Cold exposure-induced plasma exosomes impair bone mass by inhibiting autophagy.

Recently, environmental temperature has been shown to regulate bone homeostasis. However, the mechanisms by which cold exposure affects bone mass remain unclear. In our present study, we observed that exposure to cold temperature (CT) decreased bone mass and quality in mice. Furthermore, a transplant of exosomes derived from the plasma of mice exposed to cold temperature (CT-EXO) can also impair the osteogenic differentiation of BMSCs and decrease bone mass by inhibiting autophagic activity. Rapamycin, a potent inducer of autophagy, can reverse cold exposure or CT-EXO-induced bone loss. Microarray sequencing revealed that cold exposure increases the miR-25-3p level in CT-EXO. Mechanistic studies showed that miR-25-3p can inhibit the osteogenic differentiation and autophagic activity of BMSCs. It is shown that inhibition of exosomes release or downregulation of miR-25-3p level can suppress CT-induced bone loss. This study identifies that CT-EXO mediates CT-induced osteoporotic effects through miR-25-3p by inhibiting autophagy via targeting SATB2, presenting a novel mechanism underlying the effect of cold temperature on bone mass.

The Naples prognostic score serves as a predictor and prognostic indicator for cancer survivors in the community.

OBJECTIVE: Inflammation, malnutrition, and cancer are intricately interconnected. Despite this, only a few studies have delved into the relationship between inflammatory malnutrition and the risk of death among cancer survivors. This study aimed to specifically investigate the association between the categorically defined Naples prognostic score (NPS) and the prognosis of cancer survivors. METHODS: Data from 42,582 participants in the National Health and Nutrition Examination Survey (NHANES, 1999-2018) were subjected to analysis. Naples prognostic scores (NPS) were computed based on serum albumin (ALB), total cholesterol (TC), neutrophil to lymphocyte ratio (NLR), and lymphocyte to monocyte ratio (LMR), and participants were stratified into three groups accordingly. Cancer status was ascertained through a self-administered questionnaire, while mortality data were sourced from the National Death Index up to December 31, 2019. Multiple logistic regression was employed to estimate the odds ratio (OR) with a 95% confidence interval (CI) between NPS and cancer prevalence within the U.S. community population. Kaplan-Meier survival analysis and the Log-rank test were utilized to compare survival disparities among the three groups. Additionally, Cox proportional regression was utilized to estimate the hazard ratio (HR) with a 95% CI. RESULTS: The incidence of cancers was 9.86%. Among the participants, 8140 individuals (19.1%) were classified into Group 0 (NPS 0), 29,433 participants (69.1%) into Group 1 (NPS 1 or 2), and 5009 participants (11.8%) into Group 2 (NPS 3 or 4). After adjusting for confounding factors, the cancer prevalence for the highest NPS score yielded an odds ratio (OR) of 1.64 (95% CI: 1.36, 1.97) (P(for trend) < 0.05). In comparison to cancer survivors in Group 0, those with the highest NPS had adjusted hazard ratios (HRs) of 2.57 (95% CI: 1.73, 3.84) for all-cause mortality, 3.44 (95% CI: 1.64, 7.21) for cardiovascular mortality, 1.60 (95% CI: 1.01, 2.56) for cancer mortality, and 3.15 (95% CI: 1.74, 5.69) for other causes of mortality (All P(for trend) < 0.05). These associations remained consistent when stratified by age, sex, race, and body mass index. CONCLUSIONS: This study indicates that the Naples prognostic score (NPS), serving as a novel prognostic metric integrating inflammation and nutritional status, is closely linked to cancer prognosis within the general population.

Reconstruction of TNF-α with specific isoelectric point released from SPIONs basing on variable charge to enhance pH-sensitive controlled-release.

The clinical application of tumor necrosis factor-α (TNF-α) is limited by its short half-life, subeffective concentration in the targeted area and severe systemic toxicity. In this study, the recombinant polypeptide S4-TNF-α was constructed and coupled with chitosan-modified superparamagnetic iron oxide nanoparticles (S4-TNF-α-SPIONs) to achieve pH-sensitive controlled release and active tumor targeting activity. The isoelectric point (pI) of S4-TNF-α was reconstructed to approach the pH of the tumor microenvironment. The negative-charge S4-TNF-α was adsorbed to chitosan-modified superparamagnetic iron oxide nanoparticles (CS-SPIONs) with a positive charge through electrostatic adsorption at physiological pH. The acidic tumor microenvironment endowed S4-TNF-α with a zero charge, which accelerated S4-TNF-α release from CS-SPIONs. Our studies showed that S4-TNF-α-SPIONs displayed an ideal pH-sensitive controlled release capacity and improved antitumor effects. Our study presents a novel approach to enhance the pH-sensitive controlled-release of genetically engineered drugs by adjusting their pI to match the pH of the tumor microenvironment.

T cell-redirecting antibody for treatment of solid tumors via targeting mesothelin.

T cell engaging bispecific antibodies (TCBs) have recently become significant in cancer treatment. In this study we developed MSLN490, a novel TCB designed to target mesothelin (MSLN), a glycosylphosphatidylinositol (GPI)-linked glycoprotein highly expressed in various cancers, and evaluated its efficacy against solid tumors. CDR walking and phage display techniques were used to improve affinity of the parental antibody M912, resulting in a pool of antibodies with different affinities to MSLN. From this pool, various bispecific antibodies (BsAbs) were assembled. Notably, MSLN490 with its IgG-[L]-scFv structure displayed remarkable anti-tumor activity against MSLN-expressing tumors (EC50: 0.16 pM in HT-29-hMSLN cells). Furthermore, MSLN490 remained effective even in the presence of non-membrane-anchored MSLN (soluble MSLN). Moreover, the anti-tumor activity of MSLN490 was enhanced when combined with either Atezolizumab or TAA × CD28 BsAbs. Notably, a synergistic effect was observed between MSLN490 and paclitaxel, as paclitaxel disrupted the immunosuppressive microenvironment within solid tumors, enhancing immune cells infiltration and improved anti-tumor efficacy. Overall, MSLN490 exhibits robust anti-tumor activity, resilience to soluble MSLN interference, and enhanced anti-tumor effects when combined with other therapies, offering a promising future for the treatment of a variety of solid tumors. This study provides a strong foundation for further exploration of MSLN490's clinical potential.

No association between hepatitis C virus infection and risk of colorectal cancer: a systematic review and meta-analysis of cohort studies.

Background and aim: There is still uncertainty regarding whether hepatitis C virus (HCV) infection is associated with colorectal cancer (CRC). This study aims to investigate the potential association between HCV infection and CRC through a systematic review and meta-analysis of cohort studies. Methods: PubMed, Embase, and Web of Science were systematically searched from the beginning of their inception to October 2023 to find relevant cohort studies on the association between HCV infection and CRC risk. The random-effect, generic inverse variance method was used to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs) for CRC outcome among individuals with HCV infection. We also performed subgroup and sensitivity analysis. Results: A total of 8 cohort studies involving 1,939,164 participants were included in this meta-analysis. The result from the meta-analysis suggested that there was no statistically significant association between HCV and the risk of developing CRC (HR = 0.99, 95% CI: 0.82-1.88, p = 0.88) with low statistical heterogeneity (I2 = 28%, p = 0.20). Subgroup analyses that were conducted based on study design, diagnosis of HCV infection, and publication year yielded similar results. Analyses of subgroups based on study areas revealed that there was no significant association between HCV infection and CRC risk in Asia (n = 2, HR = 0.96, 95% CI: 0.71-1.29, p = 0.79; I2 = 26%), Europe (n = 3, HR = 1.06, 95% CI: 0.83-1.37, p = 0.63; I2 = 0%), and North America (n = 2, HR = 1.10, 95% CI: 0.87-1.38, p = 0.44; I2 = 0%); however, a negative correlation was found in Oceania (n = 1, HR = 0.43, 95% CI: 0.22-0.84, p = 0.01). Sensitivity analysis further reinforce the stability of our conclusion. Conclusion: Our cohort-based meta-analysis showed insufficient evidence to support the association between HCV infection and an increased risk of CRC. To gain a clearer insight into the potential association between these two conditions, it would be beneficial to conduct large, well-designed, high-quality prospective cohort studies that consider different ethnic populations and potential confounding factors.Systematic review registration: PROSPERO, identifier [CRD42023472688], https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023472688.

Deep learning in the diagnosis for cystic lesions of the jaws: a review of recent progress.

Cystic lesions of the gnathic bones present challenges in differential diagnosis. In recent years, artificial intelligence (AI) represented by deep learning (DL) has rapidly developed and emerged in the field of dental and maxillofacial radiology (DMFR). Dental radiography provides a rich resource for the study of diagnostic analysis methods for cystic lesions of the jaws and has attracted many researchers. The aim of the current study was to investigate the diagnostic performance of DL for cystic lesions of the jaws. Online searches were done on Google Scholar, PubMed, and IEEE Xplore databases, up to September 2023, with subsequent manual screening for confirmation. The initial search yielded 1862 titles, and 44 studies were ultimately included. All studies used DL methods or tools for the identification of a variable number of maxillofacial cysts. The performance of algorithms with different models varies. Although most of the reviewed studies demonstrated that DL methods have better discriminative performance than clinicians, further development is still needed before routine clinical implementation due to several challenges and limitations such as lack of model interpretability, multicentre data validation, etc. Considering the current limitations and challenges, future studies for the differential diagnosis of cystic lesions of the jaws should follow actual clinical diagnostic scenarios to coordinate study design and enhance the impact of AI in the diagnosis of oral and maxillofacial diseases.

Dexmedetomidine attenuates ferroptosis by Keap1-Nrf2/HO-1 pathway in LPS-induced acute kidney injury.

Previous research has demonstrated that Dexmedetomidine (DEX), an α2 adrenergic agonist commonly used for its sedative and analgesic properties, can attenuate lipopolysaccharide (LPS)-induced acute kidney injury (AKI). This study explores the possibility that DEX's protective effects in LPS-induced AKI are mediated through the inhibition of ferroptosis, a form of regulated cell death characterized by iron-dependent lipid peroxidation, and the activation of the antioxidant response through the Keap1/Nrf2/HO-1 signaling pathway. We induced AKI in 42 mice using LPS and divided them into six groups: saline control, LPS, LPS + DEX, LPS + Ferrostatin-1 (LPS + Fer-1; a ferroptosis inhibitor), LPS + DEX with α2-receptor antagonist Altipamizole (LPS + DEX + ATI), and LPS + DEX with Nrf2 inhibitor ML385 (LPS + DEX + ML385). After 24 h, we analyzed blood and kidney tissues. LPS exposure resulted in AKI, with increased serum creatinine, BUN, and cystatin C, and tubular damage, which DEX and Fer-1 ameliorated. However, Altipamizole and ML385 negated these improvements. The LPS group exhibited elevated oxidative stress markers and mitochondrial damage, reduced by DEX and Fer-1, but not when α2-adrenergic or Nrf2 pathways were blocked. Nrf2 and HO-1 expression declined in the LPS group, rebounded with LPS + DEX and LPS + Fer-1, and fell again with inhibitors; inversely, Keap1 expression varied. Our results demonstrate that DEX may protect against LPS-induced AKI, at least partially by regulating ferroptosis and the α2-adrenergic receptor/Keap1/Nrf2/HO-1 pathway, suggesting a potential therapeutic role for DEX in AKI management by modulating cell death and antioxidant defenses.

Preoperative Differentiation of HER2-Zero and HER2-Low from HER2-Positive Invasive Ductal Breast Cancers Using BI-RADS MRI Features and Machine Learning Modeling.

BACKGROUND: Accurate determination of human epidermal growth factor receptor 2 (HER2) is important for choosing optimal HER2 targeting treatment strategies. HER2-low is currently considered HER2-negative, but patients may be eligible to receive new anti-HER2 drug conjugates. PURPOSE: To use breast MRI BI-RADS features for classifying three HER2 levels, first to distinguish HER2-zero from HER2-low/positive (Task-1), and then to distinguish HER2-low from HER2-positive (Task-2). STUDY TYPE: Retrospective. POPULATION: 621 invasive ductal cancer, 245 HER2-zero, 191 HER2-low, and 185 HER2-positive. For Task-1, 488 cases for training and 133 for testing. For Task-2, 294 cases for training and 82 for testing. FIELD STRENGTH/SEQUENCE: 3.0 T; 3D T1-weighted DCE, short time inversion recovery T2, and single-shot EPI DWI. ASSESSMENT: Pathological information and BI-RADS features were compared. Random Forest was used to select MRI features, and then four machine learning (ML) algorithms: decision tree (DT), support vector machine (SVM), k-nearest neighbors (k-NN), and artificial neural nets (ANN), were applied to build models. STATISTICAL TESTS: Chi-square test, one-way analysis of variance, and Kruskal-Wallis test were performed. The P values <0.05 were considered statistically significant. For ML models, the generated probability was used to construct the ROC curves. RESULTS: Peritumoral edema, the presence of multiple lesions and non-mass enhancement (NME) showed significant differences. For distinguishing HER2-zero from non-zero (low + positive), multiple lesions, edema, margin, and tumor size were selected, and the k-NN model achieved the highest AUC of 0.86 in the training set and 0.79 in the testing set. For differentiating HER2-low from HER2-positive, multiple lesions, edema, and margin were selected, and the DT model achieved the highest AUC of 0.79 in the training set and 0.69 in the testing set. DATA CONCLUSION: BI-RADS features read by radiologists from preoperative MRI can be analyzed using more sophisticated feature selection and ML algorithms to build models for the classification of HER2 status and identify HER2-low. TECHNICAL EFFICACY: Stage 2.

Long-term comparison of Image-guided thermal ablation vs. lobectomy for solitary papillary thyroid microcarcinoma: a multicenter retrospective cohort study.

BACKGROUND: Image-guided thermal ablation has been applied in patients with papillary thyroid microcarcinoma(PTMC) who refuse surgery or active surveillance. However, evidence to support ablation is limited by single-center designs and lack of long-term data. The purpose of this study was to compare long-term outcomes between ablation and lobectomy for patients with solitary PTMC. MATERIALS AND METHODS: This multicenter retrospective study included 1021 consecutive patients with solitary PTMC who underwent ablation(n=444) or lobectomy(n=577) at the four university-affiliated hospitals. The primary outcomes were disease progression(lymph node metastasis[LNM], recurrent tumors, persistent tumors and distant metastasis) and disease-free survival(DFS). Secondary outcomes were complications, hospitalization, procedure time, estimated blood loss and cost. The two groups were compared using propensity score matching. RESULTS: After matching, no significant differences were observed in disease progression (4.7% vs. 3.4%, P=.307), LNM (1.6% vs. 1.6%, P=1.000), recurrent tumors (2.9% vs. 1.8%, P=.269), persistent tumors(0.2% vs. 0%, P=.317) and DFS (95.5% vs. 97.1%, P=.246) between the ablation and lobectomy groups during the median follow-up of 96.5 months. The ablation group had significantly lower complication rates (0.7% vs. 5.2%, P<.001), shorter post-treatment hospitalization (median[IQR], 0 d vs. 4.0[3.0] d, P<.001), shorter procedure time (8.5[2.8] min vs. 90.0[43.8] min, P<.001), reduced estimated blood loss (0 mL vs. 20.0[10.0] mL, P<.001), and lower cost ($1873.2[254.0] vs. $2292.9[797.8], P<.001) than the lobectomy group. CONCLUSIONS: This study revealed comparable disease progression and survival outcomes between ablation and lobectomy for solitary PTMC. Imaged-guided thermal ablation could be effective and safe alternatives to lobectomy for properly selected patients with PTMC.

Value of radiofrequency ablation for treating locally recurrent thyroid cancer: a systematic review and meta-analysis for 2-year follow-up.

PURPOSE: To evaluate the safety and efficacy of radiofrequency ablation (RFA) in treating locoregional recurrent thyroid cancer (LRTC) after a 2-year follow-up time. METHODS: PubMed, Embase and Cochrane Library were searched from inception until 20 September 2022 to find studies reporting the safety and efficacy of RFA in LRTC patients after a 2-year follow-up. Two radiologists performed the data extraction and methodological quality assessment according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. RESULTS: We analyzed 6 studies, 229 LRTC patients with 319 locally recurrent tumors were treated with RFA. The mean follow-up time of each study was ≥24 months. The pooled changes in the largest diameter and volume were 7.22 mm (95% confidence interval (CI), 6.35-8.09 mm) and 164.28 mm3 (95% CI, 87.78-240.77 mm3), respectively; the pooled volume reduction rate was 95.03% (95% CI, 87.56-102.49%). The total complete disappearance rate after treatment was 92% (95% CI, 83-100%). The pooled decrease of serum thyroglobulin levels was 0.02 ng/ml (95% CI, -0.00-0.04 ng/ml). The pooled proportion of recurrence rate was 6% (95% CI, 0-13%). The pooled complication rate was 5% (95% CI, 0-10%). The major complications were voice change and hoarseness, only one patient developed permanent vocal cord paralysis; minor complications were cough and pain. CONCLUSIONS: Ultrasound-guided RFA is an effective and safe treatment for LRTC based on 2-year follow-up results.

A domain knowledge-based interpretable deep learning system for improving clinical breast ultrasound diagnosis.

BACKGROUND: Though deep learning has consistently demonstrated advantages in the automatic interpretation of breast ultrasound images, its black-box nature hinders potential interactions with radiologists, posing obstacles for clinical deployment. METHODS: We proposed a domain knowledge-based interpretable deep learning system for improving breast cancer risk prediction via paired multimodal ultrasound images. The deep learning system was developed on 4320 multimodal breast ultrasound images of 1440 biopsy-confirmed lesions from 1348 prospectively enrolled patients across two hospitals between August 2019 and December 2022. The lesions were allocated to 70% training cohort, 10% validation cohort, and 20% test cohort based on case recruitment date. RESULTS: Here, we show that the interpretable deep learning system can predict breast cancer risk as accurately as experienced radiologists, with an area under the receiver operating characteristic curve of 0.902 (95% confidence interval = 0.882 - 0.921), sensitivity of 75.2%, and specificity of 91.8% on the test cohort. With the aid of the deep learning system, particularly its inherent explainable features, junior radiologists tend to achieve better clinical outcomes, while senior radiologists experience increased confidence levels. Multimodal ultrasound images augmented with domain knowledge-based reasoning cues enable an effective human-machine collaboration at a high level of prediction performance. CONCLUSIONS: Such a clinically applicable deep learning system may be incorporated into future breast cancer screening and support assisted or second-read workflows.

Breast cancer is one of the most common cancers, and finding it early can greatly improve patients' chances of survival and recovery. We create a tool based on artificial intelligence (AI)­whereby computer software learns to perform tasks that normally require human thinking­called MUP-Net. MUP-Net can analyze medical images to predict a patient's risk of having breast cancer. To make this AI tool usable in clinical practice, we enabled doctors to see the reasoning behind the AI's predictions by visualizing the key image features it analyzed. We showed that our AI tool not only makes doctors more confident in their diagnosis but also helps them make better decisions, especially for less experienced doctors. With further testing, our AI tool may help clinicians to diagnose breast cancer more accurately and quickly, potentially improving patient outcomes.

Indoxyl sulphate-TNFα axis mediates uremic encephalopathy in rodent acute kidney injury.

Acute kidney injury (AKI) is often accompanied by uremic encephalopathy resulting from accumulation of uremic toxins in brain possibly due to impaired blood-brain barrier (BBB) function. Anionic uremic toxins are substrates or inhibitors of organic anionic transporters (OATs). In this study we investigated the CNS behaviors and expression/function of BBB OAT3 in AKI rats and mice, which received intraperitoneal injection of cisplatin 8 and 20 mg/kg, respectively. We showed that cisplatin treatment significantly inhibited the expressions of OAT3, synaptophysin and microtubule-associated protein 2 (MAP2), impaired locomotor and exploration activities, and increased accumulation of uremic toxins in the brain of AKI rats and mice. In vitro studies showed that uremic toxins neither alter OAT3 expression in human cerebral microvascular endothelial cells, nor synaptophysin and MAP2 expressions in human neuroblastoma (SH-SY5Y) cells. In contrast, tumour necrosis factor alpha (TNFα) and the conditioned medium (CM) from RAW264.7 cells treated with indoxyl sulfate (IS) significantly impaired OAT3 expression. TNFα and CM from IS-treated BV-2 cells also inhibited synaptophysin and MAP2 expressions in SH-SY5Y cells. The alterations caused by TNFα and CMs in vitro, and by AKI and TNFα in vivo were abolished by infliximab, a monoclonal antibody designed to intercept and neutralize TNFα, suggesting that AKI impaired the expressions of OAT3, synaptophysin and MAP2 in the brain via IS-induced TNFα release from macrophages or microglia (termed as IS-TNFα axis). Treatment of mice with TNFα (0.5 mg·kg-1·d-1, i.p. for 3 days) significantly increased p-p65 expression and reduced the expressions of Nrf2 and HO-1. Inhibiting NF-κB pathway, silencing p65, or activating Nrf2 and HO-1 obviously attenuated TNFα-induced downregulation of OAT3, synaptophysin and MAP2 expressions. Significantly increased p-p65 and decreased Nrf2 and HO-1 protein levels were also detected in brain of AKI mice and rats. We conclude that AKI inhibits the expressions of OAT3, synaptophysin and MAP2 due to IS-induced TNFα release from macrophages or microglia. TNFα impairs the expressions of OAT3, synaptophysin and MAP2 partly via activating NF-κB pathway and inhibiting Nrf2-HO-1 pathway.

Prenatal Diagnosis of Oral Teratoma by Ultrasound.

A pregnant woman had a normal second-trimester anatomic survey at 22 weeks gestation. She was revealed to have a fetal oral mass with polyhydramnios and invisible stomach bubble by ultrasound at 28 weeks. A 50 mm × 36 mm × 42 mm, solid mass was found in the fetal mouth, filling the entire oral cavity. Fetal magnetic resonance imaging showed a homogeneous solid mass in the oral cavity compressing the hypopharynx. At 33 weeks, preterm labor occurred because of the continuation of increased amniotic fluid volume, and a female infant was vaginally delivered. The infant died shortly after tracheal intubation attempt failed. Autopsy confirmed the prenatal sonographic finding. The final pathologic diagnosis was oral immature teratoma. Our study indicates that although oral teratomas are rare, they are readily apparent at prenatal sonographic examinations. Respiratory compromise is the frequent complication of oral teratomas, which is associated with high perinatal mortality.

Assessment of causal association between the socio-economic status and osteoporosis and fractures: a bidirectional Mendelian randomization study in European population.

BACKGROUND: The relationship between socio-economic status and bone-related diseases is attracting increasing attention. Therefore, a bidirectional Mendelian randomization (MR) analysis was performed in this study. METHODS: Genetic data on factors associated with socio-economic status (average total household income before tax, years of schooling completed and Townsend Deprivation Index at recruitment), femoral neck bone mineral density (FN-BMD), heel bone mineral density (eBMD), osteoporosis, and five different sites of fracture (spine, femur, lower leg-ankle, foot, and wrist-hand fractures) were derived from genome-wide association summary statistics of European ancestry. The inverse variance weighted method was employed to obtain the causal estimates, complemented by alternative MR techniques, including MR-Egger, weighted median, and MR-pleiotropy residual sum and outlier (MR-PRESSO). Furthermore, sensitivity analyses, and multivariable MR was performed to enhance the robustness of our findings. RESULTS: A higher educational attainment was associated with an increased level of eBMD (beta:0.06, 95% CI:0.01-0.10, P = 7.24 × 10-3), and decreased risk of osteoporosis (OR:0.78, 95% CI:0.65-0.94, P = 8.49 × 10-3), spine fracture (OR:0.76, 95% CI:0.66-0.88, P = 2.94 × 10-4), femur fracture (OR:0.78, 95% CI:0.67-0.91, P = 1.33 × 10-3), lower leg-ankle fracture (OR:0.79, 95% CI:0.70-0.88, P = 2.05 × 10-5), foot fracture (OR:0.78, 95% CI:0.66-0.93, P = 5.92 × 10-3) and wrist-hand fracture (OR:0.83, 95% CI:0.73-0.95, P = 7.15 × 10-3). Further, material deprivation seemed to harm the spine fracture (OR:2.63, 95% CI:1.43-4.85, P = 1.91 × 10-3). A higher level of FN-BMD positively affected increased household income (beta:0.03, 95% CI:0.01-0.04, P = 6.78 × 10-3). All these estimates were adjusted for body mass index (BMI), type 2 diabetes, smoking initiation, and frequency of alcohol intake. CONCLUSIONS: The Mendelian randomization analyses show that higher educational levels is associated with higher eBMD, reduced risk of osteoporosis and fractures, while material deprivation is positively related to spine fracture. Enhanced FN-BMD correlates with increased household income. These findings offer valuable insights into the formulation of health guidelines and policy development.

We conducted stratified analyses to explore the causal links between socio-economic status and osteoporosis and various fractures and observed that education significantly reduced risk of osteoporosis and lower eBMD. It also lowered the risks of fractures of spine, femur, lower leg-ankle, foot, and wrist-hand, while material deprivation exhibited positive associations with spine fracture risk. Bidirectional MR analysis showed that an elevated score of FN-BMD was associated with a higher income level. Our study shows the importance of conducting routine BMD estimations and osteoporosis screening, to enhance knowledge and awareness among individuals to promote bone health and prevent fractures.

Interaction between systemic iron parameters and left ventricular structure and function in the preserved ejection fraction population: a two-sample bidirectional Mendelian randomization study.

BACKGROUND: Left ventricular (LV) remodeling and diastolic function in people with heart failure (HF) are correlated with iron status; however, the causality is uncertain. This Mendelian randomization (MR) study investigated the bidirectional causal relationship between systemic iron parameters and LV structure and function in a preserved ejection fraction population. METHODS: Transferrin saturation (TSAT), total iron binding capacity (TIBC), and serum iron and ferritin levels were extracted as instrumental variables for iron parameters from meta-analyses of public genome-wide association studies. Individuals without myocardial infarction history, HF, or LV ejection fraction (LVEF) < 50% (n = 16,923) in the UK Biobank Cardiovascular Magnetic Resonance Imaging Study constituted the outcome dataset. The dataset included LV end-diastolic volume, LV end-systolic volume, LV mass (LVM), and LVM-to-end-diastolic volume ratio (LVMVR). We used a two-sample bidirectional MR study with inverse variance weighting (IVW) as the primary analysis method and estimation methods using different algorithms to improve the robustness of the results. RESULTS: In the IVW analysis, one standard deviation (SD) increased in TSAT significantly correlated with decreased LVMVR (ß = -0.1365; 95% confidence interval [CI]: -0.2092 to -0.0638; P = 0.0002) after Bonferroni adjustment. Conversely, no significant relationships were observed between other iron and LV parameters. After Bonferroni correction, reverse MR analysis showed that one SD increase in LVEF significantly correlated with decreased TSAT (ß = -0.0699; 95% CI: -0.1087 to -0.0311; P = 0.0004). No heterogeneity or pleiotropic effects evidence was observed in the analysis. CONCLUSIONS: We demonstrated a causal relationship between TSAT and LV remodeling and function in a preserved ejection fraction population.

Delayed Commissuroplasty Increases Interincisal Distance in Buccogingival Cancer Patients Treated with Free Flap Reconstruction of the Oral Commissure.

BACKGROUND: Oral cavity cancers requiring excision of the oral commissure and free flap reconstruction often requires commissuroplasty to manage oral incontinence. We aimed to evaluate the implications of primary versus delayed commissuroplasty on drooling, and interincisal distance outcomes in this cohort. METHODS: A retrospective query of head and neck cancer patients operated by a single surgeon from 2017 to 2020 was performed. Patients were included if they underwent free flap reconstruction of the oral commissure, had an immediate or delayed commissuroplasty, and had 2 years of follow-up data including Thomas-Stonell and Greenberg drooling rating scales and interincisal distance measurements. RESULTS: Thirty-five patients were included in the review. Twelve patients received immediate commissuroplasty and 23 patients had delayed commissuroplasty. Interincisal distance was similar at baseline, although significantly varied between immediate and delayed commissuroplasty groups at 1 month and 2 years postoperative. Drooling scores were significantly elevated in the group treated with delayed commissuroplasty, but eventually normalized after staged surgery and follow-up. Patients treated with adjunct radiation therapy had lower interincisal distance than patients who did not have radiation. CONCLUSION: Delayed commissuroplasty increased interincisal distance and normalize drooling in patients who required full-thickness excision of the buccal mucosa and oral commissure and free tissue reconstruction. The presented data can help to educate patients on expected postoperative outcomes and likely advocates for a second-stage procedure after completion of adjunct radiotherapy to achieve optimal commissural placement and oral competence.

Terpenoids derived from Semen Ziziphi Spinosae oil enhance sleep by modulating neurotransmitter signaling in mice.

Semen Ziziphi Spinosae oil (SZSO) is a natural vegetable oil extracted from Semen Ziziphi Spinosae, a traditional Chinese medicine renowned for its sleep-promoting properties, while the mechanisms are still unclear. Our findings revealed that the terpenoids present in SZSO (T-SZSO) were identified as the active components responsible for promoting sleep. Network pharmacological analysis suggested that T-SZSO targeted different sleep-aid pathways to varying degrees and exhibited potential for preventing central nervous system diseases. Notably, lupeol and betulinicaldehyde exhibited more pronounced effects. Additionally, T-SZSO significantly elevated serotonin levels, enhanced gamma-aminobutyric acid (GABA) synthesis, promoted GABA A receptor expression, and decreased glutamate and norepinephrine expression levels. Moreover, T-SZSO was found to downregulate IL-1ß expression while upregulating superoxide dismutase and inducible nitric oxide synthase levels. In conclusion, this study presents the first investigation into the pharmacological basis of SZSO in promoting sleep and highlights the potential of nature food in improving suboptimal health conditions.

Optimization of seeding density of OP9 cells to improve hematopoietic differentiation efficiency.

BACKGROUND: OP9 mouse stromal cell line has been widely used to induce differentiation of human embryonic stem cells (hESCs) into hematopoietic stem/progenitor cells (HSPCs). However, the whole co-culture procedure usually needs 14-18 days, including preparing OP9 cells at least 4 days. Therefore, the inefficient differentiation system is not appreciated. We aimed to optimize the culture conditions to improve differentiation efficiency. METHODS: In the experimental group, we set six different densities of OP9 cells and just cultured them for 24 h before co-culture, and in the control group, OP9 cells were cultured for 4 days to reach an overgrown state before co-culture. Then we compared the hematopoietic differentiation efficiency among them. RESULTS: OP9 cells were randomly assigned into two groups. In the experimental group, six different plated numbers of OP9 cells were cultured for 1 day before co-culture with hESCs. In contrast, in the control group, OP9 cells were cultured for 4 days at a total number of 3.1 × 104 cells/cm2 in a 6-well plate to reach an overgrown state before co-culture. Hematopoietic differentiation was evaluated with CD34 immunostaining, and compared between these two groups. We could not influence the differentiation efficiency of OP9 cells with a total number of 10.4 × 104 cells/cm2 in a 6-well plate which was cultured just for 1 day, followed by co-culture with hESCs. It reached the same differentiation efficiency 5 days earlier than the control group. CONCLUSION: The peak of CD34 + cells appeared 2 days earlier compared to the control group. A total number of 1.0 × 106 cells in a 6-well plate for OP9 cells was appropriate to have high differentiation efficiency.

The Use of E-Learning in Peyton's 4-Step Approach: Evaluation of Facial Computed Tomography Scans.

Imparting procedural skills is challenging. Peyton's approach is an effective face-to-face teaching technique increasingly used in complex skills training. Institutions are beginning to incorporate online training as part of their procedural curriculum. We developed E-Peyton's to employ Peyton's approach through an electronic learning platform. The efficacy of E-Peyton's approach in teaching the interpretation of facial computed tomography (CT) scans is evaluated in this study. Naïve learners (n=41) were randomized into 2 groups based on teaching techniques employed: E-Peyton's (n=20) and Peyton's (n=21) approaches. The distance between the infraorbital margin and the posterior ledge was measured using a 3-part standardized measuring protocol on OsiriX. Twenty measurements were assessed for accuracy against the benchmark (±2 mm) at week 0 and week 1. Training durations were compared. Questionnaires were administered before and after the study to identify learners' acceptance of teaching techniques and their confidence in interpreting facial CT scans. Learners in both teaching techniques had comparable skills retention. Gap scores indicate significant improvement in learner's confidence levels regardless of teaching technique (P<0.05). Both teaching techniques were well-accepted by learners. E-Peyton's and Peyton's approaches required a similar training duration. The COVID-19 pandemic highlights the importance of effective remote learning platforms. E-Peyton's approach is comparable to that of Peyton's in all areas of assessment. E-Peyton's approach effectively automates Peyton's approach, allowing for standardized, high-quality procedural skills training while reducing manpower burden.

Novel dual-target FAAH and TRPV1 ligands as potential pharmacotherapeutics for pain management.

Dual-acting drugs that simultaneously inhibit fatty acid amide hydrolase (FAAH) and antagonize the transient receptor potential vanilloid 1 (TRPV1) is a promising stronger therapeutic approach for pain management without side effects associated with single-target agents. Here, several series of dual FAAH/TRPV1 blockers were designed and synthesized through rational molecular hybridization between the pharmacophore of classical TRPV1 antagonists and FAAH inhibitors. The studies resulted in compound 2r, which exhibited strong dual FAAH/TRPV1 inhibition/antagonism in vitro, exerted powerful analgesic effects in formalin-induced pain test (phase II, in mice), desirable anti-inflammatory activity in carrageenan-induced paw edema in rats, no TRPV1-related hyperthermia side effect, and favorable pharmacokinetic properties. Meanwhile, the contributions of TRPV1 and FAAH to its antinociceptive effects were verified by target engagement and molecular docking studies. Overall, compound 2r can serve as a new scaffold for developing FAAH/TRPV1 dual-activie ligands to counteract pain.