Search

Abstract: Measurable residual disease (MRD) monitoring in acute myeloid leukemia (AML) with an FLT3 internal tandem duplication (FLT3-ITDpos) has been hampered by the broad heterogeneity of ITD mutations. Using our recently developed FLT3-ITD paired-end next-generation sequencing (NGS)–based MRD assay (limit of detection 10−4 to 10−5), we evaluated the prognostic impact of MRD at different time points in 157 patients with FLT3-ITDpos AML who were enrolled in the German-Austrian Acute Myeloid Leukemia Study Group 16-10 trial and who were treated with a combination of intensive chemotherapy and midostaurin, followed by midostaurin maintenance. MRD negativity (MRDneg) after 2 cycles of chemotherapy (Cy2), which was observed in 111 of 142 (78%) patients, was predictive of superior 4-year rates of cumulative incidence of relapse (CIR) (4y-CIR; 26% vs 46%; P = .001) and overall survival (OS) (4y-OS; 70% vs 44%; P = .012). This survival advantage was also seen among patients who underwent allogeneic hematopoietic-cell transplantation during first complete remission (4y-CIR, 14% vs 39%; P = .001; 4y-OS, 71% vs 49%; P = .029). Multivariate models for CIR and OS after Cy2 revealed FLT3-ITD MRDneg as the only consistent favorable variable for CIR (hazard ratio [HR], 0.29; P = .006) and OS (HR, 0.39; P = .018). During follow-up, conversion from MRDneg to MRD positivity (MRDpos) was a strong, independent factor for inferior CIR (HR, 16.64; P < .001) and OS (HR, 4.05; P < .001). NGS-based FLT3-ITD MRD monitoring identifies patients at high risk for relapse and death following treatment with intensive chemotherapy and midostaurin. Using NGS-based technology.

Abstract Recent successes in developing small molecule degraders that act through the ubiquitin system have spurred efforts to extend this technology to other mechanisms, including the autophagosomal-lysosomal pathway. Therefore, reports of autophagosome tethering compounds (ATTECs) have received considerable attention from the drug development community. ATTECs are based on the recruitment of targets to LC3/GABARAP, a family of ubiquitin-like proteins that presumably bind to the autophagosome membrane and tether cargo-loaded autophagy receptors into the autophagosome. In this work, we rigorously tested the target engagement of the reported ATTECs to validate the existing LC3/GABARAP ligands. Surprisingly, we were unable to detect interaction with their designated target LC3 using a diversity of biophysical methods. Intrigued by the idea of developing ATTECs, we evaluated the ligandability of LC3/GABARAP by in silico docking and large-scale crystallographic fragment screening. Data based on approximately 1000 crystal structures revealed that most fragments bound to the HP2 but not to the HP1 pocket within the LIR docking site, suggesting a favorable ligandability of HP2. Through this study, we identified diverse validated LC3/GABARAP ligands and fragments as starting points for chemical probe and ATTEC development.

Abstract Background Guidelines recommend the identification of potential mental and/or cognitive disorders (MCD) in patients with coronary heart disease (CHD). However, compliance with these guidelines appears to be lacking in primary care. A minimal invasive intervention was tailored with experts for the primary care setting to increase the identification of this patient group and ensure proper treatment. The intervention includes: A trigger question, screening tests and question prompt sheet for patients. Following the implementation of this intervention in primary care physician (PCP) offices, the aim of this study is to evaluate the implementation outcomes. Methods Semi-structured interviews were conducted with ten PCPs who tested the intervention for six months. The study was guided by Proctor’s Framework on Implementation Outcomes to understand the appropriateness, feasibility, acceptability, fidelity and sustainability of the intervention as proxies for implementation success. Results Relevance of the topic and the need for the intervention is recognised by all of the PCPs. All PCPs were willing to try the intervention and considered it generally appropriate and feasible. Additionally, supporting implementation resources were considered helpful in familiarising with the intervention. Screening of patients with a first diagnosis of CHD, those who have had experienced a recent coronary event and those who have been hospitalised for CHD is considered practical and appropriate. Known barriers such as lack of knowledge, perceived relevance and awareness were successfully addressed. It was not possible to overcome barriers such as time pressure, forgetfulness, and patient reaction. Additionally, the paper format of the information materials was perceived as impractical, and integration into the physician information system was identified as a possible way to increase acceptance. Nevertheless, PCPs stated they will continue to be aware of the link between CHD and MCD and want to maintain their individualised approach. Conclusions The study provides important insights into the use of a minimal invasive intervention in primary care. Despite tailoring the intervention to the primary care setting, implementation success was suboptimal due to individual barriers in PCP offices. This highlights the need for tailored approaches at the level of individual PCP offices to better address context-specific barriers.

Abstract Background Regular physical activity (PA) has been proven to help prevent non-communicable diseases and is beneficial for disease management in chronically ill populations. Physical inactivity and recreational screen-based media (SBM) use are related to poor health outcomes and common among youth. This study aimed to (1) investigate PA levels and recreational SBM use of adolescents with JIA over time and (2) compare these behaviours with those of their peers. Methods Data from JIA patients and their peers enrolled in the inception cohort study ICON at 11 German centers were analyzed. Individuals aged 13 and over were followed prospectively with questionnaires concerning PA level, recreational SBM use, and health-related quality of life (HRQoL) at a two-year interval. Group by time interactions were analyzed using linear mixed models. Results Data of 214 patients (mean age at first documentation 14.4 ± 0.9 years, female 63%) and 141 peers could be considered. At first documentation, patients were less physically active compared to their peers (p

Abstract Future carbon management strategies require storage in elemental form, achievable through a sequence of CO2 hydrogenation reactions. Hydrogen is recycled from molecular intermediates by dehydrogenation, and side product acetylene selectively hydrogenated to ethylene. Existing Pd alloy catalysts for gas purification underperform in concentrated feeds, necessitating novel concepts. Atomistic simulations unveil superior selectivity of Pd:C solid solutions that optimize chemisorption energies and preclude sub-surface hydrides, verified here with model thin films. Multiple design criteria deduced from conventional catalysts facilitate synthesizing a self-repairing Pd:C system of a laterally condensed catalyst (LCC). A Pd layer prepared on a designated SiO2 buffer layer enables control of reactive interface, sub-surface volume and extended functional interface towards the buffer. Function and metric are supervised by operando micro-spectroscopy. This catalyst design shows, ethylene productivity >1 kmolC2H4/gPd/hour is reproducibly achieved and benchmarked against known catalysts. Photovoltaics deposition technologies enable scalability on real-world substrates saving active metal. A design-of-experiment approach demonstrates the improvement potential of the LCC approach.

Abstract Type 2 diabetes is associated with cardiovascular disease, possibly due to impaired vascular fibrous repair. Yet, the mechanisms are elusive. Here, we investigate alterations in the fibrous repair processes in type 2 diabetes atherosclerotic plaque extracellular matrix by combining multi-omics from the human Carotid Plaque Imaging Project cohort and functional studies. Plaques from type 2 diabetes patients have less collagen. Interestingly, lower levels of transforming growth factor-ß distinguish type 2 diabetes plaques and, in these patients, lower levels of fibrous repair markers are associated with cardiovascular events. Transforming growth factor-ß2 originates mostly from contractile vascular smooth muscle cells that interact with synthetic vascular smooth muscle cells in the cap, leading to collagen formation and vascular smooth muscle cell differentiation. This is regulated by free transforming growth factor-ß2 which is affected by hyperglycemia. Our findings underscore the importance of transforming growth factor-ß2-driven fibrous repair in type 2 diabetes as an area for future therapeutic strategies.

Abstract Background Claudin-3 (CLDN3) participates in the formation of the tight-junctions (TJs) that regulate intercellular permeability. Altered CLDN3 expression has been linked to tumor progression in multiple tumor types. Despite its widespread expression in normal epithelial cells, CLDN3 is considered an attractive drug target candidate, since it may be more accessible in cancer cells than in normal cells due to their less orchestrated cell growth. Methods To comprehensively determine the prevalence of CLDN3 expression in cancer, a tissue microarray containing 14,966 samples from 133 different tumor types and subtypes as well as 608 samples of 76 different normal tissue types was analyzed by immunohistochemistry. Results CLDN3 immunostaining was observed in 8,479 (68.9%) of 12,314 analyzable tumors, including 11.6% with weak, 6.2% with moderate, and 51.1% with strong positivity. CLDN3 staining was found in 96 of 133 tumor categories, 80 of which contained at least one strongly positive case. CLDN3 positivity was most seen in neuroendocrine neoplasms (92–100%) and in adenocarcinomas (67–100%), tumors of the female genital tract, including various subtypes of ovarian and endometrial carcinoma (up to 100%), as well as different subtypes of breast cancer (95.3–100%). CLDN3 positivity was less common in squamous cell carcinomas (0–43.2%) and mainly absent in melanoma, mesenchymal, and hematolymphatic neoplasms. In clear cell renal cell carcinoma (ccRCC), low CLDN3 was strongly linked to poor ISUP (p

Abstract Background Quantification of Amyloid beta (Aβ) oligomers in plasma enables early diagnosis of Alzheimer’s Disease (AD) and improves our understanding of underlying pathologies. However, quantification necessitates an extremely sensitive and selective technology because of very low Aβ oligomer concentrations and possible interference from matrix components. Methods In this report, we developed and validated a surface-based fluorescence distribution analysis (sFIDA) assay for quantification of Aβ oligomers in plasma. Results The blood-based sFIDA assay delivers a sensitivity of 1.8 fM, an inter- and intra-assay variation below 20% for oligomer calibration standards and no interference with matrix components. Quantification of Aβ oligomers in 359 plasma samples from the DELCODE cohort reveals lower oligomer concentrations in subjective cognitive decline and AD patients than healthy Control participants. Conclusions Correlation analysis between CSF and plasma oligomer concentrations indicates an impaired clearance of Aβ oligomers that is dependent on the ApoE ε4 status.

Abstract Background The long-established use of video consultation in mental health services has undergone significant historical development. This study reveals and discusses how video consultations influence youths’ presentation of self in video consultations and in different locations and contexts. This phenomenon will be examined in light of Goffman’s theory of frontstage and backstage in relation to the sense and impact of place, or placelessness, concidering mental health situations. The aim of this study was to explore whether and how therapy through a screen was experienced and to reveal challenges and opportunities that result from using digital tools to communicate in a therapeutic context. The study employed a hermeneutic-phenomenological approach to gain an understanding of youths' life-world experiences with video consultations in therapy. 33 qualitative interviews were performed with youths in the age between 16–23 years. The recruitment was carried out between mid-august 2021 and end of march 2022. All had participated in VC sessions with their therapist during the COVID-19 pandemic. The analysis followed an abductive approach, where iterative cycles between the empirical data and theoretical framework helped uncover both unexpected and novel insights into the youths' experiences with VC. Results The findings revealed two main themes to guide our investigation: 1) therapy through a screen versus F2F therapy and 2) different physical contexts for therapy through a screen. The findings show that youths’ experiences with the use of video consultations in therapy are diverse and heterogeneous. Conclusions Face-to-face communication may reduce ambiguity and uncertainty through the use of body language and eye contact. Face-to-face communication requires less cognitive effort to process and involves greater psychological distance than digital communication. The advantages of using video consultations include avoiding school days, avoiding long travel distances, connecting faster when needed, and having shorter conversations to catch up on challenges in collaboration. The implications of location and context may also impact youths’ presentation of self.

Abstract Background The aim of this retrospective study was to identify high-risk dental extraction patients and the timing of postoperative hemorrhage to evaluate whether preventive hospitalization should be considered in patients on antiplatelet medication (AP) or anticoagulants. Methods Our study included 1595 procedures; 1319 were conducted under monotherapy (Group I: AP; Group II: indirect oral anticoagulant [IAC]; Group III: direct oral anticoagulant [DOAC]) and 276 under dual therapy (Group IV: double AP; Group V: AP and IAC; Group VI: AP and DOAC). We evaluated the incidence, frequency and timing of hemorrhage, hospitalization rate, and treatment of bleeding incidents. Results The incidence of hemorrhagic events was significantly higher in the dual therapy groups compared to the monotherapy groups (p

Background Attractive targeted sugar baits (ATSBs) are promising new interventions that can complement existing vector control tools. However, reproducible and quantitative information on the level of attractiveness of ATSBs under field conditions is needed. Therefore, we customized camera traps for close-up imaging. We integrated them into a rugged ATSB monitoring station for day and nighttime recording of mosquitoes landing on the bait. Methods The camera traps were evaluated in a semifield system and then in the field in rural Tanzania. In semifield experiments, camera traps were set up in large cages (2 m × 5 m × 2 m) to record mosquitoes landing on an attractive sugar bait (ASB), a blank ASB, or 20% sucrose (w/v). Next, 198 mosquitoes (33 males and 33 females of Anopheles arabiensis, An. funestus and Aedes aegypti) were released into each large cage and allowed to seek a sugar meal for 72 h with a camera recording images of the mosquitoes present on the ASB at 1-min intervals. In the field, 16 camera traps were set in 16 households, 7 with ASB attractant, 7 with ASB blank, and 2 with 20% sucrose (w/v). Human landing catch (HLC) was performed on the same nights as the camera trap recordings. Results Under semifield conditions, significantly more mosquitoes visited the ASBs than the blank baits, with An. funestus visiting more frequently than An. arabiensis. There were no significant differences between female and male An. arabiensis visits, but female An. funestus visited more than their conspecific males did. The duration of visits did not vary between the ASB and blank controls or between the mosquito species. Moreover, mosquitoes visited the ASB or sucrose equally, with An. arabiensis visiting the baits more than An. funestus. Compared with male mosquitoes, female mosquitoes visited the baits more often. There was no significant difference in visit duration between the species. In the field study, a mean of 70 An. arabiensis were caught per person per night on HLC, while 1 individual was caught per night on ASBs. There were significantly more visits by mosquitoes to the ASB than to the ASB blanks or sucrose solution, with more An. arabiensis visiting the baits than An. funestus or Culex quinquefasciatus. Significantly more females than males visited the baits of all the species. Again, the duration of visits was similar among An. arabiensis, An. funestus and C. quinquefasciatus. Aedes aegypti very rarely visited ASBs in the semifield experiments, and none were observed on baits in the field. Conclusions Using camera traps to record still images of mosquitoes on ASBs offers reliable, reproducible and quantitative information on their attractiveness in various environmental conditions. Thus, camera traps serve as effective tools for evaluating and improving ATSB technology. Graphical abstract

Abstract Background Subjective Cognitive Decline (SCD) is recognized as a risk stage for future cognitive impairment and dementia. The criteria for SCD include normal performance on neuropsychological testing; however, there is a lack of consensus regarding standard score cut-offs for neuropsychological tests to define cognitive impairment and to differentiate between SCD and Mild Cognitive Impairment (MCI). This study aimed to assess the frequency of SCD diagnosis using various neuropsychological definitions of cognitive normality and to characterize the sociodemographic and neuropsychological features of SCD patients diagnosed under these criteria. Methods The Cognitive Complaints Cohort (CCC) participants were diagnosed following Subjective Cognitive Decline Initiative (SCD-I) criteria. Normal cognitive performance was defined by the absence of Mild Cognitive Impairment (MCI) according to the five sets of MCI neuropsychologically based criteria defined by Jak and Bondi. Descriptive statistics were used to analyze sociodemographic, clinical, and neuropsychological data. A bootstrap methodology was employed to estimate the mean and 95% confidence intervals (CI) for specific parameters of interest, namely the SMC scale (subjective memory complaints scale), Mini-Mental State Examination (MMSE), Blessed Dementia Rating Scale – first part (BDRS first part), and Geriatric Depression Scale (GDS). Results Among the 1268 subjects included, the prevalence of SCD diagnosis exhibited substantial variation across SCD-I criteria using different neuropsychological definitions of cognitive normality (ranging from 16.4 to 81.3%). When using the most conservative criteria to define cognitive impairment (2 tests within a cognitive domain > 1.5 SD below age-adjusted means), the resulting Conservative SCD group had poorer global cognitive function (MMSE: mean 27.15, 95% CI 27.00-27.31), whereas when using the most liberal criteria to define cognitive impairment (only one test > 1 SD below age-adjusted means) the resulting Liberal SCD group had superior performance in daily-life functioning (BDRS first part: mean 0.30, 95% CI 0.23–0.38). However, subjective cognitive complaints and neuropsychiatric symptoms did not significantly differ among SCD diagnostic groups. Conclusions The utilization of diagnostic criteria using distinct neuropsychological definitions of cognitive normality significantly impacts the frequency of SCD diagnosis and characterizes different patient populations. Consequently, it is essential to specify the criterion when diagnosing a SCD patient and to understand the risks and benefits of using different criteria to define cognitive impairment.

Abstract Background A sustainable pandemic preparedness strategy is essential to ensure equitable access to healthcare for individuals with neurodegenerative diseases. Moreover, it is vital to provide clinicians and researchers in the neurodegenerative disease fields with resources and infrastructure to ensure continuity of their work during a (health) crisis. Methods We established an international collaboration between researchers, clinicians, and patient representatives from the Netherlands, Poland, and the United Kingdom. We co-created a pandemic preparedness plan primarily informed by examples from those affected by or working in the field of Parkinson’s disease, with potential application to other neurodegenerative diseases or the general population. This plan builds upon insights and experiences from four population-based studies during the COVID-19 pandemic. Between March and November 2023, we organised two hybrid meetings in Bristol (United Kingdom) and Rotterdam (the Netherlands), and two online meetings. Results Research recommendations included three core factors in questionnaire design during health crises: 1) using existing, validated questions, 2) questionnaire adaptability and flexibility, and 3) testing within and outside the research group. Additionally, we addressed burden of participation, and we advocated for robust data sharing practices, underlining the importance of regulatory measures extending beyond the COVID-19 pandemic. We also shared clinical perspectives, including strategies to mitigate social isolation; challenges in virtual versus in-person consultations; and systemic changes to recognise and prevent moral injury in healthcare professionals. Conclusion In this pandemic preparedness plan, we provide research and clinical recommendations tailored to the field of Parkinson’s disease, with broader relevance to other neurodegenerative diseases and the general population. This establishes an essential framework for setting up new studies and safeguarding research and clinical practices when a new pandemic or other (health) crisis emerges. Graphical Abstract

Abstract Local delivery of mRNA-based immunotherapy offers a promising avenue as it enables the production of specific immunomodulatory proteins that can stimulate the immune system to recognize and eliminate cancer cells while limiting systemic exposure and toxicities. Here, we develop and employ lipid-based nanoparticles (LNPs) to intratumorally deliver an mRNA mixture encoding the cytokines interleukin (IL)−21 and IL-7 and the immunostimulatory molecule 4-1BB ligand (Triplet LNP). IL-21 synergy with IL-7 and 4-1BBL leads to a profound increase in the frequency of tumor-infiltrating CD8+ T cells and their capacity to produce granzyme B and IFN-γ, leading to tumor eradication and the development of long-term immunological memory. Mechanistically, the efficacy of the Triplet LNP depends on tumor-draining lymph nodes to tumor CD8+ T-cell trafficking. Moreover, we highlight the therapeutic potential of the Triplet LNP in multiple tumor models in female mice and its superior therapeutic efficacy to immune checkpoint blockade. Ultimately, the expression of these immunomodulators is associated with better overall survival in patients with cancer.

Abstract African trypanosomes are important parasites in sub-Saharan Africa that undergo a quorum-sensing dependent development to morphologically ‘stumpy forms’ in mammalian hosts to favour transmission by tsetse flies. However, some trypanosome clades have simplified their lifecycle by escaping dependence on tsetse allowing an expanded geographic range, with direct transmission between hosts achieved via blood-feeding biting flies and vampire bats (Trypanosoma brucei evansi, causing ‘surra’) or through sexual transmission (Trypanosoma brucei equiperdum, causing ‘dourine’). Concomitantly, stumpy formation is reduced and the isolates are described as monomorphic, with infections spread widely in Africa, Asia, South America and parts of Europe. Here, using genomic analysis of distinct field isolates, we identify molecular changes that accompany the loss of the stumpy formation in monomorphic clades. Using CRISPR-mediated allelic replacement, mutations in two exemplar genes (Tb927.2.4020; Tb927.5.2580) are confirmed to reduce stumpy formation whereas another (Tb927.11.3400) is implicated in altered motility. Using laboratory selection we identify downregulation of RNA regulators as important in the initial development of monomorphism. This identifies a trajectory of events that simplify the life cycle in emergent and established monomorphic trypanosomes, with impact on disease spread, vector control strategies, geographical range and virulence.

Abstract The enzyme complex KEOPS (Kinase, Endopeptidase and Other Proteins of Small size) installs the universally conserved and essential N6-threonylcarbamoyl adenosine modification (t6A) on ANN-decoding tRNAs in eukaryotes and in archaea. KEOPS consists of Cgi121, Kae1, Pcc1, Gon7 and the atypical kinase/ATPase Bud32. Except Gon7, all KEOPS subunits are needed for tRNA modification, and in humans, mutations in all five genes underlie the lethal genetic disease Galloway Mowat Syndrome (GAMOS). Kae1 catalyzes the modification of tRNA, but the specific contributions of Bud32 and the other subunits are less clear. Here we solved cryogenic electron microscopy structures of KEOPS with and without a tRNA substrate. We uncover distinct flexibility of KEOPS-bound tRNA revealing a conformational change that may enable its modification by Kae1. We further identified a contact between a flipped-out base of the tRNA and an arginine residue in C-terminal tail of Bud32 that correlates with the conformational change in the tRNA. We also uncover contact surfaces within the KEOPS-tRNA holo-enzyme substrate complex that are required for Bud32 ATPase regulation and t6A modification activity. Our findings uncover inner workings of KEOPS including a basis for substrate specificity and why Kae1 depends on all other subunits.

Abstract Sustainable and resilient crop production is facing many challenges. The restoration of natural reactive silicon cycles offers an opportunity to improve sustainability through reducing phosphorus fertilizer use and to increase crops’ resilience to drought stress and pests. We therefore call upon farmers, agri-food-researchers, and policymakers to pave the road for transforming agriculture to a silicon-improved sustainable crop production, which represents a promising approach to achieve food security under global change.

Abstract Background Helicopter hoist operations (HHO) are an important option for rescue operations in rugged and challenging terrain. German mid-range mountains are characterized by the versatility of ground conditions, few urban structures, and frequent use for local leisure activities, including the practice of more or less high-risk outdoor sports. This retrospective analysis aims to investigate the incidence of rescue missions in German mid-range mountains requiring HHO. The contributing air rescue bases' operational tactics and the underlying medical characteristics, such as injury patterns and the provided medical care, are also reported. Methods This study is a retrospective analysis of the documentation of HHO missions carried out at the air rescue bases in Freiburg, Nuremberg, and Bautzen staffed by emergency physicians between 01/2020 and 07/2022. Data was extracted from the German Air Rescue database. To assess the topics of interest, we conducted basic descriptive statistics. Results Data selection retrieved 410 HHO-associated rescue missions. A total of 304 datasets, including HHO, were suitable for further statistical processing. Air rescue base Freiburg contributed 152, Nuremberg 63, and Bautzen 89 missions. HHO missions showed an increased frequency in the summer season and from Friday to Sunday. In this collective, 75% of the underlying diagnoses were trauma-associated; in 33% of all patients, traumatic injury of the pelvis or lower limb occurred. 28% of the patients were in a potential or actual life-threatening condition and were scored NACA 4 or higher. The rates of invasive medical treatment, such as endotracheal intubation (5%) or venous access (79%), were considerably higher than in overall emergency missions. In terms of mission tactics and cooperation with mountain rescue services, different approaches of the three air bases resulted in differences regarding first-on-scene rates and time spans. Conclusion The results show a relevant year-round need to deploy emergency medical expertise to inaccessible terrain in the three regions examined. Detailed analysis showed relevant differences in operational tactics between the three bases and potential for optimization. Simultaneous alerting of the hoist helicopter and reliable and precise coordination with other rescue organizations involved, especially the local mountain rescue service and the rescue coordination center, can help to shorten both the treatment-free interval and the prehospital time for patients in inaccessible terrain. Trial registration: The study is registered at DRKS (DRKS00033493).

Abstract Promising therapeutic strategies are being explored to replace or regenerate the neuronal populations that are lost in patients with neurodegenerative disorders. Several research groups have attempted direct reprogramming of astrocytes into neurons by manipulating the expression of polypyrimidine tract-binding protein 1 (PTBP1) and claimed putative converted neurons to be functional, which led to improved disease outcomes in animal models of several neurodegenerative disorders. However, a few other studies reported data that contradict these claims, raising doubt about whether PTBP1 suppression truly reprograms astrocytes into neurons and the therapeutic potential of this approach. This review discusses recent advances in regenerative therapeutics including stem cell transplantations for central nervous system disorders, with a particular focus on Parkinson’s and Alzheimer’s diseases. We also provide a perspective on this controversy by considering that astrocyte heterogeneity may be the key to understanding the discrepancy in published studies, and that certain subpopulations of these glial cells may be more readily converted into neurons.

Abstract Background This paper identifies differences in all-cancer incidence and mortality between Pakistani-born (PB), Bangladeshi-born (BB), their descendants, and the White British (WB) in England and Wales. Pakistanis and Bangladeshis are the most marginalised and disadvantaged groups in England and Wales yet, are found to have low cancer mortality and low all-cause mortality. Previous studies though have not looked at generational differences, applied individual-level data nor separated Pakistanis and Bangladeshis from each other and other Asian groups. Methods We use the Office for National Statistics Longitudinal Study of England and Wales which is a 1% representative sample of the population. We apply event history analysis on a study period from 1971 to 2016, following individuals from age 20 until a first cancer incidence, censoring at emigration or death. We observe 10,885,500 person-years and 71,926 cancer incidences for WB; 125,700 person-years and 295 events for PB; 53,900 person-years and 113 events for BB and 26,900 person-years and 24 events for descendants. Following incidence, we study a maximum of ten years until a death from cancer, or censoring. In this second analysis on mortality our sample has 329,700 person-years and 31,689 cancer deaths for WB; 1,200 person-years and 104 events for PB; 400 person-years and 50 events for BB and 100 person-years and 10 events for descendants. Results Results from the fully adjusted models show that the risk of cancer incidence is lower for PB, BB and descendants compared to the WB native group. Estimated hazard ratio (HR) equals 0.42 for PB (95% confidence interval (CI): 0.38–0.47), for BB HR is 0.38 (CI: 0.32–0.46) and, for descendants HR is 0.36 (CI: 0.24–0.54). Results for cancer mortality after incidence show HR for PB is 0.93 (CI: 0.76–1.12), for BB it is 0.95 (CI: 0.72–1.25) and for descendants HR equals 1.62 (CI: 0.87–3.02 - significant at 90%). Conclusions Using high quality representative data, we show that lower incidence of cancer and not better survival is the driver of the low cancer mortality previously found. This advantage persists across immigrant generations, but all-cancer mortality following incidence may be elevated for descendants.

Abstract We have developed a population-level method for dietary assessment using low-cost wearable cameras. Our approach, EgoDiet, employs an egocentric vision-based pipeline to learn portion sizes, addressing the shortcomings of traditional self-reported dietary methods. To evaluate the functionality of this method, field studies were conducted in London (Study A) and Ghana (Study B) among populations of Ghanaian and Kenyan origin. In Study A, EgoDiet’s estimations were contrasted with dietitians’ assessments, revealing a performance with a Mean Absolute Percentage Error (MAPE) of 31.9% for portion size estimation, compared to 40.1% for estimates made by dietitians. We further evaluated our approach in Study B, comparing its performance to the traditional 24-Hour Dietary Recall (24HR). Our approach demonstrated a MAPE of 28.0%, showing a reduction in error when contrasted with the 24HR, which exhibited a MAPE of 32.5%. This improvement highlights the potential of using passive camera technology to serve as an alternative to the traditional dietary assessment methods.

Strategies to counteract the loss of arable plant diversity often target field margins. Yet there is still need for research on how arable plant diversity is impacted by the type, scale and diversity of margin management. To assess this experimentally, we combined five measures imposing different disturbance regimes (flower-strip mown twice a year, tilling in spring or autumn, adding sand as substrate, and frequent mowing as a control) at two spatial scales.We explored how plant community dynamics are affected by both single measures and their combination. We addressed four hypotheses: H1) single measures shift community weighted mean (CWM) values of functional traits and reduce the within-measure community weighted standard deviation (CWSD) of these traits; H2) heavy disturbance (early tilling and sand) causes taxonomic and functional diversity (alpha-diversity) to increase over time; H3) combining different measures increases dissimilarity (beta-diversity) and thus gamma-diversity across measures; and H4) increased spatial heterogeneity of measures promotes all levels of diversity.We found shifts in CWM and reduced CWSD in flower-strips (smaller seed mass, perennial lifespan) and late-tilling (later flowering-onset) whereas sand and early-tilling tended to increase CWSD (H1). Trends across measures indicate shifts towards species with competitive strategies (H1). Compared to frequently mown controls, heavy disturbance (sand and early-tilling) promoted alpha-diversity over time, despite lower initial diversity. Moderate disturbance (flower-strip, late tilling) initially promoted alpha-diversity, but diversity then did not increase further (H2). Combining different measures promoted diversity compared to single measures, but the similarity between measures increased over time (H3). Scale played a minor role in determining community-composition (H4).Disturbance regimes imposed by different management of field margins shape the functional composition of arable plant communities. Strategies combining different measures help to balance initial benefits of moderate disturbance with the longer-term diversity gains from heavier disturbance.

Background and objective: Urosymphyseal fistula (UF) and pubic osteomyelitis (PO) are rare and often poorly recognized long-term complications of treatment for localized prostate cancer. Our aim was to describe UF/PO in prostate cancer survivors. Methods: We performed a retrospective review of 26 patients treated for UF/PO after localized prostate cancer treatment at University Hospitals Leuven (1996–2021). We analyzed data for demographic characteristics, history, urethral manipulations (UMs), diagnostic and therapeutic approaches, microbiology, and treatment success. Key findings and limitations: Before diagnosis, 80.8% of the patients had undergone RP, 88.5% received radiotherapy, and 84.6% had at least one UM. The median time from radiotherapy (RT), the last UM, and the first symptoms to diagnosis were 102 mo, 4 mo, and 43 d, respectively. Treatment included cystectomy (n = 19), bladder-sparing interventions (n = 5), and conservative treatment (n = 2). Pubic debridement was required in 21 patients. All cystectomy patients had a history of RT. Imaging-detected UF led to cystectomy in 94.1% of cases. Full conservative treatment succeeded only in non-irradiated patients. Bone cultures were positive in 95% of cases and discordant with urine cultures in 82.4%. Reinterventions and severe complications affected 56.5% of patients; all were UF/PO-free after up to four treatment attempts. Our study is limited by the small sample size, retrospective nature, and possible information and referral bias. Conclusions and clinical implications: UF/PO can occur years after local prostate cancer treatment. Risk factors include RT and UMs. Conservative treatment rarely succeeds, particularly in irradiated patients with persistent UF. Most patients require multidisciplinary treatment involving cystectomy and pubic debridement. A perioperative bone culture to guide postoperative antibiotic treatment is crucial because of discordance with urine cultures. Postoperative complications are common, often requiring reintervention. Caution with UMs is advised after pelvic RT. Patient summary: We looked at data for patients with a rare complication that can occur after treatment for localized prostate cancer that involves a small tunnel between the lower urinary tract and the pubic bone, and infection in the pubic bone. Diagnosis occurred years after pelvic radiotherapy and shortly after a procedure performed through the urethra, typically surgery for narrowing of the urethra. Most patients needed removal of their bladder and surgical cleaning of the pubic bone, followed by long-term antibiotics. The bacteria found in bone were often different from those found in the patient’s urine, which is important in guiding antibiotic treatment after surgery.

Non–muscle-invasive bladder cancer (NMIBC) is a heterogeneous disease categorized as low, intermediate, high, or very high risk, for which recurrence and progression rates and thus management strategies differ. Current molecular subclassification of bladder cancer (BC) is mainly based on data for muscle-invasive disease, with very few data for NMIBC. A more accurate classification system is needed for better stratification of NMIBC using multiomics and immunohistopathological molecular data alongside clinical data collected in a prospective cohort. ProCaB (Prospective Sample Collection for Cancer of Bladder) is a single-center non-interventional, prospective study recruiting all eligible patients diagnosed with BC in a tertiary center in the Flanders region of Belgium. Clinical data have been collected in a prospective registry since August 2013. Biosamples (blood, urine, and BC tissue) are collected from each patient at diagnosis and are stored at −80°C at BioBank UZ Leuven after appropriate processing according to the protocol. Multiomics (genomics, epigenetics, transcriptomics, proteomics, lipidomics, metabolomics) and immunohistopathology analyses will be performed on appropriate samples. The target is to enroll 300 patients over a 5-yr period, and all patients will be followed for 5 yr. The objective is to create a biobank of samples from patients diagnosed with BC for use in multiomics and immunohistopathological analyses. Results from these analyses, together with long-term clinical data, can be used for comprehensive multilayered molecular characterization of disease recurrence and progression in intermediate- and (very) high-risk NMIBC, identification of multibiomarker panels for better stratification, and identification of a patient subgroup that does not respond to bacillus Calmette-Guérin treatment.This trial is registered on ClinicalTrials.gov as NCT04167332.

Abstract Biological neural networks effortlessly tackle complex computational problems and excel at predicting outcomes from noisy, incomplete data. Artificial neural networks (ANNs), inspired by these biological counterparts, have emerged as powerful tools for deciphering intricate data patterns and making predictions. However, conventional ANNs can be viewed as “point estimates” that do not capture the uncertainty of prediction, which is an inherently probabilistic process. In contrast, treating an ANN as a probabilistic model derived via Bayesian inference poses significant challenges for conventional deterministic computing architectures. Here, we use chaotic light in combination with incoherent photonic data processing to enable high-speed probabilistic computation and uncertainty quantification. We exploit the photonic probabilistic architecture to simultaneously perform image classification and uncertainty prediction via a Bayesian neural network. Our prototype demonstrates the seamless cointegration of a physical entropy source and a computational architecture that enables ultrafast probabilistic computation by parallel sampling.

Australia is a sink for low pathogenicity avian influenza viruses, with isolated circulation occurring on the continent. We report the incursion of a Eurasian low pathogenicity avian influenza H5 virus into Australia. This report benefits surveillance and diagnostic work because of the risk and current absence of highly pathogenic avian influenza A(H5N1).

Background: The incidence of pediatric hospitalizations has significantly increased since the spread of the omicron variant of COVID-19. Changes of characteristics in respiratory and neurological symptoms have been reported. We performed a retrospective, cross-sectional study to characterize the MRI change in children with an emphasis on the change of cerebral vasculatures. Methods: We retrospectively collected clinical and MRI data of 31 pediatric patients with neurological symptoms during the acute infection and abnormalities on MRI during the outbreak of omicron variant from April 2022 to June 2022 in Taiwan. The clinical manifestations and MRI abnormalities were collected and proportion of patients with vascular abnormalities was calculated. Results: Among 31 pediatric patients with post-COVID-19 neurological symptoms, MRI abnormalities were observed in 15 (48.4%), predominantly encephalitis/encephalopathy (73.3%). Notable MRI findings included focal diffusion-weighted imaging (DWI) hyperintensity in cerebral cortex and thalamus, diffuse cortical T2/DWI hyperintensity, and lesions in the medulla, pons, cerebellum, and splenium of corpus callosum. Vascular abnormalities were seen in 12 (80%) patients with MRI abnormalities, mainly affecting the middle cerebral arteries. The spectrum of neurological manifestations ranged from seizures to Alice in Wonderland syndrome, underscoring the diverse impact of COVID-19 on pediatric patients. Conclusion: A high proportion of vascular abnormalities was observed in pediatric patients with neurological involvements, suggesting that vascular involvement is an important mechanism of neurological manifestations in omicron variant infection.

We assessed the impact of probiotics on outcomes related to caries in children and/or adolescents without underlying systemic diseases. We performed a comprehensive meta-analysis of randomised controlled trials (RCTs). Searches were performed in Embase, PubMed, Scopus and Web of Science until March 2023 for RCTs assessing probiotics with a minimum intake duration of 0.2 months vs. control (no treatment or placebo) and reporting at least one primary or secondary outcome. Primary outcomes were number of carious, Streptococcus mutans count, and Lactobacillus count; secondary outcomes were bacterial plaque index, gingival index, salivary pH, and bleeding index. We performed meta-analyses with random effects models and the inverse variance method. Effects were described as mean difference (MD) with their 95% confidence intervals (95%CI). The risk of bias was assessed with the RoB 2.0 tool. The GRADE methodology was used to assess the quality of evidence (QoE). Nineteen RCTs were included (n = 2622), with a follow-up range of 0.2 to 108 months. Probiotics had no effect on reduction of dental caries (MD -0.24 carious pieces, 95%CI -0.72 to 0.23; I2 = 52%, low QoE) or Lactobacillus count (MD -0.78 CFU/mL, 95%CI -1.65 to 0.09; I2= 52%, very low QoE) vs. control. However, probiotics probably reduced S. mutans count vs. control (MD -0.40 CFU/mL, 95%CI -0.57 to -0.24; I2 = 11%, moderate QoE). Probiotics had no effect on bacterial plaque index (MD 0.21 units of bacterial plaque, 95%CI -0. 55-0.96; I2 = 80%, very low QoE), gingival index (MD 0.04 units of gingival index, 95%CI -0.18 to 0.27; I2= 0%, low QoE), and salivary pH (MD -0.12 pH units, 95%CI -0.72 to 0.48; I2 = 92%, very low QoE) vs. control. Probiotics were found to likely reduce S. mutans counts. However, no significant effect of probiotics was observed in reducing other outcomes compared to the control group.

Massive MIMO (Multiple-input-multiple output), crucial for 5 G and Beyond 5 G (B5G) networks, faces challenges with terahertz frequencies in B5G as the communication shifts from far-field to near-field. This shift disrupts traditional Massive MIMO channel estimation, leading to increased pilot overhead and limited performance. The current study used the hybrid-field orthogonal matching pursuit (HF-OMP) algorithm from the compressive sensing (CS) framework to estimate the channel with scatters from both far-field and near-field. The method, however, needs more flexibility regarding scatter location in the field of interest. Also, the usage of HF-OMP under a single measurement vector (SMV) scheme limits the overall performance of the existing method. To address these, we have proposed an adaptive hybrid-field simultaneous-OMP algorithm under multiple measurement vector (MMV) of the CS framework which selects multiple atoms having common support within a single iteration. This innovative approach tackles channel estimation for both far-field and near-field scatters while adapting to their varying distributions. Compared to classical methods, simulations show the new algorithm achieves up to a 14 % improvement in normalized mean square error within a 0 dB to 10 dB signal-to-noise ratio range. This translates to significant reductions in pilot overhead and enhanced channel reliability, paving the way for more efficient and robust wireless networks in the future.

Psychotherapists can differ in their effectiveness. Yet, more research is needed to determine the generalizability of between-therapist effects to cultures beyond the US and UK, and whether these effects differ by treatment context. Addressing these gaps, we examined therapist effects in a randomized trial comparing cognitive behavioral therapy (CBT) versus psychodynamic therapy (PDT) for depression in the Netherlands, hypothesizing that therapists would explain significant outcome variance across both treatments. We also explored whether the size of therapist effects differed by degree of treatment standardization; in this trial, CBT was structured and manualized, whereas PDT was flexible and principle driven. Patients were 254 adults who received 16 sessions of CBT or PDT from 59 therapists nested within the condition. As predicted, multilevel models revealed significant therapist effects (explaining 3–8% of variance) on patient depression and general distress outcomes. Moreover, PDT therapists (10–16%) accounted for more outcome variance than CBT therapists (2–6%), though differences were only statistically significant for the clinician-rated depression outcome. Results extend the cultural “reach” of therapist effects. Moreover, they highlight treatment standardization as one possible determinant of effectiveness differences, which necessitates determining for which therapists such standardization is most important for optimizing their patient’s outcomes.

Background: Porous metal materials have been widely studied for applications in orthopedic field, owing to their excellent features and properties in bone healing. Porous metal materials with different compositions, manufacturing methods, and porosities have been developed. Whereas, the systematic mechanisms on how porous metal materials promote bone healing still remain unclear. Methods: This review is concerned on the porous metal materials from three aspects with accounts of specific mechanisms, inflammatory regulation, angiogenesis and osteogenesis. We place great emphasis on different cells regulated by porous metal materials, including mesenchymal stem cells (MSCs), macrophages, endothelial cells (ECs), etc. Result: The design of porous metal materials is diversified, with its varying pore sizes, porosity material types, modification methods and coatings help researchers create the most experimentally suitable and clinically effective scaffolds. Related signal pathways presented from different functions showed that porous metal materials could change the behavior of cells and the amount of cytokines, achieving good influence on osteogenesis. Conclusion: This article summarizes the current progress achieved in the mechanism of porous metal materials promoting bone healing. By modulating the cellular behavior and physiological status of a spectrum of cellular constituents, such as macrophages, osteoblasts, and osteoclasts, porous metal materials are capable of activating different pathways and releasing regulatory factors, thus exerting pivotal influence on improving the bone healing effect. The translational potential of this article: Porous metal materials play a vital role in the treatment of bone defects. Unfortunately, although an increasing number of studies have been concentrated on the effect of porous metal materials on osteogenesis-related cells, the comprehensive regulation of porous metal materials on the host cell functions during bone regeneration and the related intrinsic mechanisms remain unclear. This review summarizes different design methods for porous metal materials to fabricate the most suitable scaffolds for bone remodeling, and systematically reviews the corresponding mechanisms on inflammation, angiogenesis and osteogenesis of porous metal materials. This review can provide more theoretical framework and innovative optimization for the application of porous metal materials in orthopedics, dentistry, and other areas, thereby advancing their clinical utility and efficacy.

Abstract Background Healthcare use by High-Need High-Cost (HNHC) patients is believed to be modifiable through better coordination of care. To identify patients for care management, a hybrid approach is recommended that combines clinical assessment of need with model-based prediction of cost. Models that predict high healthcare costs persisting over time are relevant but scarce. We aimed to develop and validate two models predicting Persistent High-Cost (PHC) status upon hospital outpatient visit and hospital admission, respectively. Methods We performed a retrospective cohort study using claims data from a national health insurer in the Netherlands—a regulated competitive health care system with universal coverage. We created two populations of adults based on their index event in 2016: a first hospital outpatient visit (i.e., outpatient population) or hospital admission (i.e., hospital admission population). Both were divided in a development (January-June) and validation (July-December) cohort. Our outcome of interest, PHC status, was defined as belonging to the top 10% of total annual healthcare costs for three consecutive years after the index event. Predictors were predefined based on an earlier systematic review and collected in the year prior to the index event. Predictor effects were quantified through logistic multivariable regression analysis. To increase usability, we also developed smaller models containing the lowest number of predictors while maintaining comparable performance. This was based on relative predictor importance (Wald χ2). Model performance was evaluated by means of discrimination (C-statistic) and calibration (plots). Results In the outpatient development cohort (n = 135,558), 2.2% of patients (n = 3,016) was PHC. In the hospital admission development cohort (n = 24,805), this was 5.8% (n = 1,451). Both full models included 27 predictors, while their smaller counterparts had 10 (outpatient model) and 11 predictors (hospital admission model). In the outpatient validation cohort (n = 84,009) and hospital admission validation cohort (n = 20,768), discrimination was good for full models (C-statistics 0.75; 0.74) and smaller models (C-statistics 0.70; 0.73), while calibration plots indicated that models were well-calibrated. Conclusions We developed and validated two models predicting PHC status that demonstrate good discrimination and calibration. Both models are suitable for integration into electronic health records to aid a hybrid case-finding strategy for HNHC care management.

Abstract Background Illicit drug toxicity (i.e., overdose) is the leading cause of death in British Columbia (BC) for people aged 10–59. Stimulants are increasingly detected among drug toxicity deaths. As stimulant use and detection in deaths rises, it is important to understand how people who die of stimulant toxicity differ from people who die of opioid toxicity. Methods BC Coroners Service records were retrieved for all people who died of unintentional illicit drug toxicity (accidental or undetermined) between January 1, 2015, and December 31, 2019, whose coroner investigation had concluded and who had an opioid and/or stimulant detected in post-mortem toxicology and identified by the coroner as relevant to the death (N = 3788). BC Chronic Disease Registry definitions were used to identify people with chronic disease. Multinomial regression models were used to examine the relationship between chronic disease diagnoses and drug toxicity death type. Results Of the 3788 deaths, 11.1% (N = 422) had stimulants but not opioids deemed relevant to the cause of death (stimulant group), 26.8% (N = 1014) had opioids but not stimulants deemed relevant (opioid group), and 62.1% (N = 2352) had both opioids and stimulants deemed relevant (opioid/stimulant group). People with ischemic heart disease (1.80 (1.14–2.85)) and people with heart failure (2.29 (1.25–4.20)) had approximately twice the odds of being in the stimulant group as compared to the opioid group. Conclusions Findings suggest that people with heart disease who use illicit stimulants face an elevated risk of drug toxicity death. Future research should explore this association and should identify opportunities for targeted interventions to reduce drug toxicity deaths among people with medical comorbidities.

Abstract This research was aimed to assess the impact of efficient microorganisms and fruit extracts (Banana and Apple) on fermentation of cacao collected in Ecuador. The work was focused on compliance with European Union regulation 2021/1323, which sets cadmium (Cd) limits at 0.80 mg kg–1 for cocoa products that are exported. The study conducted experiments on cacao of two Ecuadorian provinces, Manabí and Esmeraldas, employing two types of bioinoculants (Biol Albiobatch and EM-1 20%). Bioinoculants were analyzed for their potential in the reduction of Cd, using a Trifactorial statistical design (Completely randomized trifactorial design, CRTD) 2 × 2 × 2 added + 2. Ten treatments with three replicates were used, including two unamended controls. The Rohan Modified micro-fermentation method was employed, considering various parameters such as cacao fruit morphology, temperature, pH, and °Brix. After fermentation, the cocoa beans were sun-dried to reduce moisture content, and their fermentative state was assessed. Cd levels were determined using the USDAP 3050B method. The results showed that different treatments affected cacao fruit morphology, temperature, pH, and Brix differently. Notably, the Biol EM-1 + Banana treatment of cacao of Manabí exhibited the most favorable results in several aspects. The cutting test revealed significant improvements in fermentation quality for this treatment. Moreover, the use of microorganisms resulted in a substantial reduction in Cd levels, with cacao of Esmeraldas and Manabí provinces experiencing reductions of 63.25% and 58.20%, respectively. Overall, this research demonstrates the potential of efficient microorganisms and fruit extracts to enhance cocoa fermentation and reduce Cd content, contributing to the quality and compliance of Ecuador cocoa exports with EU regulations.

Abstract Paediatric medulloblastomas with chromothripsis are characterised by high genomic instability and are among the tumours with the worst prognosis. However, the molecular makeup and the determinants of the aggressiveness of chromothriptic medulloblastoma are not well understood. Here, we apply spatial transcriptomics to profile a cohort of 13 chromothriptic and non-chromothriptic medulloblastomas from the same molecular subgroup. Our data reveal a higher extent of spatial intra-tumour heterogeneity in chromothriptic medulloblastomas compared to non-chromothripictic tumours, which is associated with increased proliferation and stemness, but lower immune infiltration and differentiation. Spatial mapping of genetic subclones of the same tumour identify a regionally distinct architecture and clone-specific phenotypic features, with distinct degrees of differentiation, proliferation and immune infiltration between clones. We conduct temporal profiling of 11 samples from patient-derived xenografts from a patient with chromothriptic medulloblastoma, covering the transition from the minimal residual disease stage to treatment-resistant regrown tumours. In chromothriptic medulloblastoma, an ecosystem of cells from multiple genetic clones resist treatment and lead to relapse. Finally, we identify tumour microtubes in chromothriptic medulloblastoma, calling for exploration of cell network communication as a putative target.

Abstract Background Titanium plantar plates have proven successful in the fixation of the first tarsometatarsal arthrodesis (TMT). However, a second surgery is typically needed for implant removal, and potential adverse effects, carried by the conventional implantations, are not uncommon. The purpose of this study was to determine whether a novel magnesium-based plantar plate system provides similar fusion stability to a titanium-based plantar plate system under various loading conditions. Methods Six matched-pair human cadaveric specimens underwent TMT fusions using either a magnesium plantar plate system prototype or a titanium plantar plate system. Specimens were cyclically loaded with a force ranging from 5 N to 50 N for 5,000 cycles, and displacement was recorded. Axial stiffness (N/mm) was calculated from load-displacement curves. Each specimen was loaded to failure at a rate of 5 mm/min, and the ultimate load was recorded. Results No significant difference was found in the vertical displacement between Ti group and Mg group after 100 cycles (2.4 ± 1.0 mm vs. 1.3 ± 1.4 mm, p = 0.196), 500 cycles (3.3 ± 1.3 mm vs. 1.7 ± 1.7 mm, p = 0.142), 1,000 cycles (3.7 ± 1.5 mm vs. 1.9 ± 1.9 mm, p = 0.128), 2,500 cycles (4.2 ± 1.7 mm vs. 2.3 ± 2.2 mm, p = 0.172) and 5,000 cycles (4.5 ± 1.8 mm vs. 2.3 ± 3.3 mm, p = 0.125), Additionally, no significant differences were observed in initial stiffness (53.1 ± 19.2 N/mm vs. 82.2 ± 53.9 N/mm, p = 0.257), final stiffness (90.6 ± 48.9 N/mm vs. 120.0 ± 48.3 N/mm, p = 0.319), or maximum load-to-failure (259.8 ± 98.2 N vs. 323.9 ± 134.9 N, p = 0.369). Conclusions Based on the performed biomechanical testing, the magnesium plantar plate system provides mechanical stability equivalent to the titanium plantar plate system in fixation for the first TMT joint fusion.

Abstract Background The IMPACT Survey explored the humanistic, clinical, and economic burden of osteogenesis imperfecta (OI) on individuals with OI, their families, caregivers, and wider society. Two previous publications report research methodology, initial insights of the survey, and cost of illness of OI. Here, we present data on the impact of OI on the quality of life (QoL) of adults with OI and explore potential drivers of this impact. Methods The IMPACT Survey was an international mixed methods online survey in eight languages (fielded July–September 2021), aimed at adults (aged ≥ 18 years) or adolescents (aged 12–17 years) with OI, caregivers (with or without OI) of individuals with OI, and other close relatives. Survey domains included demographics, socioeconomic factors, clinical characteristics, treatment patterns, QoL, and health economics. We conducted a descriptive analysis of the QoL data, as well as exploratory regression analyses to identify drivers of impact of OI on QoL (independent associations between patient characteristics and the impact on QoL). Results 1,440 adults with OI participated in the survey. The proportion who reported an impact of OI on their QoL across individual areas in the physical, socioeconomic, and mental well-being domains ranged between 49 and 84%. For instance, 84% of adults reported an impact of OI on the types of leisure activities they could do and 74% on the type of job they could do. More severe self-reported OI and higher fracture frequency were consistently identified as drivers of OI’s impact on QoL. The proportion of adults who reported worrying about different aspects of their lives due to their OI, such as mobility loss, future fractures, and ageing, ranged between 31 and 97%. Conclusion IMPACT provides insights into the humanistic burden of OI on adults, revealing that OI has a substantial impact on the QoL of adults. OI severity and fracture frequency were consistently identified as drivers of impact on QoL across all domains. Understanding these drivers may aid in identifying areas for targeted interventions, such as fracture prevention.

Abstract Background Transport injuries are a global public health concern, causing 1.35 million deaths and over 20 million non-fatal injuries annually. Low- and middle-income countries, particularly countries in Africa, are experiencing an increase in fatalities. Ghana and the Volta Region are not exempted from the burden, prompting targeted interventions. In the development of these interventions, epidemiological data analysis is needed to identify areas for action. This study aimed to analyze the distribution, trends, and incidence of transport-related injuries in the Volta Region of Ghana. Method Secondary data was analyzed to describe transport-related injury cases and deaths in the Volta Region of Ghana from 2019 to 2023. Transport-related injuries were obtained from the monthly out-patient morbidity report form whereas transport related deaths were obtained from the inpatient morbidity and mortality, and cause of death report forms. Descriptive data analyses were performed and reported as frequencies, proportions, ratios, and choropleth maps. Result Of the 33,415 transport-related injury cases reported between 2019 and 2023, 25 were fatal. The highest proportion of cases, 35.8% (35.3–36.4), was among persons aged 20–34 years. About 66.0% (65.5–66.5) of all the cases involved males. The cumulative incidence was 387 injuries per 100,000 population with the highest incidence recorded in 2021. The incidence of cases declined from 357 per 100,000 population in 2019 to 320 per 100,000 population in 2023. The death rate was stable over the period with the highest of 1.2 per 1000 recorded in 2019 and declined from 1.2 per 1000 in 2019 to 0.9 per 1000 in 2023. Most, 56% of the deaths were reported in district hospitals. Conclusion The study showed a decreasing trend in the incidence of transport injuries, but a steady mortality rate in the Volta Region. Young adults were the highest affected group. There is the need for increased road safety campaigns and further research.

Abstract Background The objective of this research was the development and evaluation of 203Pb-labelled panitumumab (203Pb-PSC-panitumumab) as an immuno-SPECT radioligand for the detection of EGFR + head and neck squamous cell carcinoma (HNSCC) in a patient-derived xenograft (PDX) mouse model. The 51.9 h physical half-life and favourable γ-emission (279 keV; 81%) of 203Pb offer an excellent opportunity for developing immuno-SPECT radioligands. Moreover, 203Pb has a complementary therapeutic radionuclide (212Pb), making 203Pb and 212Pb an ideal matched radiotheranostic pair. Results Radiolabeling of panitumumab was performed at a pH of 5.0 and room temperature for 5–10 min with [203Pb]Pb(OAc)2, and the incorporation efficiency was determined using radio-TLC. 203Pb-PSC-panitumumab (~ 10 MBq, 140 μl of saline) was injected into the tail vein of NRG mice bearing subcutaneous (s.c.) HNSCC patient-derived xenografts (PDX). SPECT/CT images were acquired at 48 and 120 h post-injection. For biodistribution studies, mice were euthanized five days after 203Pb-panitumumab injection. The tumour and normal tissues were collected and weighed, and uptake of 203Pb was measured in a γ-counter. The uptake was calculated as the percent injected dose per gram of each tissue (ID%/g). Blocking experiments were performed by pretreating a group of mice (n = 5) with 1 mg of panitumumab 1 h before administering 203Pb-PSC-panitumumab. 4–5 chelators of a new lead-specific chelator (PSC) were attached per antibody; radiolabeling efficiency was 99.2 ± 0.7%. The isolated radiochemical yield of 203Pb-PSC-panitumumab was 41.4 ± 8% (n = 5), and the molar activity was 1.2 ± 0.35 GB/mg. SPECT imaging and biodistribution confirmed high accumulation and retention of 203Pb-PSC-panitumumab in the tumour (26% ID/g) at 120 h post-injection (p.i.), which could be reduced to 6.2%ID/g at 120 h p.i. by predosing with panitumumab (1 mg) confirming EGFR specificity of 203Pb-PSC-panitumumab uptake. Conclusions Panitumumab was successfully and reproducibly labelled with 203Pb in high radiochemical purity using the chelator PSC-NCS. 203Pb-PSC-panitumumab was specifically accumulated and retained in EGFR + tumours in NRG mice with s.c. HNSCC PDX. 203Pb-PSC-panitumumab is a suitable immuno-SPECT radioligand for imaging EGFR + tumours and has great potential for combining with 212Pb-PSC-panitumumab in a radiotheranostic strategy for imaging and treating HNSCC.

Abstract Background Comparative pharmacokinetics and pharmacodynamics (PK/PD) of apixaban and rivaroxaban have not been studied in dogs and the propensity of these drugs to cause hypercoagulability after discontinuation is unknown. Hypothesis Compare the PK/PD of clinical dosing regimens of PO apixaban and rivaroxaban administered repeatedly to healthy dogs and assess the effect of abrupt drug discontinuation on coagulation. Animals Six University‐owned, purpose‐bred, middle‐aged, mixed‐breed dogs (4 male, 2 female). Methods Dogs were given apixaban or rivaroxaban PO at 0.5 mg/kg q12h for 7 days with a 14‐day washout period between drugs. Plasma drug concentrations were quantitated, and anticoagulant effects were measured using clotting times, calibrated anti‐Xa bioactivity assays, and measurements of thrombin generation. The potential for rebound hypercoagulability was assessed by measuring D‐dimers, thrombin‐antithrombin (TAT) complexes, and antithrombin activity after drug discontinuation. Results Plasma drug concentrations and anti‐Xa bioactivities were closely correlated for both drugs, but drug concentrations varied considerably among dogs, despite consistent dose regimens. Thrombin generation variables were significantly correlated with the anti‐Xa bioactivity of both drugs and no significant differences in the effects of apixaban and rivaroxaban on thrombin generation were observed. Drug discontinuation had no effect on D‐dimer concentrations. The concentration of TAT complexes decreased after apixaban discontinuation and did not change after rivaroxaban discontinuation. Conclusions and Clinical Importance Repeated PO administration of apixaban or rivaroxaban to healthy dogs produced comparable anticoagulant effects measured by inhibition of thrombin formation. Rebound hypercoagulability after drug discontinuation was not observed and weaning of these drugs in clinical patients might not be necessary.

Abstract Background Seropositive rheumatoid arthritis (RA) is associated with significant cardiovascular and pulmonary morbidity. However, screening for early detection of pulmonary involvement especially interstitial lung disease (ILD) is not established in RA. Methods We propose a non-invasive radiation-free approach to screen for interstitial lung involvement (ILI) by means of pulmonary function tests (PFT) and pleuro-pulmonary transthoracic ultrasound (LUS) with additional cardiopulmonary exercise tests (CPET) with ECG, and echocardiography. We included patients with confirmed diagnosis of seropositive RA according to ACR criteria, but without symptoms for or known cardiopulmonary disease. ILD was suspected when significant LUS abnormalities and additional PFT changes were present. Results We included 67 consecutive patients (78% female, mean age 61 ± 12 years, 48% active or previous smokers), who fulfilled the inclusion criteria and gave written informed consent. We found 48% of patients with suspected changes in PFT with a diffusion capacity (DLCOc-SB) ≤ 80%, among them 7% with forced vital capacity (FVC) ≤ 80%. In 40% of patients, we found noticeable changes in LUS, 24% with an ILD compatible pattern. In 16% of cases, LUS abnormalities and additional PFT changes were present, and ILI was suspected. Additional findings included obstructive lung disease (n = 11), subpleural consolidation (n = 6) including one confirmed lung cancer, minimal pleural effusion (n = 6), and ischemic cardiac disease (n = 2). None of the patients showed signs of pulmonary vascular involvement. Conclusions ILI was suspected in 16% of cases using a new radiation-free screening protocol in asymptomatic RA patients. Trial registration German Register of Clinical Studies (DRKS00028871).

Abstract As SARS-CoV-2 evolves, increasing in potential for greater transmissibility and immune escape, updated vaccines are needed to boost adaptive immunity to protect against COVID-19 caused by circulating strains. Here, we report features of the monovalent Omicron XBB.1.5-adapted BNT162b2 vaccine, which contains XBB.1.5-specific sequence changes, relative to the original BNT162b2 backbone, in the encoded prefusion-stabilized SARS-CoV-2 spike protein (S(P2)). Biophysical characterization of Omicron XBB.1.5 S(P2) demonstrated that it maintains a prefusion conformation and adopts a flexible, predominantly open, state, with high affinity for the human ACE-2 receptor. When administered as a 4th dose in BNT162b2-experienced mice, the monovalent Omicron XBB.1.5 vaccine elicited substantially higher serum neutralizing titers against pseudotyped viruses of Omicron XBB.1.5, XBB.1.16, XBB.1.16.1, XBB.2.3, EG.5.1 and HV.1 sublineages and phylogenetically distant BA.2.86 lineage than the bivalent Wild Type + Omicron BA.4/5 vaccine. Similar trends were observed against Omicron XBB sublineage pseudoviruses when the vaccine was administered as a 2-dose series in naive mice. Strong S-specific Th1 CD4+ and IFNγ+ CD8+ T cell responses were also observed. These findings, together with real world performance of the XBB.1.5-adapted vaccine, suggest that preclinical data for the monovalent Omicron XBB.1.5-adapted BNT162b2 was predictive of protective immunity against dominant SARS-CoV-2 strains.

Abstract This study develops a 73-year dataset of water balance components from 1950 to 2022 for the Laurentian Great Lakes Basins. This is carried out using the Large Lakes Statistical Water Balance Model (L2SWBM), which provides a Bayesian statistical framework that assimilates binational input datasets sourced from the United States and Canada. The L2SWBM infers feasible water balance component estimates through this Bayesian framework by constraining the output with a standard water balance equation. The result is value-added time series, including expressions of uncertainty, that ultimately close the water balance across the interconnected Great Lakes system. Therefore, the L2SWBM facilitates the understanding of discrepancies in datasets and hydroclimate parameters. This enhanced reliability stemming from coordinated data, with an understanding and quantification of uncertainty, could significantly boost confidence in decision support tools for water resources practitioners and policymakers. This joint effort advances scientific understanding and strengthens strategies and policies designed to bolster resilience in Great Lakes communities and its ecosystem in the face of a shifting climate.

Abstract This paper presents the development of a fully digital controller for induction heating machines, capable of delivering up to 50 kW and operating within a frequency range of 100 kHz to 500 kHz. The controller employs a novel approach to phaseshift calculation between voltage and current using successive high-speed subtractions, allowing for the calculation of a new angle in just a few microseconds and ensuring precise power regulation by adjusting frequency. To protect the inverter, the controller effectively prevents operation in the capacitive region, a critical requirement for safeguarding system integrity. Performance evaluations demonstrate minimal phase-shift errors, ensuring stable and efficient operation within the required safety margins. The architecture, built on Intel Altera Cyclone III FPGA devices, offers scalability and adaptability for implementing various modulation techniques.

Abstract Impaired interaction of fibroblasts with pneumocytes contributes to the progression of chronic lung disease such as idiopathic pulmonary fibrosis (IPF). Mucin 5B (MUC5B) is associated with IPF. Here we analyzed the interaction of primary fibroblasts and alveolar type 2 (AT2) pneumocytes in the organoid model. Single-cell analysis, histology, and qRT-PCR revealed that fibroblasts expressing high levels of fibrosis markers regulate STAT3 signaling in AT2 cells, which is accompanied by cystic organoid growth and MUC5B expression. Cystic growth and MUC5B expression were also caused by the cytokine IL-6. The PI3K-Akt signaling pathway was activated in fibroblasts. The drug dasatinib prevented the formation of MUC5B-expressing cystic organoids. MUC5B associated with AT2 cells in samples obtained from IPF patients. Our model shows that fibrotic primary fibroblasts induce impaired differentiation of AT2 cells via STAT3 signaling pathways, as observed in IPF patients. It can be used for mechanistic studies and drug development.

Abstract Objective To review United States chiropractic state boards acceptance of chiropractic residencies and fellowships as continuing education (CE). Methods Between February 2024 and April 2024, board websites and accompanying policy documents for all 50 states and the District of Columbia were manually searched for content related to residencies and fellowships and whether they were considered CE. Information regarding CE credit requirements for new licensees was also collected. Results were tabulated in a spreadsheet and descriptive analysis was performed. Consensus among a minimum of 5 of 6 investigators was sought. Results Four states (Arizona, Indiana, Kansas, and Minnesota) accept residencies or fellowships for CE credit, 6 states possess unclear regulatory language regarding these programs, and 41 states make no mention of these training programs among approved CE. Twenty-one states required CE credits during a licensee’s initial renewal period, 1 state was unclear based on website content alone, and 29 states did not mandate CE for initial license renewal. More than 90% (19/21) of states that require CE for a licensee’s first renewal do not or are unclear if they accept residencies or fellowships for credit. Conclusion Few chiropractic state boards currently accept residencies and fellowships as approved CE. As the number of these postdoctoral training programs for chiropractors grow, more state boards may be asked to determine their CE policies on them.

Abstract Parkinson’s disease, an aging-associated neurodegenerative disorder, is characterised by nigrostriatal pathway dysfunction caused by the gradual loss of dopaminergic neurons in the substantia nigra pars compacta of the midbrain. Human in vitro models are enabling the study of the dopaminergic neurons’ loss, but not the dysregulation within the dopaminergic network in the nigrostriatal pathway. Additionally, these models do not incorporate aging characteristics which potentially contribute to the development of Parkinson’s disease. Here we present a nigrostriatal pathway model based on midbrain-striatum assembloids with inducible aging. We show that these assembloids can develop characteristics of the nigrostriatal connectivity, with catecholamine release from the midbrain to the striatum and synapse formation between midbrain and striatal neurons. Moreover, Progerin-overexpressing assembloids acquire aging traits that lead to early neurodegenerative phenotypes. This model shall help to reveal the contribution of aging as well as nigrostriatal connectivity to the onset and progression of Parkinson’s disease.