The Impact of Dual-Tasks and Disease Severity on Posture, Gait, and Functional Mobility among People Living with Dementia in Residential Care Facilities: A Pilot Study.

Gait speed and timed-up-and-go (TUG) predict cognitive decline, falls, and mortality. Dual-tasks may be useful in cognitive screening among people living with dementia (PWD), but more evidence is needed. This cross-sectional study aimed to compare single- and dual-task performance and determine the influence of dementia severity on dual-task performance and interference. Thirty PWD in two residential care facilities (Age: 81.3 ± 7.1 years; Montreal Cognitive Assessment: 10.4 ± 6.0 points) completed two trials of single- (feet apart) and dual-task posture (feet apart while counting backward), single- (walk 4 m) and dual-task gait (walk 4m while naming words), and single- (timed-up-and-go (TUG)), and dual-task functional mobility (TUG while completing a category task) with APDM inertial sensors. Dual-tasks resulted in greater sway frequency, jerk, and sway area; slower gait speed; greater double limb support; shorter stride length; reduced mid-swing elevation; longer TUG duration; reduced turn angle; and slower turn velocity than single-tasks (ps < 0.05). Dual-task performance was impacted (reduced double limb support, greater mid-swing elevation), and dual-task interference (greater jerk, faster gait speed) was related to moderate-to-severe compared to mild PWD. Moderate-to-severe PWD had poorer dynamic stability and a reduced ability to appropriately select a cautious gait during dual-tasks than those with mild PWD, indicating the usefulness of dual-tasks for cognitive screening.

Coexistence of a nonresistance-conferring IncI1 plasmid favors persistence of the blaCTX-M-bearing IncFII plasmid in Escherichia coli.

The interaction between coexisting plasmids can affect plasmid-carried resistance gene persistence and spread. However, whether the persistence of the blaCTX-M gene in clinical Enterobacteriaceae is related to the interaction of coresident nonresistance-conferring plasmids has not been reported. This study was initiated to elucidate how a nonresistance-conferring IncI1 plasmid affected the blaCTX-M-bearing IncFII plasmid colocated on the same cell. Herein, we constructed three isogenic derivatives of E. coli C600, designated as C600FII, C600I1, and C600FII+I1, which harbored the blaCTX-M-IncFII plasmid and/or the nonresistance-IncI1 one. We discovered that strain C600FII+I1 conferred higher fitness advantages than strain C600FII; also, the stability of the blaCTX-M-IncFII plasmid was noticeably improved in an antibiotic-free environment when it coexisted with the IncI1 plasmid. To further explore why the IncI1 plasmid enhanced the persistence of the blaCTX-M-IncFII plasmid, we assessed the blaCTX-M-IncFII plasmid's copy numbers, conjugation frequencies, and rep gene expressions in strains C600FII and C600FII+I1. The results demonstrated that the rep expressions of the blaCTX-M-IncFII plasmid in strain C600FII+I1 was greatly decreased, along with the plasmid's copy numbers and mating efficiencies, compared to those in strain C600FII. Moreover, further study revealed that the intracellular ATP levels of strain C600FII+I1 were far lower than those of strain C600FII. Our findings confirmed that coexistence of the nonresistance-IncI1 plasmid can keep the blaCTX-M-IncFII plasmid more stable by increasing the fitness advantages of the host bacteria, which will pose a threat to preventing the long-term presence of the plasmid-carried blaCTX-M gene in clinical Enterobacteriaceae. IMPORTANCE: So far, plasmid-carried blaCTX-M is still the most common extended-spectrum beta-lactamase (ESBL) genotype in clinical settings worldwide. Except for the widespread use of third-generation cephalosporins, the interaction between coexisting plasmids can also affect the long-term stable existence of the blaCTX-M gene; however, the study on that is still sparse. In the present study, we assess the interaction of coinhabitant plasmids blaCTX-M-IncFII and nonresistance-IncI1. Our results confirmed that the increased fitness advantages of strain C600FII+I1 were attributable to the cohabitant nonresistance-IncI1 plasmid, which largely reduced the intracellular ATP levels of host bacteria, thus decreasing the rep gene expression of the blaCTX-M-IncFII plasmid, its copy numbers, and mating efficiencies, while the higher fitness advantages of strain C600FII+I1 enhanced the persistence of the blaCTX-M-IncFII plasmid. The results indicate that the nonresistance-IncI1 plasmid contributes to the long-term existence of the blaCTX-M-IncFII plasmid, implying a potentially new strategy for controlling the spread of resistance plasmids in clinical settings by targeting nonresistance plasmids.

Horizontal transfer characterization of ColV plasmids in blaCTX-M-bearing avian Escherichia coli.

Extended-spectrum-ß-lactamases (ESBLs)-producing Escherichia coli conferred resistance to most ß-lactams, except for carbapenems. To date, the transmission mechanism of blaCTX-M, as the most common ESBLs subtype, in E. coli has received sustained attention around the worldwide, but the research on the pathogenicity of blaCTX-M-bearing E. coli is still scarce. The aims of this study were to discern the spread characteristics of ColV (encoding colicin V) plasmids in blaCTX-M-positive E. coli. The multi-drug resistance traits, phylogroups, and ColV plasmid profilings were screened in 76 blaCTX-M-positive E. coli. Thereafter, the genetic profiles of E. coli G12 and GZM7 were determined by whole genome sequencing, conjugation and S1-pulsed-field gel electrophoresis. The median lethal dose was analyzed in E. coli G12 and TG12A, the ColV-plasmid transconjugant of G12. Of all 76 blaCTX-M-bearing E. coli, 67.11% exhibited resistance to at least 2 drugs in addition to ceftiofur, 14.47% carried ColV-positive plasmids, and 53.95% were phylogroup C. Further studies demonstrated that the blaCTX-M-bearing E. coli G12 was assigned to the predominant lineage O78:H4-ST117 of phylogroup G. In addition, its ColV-positive plasmid simultaneously carried multiple resistance genes, and could be independently transferred to confer partial pathogenicity on its host by plasmid mating. E. coli GZM7 was O53:H9-ST23 of phylogroup C, which belonged to another representative lineage of APEC (avian pathogenic E. coli). Its ColV-positive plasmid could complete conjugation with the help of the other coexisting-resistance conjugative plasmid, although it failed to transfer alone. Our findings highlight the flexibly horizontal transfer of ColV plasmids along with multidrug-resistant genes among blaCTX-M-bearing E. coli poses a threat to poultry health and food safety, which contributes to elucidate the concept of "One Health" and deserves particular concern.

Racial disparities in the relationship of regional socioeconomic status and colorectal cancer survival in the five regions of Georgia.

INTRODUCTION: The study's purpose was to examine 5-year colorectal cancer (CRC) survival rates between White and Black patients. We also determined whether regional socioeconomic status (SES) is associated with CRC survival between White and Black patients in the Clayton, West Central, East Central, Southeast, and Northeast Georgia public health districts. METHODS: We performed a retrospective cohort analysis using data from the 1975 to 2016 Surveillance, Epidemiology, and End Results program. The 2015 United States Department of Agriculture Economic Research Services county typology codes were used to identify region-level SES with persistent poverty, low employment, and low education. Kaplan-Meier method and Cox proportional hazard regression were performed. RESULTS: Among 10,876 CRC patients (31.1% Black patients), 5-year CRC survival rates were lower among Black patients compared to White patients (65.4% vs. 69.9%; p < 0.001). In multivariable analysis, White patients living in regions with persistent poverty had a 1.1-fold increased risk of CRC death (HR, 1.12; 95% CI, 1.00-1.25) compared to those living in non-persistent poverty regions. Among Black patients, those living in regions with low education were at a 1.2-fold increased risk of CRC death (HR, 1.19; 95% CI, 1.01-1.40) compared to those living in non-low education regions. DISCUSSION AND CONCLUSIONS: Black patients demonstrated lower CRC survival rates in Georgia compared to their White counterparts. White patients living in regions with persistent poverty, and Black patients living in regions with low education had an increased risk of CRC death. Our findings provide important evidence to all relevant stakeholders in allocating health resources aimed at CRC early detection and prevention and timely referral for CRC treatment by considering the patient's regional SES in Georgia.

Exploring the Association Between Physical Activity and Cognitive Function Among People Living with Dementia.

Background: Physical activity preserves cognitive function in people without dementia, but the relationship between physical activity and cognitive domains among people living with dementia is unclear. Objective: The objective of this study was to explore the association between physical activity and cognition domains among people living with dementia. Methods: Participants living with dementia in residential care facilities (complete case analysis: n = 24/42) completed a battery of cognitive tests (global cognition: Montreal Cognitive Assessment; executive function: Trail-Making Test, Digit Span Forward Test; perception and orientation: Benton Judgement of Line Orientation Test; language: Boston Naming Test; learning and memory: Rey Auditory Verbal Learning Test; complex attention: Digit Symbol Substitution Test). Participants wore an actigraphy monitor on their non-dominant wrist over seven days. We conducted a linear regression for total physical activity (independent variable) with race (white/black), fall risk (Morse Fall Scale), and the number of comorbidities (Functional Comorbidities Index) as covariates, and cognitive tests as variables of interest. Results: Participants were primarily male (75%), white (87.5%), and 50%had unspecified dementia (Alzheimer's disease: 33%). Greater physical activity was associated with poorer global cognition, better executive function, and better learning and memory (ps <  0.05). Physical activity was not related to visuospatial perception, language, or complex attention. Conclusions: Physical activity may preserve executive function and learning and memory among people living with dementia. Wandering is more common in later stages of dementia, which may explain greater physical activity observed with lower global cognition. Regularly assessing physical activity may be useful in screening and monitoring cognitive changes.

Emerging roles of RNA ac4C modification and NAT10 in mammalian development and human diseases.

RNA ac4C modification is a novel and rare chemical modification observed in mRNA. Traditional biochemical studies had primarily associated ac4C modification with tRNA and rRNA until in 2018, Arango D et al. first reported the presence of ac4C modification on mRNA and demonstrated its critical role in mRNA stability and translation regulation. Furthermore, they established that the ac4C modification on mRNA is mediated by the classical N-acetyltransferase NAT10. Subsequent studies have underscored the essential implications of NAT10 and mRNA ac4C modification across both physiological and pathological regulatory processes. In this review, we aimed to explore the discovery history of RNA ac4C modification, its detection methods, and its regulatory mechanisms in disease and physiological development. We offer a forward-looking examination and discourse concerning the employment of RNA ac4C modification as a prospective therapeutic strategy across diverse diseases. Furthermore, we comprehensively summarize the functions and mechanisms of NAT10 in gene expression regulation and pathogenesis independent of RNA ac4C modification.

The correlation between early net fluid balance and the clinical outcomes of patients receiving extracorporeal cardiopulmonary resuscitation.

OBJECTIVE: To investigate correlation between early net fluid balance and the clinical outcomes of patients receiving extracorporeal cardiopulmonary resuscitation (ECPR). METHODS: Adult patients on ECPR admitted to the Department of Emergency in the First Affiliated Hospital of Nanjing Medical University from May 2015 to December 2020 were included. Net fluid balance for consecutive 4 days after ECPR was recorded. The primary outcome was survival to intensive care unit (ICU) discharge. We used multivariable logistic regression to assess the association between fluid status and clinical outcomes. RESULTS: A total of 72 patients were enrolled and divided into two groups: the survivor group and the non-survivor group. The overall rate of survival to ICU discharge was 44.4%. Daily fluid balance (DFB) in the survivor group was lower than that in the non-survivor group at day 4 (-11.47 (-19.74, 8.7) vs. -5.08 (-12.94, 13.9) mL/kg, P=0.046), as was cumulative fluid balance (CFB) over the first 4 days (-36.03 (-51.45, 19.03) vs. -7.22 (-32.79, 21.02) mL/kg, P=0.009). Both continuous renal replacement therapy (CRRT) and CFB from days 1-4 were significantly correlated with survival to ICU discharge (OR=14.617, 95% CI: 1.344, 48.847, P=0.028; OR=1.261, 95% CI: 1.091, 1.375, P=0.003, respectively). CFB from days 1-4 was determined to have a roughly linear association with the log odds of survival to ICU discharge. CONCLUSION: Early negative fluid balance maybe associated with survival to ICU discharge in patients receiving ECPR.

Aerobic exercise and metformin on intermuscular adipose tissue (IMAT): insights from multimodal MRI and histological changes in prediabetic rats.

BACKGROUND: Physical exercise is the first-line intervention for prediabetes, and metformin is the most widely used oral insulin-sensitizing agent. Moreover, intermuscular adipose tissue (IMAT) directly affects insulin resistance by helping maintain glucose homeostasis. Here, we evaluated the effects of moderate aerobic exercise and/or metformin on histological IMAT parameters in non-streptozotocin-induced prediabetes. METHODS: Male Wistar rats with prediabetes fed a high-fat diet and high-sugar drinks were randomly assigned to high-fat diet (PRE), metformin (MET), moderate aerobic exercise (EXE), combined therapy (EMC), or EMC + compound-c (EMA) groups for 4 weeks. Multimodal magnetic resonance imaging (MRI) was then performed, and tissue-specific inflammation and energy and lipid metabolism were evaluated in IMAT. RESULTS: The EXE group had lower inflammatory factor levels, lipid metabolism, and mitochondrial oxidative stress, and shorter IMAT adipocyte diameters than the MET group. The MET group exhibited lower IL-1ß and Plin5 expression than the PRE group. Furthermore, the IMAT of the EMC group had lower TNF-α and phosphorylated NF-κB levels and higher GLUT1 and GLUT4 expression than the PRE group. Multimodal MRI revealed significant changes in transverse-relaxation time 2, apparent diffusion coefficient, and fractional anisotropy values in the IMAT and muscles, as well as lower IMAT% values in the EXE and EMC groups than in the MET and PRE groups. CONCLUSION: Moderate aerobic exercise training can effectively improve IMAT function and structure via the AMP-activated protein kinase pathway in prediabetes. Combining metformin with moderate aerobic exercise might elicit modest synergy, and metformin does not counterbalance the beneficial effects of exercise.

Hepatocyte-specific Wtap deficiency promotes hepatocellular carcinoma by activating GRB2-ERK depending on downregulation of proteasome-related genes.

Wilm's tumor 1-associating protein (WTAP), a regulatory protein of the m6A methyltransferase complex, has been found to play a role in regulating various physiological and pathological processes. However, the in vivo role of WTAP in the pathogenesis of hepatocellular carcinoma (HCC) is unknown. In this study, we have elucidated the crucial role of WTAP in HCC progression and shown that hepatic deletion of Wtap promotes HCC pathogenesis through activation of multiple signaling pathways. A single dose of diethylnitrosamine injection causes more and larger HCCs in hepatocyte-specific Wtap knockout (Wtap-HKO) mice than Wtapflox/flox mice fed with either normal chow diet or a high-fat diet. Elevated CD36, IGFBP1 (insulin-like growth factor-binding protein 1), and chemokine (C-C motif) ligand 2 (CCL2) expression leads to steatosis and inflammation in the Wtap-HKO livers. The hepatocyte proliferation is dramatically increased in Wtap-HKO mice, which is due to higher activation of extracellular signal-regulated kinase (ERK) and signal transducer and activator of transcription-3 signaling pathways. Hepatic deletion of Wtap activates the ERK signaling pathway by increasing the protein stability of GRB2 and ERK1/2, which is due to the decreased expression of proteasome-related genes. Restoring PSMB4 or PSMB6 (two key components of the proteasome) leads to the downregulation of GRB2 and ERK1/2 in Wtap-HKO hepatocytes. Mechanistically, WTAP interacts with RNA polymerase II and H3K9ac to maintain expression of proteasome-related genes. These results demonstrate that hepatic deletion of Wtap promotes HCC progression through activating GRB2-ERK1/2-mediated signaling pathway depending on the downregulation of proteasome-related genes especially Psmb4 and Psmb6.

Downregulation of hepatic METTL3 contributes to APAP-induced liver injury in mice.

Background & Aims: Acetaminophen (APAP) overdose is a major cause of acute liver failure in the Western world, but its molecular mechanisms are not fully understood. Methyltransferase-like 3 (METTL3) is a core N6-methyl-adenosine (m6A) RNA methyltransferase that has been shown to regulate many physiological and pathological processes. This study aimed to investigate the role of METTL3 in APAP-induced liver injury in mice. Methods: Hepatocyte-specific Mettl3 knockout (Mettl3-HKO) mice and adenovirus-mediated gene overexpression or knockdown were used. We assayed APAP-induced liver injury by measuring serum alanine aminotransferase/aspartate aminotransferase activity, necrotic area, cell death, reactive oxygen species levels and activation of signalling pathways. We also performed mechanistic studies using a variety of assays and molecular techniques. Results: Hepatic METTL3 is downregulated in APAP-induced liver injury, and hepatocyte-specific deletion of Mettl3 accelerates APAP-induced liver injury, leading to increased mortality as a result of the dramatic activation of the mitogen-activated protein kinase kinase 4 (MKK4) / c-Jun NH2-terminal kinase (JNK) signalling pathway. Inhibition of JNK by SP600125 largely blocks APAP-induced liver injury in Mettl3-HKO mice. Hepatic deletion of Mettl3 activates the MKK4/JNK signalling pathway by increasing the protein stability of MKK4 and JNK1/2 as a result of decreased proteasome activity. Restoration of proteasome activity by overexpression of proteasome 20S subunit beta 4 (PSMB4) or proteasome 20S subunit beta 6 (PSMB6) leads to the downregulation of MKK4 and JNK in Mettl3-HKO hepatocytes. Mechanistically, METTL3 interacts with RNA polymerase II and active histone modifications such as H3K9ac, H3K27ac, and H3K36me3 to maintain the expression of proteasome-related genes. Conclusions: Our study demonstrated that downregulation of METTL3 promotes APAP-induced liver injury by decreasing proteasome activity and thereby enhancing activity of the MKK4/JNK signalling pathway. Impact and Implications: Acetaminophen (APAP) overdose is a key cause of acute liver failure in the Western world, but its molecular mechanisms are not fully understood. We demonstrated in this study that methyltransferase-like 3 (METTL3), a core m6A RNA methyltransferase, is downregulated in APAP-induced liver injury, which exacerbates APAP-induced liver injury through enhancing the MKK4/JNK signalling pathway with involvement of the decreased proteasome activity.

Hematopoietic Stem Cell: Regulation and Nutritional Intervention.

Hematopoietic stem cells (HSCs) are crucial for the life maintenance of bio-organisms. However, the mechanism of HSC regulation is intricate. Studies have shown that there are various factors, either intrinsically or extrinsically, that shape the profile of HSCs. This review systematically summarizes the intrinsic factors (i.e., RNA-binding protein, modulators in epigenetics and enhancer-promotor-mediated transcription) that are reported to play a pivotal role in the function of HSCs, therapies for bone marrow transplantation, and the relationship between HSCs and autoimmune diseases. It also demonstrates the current studies on the effects of high-fat diets and nutrients (i.e., vitamins, amino acids, probiotics and prebiotics) on regulating HSCs, providing a deep insight into the future HSC research.

Effect of hyperbaric oxygen on post-stroke depression.

BACKGROUND: In patients with post-stroke depression (PSD) in diabetes, the situation may be more complex, requiring simultaneous treatment of blood glucose, depressive symptoms, and neurological dysfunction. Hyperbaric oxygen (HBO) therapy can improve tissue oxygen content and improve the situation of ischemia and hypoxia, thus playing a role in protecting brain cells and restoring the function of brain cells. However, there are few studies on HBO therapy for patients with PSD. This study explores the clinical efficacy of such therapy for stroke complicated with depression and diabetes mellitus, and to provide reference and basis for clinical treatment and development through the application of relevant rating scales and laboratory test indicators. AIM: To evaluate the clinical effects of HBO therapy on patients with diabetes with PSD. METHODS: A total of 190 diabetic patients with PSD were randomly divided into observation and control groups (95 patients per group). The control group received escitalopram oxalate 10mg once a day for eight weeks. In addition, the ob-servation group was also given HBO therapy, once a day, five times a week, for eight weeks. The Montgomery Depression Rating Scale (MADRS), National Institutes of Health Stroke Scale (NIHSS), hypersensitive C-reactive protein, tumor necrosis factor (TNF)-α, and fasting glucose levels were compared. RESULTS: There were no significant differences in age, sex, or depression course between the groups (P > 0.05). After HBO treatment, MADRS scores in both groups decreased significantly (14.3 ± 5.2), and were significantly lower in the control group (18.1 ± 3.5). After HBO treatment, NIHSS scores in both groups decreased significantly, and scores in the observation group (12.2 ± 4.0) decreased more than in the control group (16.1 ± 3.4), the difference was statistically significant (P < 0.001). The levels of hypersensitive C-reactive protein and TNF-α in both groups were significantly decreased, and the observation group was significantly lower than the control group (P < 0.001). Fasting blood glucose levels in both groups decreased significantly, and those in the observation group decreased more (8.02 ± 1.10) than in the control group (9.26 ± 1.04), with statistical significance (t = -7.994, P < 0.001). CONCLUSION: HBO therapy can significantly improve depressive symptoms and neurological dysfunction in patients with PSD, and reduce the levels of hypersensitive C-reactive protein, TNF-α and fasting blood glucose.

The effects of strEngth aNd BaLance exercise on Executive function in people living with Dementia (ENABLED): Study protocol for a pilot randomized controlled trial.

BACKGROUND: Exercise may improve executive function among people living with all-cause dementia (PWD), but more evidence is needed. The aim of this pilot randomized controlled trial (RCT) is to examine whether exercise plus usual care improves the primary outcome of executive function, and secondary physiological (inflammation, metabolic aging, epigenetics) and behavioral (cognition, psychological health, physical function, and falls) outcomes compared to usual care alone among PWD. METHODS AND STUDY DESIGN: The strEngth aNd BaLance exercise on Executive function in people living with Dementia (ENABLED) protocol is a pilot parallel, 6-month assessor-blinded RCT (1:1) in residential care facilities, including n = 21 receiving exercise plus usual care and n = 21 usual care alone [NCT05488951]. We will collect primary (Color-Word Stroop Test) and secondary physiological (inflammation, metabolic aging, epigenetics) and behavioral (cognition, psychological health, physical function, and falls) outcomes at baseline and 6 months. We will obtain falls monthly from medical charts. We will collect physical activity, sedentary behavior, and sleep via wrist-worn accelerometers over 7 days at baseline and 6 months. The physical therapist-led adapted Otago Exercise Program will involve 1-h of strength, balance and walking 3×/week for 6 months in groups of 5-7. We will use generalized linear mixed models to examine differences over time in primary and secondary outcomes between groups and examine potential interactions with sex and race. DISCUSSION: This pilot RCT will examine the direct effects and potential underlying physiological mechanisms of exercise on executive function and other behavioral outcomes in PWD, which may have implications for clinical care management.

The Health and Economic Impact of Expanding Home Blood Pressure Monitoring.

INTRODUCTION: Home blood pressure monitoring is more convenient and effective than clinic-based monitoring in diagnosing and managing hypertension. Despite its effectiveness, there is limited evidence of the economic impact of home blood pressure monitoring. This study aims to fill this research gap by assessing the health and economic impact of adopting home blood pressure monitoring among adults with hypertension in the U.S. METHODS: A previously developed microsimulation model of cardiovascular disease was used to estimate the long-term impact of adopting home blood pressure monitoring versus usual care on myocardial infarction, stroke, and healthcare costs. Data from the 2019 Behavioral Risk Factor Surveillance System and the published literature were used to estimate model parameters. The averted cases of myocardial infarction and stroke and healthcare cost savings were estimated among the U.S. adult population with hypertension and in subpopulations defined by sex, race, ethnicity, and rural/urban area. The simulation analyses were conducted between February and August 2022. RESULTS: Compared with usual care, adopting home blood pressure monitoring was estimated to reduce myocardial infarction cases by 4.9% and stroke cases by 3.8% as well as saving an average of $7,794 in healthcare costs per person over 20 years. Non-Hispanic Blacks, women, and rural residents had more averted cardiovascular events and greater cost savings related to adopting home blood pressure monitoring compared with non-Hispanic Whites, men, and urban residents. CONCLUSIONS: Home blood pressure monitoring could substantially reduce the burden of cardiovascular disease and save healthcare costs in the long term, and the benefits could be more pronounced in racial and ethnic minority groups and those living in rural areas. These findings have important implications in expanding home blood pressure monitoring for improving population health and reducing health disparities.

Randomized controlled trial of ultra-protective vs. protective ventilation strategy in veno-arterial extracorporeal membrane oxygenation patients with refractory cardiogenic shock: a study protocol for the ultra-ECMO trial.

Background: A protective or ultra-protective tidal volume strategy is widely applied to patients with acute respiratory distress syndrome (ARDS). The use of very low tidal volume has the potential to further redece ventilation-induced lung injury (VILI) comparde with a "normal" lung protective management. Plus, cardiogenic pulmonary edema (CPE) caused by hydrostatic mechanisms in patients with cardiogenic shock has similar respiratory mechanics to those found in patients with ARDS. And no consensus exists on mechanical ventilation parameter settings in patients with VA-ECMO. The study aimed to investigate the impact of an ultra-protective tidal volume strategy on the 28-day ventilator-free day (VFD) number in VA-ECMO-supported patients with refractory cardiogenic shock, including cardiac arrest. Methods: The Ultra-ECMO trial is a randomized controlled, open-label, single-center prospective superiority trial. At the onset of ECMO initiation, we will divide patients randomly into an intervention group and a control group in a 1:1 ratio. The control group will adopt protective ventilation settings [initial tidal volume: 6 ml/kg of predicted body weight (PBW)] for ventilation, and the intervention group will adopt ultra-protective ventilation settings (initial tidal volume: 4 ml/kg of PBW) for ventilation. The procedure is expected to last 72 h, after which the ventilator settings will be at the intensivists' discretion. The primary outcome is the VFD number at 28 days after inclusion. The secondary outcomes will include respiratory mechanics; analgesic/sedation dosage; lung ultrasound score; interleukin-6, interleukin-8, and monocyte chemotactic protein-1 levels in broncho-alveolar lavage fluid at the moment of enrollment (T0), 24, 48, and 72 h (T1, T2, and T3, respectively) after ECMO initiation; total time (in days) required for ECMO weaning; length of stay in the intensive care unit; total cost of hospitalization; amounts of resuscitative fluids; and in-hospital mortality. Discussion: VA-ECMO-treated patients without ARDS possess abnormal lung function. CPE, thoracic compliance reduction, and poor pulmonary blood perfusion are frequently present, and these patients can more easily progress to ARDS. It seems that targeting the protective tidal volume can lower adverse outcome incidence rates, even in patients without ARDS. This trial seeks to answer the question of whether adopting an ultra-protective tidal volume strategy can lead to superior primary and secondary outcomes compared to adopting a protective tidal volume strategy in patients treated by VA-ECMO. The Ultra-ECMO trial will provide an innovative mechanical ventilation strategy for VA-ECMO-supported patients for improving treatment outcomes at biological and potentially clinical levels. Clinical Trial Registration: ChiCTR2200067118.

Neural biomarker diagnosis and prediction to mild cognitive impairment and Alzheimer's disease using EEG technology.

BACKGROUND: Electroencephalogram (EEG) has emerged as a non-invasive tool to detect the aberrant neuronal activity related to different stages of Alzheimer's disease (AD). However, the effectiveness of EEG in the precise diagnosis and assessment of AD and its preclinical stage, amnestic mild cognitive impairment (MCI), has yet to be fully elucidated. In this study, we aimed to identify key EEG biomarkers that are effective in distinguishing patients at the early stage of AD and monitoring the progression of AD. METHODS: A total of 890 participants, including 189 patients with MCI, 330 patients with AD, 125 patients with other dementias (frontotemporal dementia, dementia with Lewy bodies, and vascular cognitive impairment), and 246 healthy controls (HC) were enrolled. Biomarkers were extracted from resting-state EEG recordings for a three-level classification of HC, MCI, and AD. The optimal EEG biomarkers were then identified based on the classification performance. Random forest regression was used to train a series of models by combining participants' EEG biomarkers, demographic information (i.e., sex, age), CSF biomarkers, and APOE phenotype for assessing the disease progression and individual's cognitive function. RESULTS: The identified EEG biomarkers achieved over 70% accuracy in the three-level classification of HC, MCI, and AD. Among all six groups, the most prominent effects of AD-linked neurodegeneration on EEG metrics were localized at parieto-occipital regions. In the cross-validation predictive analyses, the optimal EEG features were more effective than the CSF + APOE biomarkers in predicting the age of onset and disease course, whereas the combination of EEG + CSF + APOE measures achieved the best performance for all targets of prediction. CONCLUSIONS: Our study indicates that EEG can be used as a useful screening tool for the diagnosis and disease progression evaluation of MCI and AD.

Effects of Vitamin D3 and Marine Omega-3 Fatty Acids Supplementation on Biomarkers of Systemic Inflammation: 4-Year Findings from the VITAL Randomized Trial.

Background: The VITAL study was a nationwide, randomized, double-blind, placebo-controlled, 2 × 2 factorial trial of vitamin D3 (2000 IU/day) and marine n-3 FAs (1 g/day) supplements. We recently reported that vitamin D supplementation with or without omega 3 fatty acids reduced autoimmune disease by 22% in the VITAL study. Objective: To investigate the effects of vitamin D3 and/or n-3 FAs on changes in systemic inflammatory biomarkers including pro- and anti-inflammatory cytokines over a 4-year period in the VITAL sub-cohort with in-person evaluations at the Center for Clinical Investigations (CCI) in Boston. Design: Serum levels of four inflammatory biomarkers (high-sensitivity C-reactive protein [hs-CRP], interleukin-6, interleukin-10, and tumor necrosis factor-α) were measured in a total of 2713 samples from those 1054 VITAL/CCI participants (aged 64.9 ± 6.5 years, 49% female, 84% white, and 9% black) at baseline, year 2, and year 4 follow-up visits. Results: In multiple-adjusted models, vitamin D3 supplementation decreased serum hs-CRP levels by 19% at 2-year follow-up (nominal p = 0.007; p-value after multiple comparison adjustment = 0.028), but not at 4-year follow-up (nominal and adjusted p-values > 0.05). The effects of vitamin D3 on other inflammatory markers were not statistically significant either at year 2 or year 4 (all adjusted p-values > 0.05). Marine n-3 FAs were not significantly associated with changes of all the above inflammatory markers either at years 2 and 4, after multiple comparison adjustment (all p-values > 0.05). Conclusions: Vitamin D3 supplementation with or without n-3 FAs decreased hs-CRP by 19% at year 2, but not other inflammatory biomarkers at year 2 or year 4, while n-3 FAs with or without vitamin D3 did not significantly affect these biomarkers at either time point. Our findings support a potential role of vitamin D supplementation in modulating the chronic inflammatory process, systemic inflammation, and possibly autoimmune disease progression.

Sixteen-Week Vitamin D3 Supplementation Increases Peripheral T Cells in Overweight Black Individuals: Post hoc Analysis of a Randomized, Double-Blinded, Placebo-Controlled Trial.

Background: Vitamin D is considered to modulate T-cell function, which has been implicated in the treatment of inflammatory conditions. However, there is limited knowledge on the effects of vitamin D and its influences on circulating T-cell profiles in humans, particularly in overweight Black individuals who are more likely to be vitamin D insufficient (serum 25(OH)D concentrations of ≤20 ng/mL). Thus, this study tested the hypothesis that vitamin D supplementation modulates T-cell composition, which is in a dose-dependent manner. Methods: A 16-week randomized, double-blinded, placebo-controlled trial of vitamin D3 supplementation was undertaken in 70 overweight/obese Black people (mean age = 26 years, 82% female) with 25 hydroxyvitamin D ≤ 20 ng/mL at baseline. Subjects were randomly assigned a supervised monthly oral vitamin D3 equivalent to approximately 600 IU/day (n = 17), 2000 IU/day (n = 18), 4000 IU/day (n = 18), or a placebo (n = 17). Fresh peripheral whole blood was collected and CD3+, CD4+ and CD8+ cell counts and percentages were determined by flow cytometry at baseline and at 16 weeks, among 56 subjects who were included in the analyses. Results: A statistically significant increase in CD3+% in the 2000 IU/day vitamin D3 supplementation group, and increases in CD4+% in the 2000 IU/day and 4000 IU/day vitamin D3 supplementation groups were observed (p-values < 0.05) from the changes in baseline to 16 weeks. Further adjustments for age, sex and BMI showed that 2000 IU/day vitamin D3 supplementation increased in CD3+ count, CD3%, CD4 count, and CD4%, as compared to the placebo group (p-values < 0.05). Moreover, the highest serum 25(OH)D quantile group had the highest CD3% and CD4%. Conclusions: Sixteen-week vitamin D3 supplementation increases peripheral blood T-cell numbers and percentages in overweight/obese Black patients with vitamin D insufficiency. This resulting shift in circulating T-cell composition, particularly the increase in T helper cells (CD4+ cells), suggests that vitamin D supplementation may improve immune function in Black individuals.

Sustained inhibition of NPY/AgRP neuronal activity by FGF1.

In rodent models of type 2 diabetes (T2D), central administration of FGF1 normalizes elevated blood glucose levels in a manner that is sustained for weeks or months. Increased activity of NPY/AgRP neurons in the hypothalamic arcuate nucleus (ARC) is implicated in the pathogenesis of hyperglycemia in these animals, and the ARC is a key brain area for the antidiabetic action of FGF1. We therefore sought to determine whether FGF1 inhibits NPY/AgRP neurons and, if so, whether this inhibitory effect is sufficiently durable to offer a feasible explanation for sustained diabetes remission induced by central administration of FGF1. Here, we show that FGF1 inhibited ARC NPY/AgRP neuron activity, both after intracerebroventricular injection in vivo and when applied ex vivo in a slice preparation; we also showed that the underlying mechanism involved increased input from presynaptic GABAergic neurons. Following central administration, the inhibitory effect of FGF1 on NPY/AgRP neurons was also highly durable, lasting for at least 2 weeks. To our knowledge, no precedent for such a prolonged inhibitory effect exists. Future studies are warranted to determine whether NPY/AgRP neuron inhibition contributes to the sustained antidiabetic action elicited by intracerebroventricular FGF1 injection in rodent models of T2D.

Differences of medically unexplained symptoms among patients of different ages and sexes in the psychological clinic of a general hospital and the influencing factors of MUS: A cross-sectional study.

Objective: To analyse differences in sex, age, depression, insomnia, psychological stress, resilience, and perceived social support among patients with medically unexplained symptoms (MUS) in a psychological clinic of a general hospital, and to explore the influencing factors of MUS. Methods: This is a cross-sectional study. Seven hundred forty-six first-time patients were assessed with the integrated psychosomatic comprehensive evaluation system (IPS) to evaluate their MUS, depression, insomnia, psychological stress, resilience, and perceived social support. The psychological characteristics were compared with regard to sex and age group (<25 years, low age group; 26-44 years, middle age group; >45 years, high age group). The relationships between age and MUS were explored, and how psychological stress affects MUS was analyzed using the mediator effect model. Results: Different age groups had significant differences in sex, MUS, depression, psychological stress, resilience, and perceived social support. In further pairwise comparison, no significant difference existed in depression, psychological stress, resilience and perceived social support in the middle and low age groups, depression and psychological stress were higher than those in the high age group, resilience and perceived social support were lower than those of the high age group. MUS were higher in the middle age group than in the low age group. No significant difference existed between the two groups and the high age group. Age, severity of MUS, and perceived social support were significantly different between the sexes. Differences in MUS between men and women in different age groups were analyzed using two-factor analysis of variance. It revealed no interaction between sex and different age groups on MUS. The main effect analysis showed that the effects of different age groups on MUS were statistically significant. Based on pairwise comparative analysis, the MUS score in the low age group was lower than that in the middle age group. To clarify a nonlinear relationship between age and MUS, threshold effect analysis was conducted. The results indicated that the piecewise linear regression model could better depict the relationship between age and MUS. The inflection point was at the age of 60 years. Before the age of 60 years, MUS increased with age. No significant correlation existed between age and MUS after the age of 60 years. To understand the influencing factors of MUS, the intermediary effect model was analyzed using MUS as the dependent variable, psychological stress as the independent variable, resilience as mediator variable M1, perceived social support as mediator variable M2, and depression as mediator variable M3. Resilience, perceived social support, and depression had significant mediator effects on the effects of psychological stress on MUS with a total indirect effect of 69.81%. Conclusion: The middle age group had greater MUS than the low age group. Before the age of 60 years, MUS increased with increasing age. Women had more severe MUS than men. Resilience, perceived social support, and depression had significant mediating effects on the effects of perceived stress on MUS. These findings suggest that clinicians should make more comprehensive and detailed evaluations and timely intervention for middle-aged and female patients. Improving psychological resilience and social support can reduce the impact of psychological stress on MUS. Therefore, psychotherapy and multidisciplinary comprehensive treatment are very important for patients is very important for patients.