSC low SSC high melanoma subpopulation, which is generally considered a non-viable population in cultivated melanoma cell lines. More than 90% of non-adherent FSC low SSC high CD24 +ve metastatic melanoma cells exhibited bonafide features of apoptosis on the cell surface and in the nucleus, marking apoptotic or seemingly apoptotic subpopulations of the in vitro cultivated metastatic melanoma cell lines. Unexpectedly, however, the CD24 +ve subpopulation, despite being apoptotic, showed evidence of metabolic activity and exhibited proliferative capacities, including anchorage-independent growth, when inoculated in soft agarose growth medium. These findings indicate that apoptotic FSC low SSC high CD24 +ve melanoma subpopulations are capable of reversing the progression of apoptosis. We report CD24 as the first novel cell surface marker for anastasis in melanoma cells., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

A systematic study of the impact of film thickness on the properties of thin Bi films is presented. To this end, epitaxial films of high quality have been grown on a Si (111) substrate with thicknesses ranging from 1.9 to 29.9 nm. Broadband optical spectroscopy reveals a notable decline in the optical dielectric constant and the absorption peak height as the film thickness decreases, alongside a shift of the absorption maximum to higher photon energies. Raman and pump-probe spectroscopy show that the phonon mode frequencies increase upon decreasing film thickness, with the in-plane mode frequency rising by 10% from the thickest to the thinnest sample. The X-ray diffraction analysis reveals an increasing Peierls distortion for thinner films, explaining the observed property changes. Quantum chemical bonding analysis and density functional theory calculations show that the properties of thin bismuth are influenced by the interplay between electron localization and delocalization, characteristic of metavalently bonded solids. This study shows that for solids that utilize metavalent bonding, a thickness reduction leads to significant property changes. The effect can even be employed to tailor material properties without the need to change material stoichiometry., (© 2024 The Author(s). Advanced Materials published by Wiley‐VCH GmbH.)

Bipolar disorder is a leading contributor to the global burden of disease 1 . Despite high heritability (60-80%), the majority of the underlying genetic determinants remain unknown 2 . We analysed data from participants of European, East Asian, African American and Latino ancestries (n = 158,036 cases with bipolar disorder, 2.8 million controls), combining clinical, community and self-reported samples. We identified 298 genome-wide significant loci in the multi-ancestry meta-analysis, a fourfold increase over previous findings 3 , and identified an ancestry-specific association in the East Asian cohort. Integrating results from fine-mapping and other variant-to-gene mapping approaches identified 36 credible genes in the aetiology of bipolar disorder. Genes prioritized through fine-mapping were enriched for ultra-rare damaging missense and protein-truncating variations in cases with bipolar disorder 4 , highlighting convergence of common and rare variant signals. We report differences in the genetic architecture of bipolar disorder depending on the source of patient ascertainment and on bipolar disorder subtype (type I or type II). Several analyses implicate specific cell types in the pathophysiology of bipolar disorder, including GABAergic interneurons and medium spiny neurons. Together, these analyses provide additional insights into the genetic architecture and biological underpinnings of bipolar disorder., Competing Interests: Competing interests: T.E.T., H. Stefansson and K.S. are employed by deCODE Genetics/Amgen. E.A.S. is an employee of Regeneron Genetics Center and owns stocks of Regeneron Pharmaceutical. K.-H.L. and X.W. are employed by 23andMe. Multiple additional authors work for pharmaceutical or biotechnology companies in a manner directly analogous to academic co-authors and collaborators. A.H.Y. has given paid lectures and served on advisory boards relating to drugs used in affective and related disorders for several companies (AstraZeneca, Eli Lilly, Lundbeck, Sunovion, Servier, Livanova, Janssen, Allergan, Bionomics and Sumitomo Dainippon Pharma), was Lead Investigator for the Embolden study (AstraZeneca), BCI Neuroplasticity study and Aripiprazole Mania study, and is an investigator for Janssen, Lundbeck, Livanova and Compass. J.I.N. is an investigator for Janssen. P.F.S. is on the advisory committee and a shareholder of Neumora Therapeutics. G.B. reports consultancy and speaker fees from Eli Lilly and Illumina, and grant funding from Eli Lilly. M. Landén has received speaker fees from Lundbeck. O.A.A. has served as a speaker for Janssen, Lundbeck and Sunovion, and as a consultant for Cortechs.ai. A.M.D. is a founder of and holds equity interest in CorTechs Labs and serves on its scientific advisory board; is a member of the scientific advisory board of Human Longevity and the Mohn Medical Imaging and Visualization Center; and has received research funding from General Electric Healthcare. E.V. has received grants and served as a consultant, advisor or CME speaker for the following entities: AB-Biotics, Abbott, Allergan, Angelini, AstraZeneca, Bristol Myers Squibb, Dainippon Sumitomo Pharma, Farmindustria, Ferrer, Forest Research Institute, Gedeon Richter, GlaxoSmithKline, Janssen, Lundbeck, Otsuka, Pfizer, Roche, SAGE, Sanofi-Aventis, Servier, Shire, Sunovion, Takeda, the Brain and Behaviour Foundation, the Catalan Government (AGAUR and PERIS), the Spanish Ministry of Science, Innovation, and Universities (AES and CIBERSAM), the Seventh European Framework Programme and Horizon 2020 and the Stanley Medical Research Institute. S.K.-S. received author’s, speaker’s and consultant honoraria from Janssen, Medice Arzneimittel Pütter GmbH and Takeda outside of the current work. A. Serretti is or has been a consultant and/or speaker for: Abbott, AbbVie, Angelini, AstraZeneca, Clinical Data, Boheringer, Bristol Myers Squibb, Eli Lilly, GlaxoSmithKline, Innovapharma, Italfarmaco, Janssen, Lundbeck, Naurex, Pfizer, Polifarma, Sanofi and Servier. J.R.D. has served as an unpaid consultant to Myriad-Neuroscience (formerly Assurex Health) in 2017 and 2019, and owns stock in CVS Health. B.M.N. is a member of the scientific advisory board at Deep Genomics, and consultant for Camp4 Therapeutics, Takeda Pharmaceutical and Biogen. B.-C.L., J.-W.K., Y.K.L., J.H.K., M. J. Cheon and D.J.K. are employed by Genoplan. I.B.H. is the Co-Director of Health and Policy at the Brain and Mind Centre (BMC) University of Sydney. The BMC operates an early-intervention youth services at Camperdown under contract to Headspace. I.B.H. is also the Chief Scientific Advisor to, and a 3.2% equity shareholder in, InnoWell. InnoWell was formed by the University of Sydney (45% equity) and PwC (Australia; 45% equity) to deliver the $30 M (AUD) Australian Government-funded Project Synergy (2017–2020; a 3-year program for the transformation of mental health services) and to lead transformation of mental health services internationally through the use of innovative technologies. M.J.O. and M.C.O. have received funding from Takeda Pharmaceuticals and Akrivia Health outside the scope of the current work. P. B. Mitchell. has received remuneration from Janssen (Australia) and Sanofi (Hangzhou) for lectures or advisory board membership. J.A.R.-Q. was on the speakers’ bureau and/or acted as consultant for Biogen, Idorsia, Casen-Recordati, Janssen-Cilag, Novartis, Takeda, Bial, Sincrolab, Neuraxpharm, Novartis, BMS, Medice, Rubió, Uriach, Technofarma and Raffo in the past 3 years; has also received travel awards (airplane tickets and hotel) for taking part in psychiatric meetings from Idorsia, Janssen-Cilag, Rubió, Takeda, Bial and Medice; and the Department of Psychiatry chaired by J.A.R.-Q. received unrestricted educational and research support from the following companies in the past 3 years: Exeltis, Idorsia, Janssen-Cilag, Neuraxpharm, Oryzon, Roche, Probitas and Rubió. All other authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Implementation strategies are essential to deliver evidence-based programs that align with local context, resources, priorities, and preferences. However, it is not always clear how specific strategies are selected (vs. others) and strategies are not always operationalized clearly, distinctly, and dynamically. Implementation logic models provide one useful way to conceptualize the role and selection of implementation strategies, plan evaluation of their intended impacts on implementation and effectiveness outcomes, and to communicate key aspects of a project., Methods: This paper describes our initial plans, experiences, and lessons learned from applying implementation logic models in the Quadruple Aim Quality Enhancement Research Initiative (QUERI) a large multi-study program funded by the Veterans Health Administration (VA). We began with two primary implementation strategies based on our earlier work (i.e., Iterative RE-AIM and Relational Facilitation) that were applied across three different health outcomes studies., Results: Our implementation strategies evolved over time, and new strategies were added. This evolution and reasons for changes are summarized and illustrated with the resulting logic models, both for the overall Quadruple Aim QUERI and the three specific projects. We found that implementation strategies are often not discrete, and their delivery and adaptation is dynamic and should be guided by emerging data and evolving context. Review of logic models across projects was an efficient and useful approach for understanding similarities and differences across projects., Conclusions: Implementation logic models are helpful for clarifying key objectives and issues for both study teams and implementation partners. There are challenges in logic model construction and presentation when multiple strategies are employed, and when strategies change over time. We recommend presentation of both original and periodically updated project models and provide recommendations for future use of implementation logic models., Competing Interests: Declarations. Ethics approval and consent to participate: All VHA authors of this manuscript attest that the activities that resulted in producing this manuscript were not conducted as part of a research project, but as part of the non-research evaluation conducted under the authority of Quality Enhancement Research Initiative (QUERI). The status of this work as quality improvement and not research was also confirmed following review by the Research and Development Committee at the VA Eastern Colorado Health Care System. Consent for publication: Not applicable. Competing interests: REG is an editorial board member for Implementation Science Communications., (© 2025. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Introduction: Upper limb (UL) impairment is common in people with multiple sclerosis (pwMS), and functional recovery of the UL is a key rehabilitation goal. Technology-based approaches, like virtual reality (VR), are increasingly promising. While most VR environments are task-oriented, our clinical approach integrates neuroproprioceptive 'facilitation and inhibition' (NFI) principles. To advance this, we developed immersive VR software based on NFI principles targeting UL function and sit-to-stand ability. This study aims to evaluate the effectiveness of this VR therapy compared with conventional NFI-based physical therapy in pwMS. Our study uniquely applies advanced imaging techniques, along with biological molecular assessments, to explore adaptive processes induced by VR rehabilitation., Methods and Analysis: This double-arm, randomised, assessor-blinded, controlled trial runs over 2 months (1 hour, 2 times per week). PwMS with mild to severe disability will receive either VR therapy or real-world physical therapy. Primary outcomes include the nine-hole peg test, box and block test, handgrip strength, tremor and five times sit-to-stand test. Secondary measures include the Multiple Sclerosis Impact Scale, the 5-level EQ-5D questionnaire and kinematic analysis. Adaptive processes will be monitored using imaging techniques (functional MRI and tractography), molecular genetic methods (long non-coding RNAs) and immune system markers (leukocytes, dendritic cells). The International Classification of Functioning, Disability and Health brief set for MS will map the bio-psycho-social context of participants., Ethics and Dissemination: This project and its amendments were approved by the Ethics Committee of the Institute for Clinical and Experimental Medicine and Thomayer Hospital (1983/21+4772/21 (G-21-02) and the Ethics Committee of Kralovske Vinohrady University Hospital (EK-VP/38/0/2021) in Prague, Czechia (with single enrolment). The findings of this project will be disseminated through scientific publications, conferences, professional networks, public engagement, educational materials and stakeholder briefings to ensure a broad impact across clinical, academic and public domains., Trial Registration Number: clinicaltrials.gov (NCT04807738)., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Background: Understanding the size and surface charge (ζ-potential) of particles in the mixed micellar fraction produced by in vitro digestion is crucial to understand their cellular absorption and transport. The inconsistent presentation of micellar size data, often limited to average particle diameter, makes comparison of studies difficult. The present study aimed to assess different size data representations (mean particle diameter, relative intensity- or volume-weighted size distribution) to better understand physiological mixed micelle characteristics and to provide recommendations for size reporting and sample handling., Results: Dietary compounds (RRR-α-tocopherol, retinyl-palmitate, β-carotene, curcumin and naringenin) underwent a simplified in vitro digestion, whereas foods (spinach and red cabbage) were subjected to both a simplified and the INFOGEST 2.0 digestions. Dynamic light scattering was used to measure size and surface charge of the mixed micelles. A significant percentage of particles above the 200 nm filter cut-off was observed, indicating aggregation and dynamic size changes in the mixed micellar fraction. Freezing of the mixed micelles notably enhanced the aggregation., Conclusion: The determination of particle size in polydisperse mixed micellar fractions is challenging, and relying solely on average particle diameter can be misleading. Especially in more polydisperse samples, parameters such as polydispersity index and volume-weighted distribution should accompany average particle diameter data. To minimize the effect of freezing on particle size, we recommend filtering the digesta after storage (freezing), as this leads to similar size distribution compared to mixed micellar fraction measured directly after digestion. © 2025 The Author(s). Journal of the Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry., (© 2025 The Author(s). Journal of the Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.)

Background: Recent legislative initiatives in the United States have focused on the medical and legal status of psychedelics, prompting interest in understanding public perceptions of their risks. This study investigates rural-urban differences in the perception of LSD and cannabis risks using national survey data., Methods: Data from the National Survey of Drug Use and Health (NSDUH) between 2015 and 2021 were analyzed. Logistic regression models were used to compare risk perceptions of LSD and cannabis between rural and urban respondents, adjusting for relevant factors., Results: Rural residents were 1.2 to 1.4 times more likely to perceive using LSD once or twice as of great risk compared to urban residents during the survey period. However, the perception of monthly cannabis use as having great risk was slightly higher among rural residents only until 2019, with no significant differences observed in 2020 and 2021., Conclusion: The study highlights a significant rural-urban divide in the perception of LSD risk, which could impact policymaking on psychedelic therapies. Understanding these differences is crucial for developing effective and equitable policies regarding psychedelic substances and treatments., (© 2024 National Rural Health Association.)

Background: Mobile devices for remote monitoring are inevitable tools to support treatment and patient care, especially in recurrent diseases such as major depressive disorder. The aim of this study was to learn if machine learning (ML) models based on longitudinal speech data are helpful in predicting momentary depression severity. Data analyses were based on a dataset including 30 inpatients during an acute depressive episode receiving sleep deprivation therapy in stationary care, an intervention inducing a rapid change in depressive symptoms in a relatively short period of time. Using an ambulatory assessment approach, we captured speech samples and assessed concomitant depression severity via self-report questionnaire over the course of 3 weeks (before, during, and after therapy). We extracted 89 speech features from the speech samples using the Extended Geneva Minimalistic Acoustic Parameter Set from the Open-Source Speech and Music Interpretation by Large-Space Extraction (audEERING) toolkit and the additional parameter speech rate., Objective: We aimed to understand if a multiparameter ML approach would significantly improve the prediction compared to previous statistical analyses, and, in addition, which mechanism for splitting training and test data was most successful, especially focusing on the idea of personalized prediction., Methods: To do so, we trained and evaluated a set of >500 ML pipelines including random forest, linear regression, support vector regression, and Extreme Gradient Boosting regression models and tested them on 5 different train-test split scenarios: a group 5-fold nested cross-validation at the subject level, a leave-one-subject-out approach, a chronological split, an odd-even split, and a random split., Results: In the 5-fold cross-validation, the leave-one-subject-out, and the chronological split approaches, none of the models were statistically different from random chance. The other two approaches produced significant results for at least one of the models tested, with similar performance. In total, the superior model was an Extreme Gradient Boosting in the odd-even split approach (R²=0.339, mean absolute error=0.38; both P<.001), indicating that 33.9% of the variance in depression severity could be predicted by the speech features., Conclusions: Overall, our analyses highlight that ML fails to predict depression scores of unseen patients, but prediction performance increased strongly compared to our previous analyses with multilevel models. We conclude that future personalized ML models might improve prediction performance even more, leading to better patient management and care., (© Lisa-Marie Hartnagel, Daniel Emden, Jerome C Foo, Fabian Streit, Stephanie H Witt, Josef Frank, Matthias F Limberger, Sara E Schmitz, Maria Gilles, Marcella Rietschel, Tim Hahn, Ulrich W Ebner-Priemer, Lea Sirignano. Originally published in JMIR Mental Health (https://mental.jmir.org).)

Time-resolved cryo-EM (TRCEM) makes it possible to provide structural and kinetic information on a reaction of biomolecules before the equilibrium is reached. Several TRCEM methods have been developed in the past to obtain key insights into the mechanism of action of molecules and molecular machines on the time scale of tens to hundreds of milliseconds, which is unattainable by the normal blotting method. Here we present our TRCEM setup utilizing a polydimethylsiloxane (PDMS)-based microfluidics chip assembly, comprising three components: a PDMS-based, internally SiO 2 -coated micromixer, a glass-capillary microreactor, and a PDMS-based microsprayer for depositing the reaction product onto the EM grid. As we have demonstrated in recent experiments, this setup is capable of addressing problems of severe sample adsorption and ineffective mixing of fluids, and leads to highly reproducible results in applications to the study of translation. As an example, we used our TRCEM sample preparation method to investigate the molecular mechanism of ribosome recycling mediated by High frequency of lysogenization X (HflX), which demonstrated the efficacy of the TRCEM device and its capability to yield biologically significant, reproducible information. This protocol has promise to provide structural and kinetic information on pre-equilibrium intermediates in the 10 -1000 ms time range in applications to many other biological systems., Competing Interests: Competing interests Columbia University has filed patent application (Pub. No.: US 2024/0382964 A1) related to this work for which X.F. and J.F. are inventors.

This study examines the validity of an assay that is used to report on the retainment of functional competence by ribosomes as they pass a micro-sprayer. We find a reproducible increase , rather than the expected decrease in GFP production as monitored by fluorescence, which suggests heterogeneity or partial aggregation of ribosomes in solution. An even larger increase in functional activity is observed when sonication is used, pointing to mechanical agitation as the decisive factor in both scenarios. The results have a bearing on the design and interpretation of validation experiments in time-resolved cryo-EM based on microfluidic chips.

The predictive value of the susceptibility to oxidation of LDL particles (LDLox) in cardiometabolic risk assessment is incompletely understood. The main objective of the current study was to assess its relationship with other relevant biomarkers and cardiometabolic risk factors from MARK-AGE data. A cross-sectional observational study was carried out on 1089 subjects (528 men and 561 women), aged 40-75 years old, randomly recruited age- and sex-stratified individuals from the general population. A correlation analysis exploring the relationships between LDLox and relevant biomarkers was undertaken, as well as the development and validation of several machine learning algorithms, for estimating the risk of the combined status of high blood pressure and obesity for the MARK-AGE subjects. The machine learning models yielded Area Under the Receiver Operating Characteristic Curve Score ranging 0.783-0.839 for the internal validation, while the external validation resulted in an Under the Receiver Operating Characteristic Curve Score between 0.648 and 0.787, with the variables based on LDLox reaching significant importance within the obtained predictions. The current study offers novel insights regarding the combined effects of LDL oxidation and other ageing markers on cardiometabolic risk. Future studies might be extended on larger patient cohorts, in order to obtain reproducible clinical assessment models., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Basal cell carcinoma is the most common malignant tumor in the fair-skinned population and its incidence continues to rise. An update of the S2k guideline with the participation of all specialist societies familiar with the clinical picture and previous literature research is of great importance for the quality of care for affected patients. In addition to epidemiology, diagnostics and histology are discussed. After risk stratification, therapy is divided into topical, systemic and radiation therapy. Surgical removal remains the treatment of first choice in most cases. The approval of anti-PD1 inhibitors for locally advanced and metastatic tumors has opened up a new option in second-line therapy (after hedgehog inhibitors)., (© 2024 The Author(s). Journal der Deutschen Dermatologischen Gesellschaft published by John Wiley & Sons Ltd on behalf of Deutsche Dermatologische Gesellschaft.)

Introduction: In emergency medicine, triage encompasses more than the initial prioritization of treatment; it also includes decisions about the most suitable level of care and disposition for each patient. However, the increasing use of mobile technology by patients in the emergency department (ED) introduces a new factor. This study aims to explore the relationship between patients' cellphone use at the time of initial assessment and final disposition in the ED., Methods: A prospective, cross-sectional study was conducted on 292 patients who presented to the ED between 9/1/2021 and 8/9/2022. Patients were stratified into two cohorts based on their behavior during the initial assessment: actively using a cell phone (n = 32) or not using a cell phone (n = 259). Final disposition was dichotomously recorded as admission or discharge. Hospital admission, hospital observation, and admission to the ED observation unit were consolidated into the combined category of admission., Results: Patients not actively using their cell phone on initial assessment exhibited a discharge rate of 64%, while those engaged with their cellphones displayed notably higher dismissal rates at 94%. The calculated odds ratio (OR) of 8.4 (95% confidence interval: 1.96-36.0, p = 0.004) underscores a significantly heightened likelihood of dismissal among individuals actively using their cellphones, suggesting a potential association between cellphone use and a reduced probability of hospital admission., Conclusion: The study suggests an association between cellphone use during initial ED assessment and higher discharge rates. While this introduces a novel concept, the study's potential contribution to more informed and efficient triage decisions warrants careful consideration in future research and clinical applications., Competing Interests: Declarations. Ethics approval and consent to participate: We certify that the study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. The study was approved by the Mayo Clinic Institutional Review Board. Consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: Current treatment recommendations for patients with heart failure and secondary mitral regurgitation include transcatheter edge-to-edge repair and mitral-valve surgery. Data from randomized trials comparing these therapies are lacking in this patient population., Methods: In this noninferiority trial conducted in Germany, patients with heart failure and secondary mitral regurgitation who continued to have symptoms despite guideline-directed medical therapy were randomly assigned, in a 1:1 ratio, to undergo either transcatheter edge-to-edge repair (intervention group) or surgical mitral-valve repair or replacement (surgery group). The primary efficacy end point was a composite of death, hospitalization for heart failure, mitral-valve reintervention, implantation of an assist device, or stroke within 1 year after the procedure. The primary safety end point was a composite of major adverse events within 30 days after the procedure., Results: A total of 210 patients underwent randomization. The mean (±SD) age of the patients was 70.5±7.9 years, 39.9% were women, and the mean left ventricular ejection fraction was 43.0±11.7%. Within 1 year, at least one of the components of the primary efficacy end point occurred in 16 of the 96 patients with available data (16.7%) in the intervention group and in 20 of the 89 with available data (22.5%) in the surgery group (estimated mean difference, -6 percentage points; 95% confidence interval [CI], -17 to 6; P<0.001 for noninferiority). A primary safety end-point event occurred in 15 of the 101 patients with available data (14.9%) in the intervention group and in 51 of the 93 patients with available data (54.8%) in the surgery group (estimated mean difference, -40 percentage points; 95% CI, -51 to -27; P<0.001)., Conclusions: Among patients with heart failure and secondary mitral regurgitation, transcatheter edge-to-edge repair was noninferior to mitral-valve surgery with respect to a composite of death, rehospitalization for heart failure, stroke, reintervention, or implantation of an assist device in the left ventricle at 1 year. (Funded by Abbott Vascular; MATTERHORN ClinicalTrials.gov number, NCT02371512.)., (Copyright © 2024 Massachusetts Medical Society.)

Objective: To examine how a novel payer-provider joint venture (JV) between one payer and multiple competitive delivery systems in New Hampshire (NH), which included value-based payment, care management, and non-financial supports, impacted healthcare value and payer and provider group experiences., Study Setting and Design: We conducted a mixed-methods study. We used a quasi-experimental longitudinal difference-in-differences design to examine the impact of the JV (which started in January 2016 and ended in December 2020) on healthcare utilization, quality, and spending, using members in Maine (ME) as a control group. We also analyzed patient uptake of the JV's care management program using routinely collected administrative data and assessed payer and provider group leaders' perspectives about the JV via semi-structured interviews., Data Sources and Analytic Sample: We used administrative and claims data from 2013 to 2019 in a commercially insured population under 65 years in NH and ME. We also used administrative data on care management eligibility and uptake and conducted semi-structured interviews with payer and provider group leaders affiliated with the JV., Principal Findings: The JV was associated with no sustained change in medical utilization, quality, and spending throughout the study period. In the first year of the JV, there was a $142 (95% confidence interval: $41, $243) increase in pharmaceutical spending per member and a 13% (4.4%, 25%) relative increase in days covered for diabetes medications. Only 15% of eligible members engaged in care management, which was a key component of the JV's multi-pronged approach. In a disconnect from the empirical findings, payer and provider group leaders believed that the JV reduced healthcare costs and improved quality., Conclusions: Our findings provide evidence for future payer-provider JVs and demonstrate the importance of having a valid control group when evaluating JVs and value-based payment arrangements., (© 2024 Health Research and Educational Trust.)

Purpose: Vertebral Body Tethering (VBT), an alternative treatment for adolescent idiopathic scoliosis, shows satisfactory post-operative results. However, the biomechanical quantities and consequences after VBT surgery remain largely unknown. Therefore, the aim of this study is to analyze the spinal biomechanics during different motions using a multibody simulation approach., Methods: The tether and intervertebral compression forces were simulated in a validated spine model during different physiological movements at different pre-tensions and screw positions, while considering the anatomical muscle and ligament properties., Results: The simulations showed that an augmentation of the pre-tension and an alteration of the screw position have both significant impact on the intervertebral compression and tether forces. The forces also vary depending on the movement performed, with the highest tether forces measured during lateral bending. In the upright position, with a pre-tension of 200 N, the maximum compression force increases by up to 157% compared to the untethered maximum compression force. The screw position can lead to large differences in the distribution of forces in the spine., Conclusion: The biomechanical data provide a first impression of the forces that occur along the spine during various physiological movements and are consistent with published clinical data. Forces are not evenly distributed along the spine, with higher lumbar forces. The tether forces reach values during lateral bending that can potentially destroy the tether´s integrity and thus may explain the common post-operative complication, namely tether breakage. The results of the model can therefore have an impact on future directions for improved surgical VBT treatment., (© 2024. The Author(s).)

Malignant hyperthermia (MH) is a life-threatening pharmacogenetic condition triggered by volatile anesthetics, which activate pathogenic RyR1 mutants. The small molecule therapeutic dantrolene has long been used to treat MH. However, the binding site and mechanism of dantrolene remain unclear. Here, we present cryo-EM structures of RyR1 bound to dantrolene and the MH trigger agent 4-chloro-m-cresol (4CmC), revealing the dantrolene and 4CmC binding sites in atomic detail. Dantrolene binds stacked with ATP or ADP in the RY12 domain at the corner of the receptor, inducing a conformational change in this domain which is allosterically coupled to pore closure. Functional analyses revealed that ATP or ADP was required for dantrolene inhibition, and a single point mutation that disrupts the peripheral ATP binding site abolished ATP/ADP-dependent dantrolene inhibition. Strikingly, in the absence of dantrolene, this site selectively binds two ADP molecules, suggesting a possible role in ATP/ADP ratio sensing.

Examination of all publicly available Oryctolagus cuniculus (rabbit) ribosome cryo-EM structures reveals numerous confusing inconsistencies. First, there are a plethora of single nucleotide differences among the various rabbit 28S and 18S rRNA structures. Second, two nucleotides are absent from the NCBI Reference Sequence for the 18S rRNA gene. Moving forward, we propose using the Broad Institute's rabbit whole genome shotgun sequence and numbering to reduce modeling ambiguity and improve consistency between ribosome models.

Background: To develop and validate a novel administration device for holmium-166 transarterial radioembolisation (TARE) with the purpose of facilitating controlled fractional microsphere administration for a more flexible and image-guided TARE procedure., Methods: A Controlled Administration Device (CAD) was developed using MR-conditional materials. The CAD contains a rotating syringe to keep the microspheres in suspension during administration. Different rotational speeds were tested ex vivo to optimise the homogeneity of microsphere fractions administered from the device. The technical performance, accuracy, and safety was validated in three patients in a clinical TARE setting by administering a standard clinical dose in 5 fractions (identifier: NCT05183776). MRI-based dosimetry was used to validate the homogeneity of the given fractions in vivo, and serious adverse device event ((S)A(D)E) reporting was performed to assess safety of the CAD., Results: A rotational speed of 30 rpm resulted in the most homogeneous microsphere fractions with a relative mean deviation of 1.1% (range: -9.1-8.0%). The first and last fraction showed the largest deviation with a mean of -26% (std. 16%) and 7% (std. 13%). respectively. In the three patient cases the homogeneity of the microsphere fractions was confirmed given that MRI-based dosimetry showed near linear increase of mean absorbed target liver dose over the given fractions with R 2 values of 0.98, 0.97 and 0.99. No (S)A(D)E's could be contributed to the use of the CAD., Conclusions: The newly developed CAD facilitates safe and accurate fractional microsphere administration during TARE, and can be used for multiple applications in the current and future workflows of TARE., (© 2024. The Author(s).)

Background: Given the great interest in identifying reliable predictors of the response to antidepressant drugs, the present study investigated whether polygenic scores (PGS) for Major Depressive Disorder (MDD) and antidepressant treatment response (ADR) were related to the complex trait of antidepressant response in the Early Medication Change (EMC) cohort., Methods: In this secondary analysis of the EMC trial (N = 889), 481 MDD patients were included and compared to controls from a population-based cohort. Patients were treated over eight weeks within a pre-defined treatment-algorithm. We investigated patients' genetic variation associated with MDD and ADR, using PGS and examined the association of PGS with treatment outcomes (early improvement, response, remission). Additionally, the influence of two cytochrome P450 drug-metabolizing enzymes (CYP2C19, CYP2D6) was determined., Results: PGS for MDD was significantly associated with disorder status (NkR 2  = 2.48 %, p < 1*10 -12 ), with higher genetic burden in EMC patients compared to controls. The PGS for ADR did not explain remission status. The PGS for MDD and ADR were also not associated with treatment outcomes. In addition, there were no effects of common CYP450 gene variants on ADR., Limitations: The study was limited by variability in the outcome parameters due to differences in treatment and insufficient sample size in the used ADR genome-wide association study (GWAS)., Conclusions: The present study confirms a polygenic contribution to MDD burden in the EMC patients. Larger GWAS with homogeneity in antidepressant treatments are needed to explore the genetic variation associated with ADR and realize the potential of PGS to contribute to specific response subtypes., Competing Interests: Declaration of competing interest A Tadic is designated as inventor of the European patent number 12171541.1–2404 ‘Method for predicting response or non-response to a mono-aminergic antidepressant’. He has received during the last five years consultancy fees from Janssen and ROVI. K Lieb is designated as inventor of the European patent number 12171541.1–2404 ‘Method for predicting response or non-response to a mono-aminergic antidepressant’. S Heilmann-Heimbach and P Hoffmann are employees at Life&Brain GmbH, Bonn. All other authors declare no competing interests., (Copyright © 2024. Published by Elsevier B.V.)

Structural and functional changes of the brain are assumed to contribute to excessive cocaine intake, craving, and relapse in cocaine use disorder (CUD). Epigenetic and transcriptional changes were hypothesized as a molecular basis for CUD-associated brain alterations. Here we performed a multi-omics study of CUD by integrating epigenome-wide methylomic (N = 42) and transcriptomic (N = 25) data from the same individuals using postmortem brain tissue of Brodmann Area 9 (BA9). Of the N = 1 057 differentially expressed genes (p < 0.05), one gene, ZFAND2A, was significantly upregulated in CUD at transcriptome-wide significance (q < 0.05). Differential alternative splicing (AS) analysis revealed N = 98 alternatively spliced transcripts enriched in axon and dendrite extension pathways. Strong convergent overlap in CUD-associated expression deregulation was found between our BA9 cohort and independent replication datasets. Epigenomic, transcriptomic, and AS changes in BA9 converged at two genes, ZBTB4 and INPP5E. In pathway analyses, synaptic signaling, neuron morphogenesis, and fatty acid metabolism emerged as the most prominently deregulated biological processes. Drug repositioning analysis revealed glucocorticoid receptor targeting drugs as most potent in reversing the CUD expression profile. Our study highlights the value of multi-omics approaches for an in-depth molecular characterization and provides insights into the relationship between CUD-associated epigenomic and transcriptomic signatures in the human prefrontal cortex., (© 2024. The Author(s).)

Introduction: Formal genetics studies show that smoking is influenced by genetic factors; exploring this on the molecular level can offer deeper insight into the etiology of smoking behaviours., Methods: Summary statistics from the latest wave of the GWAS and Sequencing Consortium of Alcohol and Nicotine (GSCAN) were used to calculate polygenic risk scores (PRS) in a sample of ~2200 individuals who smoke/individuals who never smoked. The associations of smoking status with PRS for Smoking Initiation (i.e., Lifetime Smoking; SI-PRS), and Fagerström Test for Nicotine Dependence (FTND) score with PRS for Cigarettes per Day (CpD-PRS) were examined, as were distinct/additive effects of parental smoking on smoking status., Results: SI-PRS explained 10.56% of variance (Nagelkerke-R 2 ) in smoking status (p=6.45x10 -30 ). In individuals who smoke, CpD-PRS was associated with FTND score (R 2 =5.03%, p=1.88x10 -12 ). Parental smoking alone explained R 2 =3.06% (p=2.43×10 -12 ) of smoking status, and 0.96% when added to the most informative SI-PRS model (total R²=11.52%)., Conclusion: These results show the potential utility of molecular genetic data for research investigating smoking prevention. The fact that PRS explains more variance than family history highlights progress from formal to molecular genetics; the partial overlap and increased predictive value when using both suggests the importance of combining these approaches., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024. Published by Elsevier B.V.)

Common beans (Phaseolus vulgaris L.) are among the most important legumes for human nutrition. The aim of the present study was to characterize the composition and in vitro bioaccessibility of tocochromanols, carotenoids, and iron from 14 different landraces and 2 commercial common bean varieties. Phytic acid, dietary fiber, and total (poly)phenolic content were determined as factors that can modify the bioaccessibility of the studied compounds. Two carotenoids were identified, namely lutein (4.6-315 ng/g) and zeaxanthin (12.2-363 ng/g), while two tocochromanols were identified, namely γ-tocopherol (2.62-18.01 µg/g), and δ-tocopherol (0.143-1.44 µg/g). The iron content in the studied samples was in the range of 58.7-144.2 µg/g. The contents of carotenoids, tocochromanols, and iron differed significantly among the studied samples but were within the ranges reported for commercial beans. After simulated gastrointestinal digestion, the average bioaccessibility of carotenoids was 30 %, for tocochromanols 50 %, and 17 % for iron. High variability in the bioaccessible content yielded by the bean varieties was observed. Dietary fiber, phytic acid and total (poly)phenol contents were negatively correlated with the bioaccessibility of carotenoids, while iron bioaccessibility was negatively correlated with the total (poly)phenol content. The principal component analysis indicated that the bioaccessibility of lutein was the main variable involved in class separations. The composition of the food matrix plays an important role in the bioaccessibility of carotenoids, tocochromanols and iron from cooked beans., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Quantitative imaging is a crucial step for dosimetry in radionuclide therapies. Traditionally, SPECT/CT imaging is quantified based on scanner-specific conversion factors or self-calibration, but recently absolute quantification methods have been introduced in commercial SPECT reconstruction software (Broad Quantification, Siemens Healthineers). In this phantom study we investigate the accuracy of three quantification methods for holmium-166 SPECT/CT imaging, and provide recommendations for clinical dosimetry., Methods: One cylindrical phantom, filled with a homogeneous holmium-166-chloride activity concentration solution, was imaged at one time point to determine a scanner-specific conversion factor, and to characterize the spatial dependency of the activity concentration recovery. One Jaszczak phantom with six fillable spheres, 10:1 sphere-to-background ratio, was imaged over a large range of holmium-166 activities (61-3130 MBq). The images were reconstructed with either an ordered subset expectation maximization (OSEM, Flash3D-reconstruction; scanner-specific quantification or self-calibration quantification) or an ordered subset conjugate gradient (OSCG, xSPECT-reconstruction; Broad Quantification) algorithm. These three quantification methods were compared for the data of the Jaszczak phantom and evaluated based on whole phantom recovered activity, activity concentration recovery coefficients (ACRC), and recovery curves., Results: The activity recovery in the Jaszczak phantom was 28-115% for the scanner-specific, and 57-97% for the Broad Quantification quantification methods, respectively. The self-calibration-based activity recovery is inherently always 100%. The ACRC for the largest sphere (Ø60 mm, ~ 113 mL) ranged over (depending on the activity level) 0.22-0.89, 0.76-0.86, 0.39-0.72 for scanner-specific, self-calibration and Broad Quantification, respectively., Conclusion: Of the three investigated quantification methods, the self-calibration technique produces quantitative SPECT images with the highest accuracy in the investigated holmium-166 activity range., (© 2024. The Author(s).)

Objective: Evidence of geographical variation in total hip replacement (THR) and deviations from treatment guidelines persists. In this exploratory study, we aim to gain an in-depth understanding of patients' healthcare trajectories by identifying and visualising medication use patterns in coxarthrosis patients before surgery. We examine their association with patient characteristics and THR, and compare them with recommendations on mild analgesics, opioid prescription and exhaustion of conservative therapy., Methods: In this exploratory study, we apply State Sequence Analysis (SSA) on German health insurance data (2012-2015). We analyse a cohort of coxarthrosis patients, half of whom underwent THR after a 1 year observation period and half of whom did not undergo surgery until at least 1 year after the observation period. Hierarchical states are defined based on prescriptions. We construct sequences, calculate sequence similarity using optimal matching and identify medication use patterns via clustering. Patterns are visualised, descriptive statistics are presented and logistic regression is employed to investigate the association of medication patterns with subsequent THR., Results: Seven distinct medication use patterns are identified, correlating strongly with patient characteristics and subsequent THR. Two patterns leading to THR demonstrate exhaustion of pharmacological therapy. Opioid use is concentrated in two small patterns with low odds for THR. The most frequent pattern lacks significant pharmacological therapy., Conclusions: This SSA uncovers heterogeneity in medication use patterns before surgery in coxarthrosis patients. Cautious opioid handling and adherence to a stepped prescription approach are observed, but many patients display low medication therapy usage and lack evidence of exhausting conservative options before surgery., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

High-impact practices (HIPs) are educational practices that foster student success. HIPs have not been widely used in cancer education and research despite the need for students to develop key transferable skills and cultivate social responsibility. Our study addresses this need by implementing four community-based learning HIPs within the context of cancer education and research. Each HIP was classified as having low, moderate, or high alignment with the traits of effective HIPs. Undergraduate science students participated in one to four HIPs as a Feedback Participant, General Volunteer, Student Leader, or Cancer Undergraduate Research and Education (CURES) Class Student. We then studied the effect of these HIPs on students' development of knowledge and skills; career interest and preparedness; and social responsibility. Results from self-reported questionnaires showed that HIPs increased students' cancer knowledge and developed their transferable and technical skills. Many students reported that these HIPs strongly impacted their career preparedness; positively influenced their interest in pursuing careers in health or biomedical sciences; and encouraged them to participate in community service activities. Thus, these findings provide new insights into the perceived benefits of HIPs in cancer education and research by undergraduate students., (© 2024 The Author(s). Biochemistry and Molecular Biology Education published by Wiley Periodicals LLC on behalf of International Union of Biochemistry and Molecular Biology.)

Background: Reducing the risks of complications is a primary goal of diabetes management, with effective glycemic control a key factor. Glucose monitoring using continuous glucose monitoring (CGM) technology is an important part of diabetes self-management, helping patients reach and maintain targeted glucose and glycated hemoglobin (HbA1c) levels. Although clinical guidelines recommended CGM use, coverage by Medicaid is limited, likely because of cost concerns., Objective: To assess the cost-effectiveness of FreeStyle Libre CGM systems, compared with capillary-based self-monitoring of blood glucose (SMBG), in US individuals with type 2 diabetes mellitus using basal insulin., Methods: A patient-level microsimulation model was used to compare CGM with SMBG for a population of 10,000 patients. A 10-year horizon was used, with an annual discount rate of 3.0% for costs and utilities. Model population characteristics were based on US national epidemiology data. Patient outcomes were based on published clinical trials and real-world studies. Annual costs, reflective of 2023 values, included CGM and SMBG acquisition costs and the costs of treating diabetic ketoacidosis, severe hypoglycemia, and diabetes complications. The effect of CGM was modeled as a persistent 1.1% reduction in HbA1c relative to SMBG based on US real-world evidence. Disutilities were based on published clinical trials and other relevant literature. The primary outcome was cost per quality-adjusted life-year (QALY) gained. Sensitivity analyses were performed to test the validity of the model results when accounting for a plausible variation of inputs., Results: In the base case analysis, CGM was dominant to SMBG, providing more QALYs (6.18 vs 5.97) at a lower cost ($70,137 vs $71,809) over the 10-year time horizon. A $10,456 increase in glucose monitoring costs was offset by a $12,127 reduction in treatment costs. Cost savings reflected avoidance of acute diabetic events (savings owing to reductions in severe hypoglycemia and diabetic ketoacidosis were $271 and $2,159, respectively) and a reduced cumulative incidence of diabetes complications, particularly renal failure (saving $5,292), myocardial infarction (saving $1,996), and congestive heart failure (saving $1,061). Scenario analyses were consistent with the base case results, and the incremental cost-effectiveness ratio for CGM vs SMBG ranged from dominant to cost-effective. In probabilistic analysis, CGM was 100% likely to be cost-effective at a willingness-to-pay threshold of $50,000/QALY., Conclusions: CGM is cost-effective compared with SMBG for US patients with type 2 diabetes mellitus receiving basal insulin therapy. This suggests that state Medicaid programs could benefit from broader coverage of CGM.

Purpose: The original aim of the study was to determine, in a double-blind 3-arm crossover human trial (n = 7), the effect of supplemental levels of iron (25 mg) and zinc (30 mg) on β-carotene (synthetic) bioavailability (10 h postprandial). However, despite the high dose of supplemental β-carotene (15 mg) consumed with the high fat (18 g), dairy-based breakfast test meal, there was a negligible postprandial response in plasma and triglyceride rich fraction β-carotene concentrations. We then systematically investigated the possible reasons for this low bioavailability of β-carotene., Methods: We determined (1) if the supplemental β-carotene could be micellised and absorbed by epithelial cells, using a Caco-2 cell model, (2) if the fat from the test meal was sufficiently bioavailable to facilitate β-carotene bioavailability, (3) the extent to which the β-carotene could have been metabolised and converted to retinoic acid/retinol and (4) the effect of the test meal matrix on the β-carotene bioaccessibility (in vitro digestion) and Caco-2 cellular uptake., Results: We found that (1) The supplemental β-carotene could be micellised and absorbed by epithelial cells, (2) the postprandial plasma triacylglycerol response was substantial (approximately 75-100 mg dL -1 over 10 h), indicating sufficient lipid bioavailability to ensure β-carotene absorption, (3) the high fat content of the meal (approximately 18 g) could have resulted in increased β-carotene metabolism, (4) β-carotene bioaccessibility from the dairy-based test meal was sixfold lower (p < 0.05) than when digested with olive oil., Conclusion: The low β-carotene bioavailability is probably due to a combination of the metabolism of β-carotene to retinol by BCMO1 and interactions of β-carotene with the food matrix, decreasing the bioaccessibility., Trail Registration: The human trail was retrospectively registered (ClinicalTrail.gov ID: NCT05840848)., (© 2024. The Author(s).)

Introduction: Large Language Models (LLMs) such as ChatGPT have rapidly brought the application of artificial intelligence into widespread use. Among many different use cases for text generation and processing, one application is the extraction of data from existing documents and conversations for simplified and automated form-filling., Objective: In the field of quality assurance and documentation of cancer diseases, there is currently a significant workload involved in transferring data under various aspects into slightly varying formats and applying interpretations such as the TNM classification of tumours. However, there is a lack of trials with real data to assess the applicability of LLM-supported processes in this area, which would enable an evaluation of efficiency and practicality. This study aims to implement and assess such a trial., Methodology: A trial was conducted with N=153 privacy-compliant and ethics committee-cleared medical reports from 25 patients. Using the publicly available version of ChatGPT 4.0, an automated script was used to extract the date of initial diagnosis and common tumor classifications. The results were then individually checked for accuracy. Based on this, the utility of a simple system for guided support in tasks related to tumour documentation was assessed. Additionally, the approach was evaluated in terms of operational costs for the model and its applicability., Results: In summary, the study concludes that the use of generative AI in this field is promising and suitable as a tool even in an untrained state. In a simplified calculation, costs of 35 cents are offset by a value creation of 61,54 euros. However, it also becomes clear that AI can only act in a supportive role, and the correct integration with pre-made specific prompts and tools into the workflow is crucial for a relevant performance., Conclusion: The use of generative AI in the context of search, transfer, and interpretation tasks in the creation of tumor documentation is a promising approach. However, its implementation in practical applications must be closely monitored, and the optimal interaction between man and machine should continue to be evaluated and must be accompanied by tools and task-specific prompts., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

Objectives: This study investigated sustainability and multimorbidity alongside barriers to employment including health and policy to demonstrate intersectional impact on return-to-work success within a UK welfare-to-work programme., Design: Cohort study design: The study calculated the proportion of time spent employed after experiencing a job start and the proportion retaining work over 6 months. Employment/unemployment periods were calculated, sequence-index plots were produced and visualisations were explored by benefit type and age., Setting: This study used confidential access to deidentified data from unemployed Work Programme clients operated by Ingeus on behalf of the UK Government in Scotland between 1 April 2013 and 31 July 2014., Participants: 13 318 unemployed clients aged 18-64 years were randomly allocated to a Work Programme provider and monitored over 2 years., Results: This study has two distinct groupings. 'Employment and Support Allowance (ESA)' corresponding to those with work-limiting disability in receipt of related state financial support, and 'Jobseeker's Allowance (JSA)' corresponding to unemployment claimants. Despite fewer and later job starts for ESA clients, those that gained employment spend relatively more subsequent time in employment when compared with individuals without work-limiting conditions (ESA clients under 50, 0.73; ESA clients over 50, 0.79; JSA clients under 50, 0.67 and JSA clients over 50, 0.68). Proportion in permanent jobs was higher among ESA than JSA clients (JSA under 50, 92%; JSA over 50, 92%; ESA under 50, 95% and ESA over 50, 97%)., Conclusion: The research demonstrated that returning to paid employment after a reliance on welfare benefits is challenging for people aged over 50 and those with disability. The study found that although fewer older ESA claimants entered employment, they typically remained in employment more than JSA clients who did not leave the Work Programme early. This indicates the importance of identifying risk factors for job loss in ageing workers and the development of interventions for extension of working lives., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Structural and functional alterations in the brain's reward circuitry are present in cocaine use disorder (CocUD), but their molecular underpinnings remain unclear. To investigate these mechanisms, we performed single-nuclei multiome profiling on postmortem caudate nucleus tissue from six individuals with CocUD and eight controls. We profiled 31,178 nuclei, identifying 13 cell types including D1- and D2-medium spiny neurons (MSNs) and glial cells. We observed 1,383 differentially regulated genes and 10,235 differentially accessible peaks, with alterations in MSNs and astrocytes related to neurotransmitter activity and synapse organization. Gene regulatory network analysis identified the transcription factor ZEB1 as exhibiting distinct CocUD-specific subclusters, activating downstream expression of ion- and calcium-channels in MSNs. Further, PDE10A emerged as a potential drug target, showing conserved effects in a rat model. This study highlights cell type-specific molecular alterations in CocUD and provides targets for further investigation, demonstrating the value of multi-omics approaches in addiction research.

Purpose: Soft tissue infections can be severe and life-threatening. Their treatment consists currently in radical surgical wound debridement and combined systemic antimicrobial therapy. Different side effects are possible. Local antibiotic therapy represents a new approach to reduce side effects and improve healing. The aim of this study is to assess the effectiveness of the local sprayed use of antibiotics with fibrin sealing compared with negative pressure wound therapy as an established treatment of soft-tissue infections., Methods: In this retrospective study, patients with soft tissue infections who underwent surgical treatment were analysed. One group consists of patients, who received local fibrin-antibiotic spray (FAS) (n = 62). Patients treated by vacuum-assisted wound therapy (VAWT) as the established treatment were the control group (n = 57). Main outcomes were differences in the success of healing, the duration until healing and the number of needed operations., Results: Clinical healing could be achieved for 55 patients (98.21%) in the FAS group vs. 47 patients (92.16%) in the VAWT group (p = 0.19). Time to require this was 10.65 ± 10.38 days in the FAS group and 22.85 ± 14.02 days in the VAWT group (p < 0.001). In the FAS group, patients underwent an average of 1.44 ± 0.72 vs.3.46 ± 1.66 operations in the VAWT group (p < 0.001)., Conclusion: Compared to vacuum-assisted wound therapy in soft tissue infections, local fibrin-antibiotic spray shows faster clinical healing and less needed operations. Leading to shorter hospital stays and more satisfied patients. The combination of sprayed fibrin and antibiotics can be seen as a promising and effective method., (© 2024. The Author(s).)

The Aeolian archipelago is known worldwide for its volcanic activity and hydrothermal emissions, of mainly carbon dioxide and hydrogen sulfide. Hydrogen, methane, and carbon monoxide are minor components of these emissions which together can feed large quantities of bacteria and archaea that do contribute to the removal of these notorious greenhouse gases. Here we analyzed the metagenome of samples taken from the Levante bay on Vulcano Island, Italy. Using a gene-centric approach, the hydrothermal vent community appeared to be dominated by Proteobacteria, and Sulfurimonas was the most abundant genus. Metabolic reconstructions highlight a prominent role of formaldehyde oxidation and the reverse TCA cycle in carbon fixation. [NiFe]-hydrogenases seemed to constitute the preferred strategy to oxidize H 2 , indicating that besides H 2 S, H 2 could be an essential electron donor in this system. Moreover, the sulfur cycle analysis showed a high abundance and diversity of sulfate reduction genes underpinning the H 2 S production. This study covers the diversity and metabolic potential of the microbial soil community in Levante bay and adds to our understanding of the biogeochemistry of volcanic ecosystems., (© 2024. The Author(s).)

General Purpose: To provide information on the association between risk factors and the development of new or worsened stage 2 to 4 pressure injuries (PIs) in patients in long-term care hospitals (LTCHs), inpatient rehabilitation facilities (IRFs), and skilled nursing facilities (SNFs)., Target Audience: This continuing education activity is intended for physicians, physician assistants, nurse practitioners, and nurses with an interest in skin and wound care., Learning Objectives/outcomes: After participating in this educational activity, the participant will:1. Compare the unadjusted PI incidence in SNF, IRF, and LTCH populations.2. Explain the extent to which the clinical risk factors of functional limitation (bed mobility), bowel incontinence, diabetes/peripheral vascular disease/peripheral arterial disease, and low body mass index are associated with new or worsened stage 2 to 4 PIs across the SNF, IRF, and LTCH populations.3. Compare the incidence of new or worsened stage 2 to 4 PI development in SNF, IRF, and LTCH populations associated with high body mass index, urinary incontinence, dual urinary and bowel incontinence, and advanced age., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Porphyrias are predominantly genetic metabolic disorders caused by dysregulation of specific enzymes in porphyrin-heme biosynthesis. The enzymatic dysfunction leads to formation and excretion of intermediate metabolic products in the form of porphyrins and/or their precursors δ‑aminolevulinic acid and porphobilinogen, which have cyto- and tissue-toxic properties. Clinically, porphyrias are extremely diverse, with symptoms ranging from skin changes on light-exposed areas of the body to potentially life-threatening neurovisceral attacks. Biochemical tests in urine, blood and stool are used for diagnosis, which can be supplemented by molecular genetic analyses. Treatment of the various forms of porphyria is complex and often requires close interdisciplinary cooperation between different medical specialties., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Lentiviral vectors (LVVs) are used as a starting material to generate chimeric antigen receptor (CAR) T cells. Therefore, LVVs need to be carefully analyzed to ensure safety, quality, and potency of the final product. We evaluated orthogonal and complementary analytical techniques for their suitability to characterize particulate matter (impurities and LVVs) in pharmaceutical LVV materials at development stage derived from suspension and adherent manufacturing processes. Microfluidic resistive pulse sensing (MRPS) with additional manual data fitting enabled the assessment of mode diameters for particles in the expected LVV size range in material from adherent production. LVV material from a suspension process, however, contained substantial amounts of particulate impurities which blocked MRPS cartridges. Sedimentation-velocity analytical ultracentrifugation (SV-AUC) resolved the LVV peak in material from adherent production well, whereas in more polydisperse samples from suspension production, presence of particulate impurities masked a potential signal assignable to LVVs. In interferometric light microscopy (ILM) and nanoparticle tracking analysis (NTA), lower size detection limits close to ∼ 70 nm resulted in an apparent peak in particle size distributions at the expected size for LVVs emphasizing the need to interpret these data with care. Interpretation of data from dynamic light scattering (DLS) was limited by insufficient size resolution and sample polydispersity. In conclusion, the analysis of LVV products manufactured at pharmaceutical scale with current state-of-the-art physical (nano)particle characterization techniques was challenging due to the presence of particulate impurities of heterogeneous size. Among the evaluated techniques, MRPS and SV-AUC were most promising yielding acceptable results at least for material from adherent production., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)