Triangulating Abuse Liability Assessment for Flavoured Cigar Products Using Physiological, Behavioural Economic and Subjective Assessments: A Within-subjects Clinical Laboratory Protocol

Introduction In the USA, Food and Drug Administration regulations prohibit the sale of flavoured cigarettes, with menthol being the exception. However, the manufacture, advertisement and sale of flavoured cigar products are permitted. Such flavourings influence positive perceptions of tobacco products and are linked to increased use. Flavourings may mask the taste of tobacco and enhance smoke inhalation, influencing toxicant exposure and abuse liability among novice tobacco users. Using clinical laboratory methods, this study investigates how flavour availability affects measures of abuse liability in young adult cigarette smokers. The specific aims are to evaluate the effect of cigar flavours on nicotine exposure, and behavioural and subjective measures of abuse liability. Methods and analyses Participants (projected n=25) are healthy smokers of five or more cigarettes per day over the past 3 months, 18–25 years old, naive to cigar use (lifetime use of 50 or fewer cigar products and no more than 10 cigars smoked in the past 30 days) and without a desire to quit cigarette smoking in the next 30 days. Participants complete five laboratory sessions in a Latin square design with either their own brand cigarette or a session-specific Black & Mild cigar differing in flavour (apple, cream, original and wine). Participants are single-blinded to cigar flavours. Each session consists of two 10-puff smoking bouts (30 s interpuff interval) separated by 1 hour. Primary outcomes include saliva nicotine concentration, behavioural economic task performance and response to various questionnaire items assessing subjective effects predictive of abuse liability. Differences in outcomes across own brand cigarette and flavoured cigar conditions will be tested using linear mixed models

Suboptimal geographic accessibility to comprehensive HIV care in the US: regional and urban–rural differences

Achieving US state and municipal benchmarks to end the HIV epidemic and promote health equity requires access to comprehensive HIV care. However, this care may not be geographically accessible for all people living with HIV (PLHIV). We estimated county-level drive time and suboptimal geographic accessibility to HIV care across the contiguous US, assessing regional and urban–rural differences. We integrated publicly available data from four federal databases to identify and geocode sites providing comprehensive HIV care in 2015, defined as the co-located provision of core HIV medical care and support services. Leveraging street network, US Census and HIV surveillance data (2014), we used geographic analysis to estimate the fastest one-way drive time between the population-weighted county centroid and the nearest site providing HIV care for counties reporting at least five diagnosed HIV cases. We summarized HIV care sites, county-level drive time, population-weighted drive time and suboptimal geographic accessibility to HIV care, by US region and county rurality (2013). Geographic accessibility to HIV care was suboptimal if drive time was \u3e30 min, a common threshold for primary care accessibility in the general US population. Tests of statistical significance were not performed, since the analysis is population-based. We identified 671 HIV care sites across the US, with 95% in urban counties. Nationwide, the median county-level drive time to HIV care is 69 min (interquartile range (IQR) 66 min). The median county-level drive time to HIV care for rural counties (90 min, IQR 61) is over twice that of urban counties (40 min, IQR 48), with the greatest urban–rural differences in the West. Nationally, population-weighted drive time, an approximation of individual-level drive time, is over five times longer in rural counties than in urban counties. Geographic access to HIV care is suboptimal for over 170,000 people diagnosed with HIV (19%), with over half of these individuals from the South and disproportionately the rural South. Nationally, approximately 80,000 (9%) drive over an hour to receive HIV care. Suboptimal geographic accessibility to HIV care is an important structural barrier in the US, particularly for rural residents living with HIV in the South and West. Targeted policies and interventions to address this challenge should become a priority

Integrated Spectroscopy of Bulge Globular Clusters and Fields. II. Implications for stellar population models and elliptical galaxies

Synthetic Lick indices (e.g. Mg_2, Fe, etc.) of Simple Stellar Population (SSP) models are calibrated for the first time up to solar metallicity with a sample of Milky Way globular clusters (GCs) which includes the metal rich GCs of the Galactic bulge. This metallicity range is relevant to elliptical galaxies. It is shown that the Bulge GCs and integrated light follow the same correlation between Mg and Fe indices of elliptical galaxies, showing weaker Fe indices at given Mg indices with respect to models that assume solar-scaled abundances. This similarity is the robust empirical evidence for enhanced alpha/Fe ratios in the stellar populations of elliptical galaxies, since the globular clusters are independently known to be alpha-enhanced. The uniqueness of this alpha-overabundance solution is checked by exploring the whole range of model ingredients. We argue that the standard models reproduce the Mg-Fe correlation at low metallicities because the stellar templates used in the synthesis are the alpha-enhanced stars of the galactic Halo. These same models, however, fail to recover the Mg-Fe pattern of Bulge clusters and ellipticals at high metallicities because the high-metallicity templates are disk stars, which are not alpha-enhanced. The new SSP models by Thomas, Maraston & Bender (2002) which incorporate the dependence on alpha/Fe reproduce the Mg and Fe indices of GCs at all metallicities, with alpha/Fe=+0.3, which is in agreement with spectroscopic abundance determinations. The Balmer indices (Hbeta, Hdelta, Hgamma) are very well calibrated, provided the Horizontal Branch morphology is taken into account. In particular, we reproduce the Balmer lines of NGC 6388 and NGC 6441, which are metal-rich GCs with a tail of warm Horizontal Branch stars. {Abridged}Comment: 19 pages, 13 figures, Astronomy and Astrophysics in press. Only minor changes after the referee repor

Role of Pleiotropy in the Evolution of a Cryptic Developmental Variation in Caenorhabditis elegans

Using vulval phenotypes in Caenorhabditis elegans, the authors show that cryptic genetic variation can evolve through selection for pleiotropic effects that alter fitness, and identify a cryptic variant that has conferred enhanced fitness on domesticated worms under laboratory conditions

Using C. elegans to decipher the cellular and molecular mechanisms underlying neurodevelopmental disorders

Prova tipográfica (uncorrected proof)Neurodevelopmental disorders such as epilepsy, intellectual disability (ID), and autism spectrum disorders (ASDs) occur in over 2 % of the population, as the result of genetic mutations, environmental factors, or combination of both. In the last years, use of large-scale genomic techniques allowed important advances in the identification of genes/loci associated with these disorders. Nevertheless, following association of novel genes with a given disease, interpretation of findings is often difficult due to lack of information on gene function and effect of a given mutation in the corresponding protein. This brings the need to validate genetic associations from a functional perspective in model systems in a relatively fast but effective manner. In this context, the small nematode, Caenorhabditis elegans, presents a good compromise between the simplicity of cell models and the complexity of rodent nervous systems. In this article, we review the features that make C. elegans a good model for the study of neurodevelopmental diseases. We discuss its nervous system architecture and function as well as the molecular basis of behaviors that seem important in the context of different neurodevelopmental disorders. We review methodologies used to assess memory, learning, and social behavior as well as susceptibility to seizures in this organism. We will also discuss technological progresses applied in C. elegans neurobiology research, such as use of microfluidics and optogenetic tools. Finally, we will present some interesting examples of the functional analysis of genes associated with human neurodevelopmental disorders and how we can move from genes to therapies using this simple model organism.The authors would like to acknowledge Fundação para a Ciência e Tecnologia (FCT) (PTDC/SAU-GMG/112577/2009). AJR and CB are recipients of FCT fellowships: SFRH/BPD/33611/2009 and SFRH/BPD/74452/2010, respectively

Effects of hospital facilities on patient outcomes after cancer surgery: an international, prospective, observational study

Background Early death after cancer surgery is higher in low-income and middle-income countries (LMICs) compared with in high-income countries, yet the impact of facility characteristics on early postoperative outcomes is unknown. The aim of this study was to examine the association between hospital infrastructure, resource availability, and processes on early outcomes after cancer surgery worldwide.Methods A multimethods analysis was performed as part of the GlobalSurg 3 study-a multicentre, international, prospective cohort study of patients who had surgery for breast, colorectal, or gastric cancer. The primary outcomes were 30-day mortality and 30-day major complication rates. Potentially beneficial hospital facilities were identified by variable selection to select those associated with 30-day mortality. Adjusted outcomes were determined using generalised estimating equations to account for patient characteristics and country-income group, with population stratification by hospital.Findings Between April 1, 2018, and April 23, 2019, facility-level data were collected for 9685 patients across 238 hospitals in 66 countries (91 hospitals in 20 high-income countries; 57 hospitals in 19 upper-middle-income countries; and 90 hospitals in 27 low-income to lower-middle-income countries). The availability of five hospital facilities was inversely associated with mortality: ultrasound, CT scanner, critical care unit, opioid analgesia, and oncologist. After adjustment for case-mix and country income group, hospitals with three or fewer of these facilities (62 hospitals, 1294 patients) had higher mortality compared with those with four or five (adjusted odds ratio [OR] 3.85 [95% CI 2.58-5.75]; p<0.0001), with excess mortality predominantly explained by a limited capacity to rescue following the development of major complications (63.0% vs 82.7%; OR 0.35 [0.23-0.53]; p<0.0001). Across LMICs, improvements in hospital facilities would prevent one to three deaths for every 100 patients undergoing surgery for cancer.Interpretation Hospitals with higher levels of infrastructure and resources have better outcomes after cancer surgery, independent of country income. Without urgent strengthening of hospital infrastructure and resources, the reductions in cancer-associated mortality associated with improved access will not be realised

Effect of alirocumab on mortality after acute coronary syndromes. An analysis of the ODYSSEY OUTCOMES randomized clinical trial

Background: Previous trials of PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitors demonstrated reductions in major adverse cardiovascular events, but not death. We assessed the effects of alirocumab on death after index acute coronary syndrome. Methods: ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) was a double-blind, randomized comparison of alirocumab or placebo in 18 924 patients who had an ACS 1 to 12 months previously and elevated atherogenic lipoproteins despite intensive statin therapy. Alirocumab dose was blindly titrated to target achieved low-density lipoprotein cholesterol (LDL-C) between 25 and 50 mg/dL. We examined the effects of treatment on all-cause death and its components, cardiovascular and noncardiovascular death, with log-rank testing. Joint semiparametric models tested associations between nonfatal cardiovascular events and cardiovascular or noncardiovascular death. Results: Median follow-up was 2.8 years. Death occurred in 334 (3.5%) and 392 (4.1%) patients, respectively, in the alirocumab and placebo groups (hazard ratio [HR], 0.85; 95% CI, 0.73 to 0.98; P=0.03, nominal P value). This resulted from nonsignificantly fewer cardiovascular (240 [2.5%] vs 271 [2.9%]; HR, 0.88; 95% CI, 0.74 to 1.05; P=0.15) and noncardiovascular (94 [1.0%] vs 121 [1.3%]; HR, 0.77; 95% CI, 0.59 to 1.01; P=0.06) deaths with alirocumab. In a prespecified analysis of 8242 patients eligible for ≥3 years follow-up, alirocumab reduced death (HR, 0.78; 95% CI, 0.65 to 0.94; P=0.01). Patients with nonfatal cardiovascular events were at increased risk for cardiovascular and noncardiovascular deaths (P<0.0001 for the associations). Alirocumab reduced total nonfatal cardiovascular events (P<0.001) and thereby may have attenuated the number of cardiovascular and noncardiovascular deaths. A post hoc analysis found that, compared to patients with lower LDL-C, patients with baseline LDL-C ≥100 mg/dL (2.59 mmol/L) had a greater absolute risk of death and a larger mortality benefit from alirocumab (HR, 0.71; 95% CI, 0.56 to 0.90; Pinteraction=0.007). In the alirocumab group, all-cause death declined wit h achieved LDL-C at 4 months of treatment, to a level of approximately 30 mg/dL (adjusted P=0.017 for linear trend). Conclusions: Alirocumab added to intensive statin therapy has the potential to reduce death after acute coronary syndrome, particularly if treatment is maintained for ≥3 years, if baseline LDL-C is ≥100 mg/dL, or if achieved LDL-C is low. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01663402

Nurses' perceptions of aids and obstacles to the provision of optimal end of life care in ICU

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