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Neuropathic deformities of the lesser toes refer to a variety of neuromuscular disorders in which a stiff lesser toe deformity is encountered. Claw toes, hammer toes, and mallet toes can be found. Each deformity is better described as which joint of a particular toe is in a flexed or extended position. This information guides the surgeon to which joint should be addressed and what additional soft tissue procedure may be needed. Interphalangeal joint fusions are the procedure of choice, together with extensor or flexor tenotomies. Good results can be expected, with low revision rates., Competing Interests: Disclosure The authors have no relevant disclosures relative to this topic., (Copyright © 2024 Elsevier Inc. All rights reserved.)

This work describes determining urea in milk samples using a multicommuted approach with a urease enzyme immobilized in bacterial cellulose and solid MOF as a colorimetric reagent. The Cu(2+)-MOF was characterized by FTIR spectroscopy, XRD, and SEM. The urea quantification was based on the urea hydrolysis reaction catalyzed by urease and reacted with Cu(2+)-MOF forming [Cu(NH 3 ) 4 ] 2+ , monitored at 450 nm. Linear responses were obtained from 1.0 to 50.0 mg dL -1 urea (R = 0.9959, n = 11), detection and quantitation limits of 0.082 mg dL -1 and 0.272 mg dL -1 respectively, analytical frequency of 8 determinations per hour, 0.8 mL sample solution consumption. Potential interfering studies have shown the selectivity of the proposed method. Addition and recovery tests were performed obtaining variation from 90 to 103%. Applying the F-test and t-test, the results showed no significant difference at the 95% confidence level Comparing the proposed and the reference method., 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 this work., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The pairing of electrons is ubiquitous in electronic systems featuring attractive inter-electron interactions, as exemplified in superconductors. Counterintuitively, it can also be mediated in certain circumstances by the repulsive Coulomb interaction alone. Quantum Hall (QH) Fabry-Pérot interferometers (FPIs) tailored in a two-dimensional electron gas under a perpendicular magnetic field have been argued to exhibit such an unusual electron pairing, seemingly without attractive interactions. Here, we show evidence in graphene QH FPIs, revealing not only a similar electron pairing at bulk filling factor ν B  = 2, but also an unforeseen emergence of electron tripling characterized by a fractional Aharonov-Bohm flux period of h/3e (h is the Planck constant and e the electron charge) at ν B  = 3. Leveraging plunger-gate spectroscopy, we demonstrate that electron pairing (tripling) involves correlated charge transport on two (three) entangled QH edge channels. This spectroscopy indicates a quantum interference flux periodicity determined by the sum of the phases acquired by the distinct QH edge channels having slightly different interfering areas. Phase jumps observed in the pajama maps can be accounted for by the frequency beating between pairing/tripling modes and the outer interfering edge., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Introduction: Approximately 30% of individuals with schizophrenia experience treatment resistance (TR), with 70% exhibiting it from the onset. Most research fails to distinguish between acquired and innate resistance, with limited data on TR in first episode psychosis (FEP). However, FEP patients with TR experience progressively worse outcomes compared to those with initial response. To further understand these findings, clinical and demographic data of FEP patients with and without TR were compared in this naturalistic study., Methods: Information was extracted on FEP patients who were antipsychotic-naive at the time of admission from a retrospective database on F2x diagnosed patients admitted to the LMU psychiatric clinic between 2008 and 2018. Clozapine was used at discharge as a marker of TR in the FEP cohort. A similarly antipsychotic-naïve FEP control group without clozapine at discharge, was generated by matching for gender and age. Thirty clinical and demographic variables were analyzed to identify differences., Results: Two-hundred forty antipsychotic-naive FEPs were included: 33 with clozapine at discharge (TRC group), and 207 in the control group (non-TRC). Significant differences were observed in inpatient stay duration, chlorpromazine-equivalent dosage, number of antipsychotics, and anticholinergic medication at discharge., Discussion: The findings indicate that longer inpatient stay, an increased number of antipsychotics, and possibly a more extended prodrome may serve as markers for non-clozapine TR in FEP. Further research is necessary to establish the robustness of these variables as early-stage TR markers., Competing Interests: EW has been invited to advisory boards from Recordati. PFalk is a co-editor of the German (DGPPN) schizophrenia treatment guidelines and a co-author of the WFSBP schizophrenia treatment guidelines; he is on the advisory boards and receives speaker fees from Janssen, Lundbeck, Otsuka, Boehringer-Ingelheim and Richter. AH is editor of the German (DGPPN) schizophrenia treatment guidelines and first author of the WFSBP schizophrenia treatment guidelines; he has been on the advisory boards of and has received speaker fees from Janssen-Cilag, Lundbeck, Recordati, Rovi and Otsuka. PF, JS,LL, MC and IP declare no conflicts of interest., (Thieme. All rights reserved.)

Background: Optical coherence tomography and electroretinography studies have revealed structural and functional retinal alterations in individuals with schizophrenia spectrum disorders (SSDs). However, it remains unclear which specific retinal layers are affected; how the retina, brain, and clinical symptomatology are connected; and how alterations of the visual system are related to genetic disease risk., Methods: Optical coherence tomography, electroretinography, and brain magnetic resonance imaging were applied to comprehensively investigate the visual system in a cohort of 103 patients with SSDs and 130 healthy control individuals. The sparse partial least squares algorithm was used to identify multivariate associations between clinical disease phenotype and biological alterations of the visual system. The association of the revealed patterns with individual polygenic disease risk for schizophrenia was explored in a post hoc analysis. In addition, covariate-adjusted case-control comparisons were performed for each individual optical coherence tomography and electroretinography parameter., Results: The sparse partial least squares analysis yielded a phenotype-eye-brain signature of SSDs in which greater disease severity, longer duration of illness, and impaired cognition were associated with electrophysiological alterations and microstructural thinning of most retinal layers. Higher individual loading onto this disease-relevant signature of the visual system was significantly associated with elevated polygenic risk for schizophrenia. In case-control comparisons, patients with SSDs had lower macular thickness, thinner retinal nerve fiber and inner plexiform layers, less negative a-wave amplitude, and lower b-wave amplitude., Conclusions: This study demonstrates multimodal microstructural and electrophysiological retinal alterations in individuals with SSDs that are associated with disease severity and individual polygenic burden., (Copyright © 2024 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Nonverbal communication habitually leaks out in ways that expose underlying thoughts, true feelings, and integrity of a counterpart. Social cognition is deficient in a wide range of mental disorders, including schizophrenia (SZ). Inferring social signals through the eyes is pivotal for social interaction but remains poorly investigated. The present work aims to fill this gap by examining whether and, if so, how reading language of the eyes is altered in SZ. We focused on male SZ, primarily because the disorder manifests a gender-specific profile. Patients and matched typically developing (TD) individuals were administered the Reading the Mind in the Eyes Test-Modified (RMET-M) and Emotions in Masked Faces (EMF) task that provide comparable visual information. The findings indicate that in SZ, the emotion recognition profile is similar to TD, with a more accurate recognition of some emotions such as fear, neutral expressions, and happiness than the others (sadness and disgust). In SZ, however, this profile is shifted down: all emotions are recognized less accurately than in TD. On the RMET-M, patients are also less precise, albeit they perform better on items with positive valence. In SZ only, recognition accuracy on both tasks is tightly linked to each other. The outcome reveals global challenges for males with SZ in inferring social information in the eyes and calls for remediation programs to shape social cognition. This work offers novel insights into the profiles of social cognitive deficits in mental disorders that differ in their gender prevalence., Competing Interests: Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Despite the great potential of DNA vaccines for a broad range of applications, ranging from prevention of infections, over treatment of autoimmune and allergic diseases to cancer immunotherapies, the implementation of such therapies for clinical treatment is far behind the expectations up to now. The main reason is the poor immunogenicity of DNA vaccines in humans. Consequently, the improvement of the performance of DNA vaccines in vivo is required. This mini-review provides an overview of the current state of DNA vaccines and the various strategies to enhance the immunogenic potential of DNA vaccines, including (i) the optimization of the DNA construct itself regarding size, nuclear transfer and transcriptional regulation; (ii) the use of appropriate adjuvants; and (iii) improved delivery, for example, by careful choice of the administration route, physical methods such as electroporation and nanomaterials that may allow cell type-specific targeting. Moreover, combining nanoformulated DNA vaccines with other immunotherapies and prime-boost strategies may help to enhance success of treatment., (© 2024 The Author(s). Microbial Biotechnology published by John Wiley & Sons Ltd.)

Purpose: Interest in intramedullary metacarpal fracture fixation (IMFF) with screws is increasing. However, the optimal screw diameter for fracture fixation is not yet established. In theory, larger screws should be more stable, but there is concern about long-term sequelae of larger metacarpal head defects and extensor mechanism injury created during insertion as well as implant cost. Therefore, the purpose of this study was to compare different diameter screws for IMFF to a popular and more cost-effective alternative of intramedullary wiring., Methods: Thirty-two cadaveric metacarpals were used in a transverse metacarpal shaft fracture model. Treatment groups consisted of IMFF with 3.0 × 60 mm, 3.5 x 60 mm, and 4.5 x 60 mm screws as well as 4 1.1-mm intramedullary wires. Cyclic cantilever bending was performed with the metacarpals mounted at 45° to simulate physiologic loading. Cyclical loading at 10, 20, and 30 N was performed to determine fracture displacement, stiffness, and ultimate force., Results: At 10, 20, and 30 N of cyclical loading, all screw diameters tested provided similar stability as measured by fracture displacement and were superior to the wire group. However, ultimate force under load to failure testing was similar between the 3.5- and 4.5-mm screws and superior to 3.0-mm screws and wires., Conclusions: For IMFF, 3.0, 3.5, and 4.5-mm diameter screws provide adequate stability for early active motion and are superior to wires. When comparing the different screw diameters, 3.5- and 4.5-mm diameter screws offer similar construct stability and strength superior to the 3.0-mm diameter screw. Therefore, to minimize metacarpal head morbidity, smaller screw diameters may be preferable., Clinical Relevance: This study suggests that IMFF with screws is biomechanically superior to wires in cantilever bending strength in the transverse fracture model. However, smaller screws may be sufficient to permit early active motion while minimizing metacarpal head morbidity., (Copyright © 2024 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.)

Advanced breast cancer, as well as ineffective treatments leading to surviving cancer cells, can result in the dissemination of these malignant cells from the primary tumor to distant organs. Recent research has shown that microRNA 200c (miR-200c) can hamper certain steps of the invasion-metastasis cascade. However, it is still unclear whether miR-200c expression alone is sufficient to prevent breast cancer cells from metastasis formation. Hence, we performed a xenograft mouse experiment with inducible miR-200c expression in MDA-MB 231 cells. The ex vivo analysis of metastatic sites in a multitude of organs, including lung, liver, brain, and spleen, revealed a dramatically reduced metastatic burden in mice with miR-200c-expressing tumors. A fundamental prerequisite for metastasis formation is the motility of cancer cells and, therefore, their migration. Consequently, we analyzed the effect of miR-200c on collective- and single-cell migration in vitro, utilizing MDA-MB 231 and MCF7 cell systems with genetically modified miR-200c expression. Analysis of collective-cell migration revealed confluence-dependent motility of cells with altered miR-200c expression. Additionally, scratch assays showed an enhanced predisposition of miR-200c-negative cells to leave cell clusters. The in-between stage of collective- and single-cell migration was validated using transwell assays, which showed reduced migration of miR-200c-positive cells. Finally, to measure migration at the single-cell level, a novel assay on dumbbell-shaped micropatterns was performed, which revealed that miR-200c critically determines confined cell motility. All of these results demonstrate that sole expression of miR-200c impedes metastasis formation in vivo and migration in vitro and highlights miR-200c as a metastasis suppressor in breast cancer., (© 2024 The Author(s). Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Background: Musculoskeletal disorders are a leading cause of healthcare utilization and disability among the millions of school employees in the United States. While school-based workplace wellness programs have demonstrated improvements in health behaviors, the long-term financial impact of these programs remains unclear., Objective: Identify factors associated with health insurance claims costs within a school district featuring a workplace wellness program emphasizing health behaviors aligned with the functional medicine model of care., Setting: Ashland School District in Oregon, USA., Participants: Ashland School District employee health plan participants., Methods: Medical and pharmacy claims from 2010 to 2021 were included for analysis. Multivariate linear regression models of medical and pharmacy claims costs were constructed including year of claim, age, sex, baseline comorbidities, and whether the participant received functional medicine care., Results: The sample included 1,178 participants with musculoskeletal disorders and a total of 92,922 claims. Older age ($46.28 per year, P < .0001) and comorbidities ($258.24 per comorbidity, P = .03) were associated with higher yearly per member medical claims. Older age ($21.84 per year, P < .0001) and comorbidities ($335.62 per comorbidity, P < .0001) were also associated with higher yearly per member pharmacy claims. Receiving functional medicine care (-$534.81, P = .0002) was associated with lower yearly per member pharmacy claims. There were no meaningful changes in total medical or pharmacy claims costs over time after adjustment for covariates (P > .4)., Conclusion: Medical and pharmacy claims remained stable over the study period among employee health plan participants with musculoskeletal disorders, and functional medicine care was associated with significantly lower pharmacy claims costs.

Although small-interfering RNAs (siRNAs) are specific silencers for numerous disease-related genes, their clinical applications still require safe and effective means of delivery into target cells. Highly efficient lipid nanoparticles (LNPs) are developed for siRNA delivery, showcasing the advantages of novel pH-responsive lipoamino xenopeptide (XP) carriers. These sequence-defined XPs are assembled by branched lysine linkages between cationizable polar succinoyl tetraethylene pentamine (Stp) units and apolar lipoamino fatty acids (LAFs) at various ratios into bundle or U-shape topologies. Formulation of siRNA-LNPs using LAF 4 -Stp 1 XPs as ionizable compounds led to robust cellular uptake, high endosomal escape, and successful in vitro gene silencing activity at an extremely low (150 picogram) siRNA dose. Of significance is the functional in vivo endothelium tropism of siRNA-LNPs with bundle LAF 4 -Stp 1 XP after intravenous injection into mice, demonstrated by superior knockdown of liver sinusoidal endothelial cell (LSEC)-derived factor VIII (FVIII) and moderate silencing of hepatocyte-derived FVII compared to DLin-MC3-DMA-based LNPs. Optimizing lipid composition following click-modification of siRNA-LNPs with ligand c(RGDfK) efficiently silenced vascular endothelial growth factor receptor-2 (VEGFR-2) in tumor endothelial cells (TECs). The findings shed light on the role of ionizable XPs in the LNP in vivo cell-type functional targeting, laying the groundwork for future therapeutic applications., (© 2024 The Author(s). Small published by Wiley‐VCH GmbH.)

Hepatotoxicity is an under-recognized and potentially fatal side effect of high-dose methotrexate (HDMTX) chemotherapy, and this risk is compounded in children with metabolic dysfunction-associated steatotic liver disease and/or metabolic-associated steatohepatitis. We present the case of a 12-year-old obese, Hispanic male with elevated hepatic transaminases of unknown etiology at initiation of high-risk B-cell acute lymphoblastic leukemia chemotherapy. He developed acute kidney injury within 24 hours of receiving intravenous HDMTX which progressed to acute hepatic failure. Liver biopsy confirmed methotrexate toxicity aggravated by undiagnosed metabolic dysfunction-associated steatotic liver disease. Rapid deterioration precluded liver transplantation, and he died 21 days after HDMTX treatment. This case highlights the need for comprehensive hepatic evaluation in patients with known or suspected liver disease when administering HDMTX. Dialysis should be considered if delayed methotrexate clearance occurs due to potential for rapid, irreversible hepatotoxicity., Competing Interests: The authors declare no conflict of interest., (© 2024 The Author(s). JPGN Reports published by Wiley Periodicals LLC on behalf of The European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

This study aims to investigate the barriers and facilitators to guideline adherence for the print format of the German schizophrenia guideline as well as for the concept of a digital living guideline for the first time. For this purpose, the schizophrenia guideline was transferred to a digital guideline format within the web-based tool MAGICapp. An online survey was performed under participation of mental healthcare professionals (medical doctors, psychologists/psychotherapists, psychosocial therapists, caregivers) in 17 hospitals for psychiatry in Southern Germany and a professional association for German neurologists and psychiatrists. 524 participants opened the survey, 439 completed the demographic questions and commenced the content-related survey and 309 provided complete data sets. Results indicate a higher occurrence of knowledge-related barriers for the living guideline. The print version is associated with more attitude-related and external barriers. Older professionals reported more attitude-related barriers to a living guideline compared to younger professionals. Differences between professions regarding barriers were found for both formats. Various barriers exist for both guideline formats and a need for facilitators was expressed across professions. Many of the mentioned obstacles and facilitators can be more easily addressed with living guidelines. However, also living guidelines face barriers. Thus, the introduction of these new formats alone cannot lead to sustainable behavior change regarding guideline adherence. Yet, living guidelines seem to be a cornerstone to improved and tailored guideline implementation as they facilitate to keep recommendations up to date and to address the need of individual professional groups., (© 2023. The Author(s).)

In the United States, Chronic Kidney Disease (CKD) affects approximately 1 in 7 adults. Despite its significant impact, CKD awareness, education, and screening are often lacking among underserved Latine populations, leading to poorer health outcomes and higher mortality rates. Various studies highlight the crucial role of Community Health Workers (CHWs) in improving health outcomes within minority communities both domestically and globally. However, there remains a gap in research on the acceptance and effectiveness of CHW-led interventions targeting CKD. This prospective intervention study employed a pre-post quasi-experimental design to evaluate a CHW-led educational program aimed at enhancing CKD knowledge, screening, and monitoring among Latines with low health literacy and English proficiency. CHWs utilized a culturally tailored CKD Flipchart, and 100 underserved patients received the intervention. Feedback from 85 participants who completed post-intervention surveys indicated high satisfaction with the program's relevance and the professionalism of the CHWs. Importantly, 85% expressed a positive intention to seek kidney care following the intervention. Preliminary analysis of medical records before and after the intervention showed improvements in glycemic control (median change = -18.0, p = 0.014) and triglyceride levels (median change = -29.0, p = 0.035), suggesting the program's effectiveness in managing CKD risk factors. These findings highlight the potential of CHW-led interventions to reduce kidney health disparities among underserved communities.

Background: Handgun purchaser licensing (HPL) laws mandate individuals to obtain a license from law enforcement before buying a firearm. Research indicates these laws effectively reduce various forms of fatal firearm violence, including homicides, suicides, and mass shootings. Our study sought to assess the impact of HPL laws on non-fatal firearm violence., Methods: Utilizing the augmented synthetic control method (ASCM), we estimated the average treatment effect on the treated (ATT) resulting from a full repeal of an HPL law in Missouri (2007), a partial repeal in Michigan (2012), and an adoption on HPL law in Maryland (2013) on firearm injury hospitalizations. We utilized RAND's healthcare cost and utilization project-based dataset from 2000 to 2016 for our outcome variable. We conducted in-time placebo testing and leave-one-out donor pool testing as sensitivity analyses., Results: Maryland's adoption was associated with a statistically significant 32.3% reduction in firearm-related injury hospitalization (FIH) rates (ATT = - 0.497, standard error (SE) = 0.123); Missouri's repeal was associated with a statistically significant 35.7% increase in FIH rates (ASCM = 0.456, SE = 0.155); and Michigan's partial repeal showed no statistically significant associations with FIH rates (ATT = - 0.074, SE = 0.129). Sensitivity analyses confirm the robustness of the estimated HPL effects., Discussion: HPL laws appear to be protective against hospitalizations for nonfatal firearm injuries. These findings align with prior research indicating that HPL laws are effective in reducing fatal firearm violence. States without such licensing systems ought to consider these robust policies as a means to address firearm violence., (© 2024. The Author(s).)

Understanding COVID-19's effects on susceptible populations remains essential for clinical implementations. Our review aimed to examine whether the pandemic significantly impacted the stress levels in the mothers of premature infants in NICUs. The review of the literature from Google Scholar and PubMed resulted in identifying specific stressors such as the disruption of healthcare systems, limited access to neonatal care, uncertainty due to frequent changes in restrictions, the risk of COVID-19 infection, social isolation, and financial stress. While some quantitative studies concerning this topic did not show a significant increase in the perception of stress in this population compared to the pre-pandemic group, various research has indicated that the COVID-19 pandemic may result in enduring impacts on the emotional and neurological development of children. This article demonstrates a correlation between the repercussions of the COVID-19 pandemic and an elevated incidence of depressive symptoms among the mothers of premature infants. Further studies are needed to assess the long-term impact of pandemic-induced stress.

Background: Cardiac hypertrophy compensates for increased biomechanical stress of the heart induced by prevalent cardiovascular pathologies but can result in heart failure if left untreated. Here, we hypothesized that the membrane fusion and repair protein dysferlin is critical for the integrity of the transverse-axial tubule (TAT) network inside cardiomyocytes and contributes to the proliferation of TAT endomembranes during pressure overload-induced cardiac hypertrophy., Methods: Stimulated emission depletion and electron microscopy were used to localize dysferlin in mouse and human cardiomyocytes. Data-independent acquisition mass spectrometry revealed the cardiac dysferlin interactome and proteomic changes of the heart in dysferlin-knockout mice. After transverse aortic constriction, we compared the hypertrophic response of wild-type versus dysferlin-knockout hearts and studied TAT network remodeling mechanisms inside cardiomyocytes by live-cell membrane imaging., Results: We localized dysferlin in a vesicular compartment in nanometric proximity to contact sites of the TAT network with the sarcoplasmic reticulum, a.k.a. junctional complexes for Ca 2+ -induced Ca 2+ release. Interactome analyses demonstrated a novel protein interaction of dysferlin with the membrane-tethering sarcoplasmic reticulum protein juncophilin-2, a putative interactor of L-type Ca 2+ channels and ryanodine receptor Ca 2+ release channels in junctional complexes. Although the dysferlin-knockout caused a mild progressive phenotype of dilated cardiomyopathy, global proteome analysis revealed changes preceding systolic failure. Following transverse aortic constriction, dysferlin protein expression was significantly increased in hypertrophied wild-type myocardium, while dysferlin-knockout animals presented markedly reduced left-ventricular hypertrophy. Live-cell membrane imaging showed a profound reorganization of the TAT network in wild-type left-ventricular myocytes after transverse aortic constriction with robust proliferation of axial tubules, which critically depended on the increased expression of dysferlin within newly emerging tubule components., Conclusions: Dysferlin represents a new molecular target in cardiac disease that protects the integrity of tubule-sarcoplasmic reticulum junctional complexes for regulated excitation-contraction coupling and controls TAT network reorganization and tubular membrane proliferation in cardiomyocyte hypertrophy induced by pressure overload., Competing Interests: None.

Cancer immunotherapy with chimeric antigen receptor (CAR) T cells can cause immune effector cell-associated neurotoxicity syndrome (ICANS). However, the molecular mechanisms leading to ICANS are not well understood. Here we examined the role of microglia using mouse models and cohorts of individuals with ICANS. CD19-directed CAR (CAR19) T cell transfer in B cell lymphoma-bearing mice caused microglia activation and neurocognitive deficits. The TGFβ-activated kinase-1 (TAK1)-NF-κB-p38 MAPK pathway was activated in microglia after CAR19 T cell transfer. Pharmacological TAK1 inhibition or genetic Tak1 deletion in microglia using Cx3cr1 CreER :Tak1 fl/fl mice resulted in reduced microglia activation and improved neurocognitive activity. TAK1 inhibition allowed for potent CAR19-induced antilymphoma effects. Individuals with ICANS exhibited microglia activation in vivo when studied by translocator protein positron emission tomography, and imaging mass cytometry revealed a shift from resting to activated microglia. In summary, we prove a role for microglia in ICANS pathophysiology, identify the TAK1-NF-κB-p38 MAPK axis as a pathogenic signaling pathway and provide a rationale to test TAK1 inhibition in a clinical trial for ICANS prevention after CAR19 T cell-based cancer immunotherapy., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Proteolysis targeting chimeras (PROTACs) have emerged as revolutionary anticancer therapeutics that degrade disease-causing proteins. However, the anticancer performance of PROTACs is often impaired by their insufficient bioavailability, unsatisfactory tumor specificity and ability to induce acquired drug resistance. Herein, we propose a polymer-conjugated PROTAC prodrug platform for the tumor-targeted delivery of the most prevalent von Hippel-Lindau (VHL)- and cereblon (CRBN)-based PROTACs, as well as for the precise codelivery of a degrader and conventional small-molecule drugs. The self-assembling PROTAC prodrug nanoparticles (NPs) can specifically target and be activated inside tumor cells to release the free PROTAC for precise protein degradation. The PROTAC prodrug NPs caused more efficient regression of MDA-MB-231 breast tumors in a mouse model by degrading bromodomain-containing protein 4 (BRD4) or cyclin-dependent kinase 9 (CDK9) with decreased systemic toxicity. In addition, we demonstrated that the PROTAC prodrug NPs can serve as a versatile platform for the codelivery of a PROTAC and chemotherapeutics for enhanced anticancer efficiency and combination benefits. This study paves the way for utilizing tumor-targeted protein degradation for precise anticancer therapy and the effective combination treatment of complex diseases., (© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

Despite impressive recent establishment of therapeutic nucleic acids as drugs and vaccines, their broader medical use is impaired by modest performance in intracellular delivery. Inefficient endosomal escape presents a major limitation responsible for inadequate cytosolic cargo release. Depending on the carrier, this endosomal barrier can strongly limit or even abolish nucleic acid delivery. Different recent endosomal escape strategies and their hypothesized mechanisms are reviewed., 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 Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Clinical practice guidelines are crucial for enhancing healthcare quality and patient outcomes. Yet, their implementation remains inconsistent across various professions and disciplines. Previous findings on the implementation of the German guideline for schizophrenia (2019) revealed low adherence rates among healthcare professionals. Barriers to guideline adherence are multifaceted, influenced by individual, contextual, and guideline-related factors. This study aims to investigate the effectiveness of a digital guideline version compared to print/PDF formats in enhancing guideline adherence., Methods: A multicenter, cluster-randomized controlled trial was conducted in South Bavaria, Germany, involving psychologists and physicians. Participants were divided into two groups: implementation of the guideline using a digital online version via the MAGICapp platform and the other using the traditional print/PDF version. The study included a baseline assessment and a post-intervention assessment following a 6-month intervention phase. The primary outcome was guideline knowledge, which was assessed using a guideline knowledge questionnaire., Results: The study included 217 participants at baseline and 120 at post-intervention. Both groups showed significant improvements in guideline knowledge; however, no notable difference was found between both study groups regarding guideline knowledge at either time points. At baseline, 43.6% in the control group (CG) and 52.5% of the interventional group (IG) met the criterion. There was no significant difference in the primary outcome between the two groups at either time point (T0: Chi 2 (1)  = 1.65, p = 0.199, T1: Chi 2 (1)  = 0.34, p = 0.561). At post-intervention, both groups improved, with 58.2% in the CG and 63.5% in the IG meeting this criterion., Conclusions: While the study did not include a control group without any implementation strategy, the overall improvement in guideline knowledge following an implementation strategy, independent of the format, was confirmed. The digital guideline version, while not superior in enhancing knowledge, showed potential benefits in shared decision-making skills. However, familiarity with traditional formats and various barriers to digital application may have influenced these results. The study highlights the importance of tailored implementation strategies, especially for younger healthcare providers., Trial Registration: https://drks.de/search/de/trial/DRKS00028895., (© 2024. The Author(s).)

Double pH-responsive xenopeptides comprising polar ionizable succinoyl tetraethylene pentamine (Stp) motifs and lipophilic ionizable lipoamino fatty acids (LAFs) were recently found to efficiently transfect mRNA and pDNA at low doses. However, potency was often accompanied with cytotoxicity at higher doses. Insertion of bioreducible disulfide building blocks (ssbb) or non-reducible hydrophobic spacers between polar and apolar ionizable domains of LAF-Stp carriers should mitigate toxicity of xenopeptides. Carriers showed stable nucleic acid complexation and endosomal pH-dependent lytic activities, both of which were abolished after reductive cleavage of ssbb-containing carriers. For pDNA, U-shaped carriers with one Stp and two LAF units or bundle carriers with two Stps and four LAFs displayed highest potency. For mRNA, best transfection was achieved with bundle carriers with one Stp and four LAFs. Both the ssbb and hydrophobic spacer containing analogs displayed improved metabolic activity, reduced membrane damage, and improved cell growth. The ssbb carriers were most beneficial regarding living cell count and low apoptosis rates. Mechanistically, inserted spacers decelerated the transfection kinetics and altered the requirement of endosomal protonation. Overall, mRNA and pDNA carriers with improved biocompatibility have been designed, with their high potency illustrated in transfection of various cell lines including low passage number colon carcinoma cells.

Purpose: Intramedullary (IM) screw fixation is gaining popularity in the treatment of metacarpal fractures. Despite its rapid adoption, there is a paucity of evidence regarding parameters to optimize effectiveness. This study aimed to quantify the relationship between stability, IM screw size, and canal fill using a cadaveric model., Methods: Thirty cadaveric metacarpals (14 index, 13 middle, and three ring fingers; mean age: 58.3 years, range: 48-70) were selected to allow for canal fill ratios of 0.7-1.1 for screws sized 3.0, 3.5, and 4.5 mm. Metacarpals underwent a 45° volar-dorsal osteotomy at the midpoint before fixation with an IM screw. Specimens were subjected to 100 cycles of loading at 10 N, 20 N, and 30 N before load-to-failure testing. Correlation coefficients for angular displacement on the final cycle at each load, peak load to failure, and average stiffness were assessed., Results: Correlation coefficients for the angular displacement on the 100th cycle were as follows: 10 N, R = 0.62, 20 N, R = 0.57, and 30N, R = 0.58. Correlation values for peak load to failure as a function of canal fit were as follows: 3.0 mm, R = 0.5, 3.5 mm, R = 0.17, and 4.5 mm, R = 0.44. The canal fill ratio that intersected the line-of-best fit at an angular deformity of 10° was 0.74. Average peak forces for 3.0-, 3.5-, and 4.5-mm screws were 79.5, 136.5, and 179.6 N, respectively. Average stiffness for each caliber was 14.8, 33.4, and 52.3 N/mm., Conclusions: Increasing screw diameter and IM fill resulted in more stable fixation, but marginal gains were seen in ratios >0.9. A minimum fill ratio of 0.74 was sufficient to withstand forces of early active motion with angular deformity <10°., Clinical Relevance: An understanding of the relationship of IM fill ratio of metacarpal screws to fracture stability may provide a framework for clinicians to optimally size these implants., Competing Interests: Conflicts of Interest No benefits in any form have been received or will be received related directly to this article., (Copyright © 2024 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.)

Neuroinflammation and blood-cerebrospinal fluid barrier (BCB) disruption could be key elements in schizophrenia-spectrum disorderś(SSDs) etiology and symptom modulation. We present the largest two-stage individual patient data (IPD) meta-analysis, investigating the association of BCB disruption and cerebrospinal fluid (CSF) alterations with symptom severity in first-episode psychosis (FEP) and recent onset psychotic disorder (ROP) individuals, with a focus on sex-related differences. Data was collected from PubMed and EMBASE databases. FEP, ROP and high-risk syndromes for psychosis IPD were included if routine basic CSF-diagnostics were reported. Risk of bias of the included studies was evaluated. Random-effects meta-analyses and mixed-effects linear regression models were employed to assess the impact of BCB alterations on symptom severity. Published (6 studies) and unpublished IPD from n = 531 individuals was included in the analyses. CSF was altered in 38.8 % of individuals. No significant differences in symptom severity were found between individuals with and without CSF alterations (SMD = -0.17, 95 %CI -0.55-0.22, p = 0.341). However, males with elevated CSF/serum albumin ratios or any CSF alteration had significantly higher positive symptom scores than those without alterations (SMD = 0.34, 95 %CI 0.05-0.64, p = 0.037 and SMD = 0.29, 95 %CI 0.17-0.41p = 0.005, respectively). Mixed-effects and simple regression models showed no association (p > 0.1) between CSF parameters and symptomatic outcomes. No interaction between sex and CSF parameters was found (p > 0.1). BCB disruption appears highly prevalent in early psychosis and could be involved in positive symptomś severity in males, indicating potential difficult-to-treat states. This work highlights the need for considering BCB breakdownand sex-related differences in SSDs clinical trials and treatment strategies., 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 Authors. Published by Elsevier Inc. All rights reserved.)

Vanadium compounds are known to exert insulin-enhancing activity, normalize elevated blood glucose levels in diabetic subjects, and show significant activity in models of insulin resistance (IR). Faced with insulin resistance, the present work investigates the antidiabetic performance of a known oxidovanadium(IV)-based coordination compound-[V IV O(octd)]-and effects associated with glucocorticoid-induced insulin resistance in mice. The effects of [V IV O(octd)] were evaluated in a female Swiss mice model of insulin resistance induced by seven days of dexamethasone treatment in comparison with groups receiving metformin treatment. Biological assays such as hematological, TyG index, hepatic lipids, glycogen, oxidative stress in the liver, and oral glucose tolerance tests were evaluated. [V IV O(octd)] was characterized with 51 V NMR, infrared spectroscopy (FTIR), electron paramagnetic resonance (EPR), electronic absorption spectroscopy, and mass spectrometry (ESI-FT-MS). The [V IV O(octd)] oral treatment (50 mg/kg) had an antioxidant effect, reducing 50% of fast blood glucose ( p < 0.05) and 25% of the TyG index, which is used to estimate insulin resistance ( p < 0.05), compared with the non-treated group. The oxidovanadium-sulfur compound is a promising antihyperglycemic therapeutic, including in cases aggravated by insulin resistance induced by glucocorticoid treatment.

Insufficient endosomal escape presents a major hurdle for successful nucleic acid therapy. Here, for the first time, a chemical electron transfer (CET) system was integrated into small interfering RNA (siRNA) lipid nanoparticles (LNPs). The CET acceptor can be chemically excited using the generated energy between the donor and hydrogen peroxide, which triggers the generation of reactive oxygen species (ROS), promoting endosomal lipid membrane destabilization. Tetra-oleoyl tri-lysino succinoyl tetraethylene pentamine was included as an ionizable lipopeptide with a U-shaped topology for effective siRNA encapsulation and pH-induced endosomal escape. LNPs loaded with siRNA and CET components demonstrated a more efficient endosomal escape, as evidenced by a galectin-8-mRuby reporter; ROS significantly augmented galectin-8 recruitment by at least threefold compared with the control groups, with a p value of 0.03. Moreover, CET-enhanced LNPs achieved a 24% improvement in apoptosis level by knocking down the tumor-protective gene nuclear factor erythroid 2-related factor 2, boosting the CET-mediated ROS cell killing.

Introduction: Effective side effects management present a challenge in antipsychotic treatment with second-generation antipsychotics (SGAs). In recent years, most of the commonly used SGAs, except for clozapine, have been shown to differ only slightly in their effectiveness, but considerably regarding perceived side effects, safety profiles, and compatibility to preexisting medical conditions., Areas Covered: The current state of available evidence on side-effect management in SGA treatment of patients with schizophrenia spectrum disorders (SSD) is reviewed. In addition, current guideline recommendations are summarized, highlighting evidence gaps., Expert Opinion: SGA safety and side effects needs to be considered in treatment planning. Shared decision-making assistants (SDMA) can support patients, practitioners and relatives to orient their decisions toward avoiding side effects relevant to patients' adherence. Alongside general measures like psychosocial and psychotherapeutic care, switching to better tolerated SGAs can be considered a relatively safe strategy. By contrast, novel meta-analytical evidence emphasizes that dose reduction of SGAs can statistically increase the risk of relapse and other unfavorable outcomes. Further, depending on the type and severity of SGA-related side effects, specific treatments can be used to alleviate induced side effects (e.g. add-on metformin to reduce weight-gain). Finally, discontinuation should be reserved for acute emergencies.

Raynaud's phenomenon (RP) is a condition that causes decreased blood flow to areas perfused by small blood vessels (e.g., fingers, toes). In severe cases, ulceration, gangrene, and loss of fingers may occur. Most treatments focus on inducing vasorelaxation in affected areas by the way of pharmaceuticals. Recently, animal studies have shown that vasorelaxation can be induced by non-coherent blue light (wavelength ~ 430-460 nm) through the actions of melanopsin, a photoreceptive opsin protein encoded by the OPN4 gene. To study this effect in humans, a reliable phototherapy device (PTD) is needed. We outline the construction of a PTD to be used in studying blue light effects on Raynaud's patients. Our design addresses user safety, calibration, electromagnetic compatibility/interference (EMC/EMI), and techniques for measuring physiological responses (temperature sensors, laser Doppler flow sensors, infrared thermal imaging of the hands). We tested our device to ensure (1) safe operating conditions, (2) predictable, user-controlled irradiance output levels, (3) an ability for measuring physiological responses, and (4) features necessary to enable a double-blinded crossover study for a clinical trial. We also include in the Methods an approved research protocol utilizing our device that may serve as a starting point for clinical study. We introduced a reliable PTD for studying the effects of blue light therapy for patients suffering from Raynaud's phenomenon and showed that our device is safe and reliable and includes the required measurement vectors for tracking treatment effects throughout the duration of a clinical study., (© 2024. The Author(s) under exclusive licence to Biomedical Engineering Society.)

Double pH-responsive xenopeptide carriers containing succinoyl tetraethylene pentamine (Stp) and lipo amino fatty acids (LAFs) were evaluated for CRISPR/Cas9 based genome editing. Different carrier topologies, variation of LAF/Stp ratios and LAF types as Cas9 mRNA/sgRNA polyplexes were screened in three different reporter cell lines using three different genomic targets (Pcsk9, eGFP, mdx exon 23). One U-shaped and three bundle (B2)-shaped lipo-xenopeptides exhibiting remarkable efficiencies were identified. Genome editing potency of top carriers were observed at sub-nanomolar EC 50 concentrations of 0.4 nM sgRNA and 0.1 nM sgRNA for the top U-shape and top B2 carriers, respectively, even after incubation in full (≥ 90%) serum. Polyplexes co-delivering Cas9 mRNA/sgRNA with a single stranded DNA template for homology directed gene editing resulted in up to 38% conversion of eGFP to BFP in reporter cells. Top carriers were formulated as polyplexes or lipid nanoparticles (LNPs) for subsequent in vivo administration. Formulations displayed long-term physicochemical and functional stability upon storage at 4 °C. Importantly, intravenous administration of polyplexes or LNPs mediated in vivo editing of the dystrophin gene, triggering mRNA exon 23 splicing modulation in dystrophin-expressing cardiac muscle, skeletal muscle and brain tissue., Competing Interests: Declaration of competing interest None., (Copyright © 2023. Published by Elsevier B.V.)

Empathetic and emotive design is becoming increasingly important in the digital age. In this research we describe the results of a combined cognitive walkthrough and heuristic evaluation using newly developed, empirically derived empathy or emotive design heuristics. We applied the heuristics to the evaluation of four commonly used survey platforms. Our preliminary findings revealed that the heuristics performed effectively in scoring survey platforms on their level of empathy. Survey platforms that are highly empathetic were scored highest.

Background: Deprescribing of medication or psychotherapy represents a critical phase in treatment. The aim of the work is to systematically analyze recommendations for deprescribing medication and discontinuation of psychotherapy in the evidence- and consensus-based S3 guidelines of the German Association for Psychiatry, Psychotherapy and Psychosomatics (DGPPN) to identify potential research gaps., Methods: A systematic analysis of the DGPPN S3 guidelines to investigate and compare information and recommendations on deprescribing., Results: Regarding deprescribing of medication, our analysis showed that eight of the 20 included S3 guidelines contain information both in the form of recommendations and background information. Regarding psychotherapy, only two guidelines provided information on deprescribing., Conclusion: Our results highlight the need to expand guidelines to include evidence-based recommendations for deprescribing medication or discontinuation of psychotherapy. Future research should focus on the development of specific, generic, and evidence-based guidelines that support both medical staff and patients during these critical phases of therapy., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

The scope of this work is the development of a method to estimate the temperature and shear rate-dependent viscosity of mixtures composed of two polymers. The viscosity curve of polymer mixtures is crucial for the modeling and optimization of extrusion-based recycling, which is the most efficient way to recycle polymeric materials. The modeling and simulation of screw extruders requires detailed knowledge of the properties of the processed material, such as the thermodynamic properties, the density, and the rheological behavior. These properties are widely known for pure materials; however, the incorporation of impurities, like other polymers in recycled materials, alters the properties. In this work, miscible, immiscible, and compatibilized immiscible polymer mixtures are considered. A new method based on shear stress is proposed and compared to the shear rate-based method. Several mixing rules are evaluated for their accuracy in predicting mixture viscosity. The developed methods allow the prediction of the viscosity of a compatibilized immiscible mixture with deviations below 5% and that of miscible polymer mixtures with deviations below 3.5%.

Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Disclosure forms for all authors are available online.

Despite a very high prevalence and substantial impairments among affected individuals, treatment-resistant schizophrenia (TRS) has not been sufficiently researched in clinical research in the field of psychiatric disorders and the pathophysiology is still poorly understood. A better clinical and pathophysiological understanding of this heterogeneous and severely affected population of people with persistent symptoms in different domains is necessary in order not only to be able to intervene early but also to develop novel therapeutic strategies or individualized treatment approaches. This review article presents the state of the art criteria of the pharmacological TRS, neurobiological disease models and predictive factors for TRS as well as the phenomenon of pseudo-treatment resistance and the clinical management of TRS. In the future, not only the use of operationalized criteria and definitions of TRS in longitudinal studies and randomized-controlled trials (RCTs) are paramount, but also the observation of trajectories with the integration of multimodal longitudinal phenotyping and the longitudinal collection of clinical routine data in academic research, which will be possible in the newly created German Center for Mental Health (DZPG)., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Formaldehyde (FA) is a highly toxic substance present in many matrices, including freshwater as well as found in natural mechanisms such as rainfall and combustion of organic matter. Consumption of water contaminated with high levels of FA can cause severe short-term or long-term health problems. Due to these health risks, procedures are necessary to determine and quantify FA in aqua sources This paper reports on a study of fluorimetric determination of FA using a nickel(2 + )-diketonate coordination compound immobilized as a solid precursor. The compound was characterized by electronic absorption, Fourier transform infrared (FTIR) spectroscopy, X-ray diffraction (XRD), thermogravimetry (TG), optical microscopy (OM), and scanner electron microscopy (SEM). The methodology was based on the reaction of the synthesized compound with an ammoniacal buffer generating a selective reagent for formaldehyde: fluoral-P. The product of the reaction generates 3,5-diacetyl-1,4-dihydrolutidine (DDL), which is responsible for the fluorescence of the system. Several parameters such as temperature, duration of heating time, and dilution effect with the best effects were studied to carry out FA determination. Under the optimum experimental conditions, a linear response ranging from 1.0 to 10.0 mg/L FA (R = 0.997 and n = 10), and a detection (3σ criterion) and quantification (10 σ criterion) limit estimated at 0.129 and 0.389 mg/L, respectively were achieved. The FA analysis was able to be conducted in 05 min with a relative standard deviation estimated at 1.10 %., 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 © 2023 Elsevier B.V. All rights reserved.)

Background: There is increasing evidence of immune dysregulation and neuroinflammation occurring in schizophrenia. The aim of this study is to combine studies on routine CSF parameters, as well as cytokines and inflammatory proteins, in individuals with schizophrenia spectrum disorders., Methods: CSF parameters were summated and inverse variance meta-analyses using a random effects model were performed comparing mean difference or odds ratios. Between study heterogeneity was assessed using the I 2 statistic. Quality assessment and sensitivity analyses were performed., Results: There were 69 studies of 5710 participants, including 3180 individuals with schizophrenia spectrum disorders. Averaged CSF parameters were within normal limits, however, between 3.1 % and 23.5 % of individual cases with schizophrenia spectrum disorders had an abnormal CSF result: Protein (abnormal in 23.5 % cases), albumin (in 18.5 %), presence of oligoclonal bands (in 9.3 %), white blood cell count (in 3.6 %), and IgG levels (3.1 %). Meta-analysis of 55 studies with non-psychiatric controls demonstrated a significant increase in CSF total protein (MD: 3.50, CI: 0.12-6.87), albumin ratio (MD: 0.55, CI: 0.02-0.09), white cell count (MD: 0.25, CI: 0.05-0.46), IL-6 (SMD: 0.53, CI: 0.29 to 0.77) and IL-8 (SMD: 0.56, CI: 0.11 to 1.01). Sensitivity analysis did not alter findings., Conclusion: Abnormal CSF parameters, cytokines and inflammatory proteins were found in a significant proportion of individuals with schizophrenia spectrum disorders. This may indicate alterations to blood brain barrier function and permeability, CSF flow dynamics or neuroinflammation. Further research is needed to explore these potential mechanisms., Competing Interests: Declaration of competing interest NW has received speaker fees from Otsuka, Lundbeck and Janssen. EW has been invited to advisory boards from Recordati. DS is supported by an NHMRC Investigator Fellowship GNT 1194635. All other authors have no declarations of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The evidence for repetitive transcranial magnetic stimulation (rTMS) to treat negative symptoms in schizophrenia (SCZ) is increasing, although variable response rates remain a challenge. Subject´s sex critically influences rTMS´ treatment outcomes. Females with major depressive disorder are more likely to respond to rTMS, while SCZ data is scarce., Methods: Using data from the 'rTMS for the Treatment of Negative Symptoms in Schizophrenia' (RESIS) trial we assessed the impact of sex on rTMS´ clinical response rate from screening up to 105 days after intervention among SCZ patients. The impact of resting motor threshold (RMT) on response rates was also assessed., Results: 157 patients received either active or sham rTMS treatment. No significant group differences were observed. Linear mixed model showed no effects on response rates (all p  > 0.519). Apart from a significant sex*time interaction for the positive subscale of the positive and negative syndrome scale (PANSS) scores ( p  = 0.032), no other significant effects of sex on continuous PANSS scores were observed. RMT had no effect on response rate., Conclusion: In the largest rTMS trial on the treatment of SCZ negative symptoms we did not observe any significant effect of sex on treatment outcomes. Better assessments of sex-related differences could improve treatment individualisation.

Background: Inpatient psychiatric treatment of prisoners is organized differently in Germany, depending on the structural conditions of the federal state and prison. There are very few findings on the different possibilities of treatment and the view of the hospitals on this issue., Objectives: Our aim was to gain an up-to-date picture of inpatient treatment of prisoners in general psychiatric departments and hospitals and the challenges these institutions face., Methods: We conducted an anonymous online survey of the frequency, extent, and challenges of inpatient treatment of prisoners. Approximately 460 chief physicians of German general psychiatric departments and hospitals were invited to participate in this survey. In addition to descriptive statistics, we calculated group differences by type of hospital and by subjective responsibility for inpatient care of prisoners., Results: A total of 74 chief physicians surveyed participated; 51.4% of the surveyed hospitals provided psychiatric inpatient treatment to prisoners in 2020. Group differences between the different types of hospitals were found only for the presence of anticipated anxiety among regular inpatients. Various differences were found between responsible and non-responsible hospitals, especially with regard to organizational aspects., Discussion: For the treatment of mentally ill prisoners, various organizational challenges as well as fears of hospital staff and fellow patients were mentioned by the participants. The type of hospital appears to play a subordinate role here, whereas the responsibility of the hospital for the inpatient treatment of mentally ill prisoners might be more decisive for anticipated concerns and barriers., Competing Interests: Elias Wagner und Manuela Dudeck berichten keine Interessenskonflikte. Felix Grubbe erhielt Reise- und Kongresskosten-Übernahmen durch Actelion und Indivior. Oliver Pogarell erhielt Vortragshonorare von Lundbeck, Otsuka, Takeda, Medice und Janssen. Alkomiet Hasan erhielt in den letzten drei Jahren Vortragshonorare von Janssen, Lundbeck, Otsuka und Recordati und war Mitglied von Advisory Boards dieser Firmen sowie von Rovi. Er ist Herausgeber der AWMF S3-Leitlinie Schizophrenie., (Thieme. All rights reserved.)

Natural killer (NK) cells are central components of the innate immunity system against cancers. Since tumor cells have evolved a series of mechanisms to escape from NK cells, developing methods for increasing the NK cell antitumor activity is of utmost importance. It is previously shown that an ex vivo stimulation of patient-derived NK cells with interleukin (IL)-2 and Hsp70-derived peptide TKD (TKDNNLLGRFELSG, aa450-461) results in a significant upregulation of activating receptors including CD94 and CD69 which triggers exhausted NK cells to target and kill malignant solid tumors expressing membrane Hsp70 (mHsp70). Considering that TKD binding to an activating receptor is the initial step in the cytolytic signaling cascade of NK cells, herein this interaction is studied by molecular docking and molecular dynamics simulation computational modeling. The in silico results showed a crucial role of the heterodimeric receptor CD94/NKG2A and CD94/NKG2C in the TKD interaction with NK cells. Antibody blocking and CRISPR/Cas9-mediated knockout studies verified the key function of CD94 in the TKD stimulation and activation of NK cells which is characterized by an increased cytotoxic capacity against mHsp70 positive tumor cells via enhanced production and release of lytic granules and pro-inflammatory cytokines., (© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH.)

X-linked hypophosphatemia (XLH) is a rare, multi-systemic, invalidating disease requiring a multi-disciplinary approach. No specific action in XLH, neither for the patients' specific needs nor for the methodology for the evaluation of these were found. Thus, to identify the needs of XLH patients and their caregivers, we organised focus groups in our reference centre with a view to build educational sessions. Focus groups including either XLH children, XLH adults, or caregivers ran in parallel. Each group was led by a person trained in therapeutic education (nurse, paediatric nephrologist) with another healthcare provider specialised in XLH (rheumatologist, nephrologist). One additional person with knowledge of XLH (clinical research associate, paediatric resident) took minutes. The duration of each session was 1.5h; XLH patients/caregivers were asked to answer age-adapted "open questions" on their daily life and quality of life. At the end, a global restitution was made. The needs identified were later grouped and analysed, which allowed us to build the educational sessions. The XLH children group included 5 children, the XLH adults group included 10 adults, and the caregivers group included 6 parents or partners. Major needs were identified: knowledge of XLH, treatment, dental care and adapted physical activity, with additional questions on socio-professional adaptations and financial support in adults. Partner patients were also identified to co-build the support programme. The study allowed us to identify the needs of XLH patients and their caregivers using the focus group method and then, using these needs, to build educational sessions and a therapeutic education programme for XLH patients., Competing Interests: Declaration of competing interest The authors have no competing interests to declare that are relevant to the content of this article., (Copyright © 2024. Published by Elsevier Masson SAS.)

As the International Space Station comes to the end of a transformative era of in-space research, NASA's Commercial Low Earth Orbit (LEO) Destinations (CLD) Program aims to catalyze a new generation of platforms with co-investment from the private sector, preventing a potential gap in research performed in LEO, while building a robust LEO economy. In this paper, we provide insight into the CLD Program focusing on Orbital Reef, describing its operational and technical characteristics as well as new opportunities it may enable. Achieving about a third of the pressurized volume of the ISS with the launch of a single pressurized module and growing to support hundreds of Middeck Locker Equivalents (MLE) in passive and active payloads internally and externally, Orbital Reef will enable government, academic, and commercial institutions to continue and expand upon research and development (R&D) efforts currently performed on ISS. Additionally, it will enable nascent markets to establish their operations in space, by initiating new lines of research and technology development and the implementation of new ventures and visions. Using Blue Origin's New Glenn heavy launch system, Sierra Space's cargo and crew Dream Chaser® vehicles, and Boeing's Starliner crew vehicle, and expertise from Amazon/Amazon Supply Chain, Arizona State University, Genesis Engineering, and Redwire, Orbital Reef is being designed to address ISS-era transportation logistics challenges. Finally, this manuscript describes some of the expected challenges from the ISS-to-CLD transition, and provides guidance on how researchers in academia and industry can shape the future of commercial destinations and work performed in LEO., (© 2024. The Author(s).)

A cationic, dendrimer-like oligo(aminoamide) carrier with four-arm topology based on succinoyl tetraethylene pentamine and histidines, cysteines, and N -terminal azido-lysines was screened for plasmid DNA delivery on various cell lines. The incorporated azides allow modification with various shielding agents of different polyethylene glycol (PEG) lengths and/or different ligands by copper-free click reaction, either before or after polyplex formation. Prefunctionalization was found to be advantageous over postfunctionalization in terms of nanoparticle formation, stability, and efficacy. A length of 24 ethylene oxide repetition units and prefunctionalization of ≥50% of azides per carrier promoted optimal polyplex shielding. PEG shielding resulted in drastically reduced DNA transfer, which could be successfully restored by active lectin targeting via novel GalNAc or mannose ligands, enabling enhanced receptor-mediated endocytosis of the carrier system. The involvement of the asialoglycoprotein receptor (ASGPR) in the uptake of GalNAc-functionalized polyplexes was confirmed in the ASGPR-positive hepatocarcinoma cell lines HepG2 and Huh7. Mannose-modified polyplexes showed superior cellular uptake and transfection efficacy compared to unmodified and shielded polyplexes in mannose-receptor-expressing dendritic cell-like DC2.4 cells.

Two different alkynyl-substituted C 3 -symmetric cyclotribenzylenes (CTB) were synthesized in racemic and enantiomerically pure forms, and six gold(I) phosphine complexes differing by the nature of the CTB and the phosphine were prepared and characterized, in particular by NMR spectroscopy, DOSY, electronic circular dichroism (ECD), and electrospray ionization mass spectrometry (ESI-MS). Their ECD patterns depended on the substitution of the starting CTBs and were shifted bathochromically by comparison with the latter. ESI-MS in the presence of HCO 2 H allowed us to detect the complexes as proton adducts. The intensities of the signals were stronger when the phosphine was more electron-rich. This technique was also used to investigate the exchange of phosphine betweeen pairs of CTB complexes. The scrambling reaction was demonstrated by the higher intensity of the signals of the complexes subjected to the exchange of a single phosphine ligand by comparison with the intensity of the signals of the starting complexes.

Carriers for RNA delivery must be dynamic, first stabilizing and protecting therapeutic RNA during delivery to the target tissue and across cellular membrane barriers and then releasing the cargo in bioactive form. The chemical space of carriers ranges from small cationic lipids applied in lipoplexes and lipid nanoparticles, over medium-sized sequence-defined xenopeptides, to macromolecular polycations applied in polyplexes and polymer micelles. This perspective highlights the discovery of distinct virus-inspired dynamic processes that capitalize on mutual nanoparticle-host interactions to achieve potent RNA delivery. From the host side, subtle alterations of pH, ion concentration, redox potential, presence of specific proteins, receptors, or enzymes are cues, which must be recognized by the RNA nanocarrier via dynamic chemical designs including cleavable bonds, alterable physicochemical properties, and supramolecular assembly-disassembly processes to respond to changing biological microenvironment during delivery., Competing Interests: Competing interests statement:The authors declare no competing interest.

Comorbid substance use disorder (SUD) in patients with schizophrenia (dual disorder, DD) is a frequent occurrence in the psychiatric clinical practice and is positively associated with poorer outcomes. Despite a very high co-prevalence, clinical guidelines for SUD and severe mental illnesses tend to give limited consideration to co-existing disorders regarding diagnosis and management. This article is the result of a meeting held in February 2023 to discuss common challenges and best clinical practice initiatives for patients with schizophrenia and DD in different treatment settings. The authors identified issues in the clinical approach to DD in schizophrenia spectrum disorders and suggested the most suitable management based on their experience as a group of experts, identifying possible improvement areas. In conclusion, the panel recommends that individuals with DD should be cared for in a single center. Pharmacologic treatment in individuals with DD needing both control of symptoms related to schizophrenia spectrum disorders and substance withdrawal should ideally be based on using a non-sedative antipsychotic with anti-craving activity.