Glucocorticoids and angiogenesis

Angiogenesis is the creation of new blood vessels from the existing vasculature that occurs through a complex series of interactions and is tightly regulated. Glucocorticoids are acknowledged to inhibit angiogenesis at high concentrations but whether endogenous glucocorticoid concentrations are sufficient to regulate angiogenesis is unclear. Adrenal synthesis is not the sole determinant of glucocorticoid tissue concentration however and 11 ßhydroxysteroid dehydrogenase type 1 (11ßHSD1) that is present in the vessel wall may regenerate active glucocorticoids from 1 lketo-substrates and therefore amplify local tissue concentrations. Thus it was hypothesised that endogenous glucocorticoids regulated by 11ßHSD1 inhibit angiogenesis.In vitro C57B16 mouse aortic ring cultures established that physiologically relevant concentrations of glucocorticoids inhibit angiogenesis in a glucocorticoid receptor dependent manner. In addition vascular 11ßHSD1 was found to modulate glucocorticoid-induced angiostasis, for 1 ldehydrocorticosterone although angiostatic in C57B16 aortae did not inhibit angiogenesis in 11ßHSD1 deficient animals.In vivo using polyester sponge subcutaneous implants in mice, endogenous glucocorticoids were found to inhibit angiogenesis: sponges in adrenalectomised C57B16 mice grew more vessels compared to sponges from sham-operated animals. 11ßHSD1 regulated the angiostatic effects of glucocorticoids, for cortisone (the human equivalent of 11dehydrocorticosterone), although angiostatic in wild types did not inhibit angiogenesis in 11ßHSD1 deficient mice. In vivo it was also noted that in placebo-impregnated sponges angiogenesis was greater in 11ßHSD1 deficient compared to C57B16 mice.In pathology in cutaneous wounds and infarcted myocardium, endogenous glucocorticoids were found to inhibit angiogenesis. RU38486 (a glucocorticoid receptor antagonist) enhanced angiogenesis in both tissues in comparison to placebo treatment. In similar studies in C57B16 or 11ßHSD1 deficient mice, 11ßHSD1 was found to tonically repress angiogenesis and impair left ventricular remodelling post infarction. Thus 11ßHSD1 deficient mice had increased myocardial revascularisation and preserved left ventricular function.In conclusion, by using in vitro, in vivo and pathological models, endogenous glucocorticoids were seen to inhibit angiogenesis. In addition 11ßHSD1 regeneration of glucocorticoids tonically repressed angiogenesis and influenced left ventricular remodelling post myocardial infarction. Thus 11ßHSD1 appears to be an attractive therapeutic target for the management of tissue revascularisation

Preoperative neutrophil-lymphocyte ratio and outcome from coronary artery bypass grafting

Background: An elevated preoperative white blood cell count has been associated with a worse outcome after coronary artery bypass grafting (CABG). Leukocyte subtypes, and particularly the neutrophil-lymphocyte (N/L) ratio, may however, convey superior prognostic information. We hypothesized that the N/L ratio would predict the outcome of patients undergoing surgical revascularization. Methods: Baseline clinical details were obtained prospectively in 1938 patients undergoing CABG. The differential leukocyte was measured before surgery, and patients were followed-up 3.6 years later. The primary end point was all-cause mortality. Results: The preoperative N/L ratio was a powerful univariable predictor of mortality (hazard ratio [HR] 1.13 per unit, P 3.36). Conclusion: An elevated N/L ratio is associated with a poorer survival after CABG. This prognostic utility is independent of other recognized risk factors.Peer reviewedAuthor versio

Clinical deterioration during antituberculosis treatment in Africa: Incidence, causes and risk factors

BACKGROUND:HIV-1 and Mycobacterium tuberculosis cause substantial morbidity and mortality. Despite the availability of antiretroviral and antituberculosis treatment in Africa, clinical deterioration during antituberculosis treatment remains a frequent reason for hospital admission. We therefore determined the incidence, causes and risk factors for clinical deterioration. METHODS: Prospective cohort study of 292 adults who initiated antituberculosis treatment during a 3-month period. We evaluated those with clinical deterioration over the following 24 weeks of treatment. RESULTS: Seventy-one percent (209/292) of patients were HIV-1 infected (median CD4+: 129 cells/muL [IQR:62-277]). At tuberculosis diagnosis, 23% (34/145) of HIV-1 infected patients qualifying for antiretroviral treatment (ART) were receiving ART; 6 months later, 75% (109/145) had received ART. Within 24 weeks of initiating antituberculosis treatment, 40% (117/292) of patients experienced clinical deterioration due to co-morbid illness (n = 70), tuberculosis related illness (n = 47), non AIDS-defining HIV-1 related infection (n = 25) and AIDS-defining illness (n = 21). Using HIV-1 uninfected patients as the referent group, HIV-1 infected patients had an increasing risk of clinical deterioration as CD4+ counts decreased [CD4+>350 cells/muL: RR = 1.4, 95% CI = 0.7-2.9; CD4+:200-350 cells/muL: RR = 2.0, 95% CI = 1.1-3.6; CD4+<200 cells/muL: RR = 3.0, 95% CI = 1.9-4.7]. During follow-up, 26% (30/117) of patients with clinical deterioration required hospital admission and 15% (17/117) died. Fifteen deaths were in HIV-1 infected patients with a CD4+<200 cells/muL. CONCLUSIONS: In multivariate analysis, HIV-1 infection and a low CD4+ count at tuberculosis diagnosis were significant risk factors for clinical deterioration and death. The initiation of ART at a CD4+ count of <350 cells/muL will likely reduce the high burden of clinical deterioration

Agricultural Biotechnology's Complementary Intellectual Assets

We formulate and test a hypothesis to explain the dramatic restructuring experienced recently by the plant breeding and seed industry. The reorganization can be explained in part by the desire to exploit complementarities between intellectual assets needed to create genetically modified organisms. This hypothesis is tested using data on agricultural biotechnology patents, notices for field tests of genetically modified organisms, and firm characteristics. The presence of complementarities is identified with a positive covariance in the unexplained variation of asset holdings. Results indicate that coordination of complementary assets have increased under the consolidation of the industry

Implementation of corticosteroids in treating COVID-19 in the ISARIC WHO Clinical Characterisation Protocol UK:prospective observational cohort study

BACKGROUND: Dexamethasone was the first intervention proven to reduce mortality in patients with COVID-19 being treated in hospital. We aimed to evaluate the adoption of corticosteroids in the treatment of COVID-19 in the UK after the RECOVERY trial publication on June 16, 2020, and to identify discrepancies in care. METHODS: We did an audit of clinical implementation of corticosteroids in a prospective, observational, cohort study in 237 UK acute care hospitals between March 16, 2020, and April 14, 2021, restricted to patients aged 18 years or older with proven or high likelihood of COVID-19, who received supplementary oxygen. The primary outcome was administration of dexamethasone, prednisolone, hydrocortisone, or methylprednisolone. This study is registered with ISRCTN, ISRCTN66726260. FINDINGS: Between June 17, 2020, and April 14, 2021, 47 795 (75·2%) of 63 525 of patients on supplementary oxygen received corticosteroids, higher among patients requiring critical care than in those who received ward care (11 185 [86·6%] of 12 909 vs 36 415 [72·4%] of 50 278). Patients 50 years or older were significantly less likely to receive corticosteroids than those younger than 50 years (adjusted odds ratio 0·79 [95% CI 0·70–0·89], p=0·0001, for 70–79 years; 0·52 [0·46–0·58], p80 years), independent of patient demographics and illness severity. 84 (54·2%) of 155 pregnant women received corticosteroids. Rates of corticosteroid administration increased from 27·5% in the week before June 16, 2020, to 75–80% in January, 2021. INTERPRETATION: Implementation of corticosteroids into clinical practice in the UK for patients with COVID-19 has been successful, but not universal. Patients older than 70 years, independent of illness severity, chronic neurological disease, and dementia, were less likely to receive corticosteroids than those who were younger, as were pregnant women. This could reflect appropriate clinical decision making, but the possibility of inequitable access to life-saving care should be considered. FUNDING: UK National Institute for Health Research and UK Medical Research Council

Procalcitonin Is Not a Reliable Biomarker of Bacterial Coinfection in People With Coronavirus Disease 2019 Undergoing Microbiological Investigation at the Time of Hospital Admission

Abstract Admission procalcitonin measurements and microbiology results were available for 1040 hospitalized adults with coronavirus disease 2019 (from 48 902 included in the International Severe Acute Respiratory and Emerging Infections Consortium World Health Organization Clinical Characterisation Protocol UK study). Although procalcitonin was higher in bacterial coinfection, this was neither clinically significant (median [IQR], 0.33 [0.11–1.70] ng/mL vs 0.24 [0.10–0.90] ng/mL) nor diagnostically useful (area under the receiver operating characteristic curve, 0.56 [95% confidence interval, .51–.60]).</jats:p

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707