Publications by authors named "Richard Gibson"

110 Publications

Differential diagnosis of acute traumatic hip pain in the elderly.

Acta Orthop Belg 2021 Mar;87(1):1-7

Elderly patients who present with an inability to weight bear following a fall, with normal radiographs, should be appropriately investigated to rule out an occult hip fracture (OHF). We aim to identify both the range and incidence of the differential diagnosis of acute traumatic hip pain in a large series of patients investigated for OHF. A retrospective analysis of consecutive patients investigated for an OHF with magnetic resonance imaging (MRI) was performed. Dedicated musculo- skeletal radiologists reported the MRI scans. All diagnoses including hip fractures, other fractures and soft tissue injuries were recorded. Case notes were reviewed for all patients to identify subsequent complications, management and outcomes. A total of 157 patients fulfilled the inclusion criteria. 52 (33%) patients had a fracture of the proximal femur. The majority of patients with proximal femoral fractures required surgical intervention. 9 patients who had fractures of the greater trochanter of the femur without fracture extension across the femoral neck were managed non-operatively. 40 (25%) patients had fractures of the pelvis, with a combined pubic rami and sacral fracture occurring frequently. The most common diagnosis was a soft tissue injury alone that was seen in 60 (38%) patients imaged. Injuries to the gluteal muscle group, iliopsaos complex and trochanteric bursa were most prevalent. All patients with soft tissue injuries or fractures of the pelvis were successfully managed non-operatively. This study highlights a wide range of differential diagnoses in elderly patients presenting with acute traumatic hip pain. The proximal femur was fractured in 33% of patients imaged for OHFs in our series. The most common diagnosis was a soft tissue injury around the hip and pelvis ; these injuries can be successfully managed without surgery.
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March 2021

An Amino Acid Polymorphism within the HIV-1 Nef Dileucine Motif Functionally Uncouples Cell Surface CD4 and SERINC5 Downregulation.

J Virol 2021 07 26;95(16):e0058821. Epub 2021 Jul 26.

Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada.

Serine incorporator 5 (SERINC5) reduces the infectivity of progeny HIV-1 virions by incorporating into the outer host-derived viral membrane during egress. To counter SERINC5, the HIV-1 accessory protein Nef triggers SERINC5 internalization by engaging the adaptor protein 2 (AP-2) complex using the [D/E]xxxL[L/I] Nef dileucine motif. Nef also engages AP-2 via its dileucine motif to downregulate the CD4 receptor. Although these two Nef functions are related, the mechanisms governing SERINC5 downregulation are incompletely understood. Here, we demonstrate that two primary Nef isolates, referred to as 2410 and 2391 Nef, acquired from acutely HIV-1 infected women from Zimbabwe, both downregulate CD4 from the cell surface. However, only 2410 Nef retains the ability to downregulate cell surface SERINC5. Using a series of Nef chimeras, we mapped the region of 2391 Nef responsible for the functional uncoupling of these two antagonistic pathways to the dileucine motif. Modifications of the first and second x positions of the 2410 Nef dileucine motif to asparagine and aspartic acid residues, respectively (ND), impaired cell surface SERINC5 downregulation, which resulted in reduced infectious virus yield in the presence of SERINC5. The ND mutation additionally partially impaired, but did not completely abrogate, Nef-mediated cell surface CD4 downregulation. Furthermore, the patient infected with HIV-1 encoding 2391 Nef had stable CD4 T cell counts, whereas infection with HIV-1 encoding 2410 Nef resulted in CD4 T cell decline and disease progression. A contributing factor to HIV-1 persistence is evasion of the host immune response. HIV-1 uses the Nef accessory protein to evade the antiviral roles of the adaptive and intrinsic innate immune responses. Nef targets SERINC5, a restriction factor which potently impairs HIV-1 infection by triggering SERINC5 removal from the cell surface. The molecular determinants underlying this Nef function remain incompletely understood. Recent studies have found a correlation between the extent of Nef-mediated SERINC5 downregulation and the rate of disease progression. Furthermore, single-residue polymorphisms outside the known Nef functional motifs can modulate SERINC5 downregulation. The identification of a naturally occurring Nef polymorphism impairing SERINC5 downregulation in this study supports a link between Nef downregulation of SERINC5 and the rate of plasma CD4 T cell decline. Moreover, the observed functional impairments of this polymorphism could provide clues to further elucidate unknown aspects of the SERINC5 antagonistic pathway via Nef.
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http://dx.doi.org/10.1128/JVI.00588-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8312866PMC
July 2021

Treating COVID-19 Acute Severe Hypoxemic Respiratory Failure: First Case Report Utilizing Dexamethasone, Remdesivir, and Convalescent Plasma in Operation Inherent Resolve.

Med J (Ft Sam Houst Tex) 2021 Jan-Mar(PB 8-21-01/02/03):28-33

Department of Pulmonary/Critical Care Medicine at Brook Army Medical Center, Fort Sam Houston, TX.

Coronavirus 2019 (COVID-19) has spread across the globe with a concerningly high infectivity resulting in the World Health Organization deeming it a pandemic. It has resulted in thousands of deaths and placed enormous strain on communities, healthcare systems and healthcare workers as they battle shortages of ventilators, supplies, and difficulties in protecting patients and hospital staff alike. Challenges in managing the disease have led to new treatment and management strategies as healthcare teams struggle to adapt. We present the first case of COVID-19 managed in the austere deployed environment of Operation Inherent Resolve in which the patient was treated with dexamethasone, remdesivir, COVID-19 convalescent plasma, positive pressure ventilation, and proning. We discuss some of the inherent and unique challenges of caring for a patient in this resource constrained environment with a brief review of the literature on the treatment and management.
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March 2021

Elective amputation and neuroprosthetic limbs.

Authors:
Richard B Gibson

New Bioeth 2021 Mar 15;27(1):30-45. Epub 2021 Jan 15.

The Centre for Social Ethics and Policy, The University of Manchester Law School, Manchester, UK.

This paper explores the impact that developments in the field of neuroprosthetics will have on the ethical viability of healthy limb amputation, specifically in cases of Body Integrity Identity Disorder (BIID). Developments in the field have meant that the prospect of such artificial components matching the utility of their biological counterparts is now a possibility. As such, arguments against the provision of therapeutic, healthy limb amputation, which are grounded in the perceived resultant harm of disability, need to be reconsidered. Drawing on philosophical insights, as well as the field of disability studies and BIID research, this paper argues that such neuroprosthetics presents a challenge for the fundamental dichotomy between the disabled and non-disabled, including the latter's perceived superiority. It goes on to suggest that healthy limb amputation, for those with BIID, should not be dismissed simply because of the distastefulness of the procedure, but rather be evaluated based upon its own merits.
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http://dx.doi.org/10.1080/20502877.2020.1869466DOI Listing
March 2021

Accumulation of integrase strand transfer inhibitor resistance mutations confers high-level resistance to dolutegravir in non-B subtype HIV-1 strains from patients failing raltegravir in Uganda.

J Antimicrob Chemother 2020 12;75(12):3525-3533

Department of Microbiology and Immunology, Western University, London, Canada.

Background: Increasing first-line treatment failures in low- and middle-income countries (LMICs) have led to increased use of integrase strand transfer inhibitors (INSTIs) such as dolutegravir. However, HIV-1 susceptibility to INSTIs in LMICs, especially with previous raltegravir exposure, is poorly understood due to infrequent reporting of INSTI failures and testing for INSTI drug resistance mutations (DRMs).

Methods: A total of 51 non-subtype B HIV-1 infected patients failing third-line (raltegravir-based) therapy in Uganda were initially selected for the study. DRMs were detected using Sanger and deep sequencing. HIV integrase genes of 13 patients were cloned and replication capacities (RCs) and phenotypic susceptibilities to dolutegravir, raltegravir and elvitegravir were determined with TZM-bl cells. Spearman's correlation coefficient was used to determine cross-resistance between INSTIs.

Results: INSTI DRMs were detected in 47% of patients. HIV integrase-recombinant virus carrying one primary INSTI DRM (N155H or Y143R/S) was susceptible to dolutegravir but highly resistant to raltegravir and elvitegravir (>50-fold change). Two patients, one with E138A/G140A/Q148R/G163R and one with E138K/G140A/S147G/Q148K, displayed the highest reported resistance to raltegravir, elvitegravir and even dolutegravir. The former multi-DRM virus had WT RC whereas the latter had lower RCs than WT.

Conclusions: In HIV-1 subtype A- and D-infected patients failing raltegravir and harbouring INSTI DRMs, there is high-level resistance to elvitegravir and raltegravir. More routine monitoring of INSTI treatment may be advised in LMICs, considering that multiple INSTI DRMs may have accumulated during prolonged exposure to raltegravir during virological failure, leading to high-level INSTI resistance, including dolutegravir resistance.
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http://dx.doi.org/10.1093/jac/dkaa355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7662175PMC
December 2020

A targeted reactivation of latent HIV-1 using an activator vector in patient samples from acute infection.

EBioMedicine 2020 Sep 9;59:102853. Epub 2020 Jul 9.

Department of Microbiology and Immunology, University of Western Ontario, London, Ontario N6A 5C1, Canada; Division of Infectious Diseases, Department of Medicine, Case Western Reserve University, Cleveland, OH 44106, United States. Electronic address:

Background: During combined anti-retroviral treatment, a latent HIV reservoir persists within resting memory CD4 T cells that initiates viral recrudescence upon treatment interruption. Strategies for HIV-1 cure have largely focused on latency reversing agents (LRAs) capable of reactivating and eliminating this viral reservoir. Previously investigated LRAs have largely failed to achieve a robust latency reversal sufficient for reduction of latent HIV pool or the potential of virus-free remission in the absence of treatment.

Methods: We utilize a polyvalent virus-like particle (VLP) formulation called Activator Vector (ACT-VEC) to 'shock' provirus into transcriptional activity. Ex vivo co-culture experiments were used to evaluate the efficacy of ACT-VEC in relation to other LRAs in individuals diagnosed and treated during the acute stage of infection. IFN-γ ELISpot, qRT-PCR and Illumina MiSeq were used to evaluate antigenicity, latency reversal, and diversity of induced virus respectively.

Findings: Using samples from HIV patients diagnosed and treated at acute/early infection, we demonstrate that ACT-VEC can reverse latency in HIV infected CD4 T cells to a greater extent than other major recall antigens as stimuli or even mitogens such as PMA/Iono. Furthermore, ACT-VEC activates more latent HIV-1 than clinically tested HDAC inhibitors or protein kinase C agonists.

Interpretation: Taken together, these results show that ACT-VEC can induce HIV reactivation from latently infected CD4 T cells collected from participants on first line combined antiretroviral therapy for at least two years after being diagnosed and treated at acute/early stage of infection. These findings could provide guidance to possible targeted cure strategies and treatments.

Funding: NIH and CIHR.
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http://dx.doi.org/10.1016/j.ebiom.2020.102853DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7502668PMC
September 2020

Elective Impairment Minus Elective Disability: The Social Model of Disability and Body Integrity Identity Disorder.

Authors:
Richard B Gibson

J Bioeth Inq 2020 Mar 19;17(1):145-155. Epub 2019 Dec 19.

Centre for Social Ethics and Policy, The University of Manchester Law School, University of Manchester, Manchester, M13 9QQ, UK.

Individuals with body integrity identity disorder (BIID) seek to address a non-delusional incongruity between their body image and their physical embodiment, sometimes via the surgical amputation of healthy body parts. Opponents to the provision of therapeutic healthy-limb amputation in cases of BIID make appeals to the envisioned harms that such an intervention would cause, harms such as the creation of a lifelong physical disability where none existed before. However, this concept of harm is often based on a normative biomedical model of health and disability, a model which conflates amputation with impairment, and impairment with a disability. This article challenges the prima facie harms assumed to be inherent in limb amputation and argues in favour of a potential treatment option for those with BIID. To do this, it employs the social model of disability as a means to separate the concept of impairment and disability and thereby separate the acute and chronic harms of the practice of therapeutic healthy-limb amputation. It will then argue that provided sufficient measures are put in place to ensure that those with atypical bodily constructions are not disadvantaged, the chronic harms of elective amputation would cease to be.
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http://dx.doi.org/10.1007/s11673-019-09959-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7260267PMC
March 2020

Accepting new patients who require opioids into family practice: results from the MAAP-NS census survey study.

BMC Fam Pract 2019 10 23;20(1):141. Epub 2019 Oct 23.

Department of Family Medicine, Dalhousie University, Suite 402, 1465 Brenton Street, Halifax, Nova Scotia, B3J 3T4, Canada.

Background: Acceptance to a family practice is key to access and continuity of care. While Canadian patients increasingly report not being able to acquire acceptance to a family practice, little is known about the association between requiring opioids and acceptance. We aim to determine the proportion of family physicians who would accept new patients who require opioids and describe physician and practice characteristics associated with willingness to accept these patients.

Methods: Census telephone survey of family physicians' practices in Nova Scotia, Canada.

Measures: physician (i.e., age, sex, years in practice) and practice (i.e., number/type of provider in the practice, care hours/week) characteristics and practice-reported willingness to accept new patients who require opioids.

Results: The survey was completed for 587 family physicians (83.7% response rate). 354 (60.3%) were taking new patients unconditionally or with conditions; 326 provided a response to whether they would accept new patients who require opioids; 91 (27.9%) reported they would not accept a new patient who requires opioids. Compared to family physicians who would not accept patients who require opioids, in bivariate analysis, those who would, tended to work in larger practices; had fewer years in practice; are female; and provided more patient care. The relationship to number of providers in the practice, having a nurse, and experience persisted in multivariate analysis.

Conclusions: The strongest predictors of willingness to accept patients who require opioids are fewer years in practice (OR = 0.96 [95% CI 0.93, 0.99]) and variables indicating a family physician has support of a larger (OR = 1.19 [95% CI 1.00, 1.42]), interdisciplinary team (e.g., nurses, mental health professionals) (OR = 1.15 [95% CI 1.11, 5.05]). Almost three-quarters (72.1%) of surveyed family physicians would accept patients requiring opioids.
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http://dx.doi.org/10.1186/s12875-019-1027-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6806488PMC
October 2019

Practice patterns among early-career primary care (ECPC) physicians and workforce planning implications: protocol for a mixed methods study.

BMJ Open 2019 09 24;9(9):e030477. Epub 2019 Sep 24.

Centre for Health Services and Policy Research, University of British Columbia, Vancouver, British Columbia, Canada.

Introduction: Canadians report persistent problems accessing primary care despite an increasing per-capita supply of primary care physicians (PCPs). There is speculation that PCPs, especially those early in their careers, may now be working less and/or choosing to practice in focused clinical areas rather than comprehensive family medicine, but little evidence to support or refute this. The goal of this study is to inform primary care planning by: (1) identifying values and preferences shaping the practice intentions and choices of family medicine residents and early career PCPs, (2) comparing practice patterns of early-career and established PCPs to determine if changes over time reflect cohort effects (attributes unique to the most recent cohort of PCPs) or period effects (changes over time across all PCPs) and (3) integrating findings to understand the dynamics among practice intentions, practice choices and practice patterns and to identify policy implications.

Methods And Analysis: We plan a mixed-methods study in the Canadian provinces of British Columbia, Ontario and Nova Scotia. We will conduct semi-structured in-depth interviews with family medicine residents and early-career PCPs and analyse survey data collected by the College of Family Physicians of Canada. We will also analyse linked administrative health data within each province. Mixed methods integration both within the study and as an end-of-study step will inform how practice intentions, choices and patterns are interrelated and inform policy recommendations.

Ethics And Dissemination: This study was approved by the Simon Fraser University Research Ethics Board with harmonised approval from partner institutions. This study will produce a framework to understand practice choices, new measures for comparing practice patterns across jurisdictions and information necessary for planners to ensure adequate provider supply and patient access to primary care.
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http://dx.doi.org/10.1136/bmjopen-2019-030477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6773300PMC
September 2019

The Democratization of Facial Feminization Surgery and the Removal of Artificial Barriers.

Authors:
Richard Gibson

Am J Bioeth 2018 12;18(12):29-31

a University of Manchester.

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http://dx.doi.org/10.1080/15265161.2018.1531169DOI Listing
December 2018

Role of co-expressed APOBEC3F and APOBEC3G in inducing HIV-1 drug resistance.

Heliyon 2019 Apr 16;5(4):e01498. Epub 2019 Apr 16.

University of Saskatchewan, Biochemistry, Microbiology, and Immunology, College of Medicine, Saskatoon, Saskatchewan, S7H 5E5, Canada.

The APOBEC3 enzymes can induce mutagenesis of HIV-1 proviral DNA through the deamination of cytosine. HIV-1 overcomes this restriction through the viral protein Vif that induces APOBEC3 proteasomal degradation. Within this dynamic host-pathogen relationship, the APOBEC3 enzymes have been found to be beneficial, neutral, or detrimental to HIV-1 biology. Here, we assessed the ability of co-expressed APOBEC3F and APOBEC3G to induce HIV-1 resistance to antiviral drugs. We found that co-expression of APOBEC3F and APOBEC3G enabled partial resistance of APOBEC3F to Vif-mediated degradation with a corresponding increase in APOBEC3F-induced deaminations in the presence of Vif, in addition to APOBEC3G-induced deaminations. We recovered HIV-1 drug resistant variants resulting from APOBEC3-induced mutagenesis, but these variants were less able to replicate than drug resistant viruses derived from RT-induced mutations alone. The data support a model in which APOBEC3 enzymes cooperate to restrict HIV-1, promoting viral inactivation over evolution to drug resistance.
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http://dx.doi.org/10.1016/j.heliyon.2019.e01498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6475876PMC
April 2019

First-line HIV treatment failures in non-B subtypes and recombinants: a cross-sectional analysis of multiple populations in Uganda.

AIDS Res Ther 2019 01 22;16(1). Epub 2019 Jan 22.

Department of Microbiology and Immunology, Western University, London, Canada.

Background: Our understanding of HIV-1 and antiretroviral treatment (ART) is strongly biased towards subtype B, the predominant subtype in North America and western Europe. Efforts to characterize the response to first-line treatments in other HIV-1 subtypes have been hindered by the availability of large study cohorts in resource-limited settings. To maximize our statistical power, we combined HIV-1 sequence and clinical data from every available study population associated with the Joint Clinical Research Centre (JCRC) in Uganda. These records were combined with contemporaneous ART-naive records from Uganda in the Stanford HIVdb database.

Methods: Treatment failures were defined by the presence of HIV genotype records with sample collection dates after the ART start dates in the JCRC database. Drug resistances were predicted by the Stanford HIVdb algorithm, and HIV subtype classification and recombination detection was performed with SCUEAL. We used Bayesian network analysis to evaluate associations between drug exposures and subtypes, and binomial regression for associations with recombination.

Results: This is the largest database of first-line treatment failures ([Formula: see text]) in Uganda to date, with a predicted statistical power of 80% to detect subtype associations at an odds ratio of [Formula: see text]. In the subset where drug regimen data were available, we observed that use of 3TC was associated with a higher rate of first line treatment failure, whereas regimens containing AZT and TDF were associated with reduced rates of failure. In the complete database, we found limited evidence of associations between HIV-1 subtypes and treatment failure, with the exception of a significantly lower frequency of failures among A/D recombinants that comprised about 7% of the population. First-line treatment failure was significantly associated with reduced numbers of recombination breakpoints across subtypes.

Conclusions: Expanding access to first-line ART should confer the anticipated public health benefits in Uganda, despite known differences in the pathogenesis of HIV-1 subtypes. Furthermore, the impact of ART may actually be enhanced by frequent inter-subtype recombination in this region.
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http://dx.doi.org/10.1186/s12981-019-0218-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6343277PMC
January 2019

Factors influencing reversion from virus infection in sweetpotato.

Ann Appl Biol 2019 6;176(2):1-13. Epub 2019 Nov 6.

Department of Agricultural Production, Makerere University, Kampala, Uganda.

Viruses limit sweetpotato () production worldwide. Many sweetpotato landraces in East Africa are, however, largely virus-free. Moreover, some plants infected by the prevalent Sweet (SPFMV) may be able to revert to virus-free status. In this study, we analysed reversion from SPFMV, (SPCSV) and using the indicator plant and PCR/reverse-transcriptase PCR. We also investigated environmental factors (temperature and soil nutrients) that may influence reversion from virus infection. We tested reversion in the East African cultivars New Kawogo, NASPOT 1 and NASPOT 11, and the United States cultivars Resisto and Beauregard. Reverted plants were asymptomatic and virus was undetectable in assayed parts of the plant. After graft inoculation, only the East African cultivars mostly reverted at a high rate and from most viruses though cultivar Beauregard fully reverted following sap inoculation with None of the tested cultivars fully reverted from single or double infections involving SPCSV, and reversion was only observed in co-infections involving potyviruses. Root sprouts derived from SPFMV-reverted plants were also virus free. Reversion generally increased with increasing temperature and by improved soil nutrition. Overall, these results indicate variation in reversion by cultivar and that the natural ability of sweetpotato plants to revert from viruses is malleable, which has implications for both breeding and virus control.
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http://dx.doi.org/10.1111/aab.12551DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7053384PMC
November 2019

Case management in primary care for frequent users of healthcare services with chronic diseases and complex care needs: an implementation and realist evaluation protocol.

BMJ Open 2018 11 25;8(11):e026433. Epub 2018 Nov 25.

Sturgeon Lake First Nation, Sturgeon Lake, Saskatchewan, Canada.

Introduction: Significant evidence in the literature supports case management (CM) as an effective intervention to improve care for patients with complex healthcare needs. However, there is still little evidence about the facilitators and barriers to CM implementation in primary care setting. The three specific objectives of this study are to: (1) identify the facilitators and barriers of CM implementation in primary care clinics across Canada; (2) explain and understand the relationships between the actors, contextual factors, mechanisms and outcomes of the CM intervention; (3) identify the next steps towards CM spread in primary care across Canada.

Methods And Analysis: We will conduct a multiple-case embedded mixed methods study. CM will be implemented in 10 primary care clinics in five Canadian provinces. Three different units of analysis will be embedded to obtain an in-depth understanding of each case: the healthcare system (macro level), the CM intervention in the clinics (meso level) and the individual/patient (micro level). For each objective, the following strategy will be performed: (1) an implementation analysis, (2) a realist evaluation and (3) consensus building among stakeholders using the Technique for Research of Information by Animation of a Group of Experts method.

Ethics And Dissemination: This study, which received ethics approval, will provide innovative knowledge about facilitators and barriers to implementation of CM in different primary care jurisdictions and will explain how and why different mechanisms operate in different contexts to generate different outcomes among frequent users. Consensual and prioritised statements about next steps for spread of CM in primary care from the perspectives of all stakeholders will be provided. Our results will offer context-sensitive explanations that can better inform local practices and policies and contribute to improve the health of patients with complex healthcare needs who frequently use healthcare services. Ultimately, this will increase the performance of healthcare systems and specifically mitigate ineffective use and costs.
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http://dx.doi.org/10.1136/bmjopen-2018-026433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6254422PMC
November 2018

Graphic illustration of impairment: science fiction, and the social model of disability.

Authors:
Richard Gibson

Med Humanit 2020 Mar 18;46(1):12-21. Epub 2018 Sep 18.

The following paper examines the cyberpunk transhumanist graphic novel through the theoretical lens of disability studies to demonstrate how science fiction, and in particular this series, illustrate and can influence how we think about disability, impairment and difference. While is most often read as a scathing political and social satire about abuse of power and the danger of political apathy, the comic series also provides readers with representations of impairment and the source of disability as understood by the Social Model of Disability (SMD). Focusing on the setting and fictional world in which takes place, as well as key events and illustration styling, this paper demonstrates that the narrative in this work encompasses many of the same theoretical underpinnings and criticisms of society's ignorance of the cause of disability as the SMD does. This paper aims, by demonstrating how can be read as an allegory for the disabling potential of society as experienced by individuals with impairments, to prompt readers into thinking more creatively about how narratives, seemingly unconcerned with disability, are informed and can be understood via disability theory.
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http://dx.doi.org/10.1136/medhum-2018-011506DOI Listing
March 2020

Evolution-Guided Structural and Functional Analyses of the HERC Family Reveal an Ancient Marine Origin and Determinants of Antiviral Activity.

J Virol 2018 07 13;92(13). Epub 2018 Jun 13.

Western University, Schulich School of Medicine and Dentistry, Department of Microbiology and Immunology, London, Ontario, Canada

In humans, homologous to the E6-AP carboxyl terminus (HECT) and regulator of chromosome condensation 1 (RCC1)-like domain-containing protein 5 (HERC5) is an interferon-induced protein that inhibits replication of evolutionarily diverse viruses, including human immunodeficiency virus type 1 (HIV-1). To better understand the origin, evolution, and function of HERC5, we performed phylogenetic, structural, and functional analyses of the entire human small-HERC family, which includes HERC3, HERC4, HERC5, and HERC6. We demonstrated that the family emerged >595 million years ago and has undergone gene duplication and gene loss events throughout its evolution. The structural topology of the RCC1-like domain and HECT domains from all HERC paralogs is highly conserved among evolutionarily diverse vertebrates despite low sequence homology. Functional analyses showed that the human small HERCs exhibit different degrees of antiviral activity toward HIV-1 and that HERC5 provides the strongest inhibition. Notably, coelacanth HERC5 inhibited simian immunodeficiency virus (SIV), but not HIV-1, particle production, suggesting that the antiviral activity of HERC5 emerged over 413 million years ago and exhibits species- and virus-specific restriction. In addition, we showed that both HERC5 and HERC6 are evolving under strong positive selection, particularly blade 1 of the RCC1-like domain, which we showed is a key determinant of antiviral activity. These studies provide insight into the origin, evolution, and biological importance of the human restriction factor HERC5 and the other HERC family members. Intrinsic immunity plays an important role as the first line of defense against viruses. Studying the origins, evolution, and functions of proteins responsible for effecting this defense will provide key information about virus-host relationships that can be exploited for future drug development. We showed that HERC5 is one such antiviral protein that belongs to an evolutionarily conserved family of HERCs with an ancient marine origin. Not all vertebrates possess all HERC members, suggesting that different HERCs emerged at different times during evolution to provide the host with a survival advantage. Consistent with this, two of the more recently emerged HERC members, HERC5 and HERC6, displayed strong signatures of having been involved in an ancient evolutionary battle with viruses. Our findings provide new insights into the evolutionary origin and function of the HERC family in vertebrate evolution, identifying HERC5 and possibly HERC6 as important effectors of intrinsic immunity in vertebrates.
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http://dx.doi.org/10.1128/JVI.00528-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6002735PMC
July 2018

Absence of HIV-1 Drug Resistance Mutations Supports the Use of Dolutegravir in Uganda.

AIDS Res Hum Retroviruses 2018 05 26;34(5):404-414. Epub 2018 Feb 26.

1 Department of Microbiology and Immunology, Western University , London, Canada .

To screen for drug resistance and possible treatment with Dolutegravir (DTG) in treatment-naive patients and those experiencing virologic failure during first-, second-, and third-line combined antiretroviral therapy (cART) in Uganda. Samples from 417 patients in Uganda were analyzed for predicted drug resistance upon failing a first- (N = 158), second- (N = 121), or third-line [all 51 involving Raltegravir (RAL)] treatment regimen. HIV-1 pol gene was amplified and sequenced from plasma samples. Drug susceptibility was interpreted using the Stanford HIV database algorithm and SCUEAL was used for HIV-1 subtyping. Frequency of resistance to nucleoside reverse transcriptase inhibitors (NRTIs) (95%) and non-NRTI (NNRTI, 96%) was high in first-line treatment failures. Despite lack of NNRTI-based treatment for years, NNRTI resistance remained stable in 55% of patients failing second-line or third-line treatment, and was also at 10% in treatment-naive Ugandans. DTG resistance (n = 366) was not observed in treatment-naive individuals or individuals failing first- and second-line cART, and only found in two patients failing third-line cART, while 47% of the latter had RAL- and Elvitegravir-resistant HIV-1. Secondary mutations associated with DTG resistance were found in 2%-10% of patients failing third-line cART. Of 14 drugs currently available for cART in Uganda, resistance was readily observed to all antiretroviral drugs (except for DTG) in Ugandan patients failing first-, second-, or even third-line treatment regimens. The high NNRTI resistance in first-line treatment in Uganda even among treatment-naive patients calls for the use of DTG to reach the UNAIDS 90:90:90 goals.
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http://dx.doi.org/10.1089/AID.2017.0205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5934975PMC
May 2018

Sensitive detection of HIV-1 resistance to Zidovudine and impact on treatment outcomes in low- to middle-income countries.

Infect Dis Poverty 2017 Dec 4;6(1):163. Epub 2017 Dec 4.

Department of Microbiology and Immunology, University of Western Ontario, 1151 Richmond St., Dental Sciences Bldg., Rm 3014, London, Ontario, N6A 5C1, Canada.

Background: Thymidine analogs, namely AZT (Zidovudine or Retrovir™) and d4T (Stavudine or Zerit™) are antiretroviral drugs still employed in over 75% of first line combination antiretroviral therapy (cART) in Kampala, Uganda despite aversion to prescribing these drugs for cART in high income countries due in part to adverse events. For this study, we explored how the continued use of these thymidine analogs in cART could impact emergence of drug resistance and impact on future treatment success in Uganda, a low-income country.

Methods: We examined the drug resistance genotypes by Sanger sequencing of 262 HIV-infected patients failing a first line combined antiretroviral treatment containing either AZT or d4T, which represents approximately 5% of the patients at the Joint Clinical Research Center receiving a AZT or d4T containing treatment. Next generation sequencing (DEEPGEN™HIV) and multiplex oligonucleotide ligation assays (AfriPOLA) were then performed on a subset of patient samples to detect low frequency drug resistant mutations. CD4 cell counts, viral RNA loads, and treatment changes were analyzed in a cohort of treatment success and failures.

Results: Over 80% of patients failing first line AZT/d4T-containing cART had predicted drug resistance to 3TC (Lamivudine) and non-nucleoside RT inhibitors (NNRTIs) in the treatment regimen but only 45% had resistance AZT/d4T associated resistance mutations (TAMs). TAMs were however detected at low frequency within the patients HIV quasispecies (1-20%) in 21 of 34 individuals who were failing first-line AZT-containing cART and lacked TAMs by Sanger. Due to lack of TAMs by Sanger, AZT was typically maintained in second-line therapies and these patients had a low frequency of subsequent virologic success.

Conclusions: Our findings suggest that continued use of AZT and d4T in first-line treatment in low-to-middle income countries may lead to misdiagnosis of HIV-1 drug resistance and possibly enhance a succession of second- and third-line treatment failures.
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http://dx.doi.org/10.1186/s40249-017-0377-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5716384PMC
December 2017

Benefits of Electronic Medical Record Banks.

Authors:
Richard F Gibson

JAMA Intern Med 2017 09;177(9):1398

Department of Medical Informatics and Clinical Epidemiology, Oregon Health and Science University, Portland.

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http://dx.doi.org/10.1001/jamainternmed.2017.2716DOI Listing
September 2017

Does socio-economic status or having a chronic condition affect whether family physicians accept a new patient? A Nova Scotia population study.

Can J Public Health 2017 Sep 1;108(5-6):e546-e550. Epub 2017 Sep 1.

Faculty of Medicine, Dalhousie University, Halifax, NS, Canada.

Objectives: To determine whether socio-economic status (SES) and presence of a chronic condition are associated with the response a prospective patient receives when seeking a family physician (FP).

Methods: Scripted telephone calls (indicating higher or lower SES and presence or absence of a chronic condition) were made to all 327 FP offices in Nova Scotia (NS) requesting an appointment. The main outcome measures were the responses to callers seeking a FP: being accepted for an appointment or being offered further assistance if not accepted (e.g., walk-in clinic, alternative provider, and telehealth), as well as the callers' perception of the experience as positive, negative, or neutral.

Results: Only 9.9% of offices accepted callers as new patients. There were no statistically significant differences by SES or chronic condition in the proportion of calls resulting in an appointment. Callers indicating high SES were more likely to be provided further assistance than those with low SES (p = 0.06), and callers indicating a chronic condition reported a better overall experience than those without (p = 0.03).

Conclusion: First contact accessibility for prospective new patients was low across NS. Lower SES was associated with fewer offers of additional assistance than higher SES. This is particularly troubling since those with lower SES may need additional support as they may have less access to resources and networks that could provide support. This study signals the need to improve general and equitable accessibility to primary care providers.
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http://dx.doi.org/10.17269/CJPH.108.5861DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6972397PMC
September 2017

'Meet and greet' intake appointments in primary care: a new pattern of patient intakes?

Fam Pract 2017 11;34(6):697-701

Department of Family Medicine, Dalhousie University, Halifax, Canada.

Background: Family physicians (FPs) are expected to take on new patients fairly and equitably and to not discriminate based on medical or social history. 'Meet and greet' appointments are initial meetings between physicians and prospective patients to establish fit between patient needs and provider scope of practice. The public often views these appointments as discriminatory; however, there is no empirical evidence regarding their prevalence or outcomes.

Objectives: To determine the proportion of FPs conducting 'meet and greets' and their outcomes.

Methods: Study design and setting: Census telephone survey of all FP practices in Nova Scotia (NS). Participants: Person who answers the FP office telephone. Main Outcomes: Proportion of FPs holding 'meet and greets'; proportion of FPs conducting 'meet and greets' who have ever decided not to continue seeing a patient after the meeting.

Results: 9.2% of FPs accept new patients unconditionally; 51.1% accept new patients under certain conditions. Of those accepting patients unconditionally or with conditions, 46.9% require a 'meet and greet'; 41.8% have a first-come, first-serve policy. Among FPs who require a 'meet and greet', 44.0% decided, at least once, not to continue seeing a patient after the first meeting.

Conclusion: 'Meet and greets' are common among FPs in NS and result in some patients not being accepted into practice. More research is needed to understand the intentions, processes, and outcomes of 'meet and greets'. We recommend that practice scope be made clear to prospective patients before their first visit, which may eliminate the need for 'meet and greets'.
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http://dx.doi.org/10.1093/fampra/cmx043DOI Listing
November 2017

Impaired human immunodeficiency virus type 1 replicative fitness in atypical viremic non-progressor individuals.

AIDS Res Ther 2017 20;14:15. Epub 2017 Mar 20.

0000 0000 9149 4843grid.443867.aUniversity Hospital Translational Laboratory, University Hospitals Cleveland Medical Center, Cleveland, OH USA ; 0000 0001 2164 3847grid.67105.35Department of Medicine, Case Western Reserve University/University Hospitals Cleveland Medical Center, 10900 Euclid Avenue, Cleveland, OH 44106-7288 USA ; 0000 0001 2164 3847grid.67105.35Department of Pathology, Case Western Reserve University, Cleveland, OH USA.

Background: Progression rates from initial HIV-1 infection to advanced AIDS vary significantly among infected individuals. A distinct subgroup of HIV-1-infected individuals-termed viremic non-progressors (VNP) or controllers-do not seem to progress to AIDS, maintaining high CD4 T cell counts despite high levels of viremia for many years. Several studies have evaluated multiple host factors, including immune activation, trying to elucidate the atypical HIV-1 disease progression in these patients; however, limited work has been done to characterize viral factors in viremic controllers.

Methods: We analyzed HIV-1 isolates from three VNP individuals and compared the replicative fitness, near full-length HIV-1 genomes and intra-patient HIV-1 genetic diversity with viruses from three typical (TP) and one rapid (RP) progressor individuals.

Results: Viremic non-progressors and typical patients were infected for >10 years (range 10-17 years), with a mean CD4 T-cell count of 472 cells/mm (442-529) and 400 cells/mm (126-789), respectively. VNP individuals had a less marked decline in CD4 cells (mean -0.56, range -0.4 to -0.7 CD4/month) than TP patients (mean -10.3, -8.2 to -13.1 CD4/month). Interestingly, VNP individuals carried viruses with impaired replicative fitness, compared to HIV-1 isolates from the TP and RP patients (p < 0.05, 95% CI). Although analyses of the near full-length HIV-1 genomes showed no clear patterns of single-nucleotide polymorphisms (SNP) that could explain the decrease in replicative fitness, both the number of SNPs and HIV-1 population diversity correlated inversely with the replication capacity of the viruses ( = -0.956 and  = -0.878,  < 0.01, respectively).

Conclusion: It is likely that complex multifactorial parameters govern HIV-1 disease progression in each individual, starting with the infecting virus (phenotype, load, and quasispecies diversity) and the intrinsic ability of the host to respond to the infection. Here we analyzed a subset of viremic controller patients and demonstrated that similar to the phenomenon observed in patients with a discordant response to antiretroviral therapy (i.e., high CD4 cell counts with detectable plasma HIV-1 RNA load), reduced viral replicative fitness seems to be linked to slow disease progression in these antiretroviral-naïve individuals.
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http://dx.doi.org/10.1186/s12981-017-0144-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5359922PMC
March 2018

Protocol for determining primary healthcare practice characteristics, models of practice and patient accessibility using an exploratory census survey with linkage to administrative data in Nova Scotia, Canada.

BMJ Open 2017 03 16;7(3):e014631. Epub 2017 Mar 16.

Department of Family Medicine, Dalhousie University, Halifax, Nova Scotia, Canada.

Introduction: There is little evidence on how primary care providers (PCPs) model their practices in Nova Scotia (NS), Canada, what services they offer or what accessibility is like for the average patient. This study will create a database of all family physicians and primary healthcare nurse practitioners in NS, including information about accessibility and the model of care in which they practice, and will link the survey data to administrative health databases.

Methods And Analysis: 3 census surveys of all family physicians, primary care nurse practitioners (ie, PCPs) and their practices in NS will be conducted. The first will be a telephone survey conducted during typical daytime business hours. At each practice, the person answering the telephone will be asked questions about the practice's accessibility and model of care. The second will be a telephone survey conducted after typical daytime business hours to determine what out-of-office services PCP practices offer their patients. The final will be a tailored fax survey that will collect information that could not be obtained in the first 2 surveys plus new information on scope of practice, practice model and willingness to participate in research. Survey data will be linked with billing data from administrative health databases. Multivariate regression analysis will be employed to assess whether access and availability outcome variables are associated with PCP and model of practice characteristics. Negative binomial regression analysis will be employed to assess the association between independent variables from the survey data and health system use outcomes from administrative data.

Ethics And Dissemination: This study has received ethical approval from the Nova Scotia Health Authority and the Health Data Nova Scotia Data Access Committee. Dissemination approached will include stakeholder engagement at local and national levels, conference presentations, peer-reviewed publications and a public website.
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http://dx.doi.org/10.1136/bmjopen-2016-014631DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5372103PMC
March 2017

Innovative and beneficial informal sweetpotato seed private enterprise in northern Uganda.

Food Secur 2017 19;9:595-610. Epub 2017 May 19.

Natural Resources Institute (NRI), University of Greenwich, London, UK.

Research conducted in the informal sweetpotato seed (vines) supply system in the Gulu region, northern Uganda (2013-2015) revealed a diverse set of actors using private enterprise in a range of selling and marketing channels. The different channels offer an efficient and effective marketing system, providing different services and conveniences for farmers at different prices. The actors include local vine multipliers, traders, dry season root farmers, transporters and town sellers. The local multipliers and dry season root farmers grow crops during the dry season in swampy areas and sell the vines in the following rainy season to the many farmers who lack access to such areas and therefore lack vines to plant. The presentation and discussion of this case study adds to an expanding argument in the literature for increased attention to support actors in informal food crop sectors who are providing sustainable production and marketing systems on a platform of beneficial and innovative private enterprise. Through their commercial operations, vine multipliers and other actors can effectively meet the demand of customers and at the right time and place. With suitable dissemination programmes installed, these actors could also offer access to new varieties otherwise unavailable to the majority of farmers.
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http://dx.doi.org/10.1007/s12571-017-0680-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7473088PMC
May 2017

Infection of rhesus macaques with a pool of simian immunodeficiency virus with the envelope genes from acute HIV-1 infections.

AIDS Res Ther 2016 11 25;13(1):41. Epub 2016 Nov 25.

Division of Infectious Diseases, School of Medicine, Case Western Reserve University, 10900 Euclid Ave, Cleveland, OH 44106 USA.

Background: New simian-human immunodeficiency chimeric viruses with an HIV-1 env (SHIVenv) are critical for studies on HIV pathogenesis, vaccine development, and microbicide testing. Macaques are typically exposed to single CCR5-using SHIVenv which in most instances does not reflect the conditions during acute/early HIV infection (AHI) in humans. Instead of individual and serial testing new SHIV constructs, a pool of SHIVenv_B derived from 16 acute HIV-1 infections were constructed using a novel yeast-based SHIV cloning approach and then used to infect macaques.

Results: Even though none of the 16 SHIVenvs contained the recently reported mutations in env genes that could significantly enhance their binding affinity to RhCD4, one SHIVenv (i.e. SHIVenv_B3-PRB926) established infection in macaques exposed to this pool. AHI SHIVenv_B viruses as well as their HIVenv_B counterparts were analyzed for viral protein content, function, and fitness to identify possible difference between SHIVenv_B3-PRB926 and the other 15 SHIVenvs in the pool. All of the constructs produced SHIV or HIV chimeric with wild type levels of capsid (p27 and p24) content, reverse transcriptase (RT) activity, and expressed envelope glycoproteins that could bind to cell receptors CD4/CCR5 and mediate virus entry. HIV-1env_B chimeric viruses were propagated in susceptible cell lines but the 16 SHIVenv_B variants showed only limited replication in macaque peripheral blood mononuclear cells (PBMCs) and 174×CEM.CCR5 cell line. AHI chimeric viruses including HIVenv_B3 showed only minor variations in cell entry efficiency and kinetics as well as replicative fitness in human PBMCs. Reduced number of N-link glycosylation sites and slightly greater CCR5 affinity/avidity was the only distinguishing feature of env_B3 versus other AHI env's in the pool, a feature also observed in the HIV establishing new infections in humans.

Conclusion: Despite the inability to propagate in primary cells and cell lines, a pool of 16 SHIVenv viruses could establish infection but only one virus, SHIVenv_B3 was isolated in the macaque and then shown to repeatedly infected macaques. This SHIVenv_B3 virus did not show any distinct phenotypic property from the other 15 SHIVenv viruses but did have the fewest N-linked glycosylation sites.
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http://dx.doi.org/10.1186/s12981-016-0125-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5124249PMC
November 2016

European Nucleotide Archive in 2016.

Nucleic Acids Res 2017 01 29;45(D1):D32-D36. Epub 2016 Nov 29.

European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Hinxton, Cambridge CB10 1SD, UK.

The European Nucleotide Archive (ENA; http://www.ebi.ac.uk/ena) offers a rich platform for data sharing, publishing and archiving and a globally comprehensive data set for onward use by the scientific community. With a broad scope spanning raw sequencing reads, genome assemblies and functional annotation, the resource provides extensive data submission, search and download facilities across web and programmatic interfaces. Here, we outline ENA content and major access modalities, highlight major developments in 2016 and outline a number of examples of data reuse from ENA.
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http://dx.doi.org/10.1093/nar/gkw1106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5210577PMC
January 2017

Addiction, 12-Step Programs, and Evidentiary Standards for Ethically and Clinically Sound Treatment Recommendations: What Should Clinicians Do?

AMA J Ethics 2016 Jun 1;18(6):646-55. Epub 2016 Jun 1.

Associate professor of medicine at the University of Tennessee in Knoxville, and a clinical investigator at the New Orleans Center for Clinical Research, and board certified in internal medicine, nephrology, and psychiatry.

Addiction is a complex phenomenon characterized by a loss of control and compulsive, habitual behavior. Since there is no single, specific cause for addiction, there is no single, standard treatment for it. A variety of approaches are used, including counseling, psychotherapy, medications, and mutual help groups (MHG). The best known and most widely available approach to addiction is 12-step (TS) programs of recovery, a variety of MHG. These have been lauded as lifesaving by some and criticized by others. We argue that TS programs are an appropriate mode of help for those seeking to quit an addiction but should not be the only approach considered.
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http://dx.doi.org/10.1001/journalofethics.2016.18.6.sect1-1606DOI Listing
June 2016

Novel high throughput pooled shRNA screening identifies NQO1 as a potential drug target for host directed therapy for tuberculosis.

Sci Rep 2016 06 14;6:27566. Epub 2016 Jun 14.

Department of Molecular Biology and Microbiology, Case Western Reserve University &University Hospitals, Cleveland, Ohio, United States of America.

Unlabelled: Chemical regulation of macrophage function is one key strategy for developing host-directed adjuvant therapies for tuberculosis (TB). A critical step to develop these therapies is the identification and characterization of specific macrophage molecules and pathways with a high potential to serve as drug targets. Using a barcoded lentivirus-based pooled short-hairpin RNA (shRNA) library combined with next generation sequencing, we identified 205 silenced host genes highly enriched in mycobacteria-resistant macrophages. Twenty-one of these "hits" belonged to the oxidoreductase functional category.

Nad(p)h: quinone oxidoreductase 1 (NQO1) was the top oxidoreductase "hit". NQO1 expression was increased after mycobacterial infection, and NQO1 knockdown increased macrophage differentiation, NF-κB activation, and the secretion of pro-inflammatory cytokines TNF-α and IL-1β in response to infection. This suggests that mycobacteria hijacks NQO1 to down-regulate pro-inflammatory and anti-bacterial functions. The competitive inhibitor of NQO1 dicoumarol synergized with rifampin to promote intracellular killing of mycobacteria. Thus, NQO1 is a new host target in mycobacterial infection that could potentially be exploited to increase antibiotic efficacy in vivo. Our findings also suggest that pooled shRNA libraries could be valuable tools for genome-wide screening in the search for novel druggable host targets for adjunctive TB therapies.
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http://dx.doi.org/10.1038/srep27566DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4906352PMC
June 2016
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