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BMC Musculoskeletal Disorders Jun 2024Osteoporosis (OS) is a systemic bone disease characterized by low bone mass and bone microstructure damage. This study.
OBJECTIVE
Osteoporosis (OS) is a systemic bone disease characterized by low bone mass and bone microstructure damage. This study.
METHODS
According to the T value, 88 elderly fracture patients were grouped as the control group (without OS, 43 cases) and observation group (with T value <-2.5, which could be diagnosed as OS, 45 cases). The content of boney containing protein (BGP), total type 1 collagen amino terminal extender peptide (TPINP), β-Crosslaps (β-CTX), parathyroid hormone (PTH) and insulin-like growth factors-1 (IGF-1) was compared. Multivariate logistic regression was adopted to analyze the correlation between biochemical indexes and the occurrence of senile OS fracture and the related risk factors. The diagnostic value in the elderly was analyzed by receiver operating characteristic (ROC) curve.
RESULTS
The levels of BGP, TPINP, β-CTX, PTH and IGF-1 were elevated, and the level of IGF-1 was decreased in the observation group compared with the control group (P < 0.05). The elevated content of BGP, TPINP, β-CTX and PTH, and the decreased expression of IGF-1 were influencing factors for OS fractures in the elderly (P < 0.05). The sensitivity and specificity to predict the occurrence of OS fractures in the elderly were 91.70% and 90.50%, respectively. The AUC of combined detection was 0.976 (95% CI: 0.952-1.000), which was memorably higher than single indicator detection (P < 0.05). Among 45 patients, 32 cases had good prognosis and 13 had poor prognosis. In comparison with the good prognosis group, the content of BGP, TPINP, β-CTX and PTH were sensibly higher, the level of IGF-1 was prominently lower, and the proportion of fracture history was much higher in poor prognosis group (P < 0.05). Fracture history, BGP, TPINP, β-CTX, PTH and IGF-1 were independent risk factors for poor prognosis of elderly OS fractures (P < 0.05).
CONCLUSION
Bone metabolism factors were associated with poor prognosis of OS in the elderly. The combined detection had higher diagnostic value in calculating the risk of OS fracture in the elderly than single indicator detection.
Topics: Humans; Aged; Female; Male; Osteoporotic Fractures; Risk Factors; Insulin-Like Growth Factor I; Aged, 80 and over; Parathyroid Hormone; Biomarkers; Osteoporosis; Predictive Value of Tests; Collagen Type I; ROC Curve; Case-Control Studies; Risk Assessment; Middle Aged
PubMed: 38840246
DOI: 10.1186/s12891-024-07560-5 -
Microbial Cell Factories Jun 2024Recombinant peptide production in Escherichia coli provides a sustainable alternative to environmentally harmful and size-limited chemical synthesis. However, in-vivo...
BACKGROUND
Recombinant peptide production in Escherichia coli provides a sustainable alternative to environmentally harmful and size-limited chemical synthesis. However, in-vivo production of disulfide-bonded peptides at high yields remains challenging, due to degradation by host proteases/peptidases and the necessity of translocation into the periplasmic space for disulfide bond formation.
RESULTS
In this study, we established an expression system for efficient and soluble production of disulfide-bonded peptides in the periplasm of E. coli. We chose model peptides with varying complexity (size, structure, number of disulfide bonds), namely parathyroid hormone 1-84, somatostatin 1-28, plectasin, and bovine pancreatic trypsin inhibitor (aprotinin). All peptides were expressed without and with the N-terminal, low molecular weight CASPON™ tag (4.1 kDa), with the expression cassette being integrated into the host genome. During BioLector™ cultivations at microliter scale, we found that most of our model peptides can only be sufficiently expressed in combination with the CASPON™ tag, otherwise expression was only weak or undetectable on SDS-PAGE. Undesired degradation by host proteases/peptidases was evident even with the CASPON™ tag. Therefore, we investigated whether degradation happened before or after translocation by expressing the peptides in combination with either a co- or post-translational signal sequence. Our results suggest that degradation predominantly happened after the translocation, as degradation fragments appeared to be identical independent of the signal sequence, and expression was not enhanced with the co-translational signal sequence. Lastly, we expressed all CASPON™-tagged peptides in two industry-relevant host strains during C-limited fed-batch cultivations in bioreactors. We found that the process performance was highly dependent on the peptide-host-combination. The titers that were reached varied between 0.6-2.6 g L, and exceeded previously published data in E. coli. Moreover, all peptides were shown by mass spectrometry to be expressed to completion, including full formation of disulfide bonds.
CONCLUSION
In this work, we demonstrated the potential of the CASPON™ technology as a highly efficient platform for the production of soluble peptides in the periplasm of E. coli. The titers we show here are unprecedented whenever parathyroid hormone, somatostatin, plectasin or bovine pancreatic trypsin inhibitor were produced in E. coli, thus making our proposed upstream platform favorable over previously published approaches and chemical synthesis.
Topics: Escherichia coli; Periplasm; Disulfides; Peptides; Recombinant Proteins; Aprotinin
PubMed: 38840157
DOI: 10.1186/s12934-024-02446-6 -
Kidney Diseases (Basel, Switzerland) Jun 2024This study aimed to develop and validate machine learning (ML) models based on serum Klotho for predicting end-stage kidney disease (ESKD) and cardiovascular disease...
INTRODUCTION
This study aimed to develop and validate machine learning (ML) models based on serum Klotho for predicting end-stage kidney disease (ESKD) and cardiovascular disease (CVD) in patients with chronic kidney disease (CKD).
METHODS
Five different ML models were trained to predict the risk of ESKD and CVD at three different time points (3, 5, and 8 years) using a cohort of 400 non-dialysis CKD patients. The dataset was divided into a training set (70%) and an internal validation set (30%). These models were informed by data comprising 47 clinical features, including serum Klotho. The best-performing model was selected and used to identify risk factors for each outcome. Model performance was assessed using various metrics.
RESULTS
The findings showed that the least absolute shrinkage and selection operator regression model had the highest accuracy (C-index = 0.71) in predicting ESKD. The features mainly included in this model were estimated glomerular filtration rate, 24-h urinary microalbumin, serum albumin, phosphate, parathyroid hormone, and serum Klotho, which achieved the highest area under the curve (AUC) of 0.930 (95% CI: 0.897-0.962). In addition, for the CVD risk prediction, the random survival forest model with the highest accuracy (C-index = 0.66) was selected and achieved the highest AUC of 0.782 (95% CI: 0.633-0.930). The features mainly included in this model were age, history of primary hypertension, calcium, tumor necrosis factor-alpha, and serum Klotho.
CONCLUSION
We successfully developed and validated Klotho-based ML risk prediction models for CVD and ESKD in CKD patients with good performance, indicating their high clinical utility.
PubMed: 38835404
DOI: 10.1159/000538510 -
BMC Musculoskeletal Disorders Jun 2024Machine learning (ML) has shown exceptional promise in various domains of medical research. However, its application in predicting subsequent fragility fractures is...
BACKGROUND
Machine learning (ML) has shown exceptional promise in various domains of medical research. However, its application in predicting subsequent fragility fractures is still largely unknown. In this study, we aim to evaluate the predictive power of different ML algorithms in this area and identify key features associated with the risk of subsequent fragility fractures in osteoporotic patients.
METHODS
We retrospectively analyzed data from patients presented with fragility fractures at our Fracture Liaison Service, categorizing them into index fragility fracture (n = 905) and subsequent fragility fracture groups (n = 195). We independently trained ML models using 27 features for both male and female cohorts. The algorithms tested include Random Forest, XGBoost, CatBoost, Logistic Regression, LightGBM, AdaBoost, Multi-Layer Perceptron, and Support Vector Machine. Model performance was evaluated through 10-fold cross-validation.
RESULTS
The CatBoost model outperformed other models, achieving 87% accuracy and an AUC of 0.951 for females, and 93.4% accuracy with an AUC of 0.990 for males. The most significant predictors for females included age, serum C-reactive protein (CRP), 25(OH)D, creatinine, blood urea nitrogen (BUN), parathyroid hormone (PTH), femoral neck Z-score, menopause age, number of pregnancies, phosphorus, calcium, and body mass index (BMI); for males, the predictors were serum CRP, femoral neck T-score, PTH, hip T-score, BMI, BUN, creatinine, alkaline phosphatase, and spinal Z-score.
CONCLUSION
ML models, especially CatBoost, offer a valuable approach for predicting subsequent fragility fractures in osteoporotic patients. These models hold the potential to enhance clinical decision-making by supporting the development of personalized preventative strategies.
Topics: Humans; Male; Female; Machine Learning; Aged; Retrospective Studies; Osteoporotic Fractures; Middle Aged; Aged, 80 and over; Predictive Value of Tests; Risk Assessment; Risk Factors; Osteoporosis; Algorithms
PubMed: 38834975
DOI: 10.1186/s12891-024-07559-y -
BMC Public Health Jun 2024This hemodialysis center experienced the pandemic from December 2022 to January 2023. Therefore, we sought to describe the clinical characteristics and mortality...
BACKGROUND
This hemodialysis center experienced the pandemic from December 2022 to January 2023. Therefore, we sought to describe the clinical characteristics and mortality outcomes in hemodialysis patients during this Omicron surge.
METHODS
According to whether they are infected, they are divided into two groups: SARS-CoV-2-positive and SARS-CoV-2-negative. The SARS-CoV-2-positive group was divided into a survival group and a non-survival group for comparison.
RESULTS
366 of 457 hemodialysis patients were infected with SARS-CoV-2. The most common symptoms observed were fever (43.2%) and cough (29.8%), Followed by diarrhea (1.4%). Hemodialysis patients with hypertension were more susceptible to SARS-CoV-2 infection. The lymphocyte count, serum creatinine, serum potassium, and serum phosphorus in the SARS-CoV-2-positive group were significantly lower than those in the SARS-CoV-2-negative group. The all-cause mortality rate for infection with SARS-CoV-2 was 5.2%. Only 7 of 366 SARS-CoV-2-positive patients were admitted to the intensive care unit, but 6 of them died. Intensive care unit hospitalization rates were significantly higher in the non-survival group compared with the survival group. White blood cells count, neutrophil count, C-reactive protein, AST, and D-dimer in the non-survival group were higher than those in the survival group. The lymphocyte count, hemoglobin concentration, serum creatinine, serum albumin, serum phosphorus and parathyroid hormone in the non-survival group were lower than those in the survival group. Age > 65 years, elevated C-reactive protein and AST are independent risk factors for death. Finally, no significant difference in vaccination status was found between the SARS-CoV-2-positive group and the negative group.
CONCLUSIONS
Hemodialysis patients are at high risk for SARS-CoV-2 infection. Ensuring the adequacy of hemodialysis treatment and maintaining good physical condition of patients are the top priorities.
Topics: Humans; COVID-19; Renal Dialysis; Male; Female; Middle Aged; Aged; SARS-CoV-2; Adult; Kidney Failure, Chronic; Hospitalization
PubMed: 38831260
DOI: 10.1186/s12889-024-18999-5 -
Journal of Lipid and Atherosclerosis May 2024This study investigated the relationship of fetuin-A with coronary calcification, carotid atherosclerosis, and mortality risk in non-dialysis chronic kidney disease...
OBJECTIVE
This study investigated the relationship of fetuin-A with coronary calcification, carotid atherosclerosis, and mortality risk in non-dialysis chronic kidney disease (CKD).
METHODS
The study included 135 adult patients with CKD at stages 3-5, who were divided into coronary artery calcification (CAC) and non-CAC groups. We excluded current smokers and individuals with diabetes mellitus, inflammatory conditions, liver diseases, acute kidney failure, chronic hemodialysis, and cancer. We conducted kidney function tests, complete blood counts, and measured serum levels of fetuin-A, tumor necrosis factor-alpha (TNF-α), high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), total cholesterol (TC), total triglycerides (TG), high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol. Cardiac spiral computed tomography was used to calculate the CAC score, employing the Agatston method. Carotid ultrasonography was performed to assess carotid intima-media thickness (CIMT) and to detect the presence of plaques.
RESULTS
CAC patients had considerably higher levels of TNF-α (<0.001), IL-6 (<0.001), hs-CRP (=0.006), TC, TG, parathyroid hormone (PTH) (<0.001) and phosphorus (<0.001) than non-CAC patients. They also had significantly lower levels of fetuin-A (<0.001). Fetuin-A was considerably lower in CKD subgroups as CKD progressed. Fetuin-A (=0.046), age (=0.009), TNF-α (=0.027), IL-6 (=0.005), TG (=0.002), PTH (=0.002), and phosphorus (=0.004) were significant predictors of CAC. CAC and fetuin-A were strong predictors of all-cause mortality and cardiovascular (CV) mortality. Fetuin-A was a significant predictor of CIMT (=0.045).
CONCLUSION
Fetuin-A reliably predicted CAC and CIMT. Fetuin-A and CAC emerged as significant risk factors for all-cause and CV mortality in non-dialysis CKD.
PubMed: 38826181
DOI: 10.12997/jla.2024.13.2.194 -
Nature Communications Jun 2024Ligand-induced activation of G protein-coupled receptors (GPCRs) can initiate signaling through multiple distinct pathways with differing biological and physiological...
Ligand-induced activation of G protein-coupled receptors (GPCRs) can initiate signaling through multiple distinct pathways with differing biological and physiological outcomes. There is intense interest in understanding how variation in GPCR ligand structure can be used to promote pathway selective signaling ("biased agonism") with the goal of promoting desirable responses and avoiding deleterious side effects. Here we present an approach in which a conventional peptide ligand for the type 1 parathyroid hormone receptor (PTHR1) is converted from an agonist which induces signaling through all relevant pathways to a compound that is highly selective for a single pathway. This is achieved not through variation in the core structure of the agonist, but rather by linking it to a nanobody tethering agent that binds with high affinity to a separate site on the receptor not involved in signal transduction. The resulting conjugate represents the most biased agonist of PTHR1 reported to date. This approach holds promise for facile generation of pathway selective ligands for other GPCRs.
Topics: Ligands; Humans; Receptor, Parathyroid Hormone, Type 1; Single-Domain Antibodies; HEK293 Cells; Signal Transduction; Receptors, G-Protein-Coupled; Protein Binding; Animals; Peptides
PubMed: 38824166
DOI: 10.1038/s41467-024-49068-5 -
Scientific Reports May 2024The close link between intestinal microbiota and bone health ('gut-bone' axis) has recently been revealed: the modulation of the amount and nature of bacteria present in...
The close link between intestinal microbiota and bone health ('gut-bone' axis) has recently been revealed: the modulation of the amount and nature of bacteria present in the intestinal tract has an impact on bone health and calcium (Ca) metabolism. Probiotics are known to favorably impact the intestinal microbiota. The objective of this study was to investigate the effect of Pediococcus acidilactici CNCM I-4622 (PA) on laying performance, egg/eggshell quality, Ca metabolism and bone mineralization and resistance in relatively old layers (50 wks old at the beginning of the experiment) during 14 weeks. 480 Hy Line brown layers were divided into 2 groups (CON and PA: 3 layers/rep, 80 rep/group) and fed with a diet formulated to be suboptimal in calcium (Ca) and phosphorus (P) (- 10% of the requirements). The total egg weight was improved by 1.1% overall with PA, related to an improvement of the weight of marketable eggs (+ 0.9%). PA induced a decreased % of downgraded eggs, mainly broken eggs (- 0.4 pts) and FCR improvement (- 0.8% for all eggs, - 0.9% for marketable eggs). PA also led to higher Haugh units (HU: + 7.4%). PA tended to decrease crypt depth after the 14 weeks of supplementation period in the jejunum (- 25.2%) and ileum (- 17.6%). As a consequence, the VH/CD ratio appeared increased by PA at the end of the trial in the jejunum (+ 63.0%) and ileum (+ 48.0%). Ca and P retention were increased by 4 pts following PA supplementation, translating into increased bone hardness (+ 19%), bone cohesiveness (+ 43%) and bone Ca & P (+ 1 pt) for PA-supplemented layers. Blood Ca and P were respectively improved by 5% and 12% with PA. In addition, blood calcitriol and osteocalcin concentrations were respectively improved by + 83% and + 3% in PA group at the end of the trial, compared to CON group. There was no difference between the 2 groups for ALP (alkaline phosphatase) and PTH (parathyroid hormone). PA significantly decreased the expression of the following genes: occludin in the small intestine, calbindin 1 in the ovarian tissue and actin B in the bone. PA therefore improved zootechnical performance of these relatively old layers, and egg quality. The parallel increase in Ca and P in the blood and in the bone following PA supplementation suggests an improvement of the mineral supply for eggshell formation without impacting bone integrity, and even increasing bone resistance.
Topics: Animals; Probiotics; Pediococcus acidilactici; Chickens; Phosphorus; Calcium; Female; Dietary Supplements; Animal Feed; Eggs; Oviposition; Gastrointestinal Microbiome
PubMed: 38821966
DOI: 10.1038/s41598-024-62779-5 -
PloS One 2024Hyperphosphatemia and hyperparathyroidism are common in end-stage kidney disease and are associated with poor outcomes. In addition to adequate dialysis, medications are...
The impact of accessibility to non-calcium-based phosphate binders and calcimimetics on mineral outcomes in patients receiving maintenance hemodialysis: A 10-year retrospective analysis of real-world data.
INTRODUCTION
Hyperphosphatemia and hyperparathyroidism are common in end-stage kidney disease and are associated with poor outcomes. In addition to adequate dialysis, medications are usually required for optimum control of serum phosphate and parathyroid hormone (PTH) levels. The use of calcium-based phosphate binders (CBPBs) and active vitamin D is associated with an increase in serum calcium and worsening vascular calcification. To overcome these limitations, non-calcium-based phosphate binders (NCBPBs) and calcimimetics have been developed. However, the coverage for these new medications remains limited in several parts of the world due to the lack of patient-level outcome data and cost. The present study examined the differences in mineral outcomes between two main categories of healthcare programs that provided different coverage for medications used to control mineral and bone disorders (MBD). The Social Security/Universal Coverage (SS/UC) program covered only CBPBs and active vitamin D, whereas the Civil Servant/State Enterprise (CS/SE) program provided coverage of CBPBs, active vitamin D, NCBPBs, and calcimimetics.
METHODS
This 10-year retrospective cohort study examined the differences in mineral outcomes between two healthcare programs in maintenance hemodialysis patients. The differences in serum calcium, phosphate, and PTH levels, as well as the aortic arch calcification score, were analyzed according to dialysis vintage by linear mixed-effects regression analyses. The difference in the composite outcome of severe hyperparathyroidism and parathyroidectomy was analyzed by the Cox-proportional hazard regression model.
RESULTS
714 patients were included in the analyses (full cohort). Of these patients, 563 required at least one type of medication to control MBD (MBD medication subgroup). Serum calcium, phosphate, and the proportions of patients with hypercalcemia and hyperphosphatemia were substantially higher in the SS/UC group compared with the CS/SE group after appropriate adjustments for confounders in both the full cohort and the MBD medication subgroup. These findings were confirmed in propensity-score matched analyses. Higher parathyroid hormone levels and a higher rate of the composite endpoint of severe hyperparathyroidism and parathyroidectomy were also observed in the SS/UC group. A more rapid progression of aortic arch calcification was suggested in the SS/UC group, but between-group changes were not significant.
CONCLUSION
Patients under the healthcare program that did not cover the use of NCBPBs and calcimimetics showed higher serum calcium and phosphate levels and a more rapid progression of hyperparathyroidism. The difference in the progression of vascular calcification could not be confirmed in the present study.
Topics: Humans; Renal Dialysis; Male; Female; Retrospective Studies; Middle Aged; Calcimimetic Agents; Hyperphosphatemia; Calcium; Aged; Phosphates; Kidney Failure, Chronic; Parathyroid Hormone; Vitamin D; Chelating Agents
PubMed: 38820324
DOI: 10.1371/journal.pone.0304649 -
Canadian Journal of Kidney Health and... 2024There is little evidence on the ideal frequency of routine blood work in maintenance dialysis patients to manage complications, including anemia, mineral bone disease...
INTRODUCTION
There is little evidence on the ideal frequency of routine blood work in maintenance dialysis patients to manage complications, including anemia, mineral bone disease (MBD), and hyperkalemia. Recent quality improvement studies from Ontario showed no negative impacts when decreasing the frequency from monthly to every 6 weeks in conventional in-center hemodialysis (ICHD) patients. In December 2020, Alberta Kidney Care-South (AKC-S) reduced the frequency of routine blood work from every 6 weeks to every 8 weeks for ICHD patients.
OBJECTIVE
We aimed to assess the impact of reducing blood work frequency on patient outcomes.
METHODS
We compared prevalent AKC-S ICHD patients in 2 cohorts: (1) retrospective control (October 31, 2019-October 31, 2020) and (2) prospective intervention (December 1, 2020-December 1, 2021). Primary outcomes were true frequency of routine blood work, odds of patients being within target for anemia and MBD, and proportion of lab values of hyperkalemia. Furthermore, we compared hospitalizations and mortality.
RESULTS
A total of 972 patients in Calgary's ICHD program were included, 787 in each period (with 602 patients overlapping both cohorts). The frequency of routine blood work decreased from every 39.5 days in the control period to every 54.2 days in the intervention period ( < .01). There was a reduction in the odds of phosphate values in targets ( = .02), and an increase in the odds of labs with hyperkalemia (>6.0 mmol/L) during the intervention period ( = .01). There was no significant change in the odds of being within the accepted targets during the intervention period compared with the control period for hemoglobin, Tsat, calcium, or parathyroid hormone (PTH). Fewer patients were hospitalized during the intervention period and the risk of death decreased as well, although additional factors such as the COVID-19 pandemic may have affected this. A cost-savings of $32 962 occurred from the reduced anemia and MBD blood work during the intervention period.
CONCLUSIONS
When ICHD units in Calgary reduced routine blood work frequency from every 6 weeks to 8 weeks, there were no negative impacts on hospitalizations or deaths. A slightly lower proportion of phosphate values were within target, and a 0.7% increase in potassium values greater than 6 mmol/L was demonstrated. Our study suggests that blood work frequency in ICHD dialysis patients may be further reduced to every 8 weeks safely. Ultimately, additional pragmatic trials are needed to identify the optimal frequency of routine blood work.
PubMed: 38812721
DOI: 10.1177/20543581241255784