Triple-gated motion and blood pool clearance corrections improve reproducibility of coronary 18F-NaF PET

PurposeTo improve the test-retest reproducibility of coronary plaque 18F-sodium fluoride (18F-NaF) positron emission tomography (PET) uptake measurements.MethodsWe recruited 20 patients with coronary artery disease who underwent repeated hybrid PET/CT angiography (CTA) imaging within 3 weeks. All patients had 30-min PET acquisition and CTA during a single imaging session. Five PET image-sets with progressive motion correction were reconstructed: (i) a static dataset (no-MC), (ii) end-diastolic PET (standard), (iii) cardiac motion corrected (MC), (iv) combined cardiac and gross patient motion corrected (2 × MC) and, (v) cardiorespiratory and gross patient motion corrected (3 × MC). In addition to motion correction, all datasets were corrected for variations in the background activities which are introduced by variations in the injection-to-scan delays (background blood pool clearance correction, BC). Test-retest reproducibility of PET target-to-background ratio (TBR) was assessed by Bland-Altman analysis and coefficient of reproducibility.ResultsA total of 47 unique coronary lesions were identified on CTA. Motion correction in combination with BC improved the PET TBR test-retest reproducibility for all lesions (coefficient of reproducibility: standard = 0.437, no-MC = 0.345 (27% improvement), standard + BC = 0.365 (20% improvement), no-MC + BC = 0.341 (27% improvement), MC + BC = 0.288 (52% improvement), 2 × MC + BC = 0.278 (57% improvement) and 3 × C + BC = 0.254 (72% improvement), all p < 0.001). Importantly, in a sub-analysis of 18F-NaF-avid lesions with gross patient motion > 10 mm following corrections, reproducibility was improved by 133% (coefficient of reproducibility: standard = 0.745, 3 × MC = 0.320).ConclusionJoint corrections for cardiac, respiratory, and gross patient motion in combination with background blood pool corrections markedly improve test-retest reproducibility of coronary 18F-NaF PET

Should public health interventions aimed at reducing childhood overweight and obesity be gender-focused?

<p>Abstract</p> <p>Background</p> <p>Overweight in childhood is a major public health concern that calls for immediate preventative action. An increasing number of reports suggest that gender specific approaches to prevention may be more effective. However, there is a paucity of information to guide gender-sensitive health promotion and population health interventions for the prevention of overweight in childhood. In the present study, we sought to determine gender-differentials in overweight and underlying behaviors, nutrition and physical activity, among pre-adolescents in Alberta, Canada, to inform the discussion on gender-focused interventions for chronic disease prevention.</p> <p>Methods</p> <p>In 2008, we surveyed 3421 grade five students and their parents of 148 randomly selected schools. Students completed the Harvard food frequency questionnaire, questions on physical activities, and had their height and weight measured. Parents completed questions on socio-economic background and child's lifestyle. We applied multilevel regression methods to assess gender differentials in overweight, nutrition and physical activity.</p> <p>Results</p> <p>Overall, the prevalence of overweight was slightly higher among boys (29.1%) than girls (27.9%) with more pronounced differences in towns and urban geographies. Boys reported to be much more physically active relative to girls (OR = 2.12, 95% CI: 1.73-2.60). Diets of boys, relative to those of girls, reportedly constituted more fat and were less likely to meet the recommendation of 6 daily servings of vegetables and fruits (OR = 0.81, 95% CI: 0.71-0.93).</p> <p>Conclusion</p> <p>Our findings confirm the existence of gender differences in physical activity and nutrition, and support gender-focused health promotion whereby priority is given to physical activity among girls and to healthy eating among boys.</p

Global Analysis of the Evolution and Mechanism of Echinocandin Resistance in Candida glabrata

The evolution of drug resistance has a profound impact on human health. Candida glabrata is a leading human fungal pathogen that can rapidly evolve resistance to echinocandins, which target cell wall biosynthesis and are front-line therapeutics for Candida infections. Here, we provide the first global analysis of mutations accompanying the evolution of fungal drug resistance in a human host utilizing a series of C. glabrata isolates that evolved echinocandin resistance in a patient treated with the echinocandin caspofungin for recurring bloodstream candidemia. Whole genome sequencing identified a mutation in the drug target, FKS2, accompanying a major resistance increase, and 8 additional non-synonymous mutations. The FKS2-T1987C mutation was sufficient for echinocandin resistance, and associated with a fitness cost that was mitigated with further evolution, observed in vitro and in a murine model of systemic candidemia. A CDC6-A511G(K171E) mutation acquired before FKS2-T1987C(S663P), conferred a small resistance increase. Elevated dosage of CDC55, which acquired a C463T(P155S) mutation after FKS2-T1987C(S663P), ameliorated fitness. To discover strategies to abrogate echinocandin resistance, we focused on the molecular chaperone Hsp90 and downstream effector calcineurin. Genetic or pharmacological compromise of Hsp90 or calcineurin function reduced basal tolerance and resistance. Hsp90 and calcineurin were required for caspofungin-dependent FKS2 induction, providing a mechanism governing echinocandin resistance. A mitochondrial respiration-defective petite mutant in the series revealed that the petite phenotype does not confer echinocandin resistance, but renders strains refractory to synergy between echinocandins and Hsp90 or calcineurin inhibitors. The kidneys of mice infected with the petite mutant were sterile, while those infected with the HSP90-repressible strain had reduced fungal burden. We provide the first global view of mutations accompanying the evolution of fungal drug resistance in a human host, implicate the premier compensatory mutation mitigating the cost of echinocandin resistance, and suggest a new mechanism of echinocandin resistance with broad therapeutic potential

Prenatal exposures and exposomics of asthma

This review examines the causal investigation of preclinical development of childhood asthma using exposomic tools. We examine the current state of knowledge regarding early-life exposure to non-biogenic indoor air pollution and the developmental modulation of the immune system. We examine how metabolomics technologies could aid not only in the biomarker identification of a particular asthma phenotype, but also the mechanisms underlying the immunopathologic process. Within such a framework, we propose alternate components of exposomic investigation of asthma in which, the exposome represents a reiterative investigative process of targeted biomarker identification, validation through computational systems biology and physical sampling of environmental medi

The development, implementation and evaluation of interventions to reduce workplace sitting: a qualitative systematic review and evidence-based operational framework

Background: Prolonged sitting is associated with increased risks of cardiovascular disease, Type 2 diabetes, some cancers, musculoskeletal disorders and premature mortality. Workplaces contribute to a large proportion of daily sitting time, particularly among office-based workers. Interventions to reduce workplace sitting therefore represent important public health initiatives. Previous systematic reviews suggest such interventions can be effective but have reported wide variations. Further, there is uncertainty as to whether effectiveness in controlled trials can be replicated when implemented outside the research setting. The aims of this review are to identify factors important for the implementation of workplace sitting interventions and to translate these findings into a useful operational framework to support the future implementation of such interventions. Methods: A qualitative systematic review was conducted. Four health and social science databases were searched for studies set in the workplace, with office-based employees and with the primary aim of reducing workplace sitting. Extracted data were primarily from author descriptions of interventions and their implementation. Inductive thematic analysis and synthesis was undertaken. Results: Forty studies met the inclusion criteria. Nine descriptive themes were identified from which emerged three higher-order analytical themes, which related to the development , implementation and evaluation of workplace sitting interventions. Key findings inc luded: the importance of groundi ng interventions in theory; utilising participative approaches during intervention development and implementation; and c onducting comprehensive proce ss and outcome evaluations. There was a general under-reporting of info rmation relating to the context within which workplace sitting interventions were implemented, such as details of local organisation processes and structures, as well as the wider political and economic landscape, which if present would aid the translation of knowledge into “ real-world ” settings. Conclusions: These findings provided the basis for an operational framework, which is a representation of all nine descriptive themes and three higher-order analytical themes, to support workplace sitting intervention development, implementation and evaluation. Once tested and refined, this framework has the potential to be incorporated into a practical toolkit, which could be used by a range of organisations to develop, implement and evaluate their own interventions to reduce workplace sitting time amongst staff

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