ABSTRACT
RATIONALE & OBJECTIVE: Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the formation of multiple kidney cysts that leads to growth in total kidney volume (TKV) and progression to kidney failure. Venglustat is a glucosylceramide synthase inhibitor that has been shown to inhibit cyst growth and reduce kidney failure in preclinical models of ADPKD. STUDY DESIGN: STAGED-PKD was a 2-stage, multicenter, double-blind, randomized, placebo-controlled phase 2/3 study in adults with ADPKD at risk of rapidly progressive disease, who were selected based on Mayo Clinic imaging classification of ADPKD class 1C, 1D, or 1E and an estimated glomerular filtration rate (eGFR) of 30-89.9mL/min/1.73m2. SETTING & PARTICIPANTS: Enrollment included 236 and 242 patients in stages 1 and 2, respectively. INTERVENTIONS: In trial stage 1, the patients were randomized 1:1:1 to venglustat, 8mg; venglustat, 15mg; or placebo. In stage 2, the patients were randomized 1:1 to venglustat, 15mg (highest dose identified as safe and well tolerated in stage 1), or placebo. OUTCOMES: Primary end points were rate of change in TKV over 18 months in stage 1 and eGFR slope over 24 months in stage 2. Secondary end points were eGFR slope over 18 months (stage 1), rate of change in TKV (stage 2), and safety/tolerability, pain, and fatigue (stages 1 and 2). RESULTS: A prespecified interim futility analysis showed that venglustat treatment had no effect on the annualized rate of change in TKV over 18 months (stage 1) and had a faster rate of decline in eGFR slope over 24 months (stage 2). Due to this lack of efficacy, the study was terminated early. LIMITATIONS: The short follow-up period after the end of treatment and limited generalizability of the findings. CONCLUSIONS: In patients with rapidly progressing ADPKD, treatment with venglustat at either 8mg or 15mg showed no change in the rate of change in TKV and a faster rate of eGFR decline in STAGED-PKD despite a dose-dependent decrease in plasma glucosylceramide levels. FUNDING: This study was funded by Sanofi. TRIAL REGISTRATION: Registered at ClinicalTrials.gov with study number NCT03523728.
Subject(s)
Polycystic Kidney, Autosomal Dominant , Renal Insufficiency , Adult , Humans , Polycystic Kidney, Autosomal Dominant/complications , Kidney , Renal Insufficiency/complications , Glomerular Filtration Rate , Disease ProgressionABSTRACT
Fabry disease (FD) is a rare lysosomal storage disorder, characterized by a reduction in α-galactosidase A enzyme activity and the progressive accumulation of globotriaosylceramide (GL3) and its metabolites in the cells of various organs. Agalsidase beta, an enzyme replacement therapy (ERT), is approved for use in patients with FD in Europe, Canada, Australia, South America, and Asia, and is the only ERT approved for use in the United States. In this review, we discuss the clinical relevance of GL3 accumulation, the effect of agalsidase beta on GL3 in target tissues, and the association between treatment-related tissue GL3 clearance and long-term structure, function, or clinical outcomes. Accumulation of GL3 in the kidney, heart, vasculature, neurons, skin, gastrointestinal tract and auditory system correlates to cellular damage and irreversible organ damage, as a result of sclerosis, fibrosis, apoptosis, inflammation, and endothelial dysfunction. Damage leads to renal dysfunction and end-stage renal disease; myocardial hypertrophy with heart failure and arrhythmias; ischemic stroke; neuropathic pain; skin lesions; intestinal ischemia and dysmotility; and hearing loss. Treatment with agalsidase beta is effective in substantially clearing GL3 in a range of cells from the tissues affected by FD. Agalsidase beta has also been shown to slow renal decline and lower the overall risk of clinical progression, demonstrating an indirect link between treatment-related GL3 clearance and stabilization of FD.
Subject(s)
Fabry Disease , alpha-Galactosidase , Humans , alpha-Galactosidase/therapeutic use , Fabry Disease/pathology , Clinical Relevance , Enzyme Replacement Therapy/adverse effects , Recombinant Proteins/therapeutic useABSTRACT
The authors designed a structurally stable nano-in-nano (NANO2) system highly capable of bioimaging via an aggregation-enhanced NIR excited emission and photoacoustic response achieved based on atomically precise gold nanoclusters protected by linear thiolated ligands [Au25(SC n H2n+1)18, n = 4-16] encapsulated in discoidal phospholipid bicelles through a one-pot synthesis. The detailed morphological characterization of NANO2 is conducted using cryogenic transmission electron microscopy, small/wide angle X-ray scattering with the support of molecular dynamics simulations, providing information on the location of Au nanoclusters in NANO2. The photoluminescence observed for NANO2 is 20-60 times more intense than that of the free Au nanoclusters, with both excitation and emission wavelengths in the near-infrared range, and the photoacoustic signal is more than tripled. The authors attribute this newly discovered aggregation-enhanced photoluminescence and photoacoustic signals to the restriction of intramolecular motion of the clusters' ligands. With the advantages of biocompatibility and high cellular uptake, NANO2 is potentially applicable for both in vitro and in vivo imaging, as the authors demonstrate with NIR excited emission from in vitro A549 human lung and the KB human cervical cancer cells.
ABSTRACT
Kidneys have a high energy demand to facilitate the reabsorption of the glomerular filtrate. For this reason, renal cells have a high density of mitochondria. Mitochondrial cytopathies can be the result of a mutation in both mitochondrial and nuclear DNA. Mitochondrial dysfunction can lead to a variety of renal manifestations. Examples of tubular manifestations are renal Fanconi Syndrome, which is often found in patients diagnosed with Kearns-Sayre and Pearson's marrow-pancreas syndrome, and distal tubulopathies, which result in electrolyte disturbances such as hypomagnesemia. Nephrotic syndrome can be a glomerular manifestation of mitochondrial dysfunction and is typically associated with focal segmental glomerular sclerosis on histology. Tubulointerstitial nephritis can also be seen in mitochondrial cytopathies and may lead to end-stage renal disease. The underlying mechanisms of these cytopathies remain incompletely understood; therefore, current therapies focus mainly on symptom relief. A better understanding of the molecular disease mechanisms is critical in order to improve treatments.
Subject(s)
Mutation , DNA, Mitochondrial/genetics , Humans , Kearns-Sayre Syndrome , Mitochondria/genetics , Mitochondrial Myopathies , Nephritis, InterstitialABSTRACT
Occasional bursts of discovery and innovation have appeared during the otherwise stagnant past several decades of drug development in nephrology. Among other recent drug discoveries, the unexpected kidney benefits observed with sodium/glucose cotransporter 2 inhibitors may herald a renaissance of drug development in kidney disease. This recent progress highlights the need to further promote and stimulate research and development of promising therapies that may ameliorate the morbidity and mortality associated with kidney disease. To help identify and address barriers to drug development in nephrology, the Duke Clinical Research Institute convened a conference in April 2019 that included stakeholders from academia, industry, government agencies, and patient advocacy. From these discussions, several opportunities were identified to improve every stage of drug development for kidney disease from early discovery to implementation into practice. Key topics reviewed in this article are the utility of interconnected data and site research networks, surrogate end points, pragmatic and adaptive trial designs, the promising uses of real-world data, and methods to improve the generalizability of trial results and uptake of approved drugs for kidney-related diseases.
Subject(s)
Drug Development/methods , Kidney Diseases/drug therapy , Research Design , Drug Approval , HumansABSTRACT
Follicular unit extraction (FUE) and follicular unit transplantation (FUT) account for 99% of hair transplant procedures. In both cases, it is important for clinicians to characterize follicle density for treatment planning and evaluation. The existing gold-standard is photographic examination. However, this approach is insensitive to subdermal hair and cannot identify follicle orientation. Here, we introduce a fast and non-invasive imaging technique to measure follicle density and angles across regions of varying density. We first showed that hair is a significant source of photoacoustic signal. We then selected regions of low, medium, and high follicle density and showed that photoacoustic imaging can measure the density of follicles even when they are not visible by eye. We performed handheld imaging by sweeping the transducer across the imaging area to generate 3D images via maximum intensity projection. Background signal from the dermis was removed using a skin tracing method. Measurement of follicle density using photoacoustic imaging was highly correlated with photographic determination (R2 = 0.96). Finally, we measured subdermal follicular angles-a key parameter influencing transection rates in FUE.
Subject(s)
Hair Follicle , Photoacoustic Techniques , Diagnostic ImagingABSTRACT
Ulcers including pressure ulcers and diabetic foot ulcers damage the skin and underlying tissue in people with compromised blood circulation. They are classified into four stages of severity and span from mild reddening of the skin to tissue damage and muscle/bone infections. Here, we used photoacoustic imaging as a noninvasive method for detecting early tissue damage that cannot be visually observed while also staging the disease using quantitative image analysis. We used a mouse model of pressure ulcers by implanting subdermal magnets in the dorsal flank and periodically applying an external magnet to the healed implant site. The magnet-induced pressure was applied in cycles, and the extent of ulceration was dictated by the number of cycles. We used both laser- and light-emitting diode (LED)-based photoacoustic imaging tools with 690 nm excitation to evaluate the change in photoacoustic signal and depth of injury. Using laser-based photoacoustic imaging system, we found a 4.4-fold increase in the photoacoustic intensity in stage I vs. baseline (no pressure). We also evaluated the depth of injury using photoacoustics. We measured a photoacoustic ulcer depth of 0.38 ± 0.09 mm, 0.74 ± 0.11 mm, 1.63 ± 0.4 mm, and 2.7 ± 0.31 mm (n = 4) for stages I-IV, respectively. The photoacoustic depth differences between each stage were significant (p < 0.05). We also used an LED-based photoacoustic imaging system to detect early stage (stage I) pressure ulcers and observed a 2.5-fold increase in photoacoustic signal. Importantly, we confirmed the capacity of this technique to detect dysregulated skin even before stage I ulcers have erupted. We also observed significant changes in photoacoustic intensity during healing suggesting that this approach can monitor therapy. These findings were confirmed with histology. These results suggest that this photoacoustic-based approach might have clinical value for monitoring skin diseases including pressure ulcers.
Subject(s)
Photoacoustic Techniques , Pressure Ulcer/diagnostic imaging , Wound Healing/physiology , Animals , Disease Models, Animal , Mice , Mice, Nude , Pressure Ulcer/pathology , Reproducibility of ResultsABSTRACT
Double-stage delay-multiply-and-sum (DS-DMAS) is an algorithm proposed for photoacoustic image reconstruction. The DS-DMAS algorithm offers a higher contrast than conventional delay-and-sum and delay-multiply and-sum but at the expense of higher computational complexity. Here, we utilized a compute unified device architecture (CUDA) graphics processing unit (GPU) parallel computation approach to address the high complexity of the DS-DMAS for photoacoustic image reconstruction generated from a commercial light-emitting diode (LED)-based photoacoustic scanner. In comparison with a single-threaded central processing unit (CPU), the GPU approach increased speeds by nearly 140-fold for 1024 × 1024 pixel image; there was no decrease in accuracy. The proposed implementation makes it possible to reconstruct photoacoustic images with frame rates of 250, 125, and 83.3 when the images are 64 × 64, 128 × 128, and 256 × 256, respectively. Thus, DS-DMAS can be efficiently used in clinical devices when coupled with CUDA GPU parallel computation.
Subject(s)
Algorithms , Computer Graphics , Image Processing, Computer-Assisted/methods , Photoacoustic Techniques/methods , Signal Processing, Computer-Assisted , Equipment Design , Phantoms, Imaging , Photoacoustic Techniques/instrumentation , Signal-To-Noise Ratio , TomographyABSTRACT
We recently reported a real-time method to measure heparin in human whole blood based on the photoacoustic change of methylene blue (MB). Intriguingly, the MB behaved unlike other "turn on" photoacoustic probes-the absorbance decreased as the photoacoustic signal increased. The underlying mechanism was not clear and motivated this study. We studied the binding mechanism of MB and heparin in water and phosphate buffer saline (PBS) with both experimental and computational methods. We found that the photoacoustic enhancement of the MB-heparin mixture was a result of MB-heparin aggregation due to charge neutralization and resulting sequestration of MB in these aggregates. The sequestration of MB in the MB-heparin aggregates led to decreased absorbance-there was simply less free dye in solution to absorb light. The highest photoacoustic signal and aggregation occurred when the number of negatively charged sulfate groups on heparin was approximately equal to the number of positively charged MB molecule. The MB-heparin aggregates dissociated when there were more sulfated groups from heparin than MB molecules because of the electrostatic repulsion between negatively charged sulfate groups. PBS facilitated MB dimer formation regardless of heparin concentration and reprecipitated free MB in aggregates due to ionic strength and ionic shielding. Further molecular dynamics experiments found that binding of heparin occurred at the sulfates and glucosamines in heparin. Phosphate ions could interact with the heparin via sodium ions to impair the MB-heparin binding. Finally, our model found 3.7-fold more MB dimerization upon addition of heparin in MB solution confirming that heparin facilitates MB aggregation. We conclude that the addition of heparin in MB decreases the absorbance of the sample because of MB-heparin aggregation leading to fewer MB molecules in solution; however, the aggregation also increases the PA intensity because the MB molecules in the MB-heparin aggregate have reduced degrees of freedom and poor heat transfer to solvent.
Subject(s)
Anticoagulants/metabolism , Coloring Agents/metabolism , Heparin/metabolism , Methylene Blue/metabolism , Anticoagulants/chemistry , Binding Sites , Coloring Agents/chemistry , Dimerization , Heparin/chemistry , Kinetics , Methylene Blue/chemistry , Molecular Docking Simulation , Photoacoustic TechniquesABSTRACT
In practice, photoacoustic (PA) waves generated with cost-effective and low-energy laser diodes, are weak and almost buried in noise. Reconstruction of an artifact-free PA image from noisy measurements requires an effective denoising technique. Averaging is widely used to increase the signal-to-noise ratio (SNR) of PA signals; however, it is time consuming and in the case of very low SNR signals, hundreds to thousands of data acquisition epochs are needed. In this study, we explored the feasibility of using an adaptive and time-efficient filtering method to improve the SNR of PA signals. Our results show that the proposed method increases the SNR of PA signals more efficiently and with much fewer acquisitions, compared to common averaging techniques. Consequently, PA imaging is conducted considerably faster.
ABSTRACT
Background: Patients with Fabry disease (FD, α-galactosidase A deficiency or absence) accumulate glycosphingolipids, leading to progressive dysfunction of kidneys, heart and nervous system. Generalizable real-world outcomes following agalsidase beta treatment initiation outside trials are limited. We investigated the associations of long-term agalsidase beta treatment with estimated glomerular filtration rate (eGFR) changes over time and the risk of developing a composite clinical event in a matched analysis of treated and untreated patients with FD. Methods: Agalsidase beta-treated adult patients (aged ≥16 years) from the Fabry Registry and adult untreated patients from a natural history cohort were matched 1:1 and X:X (with one occurrence and multiple occurrences of each untreated patient, respectively) by sex, phenotype, age and (for eGFR slope analysis) baseline eGFR. Outcomes included eGFR slope over 5 years and composite clinical event risk (cardiovascular, cerebrovascular or renal event, or death) over 10+ years. As a surrogate indicator of therapeutic response in paediatric patients, the percentage experiencing normalization in plasma globotriaosylceramide (GL-3) from treatment initiation was assessed in patients aged 2 to <16 years. Results: Overall, eGFR slopes for 1:1-matched untreated and treated adult patients [122 pairs (72.1% male)] were -3.19 and -1.47 mL/min/1.73 m2/year, respectively (reduction in rate of decline = 53.9%, P = .007), and for X:X-matched [122 untreated/950 treated (59.4% male)] were -3.29 and -1.56 mL/min/1.73 m2/year, respectively (reduction in rate of decline = 52.6%, P < .001). Agalsidase beta treatment was associated with lower risk of clinical events, with hazard ratios of 0.41 (P = .003) and 0.67 (P = .008) for 1:1-matched and X:X-matched analyses, respectively. Plasma GL-3 declined markedly in paediatric patients and normalized in most within 6 months of treatment initiation. Conclusion: Agalsidase beta treatment preserves kidney function and delays progression to severe clinical events among adult patients with FD. Plasma GL-3 levels analysed in paediatric patients showed normalization of elevated pre-treatment levels in most patients.
ABSTRACT
BACKGROUND: Nonalcoholic fatty liver disease is associated with hepatic insulin resistance and type 2 diabetes mellitus. Whether this association has a genetic basis is unknown. METHODS: In 95 healthy Asian Indian men, a group known to have a high prevalence of nonalcoholic fatty liver disease, we genotyped two single-nucleotide polymorphisms (SNPs) in the gene encoding apolipoprotein C3 (APOC3) that are known to be associated with hypertriglyceridemia (rs2854116 [T-455C] and rs2854117 [C-482T]). Plasma apolipoprotein C3 concentrations, insulin sensitivity, and hepatic triglyceride content were measured. We also measured plasma triglyceride concentrations and retinyl fatty acid ester absorption as well as plasma triglyceride clearance after oral and intravenous fat-tolerance tests. Liver triglyceride content and APOC3 genotypes were also assessed in a group of 163 healthy non-Asian Indian men. RESULTS: Carriers of the APOC3 variant alleles (C-482T, T-455C, or both) had a 30% increase in the fasting plasma apolipoprotein C3 concentration, as compared with the wild-type homozygotes. They also had a 60% increase in the fasting plasma triglyceride concentration, an increase by a factor of approximately two in the plasma triglyceride and retinyl fatty acid ester concentrations after an oral fat-tolerance test, and a 46% reduction in plasma triglyceride clearance. The prevalence of nonalcoholic fatty liver disease was 38% among variant-allele carriers and 0% among wild-type homozygotes (P<0.001). The subjects with nonalcoholic fatty liver disease had marked insulin resistance. A validation study involving non-Asian Indian men confirmed the association between APOC3 variant alleles and nonalcoholic fatty liver disease. CONCLUSIONS: The polymorphisms C-482T and T-455C in APOC3 are associated with nonalcoholic fatty liver disease and insulin resistance.
Subject(s)
Apolipoprotein C-III/genetics , Fatty Liver/genetics , Insulin Resistance/genetics , Polymorphism, Single Nucleotide , Adult , Connecticut , Fatty Liver/ethnology , Fatty Liver/physiopathology , Genetic Predisposition to Disease , Heterozygote , Homozygote , Humans , India/ethnology , Insulin Resistance/ethnology , Insulin Resistance/physiology , Linear Models , Liver/chemistry , Male , Prevalence , Statistics, Nonparametric , Triglycerides/analysis , Triglycerides/blood , Weight Loss , White People/geneticsABSTRACT
Advances in genetic mapping and sequencing techniques have led to substantial progress in the study of rare monogenic (Mendelian) forms of abnormal blood pressure. Many disease-defining pathways for hypertension have been identified in the past two decades. Perturbations in renal salt handling appear to be a common mechanism underlying these rare syndromes of hypertension. Excess activation at various points in the mineralocorticoid signaling pathway and malfunctioning of the autonomic (specifically sympathetic) nervous system have both been implicated in inducing hypertension, while complementary studies examining low blood pressure phenotypes have identified novel pathways exclusively linked to renal salt wasting in either the thick ascending limb or the distal nephron. The genetic defects and the physiological and cellular pathways affected in these various disorders are reviewed here. Importantly, studies have suggested that genetic variation affecting these same genes and pathways may play an important role in explaining the variation of blood pressure levels in the general population. The investigation of rare syndromes of human blood pressure variation has important implications for improving the diagnosis and treatment of hypertension.
Subject(s)
Blood Pressure/genetics , Hypertension/genetics , Hypotension/genetics , Kidney/physiopathology , Renal Tubular Transport, Inborn Errors/genetics , Animals , Genetic Predisposition to Disease , Humans , Hypertension/diagnosis , Hypertension/metabolism , Hypertension/physiopathology , Hypertension/therapy , Hypotension/diagnosis , Hypotension/metabolism , Hypotension/physiopathology , Hypotension/therapy , Kidney/metabolism , Phenotype , Prognosis , Renal Tubular Transport, Inborn Errors/diagnosis , Renal Tubular Transport, Inborn Errors/metabolism , Renal Tubular Transport, Inborn Errors/physiopathology , Renal Tubular Transport, Inborn Errors/therapyABSTRACT
OBJECTIVE: To customize a miniaturized ultrasound transducer to access full-mouth B-mode, color Doppler, and spectral Doppler imaging for monitoring oral health. METHODS: A customized periodontal ultrasound transducer SS-19-128 (19 MHz, 128 channels) 1.8-cm wide and 1-cm thick was developed and connected to a data acquisition (DAQ) system. B-mode, color Doppler, and spectral Doppler data could all be collected with SS-19-128. The imaging resolution and penetration capacity of SS-19-128 were characterized on phantoms. The gingival thickness was measured on 11 swine teeth by SS-19-128 for comparison with conventional transgingival probing via Bland-Altman analysis and Pearson correlation. Five human subjects were then recruited to demonstrate B-mode and Doppler imaging by SS-19-128. RESULTS: The axial and lateral spatial resolution at 5.5 mm depth is 102.1 µm and 142.9 µm, respectively. The penetration depth in a tissue-mimicking phantom is over 30 mm. In vivo B-mode imaging of all 28 teeth was demonstrated on one human subject, and imaging of tooth #18 was accessed on five human subjects. Gingival thickness measurement compared with transgingival probing showed a bias of -0.015 mm and SD of 0.031 mm, and a r = 0.9235 (p < 0.0001) correlation. In vivo color and spectral Doppler imaging of the supraperiosteal artery in human gingiva was performed to generate hemodynamic information. CONCLUSIONS: The small size of SS-19-128 offers important advantages over existing ultrasound technology-more specifically, whole-mouth scanning/charting reminiscent of radiography. This is nearly a two-fold increase in the number of teeth that can be assessed versus conventional transducers.
Subject(s)
Oral Health , Ultrasonography, Doppler , Humans , Animals , Swine , Ultrasonography , Transducers , MouthABSTRACT
OBJECTIVE: To develop a novel technique for localizing and reconstructing the greater palatine artery (GPA) using three-dimensional (3D) technology. METHODS: A miniaturized intraoral ultrasound transducer was used to imaging landmarks including the GPA, gingival margin (GM), and palatal masticatory mucosa (PMM). A 5-mm-thick solid hydrogel couplant was integrated to replace traditional ultrasound gel and avoid bubbles when moving the transducer. RESULTS: A panorama image provided the relative localization of landmarks including the GPA, PMM, and hard palate. Short- and long-axis imaging of GPA was performed in five subjects including 3D mapping of GPA branches and surrounding tissues in a volume of 10 mm × 8 mm × 10 mm. Full-mouth Doppler imaging was also demonstrated on both the dorsal and ventral tongue as well as buccal mucosa and sublingual region on two subjects. CONCLUSIONS: This study can measure the vertical distance from the GM to the GPA and depth from PMM to GPA and visualize the GPA localization in a 3D manner, which is critical to evaluate the available volume of palatal donor tissues and avoid sectioning of GPA during surgical harvesting of the tissues. Finally, the transducer's small size facilitates full-mouth Doppler imaging with the potential to improve the assessment, diagnosis, and management of oral mucosa.
Subject(s)
Arteries , Palate, Hard , Humans , Arteries/diagnostic imaging , Mouth Mucosa , FaceABSTRACT
We have developed and optimized an imaging system to study and improve the detection of brain hemorrhage and to quantify oxygenation. Since this system is intended to be used for brain imaging in neonates through the skull opening, i.e., fontanelle, we called it, Transfontanelle Photoacoustic Imaging (TFPAI) system. The system is optimized in terms of optical and acoustic designs, thermal safety, and mechanical stability. The lower limit of quantification of TFPAI to detect the location of hemorrhage and its size is evaluated using in-vitro and ex-vivo experiments. The capability of TFPAI in measuring the tissue oxygenation and detection of vasogenic edema due to brain blood barrier disruption are demonstrated. The results obtained from our experimental evaluations strongly suggest the potential utility of TFPAI, as a portable imaging modality in the neonatal intensive care unit. Confirmation of these findings in-vivo could facilitate the translation of this promising technology to the clinic.
ABSTRACT
The objective of this study was to assess the utility of hyperuricemia as a marker for diabetes and prediabetes (impaired fasting glucose) and insulin resistance in young adults. Using Cox proportional hazards regression models, the authors analyzed 15-year follow-up data on 5,012 persons in 4 US cities who were aged 18-30 years and diabetes-free at the time of enrollment. At baseline (1986), 88% of participants had a body mass index (weight (kg)/height (m)(2)) less than 30. During the follow-up period (through 2001), the incidence rates of diabetes and prediabetes (insulin resistance and impaired fasting glucose) were higher among persons with greater serum urate concentrations. In multivariable Cox regression analyses that adjusted for age, gender, race, body mass index, family history of diabetes, diastolic blood pressure, total cholesterol, smoking, and alcohol use, the hazard ratios for diabetes, insulin resistance, and prediabetes among persons with hyperuricemia (serum urate level >7 mg/dL vs. ≤7.0 mg/dL) were 1.87 (95% confidence interval (CI): 1.33, 2.62), 1.36 (95% CI: 1.23, 1.51), and 1.25 (95% CI: 1.04, 1.52), respectively. This observation was generally consistent across subgroups. The authors conclude that hyperuricemia in the midtwenties is an independent marker for predicting diabetes and prediabetes among young adults in the subsequent 15 years.
Subject(s)
Diabetes Mellitus/epidemiology , Hyperuricemia/epidemiology , Insulin Resistance , Prediabetic State/epidemiology , Adolescent , Adult , Body Mass Index , Comorbidity , Cross-Sectional Studies , Diabetes Mellitus/blood , Female , Follow-Up Studies , Humans , Hyperuricemia/blood , Incidence , Insulin Resistance/physiology , Lipids/blood , Male , Prediabetic State/blood , Proportional Hazards Models , Regression Analysis , Risk Factors , United States/epidemiology , Uric Acid/blood , Young AdultABSTRACT
Periodontitis is a public issue and imaging periodontal pocket is important to evaluate periodontitis. Regular linear transducers have limitations in imaging the posterior teeth due to their geometry restrictions. Here we characterized a transducer that can image the posterior teeth including assessment of periodontal pockets via a combination of photoacoustic and ultrasound imaging. Unlike conventional transducer design, this device has a toothbrush-shaped form factor with a side-view transducer to image molars (total size: 1 ×1.9 cm). A laser diode was integrated as the light source to reduce the cost and size and facilitates clinical transition. The in vivo imaging of a molar of a periodontal patient demonstrated that the transducer could image in the posterior area of gum in vivo; the value determined by imaging was within 7 % of the value measured clinically.
ABSTRACT
Rationale & Objective: Venglustat, a glucosylceramide synthase inhibitor, inhibits cyst growth and reduces kidney failure in mouse models of autosomal dominant polycystic kidney disease (ADPKD). STAGED-PKD aims to determine the safety and efficacy of venglustat and was designed using patient enrichment for progression to end-stage kidney disease and modeling from prior ADPKD trials. Study Design: STAGED-PKD is a 2-stage, international, double-blind, randomized, placebo-controlled trial in adults with ADPKD (Mayo Class 1C-1E) and estimated glomerular filtration rate (eGFR) 45-<90 mL/min/1.73 m2 at risk of rapidly progressive disease. Enrichment for rapidly progressing patients was identified based on retrospective analysis of total kidney volume (TKV) and eGFR slope from the combined Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease and HALT Progression of Polycystic Kidney Disease A studies. Setting & Participants: Target enrollment in stages 1 and 2 was 240 and 320 patients, respectively. Interventions: Stage 1 randomizes patients 1:1:1 to venglustat 8 mg or 15 mg once daily or placebo. Stage 2 randomizes patients 1:1 to placebo or venglustat, with the preferred dose based on stage 1 safety data. Outcomes: Primary endpoints are TKV growth rate over 18 months in stage 1 and eGFR slope over 24 months in stage 2. Secondary endpoints include: annualized rate of change in eGFR from baseline to 18 months (stage 1); annualized rate of change in TKV based on magnetic resonance imaging from baseline to 18 months (stage 2); and safety, tolerability, pain, and fatigue (stages 1 and 2). Limitations: If stage 1 is unsuccessful, patients enrolled in the trial may develop drug-related adverse events that can have long-lasting effects. Conclusions: Modeling allows the design and powering of a 2-stage combined study to assess venglustat's impact on TKV growth and eGFR slope. Stage 1 TKV assessment via a nested approach allows early evaluation of efficacy and increased efficiency of the trial design by reducing patient numbers and trial duration. Funding: This study was funded by Sanofi. Trial registration: STAGED-PKD has been registered at ClinicalTrials.gov with study number NCT03523728.
ABSTRACT
Col4a3-/- Alport mice serve as an animal model for renal fibrosis. MicroRNA-21 (miR-21) expression has been shown to be increased in the kidneys of Alport syndrome patients. Here, we investigated the nephroprotective effects of Lademirsen anti-miR-21 therapy. We used a fast-progressing Col4a3-/- mouse model with a 129/SvJ background and an intermediate-progressing F1 hybrid mouse model with a mixed genetic background, with angiotensin-converting enzyme inhibitor (ACEi) monotherapy in combination with anti-miR-21 therapy. In the fast-progressing model, the anti miR-21 and ACEi therapies showed an additive effect in the reduction in fibrosis, the decline of proteinuria, the preservation of kidney function and increased survival. In the intermediate-progressing F1 model, the anti-miR-21 and ACEi therapies individually improved kidney pathology. Both also improved kidney function and survival; however, the combination showed a significant additive effect, particularly for survival. RNA sequencing (RNA-seq) gene expression profiling revealed that the anti-miR-21 and ACEi therapies modulate several common pathways. However, anti-miR-21 was particularly effective at normalizing the expression profiles of the genes involved in renal tubulointerstitial injury pathways. In conclusion, significant additive effects were detected for the combination of anti-miR-21 and ACEi therapies on kidney function, pathology and survival in Alport mouse models, as well as a strong differential effect of anti-miR-21 on the renal expression of fibrotic factors. These results support the addition of anti-miR-21 to the current standard of care (ACEi) in ongoing clinical trials in patients with Alport syndrome.