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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 30-89.9 mL/min/1.73 m2. 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, 8 mg; venglustat, 15 mg; or placebo. In stage 2, the patients were randomized 1:1 to venglustat, 15 mg (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 8 mg or 15 mg 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.

This article introduces a novel multirate cosimulation architecture that overcomes previous challenges integrating faster real-time, microseconds-scale, power-hardware-in-the-loop (PHIL) with larger scale but slower, real-time, seconds-scale, quasi-static time-series (QSTS) simulation. Specifically, an intermediate reduced-equivalent electromagnetic transient (EMT) model duplicates the key power system topology to capture high-speed dynamics and converge hardware-power system interactions between QSTS updates. Exchanging multidimensional parameter vectors (loads, control status, etc.) between the QSTS and EMT models enables capturing the interactions of the rich, high-node-count (thousands of electrical nodes) QSTS model with the hardware. This architecture offers full spatial resolution from QSTS, including individual load dynamics, actual distribution management system controls, and nodal voltages. Simultaneously, the intermediate EMT model provides more detailed high-speed transients of key distributed energy resource hardware interactions. In addition, we use careful PHIL interface design and the exchange of complex power data, rather than current, to further improve performance. This cosimulation architecture is demonstrated by testing a simulated distribution system with an interconnected 500-kVA advanced photovoltaic (PV) inverter in PHIL. The architecture successfully captured PV local volt–volt ampere reactive (volt-VAR) control interactions with the larger network under time-varying electrical and weather conditions.

BACKGROUND AND AIMS Treatment-resistant primary focal segmental glomerulosclerosis (FSGS) is a rare glomerulopathy associated with nephrotic range proteinuria (>3.5 g/24 h). Treatment goals are reduction in proteinuria, which can delay progression to end-stage renal disease. Lack of quality repeated measures data for proteinuria in nephrotic patients is an important methodological limitation in current clinical trials research. METHOD We examined the 24-h urine collections (traditionally considered to be the gold standard for proteinuria assessment) compared with average of two consecutive first morning spot urine protein/creatinine (Up/c) ratio results for the patients in the placebo arm (n = 10)of this randomized, double-blind placebo-controlled study (3:3:2 allocation for 1 mg/kg, 4 mg/kg, and placebo treatment groups). Patients received randomized treatment for 112 days and were followed double-blind to 252 days. First morning Up/c was obtained from first morning spot urine collections for all visits; 24-h timed collections were performed for Day 1 and Day 112 visits. For first morning Up/c, the average of two collections at each study time point was used for analysis. RESULTS Median age was 42 years, 40% female, 20% black, median eGFR 60 mL/min/1.73 m2 with median Up/c 6.4 g/g (NCT01665391). Correlation coefficient between 24-h timed collection and averaged spot Up/c was r = 0.63 (P = .004). For 24-h timed urines, between subject SD = 2.015 g/24 h and within subject SD = 7.328 g/24 h. For averaged first morning spot Up/c, between subject SD = 2.5 g/g and within subject SD = 2.3 g/g. CONCLUSION In clinical trials subjects with nephrotic syndrome from biopsy-proven FSGS on stable doses of ACEi/ARB medications, 24-h timed collections do not provide additional useful data beyond average of two first morning spot Up/c. These data suggest that labour intensive, cumbersome timed 24-h urine collections should not be performed in clinical trials of nephrotic syndrome patients. Importantly, these data should allow for more precise power and sample size estimates for future interventional clinical trials of nephrotic syndrome.

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 entire human mouth 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.

ObjectiveTo customize a miniaturized ultrasound transducer to access full-mouth B-mode, color Doppler and spectral Doppler imaging for monitoring oral health.MethodsA customized periodontal ultrasound transducer SS-19-128 (19 MHz, 128 channels) with 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. Five human subjects were recruited to demonstrate B-mode and Doppler imaging by SS-19-128. Gingival thickness was measured on 11 swine teeth by SS-19-128 for comparison to conventional transgingival probing via Bland-Altman analysis and Pearson correlation.ResultsThe 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 (PIn vivo color and spectral Doppler imaging of the supraperiosteal artery in human gingiva was performed to generate hemodynamic information.ConclusionsThe small size of SS-19-128 offers important advantages over existing 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 existing transducers.

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. publishedVersion

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.

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.

Background and purpose: Cancer is the leading cause of death in today’s world, therefore the efforts to achieve anticancer drugs with higher potency and fewer side effects have always been conducted by researchers in the field of pharmaceutical chemistry. Monastrol, a cytotoxic small molecule, from dihydropyrimidinone scaffold, is an inhibitor of the kinesin-5 protein. So, efforts to identify more derivatives of this molecule have been of interest. Experimental approach: Some of monastrol’s analogs as Eg5 inhibitors with different substitution patterns were analyzed, synthesized, and their cytotoxic effects were evaluated on MCF-7 and HeLa cancerous cells in vitro using the MTT assay. The structure-activity relationship (SAR) was studied in silico by molecular docking. Findings / Results: Among all proposed structures, in ducking study, those with hydrophobic moieties on the C2-N3 region, those with a hydroxyl group on the phenyl on C4 position, and those with a carboxylic group on C5 were the best candidates. In vitro studies, on the other side, emphasized that monastrol still was the most potent derivative. Another finding was the more moderate activity of synthesized compounds on the HeLa cell compared to the MCF-7 cell line. During different challenges for substitution at 5-position, some earlier reports around the dihydropyrimidinone reactions were questioned. It seems that the change at the position 5 is not merely accessible, as earlier reports claimed. Also, we could not achieve any better cell cytotoxicity by the larger group in the thiourea region or position 5; nonetheless, it seems that the introduction of a methylene group at this position could be beneficial. Conclusion and implications: The initial results of this study were valuable in terms of design and synthesis and will be useful for future investigations.

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.

Heparin is an indispensable drug in anticoagulation therapy but with a narrow therapeutic window, which dictates regular testing and dose adjustment. However, current monitoring tools have a long turnaround time or are operator intensive. In this work, we describe a cellulose-based photoacoustic sensor for heparin. The sensors have a turnaround time of 6 min for whole blood samples and 3 min for plasma samples regardless of heparin concentration. These sensors have a limit of detection of 0.28 U/ml heparin in human plasma and 0.29 U/ml in whole blood with a linear response (Pearson's r = 0.99) from 0 to 2 U/ml heparin in plasma and blood samples. The relative standard deviation was

As photoacoustic imaging (PAI) begins to mature and undergo clinical translation, there is a need for well-validated, standardized performance test methods to support device development, quality control, and regulatory evaluation. Despite recent progress, current PAI phantoms may not adequately replicate tissue light and sound transport over the full range of optical wavelengths and acoustic frequencies employed by reported PAI devices. Here we introduce polyacrylamide (PAA) hydrogel as a candidate material for fabricating stable phantoms with well-characterized optical and acoustic properties that are biologically relevant over a broad range of system design parameters. We evaluated suitability of PAA phantoms for conducting image quality assessment of three PAI systems with substantially different operating parameters including two commercial systems and a custom system. Imaging results indicated that appropriately tuned PAA phantoms are useful tools for assessing and comparing PAI system image quality. These phantoms may also facilitate future standardization of performance test methodology.

Simultaneous visualization of the teeth and periodontium is of significant clinical interest for image-based monitoring of periodontal health. We recently reported the application of a dual-modality photoacoustic-ultrasound (PA-US) imaging system for resolving periodontal anatomy and periodontal pocket depths in humans. This work utilized a linear array transducer attached to a stepper motor to generate 3D images via maximum intensity projection. This prior work also used a medical head immobilizer to reduce artifacts during volume rendering caused by motion from the subject (e.g., breathing, minor head movements). However, this solution does not completely eliminate motion artifacts while also complicating the imaging procedure and causing patient discomfort. To address this issue, we report the implementation of an image registration technique to correctly align B-mode PA-US images and generate artifact-free 2D cross-sections. Application of the deshaking technique to PA phantoms revealed 80% similarity to the ground truth when shaking was intentionally applied during stepper motor scans. Images from handheld sweeps could also be deshaken using an LED PA-US scanner. In ex vivo porcine mandibles, pigmentation of the enamel was well-estimated within 0.1 mm error. The pocket depth measured in a healthy human subject was also in good agreement with our prior study. This report demonstrates that a modality-independent registration technique can be applied to clinically relevant PA-US scans of the periodontium to reduce operator burden of skill and subject discomfort while showing potential for handheld clinical periodontal imaging.

Accurate and fast simulation of particle physics processes is crucial for the high-energy physics community. Simulating particle interactions with the detector is both time consuming and computationally expensive. With its proton-proton collision energy of 13 TeV, the Large Hadron Collider is uniquely positioned to detect and measure the rare phenomena that can shape our knowledge of new interactions. The High-Luminosity Large Hadron Collider (HLLHC) upgrade will put a significant strain on the computing infrastructure and budget due to increased event rate and levels of pile-up. Simulation of highenergy physics collisions needs to be significantly faster without sacrificing the physics accuracy. Machine learning approaches can offer faster solutions, while maintaining a high level of fidelity. We introduce a graph generative model that provides effiective reconstruction of LHC events on the level of calorimeter deposits and tracks, paving the way for full detector level fast simulation.

Dans le cadre de la mise en place d’une station météo intelligente connectée, nous avons abordé une approchescientifique: l’acquisition des données météorologiques se fait grâce à des capteurs spécifiques, de température, d’humidité,de pression, de vitesse de vent...etc. Les données récupérées sont traitées par une unité de traitement à base de trois cartesArduino (UNO - ESP8266 Wemos mini D1). Cette unité assemblée sur un boîtier adapté, elle permet de transférer lesdifférentes mesures vers notre base de données et serveur web, qui sont reliés directement à nos applications (WEB,MOBILE).Pour consultation des mesures météorologiques à distance et à temps réel, le client communique avec l’application web viale lien “HTTP://ESISBAMETEO.DDNS.NET” ainsi que l’application mobile (Android) disponible sur le play store

Wi-Fi connectivity, a necessity in this digital era, requires careful infrastructure planning and tuning during installation. In this paper, we propose “Aparecium Wi-Fi Planner”, an open-source and cross-platform, Wi-Fi planning software tool based on an enhanced empirical path loss model. The proposed “Enhanced Solah's model” delivers more accurate results than existing models. And hence, “Aparecium Wi-Fi Planner” accurately estimates path loss attenuation, absorption attenuation by obstacles and fading effect. Moreover, the tool integrates the design and development of several algorithms to find full-coverage and optimal access point location with reduced complexity. Aparecium has been thoroughly tested and validated using both simulation and real testbed scenarios.

Background and Aims Patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD) experience various symptoms due to increasing kidney volume and its associated complications. To understand symptom burden, qualitative interviews were conducted to characterize the ADPKD patient experience pertaining to the most common and disturbing symptoms. Method Combined concept elicitation and cognitive debriefing interviews were performed by trained interviewers following a preliminary conceptual model based on a targeted literature review. We currently report on the concept elicitation component, which explored relevant and bothersome symptoms in ADPKD patients, due to either the disease or associated treatments. Nineteen telephone interviews were conducted in four waves of 5, 4, 6, and 4 patients, respectively. Results The mean age of patients was 47 years (SD: 9 years); 68% (n=13) were female, and the mean estimated glomerular filtration rate (eGFR) was 41 ml/min/1.73m2 (SD: 25 ml/min/1.73m2), with the majority 47% (n=9) in stage 3 chronic kidney disease (CKD). The classes of treatments included antihypertensives (74%, n=14), vasopressin receptor antagonists (21%, n=4); diuretics (16%, n=3), analgesics (16%, n=3) and erythropoietin (5%, n=1). The most frequently mentioned symptoms were fatigue (89%, n=17), pain (84%, n=16), and nocturia (74%, n=14); all were considered at least moderately disturbing to patients’ lives. Most patients experienced constant fatigue (74%, n=14) that worsened over time. Patients’ descriptions of pain were variable, including back and side pain, severe cystic pain, and muscle pain; a few patients also mentioned shoulder pain, or pain due to kidney stones. Among patients reporting nocturia (n=14), about half (57%, n=8) rated nocturia on the upper end of the disturbance scale, regardless of number of voids per night, often accompanied by sleep disruption. While less frequently occurring, itchy skin, muscle cramping, abdominal swelling, and inability to eat were spontaneously mentioned among the most disturbing symptoms. Conclusion The novel component of this study is the significant disruption of nocturia in patients with ADPKD even in the absence of vasopressin receptor antagonist administration. In addition, it confirms the findings of the literature review and highlights the patient experience in ADPKD, most notably fatigue, nocturia, and pain as the most frequent and bothersome symptoms experienced by patients. Subjective evaluation of the ADPKD patient experience is critical to understand symptom severity and the burden of disease, to potentially quantify disease progression, and to assess the impact of emerging therapies.

Accumulation of reactive oxygen and nitrogen species (RONS) can induce cell damage and even cell death. RONS are short-lived species, which makes direct, precise, and real-time measurement difficult. Biologically-relevant RONS levels are in the nM-µM scale; hence, there is a need for highly sensitive RONS probes. We previously used hybrid gold-core silver-shell nanoparticles with mM sensitivity to H(2)O(2). These particles reported the presence of RONS via spectral shifts which could easily be quantified via photoacoustic imaging. Here, we used halide doping to tune the electrochemical properties of these materials to better match the oxidation potential of RONS. This work describes the synthesis, characterization, and application of these AgI-coated gold nanorods (AgI/AuNR). The I:Ag molar ratio, pH, and initial Ag shell thickness were optimized for good RONS detection limits. Halide doping lowers the reduction potential of Ag from E(0)(Ag) = 0.80 V to E(0)(AgI) = − 0.15 V resulting in a 1000-fold increase in H(2)O(2) and 100,000-fold increase in ONOO(−) sensitivity. The AgI/AuNR system also etches 45-times faster than undoped Ag/AuNR. The AgI/AuNR easily reported the endogenously produced RONS in established cells lines as well as murine models.

Low fluence illumination sources can facilitate clinical transition of photoacoustic imaging because they are rugged, portable, affordable, and safe. However, these sources also decrease image quality due to their low fluence. Here, we propose a denoising method using a multi-level wavelet-convolutional neural network to map low fluence illumination source images to its corresponding high fluence excitation map. Quantitative and qualitative results show a significant potential to remove the background noise and preserve the structures of target. Substantial improvements up to 2.20, 2.25, and 4.3-fold for PSNR, SSIM, and CNR metrics were observed, respectively. We also observed enhanced contrast (up to 1.76-fold) in an in vivo application using our proposed methods. We suggest that this tool can improve the value of such sources in photoacoustic imaging., Comment: submitted to Biomedical Optics Express journal

Efforts have been made to improve the security of the Internet of Things (IoT) devices, but there remain some vulnerabilities and misimplementations. This paper describes a new threat to home security devices in which an attacker can disable all functionality of a device, but to the device’s owner, everything still appears to be operational. We targeted home security devices because their security is critical as people may rely on them to protect their homes. In particular, we exploited a feature called “heartbeat”, which is exchanged between the devices and the cloud in order to check that the devices are still connected. Even though network traffic was encrypted, we successfully identified the heartbeats due to their fixed size and periodic nature. Thereafter, we established a man-in-the-middle attack between the device and the cloud and selectively forwarded heartbeats while filtering out other traffic. As a result, the device appears to be still connected (because the heartbeat traffic is being allowed through), while in reality the device’s functionality is disabled (because non-heartbeat traffic is being filtered out). We applied this exploit on a set of six devices, and five were found to be vulnerable. Consequently, an intruder can use this exploit to disable a home security device and break into a house without the awareness of the owner. We carried out a responsible disclosure exercise with the manufacturers of the affected devices, but the response has been limited. This shows that IoT security is still not taken completely seriously and many threats are still undiscovered. Finally, we provide some recommendations on how to detect and prevent the threats posed by insecure IoT devices, which ironically include IoT home security kits.

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.

In this paper, we show that gadolinium-loaded synthetic melanin nanoparticles (Gd(III)-SMNPs) exhibit up to a 40-fold enhanced photoacoustic signal intensity relative to synthetic melanin alone and higher than other metal-chelated SMNPs. This property makes these materials useful as dual labeling agents because Gd(III)-SMNPs also behave as magnetic resonance imaging (MRI) contrast agents. As a proof-of-concept, we used these nanoparticles to label human mesenchymal stem cells. Cellular uptake was confirmed with bright-field optical and transmission electron microscopy. The Gd(III)-SMNP-labeled stem cells continued to express the stem cell surface markers CD73, CD90, and CD105 and proliferate. The labeled stem cells were subsequently injected intramyocardially in mice, and the tissue was observed by photoacoustic and MR imaging. We found that the photoacoustic signal increased as the cell number increased (R(2) = 0.96), indicating that such an approach could be employed to discriminate between stem cell populations with a limit of detection of 2.3 × 10(4) cells in in vitro tests. This multimodal photoacoustic/MRI approach combines the excellent temporal resolution of photoacoustics with the anatomic resolution of MRI.

Light-emitting diode-based photoacoustic imaging is more compact and affordable than laser-based systems, but it has low power and hence a high number of replicates. Here, we describe double-stage delay-multiply-and-sum (DS-DMAS) to improve image quality collected on a LED-based scanner. DS-DMAS was evaluated experimentally using point targets (in different laterals and depths) as well as a hair and a rabbit eye. This algorithm can compensate for the low SNR of LED-based systems and offer better lateral resolution of about 60%, 25%, higher contrast ratio of about 97%, 34%, and better full-width-half-maximum of about 60%, 25%, versus delay-and-sum) and delay-multiply-and-sum, respectively. More importantly, DS-DMAS offers this using a smaller number of frames (only 2% of all the frames). These results indicate that DS-DMAS might be a valuable tool in the translation of LED-based and other low power PAI systems. Keywords: Photoacoustic imaging, Linear-array tomography, LED-based systems, Contrast improvement, SNR enhancement

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.