Publications by authors named "David Clark"

1,353 Publications

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Chronic Pain is Associated With Reduced Sympathetic Nervous System Reactivity During Simple and Complex Walking Tasks: Potential Cerebral Mechanisms.

Chronic Stress (Thousand Oaks) 2021 Jan-Dec;5:24705470211030273. Epub 2021 Jul 7.

Pain Research & Intervention Center of Excellence, University of Florida, University of Florida, Gainesville, FL, USA.

Background: Autonomic dysregulation may lead to blunted sympathetic reactivity in chronic pain states. Autonomic responses are controlled by the central autonomic network (CAN). Little research has examined sympathetic reactivity and associations with brain CAN structures in the presence of chronic pain; thus, the present study aims to investigate how chronic pain influences sympathetic reactivity and associations with CAN brain region volumes.

Methods: Sympathetic reactivity was measured as change in skin conductance level (ΔSCL) between a resting reference period and walking periods for typical and complex walking tasks (obstacle and dual-task). Participants included 31 people with (n = 19) and without (n = 12) chronic musculoskeletal pain. Structural 3 T MRI was used to determine gray matter volume associations with ΔSCL in regions of the CAN (i.e., brainstem, amygdala, insula, and anterior cingulate cortex).

Results: ΔSCL varied across walking tasks (main effect p = 0.036), with lower ΔSCL in chronic pain participants compared to controls across trials 2 and 3 under the obstacle walking condition. ΔSCL during typical walking was associated with multiple CAN gray matter volumes, including brainstem, bilateral insula, amygdala, and right caudal anterior cingulate cortex (p's < 0.05). The difference in ΔSCL from typical-to-obstacle walking were associated with volumes of the midbrain segment of the brainstem and anterior segment of the circular sulcus of the insula (p's < 0.05), with no other significant associations. The difference in ΔSCL from typical-to-dual task walking was associated with the bilateral caudal anterior cingulate cortex, and left rostral cingulate cortex (p's < 0.05).

Conclusions: Sympathetic reactivity is blunted during typical and complex walking tasks in persons with chronic pain. Additionally, blunted sympathetic reactivity is associated with CAN brain structure, with direction of association dependent on brain region. These results support the idea that chronic pain may negatively impact typical autonomic responses needed for walking performance via its potential impact on the brain.
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http://dx.doi.org/10.1177/24705470211030273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8267022PMC
July 2021

Differences in outcome of percutaneous coronary intervention between Indigenous and non-Indigenous people in Victoria, Australia: a multicentre, prospective, observational, cohort study.

Lancet Glob Health 2021 Jul 15. Epub 2021 Jul 15.

Department of Cardiology, Royal Melbourne Hospital, Melbourne, VIC, Australia; Department of Medicine, Melbourne University, Melbourne, VIC, Australia; Centre of Cardiovascular Research and Education in Therapeutics, Monash University, Melbourne, VIC, Australia. Electronic address:

Background: Data on the patient characteristics and health outcomes of Indigenous Australians having revascularisation for treatment of coronary artery disease are scarce. The aim of this study was to assess differences in patient characteristics, presentations, and outcomes among Indigenous and non-Indigenous Australians having percutaneous coronary intervention (PCI) in urban and larger regional centres in Victoria, Australia.

Methods: In this multicentre, prospective, observational cohort study, data were prospectively collected from six government-funded tertiary hospitals in the state of Victoria, Australia. The Melbourne Interventional Group PCI registry was used to identify patients having PCI at Victorian metropolitan and large regional hospitals between Jan 1, 2005, and Dec 31, 2018. The primary outcome was long-term mortality. Secondary outcomes were 30 day mortality and 30 day major adverse cardiovascular events (MACE), defined as a composite endpoint of death, myocardial infarction, and target-vessel revascularisation. Regression analyses, adjusted for clinically relevant covariates and geographical and socioeconomic indices, were used to establish the influence of Indigenous status on these study outcomes.

Findings: 41 146 patient procedures were entered into the registry, of whom 179 (0·4%) were recorded as identifying as Indigenous Australian, 39 855 (96·9%) were not Indigenous Australian, and 1112 (2·7%) had incomplete data regarding ethnicity and were excluded. Compared with their non-Indigenous counterparts, Indigenous patients were younger, more often women, and more likely to have comorbidities. Indigenous Australians were also more likely to live in a regional community and areas of socioeconomic disadvantage. Procedural success and complication rates were similar for Indigenous and non-Indigenous patients having PCI. At 30 day follow-up, Indigenous Australians were more likely to be taking optimal medical therapy, although overall follow-up rates were lower and prevalence of persistent smoking was higher. Multivariable analysis showed that Indigenous status was independently associated with increased risk of long-term mortality (hazard ratio 2·49, 95% CI 1·79-3·48; p<0·0001), 30 day mortality (odds ratio 2·78, 95% CI 1·09-7·12; p=0·033), and 30-day MACE (odds ratio 1·87, 95% CI 1·03-3·39; p=0·039).

Interpretation: Indigenous Australians having PCI in urban and larger regional centres are at increased risk of mortality and adverse cardiac events. Clinically effective and culturally safe care pathways are urgently needed to improve health outcomes among Indigenous Australians who are having PCI.

Funding: National Health and Medical Research Council, National Heart Foundation.
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http://dx.doi.org/10.1016/S2214-109X(21)00224-2DOI Listing
July 2021

Comparison of Long-Term Outcomes in Men versus Women Undergoing Percutaneous Coronary Intervention.

Am J Cardiol 2021 Jul 5. Epub 2021 Jul 5.

Department of Cardiology, Austin Health, Melbourne, Australia; University of Melbourne, Melbourne, Australia. Electronic address:

There has been a significant decrease in mortality associated with coronary artery disease (CAD) in recent decades, although at discordant rates between men and women. Using a well-established multicenter registry, we sought to examine the impact of gender on long-term mortality stratified by indication for percutaneous coronary intervention (PCI). Data from 54,440 consecutive patients (12,805, 23.5% women) undergoing PCI from the Victorian Cardiac Outcomes Registry (2013 to 2018) were analyzed. We aimed to compare gender-related differences of patients undergoing PCI for stable angina pectoris (SAP), non-ST-elevation acute coronary syndrome (NSTEACS) and ST-elevation myocardial infarction (STEMI). The primary outcome was long-term all-cause mortality. Female patients were older across all indications (SAP: 67 vs 71 years, NSTEACS: 64 vs 69 years, STEMI 61 vs 67 years; p value for all <0.001), with age-adjusted higher rates of diabetes mellitus (p value for all <0.02) and renal impairment (p value for all <0.001), and were more likely to have femoral artery access for intervention (p value for all <0.001). Unadjusted in-hospital and 30-day mortality rates were comparable between men and women across all indications. Compared to men, women had a higher rate of unadjusted long-term mortality (9.0% vs 7.37%; p <0.001). However, after adjusting for variables significant on univariate analysis, female gender was independently associated with improved long-term survival (HR 0.76, 95% CI 0.66 to 0.87; p <0.001). In conclusion, contrary to previous studies, despite being older with a differing clinical profile and interventional approach, women undergoing PCI have a long-term survival advantage.
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http://dx.doi.org/10.1016/j.amjcard.2021.05.013DOI Listing
July 2021

Prevalence of neutralising antibodies against SARS-CoV-2 in acute infection and convalescence: A systematic review and meta-analysis.

PLoS Negl Trop Dis 2021 07 8;15(7):e0009551. Epub 2021 Jul 8.

Departments of Clinical Sciences and Tropical Disease Biology, Liverpool School of Tropical Medicine, Liverpool, United Kingdom.

Background: Individuals infected with SARS-CoV-2 develop neutralising antibodies. We investigated the proportion of individuals with SARS-CoV-2 neutralising antibodies after infection and how this proportion varies with selected covariates.

Methodology/principal Findings: This systematic review and meta-analysis examined the proportion of individuals with SARS-CoV-2 neutralising antibodies after infection and how these proportions vary with selected covariates. Three models using the maximum likelihood method assessed these proportions by study group, covariates and individually extracted data (protocol CRD42020208913). A total of 983 reports were identified and 27 were included. The pooled (95%CI) proportion of individuals with neutralising antibodies was 85.3% (83.5-86.9) using the titre cut off >1:20 and 83.9% (82.2-85.6), 70.2% (68.1-72.5) and 54.2% (52.0-56.5) with titres >1:40, >1:80 and >1:160, respectively. These proportions were higher among patients with severe COVID-19 (e.g., titres >1:80, 84.8% [80.0-89.2], >1:160, 74.4% [67.5-79.7]) than those with mild presentation (56.7% [49.9-62.9] and 44.1% [37.3-50.6], respectively) and lowest among asymptomatic infections (28.6% [17.9-39.2] and 10.0% [3.7-20.1], respectively). IgG and neutralising antibody levels correlated poorly.

Conclusions/significance: 85% of individuals with proven SARS-CoV-2 infection had detectable neutralising antibodies. This proportion varied with disease severity, study setting, time since infection and the method used to measure antibodies.
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http://dx.doi.org/10.1371/journal.pntd.0009551DOI Listing
July 2021

High-Throughput Analyses of Glycans, Glycosites, and Intact Glycopeptides Using C4-and C18/MAX-Tips and Liquid Handling System.

Curr Protoc 2021 Jul;1(7):e186

Department of Pathology, Johns Hopkins University, School of Medicine, Baltimore, Maryland.

Protein glycosylation is one of the most common and diverse modifications. Aberrant protein glycosylation has been reported to associate with various diseases. High-throughput and comprehensive characterization of glycoproteins is crucial for structural and functional studies of altered glycosylation in biological, physiological, and pathological processes. In this protocol, we detail a workflow for comprehensive analyses of intact glycopeptides (IGPs), glycosylation sites, and glycans from N-linked glycoproteins. By utilizing liquid handling systems, our workflow could enrich IGPs in a high-throughput manner while reducing sample processing time and human error involved in traditional proteomics sample processing techniques. Together, our workflow enables a high-throughput enrichment of glycans, glycosites, and intact glycopeptides from complex biological or clinical samples. © 2021 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Enzymatic digestion of glycoproteins using C4-tips Basic Protocol 2: Intact glycopeptide analysis using C18/MAX-tips Basic Protocol 3: Glycan and glycosite analysis.
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http://dx.doi.org/10.1002/cpz1.186DOI Listing
July 2021

Treating social anxiety disorder remotely with cognitive therapy.

Cogn Behav Therap 2020 Jul 16;13:e30. Epub 2020 Jul 16.

Department of Experimental Psychology, University of Oxford, Oxford, UK.

Remote delivery of evidence-based psychological therapies via video conference has become particularly relevant following the COVID-19 pandemic, and is likely to be an on-going method of treatment delivery post-COVID. Remotely delivered therapy could be of particular benefit for people with social anxiety disorder (SAD), who tend to avoid or delay seeking face-to-face therapy, often due to anxiety about travelling to appointments and meeting mental health professionals in person. Individual cognitive therapy for SAD (CT-SAD), based on the Clark and Wells (1995) model, is a highly effective treatment that is recommended as a first-line intervention in NICE guidance (NICE, 2013). All of the key features of face-to-face CT-SAD (including video feedback, attention training, behavioural experiments and memory-focused techniques) can be adapted for remote delivery. In this paper, we provide guidance for clinicians on how to deliver CT-SAD remotely, and suggest novel ways for therapists and patients to overcome the challenges of carrying out a range of behavioural experiments during remote treatment delivery.

Key Learning Aims: To learn how to deliver all of the core interventions of CT-SAD remotely.To learn novel ways of carrying out behavioural experiments remotely when some in-person social situations might not be possible.
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http://dx.doi.org/10.1017/S1754470X2000032XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7411446PMC
July 2020

Characteristics of Early-Onset vs Late-Onset Colorectal Cancer: A Review.

JAMA Surg 2021 Jun 30. Epub 2021 Jun 30.

Department of Surgery, Skåne University Hospital, Malmö, Sweden.

Importance: The incidence of early-onset colorectal cancer (younger than 50 years) is rising globally, the reasons for which are unclear. It appears to represent a unique disease process with different clinical, pathological, and molecular characteristics compared with late-onset colorectal cancer. Data on oncological outcomes are limited, and sensitivity to conventional neoadjuvant and adjuvant therapy regimens appear to be unknown. The purpose of this review is to summarize the available literature on early-onset colorectal cancer.

Observations: Within the next decade, it is estimated that 1 in 10 colon cancers and 1 in 4 rectal cancers will be diagnosed in adults younger than 50 years. Potential risk factors include a Westernized diet, obesity, antibiotic usage, and alterations in the gut microbiome. Although genetic predisposition plays a role, most cases are sporadic. The full spectrum of germline and somatic sequence variations implicated remains unknown. Younger patients typically present with descending colonic or rectal cancer, advanced disease stage, and unfavorable histopathological features. Despite being more likely to receive neoadjuvant and adjuvant therapy, patients with early-onset disease demonstrate comparable oncological outcomes with their older counterparts.

Conclusions And Relevance: The clinicopathological features, underlying molecular profiles, and drivers of early-onset colorectal cancer differ from those of late-onset disease. Standardized, age-specific preventive, screening, diagnostic, and therapeutic strategies are required to optimize outcomes.
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http://dx.doi.org/10.1001/jamasurg.2021.2380DOI Listing
June 2021

Brain activity during walking in older adults: Implications for compensatory versus dysfunctional accounts.

Neurobiol Aging 2021 May 31;105:349-364. Epub 2021 May 31.

Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, FL, USA; Norman Fixel Institute for Neurological Diseases, University of Florida, Gainesville, FL, USA.

A prominent trend in the functional brain imaging literature is that older adults exhibit increased brain activity compared to young adults to perform a given task. This phenomenon has been extensively studied for cognitive tasks, with the field converging on interpretations described in two alternative accounts. One account interprets over-activation in older adults as reflecting neural dysfunction (increased brain activity - indicates poorer performance), whereas another interprets it as neural compensation (increased brain activity - supports better performance). Here we review studies that have recorded brain activity and walking measurements in older adults, and we categorize their findings as reflecting either neural dysfunction or neural compensation. Based on this synthesis, we recommend including multiple task difficulty levels in future work to help differentiate if and when compensation fails as the locomotion task becomes more difficult. Using multiple task difficulty levels with neuroimaging will lead to a more advanced understanding of how age-related changes in locomotor brain activity fit with existing accounts of brain aging and support the development of targeted neural rehabilitation techniques.
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http://dx.doi.org/10.1016/j.neurobiolaging.2021.05.015DOI Listing
May 2021

Frailty Severity and Hospitalization After Dialysis Initiation.

Can J Kidney Health Dis 2021 10;8:20543581211023330. Epub 2021 Jun 10.

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

Background: Frailty is associated with hospitalization and mortality among dialysis patients. To now, few studies have considered the degree of frailty as a predictor of hospitalization.

Objective: We evaluated whether was associated with hospitalization after dialysis initiation.

Design: Retrolective cohort study.

Setting: Nova Scotia, Canada.

Patients: Consecutive adult, chronic dialysis patients who initiated dialysis from January 1, 2009 to June 30, 2014, (last follow-up June, 2015).

Methods: Frailty Severity, as determined by the 7-point Clinical Frailty Scale (CFS, ranging from 1 = very fit to 7 = severely frail), was measured at dialysis initiation and treated as continuous and in categories (CFS scores of 1-3, 4/5, and 6/7). Hospitalization was characterized by cumulative time admitted to hospital (proportion of days admitted/time at risk) and by the joint risk of hospitalization and death. Time at risk included time in hospital after dialysis initiation and patients were followed until transplantation or death.

Results: Of 647 patients (mean age: 62 ± 15), 564 (87%) had CFS scores. The mean CFS score was 4 ("corresponding to "vulnerable") ± 2 ("well" to "moderately frail"). In an adjusted negative binomial regression model, moderate-severely frail patients (CFS 6/7) had a >2-fold increased risk of cumulative time admitted to hospital compared to the lowest CFS category (IRR = 2.18, 95% confidence interval [CI] = 1.31-3.63). In the joint model, moderate-severely frail patients had a 61% increase in the relative hazard for hospitalization (hazard ratio [HR] = 1.61, 95% CI = 1.29-2.02) and a 93% increase in the relative hazard for death compared to the lowest CFS category (HR = 1.93, 95% CI = 1.16-3.22).

Limitations: Potential unknown confounders may have affected the association between frailty severity and hospitalization given observational study design. The CFS is subjective and different clinicians may grade frailty severity differently or misclassify patients on the basis of limited availability.

Conclusions: Among incident dialysis patients, a higher frailty severity as defined by the CFS is associated with both an increased risk of cumulative time admitted to hospital and joint risk of hospitalization and death.
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http://dx.doi.org/10.1177/20543581211023330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8202313PMC
June 2021

Comparison of Outcomes of Coronary Artery Disease Treated by Percutaneous Coronary Intervention in 3 Different Age Groups (<45, 46-65, and >65 Years).

Am J Cardiol 2021 Aug 17;152:19-26. Epub 2021 Jun 17.

Department of Cardiology, Alfred Health, Victoria, Australia; Department of Medicine, University of Melbourne, Victoria, Australia; BakerIDI Heart and Diabetes Institute, Melbourne, Victoria, Australia; Monash University, Victoria, Australia. Electronic address:

There is paucity of data examining long-term outcomes of premature coronary artery disease (CAD). We aimed to investigate the short- and long-term clinical outcomes of patients with premature CAD treated by percutaneous coronary intervention (PCI) compared to older cohorts. We analyzed data from 27,869 patients who underwent PCI from 2005-2017 enrolled in a multicenter PCI registry. Patients were divided into three age groups: young group (≤ 45 years), middle-age group (46-65 years) and older group (>65 years). There were higher rates of current smokers in the young (n = 1,711) compared to the middle-age (n = 12,830) and older groups (n = 13,328) (54.2% vs 34.6% vs 11%) and the young presented more frequently with acute coronary syndrome (ACS) (78% vs 66% vs 62%), all p <0.05. There were also greater rates of cardiogenic shock (CS), out-of-hospital cardiac arrest (OHCA) and ST-elevation myocardial infarction (STEMI) in the young, all p <0.05. The young cohort with STEMI had higher rates of in-hospital, 30-day death, and long-term mortality (3.8% vs 0.2%, 4.3% vs 0.2% and 8.6% vs 3.1%, all p <0.05, respectively) compared to the non-STEMI subgroup. There was a stepwise increase in long-term mortality from the young, to middle-age, to the older group (6.1% vs 9.9% vs 26.8%, p <0.001). Younger age was an independent predictor of lower long-term mortality (HR 0.66, 95% CI 0.52-0.84, p = 0.001). In conclusion, younger patients presenting with STEMI had worse prognosis compared to those presenting with non-STEMI. Despite higher risk presentations among young patients, their overall prognosis was favorable compared to older age groups.
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http://dx.doi.org/10.1016/j.amjcard.2021.05.002DOI Listing
August 2021

Brainstem damage is associated with poorer sleep quality and increased pain in gulf war illness veterans.

Life Sci 2021 Sep 16;280:119724. Epub 2021 Jun 16.

War Related Illness & Injury Study Center (WRIISC), VA Palo Alto Health Care System, Palo Alto, CA, United States; Stanford University, Stanford, CA, United States.

Aims: Gulf War Illness (GWI) is manifested as multiple chronic symptoms, including chronic pain, chronic fatigue, sleep problems, neuropsychiatric disorders, respiratory, gastrointestinal, and skin problems. No single target tissue or unifying pathogenic process has been identified that accounts for this variety of symptoms. The brainstem has been suspected to contribute to this multiple symptomatology. The aim of this study was to assess the role of the brainstem in chronic sleep problems and pain in GWI veterans.

Materials And Methods: We enrolled 90 veterans (Age = 50 ± 5, 87% Male) who were deployed to the 1990-91 Gulf War and presented with GWI symptoms. Sleep quality was evaluated using the global Pittsburgh Sleep Quality Index. Pain intensities were obtained with the Brief Pain Inventory sum score. Volumes in cortical, subcortical, brainstem, and brainstem subregions and diffusion tensor metrics in 10 bilateral brainstem tracts were tested for correlations with symptom measures.

Key Findings: Poorer sleep quality was significantly correlated with atrophy of the whole brainstem and brainstem subregions (including midbrain, pons, medulla). Poorer sleep quality also significantly correlated with lower fractional anisotropy in the nigrostriatal tract, medial forebrain tract, and the dorsal longitudinal fasciculus. There was a significant correlation between increased pain intensity and decreased fractional anisotropy in the dorsal longitudinal fasciculus. These correlations were not altered after controlling for age, sex, total intracranial volumes, or additional factors, e.g., depression and neurological conditions.

Significance: These findings suggest that the brainstem plays an important role in the aberrant neuromodulation of sleep and pain symptoms in GWI.
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http://dx.doi.org/10.1016/j.lfs.2021.119724DOI Listing
September 2021

Mechanisms Underlying the Association of Chronic Obstructive Pulmonary Disease With Heart Failure.

JACC Cardiovasc Imaging 2021 May 12. Epub 2021 May 12.

Manchester University NHS Foundation Trust, Wythenshawe Hospital, Manchester, United Kingdom; Division of Cardiovascular Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, United Kingdom; Division of Cell-Matrix Biology and Regenerative Medicine, Wellcome Centre for Cell-Matrix Research, School of Biology, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, United Kingdom. Electronic address:

Objectives: The purposes of this study were to determine why chronic obstructive pulmonary disease (COPD) is associated with heart failure (HF). Specific objectives included whether COPD is associated with myocardial fibrosis, whether myocardial fibrosis is associated with hospitalization for HF and death in COPD, and whether COPD and smoking are associated with myocardial inflammation.

Background: COPD is associated with HF independent of shared risk factors. The underlying pathophysiological mechanism is unknown.

Methods: A prospective, multicenter, longitudinal cohort study of 572 patients undergoing cardiac magnetic resonance (CMR), including 450 patients with COPD and 122 age- and sex-matched patients with a median: 726 days (interquartile range: 492 to 1,160 days) follow-up. Multivariate analysis was used to examine the relationship between COPD and myocardial fibrosis, measured using cardiac magnetic resonance (CMR). Cox regression analysis was used to examine the relationship between myocardial fibrosis and outcomes; the primary endpoint was composite of hospitalizations for HF or all-cause mortality; secondary endpoints included hospitalizations for HF and all-cause mortality. Fifteen patients with COPD, 15 current smokers, and 15 healthy volunteers underwent evaluation for myocardial inflammation, including ultrasmall superparamagnetic particles of iron oxide CMR.

Results: COPD was independently associated with myocardial fibrosis (p < 0.001). Myocardial fibrosis was independently associated with the primary outcome (hazard ratio [HR]: 1.14; 95% confidence interval [CI]: 1.08 to 1.20; p < 0.001), hospitalization for HF (HR: 1.25 [95% CI: 1.14 to 1.36]); p < 0.001), and all-cause mortality. Myocardial fibrosis was associated with outcome measurements more strongly than any other variable. Acute and stable COPD were associated with myocardial inflammation.

Conclusions: The associations between COPD, myocardial inflammation and myocardial fibrosis, and the independent prognostic value of myocardial fibrosis elucidate a potential pathophysiological link between COPD and HF.
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http://dx.doi.org/10.1016/j.jcmg.2021.03.026DOI Listing
May 2021

Globalization, first-foods systems transformations and corporate power: a synthesis of literature and data on the market and political practices of the transnational baby food industry.

Global Health 2021 May 21;17(1):58. Epub 2021 May 21.

School of Exercise and Nutrition Sciences, Deakin University, Geelong, Australia.

Background: The global milk formula market has 'boomed' in recent decades, raising serious concerns for breastfeeding, and child and maternal health. Despite these developments, few studies have investigated the global expansion of the baby food industry, nor the market and political practices corporations have used to grow and sustain their markets. In this paper, our aim is to understand the strategies used by the baby food industry to shape 'first-foods systems' across its diverse markets, and in doing so, drive milk formula consumption on a global scale. We used a theoretically guided synthesis review method, which integrated diverse qualitative and quantitative data sources.

Results: Global milk formula sales grew from ~US$1.5 billion in 1978 to US$55.6 billion in 2019. This remarkable expansion has occurred along two main historical axes. First, the widening geographical reach of the baby food industry and its marketing practices, both globally and within countries, as corporations have pursued new growth opportunities, especially in the Global South. Second, the broadening of product ranges beyond infant formula, to include an array of follow-up, toddler and specialized formulas for a wider range of age groups and conditions, thereby widening the scope of mother-child populations subject to commodification. Sophisticated marketing techniques have been used to grow and sustain milk formula consumption, including marketing through health systems, mass-media and digital advertising, and novel product innovations backed by corporate science. To enable and sustain this marketing, the industry has engaged in diverse political practices to foster favourable policy, regulatory and knowledge environments. This has included lobbying international and national policy-makers, generating and deploying favourable science, leveraging global trade rules and adopting corporate policies to counter regulatory action by governments.

Conclusion: The baby food industry uses integrated market and political strategies to shape first-foods systems in ways that drive and sustain milk formula market expansion, on a global scale. Such practices are a major impediment to global implementation of the International Code of Marketing of Breastmilk Substitutes, and other policy actions to protect, promote and support breastfeeding. New modalities of public health action are needed to negate the political practices of the industry in particular, and ultimately to constrain corporate power over the mother-child breastfeeding dyad.
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http://dx.doi.org/10.1186/s12992-021-00708-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8139375PMC
May 2021

An obituary: Dr. Gérard Chaouat May 6, 1944 - April 23, 2021.

J Reprod Immunol 2021 May 13;145:103329. Epub 2021 May 13.

Department of Medical Biology, Medical School, University of Pecs, Pecs, Hungary. Electronic address:

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http://dx.doi.org/10.1016/j.jri.2021.103329DOI Listing
May 2021

Is concentration an indirect link between social anxiety and educational achievement in adolescents?

PLoS One 2021 14;16(5):e0249952. Epub 2021 May 14.

Department of Experimental Psychology, University of Oxford, Oxford, United Kingdom.

Social anxiety is associated with reduced educational achievement. Given that concentration is a predictor of educational achievement, and social anxiety symptoms are associated with reduced concentration in class, this prospective study examined the possibility that social anxiety may impair educational achievement through reduced classroom concentration. A sample of 509 participants (53.8% female; M age: 12.77 years [SD = 0.81]) recruited from secondary schools completed questionnaires assessing social anxiety symptoms, depressive symptoms, and concentration in class. Educational achievement was assessed by internal grades within schools. An indirect effect of social anxiety on later educational achievement via concentration was observed, over and above baseline achievement and depression symptoms; adolescents with higher levels of social anxiety tend to have more difficulties concentrating in class, which in turn is associated with poorer academic outcomes. Findings underscore the challenges socially anxious adolescents will face trying to learn in school, and the need for education providers and clinicians to consider the effect of social anxiety symptoms on concentration and learning.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0249952PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8121284PMC
May 2021

Quantification of training load distribution in mixed martial arts athletes: A lack of periodisation and load management.

PLoS One 2021 10;16(5):e0251266. Epub 2021 May 10.

Research Institute for Sport and Exercise Sciences, Liverpool John Moores University, Liverpool, United Kingdom.

The aim of this study was to quantify typical training load and periodisation practices of MMA athletes. MMA competitors (n = 14; age = 22.4 ± 4.4 years; body mass = 71.3 ± 7.7 kg; stature = 171 ±9.9 cm) were observed during training for 8 consecutive weeks without intervention. Seven athletes were training for competitive bouts whilst the remaining 7 were not. Daily training duration, intensity (RPE), load (sRPE and segRPE), fatigue (short questionnaire of fatigue) and body region soreness (CR10 scale) were recorded. Using Bayesian analyses (BF10≥3), data demonstrate that training duration (weekly mean range = 3.9-5.3 hours), sRPE (weekly mean range = 1,287-1,791 AU), strain (weekly mean range = 1,143-1,819 AU), monotony (weekly mean range = 0.63-0.83 AU), fatigue (weekly mean range = 16-20 AU) and soreness did not change within or between weeks. Between weeks monotony (2.3 ± 0.7 AU) supported little variance in weekly training load. There were no differences in any variable between participants who competed and those who did not with the except of the final week before the bout, where an abrupt step taper occurred leading to no between group differences in fatigue. Training intensity distribution corresponding to high, moderate and low was 20, 33 and 47%, respectively. Striking drills accounted for the largest portion of weekly training time (20-32%), with MMA sparring the least (2-7%). Only striking sparring and wrestling sparring displayed statistical weekly differences in duration or load. Athletes reported MMA sparring and wrestling sparring as high intensity (RPE≥7), BJJ sparring, striking sparring and wrestling drills as moderate intensity (RPE 5-6), and striking drills and BJJ drills as low intensity (RPE≤4). We conclude that periodisation of training load was largely absent in this cohort of MMA athletes, as is the case within and between weekly microcycles.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0251266PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8109772PMC
May 2021

Optimizing differential identifiability improves connectome predictive modeling of cognitive deficits from functional connectivity in Alzheimer's disease.

Hum Brain Mapp 2021 Aug 5;42(11):3500-3516. Epub 2021 May 5.

Indiana University School of Medicine, Indianapolis, Indiana, USA.

Functional connectivity, as estimated using resting state functional MRI, has shown potential in bridging the gap between pathophysiology and cognition. However, clinical use of functional connectivity biomarkers is impeded by unreliable estimates of individual functional connectomes and lack of generalizability of models predicting cognitive outcomes from connectivity. To address these issues, we combine the frameworks of connectome predictive modeling and differential identifiability. Using the combined framework, we show that enhancing the individual fingerprint of resting state functional connectomes leads to robust identification of functional networks associated to cognitive outcomes and also improves prediction of cognitive outcomes from functional connectomes. Using a comprehensive spectrum of cognitive outcomes associated to Alzheimer's disease (AD), we identify and characterize functional networks associated to specific cognitive deficits exhibited in AD. This combined framework is an important step in making individual level predictions of cognition from resting state functional connectomes and in understanding the relationship between cognition and connectivity.
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http://dx.doi.org/10.1002/hbm.25448DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8249900PMC
August 2021

Clinically Relevant Activity of the Novel RASP Inhibitor Reproxalap in Allergic Conjunctivitis: The Phase 3 ALLEVIATE Trial.

Am J Ophthalmol 2021 May 1;230:60-67. Epub 2021 May 1.

From Aldeyra Therapeutics, Lexington, MA (D.C, B.C, T.C.B), Adelphi Values, Boston, MA (A.L.S), Kentucky Eye Institute, Lexington, KY (P.K), Virginia Eye Consultants, Norfolk, VA, USA (J.S). Electronic address:

Purpose: To assess the post-acute activity and clinical utility of reproxalap, a novel reactive aldehyde species (RASP) inhibitor, versus vehicle in patients with seasonal allergic conjunctivitis.

Design: Parallel-group, double-masked, randomized Phase 3 trial.

Methods: Two topical ocular reproxalap concentrations (0.25% and 0.5%) were evaluated versus vehicle in patients with allergic conjunctivitis randomized 1:1:1 and treated with test article 10 minutes prior to conjunctival seasonal allergen challenge. The primary endpoint was area under the post-acute ocular itching score (range = 0-4) curve from 10 to 60 minutes after challenge. The key secondary endpoint was the proportion of subjects with ≥2 points improvement from their peak ocular itching score at baseline.

Results: A total of 318 patients were randomized at 11 US sites. Both concentrations of reproxalap (0.25% and 0.5%) achieved the primary endpoint (P < .0001 and P = .003, respectively) and the key secondary endpoint (P = .0005 and P = .02, respectively). Time to complete resolution of ocular itching was statistically faster for both reproxalap concentrations than for vehicle (P < .0001 and P = .001, respectively). No safety or tolerability concerns were noted. The most common adverse event was mild and transient instillation site irritation.

Conclusion: Reproxalap was effective at reducing ocular itching in patients with allergic conjunctivitis. Reproxalap activity was clinically relevant, as assessed by responder-based and distributional analyses. ALLEVIATE represents one of the first allergic conjunctivitis Phase 3 trials of a novel mechanism of action in decades, and is unique among conjunctival allergen challenge trials in assessing clinical relevance with standard and validated techniques.
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http://dx.doi.org/10.1016/j.ajo.2021.04.023DOI Listing
May 2021

The Relationship Between Working Alliance and Symptom Improvement in Cognitive Therapy for Posttraumatic Stress Disorder.

Front Psychiatry 2021 16;12:602648. Epub 2021 Apr 16.

Department of Experimental Psychology, University of Oxford, Oxford, United Kingdom.

Working alliance has been shown to predict outcome of psychological treatments in multiple studies. Conversely, changes in outcome scores have also been found to predict working alliance ratings. To assess the temporal relationships between working alliance and outcome in 230 patients receiving trauma-focused cognitive behavioral treatment for posttraumatic stress disorder (PTSD). Ratings of working alliance were made by both the patient and therapist after sessions 1, 3, and 5 of a course of Cognitive Therapy for PTSD (CT-PTSD). Autoregressive, cross-lagged panel models were used to examine whether working alliance predicted PTSD symptom severity at the next assessment point and vice versa. Linear regressions tested the relationship between alliance and treatment outcome. Both patients' and therapists' working alliance ratings after session 1 predicted PTSD symptom scores at the end of treatment, controlling for baseline scores. At each assessment point, higher therapist working alliance was associated with lower PTSD symptoms. Crossed-lagged associations were found for therapist-rated alliance, but not for patient-rated alliance: higher therapists' alliance ratings predicted lower PTSD symptom scores at the next assessment point. Similarly, lower PTSD symptoms predicted higher therapist working alliance ratings at the next assessment point. Ruminative thinking was negatively related to therapists' alliance ratings. Working alliance at the start of treatment predicted treatment outcome in patients receiving CT-PTSD and may be an important factor in setting the necessary conditions for effective treatment. For therapists, there was a reciprocal relationship between working alliance and PTSD symptom change in their patients during treatment, suggesting that their alliance ratings predicted symptom change, but were also influenced by patients' symptom change.
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http://dx.doi.org/10.3389/fpsyt.2021.602648DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8085346PMC
April 2021

Impact of COVID-19 on care-home mortality and life expectancy in Scotland.

Age Ageing 2021 06;50(4):1029-1037

Public Health Scotland, Meridian Court, Glasgow G2 6QE, UK.

Background: COVID-19 deaths are commoner among care-home residents, but the mortality burden has not been quantified.

Methods: Care-home residency was identified via a national primary care registration database linked to mortality data. Life expectancy was estimated using Makeham-Gompertz models to (i) describe yearly life expectancy from November 2015 to October 2020 (ii) compare life expectancy (during 2016-18) between care-home residents and the wider population and (iii) apply care-home life expectancy estimates to COVID-19 death counts to estimate years of life lost (YLL).

Results: Among care-home residents, life expectancy in 2015/16 to 2019/20 ranged from 2.7 to 2.3 years for women and 2.3 to 1.8 years for men. Age-sex-specific life expectancy in 2016-18 in care-home residents was lower than in the Scottish population (10 and 2.5 years in those aged 70 and 90, respectively). Applying care home-specific life expectancies to COVID-19 deaths yield mean YLLs for care-home residents of 2.6 and 2.2 for women and men, respectively. In total YLL care-home residents have lost 3,560 years in women and 2,046 years in men. Approximately half of deaths and a quarter of YLL attributed to COVID-19 were accounted for by the 5% of over-70s who were care-home residents.

Conclusion: COVID-19 infection has led to the loss of substantial years of life in care-home residents aged 70 years and over in Scotland. Prioritising the 5% of older adults who are care-home residents for vaccination is justified not only in terms of total deaths, but also in terms of YLL.
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http://dx.doi.org/10.1093/ageing/afab080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8135527PMC
June 2021

The balance of muscle oxygen supply and demand reveals critical metabolic rate and predicts time to exhaustion.

J Appl Physiol (1985) 2021 06 29;130(6):1915-1927. Epub 2021 Apr 29.

Department of Human Physiology, grid.256410.4Gonzaga University, Spokane, Washington.

We tested the hypothesis that during whole body exercise, the balance between muscle O supply and metabolic demand may elucidate intensity domains, reveal a critical metabolic rate, and predict time to exhaustion. Seventeen active, healthy volunteers (12 males, 5 females; 32 ± 2 yr) participated in two distinct protocols. ( = 7) consisted of constant work rate cycling in the moderate, heavy, and severe exercise intensity domains with concurrent measures of pulmonary V̇o and local %SmO [via near-infrared spectroscopy (NIRS)] on quadriceps and forearm sites. Average %SmO at both sites displayed a domain-dependent response ( < 0.05). A negative %SmO slope was evident during severe-domain exercise but was positive during exercise below critical power (CP) at both muscle sites. In ( = 10), quadriceps and forearm site %SmO was measured during three continuous running trials to exhaustion and three intermittent intensity (ratio = 60 s severe: 30 s lower intensity) trials to exhaustion. Intensity-dependent negative %SmO slopes were observed for all trials ( < 0.05) and predicted zero slope at critical velocity. %SmO accurately predicted depletion and repletion of %D' balance on a second-by-second basis ( = 0.99, < 0.05; both sites). Time to exhaustion predictions during continuous and intermittent exercise were either not different or better with %SmO [standard error of the estimate (SEE) < 20.52 s for quad, <44.03 s for forearm] versus running velocity (SEE < 65.76 s). Muscle O balance provides a dynamic physiological delineation between sustainable and unsustainable exercise (consistent with a "critical metabolic rate") and predicts real-time depletion and repletion of finite work capacity and time to exhaustion. Dynamic muscle O saturation discriminates boundaries between exercise intensity domains, exposes a critical metabolic rate as the highest rate of steady state O supply and demand, describes time series depletion and repletion for work above critical power, and predicts time to exhaustion during severe domain whole body exercise. These results highlight the matching of O supply and demand as a primary determinant for sustainable exercise intensities from those that are unsustainable and lead to exhaustion.
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http://dx.doi.org/10.1152/japplphysiol.00058.2021DOI Listing
June 2021

Outcomes of major trauma among patients with chronic kidney disease and receiving dialysis in Nova Scotia: a retrospective analysis.

Trauma Surg Acute Care Open 2021 13;6(1):e000672. Epub 2021 Apr 13.

Nephrology, QEII Health Sciences Centre, Halifax, Nova Scotia, Canada.

Background: The risk of death and complications after major trauma in patients with chronic kidney disease (CKD) is higher than in the general population, but whether this association holds true among Canadian trauma patients is unknown.

Objectives: To characterize patients with CKD/receiving dialysis within a regional major trauma cohort and compare their outcomes with patients without CKD.

Methods: All major traumas requiring hospitalization between 2006 and 2017 were identified from a provincial trauma registry in Nova Scotia, Canada. Trauma patients with stage ≥3 CKD (estimated glomerular filtration rate <60 mL/min/1.73 m) or receiving dialysis were identified by cross-referencing two regional databases for nephrology clinics and dialysis treatments. The primary outcome was in-hospital mortality; secondary outcomes included hospital/intensive care unit (ICU) length of stay (LOS) and ventilator-days. Cox regression was used to adjust for the effects of patient characteristics on in-hospital mortality.

Results: In total, 6237 trauma patients were identified, of whom 4997 lived within the regional nephrology catchment area. CKD/dialysis trauma patients (n=101; 28 on dialysis) were older than patients without CKD (n=4896), with higher rates of hypertension, diabetes, and cardiovascular disease, and had increased risk of in-hospital mortality (31% vs 11%, p<0.001). No differences were observed in injury severity, ICU LOS, or ventilator-days. After adjustment for age, sex, and injury severity, the HR for in-hospital mortality was 1.90 (95% CI 1.33 to 2.70) for CKD/dialysis compared with patients without CKD.

Conclusion: Independent of injury severity, patients without CKD/dialysis have significantly increased risk of in-hospital mortality after major trauma.
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http://dx.doi.org/10.1136/tsaco-2020-000672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8051384PMC
April 2021

Global development of children's palliative care: An international survey of in-nation expert perceptions in 2017.

Wellcome Open Res 2020 14;5:99. Epub 2020 Oct 14.

School of Interdisciplinary Studies, University of Glasgow, Dumfries, DG1 4ZL, UK.

The growing interest in tracking the global development of palliative care provision is not matched by research on the development of palliative care services specifically for children. Yet it is estimated that worldwide, 21 million children annually could benefit from the provision of palliative care. We report on a global study of children's palliative care development and offer suggestions for further improvement in design and method. Primary data on the level of children's palliative care development in 2017 was collected from in-country experts through a specific question in an online questionnaire that sought to measure the overall level of palliative care provision globally. Countries were assigned to one of six categories on the basis of the responses obtained. Conflicting responses from the same country were resolved with reference to a hierarchy of preferred respondents. Our data allowed the categorisation of 113 countries, accounting for 65% of the global population aged under 20. Number of countries (% of global child population) in each category were as follows: 1) no known activity, 21 (4%); 2) capacity-building, 16 (24%); 3a) isolated provision, 55 (30%); 3b) generalized provision, 5 (1%); 4a) preliminary integration into mainstream provision, 14 (8%); 4b) advanced integration, 7 (2%). Children's palliative care at the highest level of provision is available in just 21 countries, accounting for fewer than 10% of the global population aged under 20. It is concentrated in high income settings, whilst the majority of the global need for such care is in low- and middle-income countries. Our study is a useful tool for global advocacy relating to children's palliative care and a stimulus for the creation of improved indicators to measure it at the country level.
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http://dx.doi.org/10.12688/wellcomeopenres.15815.3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042514.3PMC
October 2020

Making a business plan for starting a transitional pain service within the US healthcare system.

Reg Anesth Pain Med 2021 Aug 20;46(8):727-731. Epub 2021 Apr 20.

Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, California, USA.

Chronic pain imposes a tremendous economic burden of up to US$635 billion per year in terms of direct costs (such as the costs of treatment) and indirect costs (such as lost productivity and time away from work). In addition, the initiation of opioids for pain is associated with a more than doubling of pharmacy and all-cause medical costs. The high costs of chronic pain are particularly relevant for anesthesiologists because surgery represents an inciting event that can lead to chronic pain and long-term opioid use. While the presence of risk factors and an individual patient's postoperative pain trajectory may predict who is at high risk for chronic pain and opioid use after surgery, to date, there are few interventions proven to reduce these risks. One promising approach is the transitional pain service. Programs like this attempt to bridge the gap between acute and chronic pain management, provide continuity of care for complicated acute pain patients after discharge from the hospital, and offer interventions for patients who are on abnormal trajectories of pain resolution and/or opioid use. Despite awareness of chronic pain after surgery and the ongoing opioid epidemic, there are few examples of successful transitional pain service implementation in the USA. Key issues and concerns include financial incentives and the required investment from the hospital or healthcare system. We present an economic analysis and discussion of important considerations when developing a business plan for a transitional pain service.
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http://dx.doi.org/10.1136/rapm-2021-102669DOI Listing
August 2021

Temporal Contribution of Myeloid-Lineage TLR4 to the Transition to Chronic Pain: A Focus on Sex Differences.

J Neurosci 2021 May 12;41(19):4349-4365. Epub 2021 Apr 12.

Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, Stanford, California 94305

Complex regional pain syndrome (CRPS) is a chronic pain disorder with a clear acute-to-chronic transition. Preclinical studies demonstrate that toll-like receptor 4 (TLR4), expressed by myeloid-lineage cells, astrocytes, and neurons, mediates a sex-dependent transition to chronic pain; however, evidence is lacking on which exact TLR4-expressing cells are responsible. We used complementary pharmacologic and transgenic approaches in mice to more specifically manipulate myeloid-lineage TLR4 and outline its contribution to the transition from acute-to-chronic CRPS based on three key variables: location (peripheral vs central), timing (prevention vs treatment), and sex (male vs female). We demonstrate that systemic TLR4 antagonism is more effective at improving chronic allodynia trajectory when administered at the time of injury (early) in the tibial fracture model of CRPS in both sexes. In order to clarify the contribution of myeloid-lineage cells peripherally (macrophages) or centrally (microglia), we rigorously characterize a novel spatiotemporal transgenic mouse line, (TLR4 cKO) to specifically knock out TLR4 only in microglia and no other myeloid-lineage cells. Using this transgenic mouse, we find that early TLR4 cKO results in profound improvement in chronic, but not acute, allodynia in males, with a significant but less robust effect in females. In contrast, late TLR4 cKO results in partial improvement in allodynia in both sexes, suggesting that downstream cellular or molecular TLR4-independent events may have already been triggered. Overall, we find that the contribution of TLR4 is time- and microglia-dependent in both sexes; however, females also rely on peripheral myeloid-lineage (or other TLR4 expressing) cells to trigger chronic pain. The contribution of myeloid cell TLR4 to sex-specific pain progression remains controversial. We used complementary pharmacologic and transgenic approaches to specifically manipulate TLR4 based on three key variables: location (peripheral vs central), timing (prevention vs treatment), and sex (male vs female). We discovered that microglial TLR4 contributes to early pain progression in males, and to a lesser extent in females. We further found that maintenance of chronic pain likely occurs through myeloid TLR4-independent mechanisms in both sexes. Together, we define a more nuanced contribution of this receptor to the acute-to-chronic pain transition in a mouse model of complex regional pain syndrome.
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http://dx.doi.org/10.1523/JNEUROSCI.1940-20.2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8143203PMC
May 2021

Takotsubo cardiomyopathy complicated by cardiogenic shock secondary to left ventricular outflow tract obstruction and severe mitral regurgitation.

Cardiovasc Revasc Med 2021 Mar 20. Epub 2021 Mar 20.

Austin Hospital, Department of Cardiology, Australia; The University of Melbourne, Department of Medicine, Australia.

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http://dx.doi.org/10.1016/j.carrev.2021.03.009DOI Listing
March 2021

Pyrrole-2 carboxamides - A novel class of insect ryanodine receptor activators.

Pestic Biochem Physiol 2021 May 21;174:104798. Epub 2021 Feb 21.

FMC, Agricultural Solutions Discovery Biology, Stine Research Center, 1090 Elkton Road, Newark, DE 19711, USA.

The ryanodine receptor (RyR) is an intracellular calcium channel critical to the regulation of insect muscle contraction and the target site of diamide insecticides such as chlorantraniliprole, cyantraniliprole and flubendiamide. To-date, diamides are the only known class of synthetic molecules with high potency against insect RyRs. Target-based screening of an informer library led to discovery of a novel class of RyR activators, pyrrole-2-carboxamides. Efforts to optimize receptor activity resulted in analogs with potency comparable to that of commercial diamides when tested against RyR of the fruit fly, Drosophila melanogaster. Surprisingly, testing of pyrrole-2-carboxamides in whole-insect screens showed poor insecticidal activity, which is partially attributed to differential selectivity among insect receptors and rapid detoxification. Among various lepidopteran species field resistance to diamide insecticides has been well documented and in many cases has been attributed to a single point mutation, G4946E, of the RyR gene. As with diamide insecticides, the G4946E mutation confers greatly reduced sensitivity to pyrrole-2-carboxamides. This, coupled with findings from radioligand binding studies, indicates a shared binding domain between anthranilic diamides and pyrrole-2-carboxamides.
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http://dx.doi.org/10.1016/j.pestbp.2021.104798DOI Listing
May 2021