The development of a method for the global health community to assess the proportion of food and beverage companies’ sales that are derived from unhealthy foods

Abstract Context Corporate engagement with food and beverage companies who produce food associated with health harms is a divisive topic in the global nutrition community, with high-profile cases of conflict of interest increasingly coming under scrutiny. There is a need for an agreed method to support health organizations in deciding whether and how to engage with large food and beverage manufacturers. Aim The aim of this study was to develop a method to quantify the proportion of sales from food and beverage companies that are derived from unhealthy foods to support organizations in determining which companies might be considered high-risk for engagement. Methods The 2015 WHO Euro nutrient profile model was applied to 35,550 products from 1294 brands manufactured by the top 20 global food and beverage companies from seven countries (Australia, Brazil, China, India, South Africa, UK and USA). For the purpose of this study, products that met the WHO Euro criteria were classified as “healthier” and those that failed were classified as “unhealthy”. Products were grouped by brand and weighted by the brand’s value sales for 2020. The primary outcome was the proportion of each company’s sales that were classified as unhealthy and healthier by company and category. Results Overall, 89% of the top 20 companies’ brand sales were classified as unhealthy. For every USD$10 spent on the top 20 companies’ brands, only$1.10 was spent on products considered healthier. All companies saw the majority of their sales come from unhealthy foods, including soft drinks, confectionery and snacks. None of Red Bull or Ferrero’s sales were classified as healthier and less than 5% of total sales were healthier for Mondelēz, Mars, and PepsiCo. Some companies had higher proportions of sales deriving from healthier products, including Grupo Bimbo (48%), Danone (34%) and Conagra (32%), although the majority of their sales were still derived from unhealthy foods. Discussion The results presented in this study highlight the reliance the leading food and beverage companies have on sales of unhealthy products that are contributing to diet-related disease globally. The method and steps we have laid out here could be used by organizations in the global health community to identify companies that have conflicts of interest when it comes to engaging with governments, international organizations and public health bodies on issues of policy and regulation

Pain and itch processing in aged mice

Most reports agree that aging negatively impacts pain processing and that the prevalence of chronic pain increases significantly with age. To improve current therapies, it is critical that aged animals be included in preclinical studies. Here we compared sensitivities to pain and itch-provoking stimuli in naïve and injured young and aged mice. Surprisingly, we found that in the absence of injury, aged male and female mice are significantly less responsive to mechanical stimuli and, in females, also to noxious thermal (heat) stimuli. In both older male and female mice, compared to younger (6 month-old mice), we also recorded reduced pruritogen-evoked scratching. On the other hand, after nerve injury, aged mice nevertheless developed significant mechanical hypersensitivity. Interestingly, however, and in contrast to young mice, aged mice developed both ipsilateral and contralateral post-injury mechanical allodynia. In a parallel immunohistochemical analysis of microglial and astrocyte markers, we found that the ipsilateral to contralateral ratio of nerve injury-induced expression decreased with age. That observation is consistent with our finding of contralateral hypersensitivity after nerve injury in the aged, but not the young mice. We conclude that aging has opposite effects on baseline vs post injury pain and itch processing. PERSPECTIVE: Aged male and female mice (22-24 months) are less sensitive to mechanical, thermal (heat) and itch-provoking stimuli than are younger mice (6 months)

Contribution of dorsal horn CGRP-expressing interneurons to mechanical sensitivity.

Primary sensory neurons are generally considered the only source of dorsal horn calcitonin gene-related peptide (CGRP), a neuropeptide critical to the transmission of pain messages. Using a tamoxifen-inducible CalcaCreER transgenic mouse, here we identified a distinct population of CGRP-expressing excitatory interneurons in lamina III of the spinal cord dorsal horn and trigeminal nucleus caudalis. These interneurons have spine-laden, dorsally directed, dendrites, and ventrally directed axons. As under resting conditions, CGRP interneurons are under tonic inhibitory control, neither innocuous nor noxious stimulation provoked significant Fos expression in these neurons. However, synchronous, electrical non-nociceptive Aβ primary afferent stimulation of dorsal roots depolarized the CGRP interneurons, consistent with their receipt of a VGLUT1 innervation. On the other hand, chemogenetic activation of the neurons produced a mechanical hypersensitivity in response to von Frey stimulation, whereas their caspase-mediated ablation led to mechanical hyposensitivity. Finally, after partial peripheral nerve injury, innocuous stimulation (brush) induced significant Fos expression in the CGRP interneurons. These findings suggest that CGRP interneurons become hyperexcitable and contribute either to ascending circuits originating in deep dorsal horn or to the reflex circuits in baseline conditions, but not in the setting of nerve injury

Contribution of dorsal horn CGRP-expressing interneurons to mechanical sensitivity

Primary sensory neurons are generally considered the only source of dorsal horn calcitonin gene-related peptide (CGRP), a neuropeptide critical to the transmission of pain messages. Using a tamoxifen-inducible CalcaCreER transgenic mouse, here we identified a distinct population of CGRP-expressing excitatory interneurons in lamina III of the spinal cord dorsal horn and trigeminal nucleus caudalis. These interneurons have spine-laden, dorsally directed, dendrites, and ventrally directed axons. As under resting conditions, CGRP interneurons are under tonic inhibitory control, neither innocuous nor noxious stimulation provoked significant Fos expression in these neurons. However, synchronous, electrical non-nociceptive Aβ primary afferent stimulation of dorsal roots depolarized the CGRP interneurons, consistent with their receipt of a VGLUT1 innervation. On the other hand, chemogenetic activation of the neurons produced a mechanical hypersensitivity in response to von Frey stimulation, whereas their caspase-mediated ablation led to mechanical hyposensitivity. Finally, after partial peripheral nerve injury, innocuous stimulation (brush) induced significant Fos expression in the CGRP interneurons. These findings suggest that CGRP interneurons become hyperexcitable and contribute either to ascending circuits originating in deep dorsal horn or to the reflex circuits in baseline conditions, but not in the setting of nerve injury

Docking for EP4R antagonists active against inflammatory pain.

The lipid prostaglandin E2 (PGE2) mediates inflammatory pain by activating G protein-coupled receptors, including the prostaglandin E2 receptor 4 (EP4R). Nonsteroidal anti-inflammatory drugs (NSAIDs) reduce nociception by inhibiting prostaglandin synthesis, however, the disruption of upstream prostanoid biosynthesis can lead to pleiotropic effects including gastrointestinal bleeding and cardiac complications. In contrast, by acting downstream, EP4R antagonists may act specifically as anti-inflammatory agents and, to date, no selective EP4R antagonists have been approved for human use. In this work, seeking to diversify EP4R antagonist scaffolds, we computationally dock over 400 million compounds against an EP4R crystal structure and experimentally validate 71 highly ranked, de novo synthesized molecules. Further, we show how structure-based optimization of initial docking hits identifies a potent and selective antagonist with 16 nanomolar potency. Finally, we demonstrate favorable pharmacokinetics for the discovered compound as well as anti-allodynic and anti-inflammatory activity in several preclinical pain models in mice