Coronavirus disease 2019 (COVID-19) is a multi-system disease that can lead to various severe complications. Acute limb ischemia (ALI) has been increasingly recognized as a COVID-19-associated complication that often predicts a poor prognosis. However, the pathophysiology and molecular mechanisms underlying COVID-19-associated ALI remain poorly understood. Hypercoagulability and thrombosis are considered important mechanisms, but we also emphasize the roles of vasospasm, hypoxia, and acidosis in the pathogenesis of the disease. The angiotensin-converting enzyme 2 (ACE2) pathway, inflammation, and platelet activation may be important molecular mechanisms underlying these pathological changes induced by COVID-19. Furthermore, we discuss the hypotheses of risk factors for COVID-19-associated ALI from genetic, age, and gender perspectives based on our analysis of molecular mechanisms. Additionally, we summarize therapeutic approaches such as use of the interleukin-6 (IL-6) blocker tocilizumab, calcium channel blockers, and angiotensin-converting enzyme inhibitors, providing insights for the future treatment of coronavirus-associated limb ischemic diseases.
Humans ; COVID-19/physiopathology* ; Ischemia/etiology* ; SARS-CoV-2 ; Extremities/blood supply* ; Risk Factors ; Interleukin-6/antagonists & inhibitors* ; Acute Disease ; Angiotensin-Converting Enzyme 2

Now recognized as a global health crisis, obesity has been linked to an increased risk of many types of cancer, including those of the breast, colon, rectum, uterus, gallbladder, and ovary. Obesity and cancer share several characteristics at the cellular, molecular, and epigenetic levels. Obesity is characterized by chronic inflammation of the adipose tissue (AT), resulting in genotoxic stress that further induces metabolic complications and contributes to the initiation and progression of cancer. The excessive accumulation of AT provides adipokines and lipids to engage tumor cells with stromal and immune cells to infiltrate carcinomas and secrete a plethora of cytokines, chemokines, and growth factors within the tumor microenvironment (TME) that contribute to carcinogenesis. Obesity also alters the metabolic reprogramming of immune cells, including macrophages, neutrophils, and T cells, thereby providing a suitable environment for the growth and progression of cancer. Obesity-associated metabolic dysregulation also perturbs the gut microbiome, which produces metabolites that can further increase the risk of cancer progression. This review will discuss links between obesity and cancer progression, including several crucial pathways that bridge the crosstalk between obesity-associated changes in AT inflammation, immune cells, adipokines, chemokines, and tumor cells to support cancer progression. We will also discuss our insights into the mechanisms by which obesity-driven factors influence metabolic reprogramming and touch base on how obesity mediates microbiome dysbiosis to alter metabolite and affect cancer progression. Altogether, this review highlights the crossroads of the obesity-cancer axis, describes its salient features, and presents possible therapeutic approaches for obesity-related cancers.

Enterococcus species are Gram-positive cocci normally found in the gut but have emerged as opportunistic pathogens in healthcare settings, with rising multidrug resistance, particularly vancomycin-resistant Enterococci (VRE) posing major therapeutic challenges. This study evaluated the antibacterial and synergistic effects of plant-derived stilbenes from Reynoutria japonica against clinical VRE isolates. Ten clinical Enterococcus faecalis isolates were identified using standard morphological, biochemical, and Gram-staining methods, and antibiotic susceptibility testing. The antibacterial activity of polydatin, resveratroloside, and trans-resveratrol was assessed by agar well diffusion, and evaluation of minimum inhibitory concentrations (MICs) and evaluation of bactericidal activity concentrations (MBCs), with synergistic effects tested in combination with vancomycin.Molecular docking was performed with DapF, vanA, and gelE proteins. All isolates were resistant to vancomycin, ampicillin, imipenem, gentamicin, and ciprofloxacin but sensitive to linezolid. All three stilbenes displayed antibacterial activity. Notably, trans-resveratrol was the most active compound, with a MIC value of 0.156 mM and bactericidal activity (an MBC value equal to the MIC). Furthermore, all compounds exhibited synergistic effects when combined with vancomycin. Phytochemical analysis confirmed these stilbenes as major constituents in the root extract of R. japonica. Molecular docking studies revealed strong binding affinities of the compounds to key virulence and resistance-associated proteins (DapF, VanA, and GelE). These results indicate that transresveratrol and related stilbenes are promising candidates for development as alternative or adjunct therapeutic agents against VRE infections. Additionally, this study substantiates the traditional use of R. japonica as a source of bioactive antimicrobial compounds.

Objective: The objective of this systematic review and meta-analysis is to evaluate the efficacy, safety, time to international normalized ratio (INR) reversal, and total volume of four-factor prothrombin complex concentrate (4-PCC) administered using fixed-dose versus weight-based dosing strategies in patients requiring urgent warfarin reversal, with specific focus on clinical outcomes of hemostatic efficacy, thromboembolic events, and mortality rates. Methods: A comprehensive systematic review was conducted using the PubMed, Embase, and Cochrane databases from inception through October 2023. We searched for randomized clinical trials or observational studies that compared efficacy or safety outcomes of fixed versus variable 4-PCC dose in adult patients. Results: In the 14 included studies, the overall use of fixed-dose 4-PCC was associated with a lower likelihood of reaching the INR goal (risk ratio [RR], 0.84; 95% confidence interval [CI], 0.80–0.89) compared to the variable-dose group. In addition, a significantly larger proportion of patients (169 of 651, 26%) required an additional dose of 4-PCC. The rates of mortality (RR, 0.85; 95% CI, 0.70–1.03) and thromboembolic events (RR, 1.27; 95% CI, 0.65–2.45) were similar between the two treatment groups. Conclusion This systematic review and meta-analysis showed that variable dosing of 4-PCC more successfully achieves the target INR for warfarin reversal compared to fixed dosing. However, the dosing strategies have similar mortality and thromboembolic rates. While fixed dosing offers a simpler approach, it may require additional administration. Future studies should focus on optimizing dosing strategies to balance efficacy, safety, and practicality in various clinical scenarios

Background: Pediatric malignant bone tumors constitute an important subgroup of solid tumors and need comprehensive multidisciplinary care for optimal management. We aimed to review our local practice of managing malignant bone tumors and identify gaps to improve service. Methods: We retrospectively reviewed disease characteristics and management of twenty-five pediatric patients with malignant bone tumors from Jan 2000 to Dec 2020. Results: Median age at diagnosis was 8.75 years, male to female ratio of 0.8:1, and median follow-up was 3.6 years. Pain and swelling were the predominant symptoms at presentation, while lung was the most common metastatic site in Osteosarcoma (OS) and Ewing’s Sarcoma Family Tumors (ESFT). Metastatic disease was not associated with developing an event in OS (P=0.26) but was significantly associated with developing an event in the ESFT subgroup (P=0.002). There was no association of tumor necrosis of ＜90% or positive histological margins with developing an event in the entire cohort. The relapsed disease was associated with a mortality risk in the OS group (P=0.01). At the same time, it did not return significant results for this association in ESFT; however, a trend was noted for poor outcomes (P=0.09). Event-free survival and overall survival in OS were 54% and 69%, while in the ESFT group, they were 50% and 66%, respectively. Conclusion Metastatic disease was associated with developing relapsed disease in the ESFT cohort, while relapsed disease was associated with mortality in the OS cohort.Positive histological margins and ＜90% necrosis on resected tumor specimens did not result in poor survival. Multicenter collaboration at the national level is needed to improve the outcome of this disease group, which needs specialized multidisciplinary management.

This systematic review and meta-analysis aimed to examine the effect of the antioxidant alpha-lipoic acid (ALA) on various cardiometabolic risk factors and hormonal parameters in patients with polycystic ovary syndrome (PCOS). We searched PubMed, EMBASE, SCOPUS, Cochrane Library, and Web of Science databases without language restrictions until May 2023 to find randomized controlled trials (RCTs) that assessed the impact of ALA supplementation on anthropometric, glycemic, lipid, oxidative stress, and hormonal parameters in women with PCOS. Outcomes were summarized using the standardized mean difference (SMD) and 95% confidence interval (CI) in a random-effects model. An I2 statistic of >60% established significant between-study heterogeneity. The overall certainty of the evidence for each outcome was determined using the grading of recommendations, assessment, development, and evaluations system. Seven RCTs met the inclusion criteria. The ALA group had significant reductions in fasting blood sugar (fasting blood sugar (FBS), n=7 RCTs, SMD, -0.60; 95% CI, -1.10 to -0.10; I2=63.54%, moderate certainty of evidence) and homeostatic model assessment for insulin resistance (homeostatic model assessment of insulin resistance (HOMA-IR), n=4 RCTs, SMD, -2.03; 95% CI, -3.85 to -0.20; I2=96.32%, low certainty of evidence) compared with the control group. However, significant differences were observed between the groups in body mass index, insulin, estrogen, follicle-stimulating hormone, luteinizing hormone, testosterone, low-density lipoprotein, highdensity lipoprotein, triglyceride, total cholesterol, malondialdehyde, or total antioxidant capacity profiles. ALA supplementation improves FBS and HOMA-IR levels in women with PCOS. ALA consumption is an effective complementary therapy for the management of women with PCOS.

This study aimed to review randomized controlled trials (RCTs) investigating the effects of dietary antioxidant supplements on the severity of endometriosis-related pain symptoms. The PubMed/Medline, Scopus, and Web of Science databases were searched until April 2022. Additionally, we manually searched the reference lists. Endpoints were summarized as standardized mean difference (SMD) with 95% confidence intervals (CIs) in a random-effects model. The I2 statistic was used to assess heterogeneity. Ten RCTs were included in this meta-analysis. Overall, 10 studies were related to dysmenorrhea, four to dyspareunia, and four to pelvic pain. Antioxidants significantly reduced dysmenorrhea (SMD, -0.48; 95% CI, -0.82 to -0.13; I2=75.14%). In a subgroup analysis, a significant reduction of dysmenorrhea was observed only in a subset of trials that administered vitamin D (SMD, -0.59; 95% CI, -1.13 to -0.06; I2=69.59%) and melatonin (SMD, -1.40; 95% CI, -2.47 to -0.32; I2=79.15%). Meta-analysis results also suggested that antioxidant supplementation significantly improved pelvic pain (SMD, -1.51; 95% CI, -2.74 to -0.29; I2=93.96%), although they seem not to have a significant beneficial impact on the severity of dyspareunia. Dietary antioxidant supplementation seems to beneficially impact the severity of endometriosis-related dysmenorrhea (with an emphasis on vitamin D and melatonin) and pelvic pain. However, due to the relatively small sample size and high heterogeneity, the findings should be interpreted cautiously, and the importance of further well-designed clinical studies cannot be overstated.

PURPOSE: The objectives of the current study were to estimate the influence of self-reinforced hollow structures with a graded density on the dimensional accuracy, weight, and mechanical properties of Co-Cr objects printed with the direct metal laser sintering (DMLS) technique. MATERIALS AND METHODS: Sixty-five dog-bone samples were manufactured to evaluate the dimensional accuracy of printing, weight, and tensile properties of DMLS printed Co-Cr. They were divided into Group 1 (control) (n = 5), Group 2, 3, and 4 with incorporated hollow structures based on (spherical, elliptical, and diamond) shapes; they were subdivided into subgroups (n = 5) according to the volumetric reduction (10%, 15%, 20% and 25%). Radiographic imaging and microscopic analysis of the fractographs were conducted to validate the created geometries; the dimensional accuracy, weight, yield tensile strength, and modulus of elasticity were calculated. The data were estimated by one-way ANOVA and Duncan’s tests at P < .05. RESULTS: The accuracy test showed an insignificant difference in the x, y, z directions in all printed groups. The weight was significantly reduced proportionally to the reduced volume fraction. The yield strength and elastic modulus of the control group and Group 2 at 10% volume reduction were comparable and significantly higher than the other subgroups. CONCLUSION The printing accuracy was not affected by the presence or type of the hollow geometry. The weight of Group 2 at 10% reduction was significantly lower than that of the control group. The yield strength and elastic modulus of the Group 2 at a 10% reduction showed means equivalent to the compact objects and were significantly higher than other subgroups.

Background: Pediatric malignant bone tumors constitute an important subgroup of solid tumors and need comprehensive multidisciplinary care for optimal management. We aimed to review our local practice of managing malignant bone tumors and identify gaps to improve service. Methods: We retrospectively reviewed disease characteristics and management of twenty-five pediatric patients with malignant bone tumors from Jan 2000 to Dec 2020. Results: Median age at diagnosis was 8.75 years, male to female ratio of 0.8:1, and median follow-up was 3.6 years. Pain and swelling were the predominant symptoms at presentation, while lung was the most common metastatic site in Osteosarcoma (OS) and Ewing’s Sarcoma Family Tumors (ESFT). Metastatic disease was not associated with developing an event in OS (P=0.26) but was significantly associated with developing an event in the ESFT subgroup (P=0.002). There was no association of tumor necrosis of ＜90% or positive histological margins with developing an event in the entire cohort. The relapsed disease was associated with a mortality risk in the OS group (P=0.01). At the same time, it did not return significant results for this association in ESFT; however, a trend was noted for poor outcomes (P=0.09). Event-free survival and overall survival in OS were 54% and 69%, while in the ESFT group, they were 50% and 66%, respectively. Conclusion Metastatic disease was associated with developing relapsed disease in the ESFT cohort, while relapsed disease was associated with mortality in the OS cohort.Positive histological margins and ＜90% necrosis on resected tumor specimens did not result in poor survival. Multicenter collaboration at the national level is needed to improve the outcome of this disease group, which needs specialized multidisciplinary management.