The IKKâ related kinase TBK1 activates mTORC1 directly in response to growth factors and innate immune agonists

The innate immune kinase TBK1 initiates inflammatory responses to combat infectious pathogens by driving production of type I interferons. TBK1 also controls metabolic processes and promotes oncogeneâ induced cell proliferation and survival. Here, we demonstrate that TBK1 activates mTOR complex 1 (mTORC1) directly. In cultured cells, TBK1 associates with and activates mTORC1 through siteâ specific mTOR phosphorylation (on S2159) in response to certain growth factor receptors (i.e., EGFâ receptor but not insulin receptor) and pathogen recognition receptors (PRRs) (i.e., TLR3; TLR4), revealing a stimulusâ selective role for TBK1 in mTORC1 regulation. By studying cultured macrophages and those isolated from genome edited mTOR S2159A knockâ in mice, we show that mTOR S2159 phosphorylation promotes mTORC1 signaling, IRF3 nuclear translocation, and IFNâ β production. These data demonstrate a direct mechanistic link between TBK1 and mTORC1 function as well as physiologic significance of the TBK1â mTORC1 axis in control of innate immune function. These data unveil TBK1 as a direct mTORC1 activator and suggest unanticipated roles for mTORC1 downstream of TBK1 in control of innate immunity, tumorigenesis, and disorders linked to chronic inflammation.SynopsisTBK1, an IKKâ related kinase that drives interferon production as well cancer cell proliferation and survival, phosphorylates mTOR to activate mTORC1 in response to EGF and innate immune agonists, suggesting unanticipated roles for mTORC1 downstream of TBK1 in control of innate immunity and tumorigenesis.TBK1 interacts with mTORC1 and phosphorylates mTOR on S2159 to increase its catalytic activity.Cells lacking TBK1 or expressing a mTOR S2159A allele exhibit reduced mTORC1 signaling in response to EGFâ receptor and TLR3/4 activation.Primary macrophages derived from genome edited mTOR S2159A mice exhibit reduced mTORC1 signaling in response to TLR3/4 activation.Primary macrophages treated with rapamycin as well as those derived from mTORS2159A mice produce reduced levels of IFNâ β due to impaired nuclear translocation of the transcription factor IRF3.Innate immune kinase TBK1â dependent activation of mTORC1 occurs in response to pathogen recognition and EGF receptor activation and drives interferon production, thus highlighting the role of mTOR for innate immunity.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141029/1/embj201696164.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/141029/2/embj201696164.reviewer_comments.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/141029/3/embj201696164_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/141029/4/embj201696164-sup-0001-EVFigs.pd

Mitigating Risks and Building Resilience to HIV/AIDS: Perspectives of HIV-Negative, Middle-Aged and Older Men Who Have Sex with Men

Purpose: Although ample research has been conducted on resilience to HIV/AIDS, most studies have utilized quantitative methods and focused almost exclusively on people living with HIV/AIDS. A relatively untapped source of knowledge is the perspectives of HIV-negative, middle-aged and older men who have sex with men (MSM) who have been navigating risks and building resilience to HIV/AIDS since the 1980s. Our qualitative, community-based participatory research study examined the perspectives of HIV-negative, middle-aged and older MSM on factors that helped mitigate the risks of and build resilience to HIV/AIDS. Methods: In collaboration with community-based organizations, fourteen participants were recruited for in-depth interviews. Participants were aged 40 or older, identified as HIV-negative MSM, and resided in Ontario, Canada. Thematic analysis of interviews revealed salient themes. Results: Three themes were identified: (1) individual attributes (e.g., self-awareness/control), (2) protective relational factors (e.g., meaningful sexual relationships), and (3) community-based resources (e.g., competent healthcare/service providers). Conclusion: HIV-negative, middle-aged and older MSM recognized factors that helped mitigate risks of contracting and build resilience to HIV/AIDS based on their own lived experiences. Some of these factors have not been explicitly identified or extensively discussed in extant academic literature, and are worth considering in the development of community-based HIV/AIDS prevention and intervention programs

Funding source, trial outcome and reporting quality: are they related? Results of a pilot study

BACKGROUND: There has been increasing concern regarding the potential effects of the commercialization of research. METHODS: In order to examine the relationships between funding source, trial outcome and reporting quality, recent issues of five peer-reviewed, high impact factor, general medical journals were hand-searched to identify a sample of 100 randomized controlled trials (20 trials/journal). Relevant data, including funding source (industry/not-for-profit/mixed/not reported) and statistical significance of primary outcome (favouring new treatment/favouring conventional treatment/neutral/unclear), were abstracted. Quality scores were assigned using the Jadad scale and the adequacy of allocation concealment. RESULTS: Sixty-six percent of trials received some industry funding. Trial outcome was not associated with funding source (p= .461). There was a preponderance of favourable statistical conclusions among published trials with 67% reporting results that favored a new treatment whereas 6% favoured the conventional treatment. Quality scores were not associated with funding source or trial outcome. CONCLUSIONS: It is not known whether the absence of significant associations between funding source, trial outcome and reporting quality reflects a true absence of an association or is an artefact of inadequate statistical power, reliance on voluntary disclosure of funding information, a focus on trials recently published in the top medical journals, or some combination thereof. Continued and expanded monitoring of potential conflicts is recommended, particularly in light of new guidelines for disclosure that have been endorsed by the ICMJE

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

SummaryBackground Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatoryactions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19.Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospitalwith COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients wererandomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once perday by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatmentgroups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment andwere twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants andlocal study staff were not masked to the allocated treatment, but all others involved in the trial were masked to theoutcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treatpopulation. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) wereeligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomlyallocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall,561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days(rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days(rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, nosignificant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilationor death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24).Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or otherprespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restrictedto patients in whom there is a clear antimicrobial indication

Psychosocial Impact of Fracking: a Review of the Literature on the Mental Health Consequences of Hydraulic Fracturing

The process of natural gas extraction known as hydraulic fracturing, or fracking, is a controversial energy acquisition technique often viewed with disdain by the public, due to its potential for environmental harm. However, the mental health and psychological well-being of fracking communities, including potential benefits and detriments, are often overlooked. We reviewed the literature on the association between fracking and psychological functioning, finding that although persons living in fracking communities may experience some minimal, initial benefits such as land lease income or infrastructure development, they may also experience worry, anxiety, and depression about lifestyle, health, safety, and financial security, as well as exposure to neurotoxins and changes to the physical landscape. Indeed, entire communities can experience collective trauma as a result of the “boom/bust” cycle that often occurs when industries impinge on community life. Impacted communities are often already vulnerable, including poor, rural, or indigenous persons, who may continue to experience the deleterious effects of fracking for generations. An influx of workers to fracking communities often stokes fears about outsiders and crime; yet, it must be recognized that this population of mobile workers is also vulnerable, often ostracized, and without social support. Practitioners, researchers, and policy makers alike should continue to investigate the potential psychological ramifications of fracking, so that effective and targeted intervention strategies can be developed, disseminated, and implemented to improve mental health in fracking communities

Mitigating risks and building resilience to HIV/AIDS: Perspectives of HIV-negative, middle-aged and older men who have sex with men

Purpose: Although ample research has been conducted on resilience to HIV/AIDS, most studies have utilized quantitative methods and focused almost exclusively on people living with HIV/AIDS. A relatively untapped source of knowledge is the perspectives of HIV-negative, middle-aged and older men who have sex with men (MSM) who have been navigating risks and building resilience to HIV/AIDS since the 1980s. Our qualitative, community-based participatory research study examined the perspectives of HIV-negative, middle-aged and older MSM on factors that helped mitigate the risks of and build resilience to HIV/AIDS. Methods: In collaboration with community-based organizations, fourteen participants were recruited for in-depth interviews. Participants were aged 40 or older, identified as HIV-negative MSM, and resided in Ontario, Canada. Thematic analysis of interviews revealed salient themes. Results: Three themes were identified: (1) individual attributes (e.g., self-awareness/control), (2) protective relational factors (e.g., meaningful sexual relationships), and (3) community-based resources (e.g., competent healthcare/service providers). Conclusion: HIV-negative, middle-aged and older MSM recognized factors that helped mitigate risks of contracting and build resilience to HIV/AIDS based on their own lived experiences. Some of these factors have not been explicitly identified or extensively discussed in extant academic literature, and are worth considering in the development of community-based HIV/AIDS prevention and intervention programs