ESC Working Group Cellular Biology of the Heart: Position Paper: Improving the pre-clinical assessment of novel cardioprotective therapies

Ischemic heart disease (IHD) remains the leading cause of death and disability worldwide. As a result, novel therapies are still needed to protect the heart from the detrimental effects of acute ischemia-reperfusion injury, in order to improve clinical outcomes in IHD patients. In this regard, although a large number of novel cardioprotective therapies discovered in the research laboratory have been investigated in the clinical setting, only a few of these have been demonstrated to improve clinical outcomes. One potential reason for this lack of success may have been the failure to thoroughly assess the cardioprotective efficacy of these novel therapies in suitably designed pre-clinical experimental animal models. Therefore, the aim of this Position Paper by the European Society of Cardiology Working Group Cellular Biology of the Heart is to provide recommendations for improving the pre-clinical assessment of novel cardioprotective therapies discovered in the research laboratory, with the aim of increasing the likelihood of success in translating these new treatments into improved clinical outcomes

Bacterial Leaf Symbiosis in Angiosperms: Host Specificity without Co-Speciation

Bacterial leaf symbiosis is a unique and intimate interaction between bacteria and flowering plants, in which endosymbionts are organized in specialized leaf structures. Previously, bacterial leaf symbiosis has been described as a cyclic and obligate interaction in which the endosymbionts are vertically transmitted between plant generations and lack autonomous growth. Theoretically this allows for co-speciation between leaf nodulated plants and their endosymbionts. We sequenced the nodulated Burkholderia endosymbionts of 54 plant species from known leaf nodulated angiosperm genera, i.e. Ardisia, Pavetta, Psychotria and Sericanthe. Phylogenetic reconstruction of bacterial leaf symbionts and closely related free-living bacteria indicates the occurrence of multiple horizontal transfers of bacteria from the environment to leaf nodulated plant species. This rejects the hypothesis of a long co-speciation process between the bacterial endosymbionts and their host plants. Our results indicate a recent evolutionary process towards a stable and host specific interaction confirming the proposed maternal transmission mode of the endosymbionts through the seeds. Divergence estimates provide evidence for a relatively recent origin of bacterial leaf symbiosis, dating back to the Miocene (5–23 Mya). This geological epoch was characterized by cool and arid conditions, which may have triggered the origin of bacterial leaf symbiosis

Laparoscopy in management of appendicitis in high-, middle-, and low-income countries: a multicenter, prospective, cohort study.

BACKGROUND: Appendicitis is the most common abdominal surgical emergency worldwide. Differences between high- and low-income settings in the availability of laparoscopic appendectomy, alternative management choices, and outcomes are poorly described. The aim was to identify variation in surgical management and outcomes of appendicitis within low-, middle-, and high-Human Development Index (HDI) countries worldwide. METHODS: This is a multicenter, international prospective cohort study. Consecutive sampling of patients undergoing emergency appendectomy over 6 months was conducted. Follow-up lasted 30 days. RESULTS: 4546 patients from 52 countries underwent appendectomy (2499 high-, 1540 middle-, and 507 low-HDI groups). Surgical site infection (SSI) rates were higher in low-HDI (OR 2.57, 95% CI 1.33-4.99, p = 0.005) but not middle-HDI countries (OR 1.38, 95% CI 0.76-2.52, p = 0.291), compared with high-HDI countries after adjustment. A laparoscopic approach was common in high-HDI countries (1693/2499, 67.7%), but infrequent in low-HDI (41/507, 8.1%) and middle-HDI (132/1540, 8.6%) groups. After accounting for case-mix, laparoscopy was still associated with fewer overall complications (OR 0.55, 95% CI 0.42-0.71, p < 0.001) and SSIs (OR 0.22, 95% CI 0.14-0.33, p < 0.001). In propensity-score matched groups within low-/middle-HDI countries, laparoscopy was still associated with fewer overall complications (OR 0.23 95% CI 0.11-0.44) and SSI (OR 0.21 95% CI 0.09-0.45). CONCLUSION: A laparoscopic approach is associated with better outcomes and availability appears to differ by country HDI. Despite the profound clinical, operational, and financial barriers to its widespread introduction, laparoscopy could significantly improve outcomes for patients in low-resource environments. TRIAL REGISTRATION: NCT02179112

Pooled analysis of WHO Surgical Safety Checklist use and mortality after emergency laparotomy

Background The World Health Organization (WHO) Surgical Safety Checklist has fostered safe practice for 10 years, yet its place in emergency surgery has not been assessed on a global scale. The aim of this study was to evaluate reported checklist use in emergency settings and examine the relationship with perioperative mortality in patients who had emergency laparotomy. Methods In two multinational cohort studies, adults undergoing emergency laparotomy were compared with those having elective gastrointestinal surgery. Relationships between reported checklist use and mortality were determined using multivariable logistic regression and bootstrapped simulation. Results Of 12 296 patients included from 76 countries, 4843 underwent emergency laparotomy. After adjusting for patient and disease factors, checklist use before emergency laparotomy was more common in countries with a high Human Development Index (HDI) (2455 of 2741, 89.6 per cent) compared with that in countries with a middle (753 of 1242, 60.6 per cent; odds ratio (OR) 0.17, 95 per cent c.i. 0.14 to 0.21, P <0001) or low (363 of 860, 422 per cent; OR 008, 007 to 010, P <0.001) HDI. Checklist use was less common in elective surgery than for emergency laparotomy in high-HDI countries (risk difference -94 (95 per cent c.i. -11.9 to -6.9) per cent; P <0001), but the relationship was reversed in low-HDI countries (+121 (+7.0 to +173) per cent; P <0001). In multivariable models, checklist use was associated with a lower 30-day perioperative mortality (OR 0.60, 0.50 to 073; P <0.001). The greatest absolute benefit was seen for emergency surgery in low- and middle-HDI countries. Conclusion Checklist use in emergency laparotomy was associated with a significantly lower perioperative mortality rate. Checklist use in low-HDI countries was half that in high-HDI countries.Peer reviewe

Polygenic prediction of educational attainment within and between families from genome-wide association analyses in 3 million individuals

We conduct a genome-wide association study (GWAS) of educational attainment (EA) in a sample of ~3 million individuals and identify 3,952 approximately uncorrelated genome-wide-significant single-nucleotide polymorphisms (SNPs). A genome-wide polygenic predictor, or polygenic index (PGI), explains 12-16% of EA variance and contributes to risk prediction for ten diseases. Direct effects (i.e., controlling for parental PGIs) explain roughly half the PGI's magnitude of association with EA and other phenotypes. The correlation between mate-pair PGIs is far too large to be consistent with phenotypic assortment alone, implying additional assortment on PGI-associated factors. In an additional GWAS of dominance deviations from the additive model, we identify no genome-wide-significant SNPs, and a separate X-chromosome additive GWAS identifies 57

Reducing the Clinical and Public Health Burden of Familial Hypercholesterolemia A Global Call to Action

Q1Q1Artículo completoE1-E13IMPORTANCE Familial hypercholesterolemia (FH) is an underdiagnosed and undertreated genetic disorder that leads to premature morbidity and mortality due to atherosclerotic cardiovascular disease. Familial hypercholesterolemia affects 1 in 200 to 250 people around the world of every race and ethnicity. The lack of general awareness of FH among the public and medical community has resulted in only 10% of the FH population being diagnosed and adequately treated. The World Health Organization recognized FH as a public health priority in 1998 during a consultation meeting in Geneva, Switzerland. The World Health Organization report highlighted 11 recommendations to address FH worldwide, from diagnosis and treatment to family screening and education. Research since the 1998 report has increased understanding and awareness of FH, particularly in specialty areas, such as cardiology and lipidology. However, in the past 20 years, there has been little progress in implementing the 11 recommendations to prevent premature atherosclerotic cardiovascular disease in an entire generation of families with FH. OBSERVATIONS In 2018, the Familial Hypercholesterolemia Foundation and the World Heart Federation convened the international FH community to update the 11 recommendations. Two meetings were held: one at the 2018 FH Foundation Global Summit and the other during the 2018 World Congress of Cardiology and Cardiovascular Health. Each meeting served as a platform for the FH community to examine the original recommendations, assess the gaps, and provide commentary on the revised recommendations. The Global Call to Action on Familial Hypercholesterolemia thus represents individuals with FH, advocacy leaders, scientific experts, policy makers, and the original authors of the 1998 World Health Organization report. Attendees from 40 countries brought perspectives on FH from low-, middle-, and high-income regions. Tables listing country-specific government support for FH care, existing country-specific and international FH scientific statements and guidelines, country-specific and international FH registries, and known FH advocacy organizations around the world were created. CONCLUSIONS AND RELEVANCE By adopting the 9 updated public policy recommendations created for this document, covering awareness; advocacy; screening, testing, and diagnosis; treatment; family-based care; registries; research; and cost and value, individual countries have the opportunity to prevent atherosclerotic heart disease in their citizens carrying a gene associated with FH and, likely, all those with severe hypercholesterolemia as well