Real-World Experience of Using Etelcalcetide for Secondary Hyperparathyroidism in Community-Based Hemodialysis Centers in Singapore.

Introduction Chronic kidney disease-related mineral and bone disorder (CKD-MBD), characterized by abnormalities in calcium, phosphate, and parathyroid hormone metabolism, with impaired bone turnover and extravascular calcification is a known complication of advanced chronic kidney disease (CKD). Secondary hyperparathyroidism (SHPT) develops early in the disease and its prevalence gradually increases with the disease progression, becoming almost universal in patients with end-stage renal disease (ESRD). The treatment for SHPT includes synthetic vitamin D analogs, calcitriol or calcimimetics. Recently, intravenous etelcalcetide was introduced as a second-generation calcimimetic. This article provides the real-world experience of using etelcalcetide in multiethnic Asian patients receiving hemodialysis at community-based hemodialysis centers in Singapore. Methods This study was real-world evidence, generated by a retrospective clinical audit of routine clinical care of hemodialysis patients in community-based centers in Singapore who received etelcalcetide for treating SHPT. The information on the starting and maximum dose of etelcalcetide, duration of treatment on hemodialysis, parathyroid hormone (PTH) levels, dialysate calcium, concomitant medications, and reasons for discontinuation were collected from the medical records. PTH levels were collected at four-, eight-, and twelve-month intervals. Results A total of 148 patients received etelcalcetide during the study period. Ten patients died and twenty discontinued their treatment, with 118 patients remaining on treatment. Demographically, the patients included Chinese, Malay, Indians, and those belonging to other racial groups. The starting dose of etelcalcetide ranged from 2.5 mg once per week to 7.5 mg three times a week. There was a 16.8% reduction (p=<0.001) in intact-PTH after four months of therapy. Target intact-PTH level of less than 60 pmol/L, was reported as 1.4% at baseline, with 22.3% at four months (p<0.001) and 25.9% at eight months (p=0.028). Calcium and phosphate levels were also tracked as part of the safety and efficacy measures of using etelcalcetide. No symptomatic hypocalcemia was noted and phosphate levels were noted to decline significantly. Overall, the calcium-phosphate product reduced at four months (13.2%, p=<0.001) and eight months (12.7%, p<0.05). An analysis of concomitant medication usage, dialysate calcium utilized, and the side effects of etelcalcetide were also recorded. Finally, a brief descriptive analysis of the patient's subjective feedback regarding etelcalcetide was also reported, especially regarding the reduction in pill burden and overall compliance to medications. Conclusion Etelcalcetide is safe and effective for treating SHPT in multi-ethnic Asian hemodialysis patients and can be considered an alternative to oral cinacalcet. Our study showed no side effects, which was one of the key reasons for non-compliance to traditional calcimimetics. A favorable compliance profile with reduced pill burden was noted by using this intravenous calcimimetic.

A Real-World Experience of Hyperkalemia Management Using Sodium Zirconium Cyclosilicate in Chronic Hemodialysis: A Multicenter Clinical Audit.

INTRODUCTION:  Hyperkalemia, a common condition among hemodialysis (HD) patients, is associated with adverse health outcomes. Evidence of the safety and efficacy of a potassium-binder, sodium zirconium cyclosilicate (SZC), has been limited among Asian (HD) patients beyond phase 3 trials. This article demonstrates real-world evidence of SZC usage in an Asian cohort of HD patients. METHODS:  A retrospective clinical audit was conducted among 293 patients who received maintenance HD at community-based dialysis centers in Singapore. Patients received SZC for either management of hyperkalemia or hyperkalemia prevention during anticipated disruption to dialysis, such as during traveling. Among patients treated for hyperkalemia (N = 147), serum potassium (K+) prior to SZC initiation and at the endpoint was compared using a paired Student's t-test. Changes in K+ from baseline to endpoint were compared across various categories within each demographic and health-related variables using either Student's t-test or one-way ANOVA. Patients who experienced adverse events after SZC initiation or were deceased during the audit were reviewed to provide a descriptive account. RESULTS:  Among patients who received SZC for hyperkalemia treatment, SZC use was associated with a significant reduction of 0.812 mmol/L in serum potassium. Patients with ethnicities other than Chinese, Malay, or Indian had a nominal reduction in K+ of 0.7 mmol/L and this can be accounted for the small sample size of this sub-group. The three main ethnicities which represented more than 95% of the sample showed a significant reduction in K+ levels (all three p<0.001). This is consistent with other studies with SZC which showed efficacy across various ethnicities. Patients who received SZC for hyperkalemia treatment or prevention had a significant lowering of mortality rate. This mortality reduction may have inherent biases and confounders, due to the retrospective clinical audit study design.  Conclusions: Overall, SZC was safe and effective among the audited patients. The efficacy in the real-world setting was similar to previous trials. The novel use of SZC to manage serum potassium when HD sessions are missed, such as during traveling, warrants further investigation due to potentially significant life-saving implications.

The Impact of COVID-19 Infection Control Measures on End-Stage Renal Disease Patients in a Community Hemodialysis Setting.

INTRODUCTION: Several non-pharmaceutical infection control measures have been implemented at community-based hemodialysis centers to reduce the risk of Coronavirus Disease of 2019 (COVID-19) transmission, caused by the SARS-CoV-2 virus. However, there have been concerns that such measures may disrupt the routine and timely care required by patients, with adverse effects on their health outcomes. This cross-sectional study aims to determine the unintended consequences of COVID-19 infection control measures on hemodialysis patients. METHODS:  Electronic medical records were extracted from patients enrolled in community-based hemodialysis centers in Singapore. A baseline group prior of patients consisted of those enrolled in 2017, which was three years prior to the SARS-CoV-2-related pandemic (n = 548). This was compared with the study group of patients enrolled in 2019 (n = 426), just before the COVID-19 pandemic started. Medical records for these two groups were extracted from January to July 2018 for the baseline group and from January to July 2020, respectively. Three regression models were built to study dialysis adherence, kidney disease biomarkers, and hospitalization episodes. RESULTS:  There was no statistically significant difference in hospitalization and mortality outcomes, adherence to dialysis management, laboratory results for dialysis-related clearance, and anemia outcomes. There was a higher proportion of patients hospitalized for vascular access-related reasons in the study group as compared to the baseline group (OR 1.6, 95% CI: 1.10 to 2.29, P = 0.014). Patients in the study group had albumin levels 2.13% higher (95% CI: 0.88 to 3.39, P < 0.001) and alkaline phosphatase levels 7.3% lower (95% CI: 1.17 to 13.02, P = 0.020) than those in the baseline group. CONCLUSIONS:  From this community-based hemodialysis study in Singapore, it was shown that the COVID-19 pandemic did not disrupt regular healthcare services for these patients. With strategies instituted for a coordinated health delivery workflow, ensuring sufficient capacity in the various healthcare delivery sites and overall pandemic preparedness, the patient clinical outcomes measures continued to be met with no adverse consequences noted. Some improvements in dialysis-related laboratory values and quality of care targets may be due to more stringent measures instituted to protect these vulnerable patients in the community.

Thermo-Sensitive Spikelet Defects 1 acclimatizes rice spikelet initiation and development to high temperature.

Crop reproductive development is vulnerable to heat stress, and the genetic modulation of thermotolerance during the reproductive phase, especially the early stage, remains poorly understood. We isolated a Poaceae-specific FAR-RED ELONGATED HYPOCOTYLS3 (FHY3)/FAR-RED IMPAIRED RESPONSE1 (FAR1)family transcription factor, Thermo-sensitive Spikelet Defects 1 (TSD1), derived from transposase in rice (Oryza sativa) TSD1 was highly expressed in spikelets, induced by heat, and specifically enhanced the thermotolerance of spikelet morphogenesis. Disrupting TSD1 did not affect vegetative growth but markedly retarded spikelet initiation and development, as well as caused varying degrees of spikelet degeneration, depending on the temperature. Most tsd1 spikelets were normal at low temperature but gradually degenerated as temperature increased, and all disappeared at high temperature, leading to naked branches. TSD1 directly promoted the transcription of YABBY1 and YABBY3 and could physically interact with YABBY1 and three TOB proteins, YABBY5, YABBY4, and YABBY3. These YABBY proteins can form either homodimers or heterodimers and play an important role in spikelet morphogenesis, similar to TSD1. Notably, the knockout mutant yab5-ko and double mutant tsd1 yab5-ko resembled tsd1 in spikelet appearance and response to temperature, indicating that these genes likely participate in spikelet development through the cooperative TSD1-YABBY module. These findings reveal a distinctive function of FHY3/FAR1 family genes and a unique TSD1-YABBY complex to acclimate spikelet development to high temperature in rice, providing insight into the regulating pathway of enhancing thermotolerance in plant reproductive development.

The impact of employee compensation restrictions on labor productivity in state-owned enterprises: Evidence from China.

Employees are important stakeholders in an organization. This paper aims to examine the effectiveness of limits on employee compensation in state-owned enterprises (SOEs), a policy for employees of state-owned enterprises issued by the China State-owned Assets Supervision and Administration Commission (SASAC) in 2010. Employing a difference-in-differences analysis for a sample of Chinese listed companies from 2007 to 2013, the results show that employee compensation restriction enhances the labor productivity of SOEs. This policy effect is mainly due to the contribution of compensation limits to the external fairness of employee compensation, and the findings remain unchanged after a series of robustness testing procedures. In addition, the employee compensation restriction policy significantly affects labor productivity improvement in monopolistic industries or mature SOEs.

Treat-to-Target urate-lowering therapy in primary gout patients: A real-world retrospective study at a dedicated gout clinic in China.

BACKGROUND: Gout is the most common inflammatory arthritis affecting 1.1% of the population in mainland China with a higher prevalence in coastal areas. OBJECTIVE: The purpose of the study was to investigate the clinical outcomes following urate-lowering therapy (ULT) in a real-world group study of primary gout patients in China. METHODS: Electronic medical records of all the gout patients (n= 1588) that visited the Clinical Medical Center of Gout of the Affiliated Hospital of Qingdao University from September 2016 to February 2018 were analyzed in this study. The patients were treated with a standard treat-to-target (T2T) ULT strategy according to the 2016 EULAR Guidelines. Clinical data were collected in the first visit and one-month (defined as the baseline of ULT), 7-month, and 13-month follow-ups were completed. RESULTS: Amongst the patients in the study, 92.70% accepted ULT and 82.93% completed ULT for 3 months, 63.54% for 6 months, and 40.49% (n= 643) for 12 months. Further analysis of the 643 patients included the following data: the sUA level reduced at month 7 and reduced further at month 13. The gout flares, patient global pain visual analogue score, and health assessment questionnaire score improved at month 7 but did not improve further at month 13, and the index tophus size did not.

Three-Dimensional Interpenetrating Frameworks Based on {P4Mo6} Tetrameric Clusters and Filled with In Situ Generated Alkyl Viologens.

Four novel three-dimensional interpenetrating frameworks based on {P4Mo6} units, H[C12H14N2]4[TM4(PO4)(H2O)4Na6][TM2(Mo6O12(HPO4)3(PO4)(OH)3)4]·8H2O (1, 2) and H[C14H18N2]4[TM4(PO4)(H2O)4Na6][TM2(Mo6O12(HPO4)3(PO4)(OH)3)4]·8H2O (3, 4) (TM = Co2+ (1, 3), Mn2+ (2, 4)) were synthesized and characterized using infrared spectroscopy, elemental analyses, thermogravimetric analysis, and single-crystal X-ray diffraction. In situ generated methyl viologen (compounds 1 and 2) or ethyl viologen (compounds 3 and 4) cations function as templates to induce the generation of 2-fold interpenetrating structures in which the {P4Mo6} tetrameric clusters with [TM4(PO4)Na6] (TM = Co2+ (1, 3) and Mn2+ (2, 4)) as the core were bridged by transition metal ions. Compounds 1-4 possess high thermal stabilities and the decomposition temperature of the inorganic frameworks were all >500 °C. It is worth noting that the four compounds all exhibited the bifunctional catalytic performance that they not only had an excellent photocatalytic activity for the reduction of hexavalent chromium (Cr(VI)) under visible light irradiation but also showed a good electrocatalytic activity for the reduction reaction of hydrogen peroxide.

RETINOBLASTOMA-RELATED Genes Specifically Control Inner Floral Organ Morphogenesis and Pollen Development in Rice.

RETINOBLASTOMA-RELATED (RBR) is an essential gene in plants, but its molecular function outside of its role in cell cycle entry remains poorly understood. We characterized the functions of OsRBR1 and OsRBR2 in plant growth and development in rice using both forward- and reverse-genetics methods. The two genes were coexpressed and performed redundant roles in vegetative organs but exhibited separate functions in flowers. OsRBR1 was highly expressed in the floral meristem and regulated the expression of floral homeotic genes to ensure floral organ formation. Mutation of OsRBR1 caused loss of floral meristem identity, resulting in the replacement of lodicules, stamens, and the pistil with either a panicle-like structure or whorls of lemma-like organs. OsRBR2 was preferentially expressed in stamens and promoted pollen formation. Mutation of OsRBR2 led to deformed anthers without pollen. Similar to the protein interaction between AtRBR and AtMSI1 that is essential for floral development in Arabidopsis, OsMSI1 was identified as an interaction partner of OsRBR1 and OsRBR2. OsMSI1 was ubiquitously expressed and appears to be essential for development in rice (Oryza sativa), as the mutation of OsMSI1 was lethal. These results suggest that OsRBR1 and OsRBR2 function with OsMSI1 in reproductive development in rice. This work characterizes further functions of RBRs and improves current understanding of specific regulatory pathways of floral specification and pollen formation in rice.

Screening and analysis of proteins interacting with OsMADS16 in rice (Oryza sativa L.).

OsMADS16, a class B floral organ identity gene, plays a pivotal role in stamen formation in rice. To date, little is known about the interacting partners of OsMADS16 except for several MADS-box proteins. In this study, we constructed a high-quality cDNA library of young panicles (< 5 cm in length) and performed yeast two-hybrid (Y2H) screening using OsMADS16 as bait. Eleven candidate proteins interacting with OsMADS16 were identified by Y2H and validated by BiFC and Co-IP assays. Subcellular localization results further confirmed the possibility of the interactions of OsMADS16 with 10 of the candidate proteins in natural rice cells. Bioinformatics analysis indicated that these partners exerted various molecular, cellular and physiological functions. Some of them were known or likely to be related to reproductive events, such as stamen primordium initiation, differentiation and development (OsMADS2, OsMADS4 and OsCOP9) and pollen development (OsbHLH40 and Os6PGDH). Our results provide an important reference for further research on OsMADS16-mediated regulation mechanism on floral organ development and pollen formation.

Urate-lowering therapy alleviates atherosclerosis inflammatory response factors and neointimal lesions in a mouse model of induced carotid atherosclerosis.

Hyperuricemia (HU) is a cause of gout. Clinical studies show a link between HU and cardiovascular disease. However, the role of soluble serum urate (SU) on atherosclerosis development remains elusive. We aimed to use a new HU mouse model [Uricase/Uox knockout (KO)] to further investigate the relationship between HU and atherosclerosis. A mouse model by perivascular collar placement of induced carotid atherosclerosis was established in male Uox-KO mice. The Uox-KO mice had elevated SU levels and enhanced levels of atherosclerosis inflammatory response proteins. In contrast, Uox-KO mice with carotid atherosclerosis showed severe neointimal changes in histology staining consistent with increases in intimal area and increases in proliferating cell nuclear antigen (PCNA)- and F4/80-positive cells. Allopurinol reduced neointimal areas induced by the perivascular collar in hyperuricemic mice, accompanied by decreased expression of PCNA- and F4/80-positive cells. Urate-lowering treatment alleviated atherosclerosis inflammatory response factors and reactive oxygen species (ROS) intensities in both collar placement Uox-KO mice and urate-stimulated human umbilical vein endothelial cells (HUVECs). In vitro results using HUVECs showed ROS was induced by urate and ROS induction was abrogated using antioxidants. These data demonstrate that urate per se does not trigger atherosclerosis intima lesions in male mice. Urate worsens carotid neointimal lesions induced by the perivascular collar and urate-lowering therapy partially abrogates the effects. The current study warrants clinical studies on the possible benefits of urate-lowering therapy in atherosclerosis patients with HU.

Integrin-Linked Kinase Controls Choroidal Neovascularization by Recruitment of Endothelial Progenitor Cells.

Purpose: Vasculogenesis has been shown to contribute to the formation of choroidal neovascularization (CNV). However, the mechanism behind the recruitment of endothelial progenitor cells (EPC) to CNV is not well understood. Therefore, we were interested to know whether integrin-linked kinase (ILK) plays a role in recruiting EPC to CNV, and its possible mechanism. Methods: We investigated the effect of hypoxia on retinal pigment epithelium (RPE) cells expressing ILK, hypoxia-inducible factor 1α (HIF-1α), stromal-derived factor-1 (SDF-1), and vascular endothelial growth factor (VEGF), and we further examined the effect of ILK small interfering RNA (siRNA) on their expression. The function of ILK expressed by RPE on EPC in vitro with regard to angiogenic effect was also studied. In vivo, we determined the expression levels of the above factors in CNV. We also examined the role of ILK on their expression, on EPC recruiting, and on the growth of CNV. Results: We found that hypoxia strongly induced the expression of ILK, HIF-1α, SDF-1, and VEGF. Moreover, the silencing of ILK attenuated their expression. It also decreased the phosphorylation of protein kinase B (PKB/AKT) and extracellular regulated protein kinases (ERK) and nearly abolished the proliferation, migration, and adhesion of EPC to RPE cells. In vivo, we showed that these factors were upregulated in CNV. Inhibiting the expression of ILK prohibited the "homing" of EPC to CNV lesions and attenuated the growth of CNV. Conclusions: We demonstrate that ILK controls the development of CNV by regulating the recruitment of EPC to CNV lesions, possibly through ILK-dependent expression of SDF-1 and VEGF in RPE.

Preliminary study of retinal pathological features in preterm birth pups exposed to an animal model of oxygen-induced retinopathy in mice.

BACKGROUND: The main risk factors of retinopathy of prematurity (ROP) are low gestational age and low birth weight, which are mainly caused by preterm birth. Currently, the animal model of oxygen-induced retinopathy (OIR) in mice is the most widely used model in ROP-associated studies. However, the experimental mice are normal-term pups, and may not mimic the pathogenic status of human ROP patients. In this study, we investigated the retinal pathological features in preterm birth pups exposed to an animal model of oxygen-induced retinopathy in mice. METHODS: Preterm-birth mice were obtained from pregnant C57BL/6J mice that were induced by an intraperitoneal injection of lipopolysaccharide (LPS). The preterm and control mice were treated with high oxygen (75%) from postnatal day 7 (P7) to P12. The mice were perfused with high-molecular-weight FITC-dextran on P12, P15 and P17, and the retinas were whole-mounted and imaged. Vascular endothelial growth factor (VEGF) mRNA was also detected. Cross-sections of the retina were stained with hematoxylin and eosin (H&E) to identify preretinal neovascular tufts. For general observation, whole retinal images were also obtained using a microscope. RESULTS: Leakage of the retinal blood vessels was aggravated in the preterm mice, particularly on P12 and P15. The non-perfused areas of the retina (pixel value, 183,673 ± 28,148 vs 132,110 ± 23,732, P = 0.009) and the number of preretinal endothelial cell nuclei were smaller (30.17 ± 8.33 vs 22.17 ± 6.74, P < 0.0001) on P17. The VEGF mRNA levels in the retinas were higher on P12 and P15 but lower on P17, compared with the control mice. Retinal hemorrhage was observed in the preterm mouse group (five out of six examined eyes). CONCLUSIONS: Preterm-birth mice that were subject to OIR exhibited several pathological features, such as retinal hemorrhage, severe retinal leakage and moderate retinal neovascularization, which were similar to the clinical manifestations in ROP patients.

[Possible mechanism of endothelial progenitor cells in the development of rat choroidal neovascularization].

OBJECTIVE: To investigate the role and possible mechanism of endothelial progenitor cell (EPC) in the development of choroidal neovascularization (CNV). METHODS: Experimental study. Twenty-four BN rats were divided into 3 groups.One eye of each animal was induced by laser photocoagulation with 532 nm laser and the contralateral eye was taken as control. Three, seven and fourteen days after photocoagulation the formation of CNV was observed by histopathological study and the recruitment of EPC and the possible pro-angiogenic growth factors released by EPC during the development of CNV were examined by multi-labeled immunofluorescence staining. The difference among the 3 groups was analyzed by ANOVA and the comparison between any 2 groups was further checked by LSD-t test. RESULTS: Both the histopathological study and the immunofluorescence staining indicated that within the laser lesions proliferated and migrated cells grew into the subretinal space through the broken Bruch membrane 3 days after photocoagulation, 7 days after photocoagulation lumen-like structures were observed and CNV became stable until 14 days after photocoagulation. No EPC was observed in the normal retina whereas EPC were recruited into the laser lesions 3 days after photocoagulation, comprising (79.29 ± 11.27)% of the total endothelial cell population within CNV. At 7-day EPC constituted new vessels within CNV area and the proportion decreased to (47.13 ± 5.78)%. Then its number decreased dramatically 14 days after photocoagulation contributing to (10.83 ± 2.79)% of the endothelial cells in CNV. The differences either among the 3 groups (F = 104.623, P < 0.05) or between any 2 groups (P < 0.05) were statistically significant. Moreover, triple labelled immunofluorescence staining showed that the EPC within CNV area could also secret pro-angiogenic factors such as vascular endothelial growth factor, IL-10, bFGF and MMP9. CONCLUSION: EPC involves in the development of CNV not only through participating in the formation of new vessels within the CNV area but also through secreting pro-angiogenic factors.

[Effect of liposomal transfection of UCH-L1 siRNA on proliferation and apoptosis of lung cancer cell line H157].

BACKGROUND AND OBJECTIVE: Several reports demonstrated that the ubiquitin C terminal hydrolase-L1 (UCH-L1) has been found to be an oncogene in malignant tumors such as esophageal carcinoma, lung cancer and breast cancer. The aim of this study is to explore the effects of liposomal transfection of UCH-L1 siRNA on the proliferation and apoptosis of lung adenocarcinoma cell lines H157. METHODS: UCH-L1 siRNA was synthesized and transfected into H157 cell by liposome. Cell morphological change was observed with microscope, and cell proliferation and apoptosis index detected by flow cytometry, UCH-L1 mRNA expression was determined by RT-PCR and protein level of UCH-L1 was determined by Western blot. RESULTS: For the H157 cell transfected with siRNA, cell proliferation was inhibited significantly, cell apoptosis appeared obviously, the expression of UCH-L1 mRNA and protein level of UCH-L1 significantly decreased. CONCLUSION: UCH-L1 siRNA is able to inhibit the proliferation of lung adenocarcinoma cell lines H157 and induce the apoptosis. UCH-L1 might become a new target for lung carcinoma gene therapy.