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New-generation transcatheter heart valves have significantly improved technical success and procedural safety of transcatheter aortic valve implantation (TAVI) procedures; however, the incidence of permanent pacemaker implantation (PPI) remains a concern. This study aimed to assess the role of anatomic annulus features in determining periprocedural conduction disturbances leading to new PPI after TAVI using the last-generation Edwards SAPIEN balloon-expandable valves. In the context of a prospective single-center registry, we integrated the clinical and procedural predictors of PPI with anatomic data derived from multislice computed tomography. A total of 210 consecutive patients treated with balloon-expandable Edwards transcatheter heart valve were included in the study from 2015 to 2023. Technical success was achieved in 197 procedures (93.8%), and 26 patients (12.4%) required new PPI at the 30-day follow-up (median time to implantation 3 days). At the univariable logistic regression analysis, preprocedural right bundle branch block (odds ratio [OR] 2.24, 95% confidence interval [CI] 1.01 to 4.97, p = 0.047), annulus eccentricity ≥0.25 (OR 5.43, 95% CI 2.21 to 13.36, p <0.001), calcium volume at annulus of the right coronary cusp >48 mm3 (OR 2.60, 95% CI 1.13 to 5.96, p = 0.024), and prosthesis implantation depth greater than membranous septum length (OR 2.17, 95% CI 1.10 to 4.28, p = 0.026) were associated with new PPI risk. In the multivariable analysis, preprocedural right bundle branch block (OR 2.81, 95% CI 1.01 to 7.85, p = 0.049), annulus eccentricity ≥0.25 (OR 4.14, 95% CI 1.85 to 9.27, p <0.001), and annulusright coronary cusp calcium >48 mm3 (OR 2.89, 95% CI 1.07 to 7.82, p = 0.037) were confirmed as independent predictors of new PPI. In conclusion, specific anatomic features of the aortic valve annulus might have an additive role in determining the occurrence of conduction disturbances in patients who underwent TAVI with balloon-expandable valves. This suggests the possibility to use multislice computed tomography to improve the prediction of post-TAVI new PPI risk. [Display omitted]

Hypercalciuria is the main risk factor for recurrent calcium urolithiasis. The goal of our study is to determinate how useful an oral calcium load test is for stone formers to classify different forms of hypercalciuria in pathogenetic categories defined as renal or absorptive according to the current knowledge. Between June 2013 and February 2016, a prospective study was carried out on 117 documented recurrent hypercalciuric stone formers undergoing an oral calcium load test modified from the original description by Pak. After 2 days of calcium-restricted diet, urine and blood were analyzed at baseline and 120 min after receiving orally 1 g of calcium. Total and ionized calcium, parathyroid hormone from serum and urine calcium and creatinine were assessed in order to divide patients in three groups as previously described: resorptive, absorptive, and renal hypercalciuria. This allowed the identification of 19, 39, 34 and 33 patients with normocalcemic primary hyperparathyroidism (NPHPT), renal hypercalciuria aka renal calcium leak (RCL), absorptive hypercalciuria (AH) and unidentified cause, respectively. Patients with NPHPT (who required parathyroidectomy) experienced a lower PTH decrease (41.41 ± 12.82 vs. 54.06 ± 13.84% p < 0.01), higher beta-crosslaps, as well as lower TmP/GFR and distal third radius bone mineral density. RCL resulted in increased fasting urine calcium-to-creatinine ratio (Uca/Cr), i.e., > 0.37 mmol/mmol), without hyperparathyroidism. AH was diagnosed by the presence of ΔUCa/Cr > 0.60 mmol/mmol between baseline and 120 min without any other anomaly. For all remaining patients, results were inconclusive due to the lack of sufficient increase in serum calcium or because the cause of lithogenesis could not be clearly identified. The oral calcium load test is useful in nearly 80% of patients by identifying the different forms of hypercalciuria causing urolithiasis and by guiding treatment, including parathyroid surgery.

ABSTRACT Introduction The calcium load test (CLT) was developed by Pak et al. in 1974 to better discriminate hypercalciuria. Absorptive hypercalciuria (AH) is defined by an increase of the difference between urinary calcium/creatinine ratio (ΔUCa/Cr) of more than 0.5 mmol/mmol with a 4-hour CLT. In clinical practice and more recent studies, CLT is a 2-hour test. We hypothesized that the 4 h timepoint is more efficient in AH diagnosis. Methods We report a single-centre retrospective study including all patients who underwent CLT because of hypercalciuria or hyperparathyroidism. After a 3-day low-calcium diet and a 12-hour fast, 24-hour urines were collected. Blood and urinary samples were done at arrival and after 2 h and 4 h of oral ingestion of 1 g of calcium. AH was diagnosed by ΔUCa/Cr between baseline and 2 h or 4 h of more than 0.05 mmol/mmol. Results We included 328 patients. Baseline UCa/Cr ratio was 0.3 ± 0.2 mmol/mmol and increased significantly after 2 h and 4 h (0.6 ± 0.3 and 0.8 ± 0.4 mmol/mmol, P < 0.001). ΔUCa/Cr was significantly different between baseline and 2 h or 4 h (0.2 ± 0.2 versus 0.5 ± 0.4, P < 0.001). AH was diagnosed in 35 (10.7%) patients after 2 h, 84 (25.6%) more were diagnosed at 4 h (P < 0.001). Conclusions The 4 h CLT improves the diagnosis of AH with more than 50% of AH diagnosed within 4 h of calcium ingestion. It seems that there are cases of AH of later diagnosis with a similar clinical and biological profile depending on enteral absorption. Graphical Abstract Graphical Abstract

Pathogenesis of vascular calcification in chronic kidney disease. Hyperphosphatemia and hypercalcemia are independent risk factors for higher incidence of cardiovascular events in patients with chronic kidney disease. In addition to increased calcium-phosphate product, hyperphosphatemia accelerates the progression of secondary hyperparathyroidism with the concomitant bone loss, possibly linked to vascular calcium-phosphate precipitation. The control of serum phosphate levels reduces vascular calcification not only by decreasing the degree of secondary hyperparathyroidism and calcium-phosphate product, but also by reducing the expression of proteins responsible for active bone mineral deposition in cells of the vasculature. The calcium and aluminum-free phosphate-binders provide a new and effective therapeutic tool in preventing vascular calcifications in chronic kidney disease in animal models and in hemodialysis patients. Additional investigations are necessary to examine the benefits of different phosphate-binders in reducing mortality from cardiovascular disease.

The development of selective formulations able to target and kill tumor cells without the application of external energy has shown great promise for anti-tumor therapy. Here, we report a \"nanobomb\" that explosively increases Ca content within cells. It can selectively release Ca and generate H O in the tumor microenvironment (TME) by acid-triggered degradation of the two-layer protective shell (ie, unlocking the \"double-lock\"). This material, termed CaO @ZIF8:CUR@PAA, comprises a CaO core coated with the ZIF-8 framework, which was then loaded with curcumin (CUR) and coated again with polyacrylic acid (PAA). Under the slightly acidic conditions of the TME, the PAA shell (first lock) breaks down first exposing CaO @ZIF8 and CUR inside the cell. Then, ZIF8 (second lock) is degraded in response to acid to deposit Ca , and H O . CUR can promote the release of Ca from the endoplasmic reticulum to the cytoplasm, inhibit the outflow of Ca , and accumulates a large amount of Ca intracellularly together with exogenous Ca (calcium storms). The powerful calcium storm that causes mitochondrial dysfunction. The presence of a large amount of exogenous H O causes further oxidative damage to tumor cell membranes and mitochondria where intracellular ROS production far exceeds clearance. CaO @ZIF8:CUR@PAA NPs can induce cell S cycle arrest and apoptosis to inhibit tumor multiplication and growth. Oxidative damage-triggered immunogenic cell death (ICD) in turn leads to the polarization of macrophages to the M1 phenotype, inducing immunogenic cell death and inhibiting tumor cell proliferation and metastasis. The acid two-step unlocking nanoplatform is a therapeutic modality that combines calcium storm and oxidative damage. The mode triggers apoptosis leading to ICD of tumor cells. The material induces cycle blockade during treatment to inhibit cell proliferation. Robust in vitro and in vivo data demonstrate the efficacy of this approach and CaO @ZIF8:CUR@PAA as an anticancer platform, paving the way for nanomaterials in immune-triggered cancer therapy.

Opening of the mitochondrial membrane permeability transition pore (MPTP) is an important factor in the activation of apoptotic and necrotic processes in mammalian cells. In a previous paper we have shown that cardiac mitochondria from neonatal rats are more resistant to calcium load than mitochondria from adult animals. In this study we have analyzed the ontogenetic development of this parameter both in heart and in liver mitochondria. We found that the high resistance of heart mitochondria decreases from day 14 to adulthood. On the other hand, we did not observe a similar age-dependent sensitivity in liver mitochondria, particularly in the neonatal period. Some significant but relatively smaller increase could be observed only after day 30. When compared with liver mitochondria cardiac mitochondria were more resistant also to the peroxide activating effect on calcium-induced mitochondrial swelling. These data thus indicate that the MPTP of heart mitochondria is better protected against damaging effects of the calcium load and oxidative stress. We can only speculate that the lower sensitivity to calcium-induced swelling may be related to the higher ischemic tolerance of the neonatal heart.

The purpose of this investigation was to test the hypothesis that the decrease in bone resorption after the calcium (Ca) load can be assessed by serum type 1 collagen cross-linked C-telopeptide (Elecsys beta-CrossLaps, Roche) (S-CTX). Six young healthy women (23-27 years of age) and six healthy late postmenopausal women (63-69 years of age) with normal bone mineral density (BMD) received, after overnight fasting, 1 g of elemental Ca (in the form of calcium carbonate) dissolved in 250 ml of water or only plain water (fasting period). In addition, the late postmenopausal women were tested with an additional dose of 0.2 g of elemental Ca in 250 ml of water. Serum ionized Ca (S-iCa), S-CTX, plasma immunoreactive intact parathormone (P-PTH) were measured before and during the 5 hours after the oral intake of Ca. Urine was collected at regular intervals, and urinary Ca and creatinine were analyzed. In both the young and late postmenopausal subjects, the load with Ca resulted in a significant increase in S-iCa and urine Ca/creatinine ratio as well and a significant decrease of P-PTH and S-CTX compared with the fasting period. The comparison of the effects of 1 g Ca load between young and late postmenopausal women did not show any statistical significance in any measured parameters. In the late postmenopausal women, a significantly greater increase in S-iCa concentrations and a significantly greater decrease in P-PTH after 1 g were observed compared with those after a 0.2 g dose of Ca. During the first 3 hours, the load of both 1 g and 0.2 g of Ca induced a similar decrease in S-CTX. After 5 hours, however, S-CTX were significantly more suppressed after a 1 g dose than after a 0.2 g dose of Ca. In conclusion, a single oral morning dose of 1 g Ca suppresses bone resorption, as assessed by S-CTX, to a similar degree in both young and late postmenopausal women with normal Ca absorption. In healthy late postmenopausal women the load of 0.2 g of Ca carbonate significantly suppresses bone resorption.

The absorptive or renal origin of hypercalciuria can be discriminated using an acute oral calcium load test (ACLT). Of 86 patients with calcium oxalate kidney stones, 28 (23%) were found to be hypercalciuric (HCa) and 58 (67%) normocalciuric (NCa) on their customary free diet, containing 542 ± 29 mg/ day (mean ± SE) of calcium. Since the apparently normal 24-hour calcium excretion of many calcium stone formers (CSF) may be due to a combination of high calcium absorption with moderately low calcium intake, all patients were investigated by ACLT. Of 28 HCa patients, 13 (46%) were classified as absorptive (AH) and 15 (54%) as renal hypercalciuria (RH). Of the 58 NCa patients, 38 (65%) presented features of intestinal hyperabsorption and were therefore designated as AH-like, and 20 (35%) as RH-like. To further elucidate the role of dietary calcium in these CSF, a chronic calcium load test (CCLT), consisting of 1 g/day of oral Ca for 7 days, was designed. A positive response to the CCLT was considered to occur when urinary calcium (uCa) was ≥ 4 mg/ kg/24 h on the 7th day. Among NCa patients, 29% of AH-like subjects responded to the CCLT and 71% did not; 50% of RH-like subjects also responded and 50% did not. In HCa patients, 85% of AH and 67% of RH subjects maintained uCa ≥ 4 mg/kg/24 h after the CCLT and 15% of AH and 23% of RH subjects did not. However, a significant additional increase in mean uCa was not observed among HCa patients. All patients were submitted to a second evaluation of fasting calciuria (Ca/Cr). A modification of this parameter was noticed in 89% of RH-like and 78% of RH patients. In conclusion, these data suggest the presence of subpopulations of patients sensitive or not to calcium intake, regardless of whether the acute response to a calcium overload test suggested AH or RH. The CCLT disclosed dietary hypercalciuria in 21/58 (36%) of previously NCa patients. In these NCa patients, the ACLT may be replaced by the CCLT. The distinction between AH and RH initially evidenced by the ACLT was not further confirmed. These data suggest that either fasting Ca/Cr is not adequate for subclassification of HCa or that AH and RH represent a different spectrum of the same disease, and that a primary resorptive component should also be considered.

Severe fever with thrombocytopenia syndrome (SFTS), an emerging tick-borne infectious disease caused by a novel phlebovirus (SFTS virus, SFTSV), was listed among the top 10 priority infectious diseases by the World Health Organization due to its high fatality of 12%–50% and possibility of pandemic transmission. Currently, effective anti-SFTSV intervention remains unavailable. Here, by screening a library of FDA-approved drugs, we found that benidipine hydrochloride, a calcium channel blocker (CCB), inhibited SFTSV replication in vitro. Benidipine hydrochloride was revealed to inhibit virus infection through impairing virus internalization and genome replication. Further experiments showed that a broad panel of CCBs, including nifedipine, inhibited SFTSV infection. The anti-SFTSV effect of these two CCBs was further analyzed in a humanized mouse model in which CCB treatment resulted in reduced viral load and decreased fatality rate. Importantly, by performing a retrospective clinical investigation on a large cohort of 2087 SFTS patients, we revealed that nifedipine administration enhanced virus clearance, improved clinical recovery, and remarkably reduced the case fatality rate by >5-fold. These findings are highly valuable for developing potential host-oriented therapeutics for SFTS and other lethal acute viral infections known to be inhibited by CCBs in vitro.

Chondrocytes respond to mechanical stimuli by increasing their intracellular calcium concentration. The response depends on the cellular environment. Previous studies have investigated chondrocytes under slow strain rates or cells embedded in hydrogels, but the response of chondrocytes in their native environment under physiologically relevant cyclic loads and dynamic hydrostatic pressure has not been studied. This study investigated the calcium signaling response of in-situ chondrocytes under physiological cyclic compressive loads and hydrostatic pressure with varying frequency and load rates. Bovine cartilage explants were stained with a fluorescent calcium indicator dye and subjected to physiologically relevant cyclic loads using a custom-built loading device secured on a confocal/multiphoton microscope. Calcium fluorescence intensities of the cells were tracked and analyzed. Loading groups were compared using one-way ANOVA followed by a post-hoc test with Tukey correction (α = 0.05). The percentage of cells signaling increased in all compressive loading conditions compared to the no-load baseline. The percentage of cells responding under 1 Hz load was significantly greater than the slow ramp and 0.1 Hz group (p < 0.05). The number of compression cycles had no effect on the calcium signaling response (p > 0.05). The width and time between consecutive peaks were not different between different loading conditions (p > 0.05). Calcium signaling of in-situ chondrocytes did not increase under dynamic hydrostatic pressure of magnitudes up to 0.2 MPa at frequencies of 0.5 Hz and 0.05 Hz (p > 0.05). In conclusion, in-situ chondrocytes respond to physiological compressive loads in a strain rate-dependent manner with an increased number of responsive cells and unaltered temporal characteristics.