Publications by authors named "J Peter Rubin"

2,188 Publications

  • Page 1 of 1

Diffusion histology imaging differentiates distinct pediatric brain tumor histology.

Sci Rep 2021 Feb 26;11(1):4749. Epub 2021 Feb 26.

Department of Pediatrics, St. Louis Children's Hospital, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO, 63110, USA.

High-grade pediatric brain tumors exhibit the highest cancer mortality rates in children. While conventional MRI has been widely adopted for examining pediatric high-grade brain tumors clinically, accurate neuroimaging detection and differentiation of tumor histopathology for improved diagnosis, surgical planning, and treatment evaluation, remains an unmet need in their clinical management. We employed a novel Diffusion Histology Imaging (DHI) approach employing diffusion basis spectrum imaging (DBSI) derived metrics as the input classifiers for deep neural network analysis. DHI aims to detect, differentiate, and quantify heterogeneous areas in pediatric high-grade brain tumors, which include normal white matter (WM), densely cellular tumor, less densely cellular tumor, infiltrating edge, necrosis, and hemorrhage. Distinct diffusion metric combination would thus indicate the unique distributions of each distinct tumor histology features. DHI, by incorporating DBSI metrics and the deep neural network algorithm, classified pediatric tumor histology with an overall accuracy of 85.8%. Receiver operating analysis (ROC) analysis suggested DHI's great capability in distinguishing individual tumor histology with AUC values (95% CI) of 0.984 (0.982-0.986), 0.960 (0.956-0.963), 0.991 (0.990-0.993), 0.950 (0.944-0.956), 0.977 (0.973-0.981) and 0.976 (0.972-0.979) for normal WM, densely cellular tumor, less densely cellular tumor, infiltrating edge, necrosis and hemorrhage, respectively. Our results suggest that DBSI-DNN, or DHI, accurately characterized and classified multiple tumor histologic features in pediatric high-grade brain tumors. If these results could be further validated in patients, the novel DHI might emerge as a favorable alternative to the current neuroimaging techniques to better guide biopsy and resection as well as monitor therapeutic response in patients with high-grade brain tumors.
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http://dx.doi.org/10.1038/s41598-021-84252-3DOI Listing
February 2021

The asymmetry of antimatter in the proton.

Nature 2021 02 24;590(7847):561-565. Epub 2021 Feb 24.

Physics Division, Argonne National Laboratory, Lemont, IL, USA.

The fundamental building blocks of the proton-quarks and gluons-have been known for decades. However, we still have an incomplete theoretical and experimental understanding of how these particles and their dynamics give rise to the quantum bound state of the proton and its physical properties, such as its spin. The two up quarks and the single down quark that comprise the proton in the simplest picture account only for a few per cent of the proton mass, the bulk of which is in the form of quark kinetic and potential energy and gluon energy from the strong force. An essential feature of this force, as described by quantum chromodynamics, is its ability to create matter-antimatter quark pairs inside the proton that exist only for a very short time. Their fleeting existence makes the antimatter quarks within protons difficult to study, but their existence is discernible in reactions in which a matter-antimatter quark pair annihilates. In this picture of quark-antiquark creation by the strong force, the probability distributions as a function of momentum for the presence of up and down antimatter quarks should be nearly identical, given that their masses are very similar and small compared to the mass of the proton. Here we provide evidence from muon pair production measurements that these distributions are considerably different, with more abundant down antimatter quarks than up antimatter quarks over a wide range of momenta. These results are expected to revive interest in several proposed mechanisms for the origin of this antimatter asymmetry in the proton that had been disfavoured by previous results, and point to future measurements that can distinguish between these mechanisms.
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http://dx.doi.org/10.1038/s41586-021-03282-zDOI Listing
February 2021

Pulmonary Hemosiderosis with Calcification Associated with IgA Nephropathy.

Am J Respir Crit Care Med 2021 Feb 24. Epub 2021 Feb 24.

Massachusetts General Hospital, Pathology, Boston, Massachusetts, United States;

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http://dx.doi.org/10.1164/rccm.202009-3391IMDOI Listing
February 2021

"Here I can just be myself": How youth and adults collaboratively develop an identity-safe community across difference.

J Community Psychol 2021 Feb 24. Epub 2021 Feb 24.

Foundry10, Seattle, Washington, USA.

The aim of this study was to investigate the development of identity safety-where all participants are valued, included, and can engage without fear of stigmatization-among underrepresented youth and adults in a community-based youth development program. Qualitative in-depth interviews were conducted daily with three youth and two adult mentors about their experiences in the program (a total of 32 interviews). Data analysis revealed that participants developed identity safety through engaging in programmatic activities that explored youth's identities, practicing authenticity in daily interactions, and facilitating dynamic communication across intergenerational friendships. Participants described sustaining identity safety through formal social support spaces, mutual support in group settings, and peer support. Ultimately, these experiences set the foundation for youth and adults to engage in positive risk-taking and self-reflection. Implications for researchers and youth development programs are discussed.
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http://dx.doi.org/10.1002/jcop.22526DOI Listing
February 2021

An Update on Efficacy and Safety of Emerging Hepatic Antifibrotic Agents.

J Clin Transl Hepatol 2021 Feb 4;9(1):60-70. Epub 2021 Jan 4.

Department of Medicine, Division of Gastroenterology/Hepatology, University Hospital Osijek, Osijek, Croatia.

Liver fibrosis represents a response to chronic liver injury. Metabolic dysfunction-associated fatty liver disease and metabolic dysfunction-associated steatohepatitis are the most common chronic liver diseases, both with increasing incidence. Therefore, there is a great impetus for development of agents targeting these conditions. Accumulating data on possible treatment options for liver fibrosis are emerging in the literature. However, despite extensive research and much effort in the field, approved agents for liver fibrosis are still lacking. In this critical review, we have summarized the main data about specific treatment options for liver fibrosis gained from ongoing clinical trials, with an emphasis on efficacy and safety of these agents.
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http://dx.doi.org/10.14218/JCTH.2020.00040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868700PMC
February 2021

Translating Attention-Deficit/Hyperactivity Disorder Rating Scale-5 and Weiss Functional Impairment Rating Scale-Parent Effectiveness Scores into Clinical Global Impressions Clinical Significance Levels in Four Randomized Clinical Trials of SPN-812 (Viloxazine Extended-Release) in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder.

J Child Adolesc Psychopharmacol 2021 Feb 17. Epub 2021 Feb 17.

Supernus Pharmaceuticals, Inc., Rockville, Maryland, USA.

Clinical trials in psychiatry frequently report results from lengthy, comprehensive assessments to characterize a subject emotionally, cognitively, and behaviorally before and after treatment. However, the potential treatment implications of these results and how they translate into clinical practice remain unclear. Conversely, the Clinical Global Impressions (CGI) scales are quick, intuitive assessments used to assess the functional impact of a treatment in clinically relevant terms. The objectives of the present analyses are to translate scores from comprehensive assessments of symptom severity and functional impairment into clinically meaningful CGI levels. These analyses use data integrated from four pivotal Phase 3 trials in attention-deficit/hyperactivity disorder (ADHD) in children and adolescents treated with the novel nonstimulant SPN-812 (Viloxazine Extended-Release). In this study, we evaluated the ADHD Rating Scale-5 (ADHD-RS-5) and Weiss Functional Impairment Rating Scale-Parent (WFIRS-P), assessments of symptom severity and functional impairment, respectively, by linking these scales with the CGI scales at baseline and end of study. For participants that improved, a one-level change on the CGI-Improvement (CGI-I) was associated with a 10-15-point change on the ADHD-RS-5, and a 0.2-0.5-point change on the WFIRS-P. On the CGI-I, ratings of much improved and very much improved were associated with a percent score decrease (i.e., improvement) of ∼55% and 80% on the ADHD-RS-5 and ∼40% and 70% on the WFIRS-P, respectively. Differences between children and adolescents were minor and are unlikely to be clinically meaningful. These analyses provide clinically meaningful benchmarks for the interpretation of scores on the ADHD-RS-5 and WFIRS-P in terms of CGI evaluations in subjects with ADHD. These results may be useful for physicians seeking to understand a treatment's potential impact on their ADHD patients or for researchers looking to define their study results within a clinically relevant context. Data are from clinical trials NCT03247530, NCT03247543, NCT03247517, and NCT03247556.
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http://dx.doi.org/10.1089/cap.2020.0148DOI Listing
February 2021

Increased Intracranial Hemorrhage Amid Elevated Inflammatory Markers in those with COVID-19 Supported with Extracorporeal Membrane Oxygenation.

Shock 2021 Jan 20. Epub 2021 Jan 20.

*Division of Pulmonary and Critical Care Medicine, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, USA †Division of Cardiovascular Surgery, Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, USA ‡Division of Cardiac Anesthesia, Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, USA §Division of Cardiac Surgery, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, USA.

COVID-19-related coagulopathy is a known complication of SARS-CoV-2 infection and can lead to intracranial hemorrhage (ICH), one of the most feared complications of extracorporeal membrane oxygenation (ECMO). We sought to evaluate the incidence and etiology of ICH in patients with COVID-19 requiring ECMO. Patients at two academic medical centers with COVID-19 who required venovenous-ECMO support for acute respiratory distress syndrome (ARDS) were evaluated retrospectively. During the study period, 33 patients required ECMO support; 16 (48.5%) were discharged alive, 13 died (39.4%), and 4 (12.1%) had ongoing care. Eleven patients had ICH (33.3%). All ICH events occurred in patients who received intravenous anticoagulation. The ICH group had higher C-reactive protein (p = 0.04), and procalcitonin levels (p = 0.02), and IL-6 levels (p = 0.05), lower blood pH before and after ECMO (p < 0.01), and higher activated partial thromboplastin times throughout the hospital stay (p < 0.0001). ICH-free survival was lower in COVID-19 patients than in patients on ECMO for ARDS caused by other viruses (49% vs 79%, p = 0.02). In conclusion, patients with COVID-19 can be successfully bridged to recovery using ECMO but may suffer higher rates of ICH compared to those with other viral respiratory infections.
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http://dx.doi.org/10.1097/SHK.0000000000001730DOI Listing
January 2021

Long-term safety and efficacy of tezacaftor-ivacaftor in individuals with cystic fibrosis aged 12 years or older who are homozygous or heterozygous for Phe508del CFTR (EXTEND): an open-label extension study.

Lancet Respir Med 2021 Feb 10. Epub 2021 Feb 10.

Child Health Research Centre, University of Queensland, Brisbane, QLD, Australia.

Background: Tezacaftor-ivacaftor is an approved cystic fibrosis transmembrane conductance regulator (CFTR) modulator shown to be efficacious and generally safe and well tolerated over 8-24 weeks in phase 3 clinical studies in participants aged 12 years or older with cystic fibrosis homozygous for the Phe508del CFTR mutation (F/F; study 661-106 [EVOLVE]) or heterozygous for the Phe508del CFTR mutation and a residual function mutation (F/RF; study 661-108 [EXPAND]). Longer-term (>24 weeks) safety and efficacy of tezacaftor-ivacaftor has not been assessed in clinical studies. Here, we present results of study 661-110 (EXTEND), a 96-week open-label extension study that assessed long-term safety, tolerability, and efficacy of tezacaftor-ivacaftor in participants aged 12 years or older with cystic fibrosis who were homozygous or heterozygous for the Phe508del CFTR mutation.

Methods: Study 661-110 was a 96-week, phase 3, multicentre, open-label study at 170 clinical research sites in Australia, Europe, Israel, and North America. Participants were aged 12 years or older, had cystic fibrosis, were homozygous or heterozygous for Phe508del CFTR, and completed one of six parent studies of tezacaftor-ivacaftor: studies 661-103, 661-106, 661-107, 661-108, 661-109, and 661-111. Participants received oral tezacaftor 100 mg once daily and oral ivacaftor 150 mg once every 12 h for up to 96 weeks. The primary endpoint was safety and 'tolerability. Secondary endpoints were changes in lung function, nutritional parameters, and respiratory symptom scores; pulmonary exacerbations; and pharmacokinetic parameters. A post-hoc analysis assessed the rate of lung function decline in F/F participants who received up to 120 weeks of tezacaftor-ivacaftor in studies 661-106 (F/F) and/or 661-110 compared with a matched cohort of CFTR modulator-untreated historical F/F controls from the Cystic Fibrosis Foundation Patient Registry. Primary safety analyses were done in all participants from all six parent studies who received at least one dose of study drug during this study. This study was registered at ClinicalTrials.gov (NCT02565914).

Findings: Between Aug 31, 2015, to May 31, 2019, 1044 participants were enrolled in study 661-110 from the six parent studies of whom 1042 participants received at least one dose of study drug and were included in the safety set. 995 (95%) participants had at least one TEAE; 22 (2%) had TEAEs leading to discontinuation; and 351 (34%) had serious TEAEs. No deaths occurred during the treatment-emergent period; after the treatment-emergent period, two deaths occurred, which were both deemed unrelated to study drug. F/F (106/110; n=459) and F/RF (108/110; n=226) participants beginning tezacaftor-ivacaftor in study 661-110 had improvements in efficacy endpoints consistent with parent studies; improvements in lung function and nutritional parameters and reductions in pulmonary exacerbations observed in the tezacaftor-ivacaftor groups in the parent studies were generally maintained in study 661-110 for an additional 96 weeks. Pharmacokinetic parameters were also similar to those in the parent studies. The annualised rate of lung function decline was 61·5% (95% CI 35·8 to 86·1) lower in tezacaftor-ivacaftor-treated F/F participants versus untreated matched historical controls.

Interpretation: Tezacaftor-ivacaftor was generally safe, well tolerated, and efficacious for up to 120 weeks, and the safety profile of tezacaftor-ivacaftor in study 661-110 was consistent with cystic fibrosis manifestations and with the safety profiles of the parent studies. The rate of lung function decline was significantly reduced in F/F participants, consistent with cystic fibrosis disease modification. Our results support the clinical benefit of long-term tezacaftor-ivacaftor treatment for people aged 12 years or older with cystic fibrosis with F/F or F/RF genotypes.

Funding: Vertex Pharmaceuticals Incorporated.
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http://dx.doi.org/10.1016/S2213-2600(20)30510-5DOI Listing
February 2021

Noise distracts foraging bats.

Proc Biol Sci 2021 Feb 10;288(1944):20202689. Epub 2021 Feb 10.

Department of Biological Science, Boise State University, Boise, ID, USA.

Predators frequently must detect and localize their prey in challenging environments. Noisy environments have been prevalent across the evolutionary history of predator-prey relationships, but now with increasing anthropogenic activities noise is becoming a more prominent feature of many landscapes. Here, we use the gleaning pallid bat, , to investigate the mechanism by which noise disrupts hunting behaviour. Noise can primarily function to -obscure by spectrally overlapping a cue of interest, or -occupy an animal's attentional or other cognitive resources. Using band-limited white noise treatments that either overlapped the frequencies of a prey cue or did not overlap this cue, we find evidence that distraction is a primary driver of reduced hunting efficacy in an acoustically mediated predator. Under exposure to both noise types successful prey localization declined by half, search time nearly tripled, and bats used 25% more sonar pulses than when hunting in ambient conditions. Overall, the pallid bat does not seem capable of compensating for environmental noise. These findings have implications for mitigation strategies, specifically the importance of reducing sources of noise on the landscape rather than attempting to reduce the bandwidth of anthropogenic noise.
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http://dx.doi.org/10.1098/rspb.2020.2689DOI Listing
February 2021

Focused Ultrasound-Enhanced Delivery of Intranasally Administered Anti-Programmed Cell Death-Ligand 1 Antibody to an Intracranial Murine Glioma Model.

Pharmaceutics 2021 Feb 1;13(2). Epub 2021 Feb 1.

Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO 63130, USA.

Immune checkpoint inhibitors have great potential for the treatment of gliomas; however, their therapeutic efficacy has been partially limited by their inability to efficiently cross the blood-brain barrier (BBB). The objective of this study was to evaluate the capability of focused-ultrasound-mediated intranasal brain drug delivery (FUSIN) in achieving the locally enhanced delivery of anti-programmed cell death-ligand 1 antibody (aPD-L1) to the brain. Both non-tumor mice and mice transcranially implanted with GL261 glioma cells at the brainstem were used in this study. aPD-L1 was labeled with a near-infrared fluorescence dye (IRDye 800CW) and administered to mice through the nasal route to the brain, followed by focused ultrasound sonication in the presence of systemically injected microbubbles. FUSIN enhanced the accumulation of aPD-L1 at the FUS-targeted brainstem by an average of 4.03- and 3.74-fold compared with intranasal (IN) administration alone in the non-tumor mice and glioma mice, respectively. Immunohistochemistry staining found that aPD-L1 was mainly located within the perivascular spaces after IN delivery, while FUSIN further enhanced the penetration depth and delivery efficiency of aPD-L1 to the brain parenchyma. The delivered aPD-L1 was found to be colocalized with the tumor cells after FUSIN delivery to the brainstem glioma. These findings suggest that FUSIN is a promising technique to enhance the delivery of immune checkpoint inhibitors to gliomas.
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http://dx.doi.org/10.3390/pharmaceutics13020190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7912734PMC
February 2021

Recovery of borderline oxacillin-resistant (BORSP) from bone and soft tissue of a rheumatoid arthritis patient with severe osteoporosis: transmission from the family dog.

J Chemother 2021 Feb 1:1-6. Epub 2021 Feb 1.

University of Saskatchewan, Saskatoon, Saskatchewan, Canada.

We report a case of borderline oxacillin-resistant (BORSP) in a rheumatoid arthritis patient with severe osteoporosis. The organism is also resistant to erythromycin and clindamycin. We also present clear evidence on transmission from the family dog.
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http://dx.doi.org/10.1080/1120009X.2021.1879581DOI Listing
February 2021

Early response to SPN-812 (viloxazine extended-release) can predict efficacy outcome in pediatric subjects with ADHD: a machine learning post-hoc analysis of four randomized clinical trials.

Psychiatry Res 2021 Feb 5;296:113664. Epub 2021 Jan 5.

Supernus Pharmaceuticals, Inc.. Electronic address:

Machine learning (ML) was used to determine whether early response can predict efficacy outcome in pediatric subjects with ADHD treated with SPN-812. We used data from four Phase 3 placebo-controlled trials of 100- to 600-mg/day SPN-812 (N=1397; 6-17 years of age). The treatment response was defined as having a ≥50% reduction in change from baseline (CFB) in ADHD Rating Scale-5 (ADHD-RS-5) Total score at Week 6. The variables used were: ADHD-RS-5 Total score, age, body weight, and body mass index at baseline; CFB ADHD-RS-5 Total score at Week 1, cumulative change in ADHD-RS-5 Total score at Week 2, and cumulative change in ADHD-RS-5 Total score at Week 3; Clinical Global Impressions-Improvement (CGI-I) score at Week 1, 2, and 3; and target dose. Using the best selected model, lasso regression, to generate importance scores, we found that change in ADHD-RS-5 Total score and CGI-I score were the best predictors of efficacy outcome. Change in ADHD-RS-5 Total score at Week 2 could predict treatment response at Week 6 (75% positive predictive power, 75% sensitivity, 74% specificity). Therefore, early response after two weeks of treatment with once-daily SPN-812 in pediatric patients with ADHD can predict efficacy outcome at Week 6.
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http://dx.doi.org/10.1016/j.psychres.2020.113664DOI Listing
February 2021

Pembrolizumab and tavokinogene telseplasmid electroporation in metastatic melanoma.

Int J Surg Case Rep 2020 16;77:591-594. Epub 2020 Nov 16.

Department of Surgery, Vassar Brothers Medical Center, USA. Electronic address:

Introduction: Tavokinogene Telseplasmid Electroporation Therapy (TAVO) and Pembrolizumab therapy is being studied in subjects with immune checkpoint inhibitor (ICI) resistant melanoma. TAVO is a novel office-based local therapy shown to be effective in patients with advanced melanoma. The technique involves the direct injection of a plasmid encoding IL-12 into an accessible tumor driven by electroporation. The tumor cells have then been shown to express high levels of IL-12 resulting in a local inflammatory response within the tumor microenvironment.

Presentation Of Case: The patient with stage IIB, pT3b melanoma was treated with primary tumor resection and found to have a negative sentinel node biopsy. She subsequently developed regional recurrence and was treated with inguinal lymphadenectomy and adjuvant Nivolumab. Despite therapy, she had progression of disease with skin and subcutaneous metastases (in-transit lesions), brain and liver lesions, hilar and iliac nodal disease. She was transitioned to nivolumab + ipilimumab, and Talimogene Laherparepvec (T-VEC) therapy for the in-transit lesions, without success. Stereotactic radiosurgery was used for the brain metastasis. Groin subcutaneous and in-transit lesions were treated with TAVO and intravenous pembrolizumab. Serial physical exams and CT scans were used to assess response.

Discussion: All lesions treated with TAVO resolved. An abscopal response was also noted: hilar and mediastinal lymphadenopathy resolved. The liver mass and pelvic lymphadenopathy decreased in size, and her brain metastasis remained stable after radiation.

Conclusion: This case suggests that combination TAVO and Pembrolizumab is a safe and effective local treatment for ICI resistant metastatic melanoma in the setting of rheumatoid arthritis. An abscopal effect was also noted through control of systemic disease.
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http://dx.doi.org/10.1016/j.ijscr.2020.11.063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7708754PMC
November 2020

Potential for Mycorrhizae-Assisted Phytoremediation of Phosphorus for Improved Water Quality.

Int J Environ Res Public Health 2020 12 22;18(1). Epub 2020 Dec 22.

Plant and Soil Science, University of Vermont, Burlington, VT 05405, USA.

During this 6th Great Extinction, freshwater quality is imperiled by upland terrestrial practices. Phosphorus, a macronutrient critical for life, can be a concerning contaminant when excessively present in waterways due to its stimulation of algal and cyanobacterial blooms, with consequences for ecosystem functioning, water use, and human and animal health. Landscape patterns from residential, industrial and agricultural practices release phosphorus at alarming rates and concentrations threaten watershed communities. In an effort to reconcile the anthropogenic effects of phosphorus pollution, several strategies are available to land managers. These include source reduction, contamination event prevention and interception. A total of 80% of terrestrial plants host mycorrhizae which facilitate increased phosphorus uptake and thus removal from soil and water. This symbiotic relationship between fungi and plants facilitates a several-fold increase in phosphorus uptake. It is surprising how little this relationship has been encouraged to mitigate phosphorus for water quality improvement. This paper explores how facilitating this symbiosis in different landscape and land-use contexts can help reduce the application of fertility amendments, prevent non-point source leaching and erosion, and intercept remineralized phosphorus before it enters surface water ecosystems. This literature survey offers promising insights into how mycorrhizae can aid ecological restoration to reconcile humans' damage to Earth's freshwater. We also identify areas where research is needed.
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http://dx.doi.org/10.3390/ijerph18010007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7792571PMC
December 2020

Addressing the Covid-19 pandemic and future public health challenges through global collaboration and a data-driven systems approach.

Learn Health Syst 2020 Dec 6:e10253. Epub 2020 Dec 6.

Department of Learning Health Sciences University of Michigan Medical School Ann Arbor Michigan USA.

Covid-19 has already taught us that the greatest public health challenges of our generation will show no respect for national boundaries, will impact lives and health of people of all nations, and will affect economies and quality of life in unprecedented ways. The types of rapid learning envisioned to address Covid-19 and future public health crises require a systems approach that enables sharing of data and lessons learned at scale. Agreement on a systems approach augmented by technology and standards will be foundational to making such learning meaningful and to ensuring its scientific integrity. With this purpose in mind, a group of individuals from Spain, Italy, and the United States have formed a transatlantic collaboration, with the aim of generating a proposed comprehensive standards-based systems approach and data-driven framework for collection, management, and analysis of high-quality data. This framework will inform decisions in managing clinical responses and social measures to overcome the Covid-19 global pandemic and to prepare for future public health crises. We first argue that standardized data of the type now common in global regulated clinical research is the essential fuel that will power a global system for addressing (and preventing) current and future pandemics. We then present a blueprint for a system that will put these data to use in driving a range of key decisions. In the context of this system, we describe and categorize the specific types of data the system will require for different purposes and document the standards currently in use for each of these categories in the three nations participating in this work. In so doing, we anticipate some of the challenges to harmonizing these data but also suggest opportunities for further global standardization and harmonization. While we have scaled this transnational effort to three nations, we hope to stimulate an international dialogue with a culmination of realizing such a system.
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http://dx.doi.org/10.1002/lrh2.10253DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744897PMC
December 2020

Emphysematous Gastritis in a Transplant Recipient With Infection.

ACG Case Rep J 2020 Dec 8;7(12):e00488. Epub 2020 Dec 8.

Department of Medicine, University of Maryland School of Medicine, Baltimore, MD.

is a rare infection in poorly controlled diabetic patients with a history of gastroparesis. We present the first documented case in a transplant recipient, who underwent a simultaneous liver kidney transplant. Computed tomography showed emphysematous gastritis, endoscopy revealed gastric necrosis, and microscopy confirmed the diagnosis. Operative intervention was high risk, given the previous liver transplant. Antibiotics and proton pump inhibitor treatment with repeat endoscopy at 4 days showed resolution of gastric necrosis and elimination of microscopic evidence of infection. Combination antibiotic and proton pump inhibitor therapy may be an effective treatment for this rare, life-threatening infection.
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http://dx.doi.org/10.14309/crj.0000000000000488DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7725253PMC
December 2020

Sex-Based Disparities in Hepatocellular Carcinoma Recurrence After Liver Transplantation.

Transplantation 2020 Dec 14. Epub 2020 Dec 14.

Division of Gastroenterology and Hepatology, Department of Medicine, University of California-San Francisco, San Francisco, CA.

Background: Women with chronic liver disease have lower rates of hepatocellular carcinoma (HCC) as compared to men; it is unknown if there are sex-based differences in HCC recurrence post-liver transplant.

Methods: We conducted an analysis of patients who underwent liver transplant for HCC in the United Network for Organ Sharing/Organ Procurement and Transplantation Network from January 1, 2012 through December 31, 2017.

Results: A total of 12,711 patients underwent liver transplant for HCC: 2,909 (23%) women and 9,802 (73%) men. Women had significantly lower rates of post-liver transplant HCC recurrence than men (4.0 v. 5.4%, p=0.002). A cox-regression analysis for post-liver transplant HCC recurrence highlighted that even after accounting for etiology of cirrhosis, alpha-fetoprotein (AFP) at liver transplant, tumor diameter, tumor pathology, and vascular invasion, female sex was associated with a 25% lower risk of post-liver transplant HCC recurrence (95CI 0.57-0.99). There were no interactions between female sex and the following variables: age, type of locoregional therapy, AFP, donor sex, body mass index, or nonalcoholic steatohepatitis etiology (p>0.05 for each).

Conclusions: This study demonstrates an independent effect of sex on risk for HCC recurrence post-liver transplant. Our data highlight an opportunity to better understand HCC tumor biology by investigating the drivers of this sex-based difference in HCC recurrence.
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http://dx.doi.org/10.1097/TP.0000000000003575DOI Listing
December 2020

The roles of ascending sensory signals and top-down central control in the entrainment of a locomotor CPG.

Biol Cybern 2020 12 8;114(6):533-555. Epub 2020 Dec 8.

Department of Mathematics, University of Pittsburgh, Pittsburgh, PA, USA.

Previous authors have proposed two basic hypotheses about the factors that form the basis of locomotor rhythms in walking insects: sensory feedback only or sensory feedback together with rhythmic activity of small neural circuits called central pattern generators (CPGs). Here we focus on the latter. Following this concept, to generate functional outputs, locomotor control must feature both rhythm generation by CPGs at the level of individual joints and coordination of their rhythmic activities, so that all muscles are activated in an appropriate pattern. This work provides an in-depth analysis of an aspect of this coordination process based on an existing network model of stick insect locomotion. Specifically, we consider how the control system for a single joint in the stick insect leg may produce rhythmic output when subjected to ascending sensory signals from other joints in the leg. In this work, the core rhythm generating CPG component of the joint under study is represented by a classical half-center oscillator constrained by a basic set of experimental observations. While the dynamical features of this CPG, including phase transitions by escape and release, are well understood, we provide novel insights about how these transition mechanisms yield entrainment to the incoming sensory signal, how entrainment can be lost under variation of signal strength and period or other perturbations, how entrainment can be restored by modulation of tonic top-down drive levels, and how these factors impact the duty cycle of the motor output.
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http://dx.doi.org/10.1007/s00422-020-00852-8DOI Listing
December 2020

The Impact of Human Lipoaspirate and Adipose Tissue-Derived Stem Cells Contact Culture on Breast Cancer Cells: Implications in Breast Reconstruction.

Int J Mol Sci 2020 Dec 1;21(23). Epub 2020 Dec 1.

Department of Plastic Surgery, University of Pittsburgh, Pittsburgh, PA 15261, USA.

Background: Autologous fat transfer in the form of lipoaspirates for the reconstruction of the breast after breast cancer surgery is a commonly used procedure in plastic surgery. However, concerns regarding the oncologic risk of nutrient-rich fat tissue are widely debated. Previous studies have primarily focused on studying the interaction between adipose-derived stem cells (ASCs) and breast cancer cells.

Methods: In this study, we performed a comprehensive analysis of the paracrine- and contact-based interactions between lipoaspirates, ASCs and breast cancer cell lines. An inverted flask culture method was used to study the contact-based interaction between lipoaspirates and breast cancer cells, while GFP-expressing breast cancer cell lines were generated to study the cell-cell contact interaction with ASCs. Three different human breast cancer cell lines, MCF-7, MDA-MB-231 and BT-474, were studied. We analyzed the impact of these interactions on the proliferation, cell cycle and epithelial-to-mesenchymal (EMT) transition of the breast cancer cells.

Results: Our results revealed that both lipoaspirates and ASCs do not increase the proliferation rate of the breast cancer cells either through paracrine- or contact-dependent interactions. We observed that lipoaspirates selectively inhibit the proliferation of MCF-7 cells in contact co-culture, driven by the retinoblastoma (Rb) protein activity mediating cell cycle arrest. Additionally, ASCs inhibited MDA-MB-231 breast cancer cell proliferation in cell-cell contact-dependent interactions. Quantitative real-time PCR revealed no significant increase in the EMT-related genes in breast cancer cells upon co-culture with ASCs.

Conclusion: In conclusion, this study provides evidence of the non-oncogenic character of lipoaspirates and supports the safety of clinical fat grafting in breast reconstruction after oncological surgical procedures. In vivo studies in appropriate animal models and long-term post-operative clinical data from patients are essential to reach the final safety recommendations.
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http://dx.doi.org/10.3390/ijms21239171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7731376PMC
December 2020

Deploying an Electronic Clinical Decision Support Tool for Diagnosis and Treatment of Pneumonia Into Rural and Critical Access Hospitals: Utilization, Effect on Processes of Care, and Clinician Satisfaction.

J Rural Health 2020 Nov 26. Epub 2020 Nov 26.

Department of Medicine, Division of Respiratory, Critical Care and Occupational Pulmonary Medicine, University of Utah School of Medicine, Salt Lake City, Utah.

Purpose: Electronic clinical decision support (CDS) for treatment of community-acquired pneumonia (ePNa) is associated with improved guideline adherence and decreased mortality. How rural providers respond to CDS developed for urban hospitals could shed light on extending CDS to resource-limited settings.

Methods: ePNa was deployed into 10 rural and critical access hospital emergency departments (EDs) in Utah and Idaho in 2018. We reviewed pneumonia cases identified through ICD-10 codes after local deployment to measure ePNa utilization and guideline adherence. ED providers were surveyed to assess quantitative and qualitative aspects of satisfaction.

Findings: ePNa was used in 109/301 patients with pneumonia (36%, range 0%-67% across hospitals) and was associated with appropriate antibiotic selection (93% vs 65%, P < .001). Fifty percent of survey recipients responded, 87% were physicians, 87% were men, and the median ED experience was 10 years. Mean satisfaction with ePNa was 3.3 (range 1.7-4.8) on a 5-point Likert scale. Providers with a favorable opinion of ePNa were more likely to favor implementation of additional CDS (P = .005). Satisfaction was not associated with provider type, age, years of experience or experience with ePNa. Ninety percent of respondents provided qualitative feedback. The most common theme in high and low utilization hospitals was concern about usability. Compared to high utilization hospitals, low utilization hospitals more frequently identified concerns about adaptation for local needs.

Conclusions: ePNa deployment to rural and critical access EDs was moderately successful and associated with improved antibiotic use. Concerns about usability and adapting ePNa for local use predominated the qualitative feedback.
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http://dx.doi.org/10.1111/jrh.12543DOI Listing
November 2020

Chilblain-like lesions with prominent bullae in a patient with COVID-19.

BMJ Case Rep 2020 Nov 2;13(11). Epub 2020 Nov 2.

Center for Dermatology, Rutgers Robert Wood Johnson Medical School, Somerset, New Jersey, USA.

A 27-year-old patient presented with acral chilblain-like lesions atypical of dermatological presentations appearing in current reports of COVID-19. Prominent bullae had formed on the dorsa of her toes and became haemorrhagic 2 days after the initial presentation. The patient had no underlying medical conditions, including any history of collagen vascular disease, Raynaud's phenomenon, chilblains or cold exposure, and was not taking any medications. The patient reported 10 days of ageusia and anosmia 6 weeks prior to the manifestation of her toe lesions, with no other symptoms. A nasopharyngeal swab test for SARS-CoV-2 RNA was positive. It is important that physicians recognise the myriad of cutaneous lesions associated with COVID-19 in this ongoing pandemic.
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http://dx.doi.org/10.1136/bcr-2020-237917DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7607570PMC
November 2020

Sex differences in health and disease: A review of biological sex differences relevant to cancer with a spotlight on glioma.

Cancer Lett 2021 Feb 29;498:178-187. Epub 2020 Oct 29.

Mathematical NeuroOncology Laboratory, Precision Neurotherapeutics Innovation Program, Mayo Clinic, Phoenix, AZ, USA; Department of Neurological Surgery, Mayo Clinic, Phoenix, AZ, USA; School of Mathematical and Statistical Sciences, Arizona State University, Tempe, AZ, USA. Electronic address:

The influence of biological sex differences on human health and disease, while being increasingly recognized, has long been underappreciated and underexplored. While humans of all sexes are more alike than different, there is evidence for sex differences in the most basic aspects of human biology and these differences have consequences for the etiology and pathophysiology of many diseases. In a disease like cancer, these consequences manifest in the sex biases in incidence and outcome of many cancer types. The ability to deliver precise, targeted therapies to complex cancer cases is limited by our current understanding of the underlying sex differences. Gaining a better understanding of the implications and interplay of sex differences in diseases like cancer will thus be informative for clinical practice and biological research. Here we review the evidence for a broad array of biological sex differences in humans and discuss how these differences may relate to observed sex differences in various diseases, including many cancers and specifically glioblastoma. We focus on areas of human biology that play vital roles in healthy and disease states, including metabolism, development, hormones, and the immune system, and emphasize that the intersection of sex differences in these areas should not go overlooked. We further propose that mathematical approaches can be useful for exploring the extent to which sex differences affect disease outcomes and accounting for those in the development of therapeutic strategies.
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http://dx.doi.org/10.1016/j.canlet.2020.07.030DOI Listing
February 2021

Prevalence of β-Lactam Drug-Resistance Genes in Contaminating Ready-to-Eat Lettuce.

Foodborne Pathog Dis 2020 Dec 28;17(12):739-742. Epub 2020 Oct 28.

Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, California, USA.

Thirty-four isolates from 91 ready-to-eat lettuce packages, obtained from local supermarkets in Northern California, were genotyped by multilocus sequence typing, tested for susceptibility to antimicrobial agents, and screened for β-lactamase genes. We found 15 distinct sequence types (STs). Six of these genotypes (ST1198, ST2625, ST2432, ST2819, ST4600, and ST5143) have been reported as pathogens found in human samples. Twenty-six (76%) isolates were resistant to ampicillin, 17 (50%) to ampicillin/sulbactam, 8 (23%) to cefoxitin, and 7 (20%) to cefuroxime. was the most prevalent β-lactamase gene, identified in eight (23%) isolates. We identified a class A broad-spectrum β-lactamase SED-1 gene, , reported by others in isolated from bile of a patient. This study found that fresh lettuce carries β-lactam drug-resistant , which might serve as a reservoir for drug-resistance genes that could potentially be transmitted to pathogens that cause human infections.
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http://dx.doi.org/10.1089/fpd.2020.2792DOI Listing
December 2020

Reproductive Outcomes from Maternal Loss of Nlrp2 Are Not Improved by IVF or Embryo Transfer Consistent with Oocyte-Specific Defect.

Reprod Sci 2020 Oct 22. Epub 2020 Oct 22.

Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, USA.

Nlrp2 encodes a protein of the oocyte subcortical maternal complex (SCMC), required for embryo development. We previously showed that loss of maternal Nlrp2 in mice causes subfertility, smaller litters with birth defects, and growth abnormalities in offspring, indicating that Nlrp2 is a maternal effect gene and that all embryos from Nlrp2-deficient females that were cultured in vitro arrested before the blastocysts stage. Here, we used time-lapse microscopy to examine the development of cultured embryos from superovulated Nlrp2-deficient and wild-type mice after in vivo and in vitro fertilization. Embryos from Nlrp2-deficient females had similar abnormal cleavage and fragmentation and arrested by blastocyst stage, irrespective of fertilization mode. This indicates that in vitro fertilization does not further perturb or improve the development of cultured embryos. We also transferred embryos from superovulated Nlrp2-deficient and wild-type females to wild-type recipients to investigate if the abnormal reproductive outcomes of Nlrp2-deficient females are primarily driven by oocyte dysfunction or if a suboptimal intra-uterine milieu is a necessary factor. Pregnancies with transferred embryos from Nlrp2-deficient females produced smaller litters, stillbirths, and offspring with birth defects and growth abnormalities. This indicates that the reproductive phenotype is oocyte-specific and is not rescued by development in a wild-type uterus. We further found abnormal DNA methylation at two maternally imprinted loci in the kidney of surviving young adult offspring, confirming persistent DNA methylation disturbances in surviving offspring. These findings have implications for fertility treatments for women with mutations in NLRP2 and other genes encoding SCMC proteins.
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http://dx.doi.org/10.1007/s43032-020-00360-xDOI Listing
October 2020

Neural activity during a simple reaching task in macaques is counter to gating and rebound in basal ganglia-thalamic communication.

PLoS Biol 2020 10 13;18(10):e3000829. Epub 2020 Oct 13.

Department of Neurobiology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.

Task-related activity in the ventral thalamus, a major target of basal ganglia output, is often assumed to be permitted or triggered by changes in basal ganglia activity through gating- or rebound-like mechanisms. To test those hypotheses, we sampled single-unit activity from connected basal ganglia output and thalamic nuclei (globus pallidus-internus [GPi] and ventrolateral anterior nucleus [VLa]) in monkeys performing a reaching task. Rate increases were the most common peri-movement change in both nuclei. Moreover, peri-movement changes generally began earlier in VLa than in GPi. Simultaneously recorded GPi-VLa pairs rarely showed short-time-scale spike-to-spike correlations or slow across-trials covariations, and both were equally positive and negative. Finally, spontaneous GPi bursts and pauses were both followed by small, slow reductions in VLa rate. These results appear incompatible with standard gating and rebound models. Still, gating or rebound may be possible in other physiological situations: simulations show how GPi-VLa communication can scale with GPi synchrony and GPi-to-VLa convergence, illuminating how synchrony of basal ganglia output during motor learning or in pathological conditions may render this pathway effective. Thus, in the healthy state, basal ganglia-thalamic communication during learned movement is more subtle than expected, with changes in firing rates possibly being dominated by a common external source.
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http://dx.doi.org/10.1371/journal.pbio.3000829DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7584254PMC
October 2020

A powerful long metabarcoding method for the determination of complex diets from faecal analysis of the European pond turtle (Emys orbicularis, L. 1758).

Mol Ecol Resour 2021 Feb 4;21(2):433-447. Epub 2020 Nov 4.

Department of Environmental Sciences, Section of Conservation Biology, University of Basel, Basel, Switzerland.

High-throughput sequencing has become an accurate method for the identification of species present in soil, water, faeces, gut or stomach contents. However, information at the species level is limited due to the choice of short barcodes and based on the idea that DNA is too degraded to allow longer sequences to be amplified. We have therefore developed a long DNA metabarcoding method based on the sequencing of short reads followed by de novo assembly, which can precisely identify the taxonomic groups of organisms associated with complex diets, such as omnivorous individuals. The procedure includes 11 different primer pairs targeting the COI gene, the large subunit of the ribulose-1,5-bisphosphate carboxylase gene, the maturase K gene, the 28S rRNA and the trnL-trnF chloroplastic region. We validated this approach using 32 faeces samples from an omnivorous reptile, the European pond turtle (Emys orbicularis, L. 1758). This metabarcoding approach was assessed using controlled experiments including mock communities and faecal samples from captive feeding trials. The method allowed us to accurately identify prey DNA present in the diet of the European pond turtles to the species level in most of the cases (82.4%), based on the amplicon lengths of multiple markers (168-1,379 bp, average 546 bp), and produced by de novo assembly. The proposed approach can be adapted to analyse various diets, in numerous conservation and ecological applications. It is consequently appropriate for detecting fine dietary variations among individuals, populations and species as well as for the identification of rare food items.
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http://dx.doi.org/10.1111/1755-0998.13277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821331PMC
February 2021

Lung Histopathology in Coronavirus Disease 2019 as Compared With Severe Acute Respiratory Sydrome and H1N1 Influenza: A Systematic Review.

Chest 2021 01 7;159(1):73-84. Epub 2020 Oct 7.

Department of Pathology, Massachusetts General Hospital, Boston, MA; Harvard Medical School, Boston, MA.

Background: Patients with severe coronavirus disease 2019 (COVID-19) have respiratory failure with hypoxemia and acute bilateral pulmonary infiltrates, consistent with ARDS. Respiratory failure in COVID-19 might represent a novel pathologic entity.

Research Question: How does the lung histopathology described in COVID-19 compare with the lung histopathology described in SARS and H1N1 influenza?

Study Design And Methods: We conducted a systematic review to characterize the lung histopathologic features of COVID-19 and compare them against findings of other recent viral pandemics, H1N1 influenza and SARS. We systematically searched MEDLINE and PubMed for studies published up to June 24, 2020, using search terms for COVID-19, H1N1 influenza, and SARS with keywords for pathology, biopsy, and autopsy. Using PRISMA-Individual Participant Data guidelines, our systematic review analysis included 26 articles representing 171 COVID-19 patients; 20 articles representing 287 H1N1 patients; and eight articles representing 64 SARS patients.

Results: In COVID-19, acute-phase diffuse alveolar damage (DAD) was reported in 88% of patients, which was similar to the proportion of cases with DAD in both H1N1 (90%) and SARS (98%). Pulmonary microthrombi were reported in 57% of COVID-19 and 58% of SARS patients, as compared with 24% of H1N1 influenza patients.

Interpretation: DAD, the histologic correlate of ARDS, is the predominant histopathologic pattern identified in lung pathology from patients with COVID-19, H1N1 influenza, and SARS. Microthrombi were reported more frequently in both patients with COVID-19 and SARS as compared with H1N1 influenza. Future work is needed to validate this histopathologic finding and, if confirmed, elucidate the mechanistic underpinnings and characterize any associations with clinically important outcomes.
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http://dx.doi.org/10.1016/j.chest.2020.09.259DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7538870PMC
January 2021

Breast Reconstruction Using a Three-Dimensional Absorbable Mesh Scaffold and Autologous Fat Grafting: A Composite Strategy Based on Tissue-Engineering Principles.

Plast Reconstr Surg 2020 10;146(4):409e-413e

From private practice; the Departments of Plastic Surgery, Radiology, and Surgery, University of Pittsburgh Medical Center; Palms Surgical Associates; Price Hoffman Stone Associates; and the Department of Bioengineering and the McGowan Institute of Regenerative Medicine, University of Pittsburgh.

Breast reconstruction remains an important field in plastic surgery, with most procedures using implants and/or autologous tissue. Few series report on experience with fat grafting as the primary form of breast reconstruction. The present article describes a new method of breast reconstruction using a three-dimensional absorbable mesh construct-or Lotus scaffold-and autologous fat grafting. A retrospective review was performed for all patients who underwent breast reconstruction using the Lotus scaffold and autologous fat grafting. Postoperative mammograms and magnetic resonance imaging scans were analyzed. Tissue specimens collected at subsequent procedures were harvested and stained with hematoxylin and eosin for histologic evaluation. Lastly, compression testing of the scaffold was performed using a tensiometer and digital tracking technology. Twenty-two patients underwent reconstruction of 28 breasts using the Lotus scaffold and autologous fat grafting between February of 2015 and February of 2018. Average follow-up was 19 months. All patients were satisfied with final breast shape and size. Mean patient age was 60.5 years and the average body mass index was 28 kg/m. Patients required on average two fat grafting sessions to achieve a successful result (range, zero to four). Postoperative mammography and magnetic resonance imaging showed robust adipose tissue in the breast with a slowly resorbing mesh and no oil cysts or calcifications. Histologic evaluation showed the presence of fat tissue around the scaffold and no evidence of capsule formation. Compression testing revealed the Lotus scaffold to be compliant with a high-resilience profile. The Lotus scaffold with autologous fat grafting is a viable method for breast reconstruction, giving the patient an autologous reconstruction with less morbidity compared to free tissue transfer. CLINICAL QUESTION/LEVEL OF EVIDENCE:: Therapeutic, IV.
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http://dx.doi.org/10.1097/PRS.0000000000007172DOI Listing
October 2020

The clinical impact of untreated slow ventricular tachycardia in patients carrying implantable cardiac defibrillators.

J Interv Card Electrophysiol 2020 Sep 23. Epub 2020 Sep 23.

Arrhythmia Unit; Cardiology Department, Hospital Universitario Central de Asturias, Instituto de Investigación Sanitaria del Principado de Asturias, Av. Roma, s/n, 33011, Oviedo, Asturias, Spain.

Introduction: The clinical impact of slow ventricular tachycardia (VT), occurring in patients carrying implantable cardiac defibrillators (ICD), is still under debate.

Methods And Results: From the UMBRELLA registry (multicenter, observational, and prospective study on patients with ICD), 659 episodes of slow VT were observed in 97 patients. Untreated slow VT (n = 93) had longer duration (23.7 min, CI95%: 10-39), compared with episodes treated effectively by anti-tachycardia pacing (ATP; n = 527; 0.32 min, IC95%: 0.22-0, 48) or shock (n = 39; 1 min, CI95%: 0.8-1.2). Despite of longer duration, the time to the first contact with the medical services was similar to those episodes treated by ATP (50 days [CI95%: 45-55] vs. 41 days [CI95%: 39-44]). However, both were significantly longer than the time observed in episodes treated with shock (10 days, CI95%: 6-15). This tendency was maintained with successive interrogations of the device (2nd and 3rd). There were no significant differences in mortality during follow-up (48 ± 16 months), neither other adverse outcomes, between patients who presented untreated slow TV and those who did not (log-rank p = 0.28). In a Cox regression analysis, the variable "presenting untreated episodes of slow VT" was not able to predict mortality. However, being in sinus rhythm (vs. atrial fibrillation, OR: 0.31, p = 0.009), narrower QRS (OR: 1.036, p = 0.037) and diabetes (OR 4.673, p = 0.049) appropriately predict survival.

Conclusions: Untreated slow VT does not significantly worsen patient prognosis. Our results support the limitation of therapies to ATP only, thus avoiding therapies that have been associated with increased risk of morbidity and mortality.
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http://dx.doi.org/10.1007/s10840-020-00877-wDOI Listing
September 2020

The effects of chloride dynamics on substantia nigra pars reticulata responses to pallidal and striatal inputs.

Elife 2020 09 7;9. Epub 2020 Sep 7.

Department of Mathematics, University of Pittsburgh, Pittsburgh, United States.

As a rodent basal ganglia (BG) output nucleus, the substantia nigra pars reticulata (SNr) is well positioned to impact behavior. SNr neurons receive GABAergic inputs from the striatum (direct pathway) and globus pallidus (GPe, indirect pathway). Dominant theories of action selection rely on these pathways' inhibitory actions. Yet, experimental results on SNr responses to these inputs are limited and include excitatory effects. Our study combines experimental and computational work to characterize, explain, and make predictions about these pathways. We observe diverse SNr responses to stimulation of SNr-projecting striatal and GPe neurons, including biphasic and excitatory effects, which our modeling shows can be explained by intracellular chloride processing. Our work predicts that ongoing GPe activity could tune the SNr operating mode, including its responses in decision-making scenarios, and GPe output may modulate synchrony and low-frequency oscillations of SNr neurons, which we confirm using optogenetic stimulation of GPe terminals within the SNr.
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http://dx.doi.org/10.7554/eLife.55592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7476764PMC
September 2020