Punicalagin attenuates isoproterenol-induced myocardial infarction through nuclear factor erythroid 2-related factor 2/silent information regulator transcript-1-mediated inhibition of inflammation and cardiac stress markers in experimental animal models.

Myocardial infarction (MI) is a significant global health issue and the leading cause of death. Myocardial infarction (MI) is characterized by events such as damage to heart cells and stress generated by inflammation. Punicalagin (PCN), a naturally occurring bioactive compound found in pomegranates, exhibits a diverse array of pharmacological effects against many disorders. This study aimed to assess the preventive impact of PCN, with its potential anti-inflammatory and antioxidant properties, on myocardial injury caused by isoproterenol (ISO) in rats and elucidate the possible underlying mechanisms. Experimental rats were randomly categorized into four groups: control group (fed a regular diet for 15 days), PCN group (orally administered PCN at 50 mg/kg body weight (b.w.) for 15 days), ISO group (subcutaneously administered ISO (85 mg/kg b.w.) on days 14 and 15 to induce MI), and PCN+ISO group (orally preadministered PCN (50 mg/kg b.w.) for 15 days and administered ISO (85 mg/kg b.w.) on days 14 and 15). The rat cardiac tissue was then investigated for cardiac marker, oxidative stress marker, and inflammatory marker expression levels. PCN prevented ISO-induced myocardial injury, suppressing the levels of creatine kinase-myocardial band, C-reactive protein, homocysteine, cardiac troponin T, and cardiac troponin I in the rats. Moreover, PCN treatment reversed (P<0.01) the ISO-induced increase in blood pressure, attenuated lipid peroxidation markers, and depleted both enzymatic and nonenzymatic markers in the rats. Additionally, PCN inhibited (P<0.01) ISO-induced overexpression of oxidative stress markers (p-38, p-c-Jun N-terminal kinase, and p-extracellular signal-regulated kinase 1), inflammatory markers (nuclear factor-kappa B, tumor necrosis factor-alpha, and interleukin-6), and matrix metalloproteinases and decreased the levels (P<0.01) of apoptosis proteins in the rats. Nuclear factor erythroid 2-related factor 2/silent information regulator transcript-1 (Nrf2/Sirt1) is a major cellular defense protein that regulates and scavenges oxidative toxic substances through apoptosis. Therefore, overexpression of Nrf2/Sirt1 to inhibit inflammation and oxidative stress is considered a novel target for preventing MI. PCN also significantly enhanced the expression of Nrf2/Sirt1 in ISO-induced rats. Histopathological analyses of cardiac tissue revealed that PCN treatment exhibited a protective effect on the heart tissue, mitigating damage. These findings show that by activating the Nrf2/Sirt1 pathway, PCN regulates oxidative stress, inflammation, and apoptosis, hence providing protection against ISO-induced myocardial ischemia.

Target-Mediated Fluoroquinolone Resistance in Neisseria gonorrhoeae: Actions of Ciprofloxacin against Gyrase and Topoisomerase IV.

Fluoroquinolones make up a critically important class of antibacterials administered worldwide to treat human infections. However, their clinical utility has been curtailed by target-mediated resistance, which is caused by mutations in the fluoroquinolone targets, gyrase and topoisomerase IV. An important pathogen that has been affected by this resistance is Neisseria gonorrhoeae, the causative agent of gonorrhea. Over 82 million new cases of this sexually transmitted infection were reported globally in 2020. Despite the impact of fluoroquinolone resistance on gonorrhea treatment, little is known about the interactions of this drug class with its targets in this bacterium. Therefore, we investigated the effects of the fluoroquinolone ciprofloxacin on the catalytic and DNA cleavage activities of wild-type gyrase and topoisomerase IV and the corresponding enzymes that harbor mutations associated with cellular and clinical resistance to fluoroquinolones. Results indicate that ciprofloxacin interacts with both gyrase (its primary target) and topoisomerase IV (its secondary target) through a water-metal ion bridge that has been described in other species. Moreover, mutations in amino acid residues that anchor this bridge diminish the susceptibility of the enzymes for the drug, leading to fluoroquinolone resistance. Results further suggest that ciprofloxacin primarily induces its cytotoxic effects by enhancing gyrase-mediated DNA cleavage as opposed to inhibiting the DNA supercoiling activity of the enzyme. In conclusion, this work links the effects of ciprofloxacin on wild-type and resistant gyrase to results reported for cellular and clinical studies and provides a mechanistic explanation for the targeting and resistance of fluoroquinolones in N. gonorrhoeae.

Interactions between Gepotidacin and Escherichia coli Gyrase and Topoisomerase IV: Genetic and Biochemical Evidence for Well-Balanced Dual-Targeting.

Antimicrobial resistance is a global threat to human health. Therefore, efforts have been made to develop new antibacterial agents that address this critical medical issue. Gepotidacin is a novel, bactericidal, first-in-class triazaacenaphthylene antibacterial in clinical development. Recently, phase III clinical trials for gepotidacin treatment of uncomplicated urinary tract infections caused by uropathogens, including Escherichia coli, were stopped for demonstrated efficacy. Because of the clinical promise of gepotidacin, it is important to understand how the compound interacts with its cellular targets, gyrase and topoisomerase IV, from E. coli. Consequently, we determined how gyrase and topoisomerase IV mutations in amino acid residues that are involved in gepotidacin interactions affect the susceptibility of E. coli cells to the compound and characterized the effects of gepotidacin on the activities of purified wild-type and mutant gyrase and topoisomerase IV. Gepotidacin displayed well-balanced dual-targeting of gyrase and topoisomerase IV in E. coli cells, which was reflected in a similar inhibition of the catalytic activities of these enzymes by the compound. Gepotidacin induced gyrase/topoisomerase IV-mediated single-stranded, but not double-stranded, DNA breaks. Mutations in GyrA and ParC amino acid residues that interact with gepotidacin altered the activity of the compound against the enzymes and, when present in both gyrase and topoisomerase IV, reduced the antibacterial activity of gepotidacin against this mutant strain. Our studies provide insights regarding the well-balanced dual-targeting of gyrase and topoisomerase IV by gepotidacin in E. coli.

Efficient Spin-to-Charge Conversion via Altermagnetic Spin Splitting Effect in Antiferromagnet RuO_{2}.

The relativistic spin Hall effect and inverse spin Hall effect enable the efficient generation and detection of spin current. Recently, a nonrelativistic altermagnetic spin splitting effect (ASSE) has been theoretically and experimentally reported to generate time-reversal-odd spin current with controllable spin polarization in antiferromagnet RuO_{2}. The inverse effect, electrical detection of spin current via ASSE, still remains elusive. Here we show the spin-to-charge conversion stemming from ASSE in RuO_{2} by the spin Seebeck effect measurements. Unconventionally, the spin Seebeck voltage can be detected even when the injected spin current is polarized along the directions of either the voltage channel or the thermal gradient, indicating the successful conversion of x- and z-spin polarizations into the charge current. The crystal axes-dependent conversion efficiency further demonstrates that the nontrivial spin-to-charge conversion in RuO_{2} is ascribed to ASSE, which is distinct from the magnetic or antiferromagnetic inverse spin Hall effects. Our finding not only advances the emerging research landscape of altermagnetism, but also provides a promising pathway for the spin detection.

Chinese Preclinical Alzheimer's Disease Study (C-PAS): Design and Challenge from PET Acceptance.

BACKGROUND: Large-scale preclinical Alzheimer's disease study based on ß-amyloid positron emission tomography (PET) has not been conducted in China. OBJECTIVES: Establish a cohort on Alzheimer's disease spectrum, especially the preclinical stages, and determine the factors influencing the acceptance of ß-amyloid PET scan screening in China. DESIGN: Longitudinal. SETTING: Shanghai, China. PARTICIPANTS: A total of 4386 participants were screened and 2451 participants who met enrollment criteria were eventually included in this report. MEASUREMENTS: The multidimensional data was collected, including comprehensive assessments, PET and magnetic resonance imaging scans, genetics, and plasma biomarkers. RESULTS: There were 571 participants in the normal cognition group, 625 participants in the subjective cognitive decline group, 155 participants in the objectively defined subtle cognitive decline group, 501 participants in the mild cognitive impairment group, 471 participants in Alzheimer's disease group, and 128 participants with cognitive impairment from other known causes. Significant differences in demographics, florbetapir PET, APOE, and neuropsychological tests were found among the groups. Eight hundred and seventeen participants (33.3%) completed the florbetapir PET scanning. Non-demented individuals with higher age, lower education years, male, with a family history of dementia, and higher self-report depression prefer to undergo PET scans. Acceptance of PET scans did not correlate with objectively assessed cognitive impairment. CONCLUSIONS: The Chinese Preclinical Alzheimer's Disease Study was designed to establish a large-scale cohort with comprehensive data collection. Our findings may help to understand the factors affecting the acceptance of ß-amyloid PET in urban areas of China and help us address the low acceptance challenge.

[Clinical features of IgG4-related lung disease].

Objective: To explore the clinical features of IgG4-related lung disease. Methods: The clinical data of 60 patients diagnosed with IgG4-related lung disease in Peking University People's Hospital from February 2012 to May 2021 were retrospectively collected. Analysis was made to explore the features of clinical manifestation, laboratory, imaging, prognosis and other characteristics of the disease. Results: A total of 60 patients were included, with 40 males, age of (58.2±12.9) years, an age of onset of (57.1±13.2) years, and 31.7% (19 cases) of the patients had a history of allergic disease. 36.7% (22 cases) of the patients had respiratory symptoms during the disease. 94.6% (53/56) of patients had serum IgG4>1.35 g/L, 24.1% (14/58) of patients had increased eosinophils, 79.2% (38/48) of patients had increased IgE level, and 53.7% (29/54) of patients had decreased C3 or C4. Common imaging findings included nodular changes (38 cases, 63.3%), mediastinal and/or hilar lymphadenopathy (34 cases, 56.7%), and ground glass opacities (31 cases, 51.7%). Fifty-three cases (88.3%) showed two or more imaging changes. The pathological examination of the patient was mainly characterized by lymphoplasmacytic infiltration and fibrosis, with only one case of phlebitis obliterans. Compared with the asymptomatic group (38 cases), patients with respiratory symptoms (22 cases) showed higher level of serum total IgG and eosinophils (43.2 vs 17.8 g/L, 0.30×109/L vs 0.14×109/L, P<0.05), lower proportion of allergic diseases, and higher proportion of consolidation shadows on chest CT (P<0.05). There were no significant differences in serum IgG4, IgE, complement levels, and imaging outcomes after treatment between the two groups (P>0.05). Conclusions: The clinical manifestations of IgG4-related lung disease are atypical, and asymptomatic patients account for a high proportion. The imaging of the disease is highly heterogeneous, and patients are prone to show coexisted multiple imaging changes. The main clinical features and imaging outcomes of patients with and without respiratory symptoms are not significantly different.

Semi-automatic artifact quantification in thermal ablation probe and algorithms for the evaluation of metal artifact reduction.

OBJECTIVES: To compare metal artifacts and evaluation of metal artifact reduction algorithms during probe positioning in computed tomography (CT)-guided microwave ablation (MWA), cryoablation (CRYO), and radiofrequency ablation (RFA). MATERIALS AND METHODS: Using CT guidance, individual MWA, CRYO, and RFA ablation probes were placed into the livers of 15 pigs. CT imaging was then performed to determine the probe's position within the test subject's liver. Filtered back projection (B30f) and iterative reconstructions (I30-1) were both used with and without dedicated iterative metal artifact reduction (iMAR) to generate images from the initial data sets. Semi-automatic segmentation-based quantitative evaluation was conducted to estimate artifact percentage within the liver, while qualitative evaluation of metal artifact extent and overall image quality was performed by two observers using a 5-point Likert scale: 1-none, 2-mild, 3-moderate, 4-severe, 5-non-diagnostic. RESULTS: Among MWA, RFA, and CRYO, compared with non-iMAR in B30f reconstruction, the largest extent of artifact volume percentages were observed for CRYO (11.5-17.9%), followed by MWA (4.7-6.6%) and lastly in RFA (5.5-6.2%). iMAR significantly reduces metal artifacts for CRYO and MWA quantitatively (p = 0.0020; p = 0.0036, respectively) and qualitatively (p = 0.0001, p = 0.0005), but not for RFA. No significant reduction in metal artifact percentage was seen after applying iterative reconstructions (p > 0.05). Noise, contrast-to-noise-ratio, or overall image quality did not differ between probe types, irrespective of the application of iterative reconstruction and iMAR. CONCLUSION: A dedicated metal artifact algorithm may decrease metal artifacts and improves image quality significantly for MWA and CRYO probes. Their application alongside with dedicated metal artifact algorithm should be considered during CT-guided positioning.

[Efficacy of high-dose dual therapy for Helicobacter pylori infection eradication in servicemen: a randomized controlled trial].

Objective: To assess the efficacy and cost-effectiveness of high-dose dual therapy compared with bismuth-containing quadruple therapy for treating Helicobacter pylori(H.pylori) infection in servicemen patients. Methods: A total of 160 H. pylori-infected, treatment-naive servicemen, including 74 men and 86 women, aged from 20 years to 74 years, with a mean (SD) age of 43 (13) years, tested in the First Center of Chinese PLA General Hospital from March 2022 to May 2022 were enrolled in this open-label, randomized controlled clinical trial. Patients were randomly allocated into 2 groups: the 14-day high-dose dual therapy group and the bismuth-containing quadruple therapy group. Eradication rates, adverse events, patient compliance, and drug costs were compared between the two groups. The t-test was used for continuous variables, and the Chi-square test for categorical variables. Results: No significant difference in H. pylori eradication rates were found between high-dose dual therapy and bismuth-containing quadruple therapy by ITT, mITT and PP analysis[ITT:90.0% (95%CI 81.2%-95.6%) vs. 87.5% (95%CI 78.2%-93.8%), χ2=0.25, P=0.617;mITT:93.5% (95%CI 85.5%-97.9%) vs. 93.3% (95%CI 85.1%-97.8%), χ2<0.01, P=1.000; PP: 93.5% (95%CI 85.5%-97.9%) vs. 94.5% (95%CI 86.6%-98.5%), χ2<0.01, P=1.000 ]. The dual therapy group exhibited significantly less overall side effects compared with the quadruple therapy group [21.8% (17/78) vs. 38.5% (30/78), χ2=5.15,P=0.023]. There were no significant differences in the compliance rates between the two groups [98.7%(77/78) vs. 94.9%(74/78), χ2=0.83,P=0.363]. The cost of medications in the dual therapy was 32.0% lower compared with that in the quadruple therapy (472.10 RMB vs. 693.94 RMB). Conclusions: The dual regimen has a favorable effect on the eradication of H. pylori infection in servicemen patients. Based on the ITT analysis, the eradication rate of the dual regimen is grade B (90%, good). Additionally, it exhibited a lower incidence of adverse events, better compliance and significantly reduced cost. The dual regimen is expected to be a new choice for the first-line treatment of H. pylori infection in servicemen but needs further evaluation.

[Clinical application of a classification based on crucial curvature of coronal imbalance in degenerative lumbar scoliosis].

Objective: To present efficacy of clinical application of a classification based on crucial curvature of coronal imbalance in degenerative lumbar scoliosis (DLS). Methods: A case series study. Clinical data of 61 cases (8 males, 53 females) who underwent posterior correction surgery for DLS from January 2019 to January 2021 were retrospectively analyzed. The mean age was (71.7±6.2) years (ranged 60-82 years). According to the direction of C7 plumb line (C7PL) deviated from central sacral vertical line (CSVL) and orientation of L4 coronal tilt, the author determined which one was the crucial curve. If C7PL deviated from CSVL in the same direction as concave side of the thoracolumbar curve and L4 coronally tilts opposite direction of C7PL deviates from CSVL, then the crucial curve was thoracolumbar curve (type 1). On the contrary, if C7PL deviated from CSVL in the same direction as concave side of the lumbosacral curve and L4 coronally tilts consist with direction of C7PL deviates from CSVL, then the crucial curve was lumbosacral curve (type 2). According to absolute value of coronal balance distance (|CBD|), each type of patients was divided into two groups, respectively, namely coronal balance (CB) (|CBD|≤3 cm) and coronal imbalance (CIB) (|CBD|>3 cm). Changes of Cobb angles of thoracolumbar curve and lumbosacral curve and CBD were recorded and analyzed. Results: The rate of preoperative CIB was 55.7% (34/61) in all the patients. Of the patients, 23 cases were classified as type 1 and 38 cases as type 2. The rate of preoperative CIB was 34.8% (8/23) in type 1 patients and 68.4% (26/38) in type 2. The rate of postoperative CIB was 27.9% (17/61) in all the patients, with 13.0% (3/23) in type 1 and 36.8% (14/38) in type 2. The |CBD| of CB group in type 1 patients decreased from (2.6±1.4) cm before the operation to (1.5±1.0) cm after (P=0.015); and the correction rate of thoracolumbar curve (68.8%±18.4%) was significantly higher than that of lumbosacral curve (34.5%±23.9%) (P=0.005). The |CBD| of CB group in type 2 patients decreased from (2.6±3.0) cm before the operation to (1.6±1.2) cm after (P=0.027); the correction rate of lumbosacral curve (71.3%±18.6%) was higher than that of thoracolumbar curve (57.3%±21.1%), but the difference was not statistically significant (P=0.546). There was no significant difference in |CBD| of CIB group in type 2 patients before and after the operation (P=0.222); the correction rate of lumbosacral curve (38.3%±14.8%) was significantly lower than that of thoracolumbar curve (53.6%±16.0%) (P=0.001). There was a correlation between the change of CBD (3.8±1.5) cm and the difference in correction rate between thoracolumbar and lumbosacral curve (32.3%±19.6%) in CB group in type 1 patients after surgery (r=0.904, P<0.001). There was a correlation between the change of CBD (1.9±2.2) cm and the difference in correction rate between lumbosacral and thoracolumbar curve (14.0%±26.2%) in CB group in type 2 patients after surgery (r=0.960, P<0.001). Conclusion: Clinical application of a classification based on crucial curvature of coronal imbalance in DLS is satisfactory, and its combination with matching correction can effectively prevent the occurrence of coronal imbalance after spinal correction surgery.

[A prospective study on the development and application verification of the quantitative evaluation software for three-dimensional morphology of pathological scars based on photo modeling technology].

Objective: To develop a quantitative evaluation software for three-dimensional morphology of pathological scars based on photo modeling technology, and to verify its accuracy and feasibility in clinical application. Methods: The method of prospective observational study was adopted. From April 2019 to January 2022, 59 patients with pathological scars (totally 107 scars) who met the inclusion criteria were admitted to the First Medical Center of Chinese PLA General Hospital, including 27 males and 32 females, aged 33 (26, 44) years. Based on photo modeling technology, a software for measuring three-dimensional morphological parameters of pathological scars was developed with functions of collecting patients' basic information, and scar photography, three-dimensional reconstruction, browsing the models, and generating reports. This software and the clinical routine methods (vernier calipers, color Doppler ultrasonic diagnostic equipment, and elastomeric impression water injection method measurement) were used to measure the longest length, maximum thickness, and volume of scars, respectively. For scars with successful modelling, the number, distribution of scars, number of patients, and the longest length, maximum thickness, and volume of scars measured by both the software and clinical routine methods were collected. For scars with failed modelling, the number, distribution, type of scars, and the number of patients were collected. The correlation and consistency of the software and clinical routine methods in measuring the longest length, maximum thickness, and volume of scars were analyzed by unital linear regression analysis and the Bland-Altman method, respectively, and the intraclass correlation coefficients (ICCs), mean absolute error (MAE), and mean absolute percentage error (MAPE) were calculated. Results: A total of 102 scars from 54 patients were successfully modeled, which located in the chest (43 scars), in the shoulder and back (27 scars), in the limb (12 scars), in the face and neck (9 scars), in the auricle (6 scars), and in the abdomen (5 scars). The longest length, maximum thickness, and volume measured by the software and clinical routine methods were 3.61 (2.13, 5.19) and 3.53 (2.02, 5.11) cm, 0.45 (0.28, 0.70) and 0.43 (0.24, 0.72) cm, 1.17 (0.43, 3.57) and 0.96 (0.36, 3.26) mL. The 5 hypertrophic scars and auricular keloids from 5 patients were unsuccessfully modeled. The longest length, maximum thickness, and volume measured by the software and clinical routine methods showed obvious linear correlation (with r values of 0.985, 0.917, and 0.998, P<0.05). The ICCs of the longest length, maximum thickness, and volume of scars measured by the software and clinical routine methods were 0.993, 0.958, and 0.999 (with 95% confidence intervals of 0.989-0.995, 0.938-0.971, and 0.998-0.999, respectively). The longest length, maximum thickness, and volume of scars measured by the software and clinical routine methods had good consistency. The Bland-Altman method showed that 3.92% (4/102), 7.84% (8/102), and 8.82% (9/102) of the scars with the longest length, maximum thickness, and volume respectively were outside the 95% consistency limit. Within the 95% consistency limit, 2.04% (2/98) scars had the longest length error of more than 0.5 cm, 1.06% (1/94) scars had the maximum thickness error of more than 0.2 cm, and 2.15% (2/93) scars had the volume error of more than 0.5 mL. The MAE and MAPE of the longest length, maximum thickness, and volume of scars measured by the software and clinical routine methods were 0.21 cm, 0.10 cm, 0.24 mL, and 5.75%, 21.21%, 24.80%, respectively. Conclusions: The quantitative evaluation software for three-dimensional morphology of pathological scars based on photo modeling technology can realize the three-dimensional modeling and measurement of morphological parameters of most pathological scars. Its measurement results were in good consistency with those of clinical routine methods, and the errors were acceptable in clinic. This software can be used as an auxiliary method for clinical diagnosis and treatment of pathological scars.

[Quality of life and risk factors in patients with herpes zoster].

Objective: To evaluate the quality of life and influencing factors of patients with herpes zoster (HZ) seen in hospitals. Methods: Based on Zoster Brief Pain Inventory (ZBPI) and Five-level EuroQol Five-dimensional Questionnaire (EQ-5D-5L), a cross-sectional survey was conducted to evaluate the pain severity and quality of life of 332 HZ cases seen in 22 hospitals of Lu'an City (Anhui Province), Zibo City (Shandong Province) and Tongchuan City (Shaanxi Province) from October to December 2021. The censored least absolute deviations (CLAD) model was used to analyze the related factors affecting the changes of patients' health utility values. Results: The 45.5% of 332 HZ cases were male. The median (Q1,Q3) age was 59 (50, 68) years. 59.64% of them assessed by ZBPI had moderate to severe pain in the past 24 hours (worst pain score≥5), and that of PHN cases was 84.8%(39/46). 77.7% (258/332), 77.4% (257/332) and 74.1% (246/332) of all patients reported that pain interfered with sleep, mood and general activities, respectively. Aging [ß40-49y (95%CI)=-0.11 (-0.15, -0.08); ß50-59y (95%CI)=-0.03 (-0.05, 0.00); ß60-69y (95%CI)=-0.09 (-0.12, -0.06); ß70-90y(95%CI)=-0.16 (-0.19, -0.12)], working status (unemployed) [ßfarmer (95%CI)=0.15 (0.13, 0.18); ßretirees(95%CI)=0.21 (0.18, 0.24); ßemployee (95%CI)=0.13 (0.10, 0.16) ], complications[ßPHN (95%CI)=-0.08 (-0.13, -0.04); ßother complications (95%CI)=-0.12 (-0.15, -0.08)], within 30 days after onset [ß(95%CI)=-0.01 (-0.03, 0.01)] and treatment [ßother complications (95%CI)=-0.09 (-0.11, -0.06)] were related factors for the decline of health utility value (all P values <0.05). Conclusions: More than half of the patients with HZ had moderate to severe pain in the past 24 hours, which had a serious negative impact on the physical and mental health of the patients. Elderly patients, acute patients and patients with complications had lower health utility values and worse health status. We suggest that eligible people be vaccinated with HZ vaccine as soon as possible.

Observation of Spin Splitting Torque in a Collinear Antiferromagnet RuO_{2}.

Current-induced spin torques provide efficient data writing approaches for magnetic memories. Recently, the spin splitting torque (SST) was theoretically predicted, which combines advantages of conventional spin transfer torque (STT) and spin-orbit torque (SOT) as well as enables controllable spin polarization. Here we provide the experimental evidence of SST in collinear antiferromagnet RuO_{2} films. The spin current direction is found to be correlated to the crystal orientation of RuO_{2} and the spin polarization direction is dependent on (parallel to) the Néel vector. These features are quite characteristic for the predicted SST. Our finding not only presents a new member for the spin torques besides traditional STT and SOT, but also proposes a promising spin source RuO_{2} for spintronics.

Joint synovial macrophages as a potential target for intra-articular treatment of osteoarthritis-related pain.

Osteoarthritis is the most common form of joint disease and is one of the leading causes of chronic pain. Given the multi-factorial nature, numerous efforts have been made to clarify the multiple factors impacting the pain symptoms and joint pathology, including synovial macrophages in particular. Accumulating evidence from studies involving human participants and experimental animal models suggests that accumulating macrophages in synovial tissue are implicated in peripherally mediated pain sensitization of affected joints in osteoarthritis. Crosstalk between synovial macrophages and the innervating primary nociceptive neurons is thought to contribute to this facilitated pain processing by the peripheral nervous system. Due to high plasticity and complexity of synovial macrophages in the joint, safe therapies targeting single cells or molecules are currently lacking. Using advanced technologies (such as single-cell RNA sequencing and mass cytometry), studies have shown that diverse subpopulations of synovial macrophages exist in the distinct synovial microenvironments of specific osteoarthritis subtypes. Considerable progress has been made in delineating the molecular mechanisms of various subsets of synovial macrophages in the development of osteoarthritis. To develop a novel intra-articular treatment paradigm targeting synovial macrophages, we have summarized in this review the recent advances in identifying the functional consequences of synovial macrophage sub-populations and understanding of the molecular mechanisms driving macrophage-mediated remodeling.

Knee symptom but not radiographic knee osteoarthritis increases the risk of falls and fractures: results from the Osteoarthritis Initiative.

OBJECTIVE: To describe the effect of knee symptoms and radiographic osteoarthritis (ROA) on the risk of falls, recurrent falls, and fractures. DESIGN: Participants from the Osteoarthritis Initiative were classified as having 'no', 'unilateral' or 'bilateral' knee symptoms (≥19 on a 0-96 Western Ontario and McMaster Universities Osteoarthritis Index) and ROA (Kellgren-Lawrence grade ≥2) for each visit. Self-reported falls and fractures in the past 12 months were extracted at baseline and follow-up visits until month 96. Recurrent falls were defined as having ≥2 falls in the past 12 months. Hazard ratios (HR) with 95% confidence intervals (CI) were estimated using mixed-effects complementary log-log regression. RESULTS: Of 4465 participants, 3145 (70%), 1681 (38%), and 806 (18%) experienced at least one fall, recurrent fall, and fracture, respectively, over 96 months. Compared to participants without symptomatic knee, unilateral and bilateral knee symptoms were associated with a 17% increased risk of falls and a 36-46% increased risk of recurrent falls, and bilateral knee symptoms increased the risk of fractures (HR 1.45, 95%CI 1.17 to 1.81). Compared to participants with no ROA in either knee, bilateral ROA was associated with a reduced risk of falls (HR 0.87, 95%CI 0.77 to 0.99) and fractures (HR 0.78, 95%CI 0.64 to 0.96). No statistically significant interactions between knee symptoms and ROA were observed. CONCLUSIONS: This large population-based study showed that knee symptoms but not ROA increased the risk of falls, recurrent falls, and fractures, and that adults with bilateral ROA may have a lower risk of falls and fractures.

Elevated expression of CDT1 in childhood acute lymphoblastic leukemia promotes cell proliferation, invasion and migration through activation of EMT.

Acute lymphoblastic leukemia (ALL) is a malignant disease of the hematopoietic system. At present, the mechanism and pathogenesis of ALL have not been fully clarified. This study aimed to illustrate the roles of Cdc10 protein-dependent transcript 1 (CDT1) in ALL. Real-Time Quantitative Polymerase Chain Reaction (RT-qPCR) was performed to examine serum levels of CDT1 in childhood ALL patients and healthy volunteers. The interaction between CDT1 expression and prognosis of childhood ALL was analyzed. Meanwhile, expressions of CDT1 in ALL cell lines were determined. Furthermore, CDT1 knockdown model was constructed in ALL cells, and Cell Counting Kit-8 (CCK-8), and Transwell assays were conducted to analyze the effect of CDT1 on the biological functions of ALL cells. Potential mechanism was further explored through detecting the expressions of Epithelial-to-mesenchymal transition (EMT)-related genes. RT-qPCR results indicated that serum level of CDT1 in childhood ALL patients was remarkably higher than that of healthy volunteers. Childhood ALL patients with high expression of CDT1 had lower overall survival rate compared with those expressing low expression of CDT1. CDT1 knockdown remarkably decreased the proliferation and metastasis abilities of pediatric ALL cells. Results of western blot showed that CDT1 might contribute to the malignant progression of childhood ALL via activating EMT. The findings showed that elevated CDT1 facilitated ALL metastasis by promoting EMT, suggesting that CDT1 played a pivotal role in ALL metastasis and may serve as a novel prognostic biomarker and therapeutic target.

Nutritional Status and Risks of Cognitive Decline and Incident Neurocognitive Disorders: Singapore Longitudinal Ageing Studies.

BACKGROUND: Studies suggest that nutritional interventions using the whole diet approach such as the Mediterranean diet may delay cognitive decline and dementia onset. However, substantial numbers of older adults are non-adherent to any ideally healthy dietary pattern and are at risk of malnutrition. OBJECTIVE: The present study investigated the relationship between global malnutrition risk and onsets of cognitive decline and neurocognitive disorders (NCD), including mild cognitive impairment (MCI) or dementia in community-dwelling older adults. METHODS: Participants aged ≥ 55 years in the Singapore Longitudinal Ageing Studies (SLAS) were assessed at baseline using the Elderly Nutritional Indicators for Geriatric Malnutrition Assessment (ENIGMA) and followed up 3-5 years subsequently on cognitive decline (MMSE drop ≥ 2) among 3128 dementia-free individuals, and incident neurocognitive disorders (NCD) among 2640 cognitive normal individuals. RESULTS: Individuals at high nutritional risk score (≥ 3) were more likely to develop cognitive decline (OR=1.42, 95%CI=1.01-1.99) and incident MCI-or-dementia (OR=1.64, 95%CI=1.03-2.59), controlling for age, sex, ethnicity, low education, APOE-e4, hearing loss, physical, social, and mental activities, depressive symptoms, smoking, alcohol, central obesity, hypertension, diabetes, low HDL, high triglyceride, cardiac disease, and stroke. Among ENIGMA component indicators, low albumin at baseline was associated with cognitive decline and incident NCD, and 5 or more drugs used, few fruits/vegetables/milk products daily, and low total cholesterol were associated with incident NCD. CONCLUSION: The ENIGMA measure of global malnutrition risk predicts cognitive decline and incident neurocognitive disorders, suggesting the feasibility of identifying vulnerable subpopulations of older adults for correction of malnutrition risk to prevent neurocognitive disorders.

Radiological management of postoperative lymphorrhea.

PURPOSE: Postoperative lymphorrhea can occur after different surgical procedures and may prolong the hospital stay due to the need for specific treatment. In this work, the therapeutic significance of the radiological management of postoperative lymphorrhea was assessed and illustrated. METHOD: A standardized search of the literature was performed in PubMed applying the Medical Subject Headings (MeSH) term "lymphangiography." For the review, the inclusion criterion was "studies with original data on Lipiodol-based Conventional Lymphangiography (CL) with subsequent Percutaneous Lymphatic Intervention (PLI)." Different exclusion criteria were defined (e.g., studies with <15 patients). The collected data comprised of clinical background and indications, procedural aspects and types of PLI, and outcomes. In the form of a pictorial essay, each author illustrated a clinical case with CL and/or PLI. RESULTS: Seven studies (corresponding to evidence level 4 [Oxford Centre for Evidence-Based Medicine]) accounting for 196 patients were included in the synthesis and analysis of data. Preceding surgery resulting in postoperative lymphorrhea included different surgical procedures such as extended oncologic surgery or vascular surgery. Central (e.g., chylothorax) and peripheral (e.g., lymphocele) types of postoperative lymphorrhea with a drainage volume of 100-4000 ml/day underwent CL with subsequent PLI. The intervals between "preceding surgery and CL" and between "CL and PLI" were 2-330 days and 0-5 days, respectively. CL was performed before PLI to visualize the lymphatic pathology (e.g., leakage point or inflow lymph ducts), applying fluoroscopy, radiography, and/or computed tomography (CT). In total, seven different types of PLI were identified: (1) thoracic duct (or thoracic inflow lymph duct) embolization, (2) thoracic duct (or thoracic inflow lymph duct) maceration, (3) leakage point direct embolization, (4) inflow lymph node interstitial embolization, (5) inflow lymph duct (other than thoracic) embolization, (6) inflow lymph duct (other than thoracic) maceration, and (7) transvenous retrograde lymph duct embolization. CL-associated and PLI-associated technical success rates were 97-100% and 89-100%, respectively. The clinical success rate of CL and PLI was 73-95%. CL-associated and PLI-associated major complication rates were 0-3% and 0-5%, respectively. The combined CL- and PLI-associated 30-day mortality rate was 0%, and the overall mortality rate was 3% (corresponding to six patients). In the pictorial essay, the spectrum of CL and/or PLI was illustrated. CONCLUSION: The radiological management of postoperative lymphorrhea is feasible, safe, and effective. Standardized radiological treatments embedded in an interdisciplinary concept are a step towards improving outcomes.

[Efficacy and safety of prophylactic intravenous administration of tranexamic acid in abdominal aorta balloon-assisted pelvic tumor surgery].

Objective: To investigate the efficacy and safety of prophylactic intravenous (IV) administration of tranexamic acid (TXA) in abdominal aorta balloon-assisted pelvic tumor surgery. Methods: The data of patients who underwent abdominal aorta balloon-assisted pelvic tumor surgery in Peking University People's Hospital from January 1, 2015 to December 31, 2019 were retrospectively collected. According to whether receiving the prophylactic use of TXA, the patients were divided into two groups: TXA group and control group. After propensity score matching based on age, gender and surgeon, 51 patients in TXA group and 51 patients in control group were allocated. The baseline, intraoperative and postoperative clinical data of the two groups were compared to explore the efficacy and safety of TXA. Results: A total of 525 cases undergoing abdominal aorta balloon-assisted pelvic surgery were enrolled from 2015 to 2019, of which 51 cases received prophylactic use of TXA, with a utilization rate of 9.7%. There were no significant differences in age [(40.7±15.1) years vs (38.2±14.5) years, P=0.393], gender (male: 51.0% vs 49.0%, P=0.843), body weight, body mass index (BMI), complications, American Society of Anesthesiologists (ASA) classification, hemoglobin, hemocrit (Hct), platelet, coagulation function-related indexes and tumor pathological types between the two groups (all P>0.05). Likewise, there were no significant differences in operation time, anesthesia time, cumulative time of balloon occlusion, intraoperative blood loss, intravenous fluid volume and blood transfusion volume between the two groups (all P>0.05). Additionally, there were no significant differences in postoperative ICU admission rate and length of hospital stay between the two groups (all P>0.05), and no venous thromboembolism (VTE) or death was reported. Compared with the control group, the rate of blood transfusion at 24 hours after operation in the TXA group was lower (41.2% vs 70.6%, P=0.003). The level of fibrinogen degradation products was lower [10.4 (6.1, 22.6) mg/L vs 13.2 (7.0, 24.7) mg/L], but the difference was not statistically significant (P=0.326). Conclusions: Prophylactic IV use of TXA does not reduce intraoperative bleeding in abdominal aorta balloon-assisted pelvic tumor surgery, but can decrease the rate of postoperative blood transfusion. No increased risk of postoperative TXA-related VTE was observed.