tbuckley/cabot-search huggingface dataset:
Closing the health equity gap: A role for implementation science?
Authors: Beryne Odeny
Journal: PLoS Medicine (2021)

WHO defines health equity as "the absence of unfair and avoidable or remediable differences in health among population groups defined socially, economically, demographically, or geographically or by other means of stratification" [1].Yet, contrary to this fundamental aspiration and the international mandate on universal health coverage (UHC), almost 50% of the world's population does not receive needed health services, and progress toward health equity remains elusive [2]. Equity in clinical researchIn a new study published in PLOS Medicine, Muthukumar and colleagues address underrepresentation of minority populations, a pressing equity issue in clinical research.In a systematic analysis of ClinicalTrials.gov, the authors investigated the frequency of English language requirement in interventional United States (US) clinical trial eligibility criteria [3].Of 14,367 trials registered from January 2019 to December 2020, approximately one-fifth specified language requirements.They found that approximately 19% (n = 2,727) of clinical trials required English language proficiency, while approximately 3% (n = 390) had accommodations for non-English language.Trials related to Coronavirus Disease 2019 (COVIDAU : PleasenotethatCOVID À -19) and other infectious disease were less stringent, while depression-related trials were most stringent.That language barriers limit access to the benefits of participation in research targeting depression and noncommunicable diseases (NCDs), which disproportionately affect marginalized groups, is disconcerting.This goes against the grain of the Belmont Report on justice and equality in research conduct and propagates disparities in understanding effectiveness, appropriateness, and acceptability of interventions in marginalized groups [4]. Equity in healthcareUndertreatment or underprescription among distinct groups of individuals leads to inequities in translation of evidence to healthcare practice.This has been investigated in NCD care models as demonstrated by a recent population-based cohort study by Eastwood and colleagues.The study revealed that people with type 2 diabetes from African, African Caribbean, and South Asian backgrounds are less likely to be prescribed statins than people of White European ethnicity in the United Kingdom [5].Statins lower cholesterol and are a crucial for mitigating the risk of atherosclerotic and cardiovascular events (ASCVD),AU : Anabbreviationlisthasbeenco including heart attack and strokes, in people with type 2 diabetes.People of African/African Caribbean and South Asian ethnicity were 24% and 9% less likely, respectively, to receive statins than people of European ethnicity.Among patients receiving statin therapy, the median times to initiation were 79, 109, and 84 days for people of European, South Asian, and African or African Caribbean ethnicity, respectively.The authors estimated that up to 13,000 ASCVD-related deaths
Aging exaggerates acute‐on‐chronic alcohol‐induced liver injury in mice and humans by inhibiting neutrophilic sirtuin 1‐C/EBPα‐miRNA‐223 axis
Authors: Ruixue Ren, Yong He, Dong Ding, Aoyuan Cui, Huarui Bao, Jing Ma, Xin Hou, Yu Li, Dechun Feng, Xiaoling Li, Suthat Liangpunsakul, Bin Gao, Hua Wang
Journal: Hepatology (2021)

Abstract Background and Aims Aging exacerbates liver neutrophil infiltration and alcohol‐associated liver disease (ALD) in mice and humans, but the underlying mechanisms remain obscure. This study aimed to examine the effect of aging and alcohol consumption on neutrophilic Sirtuin 1 (SIRT1) and microRNA‐223 (miR‐223), and their contribution to ALD pathogeneses. Approach and Results Young and aged myeloid‐specific Sirt1 knockout mice were subjected to chronic‐plus‐binge ethanol feeding. Blood samples from healthy controls and patients with chronic alcohol drinking who presented with acute intoxication were analyzed. Neutrophilic Sirt1 and miR‐223 expression were down‐regulated in aged mice compared with young mice. Deletion of the Sirt1 gene in myeloid cells including neutrophils exacerbated chronic‐plus‐binge ethanol‐induced liver injury and inflammation and down‐regulated neutrophilic miR‐223 expression. Immunoprecipitation experiments revealed that SIRT1 promoted C/EBPα deacetylation by directly interacting with C/EBPα, a key transcription factor that controls miR‐223 biogenesis, and subsequently elevated miR‐223 expression in neutrophils. Importantly, down‐regulation of SIRT1 and miR‐223 expression was also observed in circulating neutrophils from middle‐aged and elderly subjects compared with those from young individuals. Chronic alcohol users with acute intoxication had a reduction in neutrophilic SIRT1 expression in young and middle‐aged patients, with a greater reduction in the latter group. The neutrophilic SIRT1 expression correlated with neutrophilic miR‐223 and serum alanine transaminase levels in those patients. Conclusions Aging increases the susceptibility of alcohol‐induced liver injury in mice and humans through the down‐regulation of the neutrophilic SIRT1‐C/EBPα‐miR‐223 axis, which could be a therapeutic target for the prevention and/or treatment of ALD.
Immunization with a Plasmid DNA Vaccine Encoding the N-Terminus of Insulin-like Growth Factor Binding Protein-2 in Advanced Ovarian Cancer Leads to High-level Type I Immune Responses
Authors: Denise L. Cecil, John B. Liao, Yushe Dang, Andrew L. Coveler, Angela Kask, Yi Yang, Jennifer S. Childs, Doreen M. Higgins, Mary L. Disis
Journal: Clinical Cancer Research (2021)

Cancer vaccines targeting nonmutated proteins elicit limited type I T-cell responses and can generate regulatory and type II T cells. Class II epitopes that selectively elicit type I or type II cytokines can be identified in nonmutated cancer-associated proteins. In mice, a T-helper I (Th1) selective insulin-like growth factor binding protein-2 (IGFBP-2) N-terminus vaccine generated high levels of IFNγ secreting T cells, no regulatory T cells, and significant antitumor activity. We conducted a phase I trial of T-helper 1 selective IGFBP-2 vaccination in patients with advanced ovarian cancer.Twenty-five patients were enrolled. The IGFBP-2 N-terminus plasmid-based vaccine was administered monthly for 3 months. Toxicity was graded by NCI criteria and antigen-specific T cells measured by IFNγ/IL10 ELISPOT. T-cell diversity and phenotype were assessed.The vaccine was well tolerated, with 99% of adverse events graded 1 or 2, and generated high levels of IGFBP-2 IFNγ secreting T cells in 50% of patients. Both Tbet+ CD4 (P = 0.04) and CD8 (P = 0.007) T cells were significantly increased in immunized patients. There was no increase in GATA3+ CD4 or CD8, IGFBP-2 IL10 secreting T cells, or regulatory T cells. A significant increase in T-cell clonality occurred in immunized patients (P = 0.03, pre- vs. post-vaccine) and studies showed the majority of patients developed epitope spreading within IGFBP-2 and/or to other antigens. Vaccine nonresponders were more likely to have preexistent IGFBP-2 specific immunity and demonstrated defects in CD4 T cells, upregulation of PD-1, and downregulation of genes associated with T-cell activation, after immunization.IGFBP-2 N-terminus Th1 selective vaccination safely induces type I T cells without evidence of regulatory responses.
Mitochondrial bioenergetics boost macrophage activation, promoting liver regeneration in metabolically compromised animals
Authors: Naroa Goikoetxea‐Usandizaga, Marina Serrano‐Maciá, Teresa C. Delgado, Jorge Simón, David Fernández Ramos, Diego Barriales, Maria E. Cornide, Mónica Jiménez, Marina Pérez‐Redondo, Sofia Lachiondo‐Ortega, Rubén Rodríguez‐Agudo, Maider Bizkarguenaga, Juan Diego Zalamea, Samuel T. Pasco, Daniel Caballero‐Díaz, Benedetta Alfano, Miren Bravo, Irene González‐Recio, Maria Mercado‐Gómez, Clàudia Gil‐Pitarch, Jon Mabe, Jordi Gracia‐Sancho, Leticia Abecia, Óscar Lorenzo, Paloma Martín‐Sanz, Nicola G. A. Abrescia, Guadalupe Sabio, Mercedes Rincón, Juan Anguita, Eduardo Miñambres, César Martín, Marina Berenguer, Isabel Fabregat, Marta Casado, Carmen Peralta, Marta Varela‐Rey, María Luz Martínez‐Chantar
Journal: Hepatology (2021)

Hepatic ischemia-reperfusion injury (IRI) is the leading cause of early posttransplantation organ failure as mitochondrial respiration and ATP production are affected. A shortage of donors has extended liver donor criteria, including aged or steatotic livers, which are more susceptible to IRI. Given the lack of an effective treatment and the extensive transplantation waitlist, we aimed at characterizing the effects of an accelerated mitochondrial activity by silencing methylation-controlled J protein (MCJ) in three preclinical models of IRI and liver regeneration, focusing on metabolically compromised animal models.Wild-type (WT), MCJ knockout (KO), and Mcj silenced WT mice were subjected to 70% partial hepatectomy (Phx), prolonged IRI, and 70% Phx with IRI. Old and young mice with metabolic syndrome were also subjected to these procedures. Expression of MCJ, an endogenous negative regulator of mitochondrial respiration, increases in preclinical models of Phx with or without vascular occlusion and in donor livers. Mice lacking MCJ initiate liver regeneration 12 h faster than WT and show reduced ischemic injury and increased survival. MCJ knockdown enables a mitochondrial adaptation that restores the bioenergetic supply for enhanced regeneration and prevents cell death after IRI. Mechanistically, increased ATP secretion facilitates the early activation of Kupffer cells and production of TNF, IL-6, and heparin-binding EGF, accelerating the priming phase and the progression through G1 /S transition during liver regeneration. Therapeutic silencing of MCJ in 15-month-old mice and in mice fed a high-fat/high-fructose diet for 12 weeks improves mitochondrial respiration, reduces steatosis, and overcomes regenerative limitations.Boosting mitochondrial activity by silencing MCJ could pave the way for a protective approach after major liver resection or IRI, especially in metabolically compromised, IRI-susceptible organs.
Practice of tracheostomy in patients with acute respiratory failure related to COVID–19 – Insights from the PRoVENT–COVID study
Authors: A.M. Tsonas, M. Botta, J. Horn, M.J. Brenner, M.S. Teng, B.A. McGrath, M.J. Schultz, F. Paulus, A. Serpa Neto
Journal: Pulmonology (2021)

Invasively ventilated patients with acute respiratory failure related to coronavirus disease 2019 (COVID–19) potentially benefit from tracheostomy. The aim of this study was to determine the practice of tracheostomy during the first wave of the pandemic in 2020 in the Netherlands, to ascertain whether timing of tracheostomy had an association with outcome, and to identify factors that had an association with timing. Secondary analysis of the 'PRactice of VENTilation in COVID–19' (PRoVENT–COVID) study, a multicenter observational study, conducted from March 1, 2020 through June 1, 2020 in 22 Dutch intensive care units (ICU) in the Netherlands. The primary endpoint was the proportion of patients receiving tracheostomy; secondary endpoints were timing of tracheostomy, duration of ventilation, length of stay in ICU and hospital, mortality, and factors associated with timing. Of 1023 patients, 189 patients (18.5%) received a tracheostomy at median 21 [17 to 28] days from start of ventilation. Timing was similar before and after online publication of an amendment to the Dutch national guidelines on tracheostomy focusing on COVID–19 patients (21 [17–28] vs. 21 [17–26] days). Tracheostomy performed ≤ 21 days was independently associated with shorter duration of ventilation (median 26 [21 to 32] vs. 40 [34 to 47] days) and higher mortality in ICU (22.1% vs. 10.2%), hospital (26.1% vs. 11.9%) and at day 90 (27.6% vs. 14.6%). There were no patient demographics or ventilation characteristics that had an association with timing of tracheostomy. Tracheostomy was performed late in COVID–19 patients during the first wave of the pandemic in the Netherlands and timing of tracheostomy possibly had an association with outcome. However, prospective studies are needed to further explore these associations. It remains unknown which factors influenced timing of tracheostomy in COVID–19 patients.
Protease activity sensors enable real-time treatment response monitoring in lymphangioleiomyomatosis
Authors: Jesse D. Kirkpatrick, Ava P. Soleimany, Jaideep S. Dudani, Heng-Jia Liu, Hilaire C. Lam, Carmen Priolo, Elizabeth P. Henske, Sangeeta N. Bhatia
Journal: European Respiratory Journal (2021)

Biomarkers of disease progression and treatment response are urgently needed for patients with lymphangioleiomyomatosis (LAM). Activity-based nanosensors, an emerging biosensor class, detect dysregulated proteases
Echocardiographic Diagnosis of Anomalous Origin of the Left Coronary Artery From Pulmonary Artery With Intramural Course
Authors: Carolina D’Anna, Alessia Del Pasqua, Marcello Chinali, Claudia Esposito, Maria Iacomino, Paolo Ciliberti, Aurelio Secinaro, Adriano Carotti, Gabriele Rinelli
Journal: JACC. Cardiovascular imaging (2021)
3D-printed dermis-specific extracellular matrix mitigates scar contraction via inducing early angiogenesis and macrophage M2 polarization
Authors: Lei Chen, Zhiyong Li, Yongtai Zheng, Fei Zhou, Jingling Zhao, Qiyi Zhai, Zhaoqiang Zhang, Tianrun Liu, Yongming Chen, Shaohai Qi
Journal: Bioactive Materials (2021)

Scar contraction frequently happens in patients with deep burn injuries. Hitherto, porcine dermal extracellular matrix (dECM) has supplied microenvironments that assist in wound healing but fail to inhibit scar contraction. To overcome this drawback, we integrate dECM into three-dimensional (3D)-printed dermal analogues (PDA) to prevent scar contraction. We have developed thermally gelled, non-rheologically modified dECM powder (dECMp) inks and successfully transformed them into PDA that was endowed with a micron-scale spatial structure. The optimal crosslinked PDA exhibited desired structure, good mechanical properties as well as excellent biocompatibility. Moreover, in vivo experiments demonstrated that PDA could significantly reduced scar contraction and improved cosmetic upshots of split thickness skin grafts (STSG) than the commercially available dermal templates and STSG along. The PDA has also induced an early, intense neovascularization, and evoked a type-2-like immune response. PDA's superior beneficial effects may attribute to their desired porous structure, the well-balanced physicochemical properties, and the preserved dermis-specific ECM cues, which collectively modulated the expression of genes such as Wnt11, ATF3, and IL1β, and influenced the crucial endogenous signalling pathways. The findings of this study suggest that PDA is a clinical translatable material that possess high potential in reducing scar contraction.
Abstract 13222: KCNQ1 Channel Dysfunction in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes Carrying a CALM2-N98S Mutation Associated With Long QT Syndrome
Authors: Yuta Yamamoto, Takeru M Makiyama, Yimin Wuriyanghai, Hirohiko Kohjitani, Sayako Hirose, Jingshan Gao, Asami Kashiwa, Huang Hai, Takanori Aizawa, Tomohiko Imamura, Taisuke Ishikawa, Seiko Ohno, Kazuhisa Chonabayashi, Hideki Motomura, Yoshinori Yoshida, Minoru Horie, Naomasa Makita, Takeshi Kimura
Journal: Circulation (2019)

Background: Recently, mutations in CALM genes (CALM1-3) encoding calmodulin (CaM) are reported to be associated with severe early-onset arrhythmias known as the calmodulinopathy. Calmodulin modulat...
Medical students involved in sex work need better support, conference hears
Authors: Elisabeth Mahase
Journal: BMJ (2021)

The General Medical Council and Medical Schools Council must ensure that medical students involved in sex work are safe from expulsion and professionalism proceedings as a result of this work, doctors at the BMA’s annual conference have said.

The motion, passed in part at the annual representative meeting on 13 September, noted that a large proportion of medical student sex workers were from marginalised backgrounds and that …
Pantothenate kinase activation relieves coenzyme A sequestration and improves mitochondrial function in mice with propionic acidemia
Authors: Chitra Subramanian, Matthew W. Frank, Rajendra Tangallapally, Mi-Kyung Yun, Anne Edwards, Stephen W. White, Richard E. Lee, Charles O. Rock, Suzanne Jackowski
Journal: Science Translational Medicine (2021)

Therapeutic relief of CoA sequestration improves mitochondrial dysfunction in a propionic acidemia mouse model.
Covid-19: Rich countries’ booster plans will impede global vaccination, experts say
Authors: Owen Dyer
Journal: BMJ (2021)

A summit convened alongside the UN's annual meeting in New York, bringing 80 governments together to discuss the global response to the covid-19 pandemic, is expected to end with a collective endorsement of the US president's call for 70% of people in countries of all income levels to be vaccinated by the time the UN General Assembly meets again 12 months from now.But this goal will not be met, experts warned, unless rich countries change course now, releasing the stocks they are currently hoarding.
Optical ventricular cardioversion by local optogenetic targeting and LED implantation in a cardiomyopathic rat model
Authors: Emile C A Nyns, Tianyi Jin, Magda S Fontes, Titus van den Heuvel, Vincent Portero, Catilin Ramsey, Cindy I Bart, Katja Zeppenfeld, Martin J Schalij, Thomas J van Brakel, Arti A Ramkisoensing, Guoqi Zhang, René H Poelma, Balazs Ördög, Antoine A F de Vries, Daniël A Pijnappels
Journal: Cardiovascular Research (2021)

Ventricular tachyarrhythmias (VTs) are common in the pathologically remodelled heart. These arrhythmias can be lethal, necessitating acute treatment like electrical cardioversion to restore normal rhythm. Recently, it has been proposed that cardioversion may also be realized via optically controlled generation of bioelectricity by the arrhythmic heart itself through optogenetics and therefore without the need of traumatizing high-voltage shocks. However, crucial mechanistic and translational aspects of this strategy have remained largely unaddressed. Therefore, we investigated optogenetic termination of VTs (i) in the pathologically remodelled heart using an (ii) implantable multi-LED device for (iii) in vivo closed-chest, local illumination.In order to mimic a clinically relevant sequence of events, transverse aortic constriction (TAC) was applied to adult male Wistar rats before optogenetic modification. This modification took place 3 weeks later by intravenous delivery of adeno-associated virus vectors encoding red-activatable channelrhodopsin or Citrine for control experiments. At 8-10 weeks after TAC, VTs were induced ex vivo and in vivo, followed by programmed local illumination of the ventricular apex by a custom-made implanted multi-LED device. This resulted in effective and repetitive VT termination in the remodelled adult rat heart after optogenetic modification, leading to sustained restoration of sinus rhythm in the intact animal. Mechanistically, studies on the single cell and tissue level revealed collectively that, despite the cardiac remodelling, there were no significant differences in bioelectricity generation and subsequent transmembrane voltage responses between diseased and control animals, thereby providing insight into the observed robustness of optogenetic VT termination.Our results show that implant-based optical cardioversion of VTs is feasible in the pathologically remodelled heart in vivo after local optogenetic targeting because of preserved optical control over bioelectricity generation. These findings add novel mechanistic and translational insight into optical ventricular cardioversion.
P12.06 Unmet needs and wish for support of informal caregivers of primary brain tumour patients
Authors: L Pointon, R Grant, S Peoples, S Erridge, P Sherwood, M Klein, F Boele
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Most primary brain tumour patients rely on informal caregivers (i.e. family members or friends) for practical and emotional support. While caregiving can be rewarding, it also commonly leads to significant burden. In developing support for caregivers, it is vital to distinguish between caregivers’ unmet needs, and their actual wish for support to resolve unmet needs. We aimed to 1) identify the presence and magnitude of unmet needs; 2) examine associations between unmet needs and desire for support; 3) evaluate perceived usefulness of caregiver needs screening in clinical practice. MATERIAL AND METHODS Family caregivers of patients with primary brain tumours were recruited and asked to complete an adapted version of the Caregiver Needs Screen (CNS). This covered the level of distress resulting from 33 common issues in neuro-oncology caregiving (scale 0–10), and wish for information or support for any issue (yes/no). In addition, participants were asked to rank (0–7) their experience of using the CNS based on items covering ‘ease of us’, ‘usefulness’ and ‘satisfaction’. Descriptive and correlational analyses were applied. RESULTS Caregivers (N=79) reported between 1–33 unmet needs (M=17.20, sd=7.98) but did not always wish for support for each need (range 0–28, M=4.71, sd=6.63). Most distressing items were patient’s fatigue (M=5.58), recognising signs of disease progression (M=5.23), changes in patients’ thinking or behaviour (M=5.04), patient distress or sadness (M=4.68), and changes in caregivers’ own emotional health (M=4.44). A weak correlation was found between the total number of unmet needs and the desire for support (r=0.296, p=0.014). Caregivers most often desired support with recognising disease progression (N=24), managing medications and side-effects (N=18), and least often with managing spiritual issues (N=0), communication with (grand)children (N=2) and communication with family members and friends (N=3). Caregivers evaluated the CNS tool positively (mean item scores ranging 4.19–6.21 out of 7). CONCLUSION Family caregivers of brain tumour patients experience distress resulting from many neuro-oncology specific needs, but this is not directly related to a wish for support or information. Caregiver needs screening could be useful to tailor support or information to suit caregivers’ preferences in clinical practice.