Rapid Decline Research Articles

Abstract PO-003: Peripheral blood and tumor tissue biomarkers associated with epcoritamab response in patients with relapsed or refractory diffuse large B-cell lymphoma: Data from the dose-expansion cohort of the phase 1/2 EPCORE NHL-1 trial (NCT03625037)

Abstract Introduction: Epcoritamab, a CD3xCD20 bispecific antibody, demonstrated deep and durable clinical responses in patients (pts) with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). We evaluated the correlation of peripheral blood (PB) and tumor tissue biomarkers with clinical response to epcoritamab. Methods: Pts received priming (0.16 mg), intermediate (0.8 mg) and full epcoritamab doses (48 mg). Absolute lymphocyte count (ALC) was analyzed locally. Blood immunophenotyping was assessed by flow cytometry, plasma cytokines by MSD assay, and %CD20+ in tumors by immunohistochemistry (n=117). Gene expression in baseline tumor biopsies was evaluated using HTG EdgeSeq (n=70). Microenvironment scores were estimated from gene expression as a sum of immune (B/T, NK, dendritic, and myeloid cells) and stromal scores (adipocytes, fibroblasts, and endothelial cells). Best overall response as of April 21, 2023 was assessed by independent review committee using Lugano criteria. P values were based on Wilcoxon rank-sum test. Results: In PB at baseline, significantly higher ALC (P=0.031), CD4+ (P=0.0038), and CD8+ (P=0.043) T-cell levels were observed in responders (R) vs nonresponders (NR). Similarly, CD4+ (P=0.02) and CD8+ (P=0.03) signatures and immune and microenvironment scores were higher in baseline tumor tissue in R vs NR. In PB CD8+ T cells, NR showed higher %PD1+ (P=0.016), %TIM3+ (P=0.048), and %TIM3+TIGIT+ (P=0.045). High tumor %CD20+ (≥90%) was observed in most pts (n=97/117); lower %CD20+ (<50%) was observed only in 6 NRs and 1 R. Epcoritamab treatment caused a rapid decline in circulating B cells irrespective of clinical response. Transient reductions in PB CD4+ and CD8+ T cells (ie, margination) were observed within 24 hours (H) after each dose during cycle (C) 1 and were more pronounced in R vs NR. Magnitude of margination for CD8+ T cells after the priming and intermediate doses was significantly lower in NR (reduced by median 22 & 41%) vs R (57 & 70%), while the difference in CD4+ T cells was not as pronounced in NR vs R, resulting in a substantially lower CD4+/CD8+ ratio in NR vs R. In C1, epcoritamab led to an increase of PB CD4+ and CD8+ T cells expressing activation/proliferation markers, with significantly higher fold change from baseline in R vs NR, especially within 24H post-priming dose. Early cytokine peaks of IFNy and IL-10 were more pronounced 6–24H post-priming dose and 6–14H post-first full dose in complete R vs pts with progressive disease. Epcoritamab also appeared to modulate NK cell numbers (under further investigation). Conclusions: In pts with R/R DLBCL, T-cell abundance and increased margination, activation, proliferation, and modulation of cytokines differed in R vs NR. These findings are consistent with epcoritamab’s mechanism of action and demonstrate the dependency on proper T-cell engagement for clinical benefit. Our findings also revealed differences in the dynamics of CD4+ and CD8+ T-cell margination in R vs NR, warranting further investigation. Previously submitted in part to EHA 2024. Citation Format: Monica Wielgos-Bonvallet, Jimin Zhang, Han Si, Kubra Karagoz, Melih Acar, Yasmin Karimi, Herve Ghesquieres, Michael Roost Clausen, Iş?l Alt?ntaş, Binhuan Wang, Wissam Assaily, Matthew Loya, Gregg Masters, Anantharaman Muthuswamy, Brandon Higgs, Mariana Sacchi, Tahi Ahmadi, Mark Fereshteh, Edith Szafer-Glusman, David Soong, Maria Jure-Kunkel, Andrew J Steele. Peripheral blood and tumor tissue biomarkers associated with epcoritamab response in patients with relapsed or refractory diffuse large B-cell lymphoma: Data from the dose-expansion cohort of the phase 1/2 EPCORE NHL-1 trial (NCT03625037) [abstract]. In: Proceedings of the Fourth AACR International Meeting on Advances in Malignant Lymphoma: Maximizing the Basic-Translational Interface for Clinical Application; 2024 Jun 19-22; Philadelphia, PA. Philadelphia (PA): AACR; Blood Cancer Discov 2024;5(3_Suppl):Abstract nr PO-003.

The Relationship Between Perioperative Blood Product Use and the Incidence of Postoperative Renal Injury in Infants Undergoing Cardiac Surgery

Cardiac Surgery Associated Acute Kidney Injury (CS-AKI) is a serious complication that occurs in patients following cardiac surgery. It is characterized by the rapid decline in kidney function, leading to potential long-term kidney damage or even kidney failure. CS-AKI is a significant health concern, as it not only prolongs hospital stays and recovery time but also increases the risk of mortality. This study, conducted as a prospective observational study, aimed to investigate the relationship between perioperative blood product use and the incidence of postoperative acute kidney injury (AKI) in infants and young children undergoing cardiac surgery. It examined the perioperative use of these blood products and its association with the occurrence of AKI. The findings of this study revealed a significant association between the use of red blood cell suspension and platelets and the development of postoperative AKI. This suggests that the administration of these blood products during cardiac surgery may increase the risk of kidney injury in infants and young children. However, it is important to note that the study did not find a statistically significant association between plasma transfusion volume and the incidence of AKI. This suggests that while the use of certain blood products may contribute to the risk of AKI, the volume of plasma transfused does not seem to have a significant impact. The findings of this study provide valuable insights into the perioperative management of infants and young children undergoing cardiac surgery. It underscores the importance of carefully considering the use of blood products during surgery and taking necessary measures to minimize the risk of AKI.

Consequences of a 2-Deoxyglucose Exposure on the ATP Content and the Cytosolic Glucose Metabolism of Cultured Primary Rat Astrocytes

The glucose analogue 2-deoxyglucose (2DG) has frequently been used as a tool to study cellular glucose uptake and to inhibit glycolysis. Exposure of primary cultured astrocytes to 2DG caused a time- and concentration-dependent cellular accumulation of 2-deoxyglucose-6-phosphate (2DG6P) that was accompanied by a rapid initial decline in cellular ATP content. Inhibitors of mitochondrial respiration as well as inhibitors of mitochondrial uptake of pyruvate and activated fatty acids accelerated the ATP loss, demonstrating that mitochondrial ATP regeneration contributes to the partial maintenance of the ATP content in 2DG-treated astrocytes. After a 30 min exposure to 10 mM 2DG the specific content of cellular 2DG6P had accumulated to around 150 nmol/mg, while cellular ATP was lowered by 50% to around 16 nmol/mg. Following such a 2DG6P-loading of astrocytes, glycolytic lactate production from applied glucose was severely impaired during the initial 60 min of incubation, but was reestablished during longer incubation concomitant with a loss in cellular 2DG6P content. In contrast to glycolysis, the glucose-dependent NADPH regeneration via the pentose phosphate pathway (PPP) was only weakly affected in 2DG6P-loaded astrocytes and in cells that were coincubated with glucose in the presence of an excess of 2DG. Additionally, in the presence of 2DG PPP-dependent WST1 reduction was found to have doubled compared to hexose-free control incubations, indicating that cellular 2DG6P can serve as substrate for NADPH regeneration by the astrocytic PPP. The data presented provide new insights on the metabolic consequences of a 2DG exposure on the energy and glucose metabolism of astrocytes and demonstrate the reversibility of the inhibitory potential of a 2DG-treatment on the glucose metabolism of cultured astrocytes.

Door-to-Needle Time for Extracorporeal Cardiopulmonary Resuscitation and Neurological Outcomes in Out-of-Hospital Cardiac Arrest: A Nationwide Study.

Extracorporeal cardiopulmonary resuscitation (ECPR) is an option for refractory cardiac arrest, and immediate initiation after indication is recommended. However, the practical goals of ECPR preparation (such as the door-to-needle time) remain unclear. This study aimed to elucidate the association between the door-to-needle time and neurological outcomes of out-of-hospital cardiac arrest. This is a post hoc analysis of a nationwide multicenter study on out-of-hospital cardiac arrest treated with ECPR at 36 institutions between 2013 and 2018 (SAVE-J [Study of Advanced Cardiac Life Support for Ventricular Fibrillation with Extracorporeal Circulation in Japan] II study). Adult patients without hypothermia (≥32 °C) in whom circulation was not returned at ECPR initiation were included. The probability of favorable neurological function at 30 days (defined as Cerebral Performance Category ≤2) was estimated using a generalized estimating equations model, in which institutional, patient, and treatment characteristics were adjusted. Estimated probabilities were then calculated according to the door-to-needle time with 3-minute increments, and a clinical threshold was assumed. Among 1298 patients eligible for this study, 136 (10.6%) had favorable neurological function. The estimated probability of favorable outcomes was highest in patients with 1 to 3 minutes of door-to-needle time (12.9% [11.4%-14.3%]) and remained at 9% to 10% until 27 to 30 minutes. Then, the probability dropped gradually with each 3-minute delay. A 30-minute threshold was assumed, and shorter door-to-extracorporeal membrane oxygenation/low-flow time and fewer adverse events related to cannulation were observed in patients with door-to-needle time <30 minutes. The probability of favorable functions after out-of-hospital cardiac arrest decreased as the door-to-needle time for ECPR was prolonged, with a rapid decline after 27 to 30 minutes. URL: https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000041577; Unique identifier: UMIN000036490.

Steady-state relative permeability measurements in rough-walled fractures: The effects of wettability and aperture

Tight subsurface geosystems provide significant prospects for the recovery and storage of mass and energy. Because of the tightness of these systems, natural and engineered fractures are the main conveyance conduits transporting the fluids from the tight rock matrix to the wellbore or vice versa. During the fracturing process, most of the newly induced fractures are considered water-wet, however during injection/production, the wettability of the fractures gradually changes. These changes are mainly due to the interactions between the resident and injected fluids, or the exposure of the virgin fracture surfaces to the resident fluids during production. This alteration in wettability can affect the trapping and flow dynamics, e.g., relative permeability, of the fluids flowing in the fracture. Furthermore, fluid injection and production into and from these systems impact the fractures pore pressure and hence the effective stress they are exposed to, resulting in variations in the fracture aperture. In this study, we present a comprehensive macro-scale experimental investigation focusing on the impact of wettability and aperture on steady-state two-phase relative permeability in rough-walled fractures. Using the stead-state measurement technique, we meticulously characterized oil-brine relative permeabilities and residual trapping in water-wet, oil-wet, and mixed-wet rough-walled fractures induced in Eagle Ford shale rock samples. Additionally, we assessed the influence of fracture aperture size on these properties during both drainage and imbibition flow processes. Our results indicate significant phase interference in oil-brine flow in non-water-wet rough-walled fractures, which renders the commonly used x-curve and Corey models inadequate to represent the steady-state oil-brine relative permeabilities measured in our study, leading to substantial overestimations. Mixed-wet fractures exhibited reduced relative permeabilities compared to oil-wet fractures, which in turn demonstrated lower relative permeabilities than water-wet counterparts. The observed trends stem from evolving fluid configuration and transport dynamics within the fractures as surface wettability transitions. Furthermore, an increase in fracture aperture corresponded with an increase in relative permeability. This was attributed to a broader flow area, diminished capillarity, attenuated impact of fracture wall roughness and tortuosity effects, and a reduction in bypassing and trapping events, all synergistically contributing to the mitigation of phase interference. Similarly, an increase in fracture aperture led to a marked decrease in post-waterflooding endpoint oil saturation and post-oil flooding endpoint brine saturation. Finally, we provided generalized correlation models based on experimental results from fractures with varying conductivities and wettability, yielding a more accurate representation of fracture relative permeabilities compared to traditional models. The data and correlation models produced in this study improve our understanding and prediction of multiphase flow in subsurface fractures and offer insights into rapid production decline in unconventional shale reservoirs.

Rapid Release of Silicon by Ultrafast Joule Heating Generates Mechanically Stable Shell-Shell Si/C Anodes with Dominant Inward Deformation.

As a promising anode material, silicon-carbon composites encounter great challenges related to internal stress release and contact between the composites during lithiation. These issues lead to material degradation and concomitantly rapid capacity decline. Here, we report a type of shell-shell silicon-carbon (SS-Si/C) composite, which consists of a carbon shell tightly coated with a silicon shell. The mechanical analysis unveils that the dominant inward expansion of the Si shell is achieved through the synergistic effect of the outer carbon shell and the inner hollow structure. Benefiting from the well-tailored shell-shell structure, the SS-Si/C anode exhibits exceptional performance, boasting a high specific capacity (1690.3 mA h g-1 after 550 cycles at 0.5 A g-1), a high areal capacity (2.05 mA h cm-2 after more than 400 cycles at 0.5 mA cm-2), and an extended cycling life (1055.6 mA h g-1 after 1000 cycles at 8 A g-1), far exceeding commercially available Si/C anodes. Using the well-designed SS-Si/C anode, full cells assembled with LiCoO2 (LCO) or LiFePO4 (LFP) cathodes achieve favorable rate capability and cyclic stability. Notably, at a high rate of 6 C (1 C = 170 and 270 mA g-1 for LFP and LCO, respectively), these full cells deliver high specific capacities of 79.5 mA h g-1 and 64.9 mA h g-1 when using LCO and LFP, respectively, demonstrating the potential of SS-Si/C anodes for practical applications. The straightforward and safe synthesis method in this work enables the rational design of hollow structures with distinct properties.

The Rise and Fall of Westmorland’s ‘County’ Racecourse: Kendal Races 1820–1834

Although many towns had race meetings in the past, most survived only a short time. It has been rare that the reasons why so many failed have been explored. Most simply stopped without any local newspaper explanation. This microstudy of a small local northern race meeting is very suggestive about just how complex and precarious the survival of any meeting could be, and aims to encourage further research. Kendal, the largest town in Westmorland, had very occasional low status race meetings in the eighteenth century on its Fell Side. But in 1820 annual races were revived on a new course to the east of the town, and the following year a new improved course was constructed to the west. The new races, the only ones in Westmorland at that time, lasted only fifteen years, from 1820 to 1834. This paper explores their nature, and the complex reasons lying behind the rise and fall of Kendal’s so-called ‘race week’. It starts by exploring its beginnings and describing the varied attractions that the ‘race week’ offered: wagering, heavy drinking, gaming and trickster activities, entertainments, a band, balloon ascent, dramas, social meals, dancing, assemblies, Wombwell’s menagerie, wrestling and cockfighting. It assesses the numbers and nature of the crowds attending. It then examines the complex reasons lying behind its brief growth and rapid decline. A perfect storm of problems came together: political divisions between the powerful landowning Tory Lowthers who held Westmorland and growing Whig and Reform opposition, which affected finances, patronage and elite attendance; middle-class Kendal attitudes, and dissenter religious opposition; funding problems; decline of gentry interest; inferior racehorse entries; low status jockeys; and bad weather.

Diagnostic and Prognostic Markers for Pancreatitis and Pancreatic Ductal Adenocarcinoma.

Diagnostic markers are desperately needed for the early detection of pancreatic ductal adenocarcinoma (PDA). We describe sets of markers expressed in temporal order in mouse models during pancreatitis, PDA initiation and progression. Cell type specificity and the differential expression of PDA markers were identified by screening single cell (sc) RNAseq from tumor samples of a mouse model for PDA (KIC) at early and late stages of PDA progression compared to that of a normal pancreas. Candidate genes were identified from three sources: (1) an unsupervised screening of the genes preferentially expressed in mouse PDA tumors; (2) signaling pathways that drive PDA, including the Ras pathway, calcium signaling, and known cancer genes, or genes encoding proteins that were identified by differential mass spectrometry (MS) of mouse tumors and conditioned media from human cancer cell lines; and (3) genes whose expression is associated with poor or better prognoses (PAAD, oncolnc.org). The developmental progression of PDA was detected in the temporal order of gene expression in the cancer cells of the KIC mice. The earliest diagnostic markers were expressed in epithelial cancer cells in early-stage, but not late-stage, PDA tumors. Other early markers were expressed in the epithelium of both early- and late-state PDA tumors. Markers that were expressed somewhat later were first elevated in the epithelial cancer cells of the late-stage tumors, then in both epithelial and mesenchymal cells, or only in mesenchymal cells. Stromal markers were differentially expressed in early- and/or late-stage PDA neoplasia in fibroblast and hematopoietic cells (lymphocytes and/or macrophages) or broadly expressed in cancer and many stromal cell types. Pancreatitis is a risk factor for PDA in humans. Mouse models of pancreatitis, including caerulein treatment and the acinar-specific homozygous deletion of differentiation transcription factors (dTFs), were screened for the early expression of all PDA markers identified in the KIC neoplasia. Prognostic markers associated with a more rapid decline were identified and showed differential and cell-type-specific expression in PDA, predominately in late-stage epithelial and/or mesenchymal cancer cells. Select markers were validated by immunohistochemistry in mouse and human samples of a normal pancreas and those with early- and late-stage PDA. In total, we present 2165 individual diagnostic and prognostic markers for disease progression to be tested in humans from pancreatitis to late-stage PDA.

AI for the prediction of early stages of Alzheimer's disease from neuroimaging biomarkers - A narrative review of a growing field.

The objectives of this narrative review are to summarize the current state of AI applications in neuroimaging for early Alzheimer's disease (AD) prediction and to highlight the potential of AI techniques in improving early AD diagnosis, prognosis, and management. We conducted a narrative review of studies using AI techniques applied to neuroimaging data for early AD prediction. We examined single-modality studies using structural MRI and PET imaging, as well as multi-modality studies integrating multiple neuroimaging techniques and biomarkers. Furthermore, they reviewed longitudinal studies that model AD progression and identify individuals at risk of rapid decline. Single-modality studies using structural MRI and PET imaging have demonstrated high accuracy in classifying AD and predicting progression from mild cognitive impairment (MCI) to AD. Multi-modality studies, integrating multiple neuroimaging techniques and biomarkers, have shown improved performance and robustness compared to single-modality approaches. Longitudinal studies have highlighted the value of AI in modeling AD progression and identifying individuals at risk of rapid decline. However, challenges remain in data standardization, model interpretability, generalizability, clinical integration, and ethical considerations. AI techniques applied to neuroimaging data have the potential to improve early AD diagnosis, prognosis, and management. Addressing challenges related to data standardization, model interpretability, generalizability, clinical integration, and ethical considerations is crucial for realizing the full potential of AI in AD research and clinical practice. Collaborative efforts among researchers, clinicians, and regulatory agencies are needed to develop reliable, robust, and ethical AI tools that can benefit AD patients and society.

Reversible Nucleic Acid Storage in Deconstructable Glassy Polymer Networks.

The rapid decline in DNA sequencing costs has fueled the demand for nucleic acid collection to unravel genomic information, develop treatments for genetic diseases, and track emerging biological threats. Current approaches to maintaining these nucleic acid collections hinge on continuous electricity for maintaining low-temperature and intricate cold-chain logistics. Inspired by the millennia-long preservation of fossilized biological specimens in calcified minerals or glassy amber, we present Thermoset-REinforced Xeropreservation (T-REX): a method for storing DNA in deconstructable glassy polymer networks. Key to T-REX is the development of polyplexes for nucleic acid encapsulation, streamlining the transfer of DNA from aqueous to organic phases, replete with initiators, monomers, cross-linkers, and thionolactone-based cleavable comonomers required to form the polymer networks. This process successfully encapsulates DNA that spans different length scales, from tens of bases to gigabases, in a matter of hours compared to days with traditional silica-based encapsulation. Further, T-REX permits the extraction of DNA using comparatively benign reagents, unlike the hazardous hydrofluoric acid required for recovery from silica. T-REX provides a path toward low-cost, time-efficient, and long-term nucleic acid preservation for synthetic biology, genomics, and digital information storage, potentially overcoming traditional low-temperature storage challenges.

Study of the Rolling Effect on MoS2-Carbon Fiber Density and Its Consequences for the Functionality of Li-Ion Batteries.

In this study, an electrode slurry composed of molybdenum disulfide (MoS2) and vapor-grown carbon fiber (VGCF) prepared through a solid-phase synthesis method was blade-coated onto copper foil to form a thick film as the anode for lithium-ion batteries. In previously reported work, MoS2-based lithium-ion batteries have experienced gradual deformation, fracture, and pulverization of electrode materials during the charge and discharge cycling process. This leads to an unstable electrode structure and rapid decline in battery capacity. Furthermore, MoS2 nanosheets tend to aggregate over charge and discharge cycles, which diminishes the surface activity of the material and results in poor electrochemical performance. In this study, we altered the density of the MoS2-carbon fiber/Cu foil anode electrode by rolling. Three different densities of electrode sheets were obtained through varying rolling repetitions. Our study shows the best electrochemical performance was achieved at a material density of 2.2 g/cm3, maintaining a capacity of 427 mAh/g even after 80 cycles.

Assessment of the reversibility of resistance in the absence of antibiotics and its relationship with the resistance gene's fitness cost: a genetic study with mcr-1

The intensive use of antibiotics has resulted in strong natural selection for the evolution of antimicrobial resistance (AMR), but whether, and under what circumstances, the removal of antibiotics would result in a rapid reduction in AMR has been insufficiently explored. We aimed to test the hypothesis that in the simple, yet common, case of AMR conferred by a single gene, removing antibiotics would quickly reduce the prevalence of resistance if the AMR gene imposes a high fitness cost and costless resistance is extremely rare among its proximal mutants. In this genetic study, to test our hypothesis, we used the mcr-1 gene in Escherichia coli, which confers resistance to the last-resort antibiotic colistin, as a model. A high-throughput reverse genetics approach was used to evaluate mcr-1 variants for their fitness cost and resistance levels relative to a non-functional construct, by measuring relative growth rates in colistin-free media and at 2 μg/mL and 4 μg/mL colistin. We identified costless resistant mcr-1 mutants, and examined their properties within the context of the sequential organisation of mcr-1's functional domains as well as the evolutionary accessibility of these mutations. Finally, a simple population genetic model incorporating the measured fitness cost was constructed and tested against previously published real-world data of mcr-1 prevalence in colonised inpatients in China since the 2017 colistin ban in fodder additives. We estimated the relative growth rates of 14 742 mcr-1 E coli variants (including the wild type), 3449 of which were single-nucleotide mutants. E coli showed 73·8% less growth per 24 h when carrying wild-type mcr-1 compared with the non-functional construct. 6252 (42·4%) of 14 741 mcr-1 mutants showed colistin resistance accompanied by significant fitness costs, when grown under 4 μg/mL colistin selection. 43 (0·3%) mcr-1 mutants exhibited costless resistance, most of which contained multiple mutations. Among the 3449 single mutants of mcr-1, 3433(99·5%) had a fitness cost when grown in colistin-free media, with a mean relative growth of 0·305 (SD0·193) compared with the non-functional variant. 3059 (88·7%) and 1833 (53·1%) of 3449 single mutants outgrew the non-functional mcr-1 in the presence of 2 μg/mL and 4 μg/mL colistin, respectively. Single mutations that gave rise to costless mutants were rare in all three domains of mcr-1 (transmembrane domain, flexible linker, and catalytic domain), but the linker domain was enriched with cost-reducing and resistance-enhancing mutations and depleted with cost-increasing mutations. The population genetics model based on the experimental data accurately predicts the rapid decline in mcr-1 prevalence in real-world data. Many identified costless resistant variants that consist of multiple mutations are unlikely to evolve easily in nature. These findings for colistin and mcr-1 might be applicable to other cases in which AMR entails a substantial fitness cost that cannot be mitigated in proximal mutants. National Natural Science Foundation of China, and National Key Research and Development Program of China.

Repeated cognitive assessments show stable function over time in patients with ALS

BackgroundAmyotrophic lateral sclerosis (ALS) is a multisystem disorder with not only motor symptoms but also extra-motor features including cognitive impairment. The most common cognitive profile observed in patients with ALS includes deficits in executive function, language, and social cognition. However, longitudinal studies on cognitive changes over time in ALS are sparse. We aimed to investigate the presence and nature of cognitive impairment at the time of ALS diagnosis and its association with survival as well as explore longitudinal cognitive change.MethodPatients (n = 216) were recruited at the Karolinska University Hospital in Stockholm, Sweden. Follow-up visits (n = 307 in total) were performed every 6 months. Cognitive impairment was assessed using the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) and/or Montreal Cognitive Assessment (MoCA).ResultsCognitive impairment was observed in 38% of the patients at the time of ALS diagnosis, and the majority of these patients had deficits in executive function and/or language. Patients with cognitive impairment at the time of diagnosis had a more rapid decline in ALSFRS-R at 12- and 18-months follow-up, and a shorter survival. Cognitive function was stable during the first 2 years after diagnosis, and did not follow the trajectories of decline in motor functions.ConclusionCognitive impairment in ALS was associated with a faster decline of motor functions, and shorter survival. However, cognitive function did not deteriorate over time. Cognitive assessment is essential for the patients and caregivers to understand the phenotypic expression of ALS.

Differences in Cognitive Trajectories of Dementia: Comparison of Alzheimer’s Disease Dementia and Dementia with Lewy Bodies in a Korean Patient Cohort

Introduction: Prediction of the dementia progression is important for patient management. We aimed to investigate the cognitive trajectories of Alzheimer’s disease dementia (ADD) and dementia with Lewy bodies (DLB) according to the initial structural change measured by comprehensive visual rating scales (CVRS). Methods: We retrospectively included the patients who initially visited the Dementia Clinic of Chonnam National University Hospital between 2010 and 2012. All patients underwent dementia workup including neuropsychological battery (Seoul Neuropsychological Screening Battery, SNSB). We recruited the participant who underwent SNSB annually for 3 years successively. A total of 136 patients of ADD and 63 patients of DLB were included for analysis. We analyzed the decline pattern of the cognitive profile according to the initial brain structural changes. Results: The general cognitive trajectories between ADD and DLB patients were not different. However, DLB patients showed more rapid decline of cognitive function in language and related function, visual memory function, and frontal executive function. The scores were lower in participants with DLB with the lesser atrophy group in attention, visuospatial function, and frontal executive function. In analysis of the cognitive trajectories, the visual memory domain declined rapidly in the DLB with lesser atrophy group compared with the ADD with lesser atrophy group. Conclusion: We founded that the differences in the visual cognitive profile in ADD and DLB patients in serial follow-up of neuropsychological tests. It is prominent in the mild structural change group of ADD and DLB.

First Application of a Mixed Porcine-Human Repopulated Bioengineered Liver in a Preclinical Model of Post-Resection Liver Failure.

In this study, a mixed porcine-human bioengineered liver (MPH-BEL) was used in a preclinical setup of extracorporeal liver support devices as a treatment for a model of post-resection liver failure (PRLF). The potential for human clinical application is further illustrated by comparing the functional capacity of MPH-BEL grafts as assessed using this porcine PRLF model with fully human (FH-BEL) grafts which were perfused and assessed in vitro. BEL grafts were produced by reseeding liver scaffolds with HUVEC and primary porcine hepatocytes (MPH-BEL) or primary human hepatocytes (FH-BEL). PRLF was induced by performing an 85% liver resection in domestic white pigs and randomized into the following three groups 24 h after resection: standard medical therapy (SMT) alone, SMT + extracorporeal circuit (ECC), and SMT + MPH-BEL. The detoxification and metabolic functions of the MPH-BEL grafts were compared to FH-BEL grafts which were perfused in vitro. During the 24 h treatment interval, INR values normalized within 18 h in the MPH-BEL therapy group and urea synthesis increased as compared to the SMT and SMT + ECC control groups. The MPH-BEL treatment was associated with more rapid decline in hematocrit and platelet count compared to both control groups. Histological analysis demonstrated platelet sequestration in the MPH-BEL grafts, possibly related to immune activation. Significantly higher rates of ammonia clearance and metabolic function were observed in the FH-BEL grafts perfused in vitro than in the MPH-BEL grafts. The MPH-BEL treatment was associated with improved markers of liver function in PRLF. Further improvement in liver function in the BEL grafts was observed by seeding the biomatrix with human hepatocytes. Methods to reduce platelet sequestration within BEL grafts is an area of ongoing research.

The injection capacity evaluation of high-pressure water injection in low permeability reservoir: numerical and case study

Low permeability oil reservoir resources are rich and their efficient development is considered an important way to solve energy security issues. However, the development process of low permeability oil reservoirs is faced with the challenges of insufficient natural energy and rapid production decline. The high-pressure water injection technology is a method that relies on high-pressure and large-volume to inject fluid into the reservoir to replenish energy. It is considered as an important technical means to quickly replenish formation energy. This study focuses on the injection capacity for the high-pressure water injection technology of low permeability oil reservoir. Firstly, the fluid-structure interaction mathematical model for two-phase fluid flow was established. The solution of the mathematical model was then obtained by coupling the phase transport in porous media module and Darcy’s law module on the COMSOL numerical simulation platform. The numerical model established in this study was verified through the Buckley-Leverett model. The study on the injection capacity of high-pressure water injection technology was conducted using the geological background and reservoir physical properties of Binnan Oilfield (Shengli, China). The results show that the production pressure difference is the key factor in determining the injection capacity. When the production pressure difference increases from 5 MPa to 30 MPa, the cumulative injection volume increases by 8.1 times. In addition, sensitivity analysis shows that the injection capacity is significantly influenced by the properties of the reformation area. The effect of these parameters from high to low is as follows: stress sensitivity factor, permeability, rock compressibility, and porosity. Compared to the reformation area, the influence of the physical parameters of the matrix area on the injection capacity is negligible. Therefore, effective reservoir reformation is essential for enhancing the injection capacity. This research provides a theoretical basis for the design and optimization of the high-pressure water injection technology schemes for low permeability oil reservoir.

The energy metabolism of the freshwater leech Whitmania pigra in response to fasting

Non-blood-feeding leeches, Whitmania pigra, have evolved unique digestive structures and physiological mechanisms to cope with fasting. However, the metabolic changes and molecular mechanisms induced by fasting remain unclear. Therefore, this study recorded the weights of leeches during the fasting process. The weight changes were divided into two stages: a rapid decline period (1–9 weeks) and a fluctuating decline period (9–24 weeks). Leeches fasted for 4 (H4), 11 (H11), and 24 (H24) weeks were selected for transcriptome sequencing. Compared to the control group (H0), 436, 1157, and 337 differentially expressed genes (DEGs) were identified, which were mainly related to glycolysis/gluconeogenesis, amino acid metabolism, and the lipid metabolism pathway. The 6-phosphofructokinase (Pfk), pyruvate kinase (PK), and phosphoenolpyruvate carboxykinase (Pck) transcription levels revealed glycolysis/gluconeogenesis activation during the early stage of fasting and peaked at 11 weeks. Decreased expression of the rate-limiting enzyme acetyl-CoA carboxylase (ACC) in fatty acid synthesis during fasting may impede fatty acid synthesis. These results indicated that the nutrient storage and energy-supplying pathways in W. pigra were modified to improve fasting resistance. The findings of this study provided guidance for exploring the mechanism underlying fasting metabolism and laid a foundation for artificial breeding to improve the resistance of leeches.

An improved method to study Phytophthora cinnamomi Rands zoospores interactions with host

Phytophthora cinnamomi Rands is a highly prevalent phytopathogen worldwide, ranking among the top ten in terms of distribution. It inflicts crown rot, canker, and root rot on numerous plant species, significantly impacting the biodiversity of both flora and fauna within affected environments. With a host range spanning over 5,000 species, including important plants like Quercus suber, Quercus ilex, Castanea sativa, and commercially significant crops such as avocado (Persea americana), maize (Zea mays), and tomato (Solanum lycopersicum), Phytophthora cinnamomi poses a substantial threat to agriculture and ecosystems. The efficient dissemination of the oomycete relies on its short-lived asexually motile zoospores, which depend on water currents to infect host roots. However, managing these zoospores in the laboratory has long been challenging due to the complexity of the life cycle. Current protocols involve intricate procedures, including alternating cycles of growth, drought, and flooding. Unfortunately, these artificial conditions often result in a rapid decline in virulence, necessitating additional steps to maintain infectivity during cultivation. In our research, we sought to address this challenge by investigating zoospore survival under various conditions. Our goal was to develop a stable stock of zoospores that is both easily deployable and highly infective. Through direct freezing in liquid nitrogen, we have successfully preserved their virulence. This breakthrough eliminates the need for repeated culture transfers, simplifying the process of plant inoculation. Moreover, it enables more comprehensive studies of Phytophthora cinnamomi and its interactions with host plants.

Ethanol Extract of the Microalga Phaeodactylum tricornutum Shows Hepatoprotective Effects against Acetaminophen-Induced Acute Liver Injury in Mice.

Acute liver failure is an infrequent yet fatal condition marked by rapid liver function decline, leading to abnormalities in blood clotting and cognitive impairment among individuals without prior liver ailments. The primary reasons for liver failure are infection with hepatitis virus or overdose of certain medicines, such as acetaminophen. Phaeodactylum tricornutum (PT), a type of microalgae known as a diatom species, has been reported to contain an active ingredient with anti-inflammatory and anti-obesity effects. In this study, we evaluated the preventive and therapeutic activities of PT extract in acute liver failure. To achieve our purpose, we used two different acute liver failure models: acetaminophen- and D-GalN/LPS-induced acute liver failure. PT extract showed protective activity against acetaminophen-induced acute liver failure through attenuation of the inflammatory response. However, we failed to demonstrate the protective effects of PT against acute liver injury in the D-GalN/LPS model. Although the PT extract did not show protective activity against two different acute liver failure animal models, this study clearly demonstrates the importance of considering the differences among animal models when selecting an acute liver failure model for evaluation.

Data driven approach to characterize rapid decline in autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is a genetic kidney disease with high phenotypic variability. Furthering insights into patients' ADPKD progression could lead to earlier detection, management, and alter the course to end stage kidney disease (ESKD). We sought to identify patients with rapid decline (RD) in kidney function and to determine clinical factors associated with RD using a data-driven approach. A retrospective cohort study was performed among patients with incident ADPKD (1/1/2002-12/31/2018). Latent class mixed models were used to identify RD patients using differences in eGFR trajectories over time. Predictors of RD were selected based on agreements among feature selection methods, including logistic, regularized, and random forest modeling. The final model was built on the selected predictors and clinically relevant covariates. Among 1,744 patients with incident ADPKD, 125 (7%) were identified as RD. Feature selection included 42 clinical measurements for adaptation with multiple imputations; mean (SD) eGFR was 85.2 (47.3) and 72.9 (34.4) in the RD and non-RD groups, respectively. Multiple imputed datasets identified variables as important features to distinguish RD and non-RD groups with the final prediction model determined as a balance between area under the curve (AUC) and clinical relevance which included 6 predictors: age, sex, hypertension, cerebrovascular disease, hemoglobin, and proteinuria. Results showed 72%-sensitivity, 70%-specificity, 70%-accuracy, and 0.77-AUC in identifying RD. 5-year ESKD rates were 38% and 7% among RD and non-RD groups, respectively. Using real-world routine clinical data among patients with incident ADPKD, we observed that six variables highly predicted RD in kidney function.