Effects of adding either a leukotriene receptor antagonist or low-dose theophylline to a low or medium dose of inhaled corticosteroid in patients with persistent asthma

STUDY OBJECTIVES: To evaluate the effect of adding zafirlukast or low-dose theophylline to a beclomethasone dipropionate (BDP) extra-fine hydrofluoroalkane aerosol on bronchial hyperresponsiveness as the primary outcome variable. METHODS: Twenty-four patients with mild-to-moderate asthma were studied using a randomized crossover design with the following three treatment blocks: (1) beclomethasone, 100 microg/d, alone for the first 2 weeks followed by 400 microg/d alone for the next 2 weeks; (2) beclomethasone, 100 microg/d, followed by 400 microg/d, with the addition of zafirlukast, 20 mg bid; (3) beclomethasone, 100 microg/d, followed by 400 microg/d, with the addition of theophylline, 200 to 300 mg bid. Measurements were made after 2 and 4 weeks of each treatment and at pretreatment baseline. RESULTS: The mean trough plasma theophylline concentration was 6.7 mg/L, coinciding with the anti-inflammatory target range (ie, 5 to 10 mg/L). The provocative dose of methacholine causing a 20% fall in FEV(1) (as doubling dose difference from baseline) was significantly (p < 0.05) greater with beclomethasone, 100 microg, plus zafirlukast (1.1 doubling dose) but not with beclomethasone, 100 microg, plus theophylline (0.7 doubling dose) compared to beclomethasone, 100 microg alone (0.4 doubling dose), but not compared to beclomethasone, 400 microg alone (1.1 doubling dose). There were also significant (p < 0.05) differences between beclomethasone, 100 microg, plus zafirlukast (but not BDP, 100 microg, plus theophylline) vs beclomethasone, 100 microg, alone in terms of nitric oxide level, midexpiratory phase of forced expiratory flow, and peak expiratory flow. There were no further significant improvements observed with the addition of zafirlukast or theophylline to beclomethasone, 400 microg. CONCLUSIONS: A leukotriene receptor antagonist, but not low-dose theophylline, conferred significant additive anti-inflammatory effects to therapy with a low-dose inhaled corticosteroid but not to that with a medium dose of an inhaled corticosteroid. Thus, optimizing the dose of inhaled corticosteroid as monotherapy would seem to be the logical first step, which is in keeping with current guidelines.     

Increasing homogeneity in global food supplies and the implications for food security

The narrowing of diversity in crop species contributing to the world’s food supplies has been considered a potential threat to food security. However, changes in this diversity have not been quantified globally. We assess trends over the past 50 y in the richness, abundance, and composition of crop species in national food supplies worldwide. Over this period, national per capita food supplies expanded in total quantities of food calories, protein, fat, and weight, with increased proportions of those quantities sourcing from energy-dense foods. At the same time the number of measured crop commodities contributing to national food supplies increased, the relative contribution of these commodities within these supplies became more even, and the dominance of the most significant commodities decreased. As a consequence, national food supplies worldwide became more similar in composition, correlated particularly with an increased supply of a number of globally important cereal and oil crops, and a decline of other cereal, oil, and starchy root species. The increase in homogeneity worldwide portends the establishment of a global standard food supply, which is relatively species-rich in regard to measured crops at the national level, but species-poor globally. These changes in food supplies heighten interdependence among countries in regard to availability and access to these food sources and the genetic resources supporting their production, and give further urgency to nutrition development priorities aimed at bolstering food security.A shared axiom of ecology and nutrition is that, within certain ranges, diversity enhances the health and function of complex biological systems. Species diversity has been shown to stimulate productivity, stability, ecosystem services, and resilience in natural (1–5) and in agricultural ecosystems (6–13). Likewise, variation in food species contributing to diet has been associated with nutritional adequacy (14–17) and food security (18).The development of sedentary agricultural societies and further rise of modern agriculture is generally considered to have led to a decline in the total number of plant species upon which humans depend for food (19, 20), particularly the wild, semidomesticated, and cultivated vegetables and fruits, spices, and other food plants that supplemented staple crops with the provision of micronutrients and that bolstered food security historically during crop failures (21). Harlan (20) warned that

most of the food for mankind comes from a small number of crops and the total number is decreasing steadily. In the United States in the past 40 years, many vegetables and fruits have disappeared from the diet, and the trend is going on all over the world. More and more people will be fed by fewer and fewer crops.

More recent analyses of dietary transition in developing countries in association with globalization have noted increases in the diversity of plants contributing to diets locally, along with a Westernization transition in preference of energy-dense foods (i.e., animal products, plant oils, and sugars) over cereals, pulses, and vegetables, and of particular major crop plants within these food categories over traditional crops (22, 23). The impact of such changes on overall crop diversity worldwide has not been comprehensively documented, although recent changes in varietal and allelic level diversity of some crops have been investigated (24–26). Given the potential food security implications of narrowing of the diversity of crop species both in production systems and in food supplies, an assessment of the global state of crop plant species diversity is warranted.Here we examine changes in the diversity of the portfolio of crop species upon which humans primarily depend for food security in regard to calories, protein, fat, and food weight. Using national per capita food supply data published by the Food and Agriculture Organization (FAO) of the United Nations, we analyzed trends in the richness, abundance, and composition of measured crop commodities in the food supplies of 152 countries comprising 98% of the world’s population from 1961 to 2009.     

Transvaginal mesh,gender and the ethics of clinical innovation

On 10 October 2018, Australian Health Minister Greg Hunt issued a national apology to the Australian women who experienced ‘horrific outcomes’ following surgery using transvaginal mesh—acknowledging the ‘historic agony and pain that has come from mesh implantation’. This apology followed many decades of ‘innovative’ use of transvaginal mesh for the treatment of pelvic organ prolapse. We use the case of transvaginal mesh to explore how clinical innovation may not only harm patients, but also entrench vulnerability and exacerbate existing inequities—in this case, those relating to gender.     

A major new alliance in Australian healthcare: the Australian consensus framework for ethical collaboration in the healthcare sector

The 'Australian Consensus Framework for Ethical Collaboration in the Healthcare Sector' (ACF) is an Australian initiative aimed at countering dysfunction and growing mistrust in the health sector through the development of a cross‐sectoral consensus framework. The development of this framework arose from Australia's involvement in the Asia Pacific Economic Cooperative (APEC) and has since become the largest of its kind internationally, with over 70 signatories representing professional bodies, industry organisations, hospital and health services associations, regulators and patient and advocacy groups. In this article, we describe and critique the framework and outline its implementation.     

Reduced release probability prevents vesicle depletion and transmission failure at dynamin mutant synapses

Endocytic recycling of synaptic vesicles after exocytosis is critical for nervous system function. At synapses of cultured neurons that lack the two "neuronal" dynamins, dynamin 1 and 3, smaller excitatory postsynaptic currents are observed due to an impairment of the fission reaction of endocytosis that results in an accumulation of arrested clathrin-coated pits and a greatly reduced synaptic vesicle number. Surprisingly, despite a smaller readily releasable vesicle pool and fewer docked vesicles, a strong facilitation, which correlated with lower vesicle release probability, was observed upon action potential stimulation at such synapses. Furthermore, although network activity in mutant cultures was lower, Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) activity was unexpectedly increased, consistent with the previous report of an enhanced state of synapsin 1 phosphorylation at CaMKII-dependent sites in such neurons. These changes were partially reversed by overnight silencing of synaptic activity with tetrodotoxin, a treatment that allows progression of arrested endocytic pits to synaptic vesicles. Facilitation was also counteracted by CaMKII inhibition. These findings reveal a mechanism aimed at preventing synaptic transmission failure due to vesicle depletion when recycling vesicle traffic is backed up by a defect in dynamin-dependent endocytosis and provide new insight into the coupling between endocytosis and exocytosis.     

Phosphatidylethanol (PEth) as a biomarker of alcohol consumption in HIV-positive patients in sub-Saharan Africa

Background: Alcohol is heavily consumed in sub‐Saharan Africa and affects HIV transmission and treatment and is difficult to measure. Our goal was to examine the test characteristics of a direct metabolite of alcohol consumption, phosphatidylethanol (PEth). Methods: Persons infected with HIV were recruited from a large HIV clinic in southwestern Uganda. We conducted surveys and breath alcohol concentration (BRAC) testing at 21 daily home or drinking establishment visits, and blood was collected on day 21 (n = 77). PEth in whole blood was compared with prior 7‐, 14‐, and 21‐day alcohol consumption. Results: (i) The receiver operator characteristic area under the curve (ROC‐AUC) was highest for PEth versus any consumption over the prior 21 days (0.92; 95% confidence interval [CI]: 0.86 to 0.97). The sensitivity for any detectable PEth was 88.0% (95% CI: 76.0 to 95.6) and the specificity was 88.5% (95% CI: 69.8 to 97.6). (ii) The ROC‐AUC of PEth versus any 21‐day alcohol consumption did not vary with age, body mass index, CD4 cell count, hepatitis B virus infection, and antiretroviral therapy status, but was higher for men compared with women (p = 0.03). (iii) PEth measurements were correlated with several measures of alcohol consumption, including number of drinking days in the prior 21 days (Spearman r = 0.74, p < 0.001) and BRAC (r = 0.75, p < 0.001). Conclusions: The data add support to the body of evidence for PEth as a useful marker of alcohol consumption with high ROC‐AUC, sensitivity, and specificity. Future studies should further address the period and level of alcohol consumption for which PEth is detectable.