Search

Novel research in the field of bioelectronic medicine requires neuromodulation systems that pair high-performance neurostimulation and bio-signal acquisition hardware with advanced signal processing and control algorithms. Although mice are the most commonly used animal in medical research, the size, weight, and power requirements of such bioelectronic systems either preclude use in mice or impose significant constraints on experimental design. Here, a fully-implantable recording and stimulation neuromodulation system suitable for use in mice is presented, measuring 2.2 cm 3 and weighing 2.8 g. The bidirectional wireless interface allows simultaneous readout of multiple physiological signals and complete control over stimulation parameters, and a wirelessly rechargeable battery provides a lifetime of up to 5 days on a single charge. The device was implanted to deliver vagus nerve stimulation (n = 12 animals) and a functional neural interface (capable of inducing acute bradycardia) was demonstrated with lifetimes exceeding three weeks. The design utilizes only commercially-available electrical components and 3D-printed packaging, with the goal of facilitating widespread adoption and accelerating discovery and translation of future bioelectronic therapeutics., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Receiving help can make or break a career, but women and racial/ethnic minorities do not always receive the support they seek. Across two audit experiments-one with politicians and another with students-as well as an online experiment (total n = 5,145), we test whether women and racial/ethnic minorities benefit from explicitly mentioning their demographic identity in requests for help, for example, by including statements like "As a Black woman…" in their communications. We propose that when a help seeker highlights their marginalized identity, it may activate prospective helpers' motivations to avoid prejudiced reactions and increase their willingness to provide support. Here we show that when women and racial/ethnic minorities explicitly mentioned their demographic identity in help-seeking emails, politicians and students responded 24.4% (7.42 percentage points) and 79.6% (2.73 percentage points) more often, respectively. These findings suggest that deliberately mentioning identity in requests for help can improve outcomes for women and racial/ethnic minorities., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

In the Concealed Information Test (CIT), differential responses between crime-relevant and crime-irrelevant items are indicative of concealed knowledge of a crime, and are used to classify an individual as either "guilty" or "innocent". However, when crime-relevant items are leaked before the test, an innocent examinee can exhibit enhanced responses to the crime-relevant items, thus causing such examinee to be wrongly classified as guilty. In an attempt to solve this problem, we examined the role of retroactive memory interference (RI) in differentiating informed innocents from guilty participants, using a P300-based CIT. Participants acquired crime-related knowledge either by committing a mock crime (guilty group) or reading a paper that described a mock crime (informed innocent group). Subsequently, the participants within each condition were randomly assigned to either an RI group, where they were exposed to new crime-related details before the CIT, or a control group. We found an interaction between guilty and RI groups: in the guilty group, there was a significant difference in P300 amplitude between the probe and irrelevant items, regardless of RI manipulation, whereas in the informed innocent group, a difference in P300 amplitude between the probe and irrelevant items was significant only in the control group, but not in the RI group. This led to an improved detection rate of the informed innocents (31% for the control group vs. 77% for the RI group). These results suggest that RI manipulation could be used to reduce the false positive outcomes of informed innocents without affecting the detection rate of guilty participants., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: Psychosis in Alzheimer's disease (AD) is associated with grave clinical consequences including a precipitous cognitive decline and a hastened demise. These outcomes are aggravated by use of existing antipsychotic medications, which are also associated with cognitive decline and increased mortality; preclinical models that would develop new therapeutic approaches are desperately needed. The current report evaluates the ability of the neoteric antipsychotic, pimavanserin, to normalize hyperkinesis and sensorimotor gating in the novel catechol- O -methyltransferase (COMT) deleted P301L/COMT- and rTg(P301L)4510 models of psychotic AD, and the impact of pimavanserin on tau pathology., Methods: Female P301L/COMT- mice were behaviorally characterized for abnormalities of locomotion and sensorimotor gating, and biochemically characterized for patterns of tau phosphorylation relative to relevant controls utilizing high-sensitivity tau enzyme-linked immunosorbent assay (ELISA). Female P301L/COMT- and rTg(P301L)4510 mice were randomized to pimavanserin or vehicle treatment to study the ability of pimavanserin to normalize locomotion and rescue sensorimotor gating. Additionally, high-sensitivity tau ELISA was used to investigate the impact of treatment on tau phosphorylation., Results: P301L/COMT- mice evidenced a hyperlocomotive phenotype and deficits of sensorimotor gating relative to wild-type mice on the same background, and increased tau phosphorylation relative to COMT-competent P301L mice. Pimavanserin normalized the hyperkinetic phenotype in both the P301L/COMT- and rTg(P301L)4510 mice but had no impact on sensorimotor gating in either model. Pimavanserin treatment had little impact on tau phosphorylation patterns., Discussion: These data suggest that pimavanserin ameliorates tau-driven excessive locomotion. Given the morbidity associated with aberrant motor behaviors such as pacing in AD and lack of effective treatments, future studies of the impact of pimavanserin on actigraphy in patients with this syndrome may be warranted., Competing Interests: Ethan S. Burstein is an employee of ACADIA Pharmaceuticals and has received stock options. Jesus Gomar has received funding from the Alzheimer's Association. All other authors have nothing to disclose., (© 2022 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Background: Individuals with chronic kidney disease (CKD) have decreased kidney cortical microvascular perfusion, which may lead to worsening kidney function over time, but methods to quantify kidney cortical microvascular perfusion are not feasible to incorporate into clinical practice. Contrast-enhanced ultrasound (CEUS) may quantify kidney cortical microvascular perfusion, which requires further investigation in individuals across the spectrum of kidney function., Methods: We performed CEUS on a native kidney of 83 individuals across the spectrum of kidney function and calculated quantitative CEUS-derived kidney cortical microvascular perfusion biomarkers. Participants had a continuous infusion of the microbubble contrast agent (Definity) with a flash-replenishment sequence during their CEUS scan. Lower values of the microbubble velocity ( β ) and perfusion index ( β ×A) may represent lower kidney cortical microvascular perfusion. Multivariable linear regression models tested the associations of the microbubble velocity ( β ) and perfusion index ( β ×A) with estimated glomerular filtration rate (eGFR)., Results: Thirty-eight individuals with CKD (mean age±SD 65.2±12.6 years, median [IQR] eGFR 31.5 [18.9-41.5] ml/min per 1.73 m 2 ), 37 individuals with end stage kidney disease (ESKD; age 54.8±12.3 years), and eight healthy volunteers (age 44.1±15.0 years, eGFR 117 [106-120] ml/min per 1.73 m 2 ) underwent CEUS without side effects. Individuals with ESKD had the lowest microbubble velocity ( β ) and perfusion index ( β ×A) compared with individuals with CKD and healthy volunteers. The microbubble velocity ( β ) and perfusion index ( β ×A) had moderate positive correlations with eGFR ( β : r s =0.44, P <0.001; β ×A: r s =0.50, P <0.001). After multivariable adjustment, microbubble velocity ( β ) and perfusion index ( β ×A) remained significantly associated with eGFR (change in natural log transformed eGFR per 1 unit increase in natural log transformed biomarker: β , 0.38 [95%, CI 0.17 to 0.59]; β ×A, 0.79 [95% CI, 0.45 to 1.13])., Conclusions: CEUS-derived kidney cortical microvascular perfusion biomarkers are associated with eGFR. Future studies are needed to determine if CEUS-derived kidney cortical microvascular perfusion biomarkers have prognostic value., Competing Interests: E.H. Chang reports research funding from Lantheus Medical Imaging and is on the medical advisory board for the North Carolina chapter of the National Kidney Foundation. P. Dayton reports consultancy for SonoVascular, Inc., SonoVol, Inc., and Triangle Biotechnology, Inc.; ownership interest in SonoVascular, Inc., SonoVol, Inc., and Triangle Biotechnology, Inc.; research funding from Kitware, LLC, SonoVol, Inc., and Triangle Biotechnology, Inc.; patents or royalties from SonoVascular, Inc., SonoVol, Inc., and Triangle Biotechnology, Inc.; an advisory or leadership role for SonoVascular, Inc., SonoVol, LLC, and Triangle Biotechnology, Inc.; and other interests or relationships with Pfizer, Inc. R. Walmer reports consultancy agreements with SonoVol, Inc. (entered into on November 2, 2021). A. Srivastava reports consultancy agreements with CVS Caremark and Tate & Latham (medicolegal consulting); honoraria from AstraZeneca, Bayer, and Horizon Therapeutics plc.; and participation in a speakers’ bureau for AstraZeneca. All remaining authors have nothing to disclose., (Copyright © 2022 by the American Society of Nephrology.)

Background: Management of sinonasal malignancy (SNM) often includes surgical resection as part of the multimodality treatment. Treatment-related surgical morbidity can occur, yet risk factors associated with complications in this population have not been sufficiently investigated., Methods: Adult patients with histologically confirmed SNM whose primary treatment included surgical resection were prospectively enrolled into an observational, multi-institutional cohort study from 2015 to 2020. Sociodemographic, disease, and treatment data were collected. Complications assessed included cerebrospinal fluid leak, orbital injury, intracranial injury, diplopia, meningitis, osteoradionecrosis, hospitalization for neutropenia, and subsequent chronic rhinosinusitis. The surgical approach was categorized as endoscopic resection (ER) or open/combined resection (O/CR). Associations between factors and complications were analyzed using Student's t test, Fisher's exact test, and logistic regression modeling., Results: Overall, 142 patients met the inclusion criteria. Twenty-three subjects had at least 1 complication (16.2%). On unadjusted analysis, adjuvant radiation therapy was associated with developing a complication (91.3% vs 65.5%, p = 0.013). Compared with the ER group (n = 98), the O/CR group (n = 44) had a greater percentage of higher T-stage lesions (p = 0.004) and more frequently received adjuvant radiation (84.1% vs 64.4%, p = 0.017) and chemotherapy (50.0% vs 30.6%, p = 0.038). Complication rates were similar between the ER and O/CR groups without controlling for other factors. Regression analysis that retained certain factors showed O/CR was associated with increased odds of experiencing a complication (odds ratio, 3.34; 95% confidence interval, 1.06-11.19)., Conclusions: Prospective, multicenter evaluation of SNM treatment outcomes is feasible. Undergoing O/CR was associated with increased odds of developing a complication after accounting for radiation therapy. Further studies are warranted to build upon these findings., (© 2021 ARS-AAOA, LLC.)

Background: Chronic rhinosinusitis (CRS) is a multifactorial disease with a high co-occurrence with asthma. In this multicohort study, we tested whether single nucleotide polymorphisms (SNPs) associated with childhood asthma and rhinovirus (RV)-associated disease are related to an increased susceptibility to adult CRS in a multicohort retrospective case-control study., Methods: Participants at two tertiary academic rhinology centers, University of Arizona (UofA) and University of Pennsylvania (UPenn) were recruited. Cases were defined as those with physician diagnosed CRS (UofA, n = 149; UPenn, n = 250), and healthy controls were those without CRS (UofA, n = 66; UPenn, n = 275). Genomic DNA was screened for the GSDMB rs7216389 SNP and CDHR3 rs6967330 SNP. Gene dosage, or the number of combined risk alleles in a single subject was calculated. Meta-analysis of the association between GSDMB or CDHR3 genotypes and CRS was performed and additive gene dosage effect for each population calculated using p for trend., Results: A meta-analysis revealed a combined increased risk for CRS in subjects with the GSDMB rs7216389 SNP (odds ratio [OR] 1.40; 95% confidence interval [CI], 1.16-1.76; p = 0.004). Both the UofA (OR 1.73; 95% CI, 1.23-2.43; p = 0.002) and UPenn (OR 1.27; 95% CI, 1.02-1.58; p = 0.035) populations showed a significant positive association between the number of combined risk alleles of GSDMB rs7216389 SNP and CDHR3 rs6967330 SNP and risk for CRS., Conclusion: Carriers of the GSDMB rs7216389 SNP and CDHR3 rs6967330 SNP are at increased susceptibility for CRS. These data suggest that therapeutic approaches to target aberrant responses to RV infection may play a role in the treatment of unified airway disease., (© 2021 ARS-AAOA, LLC.)

Background: Sinusitis is a common outpatient diagnosis made by physicians and is a reason for referral to otolaryngologists. A foundation in basic sinonasal anatomy is critical in understanding sinus pathophysiology and avoiding complications. Our objective in this study was to develop and to validate a self-directed surgical anatomy video for medical students., Methods: Two multimedia videos were developed highlighting sinonasal anatomy. In Video 1 we included audio narration and radiologic imaging. Video 2 incorporated highlighted images from a sinus surgery video. An assessment was developed to test sinonasal anatomy landmarks, spatial recognition of structures, and their clinical relevance. An expert panel of rhinologists scored face and content validity of the curriculum videos and assessment. Factor analysis was used to separate questions into face and content validity domains, and a one-sample t test was performed., Results: The panel scored face validity (Videos 1 and 2: 4.4/5) and content validity (Video 1: 4.5/5, 0.83; Video 2: 4.3/5, 0.75) significantly higher than a neutral response. There were no statistical differences for face or content validity between videos. The assessment was rated suitable (29%) or very suitable (57%) for testing basic sinonasal surgical anatomy, and the majority (71%) of respondents agreed (14%) or strongly agreed (57%) that the assessment thoroughly covered the sinus anatomy content with which medical students should be familiar., Conclusion: We have developed two videos and an assessment that highlight and test sinonasal anatomy. Future studies will aim to identify whether the use of a self-directed video curriculum improves sinonasal anatomy awareness and whether incorporation of surgical endoscopic videos augments training., (© 2021 ARS-AAOA, LLC.)

Objective: To evaluate the effectiveness of the collaboration between oncology pharmacists and anaesthesiologists for improving pain control management in cancer patients., Methods: This retrospective case-control pilot study enrolled inpatients with active cancer and a pain score of >3 at least once per day for 3 consecutive days. The study group was selected from June 2018 to January 2019. Patients with the same inclusion criteria were selected between November 2017 and May 2018 to serve as the comparison group. The primary outcome was the percentage of patients that experienced pain relief within 7 days from initial pain attack., Results: A total of 71 and 77 patients were enrolled in the study and comparison groups. More patients in the study group experienced pain relief within 7 days from the index date (78.9% [56 of 71 patients] versus 72.7% [56 of 77 patients], respectively). The service increased the rate of intervention from attending physicians within 4 days from index date and quality of opioid management., Conclusion: The collaboration between oncology pharmacists and anaesthesiologists for cancer pain management may be associated with an increase in the rate of pain relief in cancer patients with poor pain control.

Background: Gender disparities are prevalent in medicine, but their impact on surgical training is not well studied., Objective: To quantify gender disparities in trainee intraoperative experiences and explore the variables associated with ratings of surgical autonomy and performance., Methods: From September 2015 to May 2019, attending surgeons and trainees from 71 programs assessed trainee autonomy on a 4-level Zwisch scale and performance on a 5-level modified Dreyfus scale after surgical procedures. Multivariable regression models were used to examine the association of trainee gender with autonomy and performance evaluations., Results: A total of 3255 trainees and attending surgeons completed 94 619 evaluations. Attendings gave lower ratings of operative autonomy to female trainees than male trainees when controlling for training level, attending, and surgical procedure (effect size B = -0.0199, P = .008). There was no difference in ratings of autonomy at the beginning of training ( P = .32); the gap emerged as trainees advanced in years (B = -0.0163, P = .020). The gender difference in autonomy was largest for the most complex cases (B = -0.0502, P = .002). However, there was no difference in attending ratings of surgical performance for female trainees compared to male trainees (B = -0.0124, P = .066). Female trainees rated themselves as having less autonomy and worse performance than males when controlling for training level, attending, procedure, case complexity, and attending ratings (autonomy B = -0.0669, P < .001; performance B = -0.0704, P < .001)., Conclusions: While there was no significant difference in ratings of operative performance, a small difference between ratings of operative autonomy for female and male surgical trainees was identified., Competing Interests: Conflict of interest: The authors declare they have no competing interests. Drs Shari Meyerson, Brian George, and Elliott Kozin are members of the Society for Improving Medical Professional Learning's Steering Committee. Dr George is also the executive director of the organization. These positions are unpaid and without vested financial interest.

Inflammation, the body's primary defensive response system to injury and infection, is triggered by molecular signatures of microbes and tissue injury. These molecules also stimulate specialized sensory neurons, termed nociceptors. Activation of nociceptors mediates inflammation through antidromic release of neuropeptides into infected or injured tissue, producing neurogenic inflammation. Because HMGB1 is an important inflammatory mediator that is synthesized by neurons, we reasoned nociceptor release of HMGB1 might be a component of the neuroinflammatory response. In support of this possibility, we show here that transgenic nociceptors expressing channelrhodopsin-2 (ChR2) directly release HMGB1 in response to light stimulation. Additionally, HMGB1 expression in neurons was silenced by crossing synapsin-Cre (Syn-Cre) mice with floxed HMGB1 mice (HMGB1 f/f ). When these mice undergo sciatic nerve injury to activate neurogenic inflammation, they are protected from the development of cutaneous inflammation and allodynia as compared to wild-type controls. Syn-Cre/HMGB1 fl/fl mice subjected to experimental collagen antibody-induced arthritis, a disease model in which nociceptor-dependent inflammation plays a significant pathological role, are protected from the development of allodynia and joint inflammation. Thus, nociceptor HMGB1 is required to mediate pain and inflammation during sciatic nerve injury and collagen antibody-induced arthritis., Competing Interests: The authors declare no competing interest., (Copyright © 2021 the Author(s). Published by PNAS.)

What Is Known and Objective: Pharmacist-managed clinics (PMCs) are established to solve drug-related problems and enhance the quality of care of ambulatory patients. Although the benefits of such services have been demonstrated, little is known about PMC operations, especially outside the United States. The aim of this study was to explore how PMCs were established and to discuss implementation issues of PMCs in Taiwan., Methods: A purposive sample of pharmacists, pharmacy administrators and physicians involved with PMCs was recruited from hospitals of varying scales across Taiwan. Semi-structured, individual interviews were conducted to understand the perceptions of the clinical service of PMCs. Interviews were transcribed verbatim and analysed by thematic analysis to find underlying themes., Results: A total of 12 pharmacists, 5 pharmacy administrators and 3 physicians from 8 institutions were interviewed. Pharmacists spent 4 to 20 h per week at PMCs, and the practice experiences of PMC ranged from 1 to 6 years. PMCs have been provided in these institutions for 4 to 11 years with an average volume of 28 h and 25 patient visits weekly. Study participants described influential factors in establishing PMCs, including clinical expertise, attitude towards patient care and trust building with collaborating physicians. Operational concerns in implementing PMCs included role clarifications, manpower shortage, inadequate advanced training or certification, regulatory issues and a lack of service promotion., What Is New and Conclusion: This research broadens the understanding of operating PMC services and reveals key requirements and concerns regarding the care model, which can be useful for other countries. Resolving perceived barriers and collecting other stakeholders' perspectives may reinforce the integration of PMCs into patient care in the future., (© 2021 John Wiley & Sons Ltd.)

AST-120, an oral spherical activated carbon, may delay the need for kidney dialysis and improve uremia symptoms because it can adsorb acidic and basic organic compounds, especially small-molecule uremic toxins. However, previous studies produced no conclusive evidence regarding the benefits of AST-120 in delaying the progression of chronic kidney disease (CKD). Therefore, this systematic review and network meta-analysis evaluated the effects of AST-120 in patients with CKD. Related keywords of CKD and AST-120 were used to search four databases to obtain potential evidence on this topic, and two authors individually completed evidence selection, data extraction, and quality assessment. Network meta-analysis was performed for mortality, end-stage renal disease, composite renal outcomes, and laboratory outcomes based on a frequentist approach. In total, 15 randomized controlled trials ( n = 3,763) were included in the present synthesis, and the pooled results revealed non-significant differences in mortality among the treatment strategies. Low- and high-dose AST-120 were not superior to no AST-120 treatment regarding renal outcomes. However, the event rates of end-stage renal disease (risk ratio [RR] = 0.78, 95% confidence interval [CI] = 0.62-0.99) and composite renal outcomes (RR = 0.78, 95% CI: 0.63-0.97) were significantly lower in the tailored-dose AST-120 group than in no AST-120 group. The results did not reveal a small-study effect on the outcomes. Tailored dosing of AST-120 appeared to represent an optimal treatment strategy because it resulted in lower rates of composite renal outcomes and end-stage renal disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Su, Lee, Kuo, Chen, Chen, Kang and Chang.)

There is a broad and growing interest in Bioelectronic Medicine, a dynamic field that continues to generate new approaches in disease treatment. The fourth bioelectronic medicine summit "Technology targeting molecular mechanisms" took place on September 23 and 24, 2020. This virtual meeting was hosted by the Feinstein Institutes for Medical Research, Northwell Health. The summit called international attention to Bioelectronic Medicine as a platform for new developments in science, technology, and healthcare. The meeting was an arena for exchanging new ideas and seeding potential collaborations involving teams in academia and industry. The summit provided a forum for leaders in the field to discuss current progress, challenges, and future developments in Bioelectronic Medicine. The main topics discussed at the summit are outlined here.

Background: Initiating hemodialysis via an arteriovenous (AV) access is considered best practice for most patients. Despite the well-recognized advantages of AV access, 80% of US patients start hemodialysis with a catheter. Limited patient knowledge about vascular access, among other factors, may play a role in this high rate. We used iterative stakeholder input to develop novel, mixed media vascular access education materials and evaluated their preliminary acceptability., Methods: We conducted preliminary focus groups and interviews with key stakeholders to assess patient vascular access understanding and elicit perspectives on existing education materials. We then used stakeholder input to inform initial development and iterative updates to the content and design of an animated video and complementary brochure. Video development (scripting, storyboarding, animation) was guided by an evidence-based framework and two health behavior change models. We assessed acceptability of the completed materials with patients and medical providers/personnel via interviews., Results: Overall, 105 stakeholders participated in education materials development and review (80 patients/care partners, 25 medical providers/personnel). Preliminary qualitative work included 52 patients/care partners and 16 providers/personnel; video development included 28 patients/care partners and nine providers/personnel. The video script, storyboards, and animation underwent 14, four, and nine stakeholder-guided iterations, respectively. Responsive changes included aesthetic modifications, technical updates, and content additions ( e.g. , HD circuit, access self-monitoring, enhanced patient testimonials). The final 18-minute video and complementary brochure define vascular access types, describe care processes, outline potential complications, and address common patient concerns. Interviews with 28 patients/care partners and nine providers/personnel from diverse geographic regions revealed preliminary acceptability of, and enthusiasm for, the materials by patients and providers., Conclusions: In collaboration with key stakeholders, we developed mixed media vascular access education materials that were well-received by patients and providers. Preliminary findings suggest that the materials are promising to improve vascular access understanding among patients., Competing Interests: E.H. Chang reports receiving research funding from Lantheus Medical Imaging, and serving on the medical advisory board for the North Carolina chapter of the National Kidney Foundation (NKF). J.E. Flythe reports serving on the editorial board of American Journal of Kidney Diseases (2017–), CJASN (2017–), Kidney Medicine (2019–), and Nephrology Dialysis Transplantation (as the HD theme editor; 2018–), and as an associate editor for Kidney360 (2019–); receiving honoraria from American Renal Associates, American Society of Nephrology, Baxter, Dialysis Clinic Incorporated, Fresenius Medical Care North America, NKF, Renal Ventures, and numerous universities; having consultancy agreements with AstraZeneca and NxStage Medical Advisory Board; serving on the Kidney Disease Improving Global Outcomes Executive Committee (2020–) and Kidney Health Initiative (KHI) Board of Directors (2019–), and as the KHI Patient Preferences Project Chairperson (2019–); and receiving research funding from National Institutes of Health (NIH)/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH/National Heart, Lung, and Blood Institute, Patient-Centered Outcomes Research Institute, Renal Research Institute (subsidiary of Fresenius Medical Care North America), and Robert Wood Johnson Foundation. A. Hegde reports serving on the research committee for the American Society of Diagnostic and Interventional Nephrology, and having consultancy agreements with Truepill. C. Wilkie reports having consultancy agreements with KHI, the UNC at Chapel Hill, University of Pennsylvania’s HOPE Consortium, and University of Pittsburgh; and having other interests in/relationships with NKF. All remaining authors have nothing to disclose., (Copyright © 2021 by the American Society of Nephrology.)

Vagus nerve stimulation (VNS) suppresses inflammation and autoimmune diseases in preclinical and clinical studies. The underlying molecular, neurological, and anatomical mechanisms have been well characterized using acute electrophysiological stimulation of the vagus. However, there are several unanswered mechanistic questions about the effects of chronic VNS, which require solving numerous technical challenges for a long-term interface with the vagus in mice. Here, we describe a scalable model for long-term VNS in mice developed and validated in four research laboratories. We observed significant heart rate responses for at least 4 weeks in 60-90% of animals. Device implantation did not impair vagus-mediated reflexes. VNS using this implant significantly suppressed TNF levels in endotoxemia. Histological examination of implanted nerves revealed fibrotic encapsulation without axonal pathology. This model may be useful to study the physiology of the vagus and provides a tool to systematically investigate long-term VNS as therapy for chronic diseases modeled in mice., Competing Interests: IM, JH, NJ, DT, UA, EP, YC, AA, TD, EC, TZ, SL, RF, CW, YA, SZ No competing interests declared, KT holds patents broadly related to this work. He has assigned all rights to the Feinstein Institutes for Medical Research., (© 2021, Mughrabi et al.)

The cell wall of Gram-negative bacteria consists of an inner (cytoplasmic) and outer membrane (OM), separated by a thin peptidoglycan layer. Throughout growth, the outer membrane can bleb to form spherical outer membrane vesicles (OMVs). These OMVs are involved in numerous cellular functions including cargo delivery to host cells and communication with bacterial cells. Recently, the therapeutic potential of OMVs has begun to be explored, including their use as vaccines and drug delivery vehicles. Although OMVs are derived from the OM, it has long been appreciated that the lipid and protein cargo of the OMV differs, often significantly, from that of the OM. More recently, evidence that bacteria can release multiple types of OMVs has been discovered, and evidence exists that size can impact the mechanism of their uptake by host cells. However, studies in this area are limited by difficulties in efficiently separating the heterogeneously sized OMVs. Density gradient centrifugation (DGC) has traditionally been used for this purpose; however, this technique is time-consuming and difficult to scale-up. Size exclusion chromatography (SEC), on the other hand, is less cumbersome and lends itself to the necessary future scale-up for therapeutic use of OMVs. Here, we describe a SEC approach that enables reproducible separation of heterogeneously sized vesicles, using as a test case, OMVs produced by Aggregatibacter actinomycetemcomitans, which range in diameter from less than 150 nm to greater than 350 nm. We demonstrate separation of "large" (350 nm) OMVs and "small" (<150 nm) OMVs, verified by dynamic light scattering (DLS). We recommend SEC-based techniques over DGC-based techniques for separation of heterogeneously sized vesicles due to its ease of use, reproducibility (including user-to-user), and possibility for scale-up.

Objectives: We and others have previously shown that epigallocatechin gallate (EGCg) inhibits the activity of an important virulence factor, leukotoxin (LtxA), produced by the oral bacterium Aggregatibacter actinomycetemcomitans, suggesting the potential use of this molecule as an anti-virulence strategy to treat periodontal infections. Here, we sought to better understand the effects of EGCg on toxin secretion and A. actinomycetemcomitans pathogenicity in a co-culture model., Methods: We used a quantitative immunoblot assay to determine the concentrations of LtxA in the bacterial supernatant and on the bacterial cell surface. Using a co-culture model, consisting of A. actinomycetemcomitans and THP-1 cells, we studied the impact of EGCg-mediated changes in LtxA secretion on the toxicity of A. actinomycetemcomitans., Key Findings: EGCg increased production of LtxA and changed the localization of secreted LtxA from the supernatant to the surface of the bacterial cells. In the co-culture model, a single low dose of EGCg did not protect host THP-1 cells from A. actinomycetemcomitans-mediated cytotoxicity, but a multiple dosing strategy had improved effects., Conclusions: Together, these results demonstrate that EGCg has important, but complicated, effects on toxin secretion and activity; new dosing strategies and comprehensive model systems may be required to properly develop these anti-virulence activities., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Royal Pharmaceutical Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Obesity, a growing health concern, is associated with an increased risk of morbidity and mortality. Chronic low-grade inflammation is implicated in obesity-driven metabolic complications. Peripheral focused ultrasound stimulation (pFUS) is an emerging non-invasive technology that modulates inflammation. Here, we reasoned that focused ultrasound stimulation of the liver may alleviate obesity-related inflammation and other comorbidities. After 8 weeks on a high-fat high-carbohydrate "Western" diet, C57BL/6J mice were subjected to either sham stimulation or focused ultrasound stimulation at the porta hepatis. Daily liver-focused ultrasound stimulation for 8 weeks significantly decreased body weight, circulating lipids and mitigated dysregulation of adipokines. In addition, liver-focused ultrasound stimulation significantly reduced hepatic cytokine levels and leukocyte infiltration. Our findings demonstrate the efficacy of hepatic focused ultrasound for alleviating obesity and obesity-associated complications in mice. These findings suggest a previously unrecognized potential of hepatic focused ultrasound as a possible novel noninvasive approach in the context of obesity.

I., Executive Summary: BACKGROUND: The 5 years since the publication of the first International Consensus Statement on Allergy and Rhinology: Rhinosinusitis (ICAR-RS) has witnessed foundational progress in our understanding and treatment of rhinologic disease. These advances are reflected within the more than 40 new topics covered within the ICAR-RS-2021 as well as updates to the original 140 topics. This executive summary consolidates the evidence-based findings of the document., Methods: ICAR-RS presents over 180 topics in the forms of evidence-based reviews with recommendations (EBRRs), evidence-based reviews, and literature reviews. The highest grade structured recommendations of the EBRR sections are summarized in this executive summary., Results: ICAR-RS-2021 covers 22 topics regarding the medical management of RS, which are grade A/B and are presented in the executive summary. Additionally, 4 topics regarding the surgical management of RS are grade A/B and are presented in the executive summary. Finally, a comprehensive evidence-based management algorithm is provided., Conclusion: This ICAR-RS-2021 executive summary provides a compilation of the evidence-based recommendations for medical and surgical treatment of the most common forms of RS., (© 2021 ARS-AAOA, LLC.)

Charcot-Marie-Tooth disease (CMT), a genetically heterogeneous group of diseases in the peripheral nervous system, is characterized by progressive and symmetrical distal weakness resulting in gait abnormality. The necessity of the diagnostic and prognostic biomarkers has been raised for both basic research and clinical practice in CMT. Since biomarkers for animal study of CMT are limited, we evaluated the feasibility of gait parameters as tool for measuring disease phenotype of CMT mouse model. Using a Trembler-J (Tr-J) mouse, a CMT type 1 (CMT1) mouse model, we analyzed kinematic parameters such as angles of hip, knee and ankle (sagittal plane), and spatial parameters including step width and stride length (transverse plane). Regarding of kinematic parameters, Tr-J mice exhibited less plantarflexed ankle during the swing phase and more dorsiflexed ankle at the terminal stance compared to control mice. The range of motion in ankle angle of Tr-J mice was significantly greater than that of control mice. In spatial parameter, Tr-J mice exhibited wider step width compared to control mice. These results are similar to previously reported gait patterns of CMT1 patients. In comparison with other markers such as nerve conduction study and rotarod test, gait parameters dynamically reflected the disease progression of CMT1 mice. Therefore, these data imply that gait parameters can be used as useful tools to analyzed the disease phenotype and progression during preclinical study of peripheral neuropathy such as CMT., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Rationale & Objective: Underlying kidney disease is an emerging risk factor for more severe coronavirus disease 2019 (COVID-19) illness. We examined the clinical courses of critically ill COVID-19 patients with and without pre-existing chronic kidney disease (CKD) and investigated the association between the degree of underlying kidney disease and in-hospital outcomes., Study Design: Retrospective cohort study., Settings & Participants: 4,264 critically ill patients with COVID-19 (143 patients with pre-existing kidney failure receiving maintenance dialysis; 521 patients with pre-existing non-dialysis-dependent CKD; and 3,600 patients without pre-existing CKD) admitted to intensive care units (ICUs) at 68 hospitals across the United States., Predictor(s): Presence (vs absence) of pre-existing kidney disease., Outcome(s): In-hospital mortality (primary); respiratory failure, shock, ventricular arrhythmia/cardiac arrest, thromboembolic events, major bleeds, and acute liver injury (secondary)., Analytical Approach: We used standardized differences to compare patient characteristics (values>0.10 indicate a meaningful difference between groups) and multivariable-adjusted Fine and Gray survival models to examine outcome associations., Results: Dialysis patients had a shorter time from symptom onset to ICU admission compared to other groups (median of 4 [IQR, 2-9] days for maintenance dialysis patients; 7 [IQR, 3-10] days for non-dialysis-dependent CKD patients; and 7 [IQR, 4-10] days for patients without pre-existing CKD). More dialysis patients (25%) reported altered mental status than those with non-dialysis-dependent CKD (20%; standardized difference=0.12) and those without pre-existing CKD (12%; standardized difference=0.36). Half of dialysis and non-dialysis-dependent CKD patients died within 28 days of ICU admission versus 35% of patients without pre-existing CKD. Compared to patients without pre-existing CKD, dialysis patients had higher risk for 28-day in-hospital death (adjusted HR, 1.41 [95% CI, 1.09-1.81]), while patients with non-dialysis-dependent CKD had an intermediate risk (adjusted HR, 1.25 [95% CI, 1.08-1.44])., Limitations: Potential residual confounding., Conclusions: Findings highlight the high mortality of individuals with underlying kidney disease and severe COVID-19, underscoring the importance of identifying safe and effective COVID-19 therapies in this vulnerable population., (Copyright © 2020 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Currently most fluorogenic probes are developed for the analysis of enzymes, where a bond breaking or rearrangement reaction is required to transform a nonfluorescent enzymatic substrate into a fluorescent product. However, this approach cannot be used for proteins that do not possess enzymatic activities. In this article, we show that fluorogenic probes with a self-immolative difluorophenyl ester linker can mimic the bond disassembly processes of fluorogenic enzyme substrates for the rapid analysis of nonenzymatic proteins. Although numerous self-immolative reagents have shown promising applications in sensors, drug delivery systems, and material chemistry, all of them are triggered by either enzymes or small reactive molecules. In our strategy, the probe binds to the protein via a specific protein-ligand interaction, inducing a chemical reaction between the self-immolative linker and an amino acid of the protein, thereby triggering a cascade reaction that leads to the activation and release of the fluorogenic reporter. In contrast, a phenyl ester linker without the difluoro substituent cannot be triggered to release the fluorogenic reporter. With this probe design, live-cell imaging of extracellular and intracellular endogenous tumor marker proteins can be achieved with high selectivity and sensitivity.

In the brain, compact clusters of neuron cell bodies, termed nuclei, are essential for maintaining parameters of host physiology within a narrow range optimal for health. Neurons residing in the brainstem dorsal motor nucleus (DMN) project in the vagus nerve to communicate with the lungs, liver, gastrointestinal tract, and other organs. Vagus nerve-mediated reflexes also control immune system responses to infection and injury by inhibiting the production of tumor necrosis factor (TNF) and other cytokines in the spleen, although the function of DMN neurons in regulating TNF release is not known. Here, optogenetics and functional mapping reveal cholinergic neurons in the DMN, which project to the celiac-superior mesenteric ganglia, significantly increase splenic nerve activity and inhibit TNF production. Efferent vagus nerve fibers terminating in the celiac-superior mesenteric ganglia form varicose-like structures surrounding individual nerve cell bodies innervating the spleen. Selective optogenetic activation of DMN cholinergic neurons or electrical activation of the cervical vagus nerve evokes action potentials in the splenic nerve. Pharmacological blockade and surgical transection of the vagus nerve inhibit vagus nerve-evoked splenic nerve responses. These results indicate that cholinergic neurons residing in the brainstem DMN control TNF production, revealing a role for brainstem coordination of immunity., Competing Interests: Competing interest statement: A.M.K., V.A.P., S.S.C. and K.J.T. have filed a patent application relevant to this work and have assigned their rights to the Feinstein Institutes for Medical Research. Y.A.L. is an employee of SetPoint Medical., (Copyright © 2020 the Author(s). Published by PNAS.)

Transient receptor potential (TRP) channels are a superfamily of non-selective cation channels that act as polymodal sensors in many tissues throughout mammalian organisms. In the context of ion channels, they are unique for their broad diversity of activation mechanisms and their cation selectivity. TRP channels are involved in a diverse range of physiological processes including chemical sensing, nociception, and mediating cytokine release. They also play an important role in the regulation of inflammation through sensory function and the release of neuropeptides. In this review, we discuss the functional contribution of a subset of TRP channels (TRPV1, TRPV4, TRPM3, TRPM8, and TRPA1) that are involved in the body's immune responses, particularly in relation to inflammation. We focus on these five TRP channels because, in addition to being expressed in many somatic cell types, these channels are also expressed on peripheral ganglia and nerves that innervate visceral organs and tissues throughout the body. Activation of these neural TRP channels enables crosstalk between neurons, immune cells, and epithelial cells to regulate a wide range of inflammatory actions. TRP channels act either through direct effects on cation levels or through indirect modulation of intracellular pathways to trigger pro- or anti-inflammatory mechanisms, depending on the inflammatory disease context. The expression of TRP channels on both neural and immune cells has made them an attractive drug target in diseases involving inflammation. Future work in this domain will likely yield important new pathways and therapies for the treatment of a broad range of disorders including colitis, dermatitis, sepsis, asthma, and pain., (Copyright © 2020 Silverman, Chen, Kravatz, Chavan and Chang.)

There is a need for valid and reliable instruments to focus on medication aspects of health literacy and help healthcare professionals address patients' barriers to medication use. This cross-sectional study describes the conceptualization, development, and psychometric properties of the first Chinese Medication Literacy Measurement (ChMLM) to assess the level of health literacy on medication use. The 17-item ChMLM (ChMLM-17) and its short form, 13-item ChMLM (ChMLM-13), consist of four sections (vocabulary, over-the-counter labels, prescription labels, and advertisements) to cover six domains of medication-related health literacy. Multistage stratified quota sampling was attempted to recruit a representative sample in Taiwan. Receiver operating characteristic curves were used to identify the cut-off point for differentiating high and low medication literacy. Psychometric analyses were performed ( n = 1410) to assess the reliability and validity separately on all samples and sociodemographic subgroups. The 17- and 13-item versions both had high construct validity among all patients and patients with low medication literacy. The developed ChMLM-17 and ChMLM-13 is expected to help healthcare providers and researchers to accurately measure medication-related health literacy and improve medication use in the real-world practice.

Oriental melons have a relatively short shelf life as they are harvested during the summer season and susceptible to cold-induced injuries. Typical chilling injury when stored at 4 °C is expressed as browning of the fruit suture. To prolong the shelf life and reduce browning of the fruit, the effects of modified atmosphere packaging (MAP), X-tend modified atmosphere (MA)/modified humidity (MH) bulk packaging (XF), and polyethylene (PE) packaging, on oriental melons were investigated during storage at 4 °C and 10 °C for 14 days and under retail display conditions at 20 °C. The O 2 concentrations in PE packages stored at 4 °C and 10 °C ranged from 17.4 to 18.5%, whereas those in XF packages were reduced to 16.3-16.6%. The CO 2 content of XF package (4.2-4.6%) was higher than that of PE package (1.4-1.9%) stored at 4 °C or 10 °C. Relative humidity (RH) saturated in the PE packages but not in the XF packages after seven days of storage. Furthermore, PE packages performed better at maintaining melon weight and firmness than XF packages during storage at 10 °C for 14 days and under retail display conditions at 20 °C. PE and XF packages effectively reduced the browning index of the peel and white linear sutures of oriental melons compared with the unpackaged control during cold storage at 4 °C, and this observation was maintained at the retail display condition at 20 °C. The enhanced CO 2 levels, reduced O 2 levels, and optimal RH values that were provided by the MAP, prevented the browning symptoms, and improved the marketability and shelf life of oriental melons.

Medication non-adherence is a concern in chronic disease management. Currently, there is no scale that characterizes sufficient non-adherent reasons for practical use in the Chinese population. This study developed and validated the Chinese version of the Medication Adherence Reasons Scale (ChMAR-Scale) and described non-adherence reasons in adult patients taking blood pressure medicine in Taiwan. A forward-backward procedure was used to translate the original MAR-Scale, and new items pertinent to cultural differences were added. Patients aged above 20 years old who were taking blood pressure medicine were recruited from a regional hospital and eight community pharmacies in the Taipei metropolitan area. Data analyses were conducted with IBM SPSS 19 (Armonk, NY, USA). Exploratory factor analysis revealed six domains, including belief, self-perception, forgetfulness, management, availability, and miscellaneous issues, with Cronbach's alphas ranging from 0.649 to 0.852, item-total correlations ranging from 0.362 to 0.719, and factor loadings ranging from 0.365 to 0.775. Criterion-related validity with the visual analog scale and two global items were 0.525, 0.436, and 0.502. Forgetfulness, belief issues, and self-perception issues were the most common non-adherence reasons. In conclusion, the ChMAR-Scale showed good psychometric properties and identified more reasons for medication non-adherence than other existing scales. Healthcare providers should be vigilant of these problems while consulting patients.

Policy makers, employers, and insurers often provide financial incentives to encourage citizens, employees, and customers to take actions that are good for them or for society (e.g., energy conservation, healthy living, safe driving). Although financial incentives are often effective at inducing good behavior, they've been shown to have self-image costs: Those who receive incentives view their actions less positively due to the perceived incompatibility between financial incentives and intrinsic motives. We test an intervention that allows organizations and individuals to resolve this tension: We use financial rewards to kick-start good behavior and then offer individuals the opportunity to give up some or all of their earned financial rewards in order to boost their self-image. Two preregistered studies-an incentivized online experiment ( n = 763) on prosocial behavior and a large field experiment ( n = 17,968) on exercise-provide evidence that emphasizing the intrinsic rewards of a past action leads individuals to forgo or donate earned financial rewards. Our intervention allows individuals to retroactively signal that they acted for the right reason, which we call "motivation laundering." We discuss the implications of motivation laundering for the design of incentive systems and behavioral change., Competing Interests: The authors declare no competing interest., (Copyright © 2020 the Author(s). Published by PNAS.)

Background: An estimated 38% of US adults are obese. Obesity is associated with socioeconomic disparities and increased rates of comorbidities, and is a known risk factor for development of pancreatic cancer. As a fourth leading cause of death in the United States, pancreatic cancer is commonly treated with a pancreatico-duodenectomy (PD), or Whipple procedure. Data regarding the effects of obesity on post-operative complication rate primarily comes from specialized centers, however the results are mixed. Our aim is to elucidate the effects that obesity has on outcomes after PD for pancreatic head cancer using a national prospectively maintained clinical database., Method: The 2010-2015 American College of Surgeons National Surgical Quality Improvement Project (ACS NSQIP) Participant Use Files (PUF) were used as the data source. We identified cases in which PD was performed (CPT code 48150) in the setting of a postoperative diagnosis of pancreatic cancer (ICD9 code 157.0). We excluded cases that had emergency admissions, BMI ≤18.5 kg/m 2 , intraoperative wound classification of III or IV, and disseminated cancer. Cases with missing BMI, preoperative albumin, operative time, LOS data were also excluded. Multiple imputation for missing sex, race, functional status, and ASA classification using chained equations was performed. 16 Patients that had BMI ≥30 kg/m 2 were considered obese, and patients with BMI <30 kg/m 2 were used as control., Results: 3484 patients underwent pancreaticoduodenectomy for pancreatic cancer. 860 patients were identified as obese. Propensity score analysis was performed matching age, sex, race, functional status, presence of dyspnea, diabetes, hypertension, acute renal failure, dialysis dependence, ascites, steroid use, bleeding disorders, history of chronic obstructive pulmonary disease (COPD), congestive heart failure (CHF), weight loss, American Society of Anesthesiologists (ASA) classification, and preoperative albumin levels. After matching, obese patients had higher risk of 30-day postoperative complications compared to control, including organ space wound infections (OR 1.38, 95% CI 1.07-1.79, p = 0.0128), returning to the operating room (OR 1.39, 95% CI 1.01-1.91, p = 0.0461), failure to extubate for greater than 48 h (OR 1.60, 95% CI 1.09-2.34, p = 0.0153), death (OR 1.68, 95% CI 1.01-2.78, p = 0.0453), septic shock (OR 2.22, 95% CI 1.46-3.38, p = 0.0002), pulmonary embolism (OR 2.42, 95% CI 1.07-5.45, p = 0.0332), renal insufficiency (OR 2.67, 95% CI 1.33-5.38, p = 0.0058). Sensitivity analysis yielded similar results with the exception of risk for return to the operating room, death, and pulmonary embolism, P > .05., Conclusion: In this large observational study using a national clinical database, obese patients undergoing PD for head of pancreas cancer had increased risk of postoperative complications and mortality in comparison to controls., Competing Interests: Declaration of competing interest The authors report no proprietary or commercial interest in any product mentioned or concept discussed in this article. There are no organizations funding this research., (Copyright © 2019. Published by Elsevier Inc.)

Goblet cell metaplasia (GCM) and mucin overproduction are a hallmark of chronic rhinosinusitis (CRS) and chronic obstructive pulmonary disease (COPD). In the airways, cigarette smoke (CS) induces activation of the epidermal growth factor receptor (EGFR) leading to GCM and overexpression of the gel-forming mucin MUC5AC. Although previous studies have demonstrated that a membrane-bound mucin, MUC1, modulates the activation of CS-induced EGFR, the role of MUC1 in CS-induced GCM and mucin overproduction has not been explored. In response to CS exposure, wild-type (WT) rats displayed Muc1 translocation from the apical surface of airway epithelium to the intracellular compartment of hyperplastic intermediate cells, EGFR phosphorylation, GCM, and Muc5ac overproduction. Similarly, human CRS sinonasal tissues demonstrated hyperplasia of intermediate cells enriched with MUC1 in the intracellular compartment, which was accompanied by GCM and increased MUC5AC expression. To further evaluate the role of Muc1 in vivo, a Muc1 knockout (KO) rat (MUC in humans and Muc in animals) was developed. In contrast to WT littermates, Muc1-KO rats exhibited no activation of EGFR, and were protected from GCM and Muc5ac overproduction. Genetic knockdown of MUC1 in human lung or Muc1 knockout in primary rat airway epithelial cells led to significantly diminished EGF-induced MUC5AC production. Together, these findings suggest that MUC1-dependent EGFR activation mediates CS-induced GCM and mucin overproduction. Strategies designed to suppress MUC1-dependent EGFR activation may provide a novel therapeutic approach for treating mucin hypersecretion in CRS and COPD.

Background: Electrical stimulation of peripheral nerves is a widely used technique to treat a variety of conditions including chronic pain, motor impairment, headaches, and epilepsy. Nerve stimulation to achieve efficacious symptomatic relief depends on the proper selection of electrical stimulation parameters to recruit the appropriate fibers within a nerve. Recently, electrical stimulation of the vagus nerve has shown promise for controlling inflammation and clinical trials have demonstrated efficacy for the treatment of inflammatory disorders. This application of vagus nerve stimulation activates the inflammatory reflex, reducing levels of inflammatory cytokines during inflammation., Methods: Here, we wanted to test whether altering the parameters of electrical vagus nerve stimulation would change circulating cytokine levels of normal healthy animals in the absence of increased inflammation. To examine this, we systematically tested a set of electrical stimulation parameters and measured serum cytokine levels in healthy mice., Results: Surprisingly, we found that specific combinations of pulse width, pulse amplitude, and frequency produced significant increases of the pro-inflammatory cytokine tumor necrosis factor (TNF), while other parameters selectively lowered serum TNF levels, as compared to sham-stimulated mice. In addition, serum levels of the anti-inflammatory cytokine interleukin-10 (IL-10) were significantly increased by select parameters of electrical stimulation but remained unchanged with others., Conclusions: These results indicate that electrical stimulation parameter selection is critically important for the modulation of cytokines via the cervical vagus nerve and that specific cytokines can be increased by electrical stimulation in the absence of inflammation. As the next generation of bioelectronic therapies and devices are developed to capitalize on the neural regulation of inflammation, the selection of nerve stimulation parameters will be a critically important variable for achieving cytokine-specific changes., Competing Interests: Competing interestsK.J.T. and S.S.C. hold patents broadly related to this work. They have assigned all rights to the Feinstein Institutes for Medical Research., (© The Author(s) 2020.)

Cystic fibrosis (CF) is a monogenic disorder caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. Mortality in CF patients is mostly due to respiratory sequelae. Challenges with gene delivery have limited attempts to treat CF using in vivo gene therapy, and low correction levels have hindered ex vivo gene therapy efforts. We have used Cas9 and adeno-associated virus 6 to correct the ΔF508 mutation in readily accessible upper-airway basal stem cells (UABCs) obtained from CF patients. On average, we achieved 30%-50% allelic correction in UABCs and bronchial epithelial cells (HBECs) from 10 CF patients and observed 20%-50% CFTR function relative to non-CF controls in differentiated epithelia. Furthermore, we successfully embedded the corrected UABCs on an FDA-approved porcine small intestinal submucosal membrane (pSIS), and they retained differentiation capacity. This study supports further development of genetically corrected autologous airway stem cell transplant as a treatment for CF., Competing Interests: Declaration of Interests M.H.P. has equity and serves on the scientific advisory board of CRISPR Therapeutics. J.V.N. is a consultant with COOK Medical, which manufactures the pSIS graft. Neither company had any input on the design, execution, interpretation, or publication of the work in this manuscript., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Backgound: Functional endoscopic sinus surgery (FESS) can be challenging as novices become accustomed to handling endoscopes and instruments while navigating complex sinonasal anatomy. Experts demonstrate fluid and efficient motions when addressing pathology. The training process from novice to expert relies on hands-on experience in cadaveric laboratories and preceptorship models that require significant time and expense. This study aims to validate the use of a virtual coach to guide users step-by-step through a basic FESS., Methods: Seventeen surgeons were grouped into novice (n = 10) and expert (n = 7) based on self-reported levels of surgical experience. Users were trained using the maxillary antrostomy module in the Neurorhinological Surgery (NRS) simulator combining the physical craniofacial model with virtual reality (VR)-tracked surgical instruments in the VR operating room. The virtual coach guided the user using surgical videos, auditory, and visual cues. The coach recorded data for each subject including the number of times borders of the nasal cavity were encountered and time to completion. Users graded the usefulness of the virtual coach on a Likert questionnaire., Results: Face validity of our NRS simulator was replicated by user questionnaires, and construct validity replicated by differentiation between novice and expert level surgeons (p < 0.01). Novices contacted a significantly higher number of anatomic borders (n = 17) and had a longer operative time (t = 370 seconds). All users reported high scores on the benefit and usefulness of the virtual coach., Conclusion: The virtual coach provides a useful tool to enhance FESS education by providing objective real-time data in a novel mixed-reality surgical environment., (© 2019 ARS-AAOA, LLC.)

The oral pathogen, Aggregatibacter actinomycetemcomitans, produces a number of virulence factors, including a leukotoxin (LtxA), which specifically kills human white blood cells, to provide a colonization advantage to the bacterium. Strains of A. actinomycetemcomitans that produce more LtxA have been more closely linked to disease, indicating that this toxin plays a key role in pathogenesis of the bacterium. Disruption of the activity of LtxA thus represents a promising approach to reducing the pathogenicity of the bacterium. Catechins are polyphenolic molecules derived from plants, which have shown potent antibacterial and antitoxin activities. We have previously shown that galloylated catechins are able to prevent LtxA delivery to host cells by altering the toxin's secondary structure and preventing binding to cholesterol on the host cell membrane. Here, we have investigated how one particular galloylated catechin, epigallocatechin gallate (EGCg), affects A. actinomycetemcomitans growth and toxin secretion. Our results demonstrate that EGCg, at micromolar concentrations, inhibits A. actinomycetemcomitans growth, as has been reported for other bacterial species. At subinhibitory concentrations, EGCg promotes LtxA production, but the toxicity of the bacterial supernatant against human immune cells is reduced. The results of our biophysical studies indicate that this seemingly contradictory result is caused by an EGCg-mediated enhancement of LtxA affinity for the bacterial cell surface. Together, these results demonstrate the potential of EGCg in the treatment of virulent A. actinomycetemcomitans infections., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Introduction: Choosing Wisely, an international effort to reduce low value care worldwide, considers communication between clinicians and patients during routine clinical encounters a key mechanism for change. In Australia, Choosing Wisely has developed a 5 Questions resource to facilitate better conversations. The primary aim of this study is to evaluate the impact of the Choosing Wisely Australia 5 Questions resource and a video designed to prepare patients for question-asking and participation in shared decision-making on (a) self-efficacy to ask questions and participate in shared decision-making, (b) intention to participate in shared decision-making and (c) a range of secondary outcomes. The secondary aim of this study is to determine whether participants' health literacy modifies the effects of the interventions., Methods and Analysis: We will use 2×2×2 between-subjects factorial design (preparation video: yes, no × Choosing Wisely 5 Questions resource: yes, no × health literacy: adequate, inadequate). Participants will be recruited by an online market research company, presented with a hypothetical non-specific low back pain scenario, and randomised to study groups stratified by health literacy. Quantitative primary and secondary outcome data will be analysed as intention-to-treat using appropriate regression models (ie, linear regression for continuous outcomes, logistic regression for dichotomous categorical outcomes)., Ethics and Dissemination: Ethical approval for this study was obtained from the University of Sydney Human Research Ethics Committee (protocol number: 2018/965). The results from this work will be disseminated through peer-reviewed international journals, conferences and updates with collaborating public health bodies. Resources developed for this study will be made available to patients and clinicians following trial completion., Trial Registration Number: This trial has been registered with the Australia New Zealand Clinical Trials Registry (trial number: 376477) and the stage is Pre-results., Competing Interests: Competing interests: RL is an employee of NPS MedicineWise which facilitates Choosing Wisely Australia. The University of Sydney owns intellectual property on the video and DM, MT, KM and RET are contributors to the intellectual property., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Despite its anticipated clinical potential, anti-PD-1 immunotherapy has only yielded poor outcomes in recent clinical trials for glioblastoma patients. Strategies combining anti-PD-1 antibody with other treatment modalities are being explored to alter the immunosuppressive microenvironment that appears to characterize these anti-PD-1-insensitive tumors. Here, we evaluated whether introducing wild-type p53 gene via a tumor-targeting nanomedicine (termed SGT-53) could provide immune stimulation and augment anti-PD-1 therapy in mouse syngeneic GL261 tumor models (either subcutaneous or intracranial). In both models, anti-PD-1 monotherapy had no demonstrable therapeutic effect. However, combining anti-PD-1 with our investigational nanomedicine SGT-53 was very effective in inhibiting tumor growth, inducing tumor cell apoptosis and increasing intratumoral T-cell infiltration. A significant survival benefit was observed in mice bearing intracranial glioblastoma receiving combination treatment. Importantly, SGT-53 upregulated PD-L1 expression both in vitro and in vivo. Transcriptome analysis revealed modulation of genes linked to either cancer progression or immune activation after combination treatment. Our data suggest that SGT-53 can boost antitumor immunity and sensitize glioblastoma to anti-PD-1 therapy by converting immunologically "cold" tumors into "hot" tumors. Combining SGT-53 with anti-PD-1 might benefit more patients from anti-PD-1 immunotherapy and our data support evaluation of this combination in patients with glioblastoma., (© 2019 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Objectives: To examine the specific factors that the general public believes have an effect on the image of community pharmacists and also to identify community pharmacists' services that truly fulfill people's needs., Methods: A convenient sample of 401 community pharmacy customers completed the questionnaire., Results: When asked about the factors that help establish a positive image for a community pharmacist, 98.3% of the respondents reported accurate dispensing as the most important factor, followed by cordial attitude (95.5%), and wearing clothes showing pharmacist's license with a photo (94.6%). Among the services provided by community pharmacies, most people think that the most needed service is a consultation explaining drug-drug interactions (93.8%). Furthermore, 312 (77.8%) respondents indicated that there is a need for comprehensive pharmaceutical services. As for the amount that the respondents were willing to pay for such service, many (42.9%) chose 100 NT dollars (≈ 3USD)., Conclusion: The results of this study showed that correct dispensing is the most important factor that helps establish a positive image of community pharmacists and that the most needed services were those that required pharmacists' professional competence. Moreover, nearly 80% of the respondents reported that they needed comprehensive pharmaceutical services and were willing to pay for it., (© 2019 John Wiley & Sons, Ltd.)

Background: Rhinovirus (RV) infections are the most common cause of viral upper respiratory infections (URIs), and in the majority of persons they are self-limiting. However, in others, viral URIs can progress to bacterial sinusitis and induce chronic rhinosinusitis (CRS) exacerbations., Methods: We conducted a comprehensive Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) review through April 2018 based on MEDLINE, EMBASE, Web of Science-Science Citation Index (SCI), and Conference Proceedings Citation Index- Science (CPCI-S) using keywords: RV, respiratory virus, sinusitis, and airway epithelial cells. The goal of this systematic review was to: (1) determine the prevalence between RV and CRS, (2) study the changes that occur after experimental RV inoculation, (3) investigate the pathophysiologic mechanisms by which RV induces sinonasal inflammation, and (4) explore the treatment options available for RV-associated sinusitis. Data regarding study design, research question, intervention, subjects, outcomes, and biases was extracted., Results: The initial search yielded 2395 unique abstracts, of which 614 were selected for full-text review; 147 were included in the final review. We determined that (1) the prevalence of RV infections is increased in those with CRS, (2) humans challenged in vivo with RV secrete local inflammatory mediators with radiographic mucosal thickening, (3) RV species RV-A and RV-C challenges in vitro to sinonasal epithelia produce robust cytokine responses and differential gene changes, and (4) no current therapies have produced consistent and significant resolution of disease., Conclusion: RV infections are common in persons with CRS, and incite inflammatory reactions that may result in CRS exacerbations and progression of disease. Further studies assessing RV species, and the host-virome response are required to develop new strategies targeting RV-induced CRS., (© 2019 ARS-AAOA, LLC.)

The purpose of this work is to investigate whether imaging sequences of flash-replenishment contrast enhanced ultrasound (CEUS) of the kidney result in chronic or acute bioeffects. Kidneys of female Fischer 344 rats were imaged using the flash-replenishment technique. Animals were separated into four groups (N = 31). Imaging was conducted with a 4C1 probe, driven by an Acuson Sequoia system with Definity microbubbles as the ultrasound contrast agent. During the flash phase of the imaging sequence, one kidney in each animal was exposed to either a mechanical index (MI) of 1.0 or 1.9. For each MI, half of the animals were sacrificed shortly after imaging (4 h) or after 2 weeks. A blinded veterinary nephropathologist reviewed the histopathology of both the imaged and control (non-imaged) kidney. Blood urea nitrogen (BUN) was measured for each animal prior to imaging and at the time of necropsy. Histopathology assessments in both the 1.0 and 1.9 MI groups revealed no signs of hemorrhage at either the 4-h or 2-week time point. BUN showed minor but statistically significant elevations in both the 1.0 and 1.9 MI groups, but no significant difference was present at the 2-week time point in the 1.0 MI group. All BUN levels (at both time points) remained in the normal range. In conclusion, CEUS with flash-replenishment imaging sequences did not result in kidney bioeffects observable with histology at early or late time points. Increases in BUN levels were observed after imaging, but were minimized when using a moderate MI (1.0)., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Over 96% of high-grade ovarian carcinomas and 50% of all cancers are characterized by alterations in the p53 gene. Therapeutic strategies to restore and/or reactivate the p53 pathway have been challenging. By contrast, p63, which shares many of the downstream targets and functions of p53, is rarely mutated in cancer., Methods: A novel strategy is presented for circumventing alterations in p53 by inducing the tumor-suppressor isoform TAp63 (transactivation domain of tumor protein p63) through its direct downstream target, microRNA-130b (miR-130b), which is epigenetically silenced and/or downregulated in chemoresistant ovarian cancer., Results: Treatment with miR-130b resulted in: 1) decreased migration/invasion in HEYA8 cells (p53 wild-type) and disruption of multicellular spheroids in OVCAR8 cells (p53-mutant) in vitro, 2) sensitization of HEYA8 and OVCAR8 cells to cisplatin (CDDP) in vitro and in vivo, and 3) transcriptional activation of TAp63 and the B-cell lymphoma (Bcl)-inhibitor B-cell lymphoma 2-like protein 11 (BIM). Overexpression of TAp63 was sufficient to decrease cell viability, suggesting that it is a critical downstream effector of miR-130b. In vivo, combined miR-130b plus CDDP exhibited greater therapeutic efficacy than miR-130b or CDDP alone. Mice that carried OVCAR8 xenograft tumors and were injected with miR-130b in 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC) liposomes had a significant decrease in tumor burden at rates similar to those observed in CDDP-treated mice, and 20% of DOPC-miR-130b plus CDDP-treated mice were living tumor free. Systemic injections of scL-miR-130b plus CDDP in a clinically tested, tumor-targeted nanocomplex (scL) improved survival in 60% and complete remissions in 40% of mice that carried HEYA8 xenografts., Conclusions: The miR-130b/TAp63 axis is proposed as a new druggable pathway that has the potential to uncover broad-spectrum therapeutic options for the majority of p53-altered cancers., (© 2019 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.)

With the growth of contrast-enhanced ultrasound (CEUS) clinically, there are concerns about histologic bioeffects in regards to the implementation of high mechanical index (MI) imaging, such as the imaging sequence used for a specific CEUS technique known as flash-replenishment. The data presented are results from a pilot study, which explored flash-replenishment with high and moderate MI imaging sequences at time points of 24 hours and 2 weeks post imaging. This pilot study was followed by a larger study, which can be found in a journal article entitled "Histological and Blood Chemistry Examination of the Rodent Kidney After Exposure to Flash-Replenishment Ultrasound Contrast Imaging" Nyankima et al., 2019.

Mutations in myelin protein zero (MPZ) cause inherited peripheral neuropathies, including Charcot‑Marie‑Tooth disease (CMT) and Dejerine‑Sottas neuropathy. Mutant MPZ proteins have previously been reported to cause CMT via enhanced endoplasmic reticulum (ER) stress and Schwann cell (SC) death, although the pathological mechanisms have not yet been elucidated. In this study, we generated an in vitro model of rat SCs expressing mutant MPZ (MPZ V169fs or R98C) proteins and validated the increase in cell death and ER stress induced by the overexpression of the MPZ mutants. Using this model, we examined the efficacy of 3 different aminosalicylic acids (ASAs; 4‑ASA, sodium 4‑ASA and 5‑ASA) in alleviating pathological phenotypes. FACS analysis indicated that the number of apoptotic rat SCs, RT4 cells, induced by mutant MPZ overexpression was significantly reduced following treatment with each ASA. In particular, treatment with 4‑ASA reduced the levels of ER stress markers in RT4 cells induced by V169fs MPZ mutant overexpression and relieved the retention of V169fs mutant proteins in the ER. Additionally, the level of an apoptotic signal mediator (p‑JNK) was only decreased in the RT4 cells expressing R98C MPZ mutant protein following treatment with 4‑ASA. Although 4‑ASA is known as a free radical scavenger, treatment with 4‑ASA in the in vitro model did not moderate the level of reactive oxygen species, which was elevated by the expression of mutant MPZ proteins. On the whole, the findings of this study indicate that treatment with 4‑ASA reduced the ER stress and SC death caused by 2 different MPZ mutants and suggest that ASA may be a potential therapeutic agent for CMT.