VEGF-C and 5-Fluorouracil Improve Bleb Survival in a Rabbit Glaucoma Surgery Trabeculectomy Model.

Purpose: To evaluate VEGF-C-induced lymphoproliferation in conjunction with 5-fluorouracil (5-FU) antimetabolite treatment in a rabbit glaucoma filtration surgery (GFS) model. Methods: Thirty-two rabbits underwent GFS and were assigned to four groups (n = 8 each) defined by subconjunctival drug treatment: (a) VEGF-C combined with 5-FU, (b) 5-FU, (c) VEGF-C, (d) and control. Bleb survival, bleb measurements, and IOP were evaluated over 30 days. At the end, histology and anterior segment OCT were performed on some eyes. mRNA was isolated from the remaining eyes for RT-PCR evaluation of vessel-specific markers (lymphatics, podoplanin and LYVE-1; and blood vessels, CD31). Results: Qualitatively and quantitatively, VEGF-C combined with 5-FU resulted in blebs which were posteriorly longer and wider than the other conditions: vs. 5-FU (P = 0.043 for longer, P = 0.046 for wider), vs. VEGF-C (P < 0.001, P < 0.001) and vs. control (P < 0.001, P < 0.001). After 30 days, the VEGF-C combined with 5-FU condition resulted in longer bleb survival compared with 5-FU (P = 0.025), VEGF-C (P < 0.001), and control (P < 0.001). Only the VEGF-C combined with 5-FU condition showed a negative correlation between IOP and time that was statistically significant (r = -0.533; P = 0.034). Anterior segment OCT and histology demonstrated larger blebs for the VEGF-C combined with 5-FU condition. Only conditions including VEGF-C led to increased expression of lymphatic markers (LYVE-1, P < 0.001-0.008 and podoplanin, P = 0.002-0.011). Expression of CD31 was not different between the groups (P = 0.978). Conclusions: Adding VEGF-C lymphoproliferation to standard antimetabolite treatment improved rabbit GFS success and may suggest a future strategy to improve human GFSs.

Risk of Kidney Failure in Patients With Inflammatory Bowel Disease Undergoing Colectomy: A Nationwide Cohort Study.

BACKGROUND & AIMS: Inflammatory bowel disease (IBD) is frequently accompanied by kidney complications. Potential triggers or subpopulations at high-risk of kidney problems are not well-elucidated. We hypothesized that surgical interventions, specifically colectomy, might in part explain this risk. METHODS: This study was a nationwide Swedish cohort study comprising 82,051 individuals with biopsy-proven IBD diagnosed during 1965 to 2017, with follow-up until 2019. We investigated the association between incident colectomy (time-varying exposure) and future risk of acute kidney injury (AKI) and kidney failure (diagnosis of end-stage kidney disease or death due to chronic kidney disease) using Cox proportional hazard models. We also examined the impact of partial vs total colectomy and the presence/duration of a stoma. Covariates included demographics, education level, and selected comorbidities. RESULTS: Over a median follow-up of 14 years, 16,479 individuals underwent colectomy, and 2556 AKI and 1146 kidney failure events occurred. Colectomy was associated with an increased relative risk of both AKI (adjusted hazard ratio, 2.37; 95% confidence interval, 2.17-2.58) and kidney failure (adjusted hazard ratio, 1.54; 95% confidence interval, 1.34-1.76). Compared with pre-colectomy periods, undergoing total colectomy and colectomy with prolonged stoma showed higher risks of both kidney outcomes versus partial colectomy or colectomy with a temporary stoma, respectively. Subgroup analyses suggested higher risks in patients with ulcerative colitis. CONCLUSIONS: In people with IBD, rates of AKI and kidney failure are higher among those undergoing colectomy, particularly among those following total colectomy, or colectomy with a prolonged stoma. This study identifies a high-risk population that may benefit from established protocols for kidney function monitoring/surveillance and referral to nephrologist care.

An increase in albuminuria is associated with a higher incidence of malignancies.

Background: A single albuminuria measurement is reported to be an independent predictor of cancer risk. Whether change in albuminuria is also independently associated with cancer is not known. Methods: We included 64 303 subjects of the Stockholm CREAtinine Measurements (SCREAM) project without a history of cancer and with at least two urine albumin-creatinine ratio (ACR) tests up to 2 years apart. Albuminuria changes were quantified by the fold-change in ACR over 2 years, and stratified into the absence of clinically elevated albuminuria (i.e. never), albuminuria that remained constant, and albuminuria that increased or decreased. The primary outcome was overall cancer incidence. Secondary outcomes were site-specific cancer incidences. Results: During a median follow-up of 3.7 (interquartile range 3.6-3.7) years, 5126 subjects developed de novo cancer. After multivariable adjustment including baseline estimated glomerular filtration rate and baseline ACR, subjects with increasing ACR over 2 years had a 19% (hazard ratio 1.19; 95% confidence interval 1.08-1.31) higher risk of overall cancer compared with those who never had clinically elevated ACR. No association with cancer risk was seen in the groups with decreasing or constant ACR. Regarding site-specific cancer risks, subjects with increasing ACR or constant ACR had a higher risk of developing urinary tract and lung cancer. No other associations between 2-year ACR changes and site-specific cancers were found. Conclusions: Increases in albuminuria over a 2-year period are associated with a higher risk of developing overall, urinary tract and lung cancer, independent of baseline kidney function and albuminuria. These data add important weight to the link that exists between albuminuria and cancer incidence.

Bio-inspired facile strategy for programmable osmosis-driven shape-morphing elastomer composite structures.

Achieving programmable and reversible deformations of soft materials is a long-standing goal for various applications in soft robotics, flexible electronics and many other fields. Swelling-induced shape morphing has been intensively studied as one of the potential mechanisms. However, achieving an extremely large swelling ratio (>1000% in volume) remains challenging with existing swellable soft materials (e.g., hydrogels and water-swellable rubbers). Inspired by the shape change enabled by the osmosis-driven swelling in living organisms, herein, we report a polymer composite system composed of fine sodium chloride (NaCl) particles embedded in Ecoflex00-10 polymer. This Ecoflex00-10/NaCl polymer composite can achieve controllable volumetric swelling up to 3000% while maintaining a relatively high elastic stiffness. We demonstrate that this swellable polymer composite can serve as an active component to drive the shape morphing of various structures. By controlling the geometric design and the fraction of the NaCl particle, morphing structures capable of deforming sequentially are created. Finally, by encapsulating 3D printed polymer composite patterns using water-permeable PDMS membrane, a programmable braille with visual and tactile regulation is demonstrated for the purpose of information encryption. Our study provides a facile approach to generate customizable shape-morphing structures, aiming to broaden the range of techniques and applications for morphing devices.

Absolute and Relative Risks of Kidney and Urological Complications in Patients With Inflammatory Bowel Disease.

INTRODUCTION: The burden of kidney and urological complications in patients with inflammatory bowel disease (IBD) remains poorly characterized. METHODS: We analyzed association between developing IBD (as a time-varying exposure) and relative risks of receiving diagnoses of chronic kidney disease (CKD), acute kidney injury (AKI), or kidney stones, and experiencing a clinically-relevant decline in estimated glomerular filtration rate (eGFR) (CKD progression; composite of kidney failure or an eGFR decline ≥30%) in 1,682,795 individuals seeking healthcare in Stockholm, Sweden, during 2006-2018. We quantified 5- and 10-year absolute risks of these complications in a parallel matched cohort of IBD cases and random controls matched (1:5) on sex, age, and eGFR. RESULTS: During median 9 years, 10,117 participants developed IBD. Incident IBD was associated with higher risks of kidney-related complications compared with non-IBD periods: hazard ratio (HR) (95% confidence interval) was 1.24 (1.10-1.40) for receiving a CKD diagnosis and 1.11 (1.00-1.24) for CKD progression. For absolute risks, 11.8% IBD cases had a CKD event within 10-year. Of these, 6.4% received a CKD diagnosis, and 7.9% reached CKD progression. The risks of AKI (HR 1.97 [1.70-2.29]; 10-year absolute risk 3.6%) and kidney stones (HR 1.69 [1.48-1.93]; 10-year absolute risk 5.6%) were also elevated. Risks were similar in Crohn's disease and ulcerative colitis. DISCUSSION: More than 10% of patients with IBD developed CKD within 10-year from diagnosis, with many not being identified through diagnostic codes. This, together with their elevated AKI and kidney stone risks, highlights the need of established protocols for kidney function monitoring and referral to nephrological/urological care for patients with IBD.

Albuminuria and the risk of cancer: the Stockholm CREAtinine Measurements (SCREAM) project.

Background: Studies investigating the association of chronic kidney disease and cancer have focused on estimated glomerular filtration (eGFR) rather than on albuminuria. This study aimed to examine whether albuminuria is associated with cancer incidence, and whether this association is independent of eGFR. Methods: We included subjects of the Stockholm Creatinine Measurements (SCREAM) project without a history of cancer-250 768 subjects with at least one urine albumin-creatinine ratio (ACR) test (primary cohort) and 433 850 subjects with at least one dipstick albuminuria test (secondary cohort). Albuminuria was quantified as KDIGO albuminuria stages. The primary outcome was overall cancer incidence. Secondary outcomes were site-specific cancer incidence rates. Multivariable Cox proportional hazards regression models adjusted for confounders including eGFR to calculate hazard ratios and 95% confidence intervals (HRs, 95% CIs). Results: During a median follow-up of 4.3 (interquartile range 2.0-8.2) years, 21 901 subjects of the ACR cohort developed de novo cancer. In multivariable analyses, adjusting among others for eGFR, subjects with an ACR of 30-299 mg/g or ≥300 mg/g had a 23% (HR 1.23; 95% CI 1.19-1.28) and 40% (HR 1.40; 95% CI 1.31-1.50) higher risk of developing cancer, respectively, when compared with subjects with an ACR <30 mg/g. This graded, independent association was also observed for urinary tract, gastrointestinal tract, lung and hematological cancer incidence (all P < .05). Results were similar in the dipstick albuminuria cohort. Conclusions: Albuminuria was associated with the risk of cancer independent of eGFR. This association was primarily driven by a higher risk of urinary tract, gastrointestinal tract, lung and hematological cancers.

Association Between Circulating Zinc Levels and Risk Factors of Metabolic Syndrome: Insights from a Bi-directional Mendelian Randomization Analysis and Cross-Sectional Study.

Previous studies on the relationship between zinc and metabolic syndrome (MetS) have yielded inconsistent results. This comprehensive study aimed to elaborately explore the impact of zinc on MetS risk factors. The bi-directional Mendelian randomization (MR) analyses were performed to estimate the causal relationship between zinc and MetS risk factors. Additionally, a retrospective cross-sectional study incorporated 4389 subjects to provide a broader perspective in conjunction with the MR analyses. In the MR analyses, genetically instrumented zinc was positively associated with five of the MetS components in Europeans, including BMI, FBG, HbA1c, TC, and LDL-c (ß (95%CI) = 0.023 (0.019-0.027), 0.019 (0.013-0.025), 0.041 (0.022-0.060), 0.027 (0.013-0.042), and 0.018 (0.010-0.026), respectively). In the cross-sectional study, higher concentration of zinc was strongly associated with increased BMI, LDL-c, and UA (ß (95%CI) = 0.040 (0.010-0.085), 0.026 (0.018-0.035), and 1.529 (0.614-2.445), respectively). Moreover, these unfavorable associations were more obvious in women compared to men, with a borderline significant interaction effect for BMI (P=0.051). Our study showed that higher blood concentration of zinc, an essential trace element, was associated with unfavorable changes of the component metabolic risk factors of MetS, especially with BMI and LDL-c. Notably, these associations seemed to be more pronounced in women rather than in men. Further studies are warranted to elucidate the role of zinc status in the underlying mechanisms of MetS.

Antibiotic and Heavy Metal Co-Resistant Strain Isolated from Enrichment Culture of Marine Sediments, with Potential for Environmental Bioremediation Applications.

Antibiotics and heavy metals have caused serious contamination of the environment and even resulted in public health concerns. It has therefore become even more urgent to adopt a sustainable approach to combating these polluted environments. In this paper, we investigated the microbial community of marine sediment samples after 255 days of enrichment culture under Cu (II) and lincomycin stress and ZC255 was the most resistant strain obtained. The 16S rRNA gene sequence confirmed that it belonged to the genus Rossellomorea. Strain ZC255 was resistant to 12 kinds of antibiotics, and had a superior tolerance to Cu (II), Pb (II), Ni (II), Zn (II), Cr (III), and Cd (II). Moreover, it exhibits strong bioremoval ability of Cu and lincomycin. The removal efficiency of Cu (II) and lincomycin can achieve 651 mg/g biomass and 32.5 mg/g biomass, respectively. Strain ZC255 was a promising isolate for pollution bioremediation applications.

Psoriasis/Psoriatic Arthritis Patients' Long-term Treatment Patterns and Adherence to Systemic Treatments Monitoring Recommendations.

Limited information exists regarding treatment of patients with psoriasis/psoriatic arthritis in primary care. The aim of this study is to assess treatment patterns, adherence, persistence, and compliance in newly diagnosed patients with psoriasis/psoriatic arthritis from 2012 to 2018 in Stockholm, Sweden. In addition, laboratory monitoring before initiation of treatment and at recommended intervals was quantified for patients prescribed methotrexate or biologics. A total of 51,639 individuals were included, with 39% initiating treatment with topical corticosteroids and < 5% receiving systemic treatment within 6 months post-diagnosis. During a median (interquartile range) follow-up of 7 (4-8) years, 18% of patients received systemic treatments at some point. Overall, 5-year persistence rates were 32%, 45% and 19% for methotrexate, biologics, and other systemic treatments, respectively. Pre-initiation laboratory tests, as recommended by guidelines, were performed in approximately 70% and 62% of methotrexate and biologics users, respectively. Follow-up monitoring at recommended time intervals occurred in 14-20% and 31-33% of patients prescribed methotrexate and biologics, respectively. These findings highlight gaps in the pharmacological care of patients with psoriasis/psoriatic arthritis, including suboptimal adherence/persistence and inadequate laboratory monitoring.

Estimated Glomerular Filtration Rate and the Risk of Inflammatory Bowel Disease in Adults: A Swedish Population-Based Study.

BACKGROUND: Kidney complications are common in patients with long-standing inflammatory bowel disease (IBD). Whether kidney complications, defined as low estimated glomerular filtration rate (eGFR), may predispose to later IBD is unknown. METHODS: We analyzed the association between eGFR and the risk of being subsequently diagnosed with IBD among 1 612 160 adults from Stockholm. The exposure was categories of eGFR, with 90 to 104 mL/min/1.73 m2 as the reference. Cox regression models were used to investigate the association between eGFR, IBD, and IBD subtypes. Subgroup analyses included age strata, sex, education, and comorbidities. To explore the possibility of detection bias or reverse causation, we estimated IBD hazard ratios (HRs) after excluding cases and individuals censored during early years of follow-up. RESULTS: During a median of 9 years of follow-up, we detected 9663 cases of IBD (3299 Crohn's disease, 5072 ulcerative colitis, 1292 IBD unclassified). Lower eGFR levels were associated with higher IBD risk (for eGFR 30-59 mL/min/1.73 m2: adjusted HR, 1.15; 95% confidence interval [CI], 1.01-1.33; and for eGFR <30 mL/min/1.73 m2: adjusted HR, 1.65; 95% CI, 1.16-2.37). This association was stronger in magnitude for Crohn's disease (for eGFR 30-59 mL/min/1.73 m2: HR, 1.33, 95% CI, 1.04-1.72; and for eGFR <30 mL/min/1.73 m2: HR, 2.25; 95% CI, 1.26-3.99). Results were consistent across strata of age, comorbidities, and attained education but suggested the association between eGFR and IBD to be stronger in women (P for interaction <.05). Results attenuated but were robust to exclusion of early IBD cases. CONCLUSIONS: We observed an association between reduced eGFR and the risk of developing IBD, which was stronger in magnitude for Crohn's disease.

Inference of pan-cancer related genes by orthologs matching based on enhanced LSTM model.

Many disease-related genes have been found to be associated with cancer diagnosis, which is useful for understanding the pathophysiology of cancer, generating targeted drugs, and developing new diagnostic and treatment techniques. With the development of the pan-cancer project and the ongoing expansion of sequencing technology, many scientists are focusing on mining common genes from The Cancer Genome Atlas (TCGA) across various cancer types. In this study, we attempted to infer pan-cancer associated genes by examining the microbial model organism Saccharomyces Cerevisiae (Yeast) by homology matching, which was motivated by the benefits of reverse genetics. First, a background network of protein-protein interactions and a pathogenic gene set involving several cancer types in humans and yeast were created. The homology between the human gene and yeast gene was then discovered by homology matching, and its interaction sub-network was obtained. This was undertaken following the principle that the homologous genes of the common ancestor may have similarities in expression. Then, using bidirectional long short-term memory (BiLSTM) in combination with adaptive integration of heterogeneous information, we further explored the topological characteristics of the yeast protein interaction network and presented a node representation score to evaluate the node ability in graphs. Finally, homologous mapping for human genes matched the important genes identified by ensemble classifiers for yeast, which may be thought of as genes connected to all types of cancer. One way to assess the performance of the BiLSTM model is through experiments on the database. On the other hand, enrichment analysis, survival analysis, and other outcomes can be used to confirm the biological importance of the prediction results. You may access the whole experimental protocols and programs at https://github.com/zhuyuan-cug/AI-BiLSTM/tree/master.

Research on a Defecation Pre-Warning Algorithm for the Disabled Elderly Based on a Semi-Supervised Generative Adversarial Network.

The elderly population in China is continuously increasing, and the disabled account for a large proportion of the elderly population. An effective solution is urgently needed for incontinence among disabled elderly people. Compared with disposable adult diapers, artificial sphincter implantation and medication for incontinence, the defecation pre-warning method is more flexible and convenient. However, due to the complex human physiology and individual differences, its development is limited. Based on the aging trend of the population and clinical needs, this paper proposes a bowel sound acquisition system and a defecation pre-warning method and system based on a semi-supervised generative adversarial network. A network model was established to predict defecation using bowel sounds. The experimental results show that the proposed method can effectively classify bowel sounds with or without defecation tendency, and the accuracy reached 94.4%.

Advances in constructing silver nanowire-based conductive pathways for flexible and stretchable electronics.

With their soaring technological demand, flexible and stretchable electronics have attracted many researchers' attention for a variety of applications. The challenge which was identified a decade ago and still remains, however, is that the conventional electrodes based on indium tin oxide (ITO) are not suitable for ultra-flexible electronic devices. The main reason is that ITO is brittle and expensive, limiting device performance and application. Thus, it is crucial to develop new materials and processes to construct flexible and stretchable electrodes with superior quality for next-generation soft devices. Herein, various types of conductive nanomaterials as candidates for flexible and stretchable electrodes are briefly reviewed. Among them, silver nanowire (AgNW) is selected as the focus of this review, on account of its excellent conductivity, superior flexibility, high technological maturity, and significant presence in the research community. To fabricate a reliable AgNW-based conductive network for electrodes, different processing technologies are introduced, and the corresponding characteristics are compared and discussed. Furthermore, this review summarizes strategies and the latest progress in enhancing the conductive pathway. Finally, we showcase some exemplary applications and provide some perspectives about the remaining technical challenges for future research.

Sex Differences in the Recognition, Monitoring, and Management of CKD in Health Care: An Observational Cohort Study.

INTRODUCTION: Reported sex differences in the etiology, population prevalence, progression rates, and health outcomes of people with CKD may be explained by differences in health care. METHODS: We evaluated sex as the variable of interest in a health care-based study of adults (n=227,847) with at least one outpatient eGFR<60 ml/min per 1.73 m2 measurement denoting probable CKD in Stockholm from 2009 to 2017. We calculated the odds ratios for diagnosis of CKD and provision of RASi and statins at inclusion, and hazard ratios for CKD diagnosis, visiting a nephrologist, or monitoring creatinine and albuminuria during follow-up. RESULTS: We identified 227,847 subjects, of whom 126,289 were women (55%). At inclusion, women had lower odds of having received a diagnostic code for CKD and were less likely to have received RASi and statins, despite having guideline-recommended indications. In time-to-event analyses, women were less likely to have received a CKD diagnosis (HR, 0.43; 95% CI, 0.42 to 0.45) and visited a nephrologist (HR, 0.46; 95% CI, 0.43 to 0.48) regardless of disease severity, presence of albuminuria, or criteria for referral. Women were also less likely to undergo monitoring of creatinine or albuminuria, including those with diabetes or hypertension. These differences remained after adjustment for comorbidities, albuminuria, and highest educational achievement, and among subjects with confirmed CKD at retesting. Although in absolute terms all nephrology-care indicators gradually improved over time, the observed sex gap persisted. CONCLUSIONS: There were profound sex differences in the detection, recognition, monitoring, referrals, and management of CKD. The disparity was also observed in people at high risk and among those who had guideline-recommended indications. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/JASN/2022_10_11_JASN2022030373.mp3.

Discovery of pan-cancer related genes via integrative network analysis.

Identification of cancer-related genes is helpful for understanding the pathogenesis of cancer, developing targeted drugs and creating new diagnostic and therapeutic methods. Considering the complexity of the biological laboratory methods, many network-based methods have been proposed to identify cancer-related genes at the global perspective with the increasing availability of high-throughput data. Some studies have focused on the tissue-specific cancer networks. However, cancers from different tissues may share common features, and those methods may ignore the differences and similarities across cancers during the establishment of modeling. In this work, in order to make full use of global information of the network, we first establish the pan-cancer network via differential network algorithm, which not only contains heterogeneous data across multiple cancer types but also contains heterogeneous data between tumor samples and normal samples. Second, the node representation vectors are learned by network embedding. In contrast to ranking analysis-based methods, with the help of integrative network analysis, we transform the cancer-related gene identification problem into a binary classification problem. The final results are obtained via ensemble classification. We further applied these methods to the most commonly used gene expression data involving six tissue-specific cancer types. As a result, an integrative pan-cancer network and several biologically meaningful results were obtained. As examples, nine genes were ultimately identified as potential pan-cancer-related genes. Most of these genes have been reported in published studies, thus showing our method's potential for application in identifying driver gene candidates for further biological experimental verification.

Features Constituting Actionable COVID-19 Dashboards: Descriptive Assessment and Expert Appraisal of 158 Public Web-Based COVID-19 Dashboards.

BACKGROUND: Since the outbreak of COVID-19, the development of dashboards as dynamic, visual tools for communicating COVID-19 data has surged worldwide. Dashboards can inform decision-making and support behavior change. To do so, they must be actionable. The features that constitute an actionable dashboard in the context of the COVID-19 pandemic have not been rigorously assessed. OBJECTIVE: The aim of this study is to explore the characteristics of public web-based COVID-19 dashboards by assessing their purpose and users ("why"), content and data ("what"), and analyses and displays ("how" they communicate COVID-19 data), and ultimately to appraise the common features of highly actionable dashboards. METHODS: We conducted a descriptive assessment and scoring using nominal group technique with an international panel of experts (n=17) on a global sample of COVID-19 dashboards in July 2020. The sequence of steps included multimethod sampling of dashboards; development and piloting of an assessment tool; data extraction and an initial round of actionability scoring; a workshop based on a preliminary analysis of the results; and reconsideration of actionability scores followed by joint determination of common features of highly actionable dashboards. We used descriptive statistics and thematic analysis to explore the findings by research question. RESULTS: A total of 158 dashboards from 53 countries were assessed. Dashboards were predominately developed by government authorities (100/158, 63.0%) and were national (93/158, 58.9%) in scope. We found that only 20 of the 158 dashboards (12.7%) stated both their primary purpose and intended audience. Nearly all dashboards reported epidemiological indicators (155/158, 98.1%), followed by health system management indicators (85/158, 53.8%), whereas indicators on social and economic impact and behavioral insights were the least reported (7/158, 4.4% and 2/158, 1.3%, respectively). Approximately a quarter of the dashboards (39/158, 24.7%) did not report their data sources. The dashboards predominately reported time trends and disaggregated data by two geographic levels and by age and sex. The dashboards used an average of 2.2 types of displays (SD 0.86); these were mostly graphs and maps, followed by tables. To support data interpretation, color-coding was common (93/158, 89.4%), although only one-fifth of the dashboards (31/158, 19.6%) included text explaining the quality and meaning of the data. In total, 20/158 dashboards (12.7%) were appraised as highly actionable, and seven common features were identified between them. Actionable COVID-19 dashboards (1) know their audience and information needs; (2) manage the type, volume, and flow of displayed information; (3) report data sources and methods clearly; (4) link time trends to policy decisions; (5) provide data that are "close to home"; (6) break down the population into relevant subgroups; and (7) use storytelling and visual cues. CONCLUSIONS: COVID-19 dashboards are diverse in the why, what, and how by which they communicate insights on the pandemic and support data-driven decision-making. To leverage their full potential, dashboard developers should consider adopting the seven actionability features identified.

3D Printing of Antibacterial Polymer Devices Based on Nitric Oxide Release from Embedded S-Nitrosothiol Crystals.

Controlled release of drugs from medical implants is an effective approach to reducing foreign body reactions and infections. We report here on a one-step 3D printing strategy to create drug-eluting polymer devices with a drug-loaded bulk and a drug-free coating. The spontaneously formed drug-free coating dramatically reduces the surface roughness of the implantable devices and serves as a protective layer to suppress the burst release of drugs. A high viscosity liquid silicone that can be extruded based on its shear-thinning property and quickly vulcanize upon exposure to ambient moisture is used as the ink for 3D printing. S-Nitrosothiol type nitric oxide (NO) donors in their crystalline forms are selected as model drugs because of the potent antimicrobial, antithrombotic, and anti-inflammatory properties of NO. Direct ink writing of the homogenized polymer-drug mixtures generates rough and ill-defined device surfaces because of the exposed S-nitrosothiol microparticles. When a low-viscosity silicone (polydimethylsiloxane) is added into the ink, this silicone diffuses outward upon deposition to form a drug-free outermost layer without compromising the integrity of the printed structures. S-Nitrosoglutathione (GSNO) or S-nitroso-N-acetylpenicillamine (SNAP) embedded in the printed silicone matrix releases NO under physiological conditions from days to about one month. The microsized drug crystals are well-preserved in the ink preparation and printing processes, which is one reason for the sustained NO release. Biofilm and cytotoxicity experiments confirmed the antibacterial property and safety of the printed NO-releasing devices. This additive manufacturing platform does not require dissolution of drugs and involves no thermal or UV processes and, therefore, offers unique opportunities to produce drug-eluting silicone devices in a customized manner.

Simultaneous determination of naproxen and esomeprazole in beagle dog plasma by supercritical fluid chromatography-tandem mass spectrometry coupled with evaporation-free liquid-liquid extraction.

In order to avoid a risk of gastrointestinal toxic caused by naproxen (NAP), esomeprazole (ESOM) is generally used clinically in combination. The present work was undertaken to simultaneously determine NAP and ESOM in beagle dog plasma, and evaluated their pharmacokinetic behaviors in beagle dogs. Herein, ethyl acetate was used to extract the samples by using a time-saving evaporation-free liquid-liquid extraction (EF-LLE) method, then the samples were analyzed by supercritical fluid chromatography tandem mass spectrometry (SFC-MS/MS). The optimal analysis conditions were achieved with an ACQUITY UPC2™ BEH column maintained at 50℃ and eluted completely within 2 min using supercritical carbon dioxide and methanol with a gradient elution mode. Due to the large differences in plasma concentrations between NAP and ESOM, celecoxib and diazepam were selected as dual-internal standards (IS). The mass transition ion pairs were m/z 231.2 → 185.0, 346.9 → 198.2, 285.1 → 193.1 and 382.2 → 281.2 for NAP, ESOM, diazepam (IS for NAP) and celecoxib (IS for ESOM), respectively. The concentration of NAP and ESOM were linear within the range of 0.1-100 µg/mL (r > 0.993) and 0.005-5 µg/mL (r > 0.996) in beagle dog plasma, and the accuracy and precision of intra-day and inter-day of all quality control samples were within ±15 %. It was a method with the feature of rapid, sensitive and high-throughput, and would be practical for determining NAP and ESOM in biological samples simultaneously and for assessing their pharmacokinetic behaviors in clinical studies.

Justification of Biowaiver and Dissolution Rate Specifications for Piroxicam Immediate Release Products Based on Physiologically Based Pharmacokinetic Modeling: An In-Depth Analysis.

A quantitative prediction of human pharmacokinetic (PK) profiles has become an increasing demand for the reduction of the clinical failure of drug formulations. The existing in vitro and in vivo correlation (IVIVC) methodology could achieve this goal, but the development of IVIVC for immediate release (IR) products is challenging. Herein, we report that for certain weakly acidic biopharmaceutical classification system (BCS) class II molecules (piroxicam, PIRO), physiologically based PK (PBPK) modeling could be used as a tool to quantitatively predict PK in beagle dogs and to conduct an interspecies extrapolation to humans. First, robust PBPK models were constructed in beagle dogs under both fasted and fed states. Then, a Z-factor model was integrated to assess the effect of in vitro dissolution rates on the in vivo PK performance, and the results illustrated that PIRO IR products had a much wider dissolution space than was anticipated by bioequivalence. In addition, the parameter sensitivity analysis (PSA) assay showed that good oral absorption was achieved only when the particle size was below 150 µm. Finally, the combined PBPK models were extrapolated to humans to specify a quality control strategy; this extrapolation constituted an extension of a biowaiver for PIRO IR formulations. The results showed that the developed method can be utilized to quantitatively predict human PK, which would be meaningful for future scale-up or postapproval changes.