Search

Po-An Su,1 Mu-Chen Lo,2 Chiao-Ling Wang,2 Ping-Chen Yang,3 Chiao-I Chang,4 Meng-Chuan Huang,4,5 Ming-Kuo Huang,6 Kuang-I Cheng6 1Department of Operation Management, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; 2Department of Human Resource, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; 3Department of Psychiatry, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; 4Department of Public Health and Environmental Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; 5Department of Nutrition and Dietetics, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; 6Superintendent Office, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, TaiwanCorrespondence: Meng-Chuan HuangDepartment of Public Health and Environmental Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, No. 100, Shih-Chuan 1st Road, Sanmin Dist., Kaohsiung, 80708, TaiwanTel +886 7-3121101 ext. 5341Fax +886 7-3121101 ext. 5345Email mechhu@kmu.edu.twPurpose: This study investigated the association between professional quality of life, working context, and mental health outcomes among hospital personnel in Taiwan during the worldwide upsurge in COVID-19 cases.Patients and Methods: We recruited 503 hospital personnel to whom we administered online questionnaires containing items from the Professional Quality of Life (ProQoL) scale, which covers compassion satisfaction (CS), burnout (BO) and compassion fatigue (CF), the Depression, Anxiety and Stress Scale (DASS-21) and questions on work-related variables. Data were collected from 13 July to 19 August 2020.Results: The participants generally reported moderate CS and BO and low CF. Overall prevalence of mild-to-extremely-severe stress, anxiety and depression was 24.5%, 39.6% and 31.2%, respectively. Multiple logistic regression revealed that moderate-to-high BO and CF correlated with increased risks of mild-to-extremely-severe stress (OR = 4.17 and 2.23, respectively), anxiety (OR = 4.86 and 2.81, respectively) and depression (OR = 5.83 and 3.01, respectively), while moderate-to-high CS correlated with reduced risks of stress (OR = 0.53) and depression (OR = 0.45) only. There were CS and BO differences in groups categorized by marital status and profession. Anxiety increased linearly by seniority < 10, 10– 19 and ≥ 20 years (p for trend < 0.05).Conclusion: In conclusion, the subscales of ProQOL, BO and CF appeared to be associated with increased risks of stress, anxiety and depression among hospital personnel during the COVID-19 epidemic. A long-term contingency program may be needed to adjust work context variables and support emotional well-being of these workers.Keywords: COVID-19, depression, Anxiety and Stress Scale, DASS-21, hospital personnel, professional quality of life, ProQoL

Blood pressure (BP) characteristics, such as central aortic pressure and arterial stiffness, independently predict cardiovascular events. The effects of pharmacologically dissimilar β-blockers on these properties have not been fully elucidated. Patients with essential hypertension and without significant concomitant cardiovascular disease were randomly assigned to controlled-release carvedilol, force-titrated to 80 mg (n=22), or atenolol, force-titrated to 100 mg (n=19); each was given once daily for 4 weeks. Baseline characteristics were similar. At the end of week 4, atenolol and carvedilol reduced central and brachial systolic and diastolic BP to a similar extent. Central augmentation index was increased in atenolol-treated patients but not carvedilol-treated patients (atenolol 4.47% vs carvedilol -0.68%; P=.04). Mean augmented central aortic pressure increased slightly during atenolol treatment (+1.1 mm Hg) but decreased slightly during carvedilol treatment (-1.1 mm Hg), although the difference in these changes was not statistically significant (P=.23). Pulse pressure amplification was reduced more with atenolol at week 4 (atenolol -10.7% vs carvedilol -1.8%; P=.02). Therefore, we conclude that carvedilol results in more favorable pulse pressure amplification and augmentation index by increasing arterial compliance and reducing the magnitude of wave reflection, respectively, compared with atenolol. [ABSTRACT FROM AUTHOR]

Background Physician-patient racial and cultural concordance is essential to address health care disparities. Yet, limited literature on diversity, equity, and inclusion (DEI) outcomes in graduate medical education (GME) suggests the need for high-yield DEI resources. Objectives To describe and identify DEI efforts by US residency program director (PD) associations and areas for collaboration among the GME community. Methods Through bimonthly teleconferences and 5 iterative revisions from June to September 2022, the DEI workgroup of the US Organization of PD Associations developed a 17-question needs assessment survey to investigate DEI activities across residency PD associations, which was delivered twice electronically from September to November 2022 to 30 specialty PD association representatives. Results Survey response rate was 73% (22 of 30). Specialties track resident demographics more than PD demographics (11 of 22, 50% vs 7 of 22, 32%). Tracked demographics vary and include race, gender, and sexual orientation. Most PD associations have DEI committees (16 of 22, 73%) implementing various initiatives, the most common of which was providing resources to ensure diverse representation (11 of 16, 69%). Most specialties provide residency recruitment resources (14 of 22, 64%) and funding for visiting rotations or mentorship for underrepresented trainees (12 of 22, 54%). Resources for pipeline programs (7 of 22, 32%) and retention of diverse residents (7 of 22, 32%) were less common. Faculty development training focused more on teaching DEI to residents (14 of 22, 64%) than on teaching health disparities (7 of 22, 32%). Conclusions Our study demonstrates substantial DEI interventions among specialty PD associations. Yet, educational gaps exist in specific DEI content, faculty development, and curricular dissemination.

Importance: At least 10 million people in the United States have an intellectual and/or developmental disability (IDD). People with IDD experience considerably higher rates of poor overall health, chronic conditions including diabetes, mental health challenges, maternal mortality, and preventable deaths. This Special Communication proposes national goals based on a community-led consensus model that advances priority health outcomes for people with IDD and their caregivers/partners and identifies critical policy opportunities and challenges in achieving these goals. A community-led consensus agenda offers a foundation for focusing research, improving data collection and quality measurement, enhancing coverage and payment for services, and investing in a prepared clinical workforce and infrastructure in ways that align with lived experiences and perspectives of community members., Observations: People with IDD prioritize holistic health outcomes and tailored supports and services, driven by personalized health goals, which shift over their life course. Caregivers/partners need support for their own well-being, and easy access to resources to optimize how they support loved ones with IDD. Development of an adequately prepared clinical workforce to serve people with IDD requires national and regional policy changes that incentivize and structure training and continuing education. Ensuring effective and high-value coverage, payment, and clinical decisions requires investments in new data repositories and data-sharing infrastructure, shared learning across public and private payers, and development of new technologies and tools to empower people with IDD to actively participate in their own health care., Conclusions and Relevance: Consensus health priorities identified in this project and centered on IDD community members' perspectives are generalizable to many other patient populations. Public and private payers and regulators setting standards for health information technology have an opportunity to promote clinical data collection that focuses on individuals' needs, quality measurement that emphasizes person-centered goals rather than primarily clinical guidelines, and direct involvement of community members in the design of payment policies. Clinical education leaders, accrediting bodies, and investors/entrepreneurs have an opportunity to innovate a better prepared health care workforce and shared data infrastructure to support value-based care programs.

To confirm target engagement of hits from our high-throughput screening efforts, we ran biophysical assays on several hundreds of hits from 15 different high-throughput screening campaigns. Analyzing the biophysical assay results from these screening campaigns led us to conclude that we could be more strategic in our biophysical analysis of hits by first confirming activity in a thermal shift assay (TSA) and then confirming activity in either a surface plasmon resonance (SPR) assay or a temperature-related intensity change (TRIC) assay. To understand how this new workflow shapes the quality of the final hits, we compared TSA/SPR or TSA/TRIC confirmed and unconfirmed hits to one another using four measures of compound quality: quantitative estimate of drug-likeness (QED), Pan-Assay Interference Compounds (PAINS), promiscuity, and aqueous solubility. In general, we found that the biophysically confirmed hits performed better in the compound quality metrics than the unconfirmed hits, demonstrating that our workflow not only confirmed target engagement of the hits but also enriched for higher quality hits., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Christopher Fotsch reports a relationship with Amgen Inc that includes: employment and equity or stocks. Debaleena Basu reports a relationship with Amgen Inc San Francisco that includes: employment and equity or stocks. Ryan Case reports a relationship with Amgen Inc San Francisco that includes: employment and equity or stocks. Qing Chen reports a relationship with Amgen Inc that includes: employment and equity or stocks. Pratibha C. Koneru reports a relationship with Amgen Inc San Francisco that includes: employment and equity or stocks. Mei-Chu Lo reports a relationship with Amgen Inc San Francisco that includes: employment and equity or stocks. Rachel Ngo reports a relationship with Amgen Inc San Francisco that includes: employment and equity or stocks. Pooja Sharma reports a relationship with Amgen Inc that includes: employment and equity or stocks. Amit Vaish reports a relationship with Amgen Inc that includes: employment and equity or stocks. Xiang Yi reports a relationship with Amgen Inc that includes: employment and equity or stocks. Stephan Zech reports a relationship with Amgen Inc that includes: employment and equity or stocks. Peter Hodder reports a relationship with Amgen Inc that includes: employment and equity or stocks. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Wireless data traffic is expected to exponentially increase in the future, and meeting this demand will require high data rate photonic-wireless links operating in the W-band (75-110 GHz). For this purpose, pulse-amplitude-modulation with four levels (PAM-4)-based intensity modulation and direct detection (IM-DD) photonic-wireless systems are preferred due to their simplified configuration. In this Letter, we present an experimental demonstration of an IM-DD PAM-4 photonic-wireless link in the W-band, leveraging a monolithic dual-laser photonic chip to enhance integration. Through injection-locking by an optical comb, the chip generates a W-band wireless signal via photo-mixing with a photodiode. This comb injection approach facilitates the phase correlation of the chip's two modes, resulting in a stabilized beat note. Additionally, the on-chip integration of the dual lasers enables the modulation of the two modes with a single modulator, improving the signal-to-noise ratio (SNR) while eliminating the need for extra splitters or combiners. Meanwhile, the envelope detector (ED) plays a crucial role in the simplified configuration, contributing to the overall decrease in size, weight, power, and complexity of the system. The integration of the chip-based phase-locked light source and the utilization of the ED thus signify noteworthy features of our experimental setup, which functions without the necessity of both optical and electrical local oscillators. PAM-4 signal modulation is simultaneously applied to the two coherent optical carriers. Our experiments have effectively transmitted 5 and 10 Gbaud PAM-4 W-band wireless signals in a cost-effective, lightweight, and straightforward configuration, achieving a line data rate of up to 20 Gbit/s economically. These experimental results demonstrate the practical potential of implementing fully integrated photonic-wireless transmitters.

B3GNT2 is responsible for elongation of cell surface long-chain polylactosamine, which influences the regulation of the immune response, making it an attractive target for immunomodulation. In the development of amide containing B3GNT2 inhibitors guided by structure-based drug design, imidazolones were found to successfully serve as amide bioisosteres. This novel imidazolone isosteric strategy alleviated torsional strain of the amide bond on binding to B3GNT2 and improved potency, isoform selectivity, as well as certain physicochemical and pharmacokinetic properties. Herein, we present the synthesis, SAR, X-ray cocrystal structures, and in vivo PK properties of imidazol-4-ones in the context of B3GNT2 inhibition.

Traditionally, clinician educators are tasked with the responsibility of training future physician workforce. However, there is limited identification of skills required to fulfill this responsibility and a lack of consensus on effective faculty development for career growth as a clinician educator. The newly released Accreditation Council of Graduate Medical Education (ACGME) Clinician Educator (CE) Milestones framework outlines important skills for clinician educators and provides the opportunity to create robust faculty development. In this paper, members of the Society of General Internal Medicine Education Committee discuss the importance of these CE Milestones, outline the novel themes highlighted in the project, and provide recommendations for proper application on both the individual and institutional levels to optimize faculty development. The paper discusses strategies for how to apply the CE Milestones as a tool to create a culture of professional growth and self-directed learning. Using a reflective approach, CE faculty and mentors can identify areas of proficiency and opportunities for growth, thereby creating individualized professional development plans for career success. Institutions should use aggregate CE Milestones data as a needs assessment of their faculty "population" to create targeted faculty development. Most importantly, institutions should not use CE Milestones for high-stakes assessments but rather encourage reflection by CE faculty and create subsequent robust faculty development programs. The ACGME CE Milestones present an exciting opportunity and lay an important foundation for future CE faculty development., (© 2023. The Author(s), under exclusive licence to Society of General Internal Medicine.)

In Sarawak, Malaysia, several exceptional safety precautions and measures were adopted to prevent the outbreak of coronavirus disease 2019 (COVID-19) pandemic from spreading. Individuals' attitudes and opinions have impact on their obedience toward control procedures. Sarawak residents' attitudes and opinions toward COVID-19 were investigated in the present study. An online questionnaire developed using Google Forms was completed by 1,462 residents from all 12 divisions in Sarawak. The findings show that most Sarawak residents have positive attitudes and opinions about current standard operating procedures (SOPs) toward COVID-19. More than half of the respondents stand unbiased for the effectiveness of these SOPs, while most respondents have a neutral standpoint regarding the current law enforcement. The partial least square regression results found using the WarpPLS 7.0 software indicate that Sarawak residents' attitudes, opinions about current SOPs, and their effectiveness are significantly linked to practices for the prevention of COVID-19 outbreak, whereas these residents' opinions about current law enforcement were observed to have no significant relationship with proper practices for measures.

Telehealth services, specifically telemedicine audio-video and audio-only patient encounters, expanded dramatically during the COVID-19 pandemic through temporary waivers and flexibilities tied to the public health emergency. Early studies demonstrate significant potential to advance the quintuple aim (patient experience, health outcomes, cost, clinician well-being, and equity). Supported well, telemedicine can particularly improve patient satisfaction, health outcomes, and equity. Implemented poorly, telemedicine can facilitate unsafe care, worsen disparities, and waste resources. Without further action from lawmakers and agencies, payment will end for many telemedicine services currently used by millions of Americans at the end of 2024. Policymakers, health systems, clinicians, and educators must decide how to support, implement, and sustain telemedicine, and long-term studies and clinical practice guidelines are emerging to provide direction. In this position statement, we use clinical vignettes to review relevant literature and highlight where key actions are needed. These include areas where telemedicine must be expanded (e.g., to support chronic disease management) and where guidelines are needed (e.g., to prevent inequitable offering of telemedicine services and prevent unsafe or low-value care). We provide policy, clinical practice, and education recommendations for telemedicine on behalf of the Society of General Internal Medicine. Policy recommendations include ending geographic and site restrictions, expanding the definition of telemedicine to include audio-only services, establishing appropriate telemedicine service codes, and expanding broadband access to all Americans. Clinical practice recommendations include ensuring appropriate telemedicine use (for limited acute care situations or in conjunction with in-person services to extend longitudinal care relationships), that the choice of modality be done through patient-clinician shared decision-making, and that health systems design telemedicine services through community partnerships to ensure equitable implementation. Education recommendations include developing telemedicine-specific educational strategies for trainees that align with accreditation body competencies and providing educators with protected time and faculty development resources., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Telehealth visits have become an integral model of healthcare delivery since the COVID-19 pandemic. This rapid expansion of telehealthcare delivery has forced faculty development and trainee education in telehealth to occur simultaneously. In response, academic medical institutions have quickly implemented clinical training to teach digital health skills to providers across the medical education continuum. Yet, learners of all levels must still receive continual assessment and feedback on their skills to align with the telehealth competencies and milestones set forth by the Association of American Medical Colleges (AAMC) and the Accreditation Council for Graduate Medical Education (ACGME). This paper discusses key educational needs and emerging areas for faculty development in telehealth teaching and assessment of telehealth competencies. It proposes strategies for the successful integration of the AAMC telehealth competencies and ACGME milestones into medical education, including skills in communication, data gathering, and patient safety with appropriate telehealth use. Direct observation tools in the paper offer educators novel instruments to assess telehealth competencies in medical students, residents, and peer faculty. The integration of AAMC and ACGME telehealth competencies and the new assessment tools in this paper provide a unique perspective to advance clinical practice and teaching skills in telehealthcare delivery., (© 2022. The Author(s), under exclusive licence to Society of General Internal Medicine.)

Photonic generation of Terahertz (THz) carriers displays high potential for THz communications with a large tunable range and high modulation bandwidth. While many photonics-based THz generations have recently been demonstrated with discrete bulky components, their practical applications are significantly hindered by the large footprint and high energy consumption. Herein, we present an injection-locked heterodyne source based on generic foundry-fabricated photonic integrated circuits (PIC) attached to a uni-traveling carrier photodiode generating high-purity THz carriers. The generated THz carrier is tunable within the range of 0-1.4 THz, determined by the wavelength spacing between the two monolithically integrated distributed feedback (DFB) lasers. This scheme generates and transmits a 131 Gbits -1 net rate signal over a 10.7-m distance with -24 dBm emitted power at 0.4 THz. This monolithic dual-DFB PIC-based THz generation approach is a significant step towards fully integrated, cost-effective, and energy-efficient THz transmitters., (© 2022. The Author(s).)

Human genome wide association studies confirm the association of the rs738409 single nucleotide polymorphism (SNP) in the gene encoding protein patatin like phospholipase domain containing 3 ( PNPLA3 ) with nonalcoholic fatty liver disease (NAFLD); the presence of the resulting mutant PNPLA3 I148M protein is a driver of nonalcoholic steatohepatitis (NASH). While Pnpla3 -deficient mice do not display an adverse phenotype, the safety of knocking down endogenous wild type PNPLA3 in humans remains unknown. To expand the scope of a potential targeted NAFLD therapeutic to both homozygous and heterozygous PNPLA3 rs738409 populations, we sought to identify a minor allele-specific small interfering RNA (siRNA). Limiting our search to SNP-spanning triggers, a series of chemically modified siRNA were tested in vitro for activity and selectivity toward PNPLA3 rs738409 mRNA. Conjugation of the siRNA to a triantennary N -acetylgalactosamine (GalNAc) ligand enabled in vivo screening using adeno-associated virus to overexpress human PNPLA3 I148M versus human PNPLA3 I148I in mouse livers. Structure-activity relationship optimization yielded potent and minor allele-specific compounds that achieved high levels of mRNA and protein knockdown of human PNPLA3 I148M but not PNPLA3 I148I . Testing of the minor allele-specific siRNA in PNPLA3 I148M -expressing mice fed a NASH-inducing diet prevented PNPLA3 I148M -driven disease phenotypes, thus demonstrating the potential of a precision medicine approach to treating NAFLD.

Background: With growing resident burnout, Accreditation Council for Graduate Medical Education issued new requirements for program interventions to optimize resident well-being. Little evidence exists on how to best teach resiliency to residents. This study assesses the impact of both a grassroots intervention and formal resiliency curriculum on resident burnout and well-being., Materials and Methods: From November 2016 to August 2017, residents in a large Internal Medicine Residency Program participated in grassroots wellness interventions from the resident-led Gator Council in Gainesville, FL USA. From August 2017 to June 2018, residents participated in a formal program-driven resiliency curriculum. Wellness interventions included monthly morning reports, bimonthly workshops, and biannual noon conferences. Pre- and postintervention Maslach Burnout Inventory (MBI) and Physician Well-Being Index (PWBI) assessed the effect of both interventions on resident burnout and well-being. Statistical analyses used Student's t -test, Fisher's exact tests, and linear regression model., Results: One hundred and twenty-two residents participated in grassroots interventions. One hundred and seventeen (87 residents, 35 students) participated in formal curriculum. Mean MBI scores for all three sections did not differ between pre -and postgrassroots intervention (emotional exhaustion [EE] P = 0.46; depersonalization [DP] P = 0.43; personal accomplishment [PA] P = 0.73]) or between pre- and postcurriculum (EE P = 0.20; DP P = 0.40; PA P = 0.51). Students scored higher burnout levels compared to residents in EE ( P = 0.001) and PA ( P = 0.02). Pre- versus postcurriculum PWBI scores did not differ among residents ( P = 0.20), while PWBI scores improved among students ( P = 0.01)., Conclusions: This study found no improvement in resident burnout or well-being from a bottom-up and top-down approach. Our results imply the need for an early wellness curriculum to improve student well-being given their higher level of burnout. System-wide efforts are vital to combat physician burnout., Competing Interests: There are no conflicts of interest., (Copyright: © 2021 Journal of Education and Health Promotion.)

Background: Approximately half of all women with anginal symptoms and/or signs of ischemia and no obstructive coronary artery disease (INOCA) referred for coronary angiography have elevated risk for major adverse cardiac events (MACE), poor quality of life and resource consumption. Yet, guidelines focus on symptom management while clinical practice typically advocates only reassurance. Pilot studies of INOCA subjects suggest benefit with intensive medical therapy (IMT) that includes high-intensity statins and angiotensin converting enzyme inhibitors (ACE-I) or receptor blockers (ARB) to provide the rationale for a randomized pragmatic trial to limit MACE., Methods: The Women's IschemiA TRial to Reduce Events In Non-ObstRuctive CAD is a multicenter, prospective, randomized, blinded outcome evaluation (PROBE design) of a pragmatic strategy of IMT vs usual care (UC) in 4,422 symptomatic women with INOCA (NCT03417388) in approximately 70 United States sites. The hypothesis is that IMT will reduce the primary outcome of first occurrence of MACE by 20% vs. UC at ∼2.5 year followup. Secondary outcomes include quality of life, time to return to "duty"/work, healthcare utilization, angina, cardiovascular death and individual primary outcome components over 3 years follow-up. The study utilizes web-based data capture, e-consents, single IRB and centralized pharmacy distribution of strategy medications directly to patients' homes to reduce site and patient burden. A biorepository will collect blood samples to assess potential mechanisms., Conclusions: The results of this trial will provide important data necessary to inform guidelines regarding how best to manage this growing and challenging population of women with INOCA., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Since the revolutionary discovery of RNA interference (RNAi) more than 20 years ago, synthetic small interfering RNAs (siRNAs) have held great promise as therapeutic agents for treating human diseases by the specific knockdown of disease-causing gene products. To facilitate the development of siRNA therapeutics, a robust, high-throughput in vitro assay for measuring gene silencing is imperative during the initial siRNA lead sequence identification and, later, during the lead optimization with chemically modified siRNAs. There are several potential assays for measuring gene expression. Quantitative reverse transcription PCR (qRT-PCR) has been widely used to quantitate messenger RNA (mRNA). This method has a few disadvantages, however, such as the requirement for RNA isolation, complementary DNA (cDNA) generation, and PCR reaction, which are labor-intensive, limit the assay throughput, and introduce variability. We chose a high-content imaging assay, bDNA FISH, that combines the branched DNA (bDNA) technology with fluorescence in situ hybridization (FISH) to measure gene silencing by siRNAs because it is sensitive and robust with a short reagent procurement and assay development time. We also built a fully automated liquid-handling platform for executing bDNA FISH assays to increase throughput, and the system has a capacity of generating 192 concentration-response curves in a single run. We have successfully developed and executed the bDNA FISH assays for multiple targets using this automated platform to identify and optimize siRNA candidate molecules. Examples of the bDNA FISH assay for selected targets are presented.

β1,3-N-acetylglucosaminyltransferases (B3GNTs) are Golgi-resident glycosyltransferases involved in the biosynthesis of poly-N-acetyl-lactosamine chains. They catalyze the addition of the N-acetylglucosamine to the N-acetyl-lactosamine repeat as a key step of the chain elongation process. Poly-N-acetyl-lactosamine is involved in the immune system in many ways. Particularly, its long chain has been demonstrated to suppress excessive immune responses. Among the characterized B3GNTs, B3GNT2 is the major poly-N-acetyl-lactosamine synthase, and deletion of its coding gene dramatically reduced the cell surface poly-N-acetyl-lactosamine and led to hypersensitive and hyperresponsive immunocytes. Despite the extensive functional studies, no structural information is available to understand the molecular mechanism of B3GNT2, as well as other B3GNTs. Here we present the structural and kinetic studies of the human B3GNT2. Five crystal structures of B3GNT2 have been determined in the unliganded, donor substrate-bound, acceptor substrate-bound, and product(s)-bound states at resolutions ranging from 1.85 to 2.35 Å. Kinetic study shows that the transglycosylation reaction follows a sequential mechanism. Critical residues involved in recognition of both donor and acceptor substrates as well as catalysis are identified. Mutations of these invariant residues impair B3GNT2 activity in cell assays. Structural comparison with other glycosyltransferases such as mouse Fringe reveals a novel N-terminal helical domain of B3GNTs that may stabilize the catalytic domain and distinguish among different acceptor substrates., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Clinician-educator (CE) careers in academic medicine are heterogeneous. Expectations for CEs have grown, along with a need to better prepare CEs for these roles., Objective: To assess whether advanced education training is associated with productivity and success., Design: We used a sequential mixed methods approach, collecting quantitative survey data and qualitative focus groups data. We developed a three-tiered categorization of advanced training to reflect intensity by program type., Participants: We surveyed CEs in the Society of General Internal Medicine (SGIM) and conducted two focus groups at an SGIM annual meeting., Main Measures: Primary outcomes were academic productivity (manuscripts, presentations, etc.) and leadership role attainment. Secondary analysis examined the interactive effect of gender and training intensity on these outcomes., Key Results: A total of 198 completed the survey (response rate 53%). Compared with medium- or low-intensity training, high-intensity training was associated with a greater likelihood of publishing ≥ 3 first- or senior-author manuscripts (adjusted OR 2.6; CI 0.8-8.6; p = 0.002), teaching ≥ 3 lectures/workshops at the regional/national/international level (adjusted OR 5.7; CI 1.5-21.3; p = 0.001), and having ≥ 3 regional/national committee memberships (adjusted OR 3.4; CI 1.0-11.7; p = 0.04). Among participants in the "no training" and "high-intensity training" categories, men were more likely to have ≥ 3 publications (OR 4.87 and 3.17, respectively), while women in the high intensity category had a likelihood similar to men with no training (OR 4.81 vs. OR 4.87). Participants felt the value of advanced training exists not only in content but also in networking opportunities that programs provide., Conclusions: While opinions were divided as to whether advanced training is necessary to position oneself for education roles, it is associated with greater academic productivity and reduced gender disparity in the publication domain. Institutions should consider providing opportunities for CEs to pursue advanced education training.

Neurostimulation therapies for psychiatric disorders often have limited clinical efficacy. The limited efficacy might arise from a mismatch between therapy and disease mechanisms. Mental disorders are believed to arise from communication breakdown in distributed brain circuits, and thus altering connectivity between brain regions might be an effective way to restore normal brain communication. Synchronized neural oscillations (coherence) and synaptic strength are two common measures of brain connectivity. In this work, we developed an electrical stimulation method for altering narrow-frequency-band (theta, 5-8 Hz) coherence and synaptic strength. We tested this method in a circuit between infralimbic cortex (IL) and basolateral amygdala (BLA), which is broadly implicated in fear regulation. 6 Hz pulse trains were delivered into IL and BLA with various inter-train lags. These paired trains induced long-lasting synaptic strength change and a brief coherence enhancement in the IL-BLA circuit. This enhancement was specific to the "top-down" (IL-to-BLA) direction, and only occurred when the IL and BLA pulse trains had a relative lag of 180° (83 ms). Since the IL-BLA connection is known to be highly relevant to fear regulation, this method provides a tool to study the relationship between brain connectivity and fear behaviors. Further, it may be a new approach to study the relative roles of synaptic strength and oscillatory synchrony in brain network communication.

Background: Ehlers-Danlos syndrome (EDS) is a group of inherited connective tissue disorders characterized by skin hyperextensibility, joint hypermobility and soft tissue vulnerable to blunt injury. Early recognition and diagnosis are crucial to patients to provide appropriate treatment, as well as to screen for life-threatening conditions such as aortic dissection and hollow organ perforation. The diagnosis of EDS is made based on clinical presentations, skin biopsy, and electron microscopy findings. To date, mutations in at least 20 genes have been found to cause the Ehlers-Danlos syndromes. However, EDS is still underestimated due to lack of awareness of its variable clinical presentations. Here we reported an EDS case with atypical initial presentation and a novel genetic mutation., Case Presentation: This 4-year-old Taiwanese male patient presented with easy bruising, multiple ecchymoses, joint hypermobility, hyperextensible skin, and prolonged pretibial haematoma. He was initially suspected of a bleeding tendency due to coagulation disorders. The coagulation test results were normal. DNA sequencing was performed for molecular diagnosis. Subsequently, the diagnosis of classical EDS was made by identifying a novel frameshift mutation in COL5A1 [NM&#95;000093.4:c.4211&#95;4212delAG, p.Gln1404Arg]. This mutation in the type V collagen gene COL5A1 contributes to the phenotype of classical EDS. This novel frameshift mutation may disturb the structural stability of collagen V and interfere with its heparin binding capacity, explaining the chronic haematoma., Conclusion: The reported case showed the unusual features of chronic haematoma. This novel frameshift mutation and its phenotype correlation can provide useful information for practitioners about early recognition in Ehlers-Danlos syndrome.

Triple-negative breast cancer (TNBC) is an aggressive cancer subtype for which effective therapies are unavailable. TNBC has a high frequency of tumor protein p53 (Tp53/p53)- and phosphatase and tensin homolog (PTEN) deficiencies, and combined p53- and PTEN-deficiency is associated with poor prognosis and poor response to anticancer therapies. In this study, we discovered that combined p53- and PTEN-deficiency in TNBC activates expression of the transcription factor mesenchyme homeobox 1 (MEOX1). We found that MEOX1 is expressed only in TNBC cells with frequent deficiencies in p53 and PTEN, and that its expression is undetectable in luminal A, luminal B, and HER2+ subtypes, as well as in normal breast cells with wild-type (WT) p53 and PTEN. Notably, siRNA knockdown of both p53 and PTEN activated MEOX1 expression in breast cancer cells, whereas individual knockdowns of either p53 or PTEN had only minimal effects on MEOX1 expression. MEOX1 knockdown abolished cell proliferation of p53- and PTEN-deficient TNBC in vitro and inhibited tumor growth in vivo , but had no effect on the proliferation of luminal and HER2+ cancer cells and normal breast cells. RNA-Seq and immunoblotting analyses showed that MEOX1 knockdown decreased expression of tyrosine kinase 2 (TYK2), signal transducer and activator of transcription 5B (STAT5B), and STAT6 in p53- and PTEN-deficient TNBC cells. These results reveal the effects of combined p53- and PTEN-deficiency on MEOX1 expression and TNBC cell proliferation, suggesting that MEOX1 may serve as a potential therapeutic target for managing p53- and PTEN-deficient TNBC., Competing Interests: Conflict of interest—The authors declare that they have no conflicts of interest with the contents of this article., (© 2020 Gasparyan et al.)

Background: In-transit metastases (ITMs) in melanoma are associated with poor prognosis, however a significant proportion of these patients survive for extended periods without further disease progression. We routinely use locoregional treatment e.g. Diphencyprone (DPCP) and/or isolated limb infusion (ILI) as long-term palliation. This study aimed to identify correct sequencing of these therapies based on disease burden and progression., Method: Retrospective evaluation of all melanoma patients with ITMs treated with DPCP/ILI/both from 2010 to 2017 at our Cancer Centre was performed. Patients were initially assessed in a multidisciplinary setting and empirically prescribed DPCP for low-disease burden, ILI for high-disease burden. Patient demographics, tumour characteristics, response to therapy, ITM progression and patient outcomes were analysed., Results: 78 patients (M:F = 30:48), aged 47-95years (median 74years) treated with DPCP/ILI/both (n = 44/21/13) were identified. Progression-free survival (PFS) was significantly increased in patients responsive to DPCP or ILI as initial treatment. Patients who failed on DPCP and subsequently treated with ILI had a significantly increased PFS compared to DPCP alone (p = 0.026, HR = 0.048). This was not the case with patients who were treated with DPCP following failed ILI. All patients who failed to respond to the initial therapy progressed within 6 months., Conclusion: Our study shows that careful stratification ITM patients according to disease burden is fundamental to optimal outcomes. High-disease burden patients benefit from initial ILI; low-disease burden patients should commence on DPCP. ILI can be considered in DPCP patients who fail early. Systemic therapy should be considered when locoregional therapies fail after 12 months or after rapid relapse following ILI., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: For invasive primary cutaneous melanoma, wider excision is advocated to reduce local recurrence risk and improve patient outcomes. Excision detail is controversial, especially in intermediate- and high-risk primary melanoma (AJCC pT2-pT4). Guidance varies from sizes 1 to 3 cm (translating into large defects of 2-6 cm). The aim of this study was to determine the reconstructive and resource burden of wider excision margins (EMs)., Methods: Data analysis from our prospective database (2008-2017) included 1184 patients (563F:621 M) with cutaneous melanoma (pT1b-pT4b). Procedure tariff data were sourced from our financial services department., Results: Two hundred twenty-nine patients had a narrower EM (1 cm) and 995 (80.7%) had a wider EM (2-3 cm). Reconstructive requirement significantly increased with a wider EM collectively (11.3% vs 29.3%, odds ratio (OR) = 3.2; p < 0.0001), in the extremities (15.2% vs 42.0%; p < 0.0001), and in the head and neck (H&N) (23.5 % vs 64.7%; p < 0.0001). Reconstruction significantly increased hospitalisation rates (26.6% vs 63.0%, OR = 4.7; p < 0.0001) collectively, in the H&N (26.8 % vs 53.9%), and in the upper (18.9 % vs 42.3%) and lower extremities (34.8% vs 77.3%). Narrower EMs significantly reduced hospitalisation rates in the upper and lower extremities (7.1% vs 28.5%; p = 0.004, 37.9% vs 58.5%; p = 0.005, respectively). Overall procedure cost significantly increased by £180 (mean, p < 0.0001) and £346 (median, p = 0.0004) per patient when reconstruction was required., Conclusions: Our data suggest substantial impact of wider EM on patients, which more than doubled in the functionally and cosmetically sensitive extremities and the H&N region. Reconstructions add significant financial and healthcare service burden. Without randomised controlled trial (RCT) evidence demonstrating increased efficacy of wider EM, narrower EM is advocated whilst awaiting future planned RCT results specifically investigating on this., Competing Interests: Declaration of Competing Interest None., (Crown Copyright © 2019. Published by Elsevier Ltd. All rights reserved.)

Overexpression of the antiapoptotic protein Mcl-1 provides a survival advantage to some cancer cells, making inhibition of this protein an attractive therapeutic target for the treatment of certain types of tumors. Herein, we report our efforts toward the identification of a novel series of macrocyclic Mcl-1 inhibitors featuring an α-hydroxy phenylacetic acid pharmacophore or bioisostere. This work led to the discovery of 1 , a potent Mcl-1 inhibitor (IC 50 = 19 nM in an OPM-2 cell viability assay) with good pharmacokinetic properties and excellent in vivo efficacy in an OPM-2 multiple myeloma xenograft model.

Cross frequency coupling (CFC) is emerging as a fundamental feature of brain activity, correlated with brain function and dysfunction. Many different types of CFC have been identified through application of numerous data analysis methods, each developed to characterize a specific CFC type. Choosing an inappropriate method weakens statistical power and introduces opportunities for confounding effects. To address this, we propose a statistical modeling framework to estimate high frequency amplitude as a function of both the low frequency amplitude and low frequency phase; the result is a measure of phase-amplitude coupling that accounts for changes in the low frequency amplitude. We show in simulations that the proposed method successfully detects CFC between the low frequency phase or amplitude and the high frequency amplitude, and outperforms an existing method in biologically-motivated examples. Applying the method to in vivo data, we illustrate examples of CFC during a seizure and in response to electrical stimuli., Competing Interests: JN, LM, EB, ML, AW, SC, UE, MK No competing interests declared, (© 2019, Nadalin et al.)

Caloric restriction activates sirtuin 1 (SIRT1) and induces a variety of metabolic effects that are beneficial for preventing age-related disease. The present study screened a commercially available used drug library to develop small molecule activators of SIRT1 as therapeutics for treatment of metabolic disorders. Using an in vitro fluorescence assay, the cancer therapeutic camptothecin increased SIRT1 enzymatic activity by 5.5-fold, indicating it to be a potent SIRT1 activator. Camptothecin also elevated the nicotinamide adenine dinucleotide (NAD) + /NADH ratio and increased SIRT1 protein levels in differentiated C 2 C 12 myogenic cells. Treatment of C 2 C 12 myotubes with camptothecin increased phosphorylation of AMP-dependent kinase (AMPK) and acetyl-coenzyme A carboxylase, caused nuclear translocation and deacetylation of forkhead box O1 (FoxO1), increased transcription and protein expression of adipose triglyceride lipase (ATGL), decreased the amount of intracellular oil droplets, and significantly increased β-oxidation of fatty acids. These in vitro data were confirmed in vivo as camptothecin treatment of C57BL/6J mice reduced fat and plasma triglyceride levels. All of the above camptothecin-induced alterations were attenuated by the SIRT1-specific inhibitor nicotinamide and/or 6-[4-(2-piperidin-1-ylethoxy) phenyl]-3-pyridin-4-ylpyrazolo [1,5-a]pyrimidin (compound C). Thus, camptothecin activation of SIRT1 promotes lipid catabolism through AMPK/FoxO1/ATGL signaling.

Background: Literature increasingly supports the inverse relationship of vitamin D (VitD) level and type 2 diabetes (T2DM). Proposed protective mechanisms of VitD include its anti-inflammatory effects, increased insulin secretion via pancreatic β-cell stimulation, and downregulation of parathyroid hormone levels. Interventional studies show mixed results of VitD therapy in prediabetic patients with VitD deficiency or diabetic patients with normal VitD levels., Study Question: Does high-dose VitD replacement improve glycemic control and microalbuminuria (MAU) in uncontrolled T2DM and concurrent VitD deficiency?, Study Design: This placebo-controlled, double-blinded study randomized 30 subjects aged 30-65 years with an elevated HbA1c level of 7.5%-10% and a low total 25-hydroxyvitamin-D value of <20 ng/mL to either placebo (n = 16) or ergocalciferol 50,000 IU (n = 14) once weekly for 8 weeks then once monthly for 4 months., Measures and Outcomes: Primary outcome was difference in HbA1c from baseline to month 6 between the VitD-intervention group and the placebo-controlled group. Secondary end points were differences in total 25-hydroxyvitamin-D and MAU. Paired t tests and linear mixed-effects models were used for statistical analysis., Results: No significant differences were seen in HbA1c or MAU between baseline versus postintervention visits within the placebo group (HbA1c: 8.4% ± 0.2 vs. 8.1% ± 0.3, P = 0.088; MAU: 94.1 mg/g ± 43.9 vs. 45.9 mg/g ± 20.2, P = 0.152) and the intervention group (HbA1c: 8.8% ± 0.3 vs. 8.7% ± 0.4, P = 0.692; MAU: 167.8 mg/g ± 70.1 vs. 108.5 mg/g ± 39.9, P = 0.356). The difference between placebo-slope and intervention-slope was nonsignificant for MAU (β = -0.1 mg/g ± 0.4, P = 0.835) but was significant for total 25-hydroxyvitamin-D (β = 11.7 ng/mL ± 2.5, P ≤ 0.001). Greater HbA1c reduction occurred unexpectedly in the placebo group ((Equation is included in full-text article.)= -0.4% ± 0.2) than in the intervention group ((Equation is included in full-text article.)= -0.2% ± 0.4), although the difference in slopes was not significant (β = 0.2% ± 0.4, P = 0.640)., Conclusions: Our proof-of-concept study found no benefit of high-dose VitD therapy in glycemic control and MAU in uncontrolled T2DM and VitD deficiency. Post hoc analyses raise concerns for high-dose VitD therapy to delay glycemic improvement. Large-scale interventional trials are much needed in this patient population to substantiate our findings and elucidate VitD's mechanisms on glucose metabolism.

Objective: Neurostimulation technologies are important for studying neural circuits and the connections that underlie neurological and psychiatric disorders. However, current methods come with limitations such as the restraint on movement imposed by the wires delivering stimulation. The objective of this study was to assess whether the e-Particle (EP), a novel wireless neurostimulator, could sufficiently stimulate the brain to modify behavior without these limitations., Approach: Rats were implanted with the EP and a commercially available stimulating electrode. Animals received rewarding brain stimulation, and performance in a conditioned place preference (CPP) task was measured. To ensure stimulation-induced neuronal activation, immediate early gene c-fos expression was also measured., Main Results: The EP was validated in a commonly used CPP task by demonstrating that (1) wireless stimulation via the EP induced preference behavior that was comparable to that induced by standard wired electrodes and (2) neuronal activation was observed in projection targets of the stimulation site., Significance: The EP may help achieve a better understanding of existing brain stimulation methods while overcoming their limitations. Validation of the EP in a behavioral model suggests that the benefits of this technology may extend to other areas of animal research and potentially to human clinical applications.

Triple-negative breast cancer (TNBC) is the most difficult subtype of breast cancer to treat due to a paucity of effective targeted therapies. Many studies have reported that breast cancer stem cells (BCSCs) are enriched in TNBC and are responsible for chemoresistance and metastasis. In this study, we identify LRP8 as a novel positive regulator of BCSCs in TNBC. LRP8 is highly expressed in TNBC compared to other breast cancer subtypes and its genomic locus is amplified in 24% of TNBC tumors. Knockdown of LRP8 in TNBC cell lines inhibits Wnt/β-catenin signaling, decreases BCSCs, and suppresses tumorigenic potential in xenograft models. LRP8 knockdown also induces a more differentiated, luminal-epithelial phenotype and thus sensitizes the TNBC cells to chemotherapy. Together, our study highlights LRP8 as a novel therapeutic target for TNBC as inhibition of LRP8 can attenuate Wnt/β-catenin signaling to suppress BCSCs., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Iron or oxygen regulates the stability of hypoxia inducible factor-1α (HIF-1α). We investigated whether ferrous glycinate would affect HIF-1α accumulation, aerobic glycolysis and mitochondrial energy metabolism in human A549 lung cancer cells. Incubation of A549 cells with ferrous glycinate decreased the protein levels of HIF-1α, which was abrogated by proteosome inhibitor, or prolyl hydroxylase inhibitor. The addition of ferrous glycinate decreased protein levels of glucose transporter-1, hexokinase-2, and lactate dehydrogenase A, and decreased pyruvate dehydrogenase kinase-1 (PDK-1) and pyruvate dehydrogenase (PDH) phosphorylation in A549 cells. Ferrous glycinate also increased the expression of the mitochondrial transcription factor A (TFAM), and the mitochondrial protein, cytochrome c oxidase (COX-IV). Silencing of HIF-1α expression mimicked the effects of ferrous glycinate on PDK-1, PDH, TFAM and COX-IV in A549 cells. Ferrous glycinate increased mitochondrial membrane potential and ATP production in A549 cells. These results suggest that ferrous glycinate may reverse Warburg effect through down regulating HIF-1α in A549 cells.

N ε -(carboxymethyl) lysine (CML) plays causal roles in diabetic complications. In the present study, we investigated whether CML-induced HIF-1α accumulation and epithelial-mesenchymal transition (EMT) in HK-2 renal proximal tubular epithelial cells. Treatment with CML-BSA increased reactive oxygen species (ROS) production reduced the mitochondrial membrane potential and induced mitochondrial fragmentation. Pre-treatment of cells with antioxidant, α-lipoic acid, normalised the ROS production and restored the mitochondrial membrane potential. These changes were accompanied with morphological changes of epithelial mesenchymal transition. CML-BSA increased the protein level of hypoxia-inducible factor-1α (HIF-1α), and the EMT-associated transcription factor, TWIST. These effects were reversed by α-lipoic acid. CML-BSA increased the protein levels of mesenchymal-specific markers, including vimentin, α-smooth muscle actin, which were alleviated by pre-treatment with α-lipoic acid. Our data suggest that CML-BSA induces EMT through a ROS/HIF-1α/TWIST-dependent mechanism, and that α-lipoic acid may alleviate the CML-induced EMT in renal tubular cells.

Background: Researchers paid little attention to understanding the association of organizational and human factors with patients' perceived security in the context of health organizations. This study aims to address numerous gaps in this context. Patients' perceptions about employees' training on security issues, monitoring on security issues, ethics, physical & technical protection and trust in hospitals were identified as organizational and human factors., Methods: After the development of 12 hypotheses, a quantitative, cross-sectional, self-administered survey method was applied to collect data in 9 hospitals in Iran. After the collection of 382 usable questionnaires, the partial least square structural modeling was applied to examine the hypotheses and it was found that 11 hypotheses were empirically supported., Results: The results suggest that patients' trust in hospitals can significantly predict their perceived security but no significant associations were found between patients' physical protection mechanisms in the hospital and their perceived information security in a hospital. We also found that patients' perceptions about the physical protection mechanism of a hospital can significantly predict their trust in hospitals which is a novel finding by this research., Conclusions: The findings imply that hospitals should formulate policies to improve patients' perception about such factors, which ultimately lead to their perceived security.

In this paper, a monolithically integrated ∼1.55 µm semiconductor laser in the fourth harmonic colliding pulse mode locking configuration is reported. This device was developed within a multi-project wafer run at an InP-based active-passive generic foundry. The 1.66-mm Fabry-Pérot cavity is formed with two on-chip reflector building blocks rather than cleaved facets. In the cavity, three absorber sections symmetrically divide the cavity in four gain segments. This laser diode is able to emit 100-GHz pulse trains with 500-fs pulse duration as well as two-tone emissions with a frequency separation of 2.7 THz. The dependence of the spectral behavior on the forward bias current for gain sections and the reverse bias voltage for absorber sections are experimentally demonstrated.

Neural oscillations enable communication between brain regions. Closed-loop brain stimulation attempts to modify this activity by stimulation locked to the phase of concurrent neural oscillations. If successful, this may be a major step forward for clinical brain stimulation therapies. The challenge for effective phase-locked systems is accurately calculating the phase of a source oscillation in real time. The basic operations of filtering the source signal to a frequency band of interest and extracting its phase cannot be performed in real time without distortion. We present a method for continuously estimating phase that reduces this distortion by using an autoregressive model to predict the future of a filtered signal before passing it though the Hilbert transform. This method outperforms published approaches on real data and is available as a reusable open-source module. We also examine the challenge of compensating for the filter phase response and outline promising directions of future study.

Targeting cancer stem cells (CSCs) is a key strategy to prevent cancers from developing drug resistance and metastasis. Mitochondria have been reported to be a vulnerability of CSCs by multiple studies. Here, we report that doxycycline, functioning as an inhibitor of mitochondrial biogenesis, can effectively target breast cancer stem cells (BCSCs). Our results revealed that doxycycline significantly decreased the frequency of aldehyde dehydrogenase‑positive (ALDH+) BCSCs as well as mammosphere formation efficiency in HER2+ and triple‑negative breast cancer (TNBC) subtypes. Doxycycline also ameliorated paclitaxel‑induced enrichment of ALDH+ BCSCs in TNBC. Mechanistically, we showed that doxycycline decreased the level of reactive oxygen species and their downstream p38 MAPK pathway. In agreement with the key role for p38 in maintaining BCSCs, a specific inhibitor targeting this MAPK pathway significantly decreased the number of ALDH+ cells. Doxycycline is a FDA‑approved drug with minor and limited side‑effects. Given doxycycline's low toxicity and strong effect on BCSC inhibition, we report that doxycycline should be safe to be used concomitantly with chemotherapy drugs to eradicate both CSCs and bulk tumor cells.

Objective: Despite the feasibility of short-term neural recordings using implantable microelectrodes, attaining reliable, chronic recordings remains a challenge. Most neural recording devices suffer from a long-term tissue response, including gliosis, at the device-tissue interface. It was hypothesized that smaller, more flexible intracortical probes would limit gliosis by providing a better mechanical match with surrounding tissue., Approach: This paper describes the in vivo evaluation of flexible parylene microprobes designed to improve the interface with the adjacent neural tissue to limit gliosis and thereby allow for improved recording longevity. The probes were coated with an ultrafast degrading tyrosine-derived polycarbonate (E5005(2K)) polymer that provides temporary mechanical support for device implantation, yet degrades within 2 h post-implantation. A parametric study of probes of varying dimensions and polymer coating thicknesses were implanted in rat brains. The glial tissue response and neuronal loss were assessed from 72 h to 24 weeks post-implantation via immunohistochemistry., Main Results: Experimental results suggest that both probe and polymer coating sizes affect the extent of gliosis. When an appropriate sized coating dimension (100 µm  ×  100 µm) and small probe (30 µm  ×  5 µm) was implanted, a minimal post-implantation glial response was observed. No discernible gliosis was detected when compared to tissue where a sham control consisting of a solid degradable polymer shuttle of the same dimensions was inserted. A larger polymer coating (200 µm  ×  200 µm) device induced a more severe glial response at later time points, suggesting that the initial insertion trauma can affect gliosis even when the polymer shuttle degrades rapidly. A larger degree of gliosis was also observed when comparing a larger sized probe (80 µm  ×  5 µm) to a smaller probe (30 µm  ×  5 µm) using the same polymer coating size (100 µm  ×  100 µm). There was no significant neuronal loss around the implantation sites for most device candidates except the group with largest polymer coating and probe sizes., Significance: These results suggest that: (1) the degree of mechanical trauma at device implantation and mechanical mismatches at the probe-tissue interface affect long term gliosis; (2) smaller, more flexible probes may minimize the glial response to provide improved tissue biocompatibility when used for chronic neural signal recording; and (3) some degree of glial scarring did not significantly affect neuronal distribution around the probe.