Publications by authors named "David Russell"

1,088 Publications

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Cerebral Expression of Metabotropic Glutamate Receptor Subtype 5 in Idiopathic Autism Spectrum Disorder and Fragile X Syndrome: A Pilot Study.

Int J Mol Sci 2021 Mar 11;22(6). Epub 2021 Mar 11.

Department of Psychiatry and Behavioral Sciences-Child Psychiatry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

Multiple lines of evidence suggest that dysfunction of the metabotropic glutamate receptor subtype 5 (mGluR) plays a role in the pathogenesis of autism spectrum disorder (ASD). Yet animal and human investigations of mGluR expression provide conflicting findings about the nature of dysregulation of cerebral mGluR pathways in subtypes of ASD. The demonstration of reduced mGluR expression throughout the living brains of men with fragile X syndrome (FXS), the most common known single-gene cause of ASD, provides a clue to examine mGluR expression in ASD. We aimed to (A) compare and contrast mGluR expression in idiopathic autism spectrum disorder (IASD), FXS, and typical development (TD) and (B) show the value of positron emission tomography (PET) for the application of precision medicine for the diagnosis and treatment of individuals with IASD, FXS, and related conditions. Two teams of investigators independently administered 3-[F]fluoro-5-(2-pyridinylethynyl)benzonitrile ([F]FPEB), a novel, specific mGluR PET ligand to quantitatively measure the density and the distribution of mGluRs in the brain regions, to participants of both sexes with IASD and TD and men with FXS. In contrast to participants with TD, mGluR expression was significantly increased in the cortical regions of participants with IASD and significantly reduced in all regions of men with FXS. These results suggest the feasibility of this protocol as a valuable tool to measure mGluR expression in clinical trials of individuals with IASD and FXS and related conditions.
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http://dx.doi.org/10.3390/ijms22062863DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7999711PMC
March 2021

Antithrombotic therapy in diabetes: which, when, and for how long?

Eur Heart J 2021 Mar 25. Epub 2021 Mar 25.

Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Beech Hill Road, Sheffield S10 2RX, UK.

Cardiovascular disease remains the main cause of mortality in individuals with diabetes mellitus (DM) and also results in significant morbidity. Premature and more aggressive atherosclerotic disease, coupled with an enhanced thrombotic environment, contributes to the high vascular risk in individuals with DM. This prothrombotic milieu is due to increased platelet activity together with impaired fibrinolysis secondary to quantitative and qualitative changes in coagulation factors. However, management strategies to reduce thrombosis risk remain largely similar in individuals with and without DM. The current review covers the latest in the field of antithrombotic management in DM. The role of primary vascular prevention is discussed together with options for secondary prevention following an ischaemic event in different clinical scenarios including coronary, cerebrovascular, and peripheral artery diseases. Antiplatelet therapy combinations as well as combination of antiplatelet and anticoagulant agents are examined in both the acute phase and long term, including management of individuals with sinus rhythm and those with atrial fibrillation. The difficulties in tailoring therapy according to the variable atherothrombotic risk in different individuals are emphasized, in addition to the varying risk within an individual secondary to DM duration, presence of complications and predisposition to bleeding events. This review provides the reader with an up-to-date guide for antithrombotic management of individuals with DM and highlights gaps in knowledge that represent areas for future research, aiming to improve clinical outcome in this high-risk population.
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http://dx.doi.org/10.1093/eurheartj/ehab128DOI Listing
March 2021

Modernizing vascular services to meet the demands of a changing disease burden.

Authors:
David A Russell

Br J Surg 2021 Mar 22. Epub 2021 Mar 22.

Leeds Institute for Clinical Trials Research, University of Leeds, Leeds, UK.

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http://dx.doi.org/10.1093/bjs/znab080DOI Listing
March 2021

Eliciting the educational needs and priorities of home care workers on end-of-life care for patients with heart failure using nominal group technique.

Palliat Med 2021 Mar 17:269216321999963. Epub 2021 Mar 17.

Department of Healthcare Policy & Research, Division of Health Informatics, Weill Cornell Medicine, New York, NY, USA.

Background: Home care workers, as paid caregivers, assist with many aspects of home-based heart failure care. However, most home care workers do not receive systematic training on end-of-life care for heart failure patients.

Aim: To elicit the educational needs and priorities of home care workers caring for community- dwelling adults with heart failure at the end-of-life.

Design: Nominal group technique involving a semi-quantitative structured group process and point rating system was used to designate the importance of priorities elicited from home care workers. Individual responses to the question, ", were aggregated into categories using directed content analysis methods.

Setting/participants: Forty-one home care workers were recruited from a non-profit training and education organization in New York City.

Results: Individual responses to the question were aggregated into five categories: (1) how to cope and grieve; (2) assisting patients with behavior changes, (3) supporting patients to improve their quality of life, (4) assisting patients with physical symptom management, and (5) symptom recognition and assessment.

Conclusions: Our findings confirm the need for the formal development and evaluation of an educational program for home care workers to improve the care of heart failure patients at the end-of-life. There is also a need for research on integrating home care workers into the interprofessional healthcare team to support optimal health outcomes for patients with heart failure.
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http://dx.doi.org/10.1177/0269216321999963DOI Listing
March 2021

Molecular assemblies of the catalytic domain of SOS with KRas and oncogenic mutants.

Proc Natl Acad Sci U S A 2021 Mar;118(12)

Department of Chemistry, Texas A&M University, College Station, TX 77843;

Ras is regulated by a specific guanine nucleotide exchange factor Son of Sevenless (SOS), which facilitates the exchange of inactive, GDP-bound Ras with GTP. The catalytic activity of SOS is also allosterically modulated by an active Ras (Ras-GTP). However, it remains poorly understood how oncogenic Ras mutants interact with SOS and modulate its activity. Here, native ion mobility-mass spectrometry is employed to monitor the assembly of the catalytic domain of SOS (SOS) with KRas and three cancer-associated mutants (G12C, G13D, and Q61H), leading to the discovery of different molecular assemblies and distinct conformers of SOS engaging KRas. We also find KRas exhibits high affinity for SOS and is a potent allosteric modulator of its activity. A structure of the KRas•SOS complex was determined using cryogenic electron microscopy providing insight into the enhanced affinity of the mutant protein. In addition, we find that KRas-GTP can allosterically increase the nucleotide exchange rate of KRas at the active site more than twofold compared to KRas-GTP. Furthermore, small-molecule Ras•SOS disruptors fail to dissociate KRas•SOS complexes, underscoring the need for more potent disruptors. Taken together, a better understanding of the interaction between oncogenic Ras mutants and SOS will provide avenues for improved therapeutic interventions.
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http://dx.doi.org/10.1073/pnas.2022403118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8000204PMC
March 2021

Lnc(ing)RNAs to the "shock and kill" strategy for HIV-1 cure.

Mol Ther Nucleic Acids 2021 Mar 10;23:1272-1280. Epub 2021 Feb 10.

Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA.

The advent of antiretroviral therapy almost 25 years ago has transformed HIV-1 infection into a manageable chronic condition, albeit still incurable. The inability of the treatment regimen to eliminate latently infected cells that harbor the virus in an epigenetically silent state poses a major hurdle. Current cure approaches are focused on a "shock and kill" strategy that uses latency-reversing agents to chemically reverse the proviral quiescence in latently infected cells, followed by immune-mediated clearance of reactivated cells. To date, hundreds of compounds have been investigated for viral reactivation, yet none has resulted in a functional cure. The insufficiency of these latency-reversing agents (LRAs) alone indicates a critical need for additional, alternate approaches such as genetic manipulation. Long non-coding RNAs (lncRNAs) are an emerging class of regulatory RNAs with functional roles in many cellular processes, including epigenetic modulation. A number of lncRNAs have already been implicated to play important roles in HIV-1 latency and, as such, pharmacological modulation of lncRNAs constitutes a rational alternative approach in HIV-1 cure research. In this review, we discuss the current state of knowledge of the role of lncRNAs in HIV-1 infection and explore the scope for a lncRNA-mediated genetic approach within the shock and kill strategy of HIV-1 cure.
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http://dx.doi.org/10.1016/j.omtn.2021.02.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907223PMC
March 2021

Editorial: Focus on Ionization Technologies Used in MS: Fundamentals and Applications, Honoring Dr. Sarah Trimpin, Recipient of the 2019 ASMS Biemann Medal.

J Am Soc Mass Spectrom 2021 Mar;32(3):616-617

Department of Chemistry, Indiana University, Bloomington, Indiana 47405, United States.

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http://dx.doi.org/10.1021/jasms.1c00030DOI Listing
March 2021

Survival in hospice patients with dementia: the effect of home hospice and nurse visits.

J Am Geriatr Soc 2021 Feb 19. Epub 2021 Feb 19.

Department of Medicine, Weill Cornell Medicine, New York, New York, USA.

Background: Hospice patients with dementia are at increased risk for live discharge and long lengths of stay (>180 days), causing patient and family caregiver stress and burden. The location and timing of clinician visits are important factors influencing whether someone dies as expected, in hospice, or experiences a live discharge or long length of stay.

Objective: Examine how home hospice and nurse visit frequency relate to dying in hospice within the Medicare-intended 6-month period.

Design: Retrospective cohort study.

Setting: Non-profit hospice agency.

Participants: Three thousand eight hundred and thirty seven patients with dementia who received hospice services from 2013 to 2017.

Methods: Multivariable survival analyses examined the effects of receiving home hospice (vs. nursing home) and timing of nurse visits on death within 6 months of hospice enrollment, compared to live discharge or long length of stay. Models adjust for relevant demographic and clinical factors.

Results: Thirty-nine percent (39%) of patients experienced live discharge or long length of stay. Home hospice patients were more likely to experience live discharge or long length of stays (HR for death: 0.77, 95%CI: 0.69-0.86, p < 0.001). Frequency of nurse visits was inversely associated with live discharge and long lengths of stay (HR for death: 2.87, 95%CI: 2.47-3.33, p < 0.001).

Conclusion: Nearly 40% of patients with dementia in our study experienced live discharge or a long length of stay. Additional research is needed to understand why home hospice may result in live discharge or a long length of stay for patients with dementia. Nurse visits were associated with death, suggesting their responsiveness to deteriorating patient health. Hospice guidelines may need to permit longer stays so community-dwelling patients with dementia, a growing segment of hospice patients, can remain continuously enrolled in hospice and avoid burden and costs associated with live discharge.
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http://dx.doi.org/10.1111/jgs.17066DOI Listing
February 2021

Individual, social, and environmental factors for infection risk among home healthcare patients: A multi-method study.

Health Soc Care Community 2021 Feb 19. Epub 2021 Feb 19.

Columbia University School of Nursing, New York, NY, USA.

There has been limited research into the individual, social, and environmental factors for infection risk among patients in the home healthcare (HHC) setting, where the infection is a leading cause of hospitalisation. The aims of this study were to (1) explore nurse perceptions of individual, social, and environmental factors for infection risk among HHC patients; and (2) identify the frequency of environmental barriers to infection prevention and control in HHC. Data were collected in 2017-2018 and included qualitative interviews with HHC nurses (n = 50) and structured observations of nurse visits to patients' homes (n = 400). Thematic analyses of interviews with nurses suggested they perceived infection risk among patients as being influenced by knowledge of and attitudes towards infection prevention and engagement in hygiene practices, receipt of support from informal caregivers and nurse interventions aimed at cultivating infection control knowledge and practices, and the home environment. Statistical analyses of observation checklists revealed nurses encountered an average of 1.7 environmental barriers upon each home visit. Frequent environmental barriers observed during visits to HHC patients included clutter (39.5%), poor lighting (38.8%), dirtiness (28.5%), and pets (17.2%). Additional research is needed to clarify inter-relationships among these factors and identify strategies for addressing each as part of a comprehensive infection control program in HHC.
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http://dx.doi.org/10.1111/hsc.13321DOI Listing
February 2021

Cygnus X-1 contains a 21-solar mass black hole-Implications for massive star winds.

Science 2021 03 18;371(6533):1046-1049. Epub 2021 Feb 18.

Dr. Karl Remeis-Sternwarte and Erlangen Centre for Astroparticle Physics, Friedrich-Alexander-Universität Erlangen-Nürnberg, 96049 Bamberg, Germany.

The evolution of massive stars is influenced by the mass lost to stellar winds over their lifetimes. These winds limit the masses of the stellar remnants (such as black holes) that the stars ultimately produce. We used radio astrometry to refine the distance to the black hole x-ray binary Cygnus X-1, which we found to be [Formula: see text] kiloparsecs. When combined with archival optical data, this implies a black hole mass of 21.2 ± 2.2 solar masses, which is higher than previous measurements. The formation of such a high-mass black hole in a high-metallicity system (within the Milky Way) constrains wind mass loss from massive stars.
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http://dx.doi.org/10.1126/science.abb3363DOI Listing
March 2021

Liver Injury Increases the Incidence of HCC following AAV Gene Therapy in Mice.

Mol Ther 2021 02 22;29(2):680-690. Epub 2020 Oct 22.

Department of Medicine, Division of Gastroenterology and Hepatology, Oregon Health and Science University, Portland, OR 97239, USA. Electronic address:

Adeno-associated virus (AAV) integrates into host genomes at low frequency, but when integration occurs in oncogenic hotspots it can cause hepatocellular carcinoma (HCC). Given the possibility of recombinant AAV (rAAV) integration leading to HCC, common causes of liver inflammation like non-alcoholic fatty liver disease (NAFLD) may increase the risk of rAAV-induced HCC. A rAAV targeting the oncogenic mouse Rian locus was used, and as expected led to HCC in all mice infected as neonates, likely due to growth-related hepatocyte proliferation in young mice. Mice infected with rAAV as adults did not develop HCC unless they were fed a diet leading to NAFLD, with increased inflammation and hepatocyte proliferation. Female mice were less susceptible to rAAV-induced HCC, and male mice with NAFLD treated with estrogen exhibited less inflammation and immune exhaustion associated with oncogenesis compared to those without estrogen. Adult NAFLD mice infected with a non-targeted control rAAV also developed HCC, though only half as frequently as those exposed to the Rian targeted rAAV. This study shows that adult mice exposed to rAAV gene therapy in the context of chronic liver disease developed HCC at high frequency, and thus warrants further study in humans given the high prevalence of NAFLD in the population.
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http://dx.doi.org/10.1016/j.ymthe.2020.10.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7854305PMC
February 2021

Parental Factors Associated With the Decision to Participate in a Neonatal Clinical Trial.

JAMA Netw Open 2021 01 4;4(1):e2032106. Epub 2021 Jan 4.

Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.

Importance: It remains poorly understood how parents decide whether to enroll a child in a neonatal clinical trial. This is particularly true for parents from racial or ethnic minority populations. Understanding factors associated with enrollment decisions may improve recruitment processes for families, increase enrollment rates, and decrease disparities in research participation.

Objective: To assess differences in parental factors between parents who enrolled their infant and those who declined enrollment for a neonatal randomized clinical trial.

Design, Setting, And Participants: This survey study conducted from July 2017 to October 2019 in 12 US level 3 and 4 neonatal intensive care units included parents of infants who enrolled in the High-dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) trial or who were eligible but declined enrollment. Data were analyzed October 2019 through July 2020.

Exposure: Parental choice of enrollment in neonatal clinical trial.

Main Outcomes And Measures: Percentages and odds ratios (ORs) of parent participation as categorized by demographic characteristics, self-assessment of child's medical condition, study comprehension, and trust in medical researchers. Survey questions were based on the hypothesis that parents who enrolled their infant in HEAL differ from those who declined enrollment across 4 categories: (1) infant characteristics and parental demographic characteristics, (2) perception of infant's illness, (3) study comprehension, and (4) trust in clinicians and researchers.

Results: Of a total 387 eligible parents, 269 (69.5%) completed the survey and were included in analysis. This included 183 of 242 (75.6%) of HEAL-enrolled and 86 of 145 (59.3%) of HEAL-declined parents. Parents who enrolled their infant had lower rates of Medicaid participation (74 [41.1%] vs 47 [55.3%]; P = .04) and higher rates of annual income greater than $55 000 (94 [52.8%] vs 30 [37.5%]; P = .03) compared with those who declined. Black parents had lower enrollment rates compared with White parents (OR, 0.35; 95% CI, 0.17-0.73). Parents who reported their infant's medical condition as more serious had higher enrollment rates (OR, 5.7; 95% CI, 2.0-16.3). Parents who enrolled their infant reported higher trust in medical researchers compared with parents who declined (mean [SD] difference, 5.3 [0.3-10.3]). There was no association between study comprehension and enrollment.

Conclusions And Relevance: In this study, the following factors were associated with neonatal clinical trial enrollment: demographic characteristics (ie, race/ethnicity, Medicaid status, and reported income), perception of illness, and trust in medical researchers. Future work to confirm these findings and explore the reasons behind them may lead to strategies for better engaging underrepresented groups in neonatal clinical research to reduce enrollment disparities.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.32106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7804922PMC
January 2021

Inter-reader agreement of F-FDG PET/CT for the quantification of carotid artery plaque inflammation.

JRSM Cardiovasc Dis 2020 Jan-Dec;9:2048004020980941. Epub 2020 Dec 15.

Department of Nuclear Medicine, Division of Radiology and Nuclear Medicine, Oslo University Hospital, Oslo, Norway.

Introduction: A significant proportion of ischemic strokes are caused by emboli from unstable atherosclerotic carotid artery plaques. Inflammation is a key feature of plaque instability. Positron emission tomography/computed tomography (PET/CT) with 2-deoxy-2-(F)-fluoro-D-glucose (F-FDG) is a promising technique to quantify plaque inflammation, but a consensus on the methodology has not been established. High inter-reader agreement is essential if F-FDG PET/CT is to be used as a clinical tool for the assessment of unstable plaques and stroke risk.

Methods: We assessed the inter-reader variability of different methods for quantification of F-FDG uptake in 43 patients with carotid artery stenosis ≥70%. Two independent readers delineated the plaque and collected maximum standardized uptake value (SUV) from all axial PET slices containing the atherosclerotic plaque.

Results: Uptake values with and without background correction were calculated and intraclass correlation coefficients were highest for uncorrected uptake values (0.97-0.98) followed by those background corrected by subtraction (0.89-0.94) and lowest for those background corrected by division (0.74-0.79).

Conclusion: Quantification methods without background correction have the highest inter-reader agreement for F-FDG PET of carotid artery plaque inflammation. The use of the single highest uptake value (max SUV) from the plaque will facilitate the method's clinical utility in stroke prevention.
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http://dx.doi.org/10.1177/2048004020980941DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7747113PMC
December 2020

Dual RNA-Sequencing of -Infected Cells from a Murine Infection Model.

STAR Protoc 2020 Dec 6;1(3):100123. Epub 2020 Oct 6.

Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA.

Dual RNA-sequencing is a powerful technique to assess both bacterial and host transcriptomes in an unbiased way. We developed a protocol to perform Dual RNA-seq on -derived macrophage populations infected with . Here, we provide a practical step-by-step guide to execute the protocol on Mtb-infected cells from a murine infection model. Our protocol can also be easily applied to perform Dual RNA-seq on -derived cells as well as different Mtb-infected host cell types. For complete details on the use and execution of this protocol, please refer to Pisu et al. (2020).
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http://dx.doi.org/10.1016/j.xpro.2020.100123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756974PMC
December 2020

Nurse Perspectives on Urinary Incontinence in the Home Hospice Setting.

J Pain Symptom Manage 2020 Dec 1. Epub 2020 Dec 1.

Department of Urology, Weill Cornell Medicine/New York Presbyterian, New York, New York, USA. Electronic address:

Context: To date, no studies have characterized the impacts of urinary incontinence (UI) at the end of life in the home hospice (HH) setting. UI is highly prevalent at the end of life and adversely affects quality of life.

Objectives: To characterize HH nurses' perspectives on UI in HH patients.

Methods: We conducted a qualitative descriptive study of interviews between HH nurses and the study investigator. Thirty-two interviews with HH nurses were transcribed and analyzed. Nurses were mostly female, college-educated, and had several years of experience in HH nursing.

Results: We identified findings in four major themes: 1) HH nurses' definition and identification of UI, 2) the absence of formal guidelines for diagnosing UI in HH patients, 3) UI's adverse effect on HH patients and their families, and 4) the lack of standardized guidelines for the management of UI in the HH setting. We found that there was a general lack of clarity on the subtypes of UI and no standardized guidelines for management of UI in the HH setting. Nurses reported that UI was bothersome to HH patients and their caregivers, citing patient discomfort, loss of dignity, and additional labor burden as reasons for this. Management strategies for UI lacked standardization.

Conclusion: UI is a prevalent and debilitating condition in HH patients. There is a need for studies to further characterize the impacts of UI on HH patients and their caregivers. Formal training on UI subtypes and management is needed to facilitate proper documentation, research, and improve patient outcomes.
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http://dx.doi.org/10.1016/j.jpainsymman.2020.11.028DOI Listing
December 2020

"A catalyst for action": Factors for implementing clinical risk prediction models of infection in home care settings.

J Am Med Inform Assoc 2021 Feb;28(2):334-341

Columbia University School of Nursing, New York, New York, USA.

Objective: The study sought to outline how a clinical risk prediction model for identifying patients at risk of infection is perceived by home care nurses, and to inform how the output of the model could be integrated into a clinical workflow.

Materials And Methods: This was a qualitative study using semi-structured interviews with 50 home care nurses. Interviews explored nurses' perceptions of clinical risk prediction models, their experiences using them in practice, and what elements are important for the implementation of a clinical risk prediction model focusing on infection. Interviews were audio-taped and transcribed, with data evaluated using thematic analysis.

Results: Two themes were derived from the data: (1) informing nursing practice, which outlined how a clinical risk prediction model could inform nurse clinical judgment and be used to modify their care plan interventions, and (2) operationalizing the score, which summarized how the clinical risk prediction model could be incorporated in home care settings.

Discussion: The findings indicate that home care nurses would find a clinical risk prediction model for infection useful, as long as it provided both context around the reasons why a patient was deemed to be at high risk and provided some guidance for action.

Conclusions: It is important to evaluate the potential feasibility and acceptability of a clinical risk prediction model, to inform the intervention design and implementation strategy. The results of this study can provide guidance for the development of the clinical risk prediction tool as an intervention for integration in home care settings.
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http://dx.doi.org/10.1093/jamia/ocaa267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7883974PMC
February 2021

Reduced Expression of Cerebral Metabotropic Glutamate Receptor Subtype 5 in Men with Fragile X Syndrome.

Brain Sci 2020 Nov 24;10(12). Epub 2020 Nov 24.

Department of Psychiatry and Behavioral Sciences-Child Psychiatry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

Glutamatergic receptor expression is mostly unknown in adults with fragile X syndrome (FXS). Favorable behavioral effects of negative allosteric modulators (NAMs) of the metabotropic glutamate receptor subtype 5 (mGluR) in knockout (KO) mouse models have not been confirmed in humans with FXS. Measurement of cerebral mGluR expression in humans with FXS exposed to NAMs might help in that effort. We used positron emission tomography (PET) to measure the mGluR density as a proxy of mGluR expression in cortical and subcortical brain regions to confirm target engagement of NAMs for mGluRs. The density and the distribution of mGluR were measured in two independent samples of men with FXS ( = 9) and typical development (TD) ( = 8). We showed the feasibility of this complex study including MRI and PET, meaning that this challenging protocol can be accomplished in men with FXS with an adequate preparation. Analysis of variance of estimated mGluR expression showed that mGluR expression was significantly reduced in cortical and subcortical regions of men with FXS in contrast to age-matched men with TD.
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http://dx.doi.org/10.3390/brainsci10120899DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7760509PMC
November 2020

Publisher Correction: Harnessing chemical energy for the activation and joining of prebiotic building blocks.

Nat Chem 2021 Jan;13(1):99

MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge, UK.

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http://dx.doi.org/10.1038/s41557-020-00591-0DOI Listing
January 2021

TZM-gfp cells: a tractable fluorescent tool for analysis of rare and early HIV-1 infection.

Sci Rep 2020 11 16;10(1):19900. Epub 2020 Nov 16.

Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY, 14853, USA.

Here we describe TZM-gfp, a novel HIV-1 reporter cell derived from the same parental clone JC.53, used previously to generate the widely-utilized indicator cell line TZM-bl. We re-engineered JC.53 cells to express GFP under regulation of HIV Tat and Rev. We characterize the new reporter cell line to show that TZM-gfp cells are equally susceptible to HIV infection, exhibit minimal background signal, and can report HIV infection in rare cells from a bulk population of experimentally-infected human monocyte-derived macrophages. We demonstrate the utility and sensitivity of the cells in detection of even a single HIV-positive macrophage by fluorescence-assisted correlative electron microscopy, using the GFP signal to guide imaging of HIV virions in primary co-culture. Finally, we used TZM-gfp cells for viral capture during co-culture with human peripheral blood mononuclear cells, showing that TZM-gfp can support outgrowth and analyses of patient-derived primary HIV-1 isolates.
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http://dx.doi.org/10.1038/s41598-020-76422-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7670428PMC
November 2020

Large-Scale Convergence of Receptor Cell Arrays Onto Afferent Terminal Arbors in the Lorenzinian Electroreceptors of .

Front Neuroanat 2020 19;14:50. Epub 2020 Oct 19.

Department of Biological Sciences, Ohio University, Athens, OH, United States.

Certain sensory receptors contain many transducers, converging onto few afferents. Convergence creates star-topology neural networks, of iterative parallel organization, that may yield special functional properties. We quantitated large-scale convergence in electroreceptors on the rostrum of preadult paddlefish, (Acipenseriforme vertebrates), and analyzed the afferent terminal branching underlying the convergence. From neurophysiological mapping, a recorded afferent innervated 23.3 ± 9.1 (range 6-45) ampullary organs, and innervated every ampullary organ within the receptive field's sharp boundary. Ampullary organs each contained ∼665 Lorenzinian receptor cells, from imaging and modeling. We imaged three serial types of afferent branching at electroreceptors, after immunofluorescent labeling for neurite filaments, glial sheaths, or nodal ion channels, or by DiI tracing. (i) Myelinated tree: Each of 3.08 ± 0.51 (2-4) parallel afferents from a cranial nerve (ALLn) entered a receptive field from deeper tissue, then branched into a laminar tree of large myelinated dendrites, parallel to the skin, that branched radially until ∼9 extremities with heminodes, which were candidate sites of spike encoders. (ii) Inline transition: Each myelinated extremity led distally into local unmyelinated arbors originating at inline branching structures covered by terminal (satellite) glia. The unmyelinated transition zones included globular afferent modules, 4-6 microns wide, from which erupted fine fascicles of parallel submicron neurites, a possibly novel type of neuronal branching. The neurite fascicles formed loose bundles projecting ∼105 microns distally to innervate local groups of ∼3 adjacent ampullary organs. (iii) Radial arbors: Receptor cells in an electrosensory neuroepithelium covering the basal pole of each ampullary organ were innervated by bouton endings of radial neurites, unmyelinated and submicron, forming a thin curviplanar lamina distal to the lectin+ basal lamina. The profuse radial neurites diverged from thicker (∼2 micron) basolateral trunks. Overall, an average electroreceptor formed a star topology array of ∼9 sensor groups. Total convergence ratios were 15,495 ± 6,052 parallel receptor cells per afferent per mean receptive field, assuming 100% innervation. Large-scale convergence likely increases the signal-to-noise ratio (SNR) of stimulus encoding into spiking afferent output, increasing receiver sensitivity. Unmyelinated arbors may also regenerate and repair the afferent innervation of ampullary organs. urn:lsid:zoobank.org:act:09BCF04C-3C3C-4B6C-9DC9-A2BF43087369.
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http://dx.doi.org/10.3389/fnana.2020.00050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7604333PMC
October 2020

Assessment of 18F-PI-2620 as a Biomarker in Progressive Supranuclear Palsy.

JAMA Neurol 2020 11;77(11):1408-1419

Department of Nuclear Medicine, University of Leipzig, Leipzig, Germany.

Importance: Progressive supranuclear palsy (PSP) is a 4-repeat tauopathy. Region-specific tau aggregates establish the neuropathologic diagnosis of definite PSP post mortem. Future interventional trials against tau in PSP would strongly benefit from biomarkers that support diagnosis.

Objective: To investigate the potential of the novel tau radiotracer 18F-PI-2620 as a biomarker in patients with clinically diagnosed PSP.

Design, Setting, And Participants: In this cross-sectional study, participants underwent dynamic 18F-PI-2620 positron emission tomography (PET) from 0 to 60 minutes after injection at 5 different centers (3 in Germany, 1 in the US, and 1 in Australia). Patients with PSP (including those with Richardson syndrome [RS]) according to Movement Disorder Society PSP criteria were examined together with healthy controls and controls with disease. Four additionally referred individuals with PSP-RS and 2 with PSP-non-RS were excluded from final data analysis owing to incomplete dynamic PET scans. Data were collected from December 2016 to October 2019 and were analyzed from December 2018 to December 2019.

Main Outcomes And Measures: Postmortem autoradiography was performed in independent PSP-RS and healthy control samples. By in vivo PET imaging, 18F-PI-2620 distribution volume ratios were obtained in globus pallidus internus and externus, putamen, subthalamic nucleus, substantia nigra, dorsal midbrain, dentate nucleus, dorsolateral, and medial prefrontal cortex. PET data were compared between patients with PSP and control groups and were corrected for center, age, and sex.

Results: Of 60 patients with PSP, 40 (66.7%) had RS (22 men [55.0%]; mean [SD] age, 71 [6] years; mean [SD] PSP rating scale score, 38 [15]; score range, 13-71) and 20 (33.3%) had PSP-non-RS (11 men [55.0%]; mean [SD] age, 71 [9] years; mean [SD] PSP rating scale score, 24 [11]; score range, 11-41). Ten healthy controls (2 men; mean [SD] age, 67 [7] years) and 20 controls with disease (of 10 [50.0%] with Parkinson disease and multiple system atrophy, 7 were men; mean [SD] age, 61 [8] years; of 10 [50.0%] with Alzheimer disease, 5 were men; mean [SD] age, 69 [10] years). Postmortem autoradiography showed blockable 18F-PI-2620 binding in patients with PSP and no binding in healthy controls. The in vivo findings from the first large-scale observational study in PSP with 18F-PI-2620 indicated significant elevation of tracer binding in PSP target regions with strongest differences in PSP vs control groups in the globus pallidus internus (mean [SD] distribution volume ratios: PSP-RS, 1.21 [0.10]; PSP-non-RS, 1.12 [0.11]; healthy controls, 1.00 [0.08]; Parkinson disease/multiple system atrophy, 1.03 [0.05]; Alzheimer disease, 1.08 [0.06]). Sensitivity and specificity for detection of PSP-RS vs any control group were 85% and 77%, respectively, when using classification by at least 1 positive target region.

Conclusions And Relevance: This multicenter evaluation indicates a value of 18F-PI-2620 to differentiate suspected patients with PSP, potentially facilitating more reliable diagnosis of PSP.
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http://dx.doi.org/10.1001/jamaneurol.2020.2526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7341407PMC
November 2020

Development of Native MS Capabilities on an Extended Mass Range Q-TOF MS.

Int J Mass Spectrom 2020 Dec 9;458. Epub 2020 Oct 9.

Department of Chemistry, Texas A&M University, College Station, TX 77843.

Native mass spectrometry (nMS) is increasingly used for studies of large biomolecules (>100 kDa), especially proteins and protein complexes. The growth in this area can be attributed to advances in native electrospray ionization as well as instrumentation that is capable of accessing high mass-to-charge () regimes without significant losses in sensitivity and resolution. Here, we describe modifications to the ESI source of an Agilent 6545XT Q-TOF MS that is tailored for analysis of large biomolecules. The modified ESI source was evaluated using both soluble and membrane protein complexes ranging from ~127 to ~232 kDa and the ~801 kDa protein chaperone GroEL. The increased mass resolution of the instrument affords the ability to resolve small molecule adducts and analyze collision-induced dissociation products of the native complexes.
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http://dx.doi.org/10.1016/j.ijms.2020.116451DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641504PMC
December 2020

Infection prevention and control practices in the home environment: Examining enablers and barriers to adherence among home health care nurses.

Am J Infect Control 2020 Nov 4. Epub 2020 Nov 4.

Center for Home Care Policy & Research, Visiting Nurse Service of New York, New York, NY; Department of Sociology, Appalachian State University, Boone, NC.

Background: Infection Prevention and Control (IPC) practices have been established in home health care. Adherence to IPC practices has been suboptimal with limited available evidence. The study aim was to examine the impact of individual, home environment, and organizational factors on IPC practices using human factors model.

Methods: Three hundred and fifty-three nurses were surveyed across two large home care agencies to examine the relationship between IPC adherence and individual, home environment, and organizational factors.

Results: Nurses reported multiple barriers to IPC practices in patients' homes (mean = 4.34, standard deviation = 2.53). Frequent barriers included clutter (reported by 74.5% of nurses) and a dirty environment (70.3%). Nurses also reported limited availability of some IPC supplies (mean = 7.76, standard deviation = 2.44), including personal protective equipment. Home environment factors were significant barriers, and availability of IPC supplies were significant enablers of IPC adherence. Agency-provided training and decision-making resources were not significant factors for IPC adherence in the presence of home environment barriers and IPC supplies.

Conclusions: This study findings suggest that IPC adherence strategies point to addressing barriers in the home environment and increasing availability of IPC supplies. The relationship between the patient's home environment, organizational factors, and IPC practices among home health care nurses warrants further study.
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http://dx.doi.org/10.1016/j.ajic.2020.10.021DOI Listing
November 2020

Harnessing chemical energy for the activation and joining of prebiotic building blocks.

Nat Chem 2020 11 22;12(11):1023-1028. Epub 2020 Oct 22.

MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge, UK.

Life is an out-of-equilibrium system sustained by a continuous supply of energy. In extant biology, the generation of the primary energy currency, adenosine 5'-triphosphate and its use in the synthesis of biomolecules require enzymes. Before their emergence, alternative energy sources, perhaps assisted by simple catalysts, must have mediated the activation of carboxylates and phosphates for condensation reactions. Here, we show that the chemical energy inherent to isonitriles can be harnessed to activate nucleoside phosphates and carboxylic acids through catalysis by acid and 4,5-dicyanoimidazole under mild aqueous conditions. Simultaneous activation of carboxylates and phosphates provides multiple pathways for the generation of reactive intermediates, including mixed carboxylic acid-phosphoric acid anhydrides, for the synthesis of peptidyl-RNAs, peptides, RNA oligomers and primordial phospholipids. Our results indicate that unified prebiotic activation chemistry could have enabled the joining of building blocks in aqueous solution from a common pool and enabled the progression of a system towards higher complexity, foreshadowing today's encapsulated peptide-nucleic acid system.
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http://dx.doi.org/10.1038/s41557-020-00564-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610406PMC
November 2020

Active targeting of gold nanoparticles as cancer therapeutics.

Chem Soc Rev 2020 Dec 22;49(23):8774-8789. Epub 2020 Oct 22.

School of Pharmacy, University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ, UK.

Gold nanoparticles (AuNPs) are of increasing interest for their unique properties and their biocompatability, minimal toxicity, multivalency and size tunability make them exciting drug carriers. The functionalisaton of AuNPs with targeting moieties allows for their selective delivery to cancers, with antibodies, proteins, peptides, aptamers, carbohydrates and small molecules all exploited. Here, we review the recent advances in targeted-AuNPs for the treatment of cancer, with a particular focus on these classes of targeting ligands. We highlight the benefits and potential drawbacks of each ligand class and propose directions in which the field could grow.
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http://dx.doi.org/10.1039/d0cs01121eDOI Listing
December 2020

Caregivers' Experiences Regarding Training and Support in the Post-Acute Home Health-Care Setting.

J Patient Exp 2020 Aug 21;7(4):561-569. Epub 2019 Aug 21.

Department of Family and Community Medicine, University of Missouri School of Medicine, Columbia, MO, USA.

Background: Post-acute home health-care (HHC) services provide a unique opportunity to train and support family caregivers of older adults returning home after a hospitalization. To enhance family-focused training and support strategies, we must first understand caregivers' experiences.

Objective: To explore caregivers' experiences regarding training and support for managing older adults' physical functioning (PF) needs in the post-acute HHC setting.

Method: We conducted a qualitative descriptive study using semi-structured telephone interviews of 20 family caregivers. Interviews were recorded, transcribed, and analyzed using conventional content analysis.

Results: We identified the following primary categories: facilitators to learning (eg, past experience, learning methods), barriers to learning (eg, learning on their own, communication, timing/logistics, preferred information and timing of information delivery), and interactions with HHC providers (eg, positive/negative interactions, provider training and knowledge).

Conclusion: Caregivers were responsive to learning strategies to manage older adults' PF needs and, importantly, voiced ideas to improve family-focused training and support. HHC providers can use these findings to tailor training and support of family caregivers in the post-acute HHC setting.
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http://dx.doi.org/10.1177/2374373519869156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7534114PMC
August 2020

Selective regulation of human TRAAK channels by biologically active phospholipids.

Nat Chem Biol 2021 01 28;17(1):89-95. Epub 2020 Sep 28.

Department of Chemistry, Texas A&M University, College Station, TX, USA.

TRAAK is an ion channel from the two-pore domain potassium (K) channel family with roles in maintaining the resting membrane potential and fast action potential conduction. Regulated by a wide range of physical and chemical stimuli, the affinity and selectivity of K4.1 toward lipids remains poorly understood. Here we show the two isoforms of K4.1 have distinct binding preferences for lipids dependent on acyl chain length and position on the glycerol backbone. The channel can also discriminate the fatty acid linkage at the SN position. Of the 33 lipids interrogated using native mass spectrometry, phosphatidic acid had the lowest equilibrium dissociation constants for both isoforms of K4.1. Liposome potassium flux assays with K4.1 reconstituted in defined lipid environments show that those containing phosphatidic acid activate the channel in a dose-dependent fashion. Our results begin to define the molecular requirements for the specific binding of lipids to K4.1.
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http://dx.doi.org/10.1038/s41589-020-00659-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7746637PMC
January 2021

"Doing the Right Thing": Family Caregivers Managing Medical and Nursing Tasks in the Postacute Home Health Care Setting.

J Appl Gerontol 2020 Sep 27:733464820961259. Epub 2020 Sep 27.

Center for Home Care Policy & Research, Visiting Nurse Service of New York, New York City, USA.

Family caregivers often manage complex medical and nursing tasks (MNTs) for older adults transitioning from hospital to home. To explore caregivers' experiences managing MNTs in the postacute home health care (HHC) setting, we interviewed by phone 20 caregivers of older adults who received HHC following a hospitalization. Interviews were recorded, transcribed, and analyzed using directed content analysis. Caregivers highlighted the technical complexity and emotional impact of performing MNTs, as well as social (e.g., family, friends) and environmental (e.g., neighborhood, housing) resources they leveraged to meet the older adults' care needs. Caregivers also identified challenges coordinating care and services within HHC and the larger health care system. Caregiver engagement in the postacute HHC setting should incorporate tailored training and support, assessments of socioenvironmental context and resources, and facilitated navigation of the health care system. Future research should elucidate factors associated with successful collaborative relationships among HHC providers, older adults, and their caregivers in the postacute HHC setting.
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http://dx.doi.org/10.1177/0733464820961259DOI Listing
September 2020

Nutrition and the Gut Microbiota in 10- to 18-Month-Old Children Living in Urban Slums of Mumbai, India.

mSphere 2020 09 23;5(5). Epub 2020 Sep 23.

Division of Nutritional Sciences, Cornell University, Ithaca, New York, USA

In this cross-sectional study, we describe the composition and diversity of the gut microbiota among undernourished children living in urban slums of Mumbai, India, and determine how nutritional status, including anthropometric measurements, dietary intakes from complementary foods, feeding practices, and micronutrient concentrations, is associated with their gut microbiota. We collected rectal swabs from children aged 10 to 18 months living in urban slums of Mumbai participating in a randomized controlled feeding trial and conducted 16S rRNA sequencing to determine the composition of the gut microbiota. Across the study cohort, dominated the gut microbiota at over 80% relative abundance, with representation at <4%, suggesting immaturity of the gut. Increased microbial α-diversity was associated with current breastfeeding, greater head circumference, higher fat intake, and lower hemoglobin concentration and weight-for-length Z-score. In redundancy analyses, 47% of the variation in Faith's phylogenetic diversity (Faith's PD) could be accounted for by age and by iron and polyunsaturated fatty acid intakes. Differences in community structure (β-diversity) of the microbiota were observed among those consuming fats and oils the previous day compared to those not consuming fats and oils the previous day. Our findings suggest that growth, diet, and feeding practices are associated with gut microbiota metrics in undernourished children, whose gut microbiota were comprised mainly of , a phylum containing many potentially pathogenic taxa. The impact of comprehensive nutritional status, defined as growth, nutritional blood biomarkers, dietary intakes, and feeding practices, on the gut microbiome in children living in low-resource settings has remained underreported in microbiome research. Among undernourished children living in urban slums of Mumbai, India, we observed a high relative abundance of , a phylum including many potentially pathogenic species similar to the composition in preterm infants, suggesting immaturity of the gut, or potentially a high inflammatory burden. We found head circumference, fat and iron intake, and current breastfeeding were positively associated with microbial diversity, while hemoglobin and weight for length were associated with lower diversity. Findings suggest that examining comprehensive nutrition is critical to gain more understanding of how nutrition and the gut microbiota are linked, particularly in vulnerable populations such as children in urban slum settings.
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http://dx.doi.org/10.1128/mSphere.00731-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7568645PMC
September 2020

Observation of Hand Hygiene Practices in Home Health Care.

J Am Med Dir Assoc 2020 Sep 15. Epub 2020 Sep 15.

Columbia University School of Nursing, New York, NY, USA.

Objective: To describe nurse hand hygiene practices in the home health care (HHC) setting, nurse adherence to hand hygiene guidelines, and factors associated with hand hygiene opportunities during home care visits.

Design: Observational study of nurse hand hygiene practices.

Setting: and Participants: Licensed practical/vocational and registered nurses were observed in the homes of patients being served by a large nonprofit HHC agency.

Methods: Two researchers observed 400 home care visits conducted by 50 nurses. The World Health Organization's "5 Moments for Hand Hygiene" validated observation tool was used to record opportunities and actual practices of hand hygiene, with 3 additional opportunities specific to the HHC setting. Patient assessment data available in the agency electronic health record and a nurse demographic questionnaire were also collected to describe patients and nurse participants.

Results: A total of 2014 opportunities were observed. On arrival in the home was the most frequent opportunity (n = 384), the least frequent was after touching a patient's surroundings (n = 43). The average hand hygiene adherence rate was 45.6% after adjusting for clustering at the nurse level. Adherence was highest after contact with body fluid (65.1%) and lowest after touching a patient (29.5%). The number of hand hygiene opportunities was higher when patients being served were at increased risk of an infection-related emergency department visit or hospitalization and when the home environment was observed to be "dirty." No nurse or patient demographic characteristics were associated with the rate of nurse hand hygiene adherence.

Conclusions And Implications: Hand hygiene adherence in HHC is suboptimal, with rates mirroring those reported in hospital and outpatient settings. The connection between poor hand hygiene and infection transmission has been well studied, and it has received widespread attention with the outbreak of SARS-CoV-2. Agencies can use results found in this study to better inform quality improvement initiatives.
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http://dx.doi.org/10.1016/j.jamda.2020.07.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7490582PMC
September 2020