Search Results (45)

Objectives: This study aims to evaluate the efficacy and safety of valproic acid (VPA) transition regimens (from intravenous to oral tablets) for anti-seizure treatment. Methods: A retrospective analysis was conducted on inpatients treated with intravenous VPA and oral tablets for epilepsy at the Sir Run Run Shaw Hospital, affiliated with Zhejiang University, between January 2022 and December 2023. Various transition strategies from VPA injections to tablets were examined, and the efficacy and safety of different transition strategies were analyzed. Results: A total of 164 inpatients receiving VPA transition therapy were included in this study, which was divided into three groups based on the transition timing: the 0 h group, the 0–48 h group, and the >48 h group. Regarding VPA dosage, the median daily dose of intravenous VPA was separately 1076.50 mg/day, 1200 mg/day and 1438 mg/day in the 0 h group, 0–48 h group, and the >48 h group. During transition, the daily doses of VPA were significantly higher than that before and after the transition. After completely switching to oral administration, they were all decreased to 1000 mg/day. Moreover, a significant difference regarding the clinical efficacy was observed among the three groups. The >48 h group showed the highest rate of clinical efficacy, which was significantly greater than that of the 0 h group and 0–48 h group. Although there was no statistical significance detected regarding the average blood serum concentrations among the three groups; notably, a higher proportion of patients in the >48 h group (19.35%) had blood concentrations exceeding the desired therapeutic window compared with the 0–48 h group (8.06%) and 0 h group (0%). Adverse events included 30 cases in the 0 h group, 42 in the 0–48 h group, and 67 in the >48 h group, with statistically significant differences in hemoglobin reduction, headache/dizziness, and liver injury. No significant differences were found in digestive and skin-related reactions. Conclusions: The results suggest that the >48 h transition regimen may show some advantages in efficacy but also increases the risk of adverse reactions significantly. Therefore, it is recommended to complete the intravenous-to-oral switch carefully with blood drug concentrations strictly monitored. Full article

Complement factor 5 (C5) inhibitors for paroxysmal nocturnal hemoglobinuria (PNH) may cause iron overload due to residual intravascular hemolysis (IVH) and emergent extravascular hemolysis (EVH). In PEGASUS (phase 3; NCT03500549), adults with PNH with residual anemia (hemoglobin concentration < 10.5 g/dL) after ≥3 months of eculizumab received eculizumab and pegcetacoplan for 4 weeks and were then randomized (1:1) to eculizumab or pegcetacoplan monotherapy for 16 weeks; in the following 32-week, open-label period, patients either continued pegcetacoplan or switched from eculizumab to pegcetacoplan. This post hoc analysis reports PEGASUS transfusion-related data and iron-related biomarkers to evaluate pegcetacoplan’s effects on iron regulation. Of 80 patients randomized in PEGASUS, 27 (33.8%) had baseline iron overload (serum transferrin saturation ≥ 50%). Iron overload resolved within 52 weeks of pegcetacoplan treatment in 16 of 22 patients (72.7%) with baseline and postbaseline data; 10 experienced resolution after 20 weeks. With pegcetacoplan, transfusion numbers decreased for patients with and without iron overload, hepcidin concentrations increased, and absolute reticulocyte counts (ARCs) decreased to normal range. Mean ferritin concentrations were above normal throughout the study, regardless of iron overload status. Pegcetacoplan improves iron overload-related biomarkers, including increased hepcidin concentrations and decreased ARCs, by blocking IVH and EVH and preventing anemia. Full article

Background: The United Arab Emirates (UAE) faces a high burden of type 2 diabetes mellitus (T2DM) and its complications. While sodium-glucose cotransporter-2 inhibitors (SGLT2i) have demonstrated cardiorenal benefits in clinical trials, real-world evidence on their association with calculated cardiovascular risk in Middle Eastern populations remains limited. This study evaluated the long-term real-world outcomes associated with SGLT2i use in Emirati patients with T2DM. Methods: We conducted a retrospective observational study of patients with T2DM initiated on SGLT2i (empagliflozin, dapagliflozin, or canagliflozin) at Tawam Hospital, UAE, between 1 January 2018 and 31 December 2018. Patients were followed for up to 5 years. Primary outcomes included changes in glycated hemoglobin (HbA1c), estimated glomerular filtration rate (eGFR), and body mass index (BMI). A key secondary outcome was the change in 10-year atherosclerotic cardiovascular disease (ASCVD) risk, calculated using the ACC/AHA Pooled Cohort Equations. Results: We included 185 patients (mean age 57 ± 12 years, 56.2% female), with 107 (57.8%) receiving empagliflozin, 54 (29.2%) dapagliflozin, 11 (5.9%) canagliflozin, and 13 (7.0%) who switched between agents. Significant improvements were observed in HbA1c (8.7 ± 1.8% to 8.2 ± 1.9%, p < 0.001), while eGFR showed preservation of renal function with an annual decline of 1.1 mL/min/1.73 m². Among 120 patients eligible for ASCVD risk assessment (excluding 65 with established cardiovascular disease), the mean 10-year ASCVD risk decreased from 22.3 ± 5.3% at baseline to 19.3 ± 4.9% at 5 years (absolute reduction −3.0%, 95% CI −2.4 to −3.6%, p < 0.001). Serious adverse events were rare, including acute kidney injury (1.1%) and fractures (1.6%). No episodes of diabetic ketoacidosis or severe hypoglycemia were observed. Conclusions: In this real-world cohort from the UAE, SGLT2 inhibitor use was associated with sustained glycemic control, preserved renal function, and lower calculated 10-year cardiovascular risk over 5 years. These observational findings, noted in the context of comprehensive risk factor management, support the potential benefits of SGLT2i in high-risk Middle Eastern patients with T2DM, though prospective controlled studies are needed to confirm causality. Full article

Erythropoiesis, the process driving the differentiation of hematopoietic stem and progenitor cells to mature erythrocytes, unfolds through tightly orchestrated developmental stages, each defined by profound epigenetic remodeling. From the initial commitment of hematopoietic progenitors to the terminal enucleation of erythrocytes, dynamic changes in chromatin accessibility, transcription factor occupancy, and three-dimensional genome architecture govern lineage specification and stage-specific gene expression. Advances in our understanding of the regulatory genome have uncovered how non-coding elements, including enhancers, silencers, and insulators, shape the transcriptional landscape of erythroid cells. These elements work in concert with lineage-determining transcription factors to establish and maintain erythroid identity. Disruption of these epigenetic programs—whether by inherited mutations, somatic alterations, or environmental stress—can lead to a wide range of hematologic disorders. Importantly, this growing knowledge base has opened new therapeutic avenues, enabling the development of precision tools that target regulatory circuits to correct gene expression. These include epigenetic drugs, enhancer-targeted genome editing, and lineage-restricted gene therapies that leverage endogenous regulatory logic. As our understanding of erythroid epigenomics deepens, so too does our ability to design rational, cell-type-specific interventions for red blood cell disorders. Full article

Background: The efficacy of intravenous iron preparations for chronic heart failure with iron deficiency has been reported, but the efficacy of oral iron preparations has not been demonstrated. In this study, we conducted a prospective clinical study using ferric citrate hydrate tablets in patients with chronic heart failure complicated by iron deficiency anemia. Methods and Results: A prospective study was conducted using ferric citrate hydrate in patients with chronic heart failure complicated by iron deficiency anemia. The registered patients were divided into two groups: those administered ferric citrate hydrate and those switched from iron sulfate sustained-release to ferric citrate hydrate. The primary endpoint was hemoglobin level. The secondary endpoints included hematocrit, serum iron, saturation, ferritin, and cardiac-, renal-, and hepatic-related biomarkers. A total of 141 patients were enrolled in this study, including 95 patients who were newly administered ferric citrate hydrate and 46 patients who were switched from iron sulfate sustained-release to ferric citrate hydrate. Conclusions: Ferric citrate hydrate significantly increased hemoglobin, serum iron, transferrin saturation (TSAT), and ferritin levels, and decreased atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels. Ferric citrate hydrate could be continued without side effects such as gastrointestinal symptoms. Improvement in iron metabolism and anemia due to iron supplementation with ferric citrate hydrate led to improvement in heart failure biomarkers. Full article

This study examined the effect of a low-carbohydrate diet (LCD) and a low-carbohydrate ketogenic diet (LCKD) on diabetic retinopathy in high-fat diet-induced diabetes mellitus in rats and studied the mechanisms of action. Rats were divided into four groups: the Control group, which was fed a normal diet for 16 weeks; the HFD group, which was fed a high-fat diet (HFD) for the first 8 weeks and then switched to a normal diet for 8 weeks; the HFD+LCD group, fed a HFD for 8 weeks followed by an LCD for 8 weeks, and the HFD+LCKD group, which was fed a HFD for 8 weeks followed by an LCKD for 8 more weeks. Both the LCD and the LCKD effectively reduced the final body and total fat weights and decreased fasting serum levels of glucose, insulin, hemoglobin A1 (HbA1C), triglycerides, cholesterol, and LDL-c. They also reduced the levels of malondialdehyde (MDA), tumor necrosis factor-α, vascular endothelial factor, caspapse-3, and bax. In the HFD rats, we found increased serum levels of β-Hydroxybutyrate and upregulated expression of Bcl2, glutathione, superoxide dismutase, and hemeoxygenase-1. Moreover, the LCD and LCKD significantly reduced mRNA levels of Kelch-like ECH-associated protein 1 (Keap1) and enhanced mRNA and nuclear concentrations of nuclear factor erythroid factor 2 (Nrf2). All these effects were associated with improved layers of the retina in the HFD − LCD and HFD + LCKD rats but not in HFD animals. The impact of the LCKD was always more profound on all measured parameters and on improving the structure of the retina compared to the LCD. In conclusion, the LCKD is superior to the LCD in preventing diabetic retinopathy in HFD-fed rats. Mechanistically, our results suggest that the hypoglycemic and hypolipidemic conditions and the Nrf2-dependent antioxidant and anti-inflammatory effects may be involved in the preventative effects of the LCD and LCKD. Full article

Genome-Wide Association Studies (GWASs) have identified a huge number of variants associated with different traits. However, their validation through in vitro and in vivo studies often lags well behind their identification. For variants associated with traits or diseases of biomedical interest, this gap delays the development of possible therapies. This issue also impacts beta-hemoglobinopathies, such as beta-thalassemia and sickle cell disease (SCD). The definitive cures for these diseases are currently bone marrow transplantation and gene therapy. However, limitations regarding their effective use restrict their worldwide application. Great efforts have been made to identify whether modulators of fetal hemoglobin (HbF) and, to a lesser extent, hemoglobin A2 (HbA₂) are possible therapeutic targets. Herein, we performed the post-GWAS in vivo validation of two genes, cyclin D3 (CCND3) and nuclear factor I X (NFIX), previously associated with HbF and HbA₂ levels. The absence of Ccnd3 expression in vivo significantly increased g (HbF) and d (HbA₂) globin gene expression. Our data suggest that CCND3 is a possible therapeutic target in sickle cell disease. We also confirmed the association of Nfix with γ-globin gene expression and present data suggesting a possible role for Nfix in regulating Kruppel-like transcription factor 1 (Klf1), a master regulator of hemoglobin switching. This study contributes to filling the gap between GWAS variant identification and target validation for beta-hemoglobinopathies. Full article

Background/Objectives: Chronic kidney disease (CKD) and anemia are independent prognostic factors for heart failure. In recent years, hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitors have become available for the treatment of renal anemia. This prospective randomized controlled study aimed to investigate the effects of switching from a continuous erythropoietin receptor activator (CERA) to one of four HIF-PH inhibitors in patients with chronic heart failure and renal anemia. Methods: Forty patients were randomized by the envelop method to receive treatment with roxadustat, daprodustat, vadadustat, or molidustat. The primary endpoint was the change in the hemoglobin (Hb) level. Secondary endpoints included changes in erythropoietin, changes in free T3, free T4, and thyroid-stimulating hormone (TSH), adverse effects, and drug dose increases and decreases. This study was preregistered in the University Hospital Medical Information Network Clinical Trials Registry (study ID: UMIN000041651). Results: We found no statistically significant difference between Hb levels with HIF-PH inhibitors and CERA, but at month 6, the Hb level was significantly higher with roxadustat than with vadadustat and daprodustat. Erythropoietin decreased significantly after switching to HIF-PH inhibitors. HIF-PH inhibitors had various significant effects on free T3, free T4, and TSH. No adverse events occurred. The doses of some drugs had to be increased or decreased. Conclusions: In patients with heart failure and renal anemia receiving CERA, Hb, NT-ProBNP, and renal function were similar after switching from CERA to HIF-PH inhibitors. The individual HIF-PH inhibitors appear to have different effects on anemia and thyroid function. However, because this was a single-center study with a limited sample size, the efficacy and potential limitations of HIF-PH inhibitors need to be further clarified. Full article

Background: Successful conversion from insulin therapy to glucagon-like peptide 1 receptor agonist (GLP-1RA) with basal insulin in well-controlled patients has already been demonstrated. However, the data concerning individuals with poor glycaemic control are scarce. The aim of this work was to assess the success rate of insulin therapy to liraglutide transition in poorly controlled diabetes in a real-world clinical setting and to define predictors of success. We are the first to present the method of a fasting test as a way to identify the patients at higher risk of failure after treatment de-intensification. Methods: The retrospective observational study analyzed data of 62 poorly controlled obese diabetic patients on high-dose insulin therapy, who were subjected to a 72 h fasting test during hospitalization and subsequently switched to liraglutide ± basal insulin therapy. During the fasting, all antidiabetic treatment was discontinued. Patients were classified as responders if they remained on GLP-1RA treatment after 12 months. Non-responders restarted the basal-bolus insulin (BBI) regimen. Development of glycated hemoglobin (HbA1c) and body weight in both groups, alongside with parameters associated with the higher risk of return to the BBI regimen, were analyzed. Results: A total of 71% of patients were switched successfully (=responders). Responders had more significant improvement in HbA1c (−6.4 ± 19.7 vs. −3.4 ± 22.9 mmol/mol) and weight loss (−4.6 ± 7.1 vs. −2.5 ± 4.0). Statistically significant difference between groups was found in initial HbA1c (75.6 ± 17.9 vs. 90.5 ± 23.6; p = 0.04), total daily dose of insulin (67.6 ± 36.4 vs. 90.8 ± 32.4; p = 0.02), and mean glycaemia during the fasting test (6.9 ± 1.7 vs. 8.6 ± 2.2 mmol/L; p < 0.01). Conclusions: This study confirms that therapy de-intensification in poorly controlled patients with a BBI regimen is possible. Higher baseline HbA1c, total daily insulin dose, and mean glucose during fasting test are negative predictive factors of successful therapy de-escalation. Full article

Introduction. Iron deficiency is common in patients with non-dialysis-dependent chronic kidney disease (NDD-CKD). Oral iron supplementation is recommended in these patients, but it is associated with a higher incidence of gastrointestinal adverse reactions. Liposomal iron therapy has been proposed as a new iron formulation, improving iron bioavailability with less side effects; however, few data are available in patients with NDD-CKD. Methods. We designed a single-arm pilot study to evaluate the efficacy of liposomal iron administered for six months in correcting iron deficiency (defined as serum ferritin < 100 ng/mL and/or transferrin saturation < 20%) in patients with NDD-CKD stages 1–5. The primary endpoints were the achievement of serum ferritin ≥ 100 ng/mL and transferrin saturation ≥ 20%. Secondary outcomes were hemoglobin (Hb) changes and the safety of liposomal iron. Results. The efficacy population included 34/38 patients, who completed at least one visit after baseline. Liposomal iron increased the achievement of transferrin saturation targets from 11.8% at baseline to 50.0% at month 6 (p = 0.002), while no significant correction of serum ferritin (p = 0.214) and Hb was found (p = 0.465). When patients were stratified by anemia (Hb < 12 g/dL in women and Hb < 13 g/dL in men), a significant improvement of transferrin saturation was observed only in anemic patients (from 13.3 ± 5.8% to 20.2 ± 8.1%, p = 0.012). Hb values slightly increased at month 6 only in anemic patients (+0.60 g/dL, 95%CI −0.27 to +1.48), but not in those without anemia (+0.08 g/dL, 95%CI −0.73 to +0.88). In patients taking at least one dose of liposomal iron (safety population, n = 38), the study drug was discontinued in eight patients due to death (n = 2), a switch to intravenous iron (n = 2), and the occurrence of side effects (n = 4). Conclusions. The use of liposomal iron in patients with NDD-CKD is associated with a partial correction of transferrin saturation, with no significant effect on iron storage and Hb levels. Full article

Background: Negative pressure wound therapy (NPWT) is an intensely investigated topic, but its mechanism of action accounts for one of the least understood ones in the area of wound healing. Apart from a misleading nomenclature, by far the most used diagnostic tool to investigate NPWT, the laser Doppler, also has its weaknesses regarding the detection of changes in blood flow and velocity. The aim of the present study is to explain laser Doppler readings within the context of NPWT influence. Methods: The cutaneous microcirculation beneath an NPWT system of 10 healthy volunteers was assessed using two different laser Dopplers (O2C/Rad-97^®). This was combined with an in vitro experiment simulating the compressing and displacing forces of NPWT on the arterial and venous system. Results: Using the O2C, a baseline value of 194 and 70 arbitrary units was measured for the flow and relative hemoglobin, respectively. There was an increase in flow to 230 arbitrary units (p = 0.09) when the NPWT device was switched on. No change was seen in the relative hemoglobin (p = 0.77). With the Rad-97^®, a baseline of 92.91% and 0.17% was measured for the saturation and perfusion index, respectively. No significant change in saturation was noted during the NPWT treatment phase, but the perfusion index increased to 0.32% (p = 0.04). Applying NPWT compared to the arteriovenous-vessel model resulted in a 28 mm and 10 mm increase in the venous and arterial water column, respectively. Conclusions: We suspect the vacuum-mediated positive pressure of the NPWT results in a differential displacement of the venous and arterial blood column, with stronger displacement of the venous side. This ratio may explain the increased perfusion index of the laser Doppler. Our in vitro setup supports this finding as compressive forces on the bottom of two water columns within a manometer with different resistances results in unequal displacement. Full article

Background and Objectives: Degludec (Deg) and glargine U300 (Gla-300) are insulin analogs with longer and smoother pharmacodynamic action than glargine U100 (Gla-100), a long-acting insulin that has been widely used for many years in type 1 and type 2 diabetes. Both improve glycemic variability (GV) and the frequency of hypoglycemia, unlike Gla-100. However, it is unclear which insulin analog affects GV and hypoglycemia better in patients with insulin-dependent type 1 diabetes. We evaluated the effects of switching from Deg to Gla-300 on the day-to-day GV and the frequency of hypoglycemia in patients with insulin-dependent type 1 diabetes treated with Deg-containing basal-bolus insulin therapy (BBT). Materials and Methods: We conducted a retrospective study on 24 patients with insulin-dependent type 1 diabetes whose treatment was switched from Deg-containing BBT to Gla-300-containing BBT. We evaluated the day-to-day GV measured as the standard deviation of fasting blood glucose levels (SD-FBG) calculated by the self-monitoring of blood glucose records, the frequency of hypoglycemia (total, severe, and nocturnal), and blood glucose levels measured as fasting plasma glucose (FPG) levels and hemoglobin A1c (HbA1c). Results: The characteristics of the patients included in the analysis with high SD-FBG had frequent hypoglycemic events, despite the use of Deg-containing BBT. For this population, SD-FBG and the frequency of nocturnal hypoglycemia decreased after the switch from Deg to Gla-300. Despite the decrease in the frequency of nocturnal hypoglycemia, the FPG and HbA1c did not worsen by the switch. The change in the SD-FBG had a negative correlation with the SD-FBG at baseline and a positive correlation with serum albumin levels. Conclusions: Switching from Deg to Gla-300 improved the SD-FBG and decreased the frequency of nocturnal hypoglycemia in insulin-dependent type 1 diabetes treated with Deg-containing BBT, especially in cases with low serum albumin levels and a high GV. Full article

Background: Few studies have incorporated longitudinal assessments or used combinations of blood biomarkers as predictors of loss of response to biologic therapy for patients with Crohn’s disease (CD) or ulcerative colitis (UC). Methods: This is a population-based cohort study comprising Danish patients with CD or UC from 2008 to 2018. We used logistic regression to analyze whether levels and changes in levels of C-reactive protein (CRP), serum albumin, and hemoglobin, routinely measured during a 14-week infliximab induction period, predicted a change to another biologic medication or cessation of biologic therapy. Results: During the induction period, 2883 (1626 CD, 1257 UC) patients had 12,730, 12,040, and 13,538 specimens with CRP, serum albumin, and hemoglobin, respectively. In all, 284 patients (9.9%) switched to another biologic medication, and 139 (4.8%) ceased biologic therapy in the follow-up period. Only the most recent CRP and hemoglobin levels predicted the efficacy of infliximab treatment at approximately 14 weeks, a time point when the clinician often determines whether to continue treatment. Conclusion: Measurement of blood biomarkers prior to the clinical assessment does not predict the effectiveness of infliximab. Full article

Candida albicans is a major human pathogenic fungus that is distinguished by its capability to switch from a yeast to a hyphal morphology under different conditions. Here, we analyze the cellular effects of high concentrations of the iron chelator bathophenanthroline disulfonate (BPS). BPS inhibits cellular growth by withholding iron, but when iron chelation is overcome by the addition of hemoglobin as an iron source, the cells resume growth as hyphae. The BPS hyphal induction pathway was characterized by identifying the hyphal-specific transcription factors that it requires and by a forward genetic screen for mutants that fail to form hyphae in BPS using a transposon library generated in a haploid strain. Among the mutants identified are the DYRK1-like kinase Yak1 and Orf19.384, a homolog of the DYRK1-associated protein WDR68/DCAF7. Orf19.384 nuclear localization depends on Yak1, similar to their mammalian counterparts. We identified the hyphal suppressor transcription factor Sfl1 as a candidate target of Yak1-Orf19.384 and show that Sfl1 modification is similarly affected in the yak1 and orf19.384 mutant strains. These results suggest that DYRK1/Yak1 and WDR68/Orf19.384 represent a conserved protein pair that regulates cell differentiation from fungi to animals. Full article

Myelodysplastic syndromes and myeloproliferative neoplasms both represent hematologic diseases associated with bone marrow failure often resulting in anemia. For those patients, transfusion of red blood cell (RBC) units is essential but results in iron overload (IOL) that may affect various organ functions. Therefore, iron chelation therapy plays a major role in anemic patients, not only because it reduces IOL, but also because it may improve hematopoietic function by increasing hemoglobin or diminishing the requirement for RBC transfusions. To assess the utility, efficacy, and safety of the different iron chelation medications approved in Germany, as well as to examine the effect of chelation on hematopoietic insufficiency, a prospective, multicenter, noninterventional study named EXCALIBUR was designed. In total, 502 patients from 106 German hospitals and medical practices were enrolled. A large proportion of patients switched from a deferasirox dispersible tablet to a deferasirox-film-coated tablet, mainly because of more convenient application, which was reflected in the treatment satisfaction questionnaire for medication scores. Iron chelation was effective in lowering serum ferritin levels, with the observed adverse drug reactions being in line with the known safety profile. Hematologic response occurred in a few patients, comparable to other studies that examined hematologic improvement in patients with MDS. Full article