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Diabetes Therapy : Research, Treatment... Feb 2024This systematic review aimed to summarize the existing evidence from published randomized controlled trials (RCTs) on the impact of sodium-glucose cotransporter (SGLT)...
The Effect of Sodium-Glucose Cotransporter Inhibitors on Renal Function as Adjunctive to Insulin in Adults with Type 1 Diabetes: An Updated Multilevel Meta-analysis of Randomized Controlled Trials.
INTRODUCTION
This systematic review aimed to summarize the existing evidence from published randomized controlled trials (RCTs) on the impact of sodium-glucose cotransporter (SGLT) inhibitors on albuminuria levels and renal function in patients with type 1 diabetes mellitus (T1D).
METHODS
The literature search was performed through Medline (via PubMed), Cochrane Library, and Scopus until November 11, 2023. Double-independent study selection, data extraction, and quality assessment were performed. Evidence was pooled with three-level mixed-effects meta-analysis.
RESULTS
In total, 5221 participants with T1D among 11 RCTs were analyzed. All RCTs had low risk of bias according to the Cochrane Collaboration tool (RoB 2). SGLT inhibitors were associated with a significantly greater reduction in urine albumin-to-creatinine ratio (UACR) compared to controls (MD = - 23.13%; 95% CI = [- 33.69, - 12.57]; P < 0.001; level of evidence high). On the basis of subgroup analysis, this effect was consistent across all available SGLT inhibitors, irrespective of the dosage. Finally, a neutral class effect was observed on the estimated glomerular filtration rate (eGFR, MD = - 1.03 mL/min/1.73 m; 95% CI = [- 2.26, 0.19]; P = 0.1; level of evidence moderate). Only empagliflozin was associated with a significant reduction in eGFR compared to placebo (MD = - 2.23 mL/min/1.73 m; 95% CI = [- 3.62, - 0.84]; P = 0.002).
CONCLUSION
Our findings suggest that adjunctive therapy with SGLT inhibitors results in a significant reduction in albuminuria, while their use is associated with a neutral effect on creatinine clearance, as a measure of renal function. Future renal outcome trials are needed to assess SGLT inhibitors' role in the pharmacological armamentarium against diabetic nephropathy in T1D.
PubMed: 38180713
DOI: 10.1007/s13300-023-01523-0 -
United European Gastroenterology Journal May 2024Clinical remission (CR) is the principal short-term treatment target in patients with ulcerative colitis (UC). However, whether rapidly achieving CR indicates better... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Clinical remission (CR) is the principal short-term treatment target in patients with ulcerative colitis (UC). However, whether rapidly achieving CR indicates better outcomes remains unclear.
OBJECTIVES
We aimed to explore the associations between the timing of CR and therapeutic outcomes in UC.
METHODS
This study included UC patients from the UNIFI trial. Week-2 CR and time to CR were the major variables of interest. Endoscopic remission (ER) at week 52 was the primary outcome. Multivariate logistic regression was performed to evaluate the association between variables and outcomes.
RESULTS
Week-2 CR was associated with ER (aOR: 2.37 [95% CI: 1.28, 4.37], p = 0.006) and Histological remission (HR) (aOR: 2.87 [95% CI: 1.42, 5.72], p = 0.003) at week 52. Moreover, C-reactive protein (CRP) remission could further stratify patients without CR and predict week-52 outcomes. Patients with clinical activity + CRP remission (aOR: 0.49 [95% CI: 0.26, 0.93], p = 0.039) and clinical activity + CRP activity (aOR: 0.24 [95% CI: 0.11, 0.52], p < 0.001) had gradually decreased likelihood of achieving ER, when compared to those with CR. For time to CR, we found that the earlier to CR, the better endoscopic and histological outcomes patients would attain. Patients achieving CR at weeks 2, 4/8, 12/16 and >16 had gradually reduced proportions of ER (51.9% vs. 40.8% vs. 31.6% vs. 8.8%, p < 0.001) and HR (37.0% vs. 19.8% vs. 17.1% vs. 6.1%, p < 0.001) at week 52. Compared with week 2, achieving CR at weeks 4/8, 12/16 and >16 had 39%, 55% and 92% lower likelihoods of week-52 ER, respectively.
CONCLUSIONS
Week-2 CR indicates better outcomes in UC patients receiving ustekinumab. Moreover, achieving CR more rapidly is associated with higher probability of ER and HR.
Topics: Humans; Colitis, Ulcerative; Remission Induction; Male; Female; Adult; Treatment Outcome; C-Reactive Protein; Colonoscopy; Middle Aged; Time Factors; Ustekinumab
PubMed: 38159047
DOI: 10.1002/ueg2.12515 -
Current Research in Toxicology 2024Urinary cadmium excretion (E) rises with renal tissue content of the metal. Whereas glomerulopathies are sometimes associated with massive albuminuria, tubular...
BACKGROUND
Urinary cadmium excretion (E) rises with renal tissue content of the metal. Whereas glomerulopathies are sometimes associated with massive albuminuria, tubular accumulation of Cd typically causes modest albuminuria. Since β-microglobulinuria (E) is an established marker of proximal tubular dysfunction, we hypothesized that a comparison of albuminuria (E) to E in Cd-exposed subjects would provide evidence of similar mishandling of both proteins.
METHODS
To depict excretion rates per functional nephron, E, E, and E were normalized to creatinine clearance (C), a surrogate for the glomerular filtration rate (GFR). Estimation of GFR itself (eGFR) was accomplished with CKD-EPI formulas (2009). Linear and logistic regression analyses were performed to relate E/C, E/C, and eGFR to several independent variables. Simple linear regressions of eGFR, E/C, and E/C on E/C were examined before and after adjustment of dependent variables for age. All regressions were performed after log-transformation of ratios and standardization of all variables. Increments in E/C and E/C and decrements in eGFR were quantified through four quartiles of E/C.
RESULTS
As age or E/C rose, E/C and E/C also rose, and eGFR fell. In linear regressions, slopes relating E/C and E/C to E/C were similar. After adjustment of dependent variables for age, coefficients of determination (R) for all regressions rose by a multiple, and slopes approached unity. E/C and E/C were similarly associated with each other. Mean E/C and E/C rose and mean eGFR fell in stepwise fashion through quartiles of E/C. Whereas E/C did not vary with blood pressure, E/C rose in association with hypertension in two of the four quartiles.
CONCLUSIONS
Our data indicate that Cd in renal tissue affected tubular reabsorption of albumin and βM similarly in a large cohort of exposed subjects. The results suggest that Cd reduced receptor-mediated endocytosis and subsequent lysosomal degradation of each protein by a shared mechanism.
PubMed: 38116328
DOI: 10.1016/j.crtox.2023.100140 -
Frontiers in Cellular Neuroscience 2023Neuroinflammation is a pathological event associated with many neurological disorders, including dementia and stroke. The choroid plexus (ChP) is a key structure in the...
Neuroinflammation is a pathological event associated with many neurological disorders, including dementia and stroke. The choroid plexus (ChP) is a key structure in the ventricles of the brain that secretes cerebrospinal fluid (CSF), forms a blood-CSF barrier, and responds to disease conditions by recruiting immune cells and maintaining an immune microenvironment in the brain. Despite these critical roles, the exact structural and functional changes to the ChP over post-stroke time remain to be elucidated. We induced ischemic stroke in C57BL/6J mice via transient middle cerebral artery occlusion which led to reduction of cerebral blood flow and infarct stroke. At 1-7 days post-stroke, we detected time-dependent increase in the ChP blood-CSF barrier permeability to albumin, tight-junction damage, and dynamic changes of SPAK-NKCC1 protein complex, a key ion transport regulatory system for CSF production and clearance. A transient loss of SPAK protein complex but increased phosphorylation of the SPAK-NKCC1 complex was observed in both lateral ventricle ChPs. Most interestingly, stroke also triggered elevation of proinflammatory mRNA and its protein as well as infiltration of anti-inflammatory myeloid cells in ChP at day 5 post-stroke. These findings demonstrate that ischemic strokes cause significant damage to the ChP blood-CSF barrier, contributing to neuroinflammation in the subacute stage.
PubMed: 38107410
DOI: 10.3389/fncel.2023.1279385 -
International Journal of Nanomedicine 2023Sentinel lymph node (SLN) mapping-guided biopsy is crucial for cancer staging and treatment. Optical/nuclide dual-modality imaging agents for mapping SLN are ideal for...
A SPECT/NIR Fluorescence Dual-Modality Imaging Agent Composed of Drugs and Hospital Available Isotope for Preoperative Sentinel Lymph Node Mapping and Intraoperative Biopsy.
BACKGROUND
Sentinel lymph node (SLN) mapping-guided biopsy is crucial for cancer staging and treatment. Optical/nuclide dual-modality imaging agents for mapping SLN are ideal for preoperative planning and intraoperative biopsy, which are enabled by penetration-depth unlimited nuclide imaging and dynamic real-time optical imaging, respectively. However, commonly reported dual-modality imaging agents are composed of novel but safety-unproven materials, making their quick clinical translation challenging. Herein, we report a novel nanoparticle composed of facile hospital-available drugs and isotope for single-photon emission computed tomography (SPECT)/near-infrared (NIR) fluorescence imaging to detect SLNs.
METHODS
Indocyanine green-human serum albumin (ICG-HSA) nanoparticles (NPs) were synthesized by ICG-induced HSA self-assembly and further Tc-labeling via a one-step, facile hospital-available method. After injecting Tc-ICG-HSA into the rats' forepaw pads, the rats' draining axillary lymph nodes were visualized by preoperative mapping with SPECT/CT and intraoperative biopsy with NIR fluorescence. The axillary lymph nodes of rats were identified by pathology and fluorescent staining after execution. Additionally, its toxicity testing and comparison with Tc-sulfur colloid imaging were also explored.
RESULTS
The study reported a self-assembled Tc-ICG-HSA with a high radiochemical yield (85.6 ± 3.8%). Compared with conventional Tc-sulfur colloid, Tc-ICG-HSA NPs showed faster SLN identification, higher renal clearance, and lower hepatic retention. Furthermore, NIRF imaging allowed for the accurate visualization of the SLN and guided SLN biopsy intraoperatively. Notably, the Tc-ICG-HSA NPs were composed of hospital-available drugs and isotope, which are safe for acute toxicity evaluation by a certified institute.
CONCLUSION
The proposed Tc-ICG-HSA NPs are safe and capable of noninvasive SLN identification and biopsy guidance with multi-modal imaging strategies and could be a promising tool for clinically assisted SLN biopsy.
Topics: Humans; Animals; Rats; Sentinel Lymph Node; Sentinel Lymph Node Biopsy; Lymph Nodes; Indocyanine Green; Tomography, Emission-Computed, Single-Photon; Radiopharmaceuticals; Optical Imaging; Serum Albumin, Human; Colloids; Sulfur; Coloring Agents
PubMed: 38106445
DOI: 10.2147/IJN.S430502 -
Antimicrobial Agents and Chemotherapy Feb 2024Darunavir (DRV) is an HIV protease inhibitor commonly used as part of antiretroviral treatment regimens globally for children and adolescents. It requires a...
Darunavir (DRV) is an HIV protease inhibitor commonly used as part of antiretroviral treatment regimens globally for children and adolescents. It requires a pharmacological booster, such as ritonavir (RTV) or cobicistat. To better understand the pharmacokinetics (PK) of DRV in this younger population and the importance of the RTV boosting effect, a population PK substudy was conducted within SMILE trial, where the maintenance of HIV suppression with once daily integrate inhibitor + darunavir/ritonavir in children and adolescents is evaluated. A joint population PK model that simultaneously used total DRV, unbound DRV, and total RTV concentrations was developed. Competitive and non-competitive models were examined to define RTV's influence on DRV pharmacokinetics. Linear and non-linear equations were tested to assess DRV protein binding. A total of 443 plasma samples from 152 adolescents were included in this analysis. Darunavir PK was best described by a one-compartment model first-order absorption and elimination. The influence of RTV on DRV pharmacokinetics was best characterized by ritonavir area under the curve on DRV clearance using a power function. The association of non-linear and linear equations was used to describe DRV protein binding to alpha-1 glycoprotein and albumin, respectively. In our population, simulations indicate that 86.8% of total and unbound DRV trough concentrations were above 0.55 mg/L [10 times protein binding-adjusted EC for wild-type (WT) HIV-1] and 0.0243 mg/L (10 times EC for WT HIV-1) targets, respectively. Predictions were also in agreement with observed outcomes from adults receiving 800/100 mg DRV/r once a day. Administration of 800/100 mg of DRV/r once daily provides satisfactory concentrations and exposures for adolescents aged 12 years and older.
Topics: Adult; Child; Humans; Adolescent; Darunavir; Ritonavir; Anti-HIV Agents; Sulfonamides; HIV Infections; HIV Protease Inhibitors
PubMed: 38092664
DOI: 10.1128/aac.01004-23 -
Acta Biomaterialia Jan 2024Polymeric prodrugs have been applied to control the delivery of various types of therapeutics. Similarly, conjugation of peptide therapeutics to lipids has been used to...
Functionalisation of brush polyethylene glycol polymers with specific lipids extends their elimination half-life through association with natural lipid trafficking pathways.
Polymeric prodrugs have been applied to control the delivery of various types of therapeutics. Similarly, conjugation of peptide therapeutics to lipids has been used to prolong systemic exposure. Here, we extend on these two approaches by conjugating brush polyethylene glycol (PEG) polymers with different lipid components including short-chain (1C2) or medium-chain (1C12) monoalkyl hydrocarbon tails, cholesterol (Cho), and diacylglycerols composed of two medium-chain (2C12) or long-chain (2C18) fatty acids. We uniquely evaluate the integration of these lipid-polymers into endogenous lipid trafficking pathways (albumin and lipoproteins) and the impact of lipid conjugation on plasma pharmacokinetics after intravenous (IV) and subcutaneous (SC) dosing to cannulated rats. The IV and SC elimination half-lives of Cho-PEG (13 and 22 h, respectively), 2C12-PEG (11 and 17 h, respectively) and 2C18-PEG (12 h for both) were prolonged compared to 1C2-PEG (3 h for both) and 1C12-PEG (4 h for both). Interestingly, 1C2-PEG and 1C12-PEG had higher SC bioavailability (40 % and 52 %, respectively) compared to Cho-PEG, 2C12-PEG and 2C18-PEG (25 %, 24 % and 23 %, respectively). These differences in pharmacokinetics may be explained by the different association patterns of the polymers with rat serum albumin (RSA), bovine serum albumin (BSA) and lipoproteins. For example, in pooled plasma (from IV pharmacokinetic studies), 2C18-PEG had the highest recovery in the high-density lipoprotein (HDL) fraction. In conclusion, the pharmacokinetics of brush PEG polymers can be tuned via conjugation with different lipids, which can be utilised to tune the elimination half-life, biodistribution and effect of therapeutics for a range of medical applications. STATEMENT OF SIGNIFICANCE: Lipidation of therapeutics such as peptides has been employed to extend their plasma half-life by promoting binding to serum albumin, providing protection against rapid clearance. Here we design and evaluate innovative biomaterials consisting of brush polyethylene glycol polymers conjugated with different lipids. Importantly, we show for the first time that lipidated polymeric materials associate with endogenous lipoprotein trafficking pathways and this, in addition to albumin binding, controls their plasma pharmacokinetics. We find that conjugation to dialkyl lipids and cholesterol leads to higher association with lipid trafficking pathways, and more sustained plasma exposure, compared to conjugation to short and monoalkyl lipids. Our lipidated polymers can thus be utilised as delivery platforms to tune the plasma half-life of various pharmaceuticals.
Topics: Rats; Animals; Polyethylene Glycols; Polymers; Tissue Distribution; Half-Life; Peptides; Lipoproteins, HDL; Cholesterol; Serum Albumin, Bovine
PubMed: 38086497
DOI: 10.1016/j.actbio.2023.12.002 -
ERJ Open Research Nov 2023Pulmonary radioaerosol mucociliary clearance (PRMC) is a reliable method for assessing whole lung mucociliary clearance and has been used at the Danish PCD Centre as a...
BACKGROUND
Pulmonary radioaerosol mucociliary clearance (PRMC) is a reliable method for assessing whole lung mucociliary clearance and has been used at the Danish PCD Centre as a supplementary diagnostic test for primary ciliary dyskinesia (PCD) for more than two decades. This study aimed to investigate genotype-specific differences in PRMC measures and evaluate its potential as an outcome parameter.
MATERIAL AND METHODS
The study was based on a retrospective analysis of PRMC tests performed over a 24-year period (1999-2022) in individuals referred for PCD work-up and included patients with genetically confirmed PCD and non-PCD controls. Patients inhaled nebulised technetium-albumin-colloid before static and dynamic imaging was obtained. Three parameters were evaluated: 1-h lung retention (LR1), tracheobronchial velocity (TBV) and cough clearance.
RESULTS
The study included 69 patients from the Danish PCD cohort, representing 26 different PCD genotypes. Mucociliary clearance by PRMC was consistently absent in most PCD patients, regardless of genotype. However, a single patient with a mutation, preserved ciliary function and normal nasal nitric oxide levels exhibited normal LR1 and low TBV values. Voluntary cough significantly improved clearance, with a median improvement of 11% (interquartile range 4-24%).
CONCLUSION
Absent mucociliary clearance by PRMC should be expected in PCD regardless of genotype but residual ciliary function could result in measurable PRMC. This indicates a potential for PRMC to detect improvements in ciliary function if this can be restored. Addressing involuntary cough and peripheral deposition of radioaerosol is important if PRMC is to be used as an outcome measure in future clinical PCD trials.
PubMed: 38076675
DOI: 10.1183/23120541.00685-2023 -
International Journal of Molecular... Nov 2023Intrauterine growth restriction (IUGR) remains a significant concern in modern obstetrics, linked to high neonatal health problems and even death, as well as childhood...
Intrauterine growth restriction (IUGR) remains a significant concern in modern obstetrics, linked to high neonatal health problems and even death, as well as childhood disability, affecting adult quality of life. The role of maternal and fetus adaptation during adverse pregnancy is still not completely understood. This study aimed to investigate the disturbance in biological processes associated with isolated IUGR via blood plasma proteomics. The levels of 125 maternal plasma proteins were quantified by liquid chromatography-multiple reaction monitoring mass spectrometry (LC-MRM MS) with corresponding stable isotope-labeled peptide standards (SIS). Thirteen potential markers of IUGR (Gelsolin, Alpha-2-macroglobulin, Apolipoprotein A-IV, Apolipoprotein B-100, Apolipoprotein(a), Adiponectin, Complement C5, Apolipoprotein D, Alpha-1B-glycoprotein, Serum albumin, Fibronectin, Glutathione peroxidase 3, Lipopolysaccharide-binding protein) were found to be inter-connected in a protein-protein network. These proteins are involved in plasma lipoprotein assembly, remodeling, and clearance; lipid metabolism, especially cholesterol and phospholipids; hemostasis, including platelet degranulation; and immune system regulation. Additionally, 18 proteins were specific to a particular type of IUGR (early or late). Distinct patterns in the coagulation and fibrinolysis systems were observed between isolated early- and late-onset IUGR. Our findings highlight the complex interplay of immune and coagulation factors in IUGR and the differences between early- and late-onset IUGR and other placenta-related conditions like PE. Understanding these mechanisms is crucial for developing targeted interventions and improving outcomes for pregnancies affected by IUGR.
Topics: Pregnancy; Adult; Infant, Newborn; Female; Humans; Child; Fetal Growth Retardation; Proteomics; Quality of Life; Fetus; Placenta
PubMed: 38069155
DOI: 10.3390/ijms242316832 -
Diagnostics (Basel, Switzerland) Nov 2023(1) Background: Uremic pruritus (UP) is a common and taxing symptom in patients on maintenance hemodialysis (MHD). We have previously shown that blood lead levels (BLLs)...
(1) Background: Uremic pruritus (UP) is a common and taxing symptom in patients on maintenance hemodialysis (MHD). We have previously shown that blood lead levels (BLLs) and blood aluminum levels (BALs) were separately positively associated with UP in MHD patients. We also found that blood cadmium levels (BCLs) were positively associated with all-cause mortality and cardiovascular-related mortality in MHD patients. We wondered whether there is any correlation between BCLs and UP after adjusting for BLLs and BALs. (2) Methods: Patients enrolled in this study were all from three hemodialysis (HD) centers at Chang Gung Memorial Hospital, Lin-Kou Medical Center, including both the Taipei and Taoyuan branches. Correlations between UP and BLLs, BALs, BCLs, and other clinical data were analyzed. (3) Results: Eight hundred and fifty-three patients were recruited. Univariate logistic regressions showed that diabetes mellitus, hepatitis B virus infection, hepatitis C virus infection, HD duration, hemodiafiltration, dialysis clearance of urea, normalized protein catabolic rate, non-anuria, serum albumin levels, log (intact-parathyroid hormone levels), total serum cholesterol levels, serum low-density lipoprotein levels, log (blood aluminum levels), and log (blood lead levels) were associated with UP. Although log BCLs were not significantly associated with UP ( = 0.136) in univariate analysis, we still included log BCLs in multivariate logistic regression to verify their effect on UP given that our aim in this study was to verify associations between serum heavy metals and UP. Multivariate logistic regressions showed that log BLLs (OR: 27.556, 95% CI: 10.912-69.587, < 0.001) and log BALs (OR: 5.485, 95% CI: 2.985-10.079, < 0.001) were positively associated with UP. The other logistic regression, which stratified BLLs and BALs into high and low BLLs and BALs, respectively, showed that high BLLs or high BALs (low BLLs and low BALs as reference) (OR: 3.760, 95% CI: 2.554-5.535, < 0.001) and high BLLs and high BALs combined (low BLLs and low BALs as reference) (OR: 10.838, 95% CI: 5.381-21.828, < 0.001) were positively correlated with UP. (4) Conclusions: BLLs and BALs were positively correlated with UP. BCLs were not correlated with UP. Clinicians should pay more attention to the environmental sources of lead and aluminum to prevent UP.
PubMed: 38066806
DOI: 10.3390/diagnostics13233565