The impact of AIM2 inflammasome-induced pyroptosis on acute gouty arthritis and asymptomatic hyperuricemia patients.

Objective: This study aimed to evaluate the role of absent in melanoma 2 (AIM2) inflammasome-mediated pyroptosis in the pathogenesis of acute gouty arthritis (AGA) and asymptomatic hyperuricemia(AHU). Methods: A cohort of 30 AGA patients, 30 AHU individuals, and 30 healthy controls (HC) was assembled. Demographic and biochemical data, along with blood samples, were collected. Serum double-stranded DNA (dsDNA) levels were quantified using a fluorescent assay. Transcriptomic and proteomic analysis of AIM2, Caspase-1, GSDMD, IL-1ß, and IL-18 in peripheral blood mononuclear cells was performed using qRT-PCR and Western blot. Enzyme-linked immunosorbent assay (ELISA) was employed to measure serum IL-1ß and IL-18. Spearman correlation analysis was utilized to assess relationships between variables. Results: Both AGA and AHU groups demonstrated elevated metabolic indicators and serum levels of dsDNA, IL-1ß, and IL-18 compared to the HC group. AGA patients exhibited higher inflammatory markers than the AHU group. In the AGA group, there was a significant increase in the mRNA and protein levels of AIM2, Caspase-1, GSDMD, IL-1ß, and IL-18 (P<0.05 to P<0.001). The AHU group showed higher AIM2, Caspase-1, GSDMD, and IL-18 mRNA levels than the HC group (P<0.001 to P<0.01), with a non-significant increase in AIM2, GSDMD, and IL-1ß proteins (P>0.05). In contrast, Caspase-1 and IL-18 proteins were significantly higher in the AHU group (P<0.05). Notable correlations were observed between AIM2 protein expression and levels of Caspase-1 and GSDMD in both AGA and AHU groups. In the AGA group, AIM2 protein correlated with IL-1ß, but not in the AHU group. The AIM2 protein in the AHU group was positively associated with IL-18, with no such correlation in the AGA group. Conclusion: AIM2 inflammasome may play a role in the inflammatory processes of AGA and AHU and that its activation may be related to the pyroptosis pathway.

Taxonomic characterization and comparative genomic analysis of a novel Devosia species revealed that phenolic acid-degrading traits are ubiquitous in the Devosia genus.

Phenolic acids (PAs) are widely distributed allelochemicals in various environments. To better understand the fate of PAs in environments, a halotolerant PAs-degrading bacterium (named strain RR2S18T) isolated from rhizosphere soil was identified as a novel species of Devosia, named Devosia rhizosphaerae sp. nov. The strain initially degraded PAs into central ring-fission intermediates (protocatechuic acid) using the CoA-dependent non-ß-oxidation pathway. The produced ring-fission intermediates were then consecutively degraded by an ortho-cleavage reaction and the ß-ketoadipic acid pathway. A comparative genomics analysis of 62 Devosia strains revealed that PAs-degrading genes were ubiquitous in their genomes, indicating that PAs degradation is universal among members of this genus. The analysis also suggested that the genes involved in CoA-dependent non-ß-oxidation are inherent to Devosia strains, while those involved in ring-fission and ß-ketoadipic acid pathways were obtained by horizontal gene transfer.

Application of the Unbalanced Ensemble Algorithm for Prognostic Prediction Outcomes of All-Cause Mortality in Coronary Heart Disease Patients Comorbid with Hypertension.

Purpose: This study sought to develop an unbalanced-ensemble model that could accurately predict death outcomes of patients with comorbid coronary heart disease (CHD) and hypertension and evaluate the factors contributing to death. Patients and Methods: Medical records of 1058 patients with coronary heart disease combined with hypertension and excluding those acute coronary syndrome were collected. Patients were followed-up at the first, third, sixth, and twelfth months after discharge to record death events. Follow-up ended two years after discharge. Patients were divided into survival and nonsurvival groups. According to medical records, gender, smoking, drinking, COPD, cerebral stroke, diabetes, hyperhomocysteinemia, heart failure and renal insufficiency of the two groups were sorted and compared and other influencing factors of the two groups, feature selection was carried out to construct models. Owing to data unbalance, we developed four unbalanced-ensemble prediction models based on Balanced Random Forest (BRF), EasyEnsemble, RUSBoost, SMOTEBoost and the two base classification algorithms based on AdaBoost and Logistic. Each model was optimised using hyperparameters based on GridSearchCV and evaluated using area under the curve (AUC), sensitivity, recall, Brier score, and geometric mean (G-mean). Additionally, to understand the influence of variables on model performance, we constructed a SHapley Additive explanation (SHAP) model based on the optimal model. Results: There were significant differences in age, heart rate, COPD, cerebral stroke, heart failure and renal insufficiency in the nonsurvival group compared with the survival group. Among all models, BRF yielded the highest AUC (0.810; 95% CI, 0.778-0.839), sensitivity (0.990; 95% CI, 0.981-1.000), recall (0.990; 95% CI, 0.981-1.000), and G-mean (0.806; 95% CI, 0.778-0.827), and the lowest Brier score (0.181; 95% CI, 0.178-0.185). Therefore, we identified BRF as the optimal model. Furthermore, red blood cell count (RBC), body mass index (BMI), and lactate dehydrogenase were found to be important mortality-associated risk factors. Conclusion: BRF combined with advanced machine learning methods and SHAP is highly effective and accurately predicts mortality in patients with CHD comorbid with hypertension. This model has the potential to assist clinicians in modifying treatment strategies to improve patient outcomes.

Targeted lipidomics-based study of radiation-induced metabolite profiles changes in plasma of total body irradiation cases.

PURPOSE: Lipidomics is an important tool for triaging exposed individuals, and helps early adoption of prevention and control strategies. The purpose of this study was to screen significantly perturbed lipids between pre- and post-irradiation of human plasma samples after total body irradiation (TBI) and explore potential radiation biomarkers for early radiation classification. METHODS: Plasma samples were collected before and after irradiation from 22 hospitalized cases of acute myeloid leukemia (AML) prepared for bone marrow transplantation. Acute total-body γ irradiation was performed at doses of 0, 4, 8, and 12 Gy. Ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) with multiple reaction monitoring (MRM) method was utilized. Self-paired studies before and after irradiation were performed to screen potential lipid categorization markers and markers of dose-response relationships for radiation perturbation in humans. Based on the screened potential markers, a human TBI dose estimation model was developed. RESULTS: In total, 426 individual lipids from 14 major classes were quantified and 152 potential biomarkers with categorical characteristics were screened. A total of 80 lipids (32 TGs, 29 SMs, 9 FAs, 5 CEs, 5 PIs) were upregulated at 4 Gy, and a total of 91 lipids (39 SMs, 18 TGs, 15 HexCers, 7 CEs, 6 Cers, 3 LacCers, 2 LPEs, 1 PI) were upregulated at 12 Gy. Comparison of the ROC curves between the non-exposed and exposed groups at different doses showed AUC values ranging from 0.807 to 0.876. The metabolic pathways of potential lipid markers are mainly sphingolipid and glycerolipid metabolism, unsaturated fatty acid biosynthesis, fatty acid degradation and biosynthesis. Among the 13 dose-dependent radiosensitive lipids, CE (20:5), CE (18:1) and PI (18:2/18:2) were gradually incorporated into the TBI dose estimation model. CONCLUSION: This study suggested that it was feasible to acquire quantitative lipid biomarker panels using targeted lipidomics platforms for rapid, high-throughput triage. Lipidomics strategies for radiation biodosimetry in humans were established with lipid biomarkers with good dose-response relationship.

Dietary supplementation with Clostridium autoethanogenum protein improves growth performance and promotes muscle protein synthesis by activating the mTOR signaling pathway of the broiler.

The experiment aimed to evaluate the effects of different ratios of Clostridium autoethanogenum protein (CAP) used in the diets on the growth performance, muscle quality, serum indexes, and mTOR pathway of white feather broilers. Four hundred and eighty 1-day-old Arbor Acres (AA) broilers, comprising equal numbers of males and females, were randomly assigned to one of four treatments, and each treatment consisted of 12 replicates of 10 birds. Four diets were formulated based on isoenergetic and isonitrogenous principles. The control group (CAP 0) did not receive any CAP, while the experimental groups received 2% (CAP 2), 3% (CAP 3), and 4% (CAP 4) of CAP for six weeks. Compared with the CAP0, (1) The feed conversion ratio (FCR) was lower (p < 0.05), and the leg muscle yield was higher (p < 0.05) in the CAP3 and CAP4; (2) The serum levels of TP, ALB, T-AOC, and SOD were improved in the CAP3 (p < 0.05); (3) The expression of Lipin-1 gene was down-regulated and AMPKɑ2, Akt, and 4E-BP1 genes were up-regulated in the experiment group (p < 0.05); (4) The inclusion of 3% CAP in the diet increased the levels of 4E-BP1, S6K1, Akt, and AMPKɑ2 phosphorylation by modulating the mTOR signaling pathway (p < 0.05). In conclusion, broiler diets containing 3% CAP can activate the mTOR signaling pathway to promote muscle synthesis and improve growth performance.

In situ Raman reveals the critical role of Pd in electrocatalytic CO2 reduction to CH4 on Cu-based catalysts.

Electrocatalytic CO2 reduction reaction (CO2RR) for CH4 production presents a promising strategy to address carbon neutrality, and the incorporation of a second metal has been proven effective in enhancing catalyst performance. Nevertheless, there remains limited comprehension regarding the fundamental factors responsible for the improved performance. Herein, the critical role of Pd in electrocatalytic CO2 reduction to CH4 on Cu-based catalysts has been revealed at a molecular level using in situ surface-enhanced Raman spectroscopy (SERS). A "borrowing" SERS strategy has been developed by depositing Cu-Pd overlayers on plasmonic Au nanoparticles to achieve the in situ monitoring of the dynamic change of the intermediate during CO2RR. Electrochemical tests demonstrate that Pd incorporation significantly enhances selectivity toward CH4 production, and the Faradaic efficiency (FE) of CH4 is more than two times higher than that for the catalysts without Pd. The key intermediates, including *CO2-, *CO, and *OH, have been directly identified under CO2RR conditions, and their evolution with the electrochemical environments has been determined. It is found that Pd incorporation promotes the activation of both CO2 and H2O molecules and accelerates the formation of abundant active *CO and hydrogen species, thus enhancing the CH4 selectivity. This work offers fundamental insights into the understanding of the molecular mechanism of CO2RR and opens up possibilities for designing more efficient electrocatalysts.

Selenoprotein W modulates tau homeostasis in an Alzheimer's disease mouse model.

Lower selenium levels are observed in Alzheimer's disease (AD) brains, while supplementation shows multiple benefits. Selenoprotein W (SELENOW) is sensitive to selenium changes and binds to tau, reducing tau accumulation. However, whether restoration of SELENOW has any protective effect in AD models and its underlying mechanism remain unknown. Here, we confirm the association between SELENOW downregulation and tau pathology, revealing SELENOW's role in promoting tau degradation through the ubiquitin‒proteasome system. SELENOW competes with Hsp70 to interact with tau, promoting its ubiquitination and inhibiting tau acetylation at K281. SELENOW deficiency leads to synaptic defects, tau dysregulation and impaired long-term potentiation, resulting in memory deficits in mice. Conversely, SELENOW overexpression in the triple transgenic AD mice ameliorates memory impairment and tau-related pathologies, featuring decreased 4-repeat tau isoform, phosphorylation at Ser396 and Ser404, neurofibrillary tangles and neuroinflammation. Thus, SELENOW contributes to the regulation of tau homeostasis and synaptic maintenance, implicating its potential role in AD.

Associations of phosphorus concentrations with medial arterial calcification in lower-extremity arteries and diabetic foot in people with diabetes: a retrospective cross-sectional study.

BACKGROUND: The aim of this study was to investigate the associations of blood phosphorus levels with the risk of developing medial arterial calcification (MAC) in lower-limb arteries and diabetic foot (DF) in diabetes patients. We sought to enhance the understanding of the pathophysiology of diabetic complications and develop strategies to mitigate diabetes-related risks. METHODS: We conducted a retrospective analysis of 701 diabetic patients from the Department of Endocrinology at Sun Yat-Sen Memorial Hospital (2019-2023). We utilized multimodel-adjusted logistic regression to investigate the associations of serum phosphorus levels and the risk of developing MAC and DF. Restricted cubic spline plots were employed to model the relationships, and threshold analysis was used to identify inflection points. Subgroup analyses were performed to explore variations across different demographics. The diagnostic utility of phosphorus concentrations was assessed via the C index, net reclassification improvement (NRI), and integrated discrimination improvement (IDI). RESULTS: Of the 701 patients (mean age 63.9 years; 401 (57.20%) were male), 333 (47.50%) had MAC, and 329 (46.93%) had DF. After controlling for numerous confounding variables, each one-unit increase in phosphorus concentrations was associated with an increased risk of developing MAC (OR 2.65, 95% CI 1.97-3.57, p < 0.001) and DF (OR 1.54, 95% CI 1.09-2.18, p = 0.014). Phosphorus levels demonstrated a linear risk association, with risk not being uniform on either side of the inflection point, which was approximately 3.28 mg/dL for MAC and varied for DF (3.26 to 3.81 mg/dL). Adding the phosphorus as an independent component to the diagnostic model for MAC and DF increased the C index, NRI, and IDI to varying degrees. CONCLUSIONS: Elevated serum phosphorus levels are significantly associated with an increased risk of developing MAC and DF among diabetic people. These findings suggest that phosphorus management could be integrated into routine diagnostic processes to improve the identification and management of lower-extremity diabetic complications.

Low expression of selenoprotein S induces oxidative damage in cartilages.

Low levels of the indispensable trace element selenium (Se) can cause oxidative stress and disrupt environmental homeostasis in humans and animals. Selenoprotein S (Selenos), of which Se is a key component, is a member of the selenoprotein family involved in various biological processes. This study aimed to investigate whether low-level SELENOS gene expression can induce oxidative stress and decrease the antioxidative capacity of chondrocytes. Compared with control cells, SELENOS-knockdown ATDC5 cells showed substantially higher dihydroethidium, reactive oxygen species and malondialdehyde levels, and lower superoxide dismutase (SOD) expression. Knockout of the gene in C57BL/6 mice increased the 8-hydroxy-2-deoxyguanosine level considerably and decreased SOD expression in cartilages relative to the levels in wild-type mice. The results showed that the increased nuclear factor erythroid 2-related factor 2/heme oxygenase-1 signaling mediated by low-level SELENOS expression was involved in oxidative damage. The proliferative zone of the cartilage growth plate of SELENOS-knockout mice was shortened, suggesting cartilage differentiation dysfunction. In conclusion, this study confirmed that low-level Selenos expression plays a role in oxidative stress in cartilages.

Artificial antibody-antigen-directed immobilization of α-amylase to hydrolyze starch for cascade reduction of 2-nitro-4-methylphenol to 2-amino-4-methylphenol.

Nitrophenol is a hazardous substance that poses a threat to the environment and human health, and its treatment has attracted widespread attention. The purpose of this study is to establish an environmentally friendly α-amylase system for the hydrolysis of starch to reduce nitrophenol to aminophenol through cascade reactions. The α-amylase system was obtained through artificial antibody-antigen-directed immobilization, including the synthesis of artificial antibodies, synthesis of artificial antigens, and affinity assembly. In this process, catechol and protocatechuic aldehyde were used to prepare artificial antibodies and artificial antigens respectively through polymerization and Schiff base reactions. Then, artificial antibodies captured the catechol in the artificial antigen structure to form immobilized α-amylases. Compared with free α-amylase, the immobilized α-amylase showed a good reusability and excellent regenerative ability. Subsequently, the immobilized α-amylase were used in the reaction of catalyzing starch hydrolysis to synthesize 2-amino-4-methylphenol, and the yield of 2-amino-4-methylphenol was 58.88 ± 0.19 %. After 5 consecutive catalytic reactions, a yield of 47.61 ± 1.27 % can still be achieved.

[Corrigendum] Exosomal microRNA­4516, microRNA­203 and SFRP1 are potential biomarkers of acute myocardial infarction.

Subsequently to the publication of the above article, the authors have realized that, in Fig. 1A, the incorrect image was uploaded to show the ultrastructure of exos isolated from plasma and examined using transmission electron microscopy (essentially, the image in question had already appeared in an article published by the same research group in Journal of Cellular and Molecular Medicine). In addition,  the '+' and '-' signs for the 'Cell lysis' experiments shown underneath the gels in Fig. 1B were incorporated the wrong way around. The revised version of Fig. 1, showing the correct image in Fig. 1A and the correct labels in Fig. 1B, is shown below. Note that the errors made in assembling this figure did not have a major impact on either the results or the conclusions reported in this paper. The authors are grateful to the Editor of Molecular Medicine Reports for allowing them this opportunity to publish a corrigendum, and apologize to the readership of the Journal for any inconvenience caused. [Molecular Medicine Reports 27: 124, 2023; DOI: 10.3892/mmr.2023.13010].

Prevalence and incidence of skin tear in older adults：A systematic review and meta-analysis.

BACKGROUND: Skin tear (ST) is a public health problem in older adults; they substantially increase the risk of complications and cause serious adverse consequences and health care burden. AIM: To estimate the pooled prevalence and incidence of ST among older adults. METHODS: Ten databases were systematically searched from their inception to July 27, 2023. Two researchers performed a systematic review independently according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. All inconsistencies were resolved by a principal researcher. The pooled prevalence and incidence of ST were estimated in R 4.3.1 program. RESULTS: Thirteen studies were included in this review. The pooled prevalence of ST was 6.0 % (95 % confidence interval (CI): 3.0%-11.0 %, I2 = 98 %), and the pooled incidence was 11.0 % (95 % CI: 5.0%-19.0 %, I2 = 94 %). The prevalence of ST was 11.0 % (95 % CI: 5.0%-19.0 %, I2 = 95 %) in long-term care facilities, 5.0 % (95 % CI: 3.0%-9.0 %, I2 = 86 %) in Europe, and 7.0 % (95 % CI: 1.0%-16.0 %, I2 = 82 %) in the Skin Tear Audit Research classification system (STAR). It has stabilized at 6.0 % since 2021. The incidence of ST was 15.0 % (95 % CI: 11.0%-20.0 %, I2 = 66 %) in long-term care facilities in Japan and 4.0 % (95 % CI: 2.0%-6.0 %) in Canada. CONCLUSIONS: Older adults are at a high risk for ST. Our findings emphasize the importance of epidemiologic studies and further exploring assessment tools for ST. Healthcare professionals should pay attention to ST, identify high-risk individuals and associated factors, and implement targeted prevention strategies for older adults.

Preclinical studies of BB-1701, a HER2-targeting eribulin-containing ADC with potent bystander effect and ICD activity.

BACKGROUND: Several HER2-targeting antibody-drug conjugates (ADC) have gained market approval for the treatment of HER2-expressing metastasis. Promising responses have been reported with the new generation of ADCs in patients who do not respond well to other HER2-targeting therapeutics. However, these ADCs still face challenges of resistance and/or severe adverse effects associated with their particular payload toxins. Eribulin, a therapeutic agent for the treatment of metastatic breast cancer and liposarcoma, is a new choice of ADC payload with a distinct mechanism of action and safety profile. METHODS: We've generated a novel HER2-tageting eribulin-containing ADC, BB-1701. The potency of BB-1701 was tested in vitro and in vivo against cancer cells where HER2-expressing levels vary in a large range. Bystander killing effect and toxin-induced immunogenic cell death (ICD) of BB-1701 were also tested. RESULTS: In comparison with HER2-targeting ADCs with DM1 and Dxd payload, eribulin-containing ADC demonstrated higher in vitro cytotoxicity in HER2-low cancer cell lines. BB-1701 also effectively suppressed tumors in models resistant to DM1 or Dxd containing ADCs. Mode of action studies showed that BB-1701 had a significant bystander effect on HER2-null cells adjacent to HER2-high cells. In addition, BB-1701 treatment induced ICD. Repeated doses of BB-1701 in nonhuman primates showed favorable pharmacokinetics and safety profiles at the intended clinical dosage, route of administration, and schedule. CONCLUSIONS: The preclinical data support the test of BB-1701 in patients with various HER2-expressing cancers, including those resistant to other HER2-targeting ADCs. A phase I clinical trial of BB-1701 (NCT04257110) in patients is currently underway.

Building Dual AI Models and Nomograms Using Noninvasive Parameters for Aiding Male Bladder Outlet Obstruction Diagnosis and Minimizing the Need for Invasive Video-Urodynamic Studies: Development and Validation Study.

BACKGROUND: Diagnosing underlying causes of nonneurogenic male lower urinary tract symptoms associated with bladder outlet obstruction (BOO) is challenging. Video-urodynamic studies (VUDS) and pressure-flow studies (PFS) are both invasive diagnostic methods for BOO. VUDS can more precisely differentiate etiologies of male BOO, such as benign prostatic obstruction, primary bladder neck obstruction, and dysfunctional voiding, potentially outperforming PFS. OBJECTIVE: These examinations' invasive nature highlights the need for developing noninvasive predictive models to facilitate BOO diagnosis and reduce the necessity for invasive procedures. METHODS: We conducted a retrospective study with a cohort of men with medication-refractory, nonneurogenic lower urinary tract symptoms suspected of BOO who underwent VUDS from 2001 to 2022. In total, 2 BOO predictive models were developed-1 based on the International Continence Society's definition (International Continence Society-defined bladder outlet obstruction; ICS-BOO) and the other on video-urodynamic studies-diagnosed bladder outlet obstruction (VBOO). The patient cohort was randomly split into training and test sets for analysis. A total of 6 machine learning algorithms, including logistic regression, were used for model development. During model development, we first performed development validation using repeated 5-fold cross-validation on the training set and then test validation to assess the model's performance on an independent test set. Both models were implemented as paper-based nomograms and integrated into a web-based artificial intelligence prediction tool to aid clinical decision-making. RESULTS: Among 307 patients, 26.7% (n=82) met the ICS-BOO criteria, while 82.1% (n=252) were diagnosed with VBOO. The ICS-BOO prediction model had a mean area under the receiver operating characteristic curve (AUC) of 0.74 (SD 0.09) and mean accuracy of 0.76 (SD 0.04) in development validation and AUC and accuracy of 0.86 and 0.77, respectively, in test validation. The VBOO prediction model yielded a mean AUC of 0.71 (SD 0.06) and mean accuracy of 0.77 (SD 0.06) internally, with AUC and accuracy of 0.72 and 0.76, respectively, externally. When both models' predictions are applied to the same patient, their combined insights can significantly enhance clinical decision-making and simplify the diagnostic pathway. By the dual-model prediction approach, if both models positively predict BOO, suggesting all cases actually resulted from medication-refractory primary bladder neck obstruction or benign prostatic obstruction, surgical intervention may be considered. Thus, VUDS might be unnecessary for 100 (32.6%) patients. Conversely, when ICS-BOO predictions are negative but VBOO predictions are positive, indicating varied etiology, VUDS rather than PFS is advised for precise diagnosis and guiding subsequent therapy, accurately identifying 51.1% (47/92) of patients for VUDS. CONCLUSIONS: The 2 machine learning models predicting ICS-BOO and VBOO, based on 6 noninvasive clinical parameters, demonstrate commendable discrimination performance. Using the dual-model prediction approach, when both models predict positively, VUDS may be avoided, assisting in male BOO diagnosis and reducing the need for such invasive procedures.

From Chips-in-Lab to Point-of-Care Live Cell Device: Development of a Microfluidic Device for On-Site Cell Culture and High-Throughput Drug Screening.

Live cell assays provide real-time data of cellular responses. In combination with microfluidics, applications such as automated and high-throughput drug screening on live cells can be accomplished in small devices. However, their application in point-of-care testing (POCT) is limited by the requirement for bulky equipment to maintain optimal cell culture conditions. In this study, we propose a POCT device that allows on-site cell culture and high-throughput drug screening on live cells. We first observe that cell viabilities are substantially affected by liquid evaporation within the microfluidic device, which is intrinsic to the polydimethylsiloxane (PDMS) material due to its hydrophobic nature and nanopatterned surface. The unwanted PDMS-liquid-air interface in the cell culture environment can be eliminated by maintaining a persistent humidity of 95-100% or submerging the whole microfluidic device under water. Our results demonstrate that in the POCT device equipped with a water tank, both primary cells and cell lines can be maintained for up to 1 week without the need for external cell culture equipment. Moreover, this device is powered by a standard alkali battery and can automatically screen over 5000 combinatorial drug conditions for regulating neural stem cell differentiation. By monitoring dynamic variations in fluorescent markers, we determine the optimal doses of platelet-derived growth factor and epidermal growth factor to suppress proinflammatory S100A9-induced neuronal toxicities. Overall, this study presents an opportunity to transform lab-on-a-chip technology from a laboratory-based approach to actual point-of-care devices capable of performing complex experimental procedures on-site and offers significant advancements in the fields of personalized medicine and rapid clinical diagnostics.

Chronic pain in multiple sites is associated with cardiovascular dysfunction: an observational UK Biobank cohort study.

BACKGROUND: Chronic pain is associated with development of cardiovascular disease. We investigated the association between how widespread chronic pain is and the development of cardiovascular dysfunction. METHODS: We analysed data from participants enrolled in the UK Biobank study who underwent examinations at baseline, plus first follow-up and two imaging visits. Pain sites (including hip, knee, back, neck/shoulder, or 'all over the body') and pain duration were recorded at each visit. Chronic pain was defined as pain lasting for ≥3 months. Participants were categorised into six groups: no chronic pain, chronic pain in one, two, three, or four sites, or 'all over the body'. Arterial stiffness index was measured at each time point. Carotid intima-media thickness, cardiac index, and left ventricular ejection fraction (LVEF) were measured using ultrasound and heart MRI at two additional imaging visits in a subset of participants. Mixed-effect linear regression models were used for the analyses. RESULTS: The number of chronic pain sites was directly related to increased arterial stiffness index (n=159,360; ß=0.06 per one site increase, 95% confidence interval 0.04 to 0.08). In 23,899 participants, lower LVEF was associated with widespread chronic pain (ß=-0.17 per one site increase, 95% confidence interval -0.27 to -0.07). The number of chronic pain sites was not associated with carotid intima-media thickness (n=30,628) or cardiac index (n=23,899). CONCLUSION: A greater number of chronic pain sites is associated with increased arterial stiffness and poorer cardiac function, suggesting that widespread chronic pain is an important contributor to cardiovascular dysfunction.

Experiences of older people with multimorbidity regarding self-management of diseases: A systematic review and qualitative meta-synthesis.

AIM: This qualitative systematic review aimed to consolidate existing evidence on the self-management experience of older patients with multimorbidity worldwide. METHODS: Nine databases were searched, for papers published from database inception to April 2023. The systematic review was conducted according to the systematic review method of qualitative evidence by the Joanna Briggs Institute (JBI). RESULTS: Seven studies were included. Finally, four themes and 12 subthemes were formed: (1) physical level: reduced physical function and lack of coordinated care; (2) psychological level: mental state of anxiety and positive attitude towards life; (3) social level: technical support, support from family, support from healthcare workers and support from others; and (4) practical level: economic burden, lifestyle changes, self-care in daily life and compliance was much lower than expected. CONCLUSIONS: To improve self-management in older people with multimorbidity, nurses should provide more guidance to patients to improve their self-management skills, and clinicians should recommend effective self-management behaviours.

Minocycline Inhibits Tick-Borne Encephalitis Virus and Protects Infected Cells via Multiple Pathways.

Tick-borne Encephalitis (TBE) is a zoonotic disease caused by the Tick-borne Encephalitis virus (TBEV), which affects the central nervous system of both humans and animals. Currently, there is no specific therapy for patients with TBE, with symptomatic treatment being the primary approach. In this study, the effects of minocycline (MIN), which is a kind of tetracycline antibiotic, on TBEV propagation and cellular protection in TBEV-infected cell lines were evaluated. Indirect immunofluorescence, virus titers, and RT-qPCR results showed that 48 h post-treatment with MIN, TBEV replication was significantly inhibited in a dose-dependent manner. In addition, the inhibitory effect of MIN on different TBEV multiplicities of infection (MOIs) in Vero cells was studied. Furthermore, the transcriptomic analysis and RT-qPCR results indicate that after incubation with MIN, the levels of TBEV and CALML4 were decreased, whereas the levels of calcium channel receptors, such as RYR2 and SNAP25, were significantly increased. MIN also regulated MAPK-ERK-related factors, including FGF2, PDGFRA, PLCB2, and p-ERK, and inhibited inflammatory responses. These data indicate that administering MIN to TBEV-infected cells can reduce the TBEV level, regulate calcium signaling pathway-associated proteins, and inhibit the MAPK-ERK signaling pathway and inflammatory responses. This research offers innovative strategies for the advancement of anti-TBEV therapy.

Frequency-Specific Alterations of Fractional Amplitude of Low-Frequency Fluctuations in Adult-Onset Hypothyroidism.

BACKGROUND: The neuropathophysiological mechanisms of brain damage underlying hypothyroidism remain unclear. Fractional amplitude of low-frequency fluctuations (fALFF) has been established as a reliable indicator for investigation of abnormal spontaneous brain activity that occurs at specific frequencies in different types of mental disorder. However, the changes of fALFF in specific frequency bands in hypothyroidism have not yet been investigated. METHODS: Fifty-three hypothyroid patients and 39 healthy controls (HCs) underwent thyroid-related hormone levels tests, neuropsychological assessment, and magnetic resonance imaging (MRI) scans. The fALFF in the standard band (0.01-0.1 Hz), slow-4 (0.027-0.073 Hz), and slow-5 bands (0.01-0.027 Hz) were analyzed. An analysis of Pearson correlation was conducted between fALFF, thyroid-related hormone levels, and neuropsychological scores in hypothyroid patients. RESULTS: Compared to HCs, within the routine band, hypothyroidism group showed significantly decreased fALFF in left lingual gyrus, middle temporal gyrus (MTG), precentral gyrus, calcarine cortex, and right inferior occipital gyrus; within the slow-5 band, the hypothyroidism group exhibited decreased fALFF in left lingual gyrus, MTG, superior temporal gyrus, postcentral gyrus, and paracentral lobule, and increased fALFF in supplementary motor area (SMA) and right middle frontal gyrus; additionally, fALFF in the left lingual gyrus within the routine and slow-5 bands were negatively correlated with the level of thyroid stimulating hormone. CONCLUSIONS: In this study, the slow-5 frequency band exhibits better sensitivity than the standard band in detecting fALFF values. A decrease of fALFF values in the lingual gyrus and MTG was observed in both the standard and slow-5 bands and might present potential neuroimaging biomarkers for hypothyroidism. CLINICAL TRIAL REGISTRATION: No: ChiCTR2000028966. Registered 9 January, 2020, https://www.chictr.org.cn.