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Abstract Accurate diagnosis and monitoring of neurodegenerative diseases require reliable biomarkers. Cerebrospinal fluid (CSF) proteins are promising candidates for reflecting brain pathology; however, their diagnostic utility may be compromised by natural variability between individuals, weakening their association with disease. Here, we measured the levels of 69 pre-selected proteins in cerebrospinal fluid using antibody-based suspension bead array technology in a multi-disease cohort of 499 individuals with neurodegenerative disorders including Alzheimer’s disease (AD), behavioral variant frontotemporal dementia, primary progressive aphasias, amyotrophic lateral sclerosis (ALS), corticobasal syndrome, primary supranuclear palsy, along with healthy controls. We identify significant inter-individual variability in overall CSF levels of brain-derived proteins, which could not be attributed to specific disease associations. Using linear modelling, we show that adjusting for median CSF levels of brain-derived proteins increases the diagnostic accuracy of proteins previously identified as altered in CSF in the context of neurodegenerative disorders. We further demonstrate a simplified approach for the adjustment using pairs of correlated proteins with opposite alteration in the diseases. With this approach, the proteins adjust for each other and further increase the biomarker performance through additive effect. When comparing the diseases, two proteins—neurofilament medium and myelin basic protein—showed increased levels in ALS compared to other diseases, and neurogranin showed a specific increase in AD. Several other proteins showed similar trends across the studied diseases, indicating that these proteins likely reflect shared processes related to neurodegeneration. Overall, our findings suggest that accounting for inter-individual variability is crucial in future studies to improve the identification and performance of relevant biomarkers. Importantly, we highlight the need for multi-disease studies to identify disease-specific biomarkers.

Abstract Primary lateral sclerosis (PLS) is a motor neuron disease (MND) which mainly affects upper motor neurons. Within the MND spectrum, PLS is much more slowly progressive than amyotrophic laterals sclerosis (ALS). `Classical` ALS is characterized by catabolism and abnormal energy metabolism preceding onset of motor symptoms, and previous studies indicated that the disease progression of ALS involves hypothalamic atrophy. Very limited weight loss is observed in patients with PLS, which raises the question of whether there are also less hypothalamic alterations. The purpose of this study was to quantitatively investigate the hypothalamic volume in a group of PLS patients and to compare it with ALS and controls. Recently, we have introduced automatic hypothalamic quantification method based on the use of convolutional neural network (CNN) to reduce human variability and enhance analysis robustness. This CNN of U-Net architecture was applied for automatic segmentation of the hypothalamus and intracranial volume (ICV) to allow adjustments of the hypothalamic volume between subjects with different head sizes respectively. Automatic segmentation and volumetric analysis were performed in high resolution T1 weighted MRI volumes (acquired on a 1.5 T MRI scanner) of 46 PLS patients in comparison to 107 healthy controls and 411 `classical` ALS patients, respectively. Significant hypothalamic volume reduction was observed in PLS (818 ± 73 mm3) when compared to controls (852 ± 77 mm3); significant hypothalamic volume reduction was also confirmed in ALS (823 ± 84 mm3), in support of previous studies. No significant differences were found in normalized hypothalamic volumes between ALS patients and PLS patients at the group level. This unbiased CNN-based hypothalamus volume quantification study demonstrated similarly reduced hypothalamus volume in PLS and ALS patients, despite the clinical phenotypic differences.

Abstract Previously, a synchrotron‐based horizontal proton beamline (87.2 MeV) was successfully commissioned to deliver radiation doses in FLASH and conventional dose rate modes to small fields and volumes. In this study, we developed a strategy to increase the effective radiation field size using a custom robotic motion platform to automatically shift the positions of biological samples. The beam was first broadened with a thin tungsten scatterer and shaped by customized brass collimators for irradiating cell/organoid cultures in 96‐well plates (a 7‐mm‐diameter circle) or for irradiating mice (1‐cm2 square). Motion patterns of the robotic platform were written in G‐code, with 9‐mm spot spacing used for the 96‐well plates and 10.6‐mm spacing for the mice. The accuracy of target positioning was verified with a self‐leveling laser system. The dose delivered in the experimental conditions was validated with EBT‐XD film attached to the 96‐well plate or the back of the mouse. Our film‐measured dose profiles matched Monte Carlo calculations well (1D gamma pass rate >95% with the criteria of 2%/1 mm/2% dose threshold). The FLASH dose rates were 113.7 Gy/s for cell/organoid irradiation and 191.3 Gy/s for mouse irradiation. These promising results indicate that this robotic platform can be used to effectively increase the field size for preclinical experiments with proton FLASH.

The chemistry of hypervalent iodine (HVI) reagents has gathered increased attention towards the synthesis of a wide range of chemical structures. HVI reagents are characterized by their diverse reactivity as oxidants and electrophilic reagents. In addition, they are inexpensive, non-toxic and considered to be environmentally friendly. An important application of HVI reagents is the synthesis of halogenated cyclic compounds, in particular, the intramolecular HVI-mediated halocyclisation of alkenes using carbon, oxygen, nitrogen or sulfur nucleophiles. Herein, we describe the examples reported in the literature, which are organised by the different halogens involved and the internal nucleophiles.

Abstract Understanding abiotic carbon fixation provides insights into early Earth’s carbon cycles and life’s emergence in terrestrial hot springs, where iron sulfide (FeS), similar to cofactors in metabolic enzymes, may catalyze prebiotic synthesis. However, the role of FeS-mediated carbon fixation in such conditions remains underexplored. Here, we investigate the catalytic behaviors of FeS (pure and doped with Ti, Ni, Mn, and Co), which are capable of H2-driven CO2 reduction to methanol under simulated hot spring vapor-zone conditions, using an anaerobic flow chamber connected to a gas chromatograph. Specifically, Mn-doped FeS increases methanol production five-fold at 120 °C, with UV−visible light (300–720 nm) and UV-enhanced light (200–600 nm) further increasing this activity. Operando and theoretical investigations indicate the mechanism involves a reverse water-gas shift with CO as an intermediate. These findings highlight the potential of FeS-catalyzed carbon fixation in early Earth’s terrestrial hot springs, effective with or without UV light.

Abstract Background Past research has highlighted that bipolar I disorder is associated with significant changes in brain structure and function. Notably, the manifestation and progression of bipolar I disorder have been known to differ between males and females. However, the relationship between sex-related differences and bipolar I disorder diagnosis affecting these changes was not fully understood. This study aimed to investigate the sex-by-diagnosis interactions concerning the structural and functional features of the brain in individuals with bipolar I disorder. Methods Both structural and functional MRI data were obtained from 105 individuals with bipolar I disorder (36 males and 69 females) and 210 healthy controls (72 males and 138 females). Voxel-wise analyses of gray matter volume and functional connectivity were conducted using a general linear regression model. This model included age, sex, diagnosis, and a sex-by-diagnosis interaction as predictors to explore potential sex-related differences in the brain features of participants with bipolar I disorder. Results The gray matter volume analysis revealed significant sex-by-diagnosis interactions in six brain regions: the left caudate (p

The Visayan Spotted Deer (VSD), or Rusa alfredi, is an endangered and endemic species in the Philippines. Despite its status, genomic information on R. alfredi, and the genus Rusa in general, is missing. This study presents the first draft genome assembly of the VSD using the Illumina short-read sequencing technology. The resulting RusAlf_1.1 assembly has a 2.52 Gb total length, with a contig N50 of 46 Kb and scaffold N50 size of 75 Mb. The assembly has a BUSCO complete score of 95.5%, demonstrating the genome’s completeness, and includes the annotation of 24,531 genes. Our phylogenetic analysis based on single-copy orthologs revealed a close evolutionary relationship between R. alfredi and the genus Cervus. RusAlf_1.1 represents a significant advancement in our understanding of the VSD. It opens opportunities for further research in population genetics and evolutionary biology, potentially contributing to more effective conservation and management strategies for this endangered species.

Albert C. Hergenroeder, MD, Professor of Pediatrics, Chief, Adolescent Medicine and Sports Medicine, Baylor College of Medicine The paper is based on the author’s opening address for the 25th annual Chronic Illness and Disability: Transition from Pediatric to Adult-based care conference at Baylor College of Medicine/Texas Children’s Hospital conference delivered October 10, 2024

Wire-based Directed Energy Deposition (DED) is a widely-used manufacturing method due to its high productivity and large part fabrication capability. Meanwhile, Friction Stir Processing (FSP) is a solid-state joining process that can modify microstructure and weld lightweight alloys. Additionally, wire-based DED printed parts need machining process to achieve the desired dimensional accuracy. To take advantage of all these three processes, this work proposes an integrated hybrid system by combining the wire-arc DED, FSP, and milling processes into a standalone system which can fabricate superior materials in a multi-track, multi-layer manner for the first time. The integrated system can improve dimensional accuracy and productivity by processing the workpiece without the need to move it between different systems. It is demonstrated that a 150 × 40 × 21 mm3 block of aluminum alloy AA5183 can be fabricated using the hybrid wire-DED/FSP/milling process from wire feedstock. Material characterization shows that the hybrid process is able to refine the grain size by two orders of magnitude to sub-micron scale, while eliminating all the pores and microcracks produced by the DED process. These enhancements result in significantly improved mechanical properties including Young's modulus (15 %), yield strength (161 %), ultimate strength (33 %), and hardness (55 %) without compromising ductility.

PD-1 checkpoint inhibition has revolutionized the care of cancer. A small portion of patients with stage IV cancer achieve durable control. But, early progression is common and dramatic control is achieved for only a minority. We hypothesized that ilixadencel, an allogeneic monocyte-derived dendritic cell product could be injected into tumor to potentiate PD-1 response and thus conducted a phase I study of pembrolizumab plus ilixadencel. Twenty-one patients were accrued. The most common treatment emergent adverse events were fatigue, injection site pain, anemia, weight decreased and hyponatremia, mostly grade 1-2. No dose limiting toxicities were observed and the recommended phase II dose was established at 10 million cells administered twice. Two unconfirmed responses were observed, with no confirmed responses.

We hypothesized that pre-consult patient education videos can improve patient understanding about their diagnosis, lead to high satisfaction and low distress. In this pilot study, we developed a patient education video curriculum for patients with newly-diagnosed anal cancer. Comprehension of key content was evaluated by comparing pre- and post-test scores. Patient satisfaction scores were collected. Patient distress scores (0–10) were collected at the beginning of their consult visit prior to seeing the physician. We found that patient education videos prior to consult improved patient understanding, resulted in high patient satisfaction, and low patient distress at the time of consult.

Purpose: There currently are no established formal mentorship and training programs for radiation oncology (RO) trainees to learn trial design, creation, writing, or implementation. There only exists informal training on analyzing clinical trials in RO residency programs. The integration of a longitudinal formal training and mentorship program for clinical trialists—consisting of clinical trial education, design, mentorship, and implementation during the RO residency education—will give residents not only formal teaching in the subject but also strong tools and requisite mentorship in hopes to help them succeed as future academic physicians and leaders in the field of RO. Methods and Materials: We developed a clinical trial training pathway in 2018 at MD Anderson Cancer Center, proposing it as a pilot program. The “Fletcher-Cox Pathway” was accepted with a highly positive response by trainees and is now offered as a standard option to RO trainees at our institution. Results: With the guidance of their principal investigator, residents participating in this pathway design and submit a clinical trial for institutional review board review. In 2019, after implementation of the pilot program, 4 of the incoming 7 residents joined the pathway. The program continues, and the current cohort of trainees have received training in clinical trial design and worked with dedicated mentor(s) regarding clinical trial ideas; their studies are currently accruing patients. Conclusions: This pilot program has been viewed by trainees and mentors as successful; it highlights how a structured approach meets a clear need within RO training. We envision the creation of a national platform to increase access, whereby programs adopt this clinical trialist educational pathway, which ultimately leads to the development of a robust clinical trial community with communal resources. We hope that this not only improves and provides educational initiatives to all trainees but also initiates further collaboration.

Recent clinical outcomes of multi-regimen chemotherapy in patients with cholangiocarcinoma (CCC) have shown benefits in terms of overall survival. However, repeated endoscopic biliary drainage (EBD) and serious adverse events negatively affect prolongation of the survival period. The aim of this study was to investigate the prevalence of massive hemobilia and the outcomes of its management with fully covered self-expandable metal stents (FC-SEMSs) in patients with hilum-involving CCC receiving multi-regimen chemotherapy. The methods and effects of FC-SEMS placement were retrospectively investigated following the occurrence of massive hemobilia during EBD. A total of 356 patients with CCC received multi-regimen chemotherapy. Among them, 181 patients had hilar invasion, and seven patients (3.9%) developed massive hemobilia during repeated EBD using removable stents. In all cases, the tumor encased the right hepatic artery. In six patients (85.7%), hemostasis was immediately and completely achieved by inserting one or two FC-SEMSs proximal to the hilar invasion area. Therefore, if the tumor encases the right hepatic artery, massive hemobilia is likely to occur during multi-regimen chemotherapy. Thus, prompt placement of a FC-SEMS would be an effective treatment option for massive hemobilia in patients with hilum-involving CCC.

The United States Veterans Affairs (VA) Health Care System has a strong history of conducting impactful oncology randomized clinical trials (RCTs). We developed a phase II/III RCT to test the use of metastasis-directed therapy in Veterans with oligometastatic prostate cancer (OMPC)—the first VA RCT in OMPC that leverages novel imaging and advanced radiotherapy techniques. To accomplish this, we developed a clinical trial network to conduct the study. In this manuscript, we describe several challenges we encountered in study development/conduct and our strategies to address them, with the goal of helping investigators establish robust study networks to conduct clinical trials. In the study start-up, we encountered challenges in timely site activation, and leveraged project management to maximize efficiency. Additionally, there were several changes in the clinical paradigms in imaging and treatment that led to protocol amendments to ensure maximum equipoise, recruitment, and impact of the study. Specifically, we amended the trial to add de novo OMPC patients (from initially only recurrent OMPC) and expanded the study to allow up to 10 metastases (from initially five). Finally, in order to maintain local study team engagement, we developed initiatives to maximize collaboration and add value to the overall clinical program through study participation.

Abstract We quantified and determined for the first time the distribution pattern of the neuropeptide NPFF in the human cerebral cortex and subjacent white matter. To do so, we studied n = 9 cases without neurological disorders and n = 22 cases with neurodegenerative diseases, including sporadic amyotrophic lateral sclerosis (ALS, n = 8), Alzheimer’s disease (AD, n = 8), Pick’s disease (PiD, n = 3), and schizophrenia (n = 3). NPFF-immunopositive cells were located chiefly, but not exclusively, in the superficial white matter and constituted there a subpopulation of white matter interstitial cells (WMIC): Pyramidal-like and multipolar somata predominated in the gyral crowns, whereas bipolar and ovoid somata predominated in the cortex surrounding the sulci. Their sparsely ramified axons were unmyelinated and exhibited NPFF-positive bead-like varicosities. We found significantly fewer NPFF-immunopositive cells in the gray matter of the frontal, cingulate, and superior temporal gyri of both sporadic ALS and late-stage AD patients than in controls, and significantly fewer NPFF-positive cells in the subjacent as well as deep white matter of the frontal gyrus of these patients compared to controls. Notably, the number of NPFF-positive cells was also significantly lower in the hippocampal formation in AD compared to controls. In PiD, NPFF-positive cells were present in significantly lower numbers in the gray and white matter of the cingulate and frontal gyrii in comparison to controls. In schizophrenic patients, lower wNPFF cell counts in the neocortex were significant and global (cingulate, frontal, superior temporal gyrus, medial, and inferior gyri). The precise functions of NPFF-positive cells and their relationship to the superficial corticocortical white matter U-fibers are currently unknown. Here, NPFF immunohistochemistry and expression characterize a previously unrecognized population of cells in the human brain, thereby providing a new entry-point for investigating their physiological and pathophysiological roles.

Background The applicability of quantitative flow ratio (QFR), a nonhyperemic, invasive coronary angiography‐derived computation of fractional flow reserve (FFR), has not been studied in coronary artery bypass grafts. We sought to explore the correlation and diagnostic agreement between QFR and FFR in saphenous vein grafts (SVGs). Methods and Results A total of 129 prospectively included patients (mean age 73±8 years, 84% male) with prior coronary artery bypass grafting underwent invasive coronary angiography and pressure‐derived functional assessment in 150 nonoccluded SVGs. QFR dedicated angiography images of the SVGs were acquired and used for offline QFR computation. The diagnostic performance of QFR was compared with 2‐dimensional quantitative coronary angiography, using FFR as a reference. A threshold of ≤0.80 was used to define functional significance. QFR was successfully computed in 140 (93%) SVGs. We found a significant correlation between QFR and FFR (r=0.72, P

Amyotrophic lateral sclerosis (ALS) is a fatal, adult-onset disease marked by a progressive degeneration of motor neurons (MNs) present in the spinal cord, brain stem and motor cortex. Death in most patients usually occurs within 2–4 years after symptoms onset. Despite promising progress in delineating underlying mechanisms, such as disturbed proteostasis, DNA/RNA metabolism, splicing or proper nucleocytoplasmic shuttling, there are no effective therapies for the vast majority of cases. A reason for this might be the disease heterogeneity and lack of substantial clinical and molecular biomarkers. The identification and validation of such pathophysiology driven biomarkers could be useful for early diagnosis and treatment stratification. Recent advances in next generation RNA-sequencing approaches have provided important insights to identify key changes of non-coding RNAs (ncRNAs) implicated with ALS disease. Especially, microRNAs (miRNAs) have emerged as key post-transcriptional regulators of gene expression to target several genes/pathways by degrading messenger RNAs (mRNAs) or repressing levels of gene expression. In this study, we expand our previous work to identify top-regulated differentially expressed (DE)-miRNAs by combining different normalizations to search for important and generalisable pathomechanistic dysregulations in ALS as putative novel biomarkers of the disease. For this we performed a consensus pipeline of existing datasets to investigate the transcriptomic profile (mRNAs and miRNAs) of MN cell lines from iPSC-derived SOD1- and TARDBP (TDP-43 protein)-mutant-ALS patients and healthy controls to identify potential signatures and their related pathways associated with neurodegeneration. Transcriptional profiling of miRNA–mRNA interactions from MN cell lines in ALS patients revealed differential expression of genes showed greater vulnerability to KEAP1-NRF2 stress response pathway, sharing a common molecular denominator linked to both disease conditions. We also reported that mutations in above genes led to significant upregulation of the top candidate miR-10b-5p, which we could validate in immortalized lymphoblast cell lines (LCLs) derived from sporadic and familial ALS patients and postmortem tissues of familial ALS patients. Collectively, our findings suggest that miRNA analysis simultaneously performed in various human biological samples may reveal shared miRNA profiles potentially useful as a biomarker of the disease.

Abstract Cellular sensitivity to ferroptosis is primarily regulated by mechanisms mediating lipid hydroperoxide detoxification. We show that inositol-requiring enzyme 1 (IRE1α), an endoplasmic reticulum (ER) resident protein critical for the unfolded protein response (UPR), also determines cellular sensitivity to ferroptosis. Cancer and normal cells depleted of IRE1α gain resistance to ferroptosis, while enhanced IRE1α expression promotes sensitivity to ferroptosis. Mechanistically, IRE1α’s endoribonuclease activity cleaves and down-regulates the mRNA of key glutathione biosynthesis regulators glutamate-cysteine ligase catalytic subunit (GCLC) and solute carrier family 7 member 11 (SLC7A11). This activity of IRE1α is independent of its role in regulating the UPR and is evolutionarily conserved. Genetic deficiency and pharmacological inhibition of IRE1α have similar effects in inhibiting ferroptosis and reducing renal ischemia–reperfusion injury in mice. Our findings reveal a previously unidentified role of IRE1α to regulate ferroptosis and suggests inhibition of IRE1α as a promising therapeutic strategy to mitigate ferroptosis-associated pathological conditions.

Abstract Objective Monosynaptically cortically innervated α‐motoneurons are early and strongly involved in amyotrophic lateral sclerosis (ALS). Consequently, the muscles that receive the strongest direct corticomotoneuronal input are the clinically most affected. To objectify this concept in vivo through morphological image correlates, whole‐body magnetic resonance imaging (MRI) with muscle signal analysis was performed in patients with ALS compared to healthy controls. Methods Modified Dixon‐based whole‐body MRI was acquired in patients with ALS (n = 33) and matched healthy controls (n = 30). Manual labeling of limb muscle MRI was performed, and a specific subset of nine muscles, selected as pairs of muscle groups with different corticomotoneuronal input, was analyzed per subject based on their volume, fat fraction, and functional remaining muscle area (fRMA). Results Statistical analysis of 978 muscles in total revealed significantly decreased volumes, decreased fRMA, and increased fat fraction in the muscles of patients with ALS compared to controls. The clinical degree of pareses of directly innervated muscles was significantly worse than that of less directly innervated muscles in each comparison. The muscles receiving stronger direct corticomotoneuronal input showed more pronounced morphological involvement compared to those with less monosynaptic corticomotoneuronal input (fRMA, significant in three pairwise comparisons). Interpretation In conclusion, whole‐body MRI‐based muscle analysis provided additional evidence for a characteristic pattern of pareses in ALS. This technical approach (parameterization and quantification of muscle alterations from MRI) to patients with ALS could pave the way for the future establishment of a diagnostic algorithm of muscle MRI for ALS and may serve as a biomarker.

Abstract Background Alzheimer’s disease is characterized by large-scale structural changes in a specific pattern. Recent studies developed morphological similarity networks constructed by brain regions similar in structural features to represent brain structural organization. However, few studies have used local morphological properties to explore inter-regional structural similarity in Alzheimer’s disease. Methods Here, we sourced T1-weighted MRI images of 342 cognitively normal participants and 276 individuals with Alzheimer’s disease from the Alzheimer's Disease Neuroimaging Initiative database. The relationships of grey matter intensity between adjacent voxels were defined and converted to the structural pattern indices. We conducted the information-based similarity method to evaluate the structural similarity of structural pattern organization between brain regions. Besides, we examined the structural randomness on brain regions. Finally, the relationship between the structural randomness and cognitive performance of individuals with Alzheimer’s disease was assessed by stepwise regression. Results Compared to cognitively normal participants, individuals with Alzheimer’s disease showed significant structural pattern changes in the bilateral posterior cingulate gyrus, hippocampus, and olfactory cortex. Additionally, individuals with Alzheimer’s disease showed that the bilateral insula had decreased inter-regional structural similarity with frontal regions, while the bilateral hippocampus had increased inter-regional structural similarity with temporal and subcortical regions. For the structural randomness, we found significant decreases in the temporal and subcortical areas and significant increases in the occipital and frontal regions. The regression analysis showed that the structural randomness of five brain regions was correlated with the Mini-Mental State Examination scores of individuals with Alzheimer’s disease. Conclusions Our study suggested that individuals with Alzheimer’s disease alter micro-structural patterns and morphological similarity with the insula and hippocampus. Structural randomness of individuals with Alzheimer’s disease changed in temporal, frontal, and occipital brain regions. Morphological similarity and randomness provide valuable insight into brain structural organization in Alzheimer’s disease.

Progressive supranuclear palsy (PSP) is an atypical Parkinsonian syndrome characterized initially by falls and eye movement impairment. This multimodal imaging study aimed at eliciting structural and functional disease-specific brain alterations. T1-weighted and resting-state functional MRI were applied in multi-centric cohorts of PSP and matched healthy controls. Midbrain, cerebellum, and cerebellar peduncles showed severely low gray/white matter volume, whereas thinner cortical gray matter was observed in cingulate cortex, medial and temporal gyri, and insula. Eigenvector centrality analyses revealed regionally specific alterations. Multivariate pattern recognition classified patients correctly based on gray and white matter segmentations with up to 98 % accuracy. Highest accuracies were obtained when restricting feature selection to the midbrain. Eigenvector centrality indices yielded an accuracy around 70 % in this comparison; however, this result did not reach significance. In sum, the study reveals multimodal, widespread brain changes in addition to the well-known midbrain atrophy in PSP. Alterations in brain structure seem to be superior to eigenvector centrality parameters, in particular for prediction with machine learning approaches.

ABSTRACT Bakground It is important to understand the outcomes of adult acute lymphoblastic leukemia (ALL) patients at different facilities as treatment paradigms change. Aims Our primary objective was to determine adult ALL overall survival (OS) by facility volume and type. Secondary objectives included identifying sociodemographic factors that may have impacted outcomes and analyzing treatment patterns by facility volume and type. Methods This was a retrospective analysis of the National Cancer Database (NCDB) that included patients ≥40 years diagnosed with ALL between 2004 and 2016. Results A total of 14 593 patients were included in this study. Univariate OS was greatest at low volume (LV) and community programs (CPs) and the least at high volume (HV) and academic programs (AP). This difference was lost after multivariable Cox proportional hazards model analysis, which found no difference in survival by facility volume or type, however, survival was significantly influenced by age, race, Hispanic ethnicity, insurance, and residence location (p

Background: This prospective study investigates the pattern of pareses in 5q-associated spinal muscular atrophy (SMA) to identify disease-specific characteristics and potential differences from amyotrophic lateral sclerosis (ALS) and spinobulbar muscular atrophy (SBMA). Detailed knowledge about pareses patterns in SMA facilitates differential diagnosis and supports therapeutic monitoring. Methods: Between January 2021, and June 2021, 66 SMA patients (59.1% male, aged 33.6 ± 15.2 years) were included in the study. Most patients had SMA type II ( n = 28) or SMA type III ( n = 28), seven patients had SMA type I, and three patients had SMA type IV. We analyzed the pattern of pareses using the UK Medical Research Council (MRC) scoring system. Results: In both, upper and lower limbs muscle weakness was less pronounced in distal (upper limbs: MRC median 3.0 (interquartile range 1.5–3.5); lower limbs: 1.5 (0.5–3.0)) compared to proximal muscle groups (upper limbs: 2.0 (1.5–2.6); p

Purpose: Recruiting prospective physicians to radiation oncology can be challenging, because of limited familiarity with the field. The Assistant Clinical Research Coordinator (ACRC) program can help provide trainees early exposure to radiation oncology. Methods and Materials: The ACRC program involves hiring a college graduate to provide administrative and research support for faculty members. The program was developed with our institution's clinical trials office, which provided guidance on regulatory compliance and training. A structured selection process identifies top candidates, and a rigorous onboarding process ensures smooth transitions between ACRCs. We report characteristics and outcomes of ACRC employees and surveyed them to assess their program experience using a Likert scale. Results: From 2005 to 2023, the ACRC program paired 73 ACRCs with faculty. Most faculty (68%) are currently supported by ACRCs. In 2023, 113 applications were received for 4 positions. ACRCs have contributed to research publications (293 as coauthors and 43 as first authors) and taken on leadership roles in the department. Most program alumni have attended medical school (34 of 64 program graduates; 53%). Eight have chosen to specialize in radiation oncology (13%; 2 applying into radiation oncology, 1 in residency, and 5 attendings). Of the 25% of alumni who responded to our survey, 77% responded that the mentorship provided by the ACRC program was very or extremely effective in guiding their academic development. All respondents rated the research opportunities as good or excellent, and 77% rated the clinical experience opportunities as good or excellent. Most (77%) reported that the ACRC program had substantial or significant influence on their choice of career path. Conclusions: The ACRC program provides an opportunity to address recruitment challenges in radiation oncology by offering early exposure to the field, clinical research skills, and mentorship. With the strong interest in our job posting this year, there is potential to expand this program to other institutions.

The repeated melting and solidification cycles in the laser powder bed fusion (L-PBF) process lead to significant thermal gradients, resulting in notable distortion in the as-built part. Distortion compensation methods, which pre-deform the part design so the as-built shape aligns with the target, have been widely adopted to mitigate this issue. This research introduces a data-driven distortion compensation framework for the L-PBF process. It employs an experimentally-calibrated inherent strain method to generate a dataset and utilizes Gaussian process regression to create the compensated geometry. Experimental validation shows that the proposed method can reduce the maximum distortion by up to 82.5% for a lattice structure and 77.8% for a canonical part. Furthermore, the compensation results reveal that (1) the lumped layer thickness in finite element models has little impact on simulated distortion reduction but can notably affect the experimental reduction; (2) discrepancies between simulated and experimental compensation performance are largely attributed to the curvy surfaces with sharp transitions in trial and compensated shapes, a result of pre-deforming the design; (3) the number of trial geometries considerably affects the effectiveness of compensation, while the number of deformation states does not have a statistically significant impact.

Abstract Introduction With locally advanced pancreatic cancer (LAPC), uncontrolled local tumor growth frequently leads to mortality. Advancements in radiotherapy (RT) techniques have enabled conformal delivery of escalated‐dose RT (EDR), which may have potential local control and overall survival (OS) benefits based on retrospective and early prospective studies. With evidence for EDR emerging, we characterized the adoption of EDR across the United States and its associated outcomes. Methods We searched the National Cancer Database for nonsurgically managed LAPC patients diagnosed between 2004 and 2019. Pancreas‐directed RT with biologically effective doses (BED10) ≥39 and ≤70 Gy was labeled conventional‐dose RT (CDR), and BED10 >70 and ≤132 Gy was labeled EDR. We identified associations of EDR and OS using logistic and Cox regressions, respectively. Results Among the definitive therapy subset (n = 54,115) of the entire study cohort (n = 91,493), the most common treatments were chemotherapy alone (69%), chemotherapy and radiation (29%), and RT alone (2%). For the radiation therapy subset (n = 16,978), use of pancreas‐directed RT remained between 13% and 17% over the study period (ptrend > 0.999). Using multivariable logistic regression, treatment at an academic/research facility (adjusted odds ratio [aOR] 1.46, p

Abstract Objective Progression prediction is a significant unmet need in people with progressive multiple sclerosis (pwPMS). Studies on glial fibrillary acidic protein (GFAP) have either been limited to single center with relapsing MS or were based solely on Expanded Disability Status Scale (EDSS), which limits its generalizability to state‐of‐the‐art clinical settings and trials applying combined outcome parameters. Methods Serum GFAP and NfL (neurofilament light chain) were investigated in EmBioProMS participants with primary (PP) or secondary progressive MS. Six months confirmed disability progression (CDP) was defined using combined outcome parameters (EDSS, timed‐25‐foot walk test (T25FW), and nine‐hole‐peg‐test (9HPT)). Results 243 subjects (135 PPMS, 108 SPMS, age 55.5, IQR [49.7–61.2], 135 female, median follow‐up: 29.3 months [17.9–40.9]) were included. NfL (age‐) and GFAP (age‐ and sex‐) adjusted Z scores were higher in pwPMS compared to HC (p 3 was associated with higher risk for CDP in participants with low NfL Z score (i.e., ≤1.0) (HR: 2.38 [1.12–5.08], p = 0.025). In PPMS, GFAP Z score >3 was associated with higher risk for CDP (HR: 2.88 [1.21–6.84], p = 0.016). Risk was further increased in PPMS subjects with high GFAP when NfL is low (HR: 4.31 [1.53–12.13], p = 0.006). Interpretation Blood GFAP may help identify pwPPMS at risk of progression. Combination of high GFAP and low NfL levels could distinguish non‐active pwPMS with particularly high progression risk.

Abstract Background Autosomal dominant polycystic kidney disease (ADPKD) leads to progressive renal cyst formation and loss of kidney function in most patients. Vasopressin 2 receptor antagonists (V2RA) like tolvaptan are currently the only available renoprotective agents for rapidly progressive ADPKD. However, aquaretic side effects substantially limit their tolerability and therapeutic potential. In a preliminary clinical study, the addition of hydrochlorothiazide (HCT) to tolvaptan decreased 24-h urinary volume and appeared to increase renoprotective efficacy. The HYDRO-PROTECT study will investigate the long-term effect of co-treatment with HCT on tolvaptan efficacy (rate of kidney function decline) and tolerability (aquaresis and quality of life) in patients with ADPKD. Methods The HYDRO-PROTECT study is an investigator-initiated, multicenter, double-blind, placebo-controlled, randomized clinical trial. The study is powered to enroll 300 rapidly progressive patients with ADPKD aged ≥ 18 years, with an eGFR of > 25 mL/min/1.73 m2, and on stable treatment with the highest tolerated dose of tolvaptan in routine clinical care. Patients will be randomly assigned (1:1) to daily oral HCT 25 mg or matching placebo treatment for 156 weeks, in addition to standard care. Outcomes The primary study outcome is the rate of kidney function decline (expressed as eGFR slope, in mL/min/1.73 m2 per year) in HCT versus placebo-treated patients, calculated by linear mixed model analysis using all available creatinine values from week 12 until the end of treatment. Secondary outcomes include changes in quality-of-life questionnaire scores (TIPS, ADPKD-UIS, EQ-5D-5L, SF-12) and changes in 24-h urine volume. Conclusion The HYDRO-PROTECT study will demonstrate whether co-treatment with HCT can improve the renoprotective efficacy and tolerability of tolvaptan in patients with ADPKD.

The Surface Water and Ocean Topography (SWOT) satellite and AirSWOT airborne instrument are the first imaging radar-altimeters designed with near-nadir and low incidence, 35.75 GHz Ka-band InSAR for mapping terrestrial water storage variability. Remotely sensed surface water extents are crucial for assessing such variability but are confounded by emergent and inundated vegetation along shorelines. However, because SWOT-like measurements are novel, there remains some uncertainty in the ability to detect certain land and water classes. This study examines the likelihood of misclassification between 15 land cover types and develops the Ka-band Phenomenology Scattering (KaPS) model to simulate changes to Ka-band backscatter as a result of changing surface water fraction and surface structure, including vegetation morphology and water surface waves. Using a separability metric, the study finds that water is five times more distinct compared with dry land classes, but has the potential to be confused with littoral zone and wet soil cover types. The KaPS scattering model simulates AirSWOT backscatter for incidence angles 1–27°, identifying the conditions under which open water is likely to be confused with littoral zone and wet soil cover types. KaPS characterization of the sensitivity of near-nadir and low incidence Ka-band SAR to small changes in both wet area fraction and surface structure enables a more nuanced classification of inundation area. These results provide additional confidence in the ability of SWOT to classify water inundation extent and open the door for novel hydrological and ecological applications of future Ka-band SAR missions.

Abstract Post-acute sequelae of SARS-CoV-2 (PASC) is a significant public health concern. We describe Patient Reported Outcomes (PROs) on 590 participants prospectively assessed from hospital admission for COVID-19 through one year after discharge. Modeling identified 4 PRO clusters based on reported deficits (minimal, physical, mental/cognitive, and multidomain), supporting heterogenous clinical presentations in PASC, with sub-phenotypes associated with female sex and distinctive comorbidities. During the acute phase of disease, a higher respiratory SARS-CoV-2 viral burden and lower Receptor Binding Domain and Spike antibody titers were associated with both the physical predominant and the multidomain deficit clusters. A lower frequency of circulating B lymphocytes by mass cytometry (CyTOF) was observed in the multidomain deficit cluster. Circulating fibroblast growth factor 21 (FGF21) was significantly elevated in the mental/cognitive predominant and the multidomain clusters. Future efforts to link PASC to acute anti-viral host responses may help to better target treatment and prevention of PASC.

Abstract Electric fields have been highlighted as a smart reagent in nature’s enzymatic machinery, as they can directly trigger or accelerate chemical processes with stereo- and regio-specificity. In enzymatic catalysis, controlled mass transport of chemical species is also key in facilitating the availability of reactants in the active reaction site. However, recent progress in developing a clean catalysis that profits from oriented electric fields is limited to theoretical and experimental studies at the single molecule level, where both the control over mass transport and scalability cannot be tested. Here, we quantify the electrostatic catalysis of a prototypical Huisgen cycloaddition in a large-area electrode surface and directly compare its performance to the conventional Cu(I) catalysis. Our custom-built microfluidic cell enhances reagent transport towards the electrified reactive interface. This continuous-flow microfluidic electrostatic reactor is an example of an electric-field driven platform where clean large-scale electrostatic catalytic processes can be efficiently implemented and regulated.

Abstract The hypothalamus is a small structure of the brain with an essential role in metabolic homeostasis, sleep regulation, and body temperature control. Some neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and dementia syndromes are reported to be related to hypothalamic volume alterations. Despite its crucial role in human body regulation, neuroimaging studies of this structure are rather scarce due to work-intensive operator-dependent manual delineations from MRI and lack of automated segmentation tools. In this study we present a fully automatic approach based on deep convolutional neural networks (CNN) for hypothalamic segmentation and volume quantification. We applied CNN of U-Net architecture with EfficientNetB0 backbone to allow for accurate automatic hypothalamic segmentation in seconds on a GPU. We further applied our approach for the quantification of the normalized hypothalamic volumes to a large neuroimaging dataset of 432 ALS patients and 112 healthy controls (without the ground truth labels). Using the automated volumetric analysis, we could reproduce hypothalamic atrophy findings associated with ALS by detecting significant volume differences between ALS patients and controls at the group level. In conclusion, a fast and unbiased AI-assisted hypothalamic quantification method is introduced in this study (whose acceptance rate based on the outlier removal strategy was estimated to be above 95%) and made publicly available for researchers interested in the conduction of hypothalamus studies at a large scale.

Abstract Persistence represents a crucial trait in learning. A lack of persistence prevents learners from fully mastering their current skills and makes it difficult for them to acquire new skills. It further hinders the administration of effective interventions by learning systems. Although most studies have focused on identifying non-persistence and unproductive persistence behaviors, few have attempted to model students’ persistence propensity in learning. In the present study, we evaluated students’ persistence propensity in formative assessments by using an item response theory model with their attempt data. In addition, we modeled their wheel-spinning propensity. The students (N = 115) of first-level mathematics classes at a high school in Japan underwent the aforementioned formative assessments; their log data were collected. Persistence propensity was found to be correlated with frequency-related statistics, and wheel-spinning propensity was correlated with correctness-related statistics. However, persistence and wheel-spinning propensities were not correlated. A comparison of the students’ scores with various persistence and wheel-spinning propensities revealed that both traits considerably influenced their academic performance. The present study provides insights into the use of attempt data to evaluate various characteristics crucial for learning, which are otherwise difficult to evaluate.

Abstract The Patient Preference Survey aims to understand unmet needs related to riluzole management in people with Amyotrophic Lateral Sclerosis (ALS) and to identify which characteristics of a new formulation could better match their preferences. The survey involved 117 people with ALS (PALS) treated with riluzole in four European countries. The dysphagic PALS were least satisfied with the riluzole tablet and oral suspension and with ease in self-administration; up to 68% of respondents postponed or missed the treatment due to swallowing difficulties and need of caregiver assistance. Overall, 51% of tablet and 53% of oral suspension users regularly crushed or mixed riluzole with beverages, respectively; PALS who always manipulated riluzole showed low satisfaction with the formulation and considered the risk of choking and pneumonia the most worrisome event. The survey evaluated the driving factors in choosing/switching the therapy: 67% of PALS declared a low risk of choking. The research finally evaluated which attributes of a new formulation would be preferred: the most relevant were ease of use (4.3/5), convenient/portable packaging (4.0/5) and oral-dissolving properties without tongue motility (3.9/5). The Patient Preference Survey suggests that patients have several unmet needs and preferences that could be addressed by a different formulation, e.g. using oral film technologies.

Computer tomography (CT) scans’ capabilities in detecting lesions have been increasing remarkably in the past decades. In this paper, we propose a multi-organ lesion detection (MOLD) approach to better address real-life chest-related clinical needs. MOLD is a challenging task, especially within a large, high resolution image volume, due to various types of background information interference and large differences in lesion sizes. Furthermore, the appearance similarity between lesions and other normal tissues demands more discriminative features. In order to overcome these challenges, we introduce depth-aware (DA) and skipped-layer hierarchical training (SHT) mechanisms with the novel Dense 3D context enhanced (Dense 3DCE) lesion detection model. The novel Dense 3DCE framework considers the shallow, medium, and deep-level features together comprehensively. In addition, equipped with our SHT scheme, the backpropagation process can now be supervised under precise control, while the DA scheme can effectively incorporate depth domain knowledge into the scheme. Extensive experiments have been carried out on a publicly available, widely used DeepLesion dataset, and the results prove the effectiveness of our DA-SHT Dense 3DCE network in the MOLD task.

Abstract Wire-arc directed energy deposition (DED) processed Inconel (IN) 718 is known to have coarse columnar grains, strong texture, and significant chemical and microstructural inhomogeneity in the as-fabricated condition. Homogenization treatment is commonly used prior to aging to eliminate the inhomogeneity and detrimental precipitation for better mechanical properties. In this study, however, direct aging (DA) at 700 °C without homogenization has resulted in room-temperature yield strength, ultimate tensile strength (UTS), and elongation that are comparable to wrought condition and among the highest reported properties for wire-arc DED IN718. The DA samples at between 650 and 750 °C aging also demonstrates remarkable ductility when deformed at elevated temperatures. In addition, when aged below 750 °C the DA IN718 possesses significantly higher UTS compared to those with homogenization treatment. These superior mechanical properties are highly likely due to the non-uniform and hierarchical precipitation consisting of disk-shaped γ″ in diameter from a few to tens of nm in the dendritic core area and micron-sized Laves phase and carbides in the inter-dendritic region.

Abstract Kidney function as part of metabolic changes could be associated with amyotrophic lateral-sclerosis (ALS). We investigated the associations between estimated chronic kidney disease (CKD), based on the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) cystatin C equation, and the risk at onset and prognostic value of CKD for ALS. Between October 2010 and June 2014, 362 ALS cases (59.4% men, mean age 65.7 years) and 681 controls (59.5% men, means age 66.3 years) were included in a population-based case–control study based on the ALS registry Swabia in Southern Germany. All ALS cases were followed-up (median 89.7 months), 317 died. Serum samples were measured for cystatin C to estimate the glomerular filtration rate (eGFR) according to the CKD-EPI equation. Information on covariates were assessed by an interview-based standardized questionnaire. Conditional logistic regression models were applied to calculate odds ratios (OR) for risk of ALS associated with eGFR/CKD stages. Time-to-death associated with renal parameters at baseline was assessed in ALS cases only. ALS cases were characterized by lower body mass index, slightly lower smoking prevalence, more intense occupational work and lower education than controls. Median serum cystatin-C based eGFR concentrations were lower in ALS cases than in controls (54.0 vs. 59.5 mL/min pro 1.73 m2). The prevalence of CKD stage ≥ 3 was slightly higher in ALS cases than in controls (14.1 vs. 11.0%). In the adjusted models, CKD stage 2 (OR 1.82, 95% CI 1.32, 2.52) and stage 3 (OR 2.34, 95% CI 1.38, 3.96) were associated with increased ALS risk. In this cohort of ALS cases, eGFR and CKD stage ≥ 3 (HR 0.94; 95% CI 0.64, 1.38) were not associated with prognosis. In this case–control study, higher CKD stages were associated with increased ALS risk, while in the prospective cohort of ALS cases, no indication of an association of CysC-based CKD on mortality was seen. In addition, our work strengthens the importance to evaluate renal function using a marker independent of muscle mass in ALS patients.

Abstract Aims Impaired myocardial energy homeostasis plays an import role in the pathophysiology of heart failure with preserved ejection fraction (HFpEF). Left ventricular relaxation has a high energy demand, and left ventricular diastolic dysfunction has been related to impaired energy homeostasis. This study investigated whether trimetazidine, a fatty acid oxidation inhibitor, could improve myocardial energy homeostasis and consequently improve exercise haemodynamics in patients with HFpEF. Methods and results The DoPING‐HFpEF trial was a phase II single‐centre, double‐blind, placebo‐controlled, randomized cross‐over trial. Patients were randomized to trimetazidine treatment or placebo for 3 months and switched after a 2‐week wash‐out period. The primary endpoint was change in pulmonary capillary wedge pressure, measured with right heart catheterization at multiple stages of bicycling exercise. Secondary endpoint was change in myocardial phosphocreatine/adenosine triphosphate, an index of the myocardial energy status, measured with phosphorus‐31 magnetic resonance spectroscopy. The study included 25 patients (10/15 males/females; mean (standard deviation) age, 66 (10) years; body mass index, 29.8 (4.5) kg/m2); with the diagnosis of HFpEF confirmed with (exercise) right heart catheterization either before or during the trial. There was no effect of trimetazidine on the primary outcome pulmonary capillary wedge pressure at multiple levels of exercise (mean change 0 [95% confidence interval, 95% CI −2, 2] mmHg over multiple levels of exercise, P = 0.60). Myocardial phosphocreatine/adenosine triphosphate in the trimetazidine arm was similar to placebo (1.08 [0.76, 1.76] vs. 1.30 [0.95, 1.86], P = 0.08). There was no change by trimetazidine compared with placebo in the exploratory parameters: 6‐min walking distance (mean change of −6 [95% CI −18, 7] m vs. −5 [95% CI −22, 22] m, respectively, P = 0.93), N‐terminal pro‐B‐type natriuretic peptide (5 (−156, 166) ng/L vs. −13 (−172, 147) ng/L, P = 0.70), overall quality‐of‐life (KCCQ and EQ‐5D‐5L, P = 0.78 and P = 0.51, respectively), parameters for diastolic function measured with echocardiography and cardiac magnetic resonance, or metabolic parameters. Conclusions Trimetazidine did not improve myocardial energy homeostasis and did not improve exercise haemodynamics in patients with HFpEF.

To improve students’ learning performance through review learning activities, we developed a personalized intervention tutoring approach that leverages learning analysis based on artificial intelligence. The proposed intervention first uses text-processing artificial intelligence technologies, namely bidirectional encoder representations from transformers and generative pretrained transformer-2, to automatically generate Python programming remedial materials; subsequently, learning performance prediction models constructed using various machine learning methods are used to determine students’ learning type, enabling the automatic generation of personalized remedial materials. The participants in this study were 78 students from a university in northern Taiwan enrolled in an 8-week Python course. Students in the experimental (n = 36) and control (n = 42) groups engaged in the same programming learning activities during the first 5 weeks of the course, and they completed a pretest of programming knowledge in Week 6. For the review activity in Week 7, the 36 students in the experimental group received personalized intervention, whereas those in the control group received traditional class tutoring. We examined the effect of the self-regulated learning and personalized intervention on the learning performance of students. Compared with the traditional class tutoring, the personalized intervention review activity not only helped students obtain higher learning performance but also prompted greater improvements in the following learning strategies: rehearsal, critical thinking, metacognitive self-regulation, effort regulation, and peer learning. We also observed that students’ rehearsal and help-seeking learning strategies indirectly affected learning performance through students’ note-taking in the provided e-book.

Abstract Nanoscale electro-mechanical systems (NEMS) displaying piezoresistance offer unique measurement opportunities at the sub-cellular level, in detectors and sensors, and in emerging generations of integrated electronic devices. Here, we show a single-molecule NEMS piezoresistor that operates utilising constitutional and conformational isomerisation of individual diaryl-bullvalene molecules and can be switched at 850 Hz. Observations are made using scanning tunnelling microscopy break junction (STMBJ) techniques to characterise piezoresistance, combined with blinking (current-time) experiments that follow single-molecule reactions in real time. A kinetic Monte Carlo methodology (KMC) is developed to simulate isomerisation on the experimental timescale, parameterised using density-functional theory (DFT) combined with non-equilibrium Green’s function (NEGF) calculations. Results indicate that piezoresistance is controlled by both constitutional and conformational isomerisation, occurring at rates that are either fast (equilibrium) or slow (non-equilibrium) compared to the experimental timescale. Two different types of STMBJ traces are observed, one typical of traditional experiments that are interpreted in terms of intramolecular isomerisation occurring on stable tipped-shaped metal-contact junctions, and another attributed to arise from junction‒interface restructuring induced by bullvalene isomerisation.

Abstract Background Phelan-McDermid syndrome (PMS) is a rare multisystem disease with global developmental delay and autistic features. Genetically, the disease is based on a heterozygous deletion of chromosome 22q13.3 with involvement of at least part of the SHANK3 gene or heterozygous pathogenic variants in SHANK3. Pathophysiologically, this syndrome has been regarded as a synaptopathy, but current data suggest an additional concept, since axonal functions of neurons are also impaired, thus, the specific pathophysiological processes in this disease are not yet fully understood. Since symptoms of the autism spectrum, regression, and stagnation in development occur, we investigated whether neuroinflammatory and neurodegenerative processes may also play a role. To this end, we analysed biomarkers in cerebrospinal fluid (CSF) and parameters from magnetic resonance imaging with high-resolution structural T1w volumetry and diffusion tensor imaging analysis in 19 Phelan-McDermid syndrome patients. Results CSF showed no inflammation but abnormalities in tau protein and amyloid-ß concentrations, however, with no typical biomarker pattern as in Alzheimer’s disease. It could be demonstrated that these CSF changes were correlated with integrity losses of the fibres in the corticospinal tract as well as in the splenium and dorsal part of the cingulum. High CSF levels of tau protein were associated with loss of integrity of fibres in the corticospinal tract; lower levels of amyloid-ß were associated with decreasing integrity of fibre tracts of the splenium and posterior cingulate gyrus. Volumetric investigations showed global atrophy of the white matter, but not the grey matter, and particularly not in temporal or mesiotemporal regions, as is typical in later stages of Alzheimer’s disease. Conclusions In summary, alterations of neurodegenerative CSF markers in PMS individuals could be demonstrated which were correlated with structural connectivity losses of the corticospinal tract, the splenium, and the dorsal part of the cingulum, which can also be associated with typical clinical symptoms in these patients. These findings might represent a state of dysfunctional processes with ongoing degenerative and regenerative processes or a kind of accelerated aging. This study should foster further clinical diagnostics like tau- and amyloid-PET imaging as well as novel scientific approaches especially in basic research for further mechanistic proof.

Summary: Background: Evidence for the efficacy of nusinersen in adults with 5q-associated spinal muscular atrophy (SMA) has been demonstrated up to a period of 16 months in relatively large cohorts but whereas patients reach a plateau over time is still to be demonstrated. We investigated the efficacy and safety of nusinersen in adults with SMA over 38 months, the longest time period to date in a large cohort of patients from multiple clinical sites. Methods: Our prospective, observational study included adult patients with SMA from Germany, Switzerland, and Austria (July 2017 to May 2022). All participants had genetically-confirmed, 5q-associated SMA and were treated with nusinersen according to the label. The total Hammersmith Functional Motor Scale Expanded (HFMSE) and Revised Upper Limb Module (RULM) scores, and 6-min walk test (6 MWT; metres), were recorded at baseline and 14, 26, and 38 months after treatment initiation, and pre and post values were compared. Adverse events were also recorded. Findings: Overall, 389 patients were screened for eligibility and 237 were included. There were significant increases in all outcome measures compared with baseline, including mean HFMSE scores at 14 months (mean difference 1.72 [95% CI 1.19–2.25]), 26 months (1.20 [95% CI 0.48–1.91]), and 38 months (1.52 [95% CI 0.74–2.30]); mean RULM scores at 14 months (mean difference 0.75 [95% CI 0.43–1.07]), 26 months (mean difference 0.65 [95% CI 0.27–1.03]), and 38 months (mean difference 0.72 [95% CI 0.25–1.18]), and 6 MWT at 14 months (mean difference 30.86 m [95% CI 18.34–43.38]), 26 months (mean difference 29.26 m [95% CI 14.87–43.65]), and 38 months (mean difference 32.20 m [95% CI 10.32–54.09]). No new safety signals were identified. Interpretation: Our prospective, observational, long-term (38 months) data provides further real-world evidence for the continuous efficacy and safety of nusinersen in a large proportion of adult patients with SMA. Funding: Financial support for the registry from Biogen, Novartis and Roche.

In this study, we investigated the microstructural variation of Ti-6Al-4 V in inverted pyramid parts built using Laser Powder Bed Fusion (LPBF). Two parts were fabricated with and without ghost parts to study the effects of interlayer delay time on thermal history and microstructure. Finite Element Method (FEM) based process simulation was used to predict the thermal history and cooling rates during the LPBF process to understand the location-specific microstructure and mechanical properties variation. The thermal analysis findings revealed that the variations in the cooling rates and pre-deposition temperature were notably significant. Within the same part, the cooling rates exhibited significant variations, differing by up to three orders of magnitude in two scenarios: (1) within the same layer, influenced by the proximity to the edges, and (2) at different heights, attributable to the strongly varying cross-section. Comparing the two parts, the cooling rates of the part with ghost parts were approximately two orders of magnitude higher than in the part without the ghost parts. This significant difference can be attributed to the extended interlayer cooling time and lower pre-deposition temperature resulting from the presence of two ghost parts which introduced an effective delay time between laser scans. Experimental validation against microstructure images and hardness measurements showed similar trends with the predicted results. These findings provide valuable insights into controlling microstructure at specific locations during LPBF fabrication, which is essential for building complex geometries with controlled material properties.

Introduction: Functional brain networks (FBNs) coordinate brain functions and are studied in fMRI using blood-oxygen-level-dependent (BOLD) signal correlations. Previous research links FBN changes to aging and cognitive decline, but various physiological factors influnce BOLD signals. Few studies have investigated the intrinsic components of the BOLD signal in different timescales using signal decomposition. This study aimed to explore differences between intrinsic FBNs and traditional BOLD-FBN, examining their associations with age and cognitive performance in a healthy cohort without dementia. Materials and methods: A total of 396 healthy participants without dementia (men = 157; women = 239; age range = 20–85 years) were enrolled in this study. The BOLD signal was decomposed into several intrinsic signals with different timescales using ensemble empirical mode decomposition, and FBNs were constructed based on both the BOLD and intrinsic signals. Subsequently, network features—global efficiency and local efficiency values—were estimated to determine their relationship with age and cognitive performance. Results: The findings revealed that the global efficiency of traditional BOLD-FBN correlated significantly with age, with specific intrinsic FBNs contributing to these correlations. Moreover, local efficiency analysis demonstrated that intrinsic FBNs were more meaningful than traditional BOLD-FBN in identifying brain regions related to age and cognitive performance. Conclusions: These results underscore the importance of exploring timescales of BOLD signals when constructing FBN and highlight the relevance of specific intrinsic FBNs to aging and cognitive performance. Consequently, this decomposition-based FBN-building approach may offer valuable insights for future fMRI studies.

BackgroundAmyotrophic lateral sclerosis (ALS) is a fatal disorder, which imposes a severe emotional burden on patients. Appropriate coping mechanisms may alleviate this burden and facilitate wellbeing, with social support known to be a successful coping strategy. This observational study aimed to determine the interplay of general coping traits of hope for success and fear of failure, coping behavior of social activity, and patients' wellbeing.MethodsIn this cross-sectional study, patients with ALS from a clinical-epidemiological registry in Southwestern Germany were interviewed regarding coping traits (achievement-motivated behavior: hope for success and fear of failure), coping behavior of social activity, and psychosocial adjustment, determined using measures of depressiveness, anxiety [both measured by Hospital Anxiety and Depression Scale (HADS)], and quality of life [Anamnestic Comparative Self-Assessment (ACSA)]. Demographics, clinical [ALS Functional Rating Scale revised version (ALSFRS-R)], and survival data were recorded.ResultsA total of 868 patients [60.70% male patients, mean age: 64.70 (±10.83) years, mean ALSFRS-R: 37.36 ± 7.07] were interviewed. Anxiety in patients was found to be associated with a high fear of failure. In contrast, a generally positive attitude in patients exemplified in high hopes for success was associated with better wellbeing. Finally, coping behavior of social activity explained up to 65% of the variance of depressiveness among the patients with ALS.ConclusionIn this study, we present evidence that the wellbeing of patients with ALS is not an immediate fatalistic consequence of physical degradation but rather determined by coping traits and behavior, which may be trained to substantially increase the wellbeing of patients with ALS.

Background: Paraneoplastic ischemic stroke has a poor prognosis. We have recently reported an algorithm based on the number of ischemic territories, C-reactive protein (CRP), lactate dehydrogenase (LDH), and granulocytosis to predict the underlying active cancer in a case-control setting. However, co-occurrence of cancer and stroke might also be merely incidental. Objective: To detect cancer-associated ischemic stroke in a large, unselected cohort of consecutive stroke patients by detailed analysis of ischemic stroke associated with specific cancer subtypes and comparison to patients with bacterial endocarditis. Methods: Retrospective single-center cohort study of consecutive 1612 ischemic strokes with magnetic resonance imaging, CRP, LDH, and relative granulocytosis data was performed, including identification of active cancers, history of now inactive cancers, and the diagnosis of endocarditis. The previously developed algorithm to detect paraneoplastic cancer was applied. Tumor types associated with paraneoplastic stroke were used to optimize the diagnostic algorithm. Results: Ischemic strokes associated with active cancer, but also endocarditis, were associated with more ischemic territories as well as higher CRP and LDH levels. Our previous algorithm identified active cancer-associated strokes with a specificity of 83% and sensitivity of 52%. Ischemic strokes associated with lung, pancreatic, and colorectal (LPC) cancers but not with breast and prostate cancers showed more frequent and prominent characteristics of paraneoplastic stroke. A multiple logistic regression model optimized to identify LPC cancers detected active cancer with a sensitivity of 77.8% and specificity of 81.4%. The positive predictive value (PPV) for all active cancers was 13.1%. Conclusion: Standard clinical examinations can be employed to identify suspect paraneoplastic stroke with an adequate sensitivity, specificity, and PPV when it is considered that the association of ischemic stroke with breast and prostate cancers in the stroke-prone elderly population might be largely incidental.

Abstract INTRODUCTION This study aimed to assess whether social relationships in mid‐life reduce the risk of dementia related to amyloid burden. METHODS Participants in the Atherosclerosis Risk in Communities (ARIC) study were assessed for social support and isolation (visit 2; 1990–1992). A composite measure, “social relationships,” was generated. Brain amyloid was evaluated with florbetapir positron emission tomography (PET); (visit 5; 2012–2014). Incident dementia cases were identified following visit 5 through 2019 using ongoing surveillance. Relative contributions of mid‐life social relationships and elevated brain amyloid to incident dementia were evaluated with Cox regression models. RESULTS Among 310 participants without dementia, strong mid‐life social relationships were associated independently with lower dementia risk. Elevated late‐life brain amyloid was associated with greater dementia risk. DISCUSSION Although mid‐life social relationships did not moderate the relationship between amyloid burden and dementia, these findings affirm the importance of strong social relationships as a potentially protective factor against dementia.