bluuebunny/crossref_metadata_2025_split huggingface dataset:
ENVISION: Increasing diversity of a large phase 3b/4 confirmatory trial of aducanumab to better understand the efficacy and safety among historically underrepresented participants of Alzheimer’s disease research and clinical trials.
Authors: Montenigro Philip H. , Cheng Wenting , O'Gorman John , Murphy Jennifer , Gillis Cai , Maserejian Nancy Nairi , Mascherino Liz , Butts Cherie , Ashraf Daanish , Racine Annie M , Aisen Paul , Castrillo‐Viguera Carmen , Haeberlein Samantha Budd 
Published: December 2022

AbstractBackgroundWhile Black/African Americans and Latinx/Hispanics have nearly twice the risk of developing Alzheimer’s disease compared to Non‐Hispanic Whites, their involvement in clinical research and trials remains low. Due to the lack of data and underrepresentation in research, it is unknown if there are clinicopathological differences in Alzheimer’s disease or response to therapies. We have established specific recruitment goals for underrepresented groups in the aducanumab Phase 3b/4 confirmatory ENVISION study, which is a multicenter, randomized, double‐blind, placebo‐controlled, parallel‐group study of participants with mild cognitive impairment and mild dementia stages of Alzheimer’s disease (Stages 3 and 4; NCT05310071), designed to better understand the efficacy and safety of aducanumab treatment for these populations.MethodEpidemiological and clinical data by race/ethnicity in the United States (US) were obtained from systematic literature reviews and Clinical trial data were then used to characterize the clinicopathological profile of Alzheimer’s disease among diverse groups. Data from underrepresented participants were pooled and analyzed contemporaneous Alzheimer’s disease clinical trials to identify potential differences (i.e., heterogeneity) in clinical and biomarker outcomes.ResultBased on epidemiological analyses, the ENVISION has an enrollment target of 18% for patient populations historically underrepresented in clinical trials in the US. Limited pooled clinical trial data suggests there may be greater heterogeneity in clinical and biomarker endpoints in underrepresented groups.ConclusionResearch and clinical trial data from diverse patient populations with Alzheimer’s disease are lacking. Inclusive research is essential to advancing the mission to develop treatments for this devastating disease. Data‐driven recruitment goals have been established and analyses planned to address the safety and efficacy of aducanumab in historically underrepresented populations in the ENVISION study. This could serve as a model for evaluating differences in treatment outcomes across racial/ethnic groups.
Using Community Engagement Studios to Increase Recruitment and Retention of Under‐Resourced Participants in Aging Research
Authors: Person Elisa , Orellana Minerva , Myers Peter , Foster Erin , Campbell Meghan , Mozersky Jessica , Denny Andrea , Clark Pechaz , Johnson Charis , Johnson Charis , Balls‐Berry Joyce E 
Published: December 2022

AbstractBackgroundAs the population ages in the United States, the prevalence of many diseases like Alzheimer disease, related dementias, and Parkinson disease disproportionately affect those already at greatest risk for premature morbidity and mortality. Aging research has an opportunity to engage and support patients, communities, and caregivers most impacted by these diseases. However, under‐resourced communities frequently lack representation in research, causing decreased generalizability of study results and health inequities among these communities.MethodsUsing a community and patient engaged framework, we conducted three community engagement studios (studios) with caregivers, patients, providers, researchers, and advocates from the St. Louis community. The studios provide community input and recommendations on project feasibility, design, and cultural appropriateness. Proposed projects were presented during each studio, followed by a facilitated discussion with a neutral facilitator. Themes were derived using traditional qualitative content analysis.ResultsStakeholders included under‐resourced community members, LGBTQIA+ participants, and those without/inadequate health insurance. The main themes included participant commitment to health, culturally appropriate research design, and incentives. In addition, participants desired collaboration between researchers and the community, including connecting with local Alzheimer’s Disease Associations, faith‐based groups, and philanthropic organizations.ConclusionOur community stakeholders provided feedback on how we could modify the research design to increase community involvement, enhance participant recruitment and commitment, and reach populations currently underrepresented in aging research, especially Alzheimer’s disease. The early inclusion of stakeholders in research design and implementation constitutes a preliminary step to building trust within under‐resourced communities and increasing the recruitment and retention of diverse populations.
Perturbed astrocyte Ca2+ signaling in a diet‐based mouse model of small cerebral vessel disease
Authors: Norris Christopher M , Sompol Pradoldej M , Weiss Blaine E. , Gant Christopher C , Wilcock Donna M , Lin Ruei‐Lung , Thibault Olivier 
Published: December 2022

AbstractBackgroundThe hyperhomocysteinemia (HHcy) diet model of small cerebral vessel disease exhibits vascular inflammation, cerebral hypoperfusion, impaired neurovascular coupling, synapse dysfunction, and cognitive decline. Pathological changes in astrocyte structural features have also been noted, but functional astrocyte phenotypes have not been characterized. Here, we assessed Ca2+ signaling in individual astrocytes and astrocyte networks in barrel cortex of mice, pretreated with control or HHcy diet. Investigations were performed in fully awake mice to avoid confounding interactions between anesthetics, neural circuit activity, and vasoactive factors.MethodAdult C57/BL6 mice were fed for 15 weeks with control chow, or chow deficient in vitamins B6/B12 and enriched in methionine (HHcy diet). At week 11‐12, mice were injected with AAV‐Gfa104‐lck‐GCaMP6f into barrel cortex, followed by craniotomies and installation of a glass cranial windows with headmounts. Three weeks later, fully awake mice were head‐mounted under a two photon microscope to assess GCaMP6/Ca2+ transient activity in barrel cortex astrocytes during a 10 minute baseline (spontaneous activity) and also before, during, and air puff stimulation of contralateral whiskers (10Hz, 10 sec) . Mean Ca2+ transient amplitudes, transient rise/decay times, and number of transients per region of interest (ROI) were measured and averaged across the field of view (FOV). Functional relationships between multiple ROIs within the FOV were assessed to evaluate astrocyte network activityResultSpontaneous Ca2+ transients were comparable in amplitude and rise/decay kinetics across diet conditions. However, the number of transients per ROI was reduced in HHcy diet mice. Whisker stimulation evoked a primary Ca2+ elevation per ROI followed 10‐15 seconds later by a smaller amplitude Ca2+‐“aftershock”. Evoked Ca2+ signals were highly coordinated across ROIs within the FOV. However, the number of active ROIs and the functional connectivity between ROIs were significantly reduced in HHcy vs. control diet mice. Despite these network deficits, evoked Ca2+ transient amplitudes and aftershocks in individual ROIs were significantly larger with faster activation/decay kinetics in HHcy mice.ConclusionThe results suggest that altered astrocyte Ca2+ signaling, as a result of vascular pathology, may play an important role in the dynamic interplay between cerebral blood flow and neuronal activity, leading to overall neural dysfunction and cognitive impairment.
iWHELD, A Novel Digital Non‐Pharmacological Intervention with Live Virtual Coaching Reduces Antipsychotic Use in Nursing Home Residents with Dementia Compared to Usual Care in a 16‐week RCT
Authors: Ballard Clive G , McDermid Joanne , Aarsland Dag , Khan Zunera , Sweetnam Adrienne 
Published: December 2022

AbstractBackgroundImplementation of evidence‐based training into real world practice in nursing home settings is a major challenge. Digital approaches provide real potential to addressing the barriers, particularly over the difficult period of the COVID‐19 pandemic.MethodiWHELD is a first‐of‐its‐kind digital programme evolving the principles of the WHELD intervention combining person centred care, social interaction, and antipsychotic review, combining virtual coaching with a digital resource for nursing homes. The intervention utilising a Dementia Champion model supported by live virtual coaching set within a digital resource hub and peer networking platform was compared to usual care in a 16‐week randomised control cluster study of 741 people with dementia across 149 nursing homes in the UK. The initial outcomes evaluated are the use of antipsychotic drugs and neuropsychiatric symptoms (using the Neuropsychiatric Inventory NH).Result36/72 (53%) of nursing homes allocated to the active treatment arm engaged successfully with the digital intervention, with 563 residents completing the treatment period. The average age of residents was 84.5 years, 71% were female, and there were no significant differences between treatment arms. There was a significant reduction in antipsychotic use in the digital iWHELD treatment group from 49% to 31% compared to no change in the group receiving usual care (p = 0.046). Initial analysis of neuropsychiatric symptoms indicates a non‐significant improvement in the intervention group compared to those receiving usual care.ConclusionThe current RCT using an online programme with live virtual coaching delivered through a Dementia Champion achieved better than 50% engagement, which compares favourably with previous studies of digital interventions in other therapeutic areas. The intervention also achieved significant reductions in antipsychotic use without any worsening of neuropsychiatric symptoms, and provides an important potential approach to safely reducing the rise in antipsychotic use in nursing home residents with dementia that has become a major challenge during the COVID‐19 pandemic.
A Drosophila ortholog of Toll‐like receptors modulates c‐Jun N‐terminal kinase signaling and protects against tau‐mediated neurodegeneration independent of innate immune response
Authors: Sakakibara Yasufumi , Yamashiro Risa , Chikamatsu Sachie , Tsubokawa Yoko , Nishijima Risa , Takei Kimi , Sekiya Michiko , Iijima Koichi M. 
Published: December 2022

AbstractBackgroundInnate immunity is dysregulated in aging and neurodegenerative diseases, and Toll‐like receptors (TLRs) play a central role in innate immune response. Nine Toll family receptors (Toll‐1 to Toll‐9) exist in Drosophila, and Toll‐9 is structurally most closely related to mammalian TLRs such as TLR1, 2, 6, 10. However, physiological roles of Toll‐9 in innate immunity and neurodegeneration are largely unknown. In this study, we examined roles of Toll‐9 in fly brains under neurodegenerative conditions.MethodWe systematically investigated potential roles of Toll‐9 in the maintenance of the brain integrity under neurodegenerative conditions, using Drosophila models of acute axon injury and human tau‐mediated neurodegeneration.ResultExpression level of Toll‐9 was very low in brains under normal condition but was dramatically increased upon acute nerve injury, suggesting a potential role of Toll‐9 in neurodegeneration. Innate immune response including induction of antimicrobial peptides and glial phagocytic activity of degenerating neurons were activated by nerve injury in fly brains, though Toll‐9 knockout did not affect these responses. Interestingly, however, Toll‐9 knockout significantly impaired activation of stress signaling cascades including c‐Jun N‐terminal kinase pathway. To ask whether Toll‐9 modify severity of neurodegeneration, we employed a fly model of tauopathy and found that Toll‐9 knockdown significantly exacerbated axon degeneration accompanied by pathological tau phosphorylation.ConclusionThese results demonstrate that Drosophila Toll‐9 confers neuroprotective effects through activation of stress kinase signaling independent of induction of innate immune genes, which may provide insights into the pathogenesis of neurodegenerative diseases.
Neuropathology of a patient with AD treated with low doses of verubecestat
Authors: Lleó Alberto 
Published: December 2022

AbstractBackgroundBACE‐1 inhibition in humans is limited by the existence of cognitive adverse effects. Understanding the specific effects of these compounds on brain histopathology is key to refining this drug target.Methodsneuropathological examination of a patient with Alzheimer’s disease (AD) treated for 38 months with low doses of the BACE‐1 inhibitor verubecestat.Resultsbrain examination showed small plaque size, reduced dystrophic neurites around plaques and reduced synaptic‐associated Aβ compared with a group of age‐matched untreated AD cases.Conclusionalthough the overall findings were mild, our findinds suggest that BACE‐1 inhibition has an impact on synaptic soluble Aβ accumulation. We will discuss the implications for future trials.
β‐secretase inhibition prevents structural spine plasticity deficits in AppNL‐G‐F mice
Authors: Herms Jochen 
Published: December 2022

AbstractBackgroundBACE1‐inhibitor trials for the treatment of Alzheimer´s Disease (AD) have failed due to insufficient efficacy or side effects like cognitive worsening. However, the scientific evidence to date suggests that BACE1‐inhibition could be an effective preventative measure if applied early enough and in the correct dose. Preclinical studies have associated strong BACE1‐inhibition with decreased dendritic spine density in the cerebral cortex of wildtype mice (GFP‐M) only.MethodWe investigated dose‐dependent effects of BACE1‐inhibition on hippocampal dendritic spine dynamics in the APP knock‐in mouse line for the first time. We conducted in vivo two‐photon microscopy in the stratum oriens of hippocampal CA1 neurons in 3.5‐month‐old AppNL‐G‐FGFP‐M mice over 6 weeks to monitor the effect of Bace1 inhibition (NB‐360) in low and high doses on dendritic spine plasticity.ResultsStructural spine plasticity is already impaired in CA1 neurons in untreated AppNL‐G‐F mice of this early age. Interestingly, prolonged high‐dose but not low‐dose BACE1‐inhibition was found to enhance spine formation and did not cause spine loss as observed in wildtype control mice.ConclusionIn an early stage of amyloid pathology in a transgenic beta‐amyloid mouse model, BACE1‐inhibition successfully holds the progressive changes in dendritic spine plasticity in hippocampal CA1 neurons.
The Alzheimer's Association Appropriate Use Recommendations for Blood Biomarkers in Alzheimer’s Disease
Authors: Hansson Oskar , Edelmayer Rebecca M. , Boxer Adam L. , Carrillo Maria C. , Mielke Michelle M , Rabinovici Gil D. , Salloway Stephen P. , Sperling Reisa A. , Zetterberg Henrik , Teunissen Charlotte E. 
Published: December 2022

AbstractBackgroundBlood‐based markers (BBMs) have recently showed promise to revolutionize the diagnostic and prognostic work‐up of Alzheimer's disease (AD), as well as to improve the design of interventional trials.MethodHere we discuss in detail further research needed to be performed before widespread use of BBMs.ResultWe already now recommend use of BBMs as (pre‐)screeners to identify individuals likely to have AD pathological changes for inclusion in trials evaluating disease‐modifying therapies, provided the AD status is confirmed with positron emission tomography (PET) or cerebrospinal fluid (CSF) testing. We also encourage studying longitudinal BBM changes in ongoing as well as future interventional trials. However, BBMs should not yet be used as primary endpoints in pivotal trials. Further, we recommend to cautiously start using BBMs in specialized memory clinics as part of the diagnostic work‐up of patients with cognitive symptoms and the results should be confirmed whenever possible with CSF or PET. Additional data are needed before use of BBMs as stand‐alone diagnostic AD markers, or before considering use in primary care.ConclusionWe recommend use of AD‐associated BBMs as (pre‐)screeners in trials and cautious introduction of BBMs in clinical practice, provided AD status in confirmed whenever possible using CSF or PET. We summarize prioritized research needed to be performed before widespread use of AD‐associated BBMs in clinical trials and practice, including different types of preanalytical, analytical and real‐world clinical studies.
Esterification of tripalmitin using calcined scallop shell as a heterogeneous basic catalyst
Authors: Maruyama Hideo , Seki Hideshi 
Published: December 2022

AbstractCalcined waste scallop shell (Patinopecten yessoensis) was used as a basic heterogeneous solid catalyst for the transesterification of tripalmitin as a model triglyceride for assuming biodiesel production. The scallop shell was pulverized and calcined at 900 and 1000°C for 4 h. Calcined reagent calcium carbonate was also used as a control catalyst. The transesterification experiments were carried out at 30°C with varying catalyst dosage and calcination conditions. In the most experimental condition, the yield reached ~90% within 8–10 h. The overall reaction rate constant, k, was determined by simple first‐order reaction kinetics. The calcined catalyst was characterized using SEM, EDS, and XRD analysis. The number of basic active sites on the surface was determined by titration with benzoic acid. A linear relationship between k and the number of the basic active sites was obtained. The time course of the concentration of the products could be estimated using this relationship.
Mediation of the Same Epigenetic and Transcriptional Effect by Independent Osteoarthritis Risk–Conferring Alleles on a Shared Target Gene, COLGALT2
Authors: Kehayova Yulia S. , Wilkinson J. Mark , Rice Sarah J. , Loughlin John 
Published: December 2022

ObjectiveOver 100 DNA variants have been associated with osteoarthritis (OA), including rs1046934, located within a linkage disequilibrium block encompassing part of COLGALT2 and TSEN15. The present study was undertaken to determine the target gene(s) and the mechanism of action of the OA locus using human fetal cartilage, cartilage from OA and femoral neck fracture arthroplasty patients, and a chondrocyte cell model.MethodsGenotyping and methylation array data of DNA from human OA cartilage samples (n = 87) were used to determine whether the rs1046934 genotype is associated with differential DNA methylation at proximal CpGs. Results were replicated in DNA from human arthroplasty (n = 132) and fetal (n = 77) cartilage samples using pyrosequencing. Allelic expression imbalance (AEI) measured the effects of genotype on COLGALT2 and TSEN15 expression. Reporter gene assays and epigenetic editing determined the functional role of regions harboring differentially methylated CpGs. In silico analyses complemented these experiments.ResultsThree differentially methylated CpGs residing within regulatory regions were detected in the human OA cartilage array data, and 2 of these were replicated in human arthroplasty and fetal cartilage. AEI was detected for COLGALT2 and TSEN15, with associations between expression and methylation for COLGALT2. Reporter gene assays confirmed that the CpGs are in chondrocyte enhancers, with epigenetic editing results directly linking methylation with COLGALT2 expression.ConclusionCOLGALT2 is a target of this OA locus. We previously characterized another OA locus, marked by rs11583641, that independently targets COLGALT2. The genotype of rs1046934, like rs11583641, mediates its effect by modulating expression of COLGALT2 via methylation changes to CpGs located in enhancers. Although the single‐nucleotide polymorphisms, CpGs, and enhancers are distinct between the 2 independent OA risk loci, their effect on COLGALT2 is the same. COLGALT2 is the target of independent OA risk loci sharing a common mechanism of action.
From Battery Manufacturing to Smart Grids: Towards a Metaverse for the Energy Sciences
Authors: Franco Alejandro A. , Loup‐Escande Emilie , Loiseaux Goran , Chotard Jean‐Noël , Zapata‐Dominguez Diana , Ciger Jan , Leclere Aubin , Denisart Lucie , Lelong Romain 
Published: December 2022

AbstractInvited for this month's cover picture is the work from Prof. Alejandro A. Franco's group at the Université de Picardie Jules Verne. The front cover shows three screenshots of the reported virtual reality digital twin of a battery manufacturing pilot line, designed as an educative game to engage students and the general public on battery sciences. Read the full text of the Concept at 10.1002/batt.202200369.
Ten‐year outcomes of whole‐pelvic intensity‐modulated radiation therapy for prostate cancer with regional lymph node metastasis
Authors: Nakamura Kiyonao , Norihisa Yoshiki , Ikeda Itaru , Inokuchi Haruo , Aizawa Rihito , Kamoto Toshiyuki , Kamba Tomomi , Inoue Takahiro , Yamasaki Toshinari , Akamatsu Shusuke , Kobayashi Takashi , Ogawa Osamu , Mizowaki Takashi 
Published: December 2022

AbstractBackgroundManagement of pelvic node‐positive prostate cancer has been challenging and controversial. We conducted a study to evaluate the outcomes of whole‐pelvic (WP) simultaneous integrated boost (SIB) intensity‐modulated radiation therapy (IMRT) combined with androgen deprivation therapy (ADT).MethodsA total of 67 consecutive patients with cT1c‐4N1M0 prostate cancer were definitively treated by WP SIB‐IMRT. Neoadjuvant ADT (median: 8.3 months) was administered in all cases. WP SIB‐IMRT was designed to simultaneously deliver 78, 66.3, and 58.5 Gy in 39 fractions to the prostate plus seminal vesicles, metastatic lymph nodes (LNs), and the pelvic LN region, respectively. Adjuvant ADT (median: 24.7 months) was administered in 66 patients.ResultsThe median follow‐up period was 81.6 months (range: 30.5–160.7). Biochemical relapse‐free, overall, and prostate cancer‐specific survival rates at 10 years were 59.8%, 79.6%, and 86.3%, respectively. Loco‐regional recurrence was not observed. Being in International Society of Urological Pathology grade group 5 and having a posttreatment detectable nadir prostate‐specific antigen (PSA) level (≥0.010 ng/ml) were significantly associated with worse prostate cancer‐specific survival and progression of castration resistance. The 10‐year cumulative incidence rates of grade 2 and 3 late toxicities were, respectively, 1.5% and 0% for genitourinary, 0% and 1.5% for gastrointestinal events. No grade 4 acute or late toxicities were observed.ConclusionsWP SIB‐IMRT can be safely administered to patients with pelvic node‐positive prostate cancer. Since grade group 5 and detectable nadir PSA levels are risks for castration resistance, we may need to increase the intensity of treatment for such cases.