Development and validation of a clinic-radiomics model based on intratumoral habitat imaging for progression-free survival prediction of patients with clear cell renal cell carcinoma: A multicenter study.

PURPOSE: To develop and validate a clinicoradiomics model based on intratumoral habitat imaging for preoperatively predicting of progression-free survival (PFS) of clear cell renal cell carcinoma (ccRCC) and analyzing progression-associated genes expression. METHODS: This retrospective study included 691 ccRCC patients from multicenter databases. Entire tumor segmentation was performed with handcrafted process to generate habitat subregions based on a pixel-wise gray-level co-occurrence matrix analysis. Cox regression models for PFS prediction were constructed using conventional volumetric radiomics features (Radiomics), habitat subregions-derived radiomics (Rad-Habitat), and an integration of habitat radiomics and clinical characteristics (Hybrid Cox). Training (n = 393) and internal validation (n = 118) was performed in a Nanjing cohort, external validation was performed in a Wuhan and Zhejiang cohort (n = 227) and in a TCGA-KIRC (n =71) with imaging-genomic correlation. Statistical analysis included the area-under-ROC curve analysis, C-index, decision curve analysis (DCA) and Kaplan-Meier survival analysis. RESULTS: Hybrid Cox model resulted in a C-index of 0.83 (95% CI, 0.73-0.93) in internal validation and 0.79 (95% CI, 0.74-0.84) in external validation for PFS prediction, higher than Radiomics and Rad-Habitat model. Patients stratified by Hybrid Cox model presented with significant difference survivals between high-risk and low-risk group in 3 data sets (all P < 0.001 at Log-rank test). TCGA-KIRC data analysis revealed 37 upregulated and 81 downregulated genes associated with habitat imaging features of ccRCC. Differentially expressed genes likely play critical roles in protein and mineral metabolism, immune defense, and cellular polarity maintenance.

Contrasting but interconnecting metatranscriptome between large buoyant and small suspended particles during cyanobacterial blooming in the large shallow eutrophic Taihu Lake.

Large cyanobacterial colonies as visible particles floating on the water surface provide different microbial niches from small particles suspended in the water column in eutrophic freshwaters. However, functional potential differences among microbes colonizing on these contrasting particles are not well understood. Here, the metatranscriptome of microbes inhabiting these two kinds of particles during cyanobacterial bloom (dominated by Microcystis spp.) was analyzed and compared. Community compositions of active bacteria associated with small suspended particles (SA, aggregates dominated by small cyanobacteria colonies, other algae and detritus, etc.) were much more diverse than those associated with large buoyant cyanobacterial colonies (LA), but functional diversity was not significantly different between them. Transcripts related to phosphorus and nitrogen metabolism from Proteobacteria, and respiration from Bacteroidetes were enriched in LA, whereas many more pathways such as photosynthesis from Cyanobacteria, cofactors, and protein metabolism from all dominant phyla were enriched in SA. Nevertheless, many transcripts were significantly correlated within and between LA and SA. These results indicated interconnection of bacteria between LA and SA. Moreover, many transcripts in SA were significantly correlated with transcripts from cyanobacterial phycobilisome in LA, indicating that bacterial metabolism in SA may influence cyanobacterial biomass in LA. Thus, the prediction of cyanobacterial blooms by bacterial activity in SA may be possible when there is no visible bloom on the water surface.

Novel insights into the mechanisms of bioaccumulation and tissue-specific distribution of hexafluoropropylene oxide homologues, novel PFOA alternatives, in zebrafish (Danio rerio).

Hexafluoropropylene oxide trimer acid (HFPO-TA) and hexafluoropropylene oxide tetramer acid (HFPO-TeA) are two novel alternatives of perfluorooctanoic acid (PFOA). However, their toxicokinetics and accumulation mechanisms in fish are still unknown. This study provides the first line of in vivo uptake and depuration kinetic, bioaccumulation mechanism and tissue-specific distribution for HFPO-TA and HFPO-TeA, upon a 28-day water exposure and a 14-day depuration in zebrafish (Danio rerio). HFPO-TeA and HFPO-TA could quickly accumulate in zebrafish, and the highest concentrations of HFPO-TeA (15.4 ± 1.6 nmol/g ww), HFPO-TA (4.95 ± 0.19 nmol/g ww) and PFOA (0.47 ± 0.03 nmol/g ww) were consistently present in the blood, which was followed by liver, kidney, intestine, gill, gonad and brain, while the lowest were observed in the muscle (1.01 ± 0.11, 0.16 ± 0.02, and 0.01 ± 0.001 nmol/g ww, respectively), indicating both higher accumulation potentials of both HFPO homologs than their predecessor PFOA. The tissue protein content, rather than lipid content, played an enhancing role in the enrichment of three target chemicals, exhibiting a significant positive correlation (r = 0.735, p = 0.038 for HFPO-TeA; r = 0.770, p = 0.026 for HFPO-TA and r = 0.942, p = 0.001 for PFOA) between the tissue bioconcentration factor (BCF) and the protein contents in corresponding tissues. This phenomenon was validated by the equilibrium dialysis experiment, molecular docking analysis and molecular dynamics simulation, which consistently indicated that the binding affinities of serum and liver proteins were greatest with HFPO-TeA, followed by HFPO-TA and least with PFOA. These results suggested that the binding of the target chemicals to specific proteins determined their tissue-specific accumulation potentials. Nontarget screening by high resolution mass spectrometry (HRMS) did not identify suspicious degradation products for HFPO-TA, implying the strong persistence of HFPO-TA in fish.

Bidirectional association identified between synovitis and knee and hand osteoarthritis: a general population-based study.

Background: Synovitis has long been considered a common and modifiable inflammatory feature of osteoarthritis (OA), but current disease-modifying anti-inflammatory treatments appear ineffective in OA clinical trials. Elucidating the temporal relationship between synovitis and OA could provide insight into the role of synovitis in OA. Methods: We conducted a prospective cohort study based on the baseline and three-year follow-up data from the Xiangya Osteoarthritis (XO) Study. We assessed bidirectional associations between ultrasound-detected synovitis and radiographic and symptomatic OA at knee and hand sites using generalized estimating equations. Additionally, we performed bidirectional Mendelian randomization (MR) analyses to test these hypotheses utilising whole-genome sequencing data in the XO population. Age, sex, body mass index, smoking, alcohol consumption, educational level, physical activity, and joint injury history were adjusted for these analyses. Findings: A total of 2211, 2420, 2280, and 2600 participants were enrolled for analyses of radiographic knee OA (RKOA), symptomatic knee OA (SKOA), radiographic hand OA (RHOA) and symptomatic hand OA (SHOA), respectively. The baseline synovitis (i.e., with synovitis vs. without synovitis) was associated with the incident RKOA (76/277 vs. 557/3674 knees), SKOA (49/387 vs. 287/4213 knees), RHOA (171/358 vs. 686/3664 hands) and SHOA (35/689 vs. 76/4327 hands), with adjusted odds ratio (aORs) of 2.2 (95% CI 1.7-3.1), 2.0 (1.3-2.9), 3.4 (2.7-4.4), and 2.4 (1.5-3.8), respectively. The baseline RKOA (with OA vs. without OA: 409/1246 vs. 481/3758 knees), SKOA (200/576 vs. 675/4356 knees), RHOA (192/778 vs. 410/3723 hands), and SHOA (41/162 vs. 548/4285 hands) were also associated with the incident synovitis, with aORs of 3.4 (95% CI 2.9-4.1), 2.7 (2.1-3.4), 2.3 (1.8-2.9) and 1.9 (1.2-2.8), respectively. These bidirectional associations were stronger when more active synovitis was compared with the reference group (all P < 0.05). MR analyses further supported bidirectional associations that synovitis significantly increased the odds of incident OA at both sites and vice versa (all ORs ranged from 1.2-1.7). Interpretation: Our population-based cohort study found novel evidence of a bidirectional association between synovitis and OA, which was further validated through MR analysis and suggested that the bidirectional association is likely causal. Our findings indicated that synovitis is both a risk factor and a consequence of the OA rather than solely a risk factor. Funding: The National Key Research and Development Plan, the National Natural Science Foundation of China, the Key Research and Development Program of Hunan Province, the Natural Science Foundation of Hunan Province, the Central South University Innovation-Driven Research Programme, and the Fundamental Research Funds for the Central Universities of Central South University.

A new method to immobilize urease in silk fibroin membrane by unidirectional nanopore dehydration.

The immobilization of free enzymes is crucial for enhancing their stability in different environments, enabling reusability, and expanding their applications. However, the development of a straightforward immobilization method that offers stability, high efficiency, biocompatibility, and modifiability remains a significant challenge. Silk fibroin (SF) is a good carrier for immobilized enzymes and drugs. Here, we employed urease as a model enzyme and utilized our developed technology called unidirectional nanopore dehydration (UND) to efficiently dehydrate a regenerated SF solution containing urease in a single step, resulting in the preparation of a highly functionalized SF membrane immobilizing urease (UI-SFM). The preparation process of UI-SFM is based on an all-water system, which is mild, green and able to efficiently and stably immobilize urease in the membranes, maintaining 92.7% and 82.8% relative enzyme activity after 30 days of storage in dry and hydrated states, respectively. Additionally, we performed additional post-treatments, including stretching and cross-linking with polyethylene glycol diglycidyl ether (PEGDE), to obtain two more robust immobilized urease membranes (UI-SFMs and UI-SFMc). The thermal and storage stability of these two membranes were significantly improved, and the recovery ratio of enzyme activity reached more than 90%. After 10 repetitions of the enzymatic reaction, the activity recovery of UI-SFMs and UI-SFMc remained at 92% and 88%, respectively. The results suggest that both UND-based and post-treatment-developed membranes exhibit excellent urease immobilization capabilities. Furthermore, the enzyme immobilization method offers a straightforward and versatile approach for efficient and stable enzyme immobilization, while its flexible modifiability caters to diverse application requirements.

Extreme trophic tales: deciphering bacterial diversity and potential functions in oligotrophic and hypereutrophic lakes.

BACKGROUND: Oligotrophy and hypereutrophy represent the two extremes of lake trophic states, and understanding the distribution of bacterial communities across these contrasting conditions is crucial for advancing aquatic microbial research. Despite the significance of these extreme trophic states, bacterial community characteristics and co-occurrence patterns in such environments have been scarcely interpreted. To bridge this knowledge gap, we collected 60 water samples from Lake Fuxian (oligotrophic) and Lake Xingyun (hypereutrophic) during different hydrological periods. RESULTS: Employing 16S rRNA gene sequencing, our findings revealed distinct community structures and metabolic potentials in bacterial communities of hypereutrophic and oligotrophic lake ecosystems. The hypereutrophic ecosystem exhibited higher bacterial α- and ß-diversity compared to the oligotrophic ecosystem. Actinobacteria dominated the oligotrophic Lake Fuxian, while Cyanobacteria, Proteobacteria, and Bacteroidetes were more prevalent in the hypereutrophic Lake Xingyun. Functions associated with methanol oxidation, methylotrophy, fermentation, aromatic compound degradation, nitrogen/nitrate respiration, and nitrogen/nitrate denitrification were enriched in the oligotrophic lake, underscoring the vital role of bacteria in carbon and nitrogen cycling. In contrast, functions related to ureolysis, human pathogens, animal parasites or symbionts, and phototrophy were enriched in the hypereutrophic lake, highlighting human activity-related disturbances and potential pathogenic risks. Co-occurrence network analysis unveiled a more complex and stable bacterial network in the hypereutrophic lake compared to the oligotrophic lake. CONCLUSION: Our study provides insights into the intricate relationships between trophic states and bacterial community structure, emphasizing significant differences in diversity, community composition, and network characteristics between extreme states of oligotrophy and hypereutrophy. Additionally, it explores the nuanced responses of bacterial communities to environmental conditions in these two contrasting trophic states.

Therapeutic Measures for Infections Originating from Scalp Incisions Following Deep Brain Stimulation in Patients with Parkinson's Disease.

BACKGROUND: Deep brain stimulation (DBS) is a well-established treatment for Parkinson's disease (PD). However, infection following DBS surgery is a serious complication that can lead to the recurrence and worsening of Parkinson's symptoms or related hardware re-implantation, causing considerable patient suffering and financial burden. OBJECTIVE: This study aims to compare the therapeutic efficiency of different treatment approaches for scalp incision infections after DBS surgery in PD patients. METHODS: We conducted a retrospective review of patients with Parkinson's disease who experienced scalp infections following deep brain stimulation at our hospital between January 2017 and December 2021. The patients were divided into two groups based on whether affected implants were removed or not. Fisher's exact test was applied to compare the reinfection rates between groups A and B. RESULTS: In group A, four patients underwent debridement only, and all of them experienced reinfection between 2-25 months after the initial treatment. In group B, nine patients underwent debridement and removal of potentially affected implants. Among them, eight patients underwent re-implantation of the DBS device within 3-6 months after the initial treatment, and no cases of reinfection occurred. However, one patient experienced reinfection in the postauricular incision and percutaneous tunnel 5 months after the initial treatment, resulting in the complete removal of the entire DBS system. The reinfection rate in group B (11.11%) was significantly lower than that in group A (100%, P=0.007). CONCLUSION: Scalp incision infections following DBS surgery can affect deep tissues, and the implementation of a comprehensive treatment strategy involving local debridement and removal of potentially affected implants can significantly reduce the risk of infection recurrence and its spread.

Exogenous gibberellin suppressed taproot secondary thickening by inhibiting the formation and maintenance of vascular cambium in radish (Raphanus sativus L.).

Introduction: The thickening of radish taproots is primarily determined by secondary growth driven by the vascular cambium and is a highly intricate process regulated by plant hormones, transcription factors, and many metabolic pathways. Gibberellin (GA), a plant hormone associated with cell elongation, is essential in secondary growth. However, the mechanism through which exogenous GA3 regulates secondary taproot growth in radishes remains unclear. Methods: Integrated morphological, anatomical, hormonal, and transcriptomic analyses of taproots in radishes treated with GA3 and its biosynthesis inhibitor paclobutrazol (PBZ) were performed to explore their effects on taproot secondary growth and key regulatory pathways. Results: GA3 significantly hindered taproot thickening by inhibiting the formation and maintenance of the vascular cambium, and PBZ promoted root development by increasing root length rather than root diameter. Transcriptome analysis revealed 2,014, 948, and 1,831 differentially expressed genes identified from the control vs. GA3, control vs. PBZ, and GA3 vs. PBZ comparisons, respectively. Kyoto Encyclopedia of Genes and Genome pathway enrichment analysis revealed that differentially expressed genes were primarily involved in the biosyntheses of secondary metabolites and metabolic pathways. GA3 significantly increased the levels of endogenous indole-acetic acid and the expression of auxin synthesis and signal transduction genes. Discussion: Exogenous GA3 significantly inhibited the expression of genes involved in the maintenance and differentiation of vascular cambium, including WOX14, ER/ERL1, and XCP2. Exogenous GA3 affects root thickening in radishes primarily by regulating hormone signal transduction pathways, vascular cambium activity, and substance and energy metabolisms. Our findings provide insights into the mechanisms underlying taproot thickening in radishes and provide a valuable gene database for future studies.

Optimal blood pressure control with fewer antihypertensive medications: Achieved mostly in low-risk hypertensive patients.

Recent studies indicate that intensive blood pressure (BP) targets can be reached with less than two medications. This cross-sectional study, involving 4991 individuals from the Majiapu community, assessed the correlation between BP control and the burden of antihypertensive drugs. Participants on medication were categorized into controlled (BP < 140/90 mm Hg) and uncontrolled (BP ≥ 140/90 mm Hg) groups, with the former further divided into optimal (BP < 130/80 mm Hg) and good control (BP < 140/90 but >130/80 mm Hg) subgroups. Multivariate logistic regression analyzed factors affecting hypertension control across these BP categories. The study found that, 54% of participants had hypertension. Of those treated (62.5%), 55.7% achieved BP control, including 23.15% maintaining BP below 130/80 mm Hg. The average number of antihypertensive medications was 1.61 for the controlled group (with an average BP of 126.6/76 mm Hg) and 1.75 for the uncontrolled group (with an average BP of 150.6/84.0 mm Hg). Additionally, the average number of antihypertensive medications was 1.66 in the good control group and 1.55 in the optimal control group. The uncontrolled group had a higher mean systematic coronary risk estimation (SCORE) of 5.59, against 3.97 and 2.5 in the good and optimal control groups, respectively. Key factors linked to poor BP control included age over 65, male sex, obesity, and former smoking, whereas lipid-lowering medication use was associated with better control. In conclusions, patients needing fewer antihypertensive drugs to achieve stricter targets may have a lower risk profile. Notably, only a small proportion of treated patients are low-risk individuals who can easily achieve BP levels below 130/80 mm Hg.

Systemic lupus erythematosus and epilepsy: A Mendelian randomization study.

OBJECTIVE: Numerous observational studies have found a relationship between systemic lupus erythematosus (SLE) and epilepsy; however, their causal relationship remains unclear. This study aimed to investigate the causal role of SLE in epilepsy or any of its subtypes using a two-sample Mendelian randomization (MR) analysis. METHODS: Single nucleotide polymorphisms (SNPs) linked to SLE were utilized as instrumental variables in MR analysis to assess their causal impact on epilepsy. The primary MR findings were derived using the inverse variance weighted (IVW) method, which was further supported by the weighted median and MR-Egger regression techniques. Additionally, sensitivity analyses, including Cochran's Q test and pleiotropy tests, were conducted to evaluate the influence of these SNPs on epilepsy, particularly looking for signs of horizontal pleiotropy and heterogeneity. RESULTS: We selected 43 SNPs that reached genome-wide significance from genome-wide association studies (GWASs) on SLE to serve as instrumental variables in this study. The IVW method showed no evidence to support a causal association between SLE and epilepsy (all epilepsy: odds ratio (OR) = 1.006, 95% confidence interval (CI) = 0.994-1.018; focal epilepsy: OR = 1.006, 95% CI = 0.994-1.019; generalized epilepsy: OR = 1.015, 95% CI = 0.996-1.035). Other MR complementary methods revealed consistent results. Furthermore, there was no evidence indicating heterogeneity or horizontal pleiotropy. SIGNIFICANCE: The findings of MR analysis did not support a genetically predicted causal relationship between SLE and epilepsy, but emphasized the need for further research on shared pathophysiological mechanisms, particularly the role of immune system abnormalities and potential influences such as chronic inflammation and therapeutic interventions. PLAIN LANGUAGE SUMMARY: The etiology of epilepsy is complex and diverse, including immune factors. Through a Mendelian randomization analysis, we did not find evidence of a genetic causal relationship between systemic lupus erythematosus and epilepsy. However, this does not invalidate epidemiological evidence, and further exploration is needed to investigate factors influencing the relationship between the two.

Vertical distribution of aerosols and association with atmospheric boundary layer structures during regional aerosol transport over central China.

Atmospheric boundary layer (ABL) structure was a crucial factor in altering the vertical aerosol distribution and modulating the impact of regional aerosol transport on the atmospheric environment in the receptor region. The long-term characteristics of ABL structures for different vertical aerosol distributions and the distinct influencing mechanisms between daytime and nighttime aerosol transport interacting with the diurnal ABL transition have rarely been studied in the receptor regions. Based on 9-year (2013-2021) satellite-retrieved profiles of aerosol extinction coefficients and meteorological sounding data, we targeted Wuhan, an urban city with noteworthy transport contribution in central China, to reveal the general wintertime transport height of ∼500 m and the corresponding unstable ABL structure during regional transport. By comparing typical daytime and nighttime aerosol transport with high-resolution Lidar observations, the aerosol transport near the ABL top coupled with intense mechanical mixing provided sufficient meteorological conditions for heavy aerosol pollution formation in the receptor regions, which was more favorable during nighttime transport followed by the adequate ABL development after sunrise. These findings enhance our comprehension of the ABL impact on air pollution in the receptor regions, which have implications for the precise prevention and control of the regional atmospheric environment.

Individual-specific metabolic network based on 18F-FDG PET revealing multi-level aberrant metabolisms in Parkinson's disease.

Metabolic network analysis in Parkinson's disease (PD) based on 18F-FDG PET has revealed PD-related metabolic patterns. However, alterations at the systemic metabolic network level and at the connection level between different brain regions still remain unknown. This study aimed to explore metabolic network alterations at multiple network levels among PD patients using an individual-specific metabolic network (ISMN) approach. 18F-FDG-PET images of patients with PD (n = 34) and healthy subjects (n = 47) were collected. Healthy subjects were further separated into reference group (n = 28) and control group (n = 19) randomly. Standardized uptake value normalized by lean body mass ratio (SULr) maps was calculated from the PET images. ISMNs were constructed based on SULr maps for PD patients and controls with reference to the reference group. Comparisons of nodal and edge features were performed between PD and control groups. Correlation analysis was conducted between multilevel network properties and clinical scales in PD group. A linear classifier was trained based on nodal or edge features to distinguish PD from controls. The distance from each patient's ISMN to the group-level difference network showed a negative correlation with Hoehn and Yahr stage (r = -0.390, p = .023). Eight nodes from ISMN were identified which exhibited significantly increased nodal degree in PD patients compared to controls (p < .05). Eleven edges were observed which demonstrated significant distinctions in Z-score values in comparisons to the control group (p < .05). Furthermore, the nodal and edge features showed comparable performances in PD diagnosis compared to the traditional SULr values, with area under the receiver operating characteristic curve larger than 0.91. The proposed ISMN approach revealed systemic metabolic deviations, as well as nodal and edge distinctions in PD, which might be supplementary to the existing findings on PD-related metabolic patterns.

LuCl3/B(C6F5)3 Cocatalyzed Reductive Deoxygenation of Ketones, Aldehydes, Alcohols, and Ethers to Alkanes with Pinacolborane.

This report describes the LuCl3/B(C6F5)3 cocatalyzed reductive deoxygenation of 67 ketones, aldehydes, alcohols, and ethers to alkanes under mild conditions. The strategy tolerates reactive amino, hydroxyl, nitro, halogen, vinyl, and ester functional groups, and the results demonstrate rare chemoselective deoxygenation of α,ß-unsaturated ketones. Isotopic labeling experiments, control experiments, and derivatization studies are used to elucidate the reaction mechanism.

Finely ordered intracellular domain harbors an allosteric site to modulate physiopathological function of P2X3 receptors.

P2X receptors, a subfamily of ligand-gated ion channels activated by extracellular ATP, are implicated in various physiopathological processes, including inflammation, pain perception, and immune and respiratory regulations. Structural determinations using crystallography and cryo-EM have revealed that the extracellular three-dimensional architectures of different P2X subtypes across various species are remarkably identical, greatly advancing our understanding of P2X activation mechanisms. However, structural studies yield paradoxical architectures of the intracellular domain (ICD) of different subtypes (e.g., P2X3 and P2X7) at the apo state, and the role of the ICD in P2X functional regulation remains unclear. Here, we propose that the P2X3 receptor's ICD has an apo state conformation similar to the open state but with a less tense architecture, containing allosteric sites that influence P2X3's physiological and pathological roles. Using covalent occupancy, engineered disulfide bonds and voltage-clamp fluorometry, we suggested that the ICD can undergo coordinated motions with the transmembrane domain of P2X3, thereby facilitating channel activation. Additionally, we identified a novel P2X3 enhancer, PSFL77, and uncovered its potential allosteric site located in the 1α3ß domain of the ICD. PSFL77 modulated pain perception in P2rx3+/+, but not in P2rx3-/-, mice, indicating that the 1α3ß, a "tunable" region implicated in the regulation of P2X3 functions. Thus, when P2X3 is in its apo state, its ICD architecture is fairly ordered rather than an unstructured outward folding, enabling allosteric modulation of the signaling of P2X3 receptors.

Weight loss after initiating anti-obesity medications and gout among overweight and obesity individuals: a population-based cohort study.

OBJECTIVES: Weight loss is conditionally recommended for gout management; however, its impact on incident gout and recurrent gout flares among overweight and obese individuals remains unknown. We aimed to investigate the relationship between weight loss rate following the initiation of anti-obesity medications and the risk of incident gout and recurrent gout flares among overweight/obese individuals. METHODS: Using data from The Health Improvement Network, we selected individuals aged 18 and older who were overweight or obese and started anti-obesity medication. We emulated a target trial to examine the association of different weight loss rates, slow (2-5%), moderate (5-10%), or fast (≥10%), within the first year of treatment with incident gout and recurrent gout flares during a 5-year follow-up period. RESULTS: Among 131,000 participants without gout starting orlistat, the 5-year risk of incident gout was 1.6% for those with weight gain/stable, compared with 1.5%, 1.3%, and 1.2% for those with slow, moderate, and fast weight loss, respectively. Compared with the weight gain/stable arm, the hazard ratios were 0.91 (95% confidence interval [CI]: 0.81 to 1.01), 0.82 (95%CI: 0.72 to 0.92), and 0.73 (95%CI: 0.62 to 0.86) for slow, moderate and fast rate of weight loss arms, respectively. Similar results were observed for the recurrent gout flares among 3,847 overweight or obese individuals with gout starting orlistat. CONCLUSIONS: A higher rate of weight loss after initiating orlistat within 1-year was associated with lower risks of incident gout and lower rates of recurrent gout flares among overweight or obese people.

Development of a urea-bond cleavage reaction induced by nitric oxide for fluorescence imaging.

Nitric oxide (NO) is a multifunctional signalling molecule with indispensable roles in physiological processes, but its abnormal production is implicated in various disease conditions. Detecting NO is crucial for interrogating its biological roles. Although many o-phenylenediamine-based fluorescent probes have been developed, only a small fraction has been employed in vivo. Moreover, these probes largely require direct modifications of the fluorophore backbones to render NO responsiveness, which restricts the general applicability of o-phenylenediamine-based probe designs to other types of fluorophores. Here, we report the rational development, optimization, and application of a NO-induced urea-bond cleavage reaction for selective fluorescence detection and imaging of NO in living systems. Through rational design and extensive screening, we identified a 2-aminophenylurea-derived functionality that can react with NO through N-nitrosation, acyltriazole formation, and hydrolysis to induce the cleavage of the urea bond and release of the amino-containing coumarin fluorophore. By caging different amino-containing fluorophore scaffolds with the 2-aminophenylurea-derived functionality, we modularly developed a series of NO fluorescent probes with different excitation and emission profiles for the detection of NO in aqueous solutions and live cells. Among these probes, the near-infrared probe has been demonstrated to enable in vivo fluorescence visualization of elevated endogenous levels of NO in a murine inflammation model. Overall, this study provides a NO-induced urea-bond cleavage reaction and establishes the utility of this reaction for the general and modular development of NO fluorescent probes, thus opening new opportunities for studying and manipulating NO in biological systems.

Efficacy and safety of targeted therapy for radioiodine-refractory differentiated thyroid cancer: a meta-analysis.

PURPOSE: To evaluate the efficacy and safety of current targeted drug therapies for radioiodine-refractory differentiated thyroid cancer (RR-DTC). METHODS: This was a meta-analysis of relevant randomized controlled trials (RCTs) and single-arm studies searched across PubMed, Embase, Cochranes, and Web of Sciences up to September 12, 2023. Stata15.0 software was used to assess overall survival (OS), progression-free survival (PFS), disease control rate (DCR), objective response rate (ORR), and adverse effects (AEs). The Cochrane Bias Risk tool was used to assess literature quality and trial bias and RevMan 5.4 was used to generate a quality assessment map. RESULTS: A total of 8 RCTs and 17 single-arm studies with 3,270 patients on 7 drugs-vandetanib, sorafenib, lenvatinib, cabozantinib, apatinib, donafenib, and anlotinib-were included. Targeted therapy with these drugs effectively prolonged PFS and OS in patients with RR-DTC with overall HRs of 0.35 (95% CI 0.23-0.53, P < 0.00001) and 0.53 (95% CI 0.32-0.86, P < 0.00001), respectively. ORR and DCR were also prolonged, with overall RRs of 27.63 (95% CI 12.39-61.61, P<0.00001) and 1.66 (95% CI 1.48-1.86, P<0.00001), respectively. The subgroup analysis using Effect Size (ES) showed that apatinib had the best effect on ORR with an ES of 0.66 (95% CI 0.49-0.83, P<0.00001) and DCR with a ES of 0.95 (95% CI 0.91-1.00, P<0.00001). Common drug adverse effects included hypertension, diarrhea, proteinuria, and fatigue. CONCLUSION: The currently used targeted drug therapies for RR-DTC can significantly improve clinical outcomes and the new drug apatinib demonstrates promise for potentially superior performance.

The effects of age and frailty on the risks of end-stage renal disease, death, and severe infection in older adults with antineutrophil cytoplasmic antibody-associated vasculitis: a retrospective cohort study.

BACKGROUND: Frailty, a measure of biological age, might predict poor outcomes in older adults better than chronological age. We aimed to compare the effect of age and frailty on end-stage renal disease, death, and severe infection within 2 years of diagnosis in older adults with incident antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. METHODS: This retrospective cohort study included individuals aged 65 years or older from the Mass General Brigham ANCA-associated vasculitis cohort in the USA who were treated between Jan 1, 2002, and Dec 31, 2019. Individuals with a diagnosis of eosinophilic granulomatosis with polyangiitis were excluded from the analysis. Baseline frailty was measured with a claims-based frailty index using data collected in the year before the date of treatment initiation in individuals with at least one health-care encounter before baseline; individuals who did not have an encounter within the 12 months before baseline were classified as pre-frail. Incidence rates of end-stage renal disease or death and severe infections (ie, infections leading to hospital admission or death) at 2 years were estimated, and multivariable analyses were performed to compare the association of age and frailty with these outcomes. Cumulative incidence rates and an additive interaction analysis were used to assess the interaction of age and frailty groupings. FINDINGS: Of the 234 individuals included, 136 (58%) were women, 98 (42%) were men, 198 (85%) were White, and 198 (85%) were positive for myeloperoxidase-specific ANCA. Frailty was present in 25 (22%) of 116 individuals aged 65-74 years and 44 (37%) of 118 aged 75 years or older. In the multivariable analysis, an age of 75 years or older was associated with an increased risk of end-stage renal disease or death (hazard ratio [HR] 4·50 [95% CI 1·83-11·09]), however, frailty was not (1·08 [0·50-2·36]). Both an age of 75 years or older (HR 2·52 [95% CI 1·26-5·04]) and frailty (8·46 [3·95-18·14]) were independent risk factors for severe infections. The effect of frailty on the incidence of end-stage renal disease or death was greater in individuals aged 65-74 years (frail vs non-frail or pre-frail incidence rate 7·5 cases vs 2·0 cases per 100 person-years) than in those aged 75 years or older (13·5 cases vs 16·0 cases per 100 person-years). The effect of frailty on the incidence of serious infections varied by age, with large differences observed among both individuals aged 65-74 years (frail vs non-frail or pre-frail incidence rate 38·9 cases vs 0·8 cases per 100 person-years) and individuals aged 75 years or older (61·9 cases vs 12·3 cases per 100 person-years). Despite the observed differences between the age groups, the additive interaction terms were not statistically significant for either frailty and end-stage renal disease or death (p for interaction=0·276) or frailty and serious infections (p for interaction=0·650). INTERPRETATION: Adults with ANCA-associated vasculitis aged 75 years or older had a higher incidence of end-stage renal disease, death, and severe infections within 2 years of diagnosis than adults aged 65-74 years. Frailty, an approximation of biological age, was a risk factor for severe infection. Assessment beyond chronological age could better inform management decisions in older adults with ANCA-associated vasculitis. FUNDING: National Institutes of Health and National Institute of Arthritis and Musculoskeletal and Skin Diseases.

Protocol for establishing and evaluating a cancer cachexia mouse model.

Cancer cachexia mouse models are needed to recapitulate the clinical features of patients with cachexia. Here, we present a protocol for the establishment and evaluation of cancer cachexia mouse models. We delineate the steps in preparing tumor cells for inoculation and surgical procedures. After the establishment of these mouse models, we describe essential techniques to assess cancer cachexia, including grip strength evaluation, tissue collection, and the calculation of cross-sectional areas of muscle tissue. For complete details on the use and execution of this protocol, please refer to Liu et al.,1 Yang et al.,2 Shi et al.,3 and Zhou et al.4.

Correlation between serum levels of circ_0001879 and circ_0004104, coronary microcirculation disorders and prognosis after percutaneous coronary intervention (PCI) in patients with stable coronary heart disease.

OBJECTIVE: This study aims to elucidate the association between serum levels of circular RNAs circ_0001879 and circ_0004104 and the occurrence of coronary microcirculation disorders along with post-PCI prognosis in individuals with stable coronary heart disease. METHODS: A cohort of 92 patients diagnosed with stable coronary heart disease and subjected to PCI between June 2020 and June 2022 at our institution was assembled. Patients were categorized into an exposed group (n = 60) and a non-exposed group (n = 32), predicated on the coronary angiography-derived microcirculation resistance index (caIMR). RESULTS: Comparative analysis revealed significantly elevated levels of circ_0001879 and circ_0004104 in the serum of the exposed group compared to the non-exposed group, with statistical significance (P < 0.05). Post-PCI, both caFFR and caIMR values demonstrated a marked increase in comparison to pre-surgical measurements within both groups, with the exposed group exhibiting lower indices post-surgery relative to the non-exposed group, indicative of superior microcirculatory outcomes (P < 0.05). Furthermore, serum levels of circ_0001879 and circ_0004104 were inversely correlated with favorable prognosis, with lower levels observed in patients with positive outcomes (P < 0.05). The predictive accuracy for poor prognosis, as indicated by the area under the curve (AUC), was enhanced when circ_0001879 and circ_0004104 were considered in tandem (AUC = 0.934), surpassing the predictive power of individual assessments (Z combination vs circ_0001879 = 2.439, Z combination vs circ_0004104 = 2.317, P < 0.05). CONCLUSION: Elevated serum levels of circ_0001879 and circ_0004104 are observed in stable coronary heart disease patients and are significantly associated with the presence of coronary microcirculation disorders and post-PCI prognosis, underscoring their potential as prognostic biomarkers.