Open Pharma recommendations for plain language summaries of peer-reviewed medical journal publications.

Plain language summaries of peer-reviewed medical journal publications are a means of sharing research with a broad range of audiences and may improve the transparency, accountability, accessibility, discoverability, and inclusivity of medical research. There is currently an ongoing, industry-wide effort to establish consensus on plain language summaries, and initiatives are already in place that provide detailed guidance on plain language best practice, co-creation methods, patient-focused content, graphic and digital considerations, and publisher-specific guidelines. However, there remains a need for a foundational set of recommendations that complement existing initiatives to outline the minimum steps needed to develop discoverable, plain language summaries that are trustworthy, credible, and of high quality. Here, we present the Open Pharma recommendations for plain language summaries of peer-reviewed medical journal publications. These recommendations were initially developed by the Open Pharma Accessibility workstream and were extensively reviewed and refined during an expert roundtable and a focused, public consultation. Open Pharma is a multi-sponsor collaboration of pharmaceutical companies, non-pharmaceutical funders, publishers, patients, academics, regulators, editors, and societies seeking to identify and drive positive changes in the publishing of pharmaceutical company-funded research. We recommend that plain language summaries should be in the style of an abstract, free of technical jargon, unbiased, non-promotional, peer reviewed, and easily accessed. Plain language summaries should also meet the technical requirements to be indexed in directories such as PubMed. Ultimately, these recommendations are intended to be a concise outline of a minimum standard that provides top-line guidance on plain language summaries for authors, medical writers, publishers, and research funders.

PLAIN LANGUAGE SUMMARYArticles published in peer-reviewed medical journals are written using technical language. Plain language summaries are short summaries of these articles, written in everyday language that is easy to understand by anyone interested in medical research. This can include patients, patient advocates, caregivers, healthcare professionals, and policymakers. Sharing research through plain language summaries makes medical information more accessible and inclusive. However, few medical research articles include plain language summaries. The pharmaceutical industry has an opportunity to improve everyone's understanding of medical research by regularly developing plain language summaries of their articles. Plain language summaries can come in many different formats such as infographics and videos. However, text-only summaries are the easiest to find on internet search engines and research websites such as PubMed. Currently, there is limited guidance available to help researchers and medical journal publishers develop plain language summaries for their articles. In this article, 'Open Pharma recommendations for plain language summaries of peer-reviewed medical journal publications', we suggest a set of simple rules to help authors make and share text-only plain language summaries that we believe are possible for all articles reporting medical research. Once these have been met, we encourage researchers to consider making and sharing infographics and video summaries as well, to help people to understand their research even more.

Neuro-immune Interactions Drive Tissue Programming in Intestinal Macrophages.

Proper adaptation to environmental perturbations is essential for tissue homeostasis. In the intestine, diverse environmental cues can be sensed by immune cells, which must balance resistance to microorganisms with tolerance, avoiding excess tissue damage. By applying imaging and transcriptional profiling tools, we interrogated how distinct microenvironments in the gut regulate resident macrophages. We discovered that macrophages exhibit a high degree of gene-expression specialization dependent on their proximity to the gut lumen. Lamina propria macrophages (LpMs) preferentially expressed a pro-inflammatory phenotype when compared to muscularis macrophages (MMs), which displayed a tissue-protective phenotype. Upon luminal bacterial infection, MMs further enhanced tissue-protective programs, and this was attributed to swift activation of extrinsic sympathetic neurons innervating the gut muscularis and norepinephrine signaling to ß2 adrenergic receptors on MMs. Our results reveal unique intra-tissue macrophage specialization and identify neuro-immune communication between enteric neurons and macrophages that induces rapid tissue-protective responses to distal perturbations.

Chloride-led disruption of the intestinal mucous layer impedes Salmonella invasion: evidence for an 'enteric tear' mechanism.

METHODS: The intestinal epithelial layer can switch from a net absorptive state to one of net secretion in the presence of luminal toxins and pathogens. This suggests an innate defence role for regulated secretion of mucus, electrolytes and water. We hypothesised that chloride-led fluid secretion across the mucus-covered intestinal epithelium alters barrier properties by influencing the overlying mucous-gel layer. RESULTS: We demonstrated that chloride-led disruption of the epithelial-associated mucus-gel covering HT29-MTX-E12 (E12) human colonic epithelial monolayers, a goblet-cell like line derived from parental HT29 cells, resulted in reduction of associated mucus as well as a reduction in mucous-gel density and barrier properties. Changes in epithelial secretory state were accompanied by increased water transport, and the resulting loss of gel integrity reduced Salmonella typhimurium invasion of epithelia in both E12 monolayers and of isolated rat ileal mucosae. However, neither chloride secretion nor mucus disruption altered numbers of adhering bacteria. CONCLUSION: These data suggest a role for chloride led fluid secretion in the shedding of the adherent mucous-gel layer, possibly as a rate-limiting innate defence mechanism, and offer evidence for "enteric tears" in intestinal host defence.

Cracking the junction: update on the progress of gastrointestinal absorption enhancement in the delivery of poorly absorbed drugs.

There are many challenges to the oral delivery of peptide-based drugs. In addition to overcoming issues relating to the metabolic stability of peptides and maximizing adherence and penetration through the mucus layer, new formulations to enhance absorption across the intestinal epithelium are required for effective delivery. The tight junctions between epithelial cells usually permit the flux of small hydrophilic drugs, while restricting the movement of larger hydrophilic drugs. Efforts to reversibly open tight junctions with paracellular permeability enhancers (PPE) have been shown to promote the absorption of larger molecules, including protein therapeutics. This review describes the proteins that comprise the tight junction and outlines various methods that have been explored to enhance class III solute absorption across this barrier, with particular attention to efforts to enhance oral peptide delivery. In particular, peptide-based PPEs are highlighted. Being proteins themselves, they potentially share physicochemical properties, diffusional characteristics, and stability issues with the therapeutic proteins being delivered. By understanding the mechanisms by which these PPEs act, analogues and peptidomimetics can be designed in order to safely enhance the delivery of biotech cargoes via the oral route.

Increased intestinal permeability in rats subjected to traumatic frontal lobe percussion brain injury.

BACKGROUND: Dysfunction of the gastrointestinal tract is a common occurrence after traumatic brain injury (TBI). We hypothesized that increased intestinal permeability may result from a precisely controlled percussion injury to the exposed brains of anesthetized rats and that such an effect could be assessed in vitro using excised intestinal mucosae mounted in Ussing chambers. METHODS: After craniotomy over the left medial prefrontal cortex on anesthetized rats, neurotrauma was produced using a pneumatically driven impactor on the exposed brain. Control rats were subjected to identical procedures but did not receive an impact. Muscle-stripped rat intestinal ileal and colonic segments were mounted in Ussing chambers within 30 minutes of death. Transepithelial electrical resistance (TEER) and the apparent permeability coefficient (Papp) of [C]-mannitol were recorded from intestinal tissue for 120 minutes. Histopathologic analysis was also performed to determine any gross morphologic changes in the intestine. RESULTS: Ileal and colonic mucosae showed no differences in TEER in ileum or colon of TBI rats compared with controls. The Papp of mannitol was significantly increased in ilea from rats previously exposed to TBI compared with controls. Histologic analysis showed gross changes to 50% of the ileal but not the colonic sections from TBI rats. CONCLUSION: TBI results in significantly reduced ileal barrier function, most likely mediated by open tight junctions. For patients with acute head injury, this may have implications for subsequent oral absorption of nutrients. Systemic delivery of luminal endotoxins may contribute to multiple organ failure.

Myosin light chain kinase inhibition: correction of increased intestinal epithelial permeability in vitro.

PURPOSE: To examine whether myosin light chain kinase (MLCK) inhibitors can reduce intestinal epithelial permeability increases in vitro. MATERIALS AND METHODS: Isolated rat, mouse and human colonic tissue mucosae and Caco-2 monolayers were exposed to cytochalasin D (cD) and sodium caprate (C10), in the absence and presence of the MLCK inhibitors, ML-9 and D PIK. Transepithelial electrical resistance (TEER) and Papp of [14C]-mannitol or FITC-dextran 4000 (FD-4) were measured. Western blots were used to measure MLC phosphorylation. RESULTS: Increases in Papp of [14C]-mannitol and decreases in TEER were induced by tight junction openers. These changes were attenuated by ML-9. D-PIK offset the FD-4 Papp increase induced by C10 in Caco-2 only, while ML-9 and PIK inhibited MLC directly, cD induced constriction of peri-junctional actin in Caco-2 monolayers, but this was prevented by ML-9. Although mannitol fluxes across colonic mucosae from dextran-sulphate (DSS)-treated mice were higher than control, they were not ameliorated by either ML-9 or PIK in vitro. CONCLUSIONS: ML-9 inhibits paracellular permeability increases in several intestinal epithelial models. D-PIK reduced stimulated paracellular fluxes in Caco-2 monolayers, but not in tissue. Pre-established increases were not modified by two MLCK inhibitors in a mouse model of IBD.

Effects of Lactobacillus salivarius 433118 on intestinal inflammation, immunity status and in vitro colon function in two mouse models of inflammatory bowel disease.

The probiotic, Lactobacillus salivarius subsp. salivarius 433118 (UCC118), was investigated for its potential to attenuate colitis, modulate immune responses and alter intestinal barrier dysfunction in two different mouse models of inflammatory bowel disease (IBD). Following oral treatment with UCC118, faecal microbial analysis indicated that viable intact bacteria reached the colons of interleukin (IL)-10(-/-) mice and dextran sodium sulphate (DSS)-treated mice. Neither prophylactic nor therapeutic UCC118 treatment significantly prevented or attenuated inflammation in either model. In all studies, the probiotic-treated mice had comparable cytokine responses as vehicle-treated animals. Mannitol permeability was increased across colonic mucosae mounted in Ussing chambers from DSS-treated mice, but not in IL-10(-/-) mice. However, colonic mucosae from UCC118-treated mice had unchanged transepithelial electrical resistance (TEER) values and mannitol fluxes compared to controls. In two different mouse colitis models examined under a range of histological and functional criteria, the data therefore suggest that this Lactobacillus subsp. has limited potential as a prophylactic or therapeutic treatment for inflammatory bowel disease. While several studies have shown therapeutic activity for this probiotic in mouse models of IBD, our data suggest that there are inter-study variables in formulation, study design, animal models and assessment criteria that may impact on interpretation of probiotic efficacy.

Melittin as a permeability enhancer II: in vitro investigations in human mucus secreting intestinal monolayers and rat colonic mucosae.

PURPOSE: Melittin has shown potential as a non-cytotoxic absorption enhancer in Caco-2 monolayers. Our objectives were to assess in vitro efficacy and cytotoxicity of melittin in two intestinal permeability models and investigate the potential mechanism by which melittin might enhance gastrointestinal absorption. MATERIALS AND METHODS: The effects of melittin were examined in the mucus-secreting intestinal cell monolayers, HT29-MTX-E12 (E12), using transepithelial electrical resistance (TER), transmission electron microscopy (TEM) and the MTT viability assay. The effects of melittin on TER, permeability and short circuit current (Isc) were also investigated in rat colon mucosae mounted in Ussing chambers. Ion transporting capacity of tissue was measured in response to secretagogues as surrogate markers of cytotoxicity. Melittin stability was examined by a means of a hemolytic assay. The mechanism by which melittin decreases TER across the rat mucosa was examined with a range of enzymatic inhibitors. RESULTS: Apical addition of melittin resulted in a reversible non-cytotoxic concentration-dependent decrease in TER across E12 monolayers, which was independent of the presence of mucus. Apical addition of melittin reduced TER and increased the permeability of [(14)C]-mannitol across rat colonic mucosae. The melittin-induced drop in TER in rat colon was significantly attenuated by W7 suggesting partial mediation by calmodulin. CONCLUSIONS: The rapid and reversible nature of melittin's permeation enhancing properties and its limited cytotoxicity in polarized intestinal epithelia, suggests a potential drug delivery role for the peptide in oral formulations of poorly absorbed drugs.

Melittin as an epithelial permeability enhancer I: investigation of its mechanism of action in Caco-2 monolayers.

PURPOSE: Melittin is an amphipathic antimicrobial peptide which has been shown to enhance the permeability of mannitol and reduce transepithelial electrical resistance (TER) across Caco-2 monolayers. The aim of this work was to further examine the potential of melittin as a paracellular permeability enhancer and to investigate the mechanism of interaction with tight junction proteins in Caco-2. MATERIALS AND METHODS: The permeability of a range of fluorescent markers of differing molecular weights across monolayers was examined and immunofluorescence and western blotting analysis of tight junction proteins were also carried out. The mechanism of TER reduction was also examined using cell signalling inhibitors. RESULTS: Apical but not basolateral addition of melittin increased the permeability of a range FITC-dextrans (4-70 kDa) across monolayers. Melittin effects were reversible and no cytotoxicity was evident in polarized Caco-2 epithelia at the concentrations used. Altered expression of ZO-1, E-cadherin and F-actin was also detected. The phospholipase A2 inhibitors, aristolochic acid and indomethacin and the cyclooxygenase inhibitor, piroxicam, partially attenuated melittin-induced TER reduction, suggesting that part of the mechanism by which melittin opens tight junctions involves prostaglandin signalling. CONCLUSIONS: Apically-added melittin opens tight junctions, causing dramatic TER reductions with significant increases in flux of dextrans. These effects appear mediated in part via PLA2 and involve alterations in specific tight junction proteins.