Phosphorus balance calculator: an individualized tool for treatment of hyperphosphatemia in hemodialysis patients.

BACKGROUND AND HYPOTHESIS: Lack of evaluations of the dietary phosphorus and dialysis phosphorus removal in daily clinical practice are the common obstacle to assess phosphorus balance and control phosphorus in hemodialysis patients. We aimed to investigate whether the individualized therapy using phosphorus balance calculator improves phosphorus control. METHODS: A randomized, open-label, multicenter, 4-week clinical trial was conducted. 119 maintenance hemodialysis patients aged 18 to 85 years old and with serum phosphorus level higher than 1.45mmol/l from 3 university teaching hospitals in Shanghai were enrolled. Patients were randomized in a 1:1 ratio to individualized therapy (n=60), or conventional therapy (n=59). The primary outcome was the serum phosphorus concentration after 4-week treatment. Secondary outcomes included the serum calcium and parathyroid hormone (PTH) concentrations, changes in serum phosphorus, calcium and PTH concentrations, and the proportion of patients achieving target ranges of serum phosphorus, calcium and PTH after 4-week treatment. RESULTS: Among 119 randomized participants (mean age, 62 years; 68 male[57%]), 116 completed the trial. By using the phosphorus balance calculator, the individualized group achieved a better phosphorus balance state, significantly reduced the serum phosphorus (1.62±0.45mmol/l versus 1.85±0.45 mmol/l, P=0.006), increased the proportions of patients achieving target serum phosphorus range (41% versus 18%, P=0.006), and had greater adjusted mean difference in change in serum phosphorus over the 4 weeks (-0.47 versus -0.23mmol/l, P=0.010) when compared to conventional therapy. No significant changes were observed in serum calcium and PTH levels, the proportion of patients achieving target serum calcium or PTH levels, and adjusted mean difference of serum calcium and PTH levels over the treatment period. CONCLUSION: Phosphorus balance calculator was proved to improve serum phosphorus control in patients undergoing maintenance hemodialysis, offering a new tool for managing hyperphosphatemia.

AIM2 inflammasome contributes to aldosterone-induced renal injury via endoplasmic reticulum stress.

Inflammatory response and renal fibrosis are the hallmarks of chronic kidney disease (CKD). However, the specific mechanism of aldosterone-induced renal injury in the progress of CKD requires elucidation. Emerging evidence has demonstrated that absent in melanoma 2 (AIM2)-mediated inflammasome activation and endoplasmic reticulum stress (ERS) play a pivotal role in the renal fibrosis. Here, we investigated whether overexpression or deficiency of AIM2 affects ERS and fibrosis in aldosterone-infused renal injury. Interestingly, we found that AIM2 was markedly expressed in the diseased proximal tubules from human and experimental CKD. Mechanically, overactivation of AIM2 aggravated aldosterone-induced ERS and fibrotic changes in vitro while knockdown of AIM2 blunted these effects in vivo and in vitro. By contrast, AIM2 deficiency ameliorated renal structure and function deterioration, decreased proteinuria levels and lowered systolic blood pressure in vivo; silencing of AIM2 blocked inflammasome-mediated signaling pathway, relieved ERS and fibrotic changes in vivo. Furthermore, mineralocorticoid receptor (MR) antagonist eplerenone and ERS inhibitor tauroursodeoxycholic acid (TUDCA) had nephroprotective effects on the basis of AIM2 overactivation in vitro, while they failed to produce a more remarkable renoprotective effect on the treatment of AIM2 silence in vitro. Notably, the combination of TUDCA with AIM2 knockdown significantly reduced proteinuria levels in vivo. Additionally, immunofluorescence assay identified that apoptosis-associated speck-like protein (ASC) recruitment and Gasdermin-D (GSDMD) cleavage respectively occurred in the glomeruli and tubules in vivo. These findings establish a crucial role for AIM2 inflammasome in aldosterone-induced renal injury, which may provide a novel therapeutic target for the pathogenesis of CKD.

Morphological Lesion Types Are Associated with Primary and Secondary Patency Rates after High-Pressure Balloon Angioplasty for Dysfunctional Arteriovenous Fistulas.

BACKGROUND: Neointimal hyperplasia (NIH) is believed to be the main reason for arteriovenous fistula (AVF) dysfunction, but other mechanisms are also recognized to be involved in the pathophysiological process. This study investigated whether different morphological types of AVF lesions are associated with the patency rate after percutaneous transluminal angioplasty (PTA). METHODS: This retrospective study included 120 patients who underwent PTA for autogenous AVF dysfunction. All the cases were evaluated under Doppler ultrasound (DU) before intervention and divided into 3 types: Type I (NIH type), Type II (non-NIH type), and Type III (mixed type). Prognostic and clinical data were analyzed by Kaplan-Meier analysis and the Cox proportional hazards model. RESULTS: There was no statistical difference in baseline variables among groups, except for lumen diameter. The primary patency rates in Type I, Type II, and Type III groups were 78.4, 93.2, and 83.2% at 6 months and 59.5, 84.7, and 75.5% at 1 year, respectively. The secondary patency rates in Type I, Type II, and Type III groups were 94.4, 97.1, and 100% at 6 months and 90.5, 97.1, and 94.7% at 1 year, respectively. The Kaplan-Meier curve showed that the primary and secondary patency rates of Type I group were lower than those of Type II group. Multivariable Cox regression analysis demonstrated that postoperative primary patency was correlated with end-to-end anastomosis (hazard ratio [HR] = 2.997, p = 0.008, 95% confidence interval [CI]: 1.328-6.764) and Type I lesion (HR = 5.395, p = 0.004, 95% CI: 1.730-16.824). CONCLUSIONS: NIH-dominant lesions of AVF evaluated by DU preoperatively were a risk factor for poor primary and secondary patency rate after PTA in hemodialysis patients.

Early Renal-Replacement Therapy May Reduce the All-Cause Mortality of Severe COVID-19: An Observational Cohort Study.

INTRODUCTION: The efficacy of renal-replacement treatment (RRT) remains to be validated in COVID-19. In this retrospective cohort study, we aimed to assess the efficacy of early initiation of RRT in intensive care unit (ICU) adults with severe COVID-19. METHODS: Fifty-eight adult patients in ICU with critically ill or severe COVID-19 with a tendency of critical illness were recruited from February 9, 2020, to March 30, 2020. Early RRT were determined by the ICU medical team based on boom in cytokines levels, increased organs injury/failure, and rapid aggravation of condition. All participants were followed up from the first day of ICU admission to March 30, 2020. The primary outcome was all-cause mortality in ICU. RESULTS: The mean age of the cohort was 68.4 ± 14.6 years, with 81.0% having at least one comorbidity before hospitalization. Twenty patients (34.5%) initiated early RRT after 24.1 ± 10.4 days from the onset and 6.4 ± 3.6 days from ICU admission. Thirty-four of 58 participants (58.6%) died during ICU follow-up. Univariate and multivariate Cox proportional-hazards model showed that early RRT was associated with a lower risk of all-cause mortality in ICU with an adjusted HR of 0.280 (95% CI: 0.106-0.738, p = 0.010). Sudden unexpected death (SUD) was remarkably reduced in the early RRT group, compared with the control group (0.2 vs. 2.9 per 100 person-day, p = 0.02). CONCLUSION: Early RRT can reduce the all-cause in-hospital mortality, especially SUD in patients with severe COVID-19, but not improve multi-organ impairment or increase the risk of AKI. Early initiation of RRT merits an optional strategy in critically ill patients with COVID-19 (ChiCTR2000030773).

Effect of endothelial glycocalyx on water and LDL transport through the rat abdominal aorta.

The surface of vascular endothelial cells (ECs) is covered by a protective negatively charged layer known as the endothelial glycocalyx. Herein, we hypothesized its transport barrier and mechanosensory role in transmural water flux and low-density lipoprotein (LDL) transport in an isolated rat abdominal aorta perfused under 85 mmHg and 20 dyn/cm2 ex vivo. The endothelial glycocalyx was digested by hyaluronidase (HAase) from bovine tests. Water infiltration velocity (Vw) was measured by a graduated pipette. LDL coverage and mean maximum infiltration distance (MMID) in the vessel wall were quantified by confocal laser scanning microscopy. EC apoptosis was determined by the terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) technique, and leaky junction rates were evaluated by electron microscopy. The results showed that a 42% degradation of the endothelial glycocalyx by HAase treatment increased Vw, LDL coverage, and MMID. Shear stress increased Vw, which cannot be inhibited by HAase treatment. Four hour-shear application increased about fourfolds of LDL coverage, whereas exerted no significant effects on its MMID, EC apoptosis, and the leaky junctions. On the contrary, 24-h shear exposure has no significant effects on LDL coverage, whereas increased 2.74-folds of MMID and about 53% of EC apoptotic rates that could be inhibited by HAase treatment. These results suggest endothelial glycocalyx acts as a transport barrier by decreasing water and LDL transport, as well as a mechanosensor of shear to regulate EC apoptosis, thus affecting leaky junctions and regulating LDL transport into the vessel wall.NEW & NOTEWORTHY A 42% degradation of the endothelial glycocalyx by hyaluronidase of the isolated rat abdominal aorta facilitated water and LDL transport across the vessel wall, suggesting endothelial glycocalyx as a transport barrier. A 24-h shear exposure increased LDL mean maximum infiltration distance, and enhanced EC apoptosis, which could be both inhibited by hyaluronidase treatment, suggesting endothelial glycocalyx may also act as a mechanosensor of shear to regulate EC apoptosis, thus affecting leaky junctions and regulating LDL transport.

Frailty and the risk of kidney function decline in the elderly population: the Rugao Longevity and Ageing Study.

BACKGROUND: The diverse risk factors for kidney impairments suggest that kidney function decline is more likely to occur in individuals with a broadly constituted health deficit. Here we conducted a longitudinal cohort study to evaluate the association of baseline frailty status with the risk of estimated glomerular filtration rate (eGFR) decline. METHODS: Overall, 1269 participants aged 70-84 years from Rugao Longevity and Ageing cohort with 3-year follow-up were included. Frailty was measured using a modified Fried frailty assessment. GFR was estimated using the Chronic Kidney Disease Epidemiology Collaboration equation. Associations between baseline frailty status and rapid eGFR decline were examined by multinomial logistic analysis. A linear mixed-effect model was used to determine eGFR decline in mL/min/1.73 m2 over the study period comparing those with frail or prefrail at baseline versus those with robust status. RESULTS: The mean (± standard deviation) age of participants was 75.1 ± 3.8 years. A total of 144 (11%) participants had rapid eGFR decline by at least 10% during the 3-year follow-up. Compared with robust status, baseline frail status was associated with a 2.48-fold [95% confidence interval (CI) 1.24-4.95] increased risk of rapid eGFR decline after multiple adjustments. In multivariate linear mixed model analysis, subjects with frail status but not prefrail status at baseline had a significant coefficient of -1.70 (95% CI -3.35 to -0.04) for the frail × visit term, which indicates an accelerated eGFR decline compared with robust subjects over the study period (P = 0.044). CONCLUSIONS: Frailty may serve as an independent biomarker to predict the decline of kidney function.

Modification and Validation of the Phosphate Removal Model: A Multicenter Study.

BACKGROUND: Our research group has previously reported a noninvasive model that estimates phosphate removal within a 4-h hemodialysis (HD) treatment. The aim of this study was to modify the original model and validate the accuracy of the new model of phosphate removal for HD and hemodiafiltration (HDF) treatment. METHODS: A total of 109 HD patients from 3 HD centers were enrolled. The actual phosphate removal amount was calculated using the area under the dialysate phosphate concentration time curve. Model modification was executed using second-order multivariable polynomial regression analysis to obtain a new parameter for dialyzer phosphate clearance. Bias, precision, and accuracy were measured in the internal and external validation to determine the performance of the modified model. RESULTS: Mean age of the enrolled patients was 63 ± 12 years, and 67 (61.5%) were male. Phosphate removal was 19.06 ± 8.12 mmol and 17.38 ± 6.75 mmol in 4-h HD and HDF treatments, respectively, with no significant difference. The modified phosphate removal model was expressed as Tpo4 = 80.3 × C45 - 0.024 × age + 0.07 × weight + ß × clearance - 8.14 (ß = 6.231 × 10-3 × clearance - 1.886 × 10-5 × clearance2 - 0.467), where C45 was the phosphate concentration in the spent dialysate measured at the 45th minute of HD and clearance was the phosphate clearance of the dialyzer. Internal validation indicated that the new model was superior to the original model with a significantly smaller bias and higher accuracy. External validation showed that R2, bias, and accuracy were not significantly different than those of internal validation. CONCLUSIONS: A new model was generated to quantify phosphate removal by 4-h HD and HDF with a dialyzer surface area of 1.3-1.8 m2. This modified model would contribute to the evaluation of phosphate balance and individualized therapy of hyperphosphatemia.

Higher one-year achievement rate of serum phosphate associated with lower cardiovascular mortality in hemodialysis patients.

BACKGROUND: Estimation of phosphate load in hemodialysis patients is always controversial in clinical practice. The aim of this study was to verify individual achievement rate of serum phosphate as the evaluation of phosphate load through investigating its impact on cardiovascular mortality in hemodialysis patients. METHODS: This was a single-center, retrospective cohort study. A total of 251 maintenance hemodialysis patients were enrolled. The individual achievement rate of serum phosphate was defined as the times of tests within the target range divided by total times of tests over a period of time. Cox regression model was used to examine the relationship between individual achievement rate of serum phosphate and cardiovascular mortality. RESULTS: The mean age of the study population was 61 ± 13 years old. A total of 44 (17.5%) patients died from cardiovascular disease (CVD) during a median follow-up of 65 months. Multivariable Cox analysis showed that one-year serum phosphate achievement rate of 0% (HR = 4.117, P = 0.016) and 25% (HR = 3.343, P = 0.023) increased the risk of cardiovascular mortality while the achievement rate of 50% (HR = 2.129, P = 0.162) and 75% (HR = 1.080, P = 0.902) did not, compared to the rate of 100%. Urea reduction ratio (URR) was positively, while serum intact parathyroid hormone (iPTH), alkaline phosphatase (ALP), normalized protein catabolic rate (nPCR), and total phosphate-binding capacity of drug were negatively associated with achievement in target of serum phosphate. CONCLUSIONS: Keeping one-year achievement rate of serum phosphate higher than 50% provides significant clinical benefits in reducing cardiovascular mortality.

Dominant factors of the phosphorus regulatory network differ under various dietary phosphate loads in healthy individuals.

BACKGROUND: The purpose of this study was to explore the contribution of each factor of the phosphorus metabolism network following phosphorus diet intervention via Granger causality analysis. METHODS: In this study, a total of six healthy male volunteers were enrolled. All participants sequentially received regular, low-, and high-phosphorus diets. Consumption of each diet lasted for five days, with a 5-day washout period between different diets. Blood and urinary samples were collected on the fifth day of consumption of each diet at 9 time points (00:00, 04:00, 08:00, 10:00, 12:00, 14:00, 16:00, 20:00, 24:00) for measurements of serum levels of phosphate, calcium, PTH, FGF23, BALP, α-Klotho, and 1,25 D and urinary phosphorus excretion. Granger causality and the centrality of the above variables in the phosphorus network were analyzed by pairwise panel Granger causality analysis using the time-series data. RESULTS: The mean age of the participants was 28.5 ± 2.1 years. By using Granger causality analysis, we found that the α-Klotho level had the strongest connection with and played a key role in influencing the other variables. In addition, urinary phosphorus excretion was frequently regulated by other variables in the network of phosphorus metabolism following a regular phosphorus diet. After low-phosphorus diet intervention, serum phosphate affected the other factors the most, and the 1,25 D level was the main outcome factor, while urinary phosphorus excretion was the most strongly associated variable in the network of phosphorus metabolism. After high-phosphorus diet intervention, FGF23 and 1,25 D played a more critical role in active regulation and passive regulation in the Granger causality analysis. CONCLUSIONS: Variations in dietary phosphorus intake led to changes in the central factors involved in phosphorus metabolism.

Atherogenic diet-diminished endothelial glycocalyx contributes to impaired vasomotor properties in rat.

Hypercholesterolemia- and atherosclerosis-caused vasomotor property dysfunction may be involved in many clinic manifestations of atherosclerosis, including angina, acute myocardial infarction, and sudden cardiac death. However, its underlying mechanism is not clear. The endothelial glycocalyx is a protective surface layer on the endothelial cells, serving as a molecular sieve, cell adhesion modulator, and mechanosensor for blood flow. In the present study, we demonstrated by confocal microscopy in Sprague-Dawley (SD) male rats fed a 12-wk high-cholesterol diet (HC) compared with the normal diet (NC) that the dimension of the endothelial glycocalyx reduced significantly in both the common carotid artery (2.89 ± 0.41 µm and 3.25 ± 0.44 µm, respectively) and the internal sinus region (2.35 ± 0.07 µm and 3.46 ± 0.86 µm, respectively). Furthermore, we showed by real-time PCR that this dimension modification of endothelial glycocalyx may be attributed to a significant downregulation of heparan sulfate proteoglycan (HSPG)-related genes, including syndecan-3, glypican-1, and EXT1, not resulting from an enhanced shedding of sulfated glycosaminoglycans (sGAGs) from the vessel wall to the plasma. Meanwhile, the mean contraction and relaxation forces of the common carotid artery with responses to norepinephrine (NE) and acetylcholine (ACh) decreased ~0.34- and 0.13-fold, respectively, accompanied by a lower level of nitric oxide (NO) release. These findings suggest that the atherogenic high cholesterol diet diminished endothelial glycocalyx and disturbed the local NO release, thus contributing to the impaired vasomotor properties of the vessel.NEW & NOTEWORTHY Twelve-week high-cholesterol (HC) diet reduces the thickness of the endothelial glycocalyx in Sprague-Dawley (SD) male rats, which is mainly attributed to a downregulation of heparan sulfate proteoglycan-related genes (syndecan-3, glypican-1, EXT1), not resulting from an enhanced shedding of sulfated glycosaminoglycans (sGAGs) into the plasma. HC-diminished glycocalyx may disturb its mechanotransduction of local shear stress, lower nitric oxide (NO) release, and impair vasomotor responses to norepinephrine (NE) and acetylcholine (ACh).

Adaptation of glycocalyx, nitric oxide synthase expression and vascular cell apoptosis in conduit arteries of tail-suspended rats.

The importance of vascular cell glycocalyx in mechanotransduction has been demonstrated by many studies. The simulated microgravity induced a region-dependent adaptation of arterial glycocalyx including its thickness, coverage, and gene expression in conduit arteries of tail-suspended rats has been reported in our previous studies. Herein, we extended this line of research by quantifying the mRNA levels of three nitric oxide synthase (NOSI, NOSII, and NOSIII) and evaluating the apoptotic rates of endothelial cells (ECs) and smooth muscle cells (SMCs) in the common carotid artery, abdominal aorta, and femoral artery of 3 week tail-suspended rats. Results indicated that the tail suspension of rats induced about 0.36, 0.22, and 0.33 fold down-regulation of NOSI, NOSII, and NOSIII in the abdominal aorta, while 3.21, and 3.48 fold up-regulation of NOSII and NOSIII in the carotid artery and no significant effects on three NOS isoforms in the femoral artery. Moreover, the apoptosis of ECs and SMCs were significantly inhibited in both carotid artery and abdominal aorta, while enhanced in the femoral artery of the tail-suspended rats. A linear positive correlation exists between the normalized coverage of the glycocalyx and the normalized NOSI and NOSIII mRNA levels. These results indicated that the redistribution of haemodynamics in the conduit arteries of 3 week tail-suspended rats regulated the glycocalyx, NOS expression, and vascular cell apoptosis in a region-dependent manner, contributing to the final vascular remodelling under simulated microgravity condition.

Synthesis and antitumor activity evaluation of asiatic acid derivatives as survivin inhibitor.

A series of asiatic acid derivatives were synthesized and their cytotoxicities in vitro against two cancer cell lines (HepG2 and SGC7901) were evaluated by MTT assay. The results showed that compounds I2, I6, and II6 have more potent anticancer activity than that of the positive control drug paclitaxel. The interactions between the compounds I2, I6, and II6 and survivin were also studied by docking simulations.

BRAFV600E and MAP2K1 mutations in Langerhans cell histiocytosis occur predominantly in children.

Langerhans cell histiocytosis (LCH) is a proliferative disease of CD1a+ /CD207+ dendritic cells. Recurrent BRAFV600E and MAP2K1 mutations have been reported in LCH. To investigate the relationship among the mutation, clinical findings, and differentiation status of LCH, respectively, we studied 97 cases of LCH by using Sanger sequencing and immunohistochemistry. The mutually exclusive BRAFV600E and MAP2K1 mutation rates were 32% and 17.5%, respectively. All MAP2K1 mutations were missense mutations without any in-frame deletions; 2 new recurrent missense mutations (ie, p.E38K and p.P105S) were also found. More BRAFV600E and MAP2K1 mutations occurred in children compared with those in adult patients (P = .001), and BRAF mutation was correlated with relapse (P = .009). To the differentiation-related markers, the BRAF/MAP2K1-mut LCH expressed CD14 but rarely expressed CD83 or CD86 (P < .001). On the contrary, BRAF/MAP2K1-wt LCH cells rarely expressed CD14 but expressed CD86, and some also expressed CD83 (P < .001). This indicated that the BRAF/MAP2K1-mut LCH cells had a more immature state than BRAF/MAP2K1-wt LCH cells. Moreover, we also found the BRAFV600E and MAP2K1 mutations were significantly associated with pERK expression (P < .001). Therefore, the RAS/RAF/MEK/ERK pathway might play a more important role in children than in adult patients with LCH.

MicroRNA-142-5p contributes to Hashimoto's thyroiditis by targeting CLDN1.

BACKGROUND: MicroRNAs have the potential as diagnostic biomarkers and therapeutic targets in autoimmune diseases. However, very limited studies have evaluated the expression of microRNA profile in thyroid gland related to Hashimoto's thyroiditis (HT). METHODS: MicroRNA microarray expression profiling was performed and validated by quantitative RT-PCR. The expression pattern of miR-142-5p was detected using locked nucleic acid-in situ hybridization. The target gene was predicted and validated using miRNA targets prediction database, gene expression analysis, quantitative RT-PCR, western blot, and luciferase assay. The potential mechanisms of miR-142-5p were studied using immunohistochemistry, immunofluorescence, and quantitative assay of thyrocyte permeability. RESULTS: Thirty-nine microRNAs were differentially expressed in HT (Fold change ≥2, P < 0.05) and miR-142-5p, miR-142-3p, and miR-146a were only high expression in HT thyroid gland (P < 0.001). miR-142-5p, which was expressed at high levels in injured follicular epithelial cells, was also detected in HT patient serum and positively correlated with thyroglobulin antibody (r ≥ 0.6, P < 0.05). Furthermore, luciferase assay demonstrated CLDN1 was the direct target gene of miR-142-5p (P < 0.05), and Immunohistochemical staining showed a reverse expression patterns with miR-142-5p and CLDN1. Overexpression of miR-142-5p in thyrocytes resulted in reducing of the expression of claudin-1 both in mRNA and protein level (P = 0.032 and P = 0.009 respectively) and increasing the permeability of thyrocytes monolayer (P < 0.01). CONCLUSIONS: Our findings indicate a previously unrecognized mechanism that miR-142-5p, targeting CLDN1, plays an important role in HT pathogenesis.

Sotagliflozin versus dapagliflozin to improve outcome of patients with diabetes and worsening heart failure: a cost per outcome analysis.

Background and aim: Dapagliflozin inhibits the sodium-glucose cotransporter protein 2 (SGLT-2), while sotagliflozin, belonging to a new class of dual-acting SGLT-1/SGLT-2 inhibitors, has garnered considerable attention due to its efficacy and safety. Both Dapagliflozin and sotagliflozin play a significant role in treating worsening heart failure in diabetes/nondiabetes patients with heart failure. Therefore, this article was to analyze and compare the cost per outcome of both drugs in preventing one event in patients diagnosed with diabetes-related heart failure. Method: The Cost Needed to Treat (CNT) was employed to calculate the cost of preventing one event, and the Number Needed to Treat (NNT) represents the anticipated number of patients requiring the intervention treatment to prevent a single adverse event, or the anticipated number of patients needing multiple treatments to achieve a beneficial outcome. The efficacy and safety data were obtained from the results of two published clinical trials, DAPA-HF and SOLOIST-WHF. Due to the temporal difference in the drugs' releases, we temporarily analyzed the price of dapagliflozin to calculate the price of sotagliflozin within the same timeframe. The secondary analyses aimed to assess the stability of the CNT study and minimize differences between the results of the RCT control and trial groups, employing one-way sensitivity analyses. Result: The final results revealed an annualized Number Needed to Treat (aNNT) of 4 (95% CI 3-7) for preventing one event with sotagliflozin, as opposed to 23 (95% CI 16-55) for dapagliflozin. We calculated dapagliflozin's cost per prevented event (CNT) to be $109,043 (95% CI $75,856-$260,755). The price of sotagliflozin was set below $27,260, providing a favorable advantage. Sensitivity analysis suggests that sotagliflozin may hold a cost advantage. Conclusion: In this study, sotagliflozin was observed to exhibit a price advantage over dapagliflozin in preventing one events, cardiovascular mortality, or all-cause mortality in patients with diabetes.

Clinical application and effect evaluation of acupoint thread embedding therapy and traditional Chinese medicine treatment based on menstrual cycle characteristics in the management of breast hyperplasia: An observational study.

To evaluate the effectiveness of the combination of acupoint embedding therapy and traditional Chinese medicine dialectical treatment regimen in improving clinical symptoms, promoting tumor regression, controlling adverse reactions and complications, and enhancing patient satisfaction by comparing and analyzing the clinical data of 120 breast tumor patients. One hundred twenty patients with breast cancer were divided into a treatment group (60 cases) and a control group (60 cases) according to different treatment plans. Patients in the treatment group received a combination of acupoint embedding therapy and traditional Chinese medicine dialectical treatment based on different time points of the menstrual cycle. Including the proportion of reduction in the number of breast masses, the proportion of reduction in mass size, changes in pain severity scores, tumor regression rate, regression time, incidence of adverse reactions and complications, and patient satisfaction. Statistical software was used to analyze the data to evaluate differences between the 2 groups. In terms of clinical symptoms, the proportion of reduction in the number of breast masses in the treatment group averaged 50%, significantly higher than the 25% in the control group; the proportion of reduction in mass size averaged 40%, also higher than the 15% in the control group; and the improvement in pain severity scores was also superior to the control group. Regarding tumor regression, the tumor regression rate in the treatment group reached 85%, with an average regression time of 6.2 weeks, both significantly better than the 55% and 9.8 weeks in the control group. In terms of adverse reactions and complications, the incidence rate in the treatment group was relatively low, and no serious adverse events occurred. Patient satisfaction surveys showed that the treatment group had significantly higher satisfaction with treatment effectiveness, treatment process, and physician service attitude compared to the control group. Based on clinical data from 120 breast tumor patients, the results of this study indicate that breast tumor patients treated with a specific treatment regimen have significant advantages in improving clinical symptoms, tumor regression, controlling adverse reactions and complications, and patient satisfaction. This treatment regimen has high clinical application value and deserves further promotion.

Ferroelectric tungsten bronze-based ceramics with high-energy storage performance via weakly coupled relaxor design and grain boundary optimization.

A multiscale regulation strategy has been demonstrated for synthetic energy storage enhancement in a tetragonal tungsten bronze structure ferroelectric. Grain refining and second-phase precipitation (perovskite phase) are introduced in the BaSrTiNb2-xTaxO9 ceramics by regulating the composition and sintering process. Disordered polarization and distribution, chemical inhomogeneity, and insulating boundary layers are achieved to provide the fundamental structural origin of the relaxation characteristic, high breakdown strength, and superior energy storage performance. Thus, an ultrahigh energy storage density of 12.2 J cm-3 with an low energy consumption was achieved at an electric field of 950 kV cm-1. This is the highest known energy storage performance in tetragonal tungsten bronze-based ferroelectric. Notably, this ceramic shows remarkable stability over frequency, temperature, and cycling electric fields. This work brings new material candidates and structure design for developing of energy storage capacitors apart from the predominant perovskite ferroelectric ceramics.

6:2 Cl-PFESA, a proposed safe alternative for PFOS, diminishes the gemcitabine effectiveness in the treatment of pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC)/pancreatic cancer, is a highly aggressive malignancy with poor prognosis. Gemcitabine-based chemotherapy remains the cornerstone of PDAC treatment. Nonetheless, the development of resistance to gemcitabine among patients is a major factor contributing to unfavorable prognostic outcomes. The resistance exhibited by tumors is modulated by a constellation of factors such as genetic mutations, tumor microenvironment transforms, environmental contaminants exposure. Currently, comprehension of the relationship between environmental pollutants and tumor drug resistance remains inadequate. Our study found that PFOS/6:2 Cl-PFESA exposure increases resistance to gemcitabine in PDAC. Subsequent in vivo trials confirmed that exposure to PFOS/6:2 Cl-PFESA reduces gemcitabine's efficacy in suppressing PDAC, with the inhibition rate decreasing from 79.5 % to 56.7 %/38.7 %, respectively. Integrative multi-omics sequencing and molecular biology analyses have identified the upregulation of ribonucleotide reductase catalytic subunit M1 (RRM1) as a critical factor in gemcitabine resistance. Subsequent research has demonstrated that exposure to PFOS and 6:2 Cl-PFESA results in the upregulation of the RRM1 pathway, consequently enhancing chemotherapy resistance. Remarkably, the influence exerted by 6:2 Cl-PFESA exceeds that of PFOS. Despite 6:2 Cl-PFESA being regarded as a safer substitute for PFOS, its pronounced effect on chemotherapeutic resistance in PDAC necessitates a thorough evaluation of its potential risks related to gastrointestinal toxicity.