Evaluation of Compounded Transdermal Analgesic Formulations Using the Franz Finite Dose Model.

To evaluate the transdermal delivery of six analgesic drugs (i.e., ketamine, gabapentin, clonidine, lidocaine, ketoprofen, and amitriptyline) that were compounded into three commercially available bases, Salt Stable LS Base, Transdermal Pain Base, and Lipoderm ActiveMax Base, the Franz finite dose model was used for an in vitro penetration study using porcine skin over 48 hours. Rapid penetration with a steady-state flux after the first 24 hours was detected in all the formulations. The present study demonstrates the successful delivery of six compounded analgesic drugs, using all of the noted bases. A high flux rate within 1 hour to 4 hours of application would correlate to effective pain relief, and the prolonged delivery over the first 24 hours would reduce the need for frequent reapplication. This can aid in pain management with the potential for enhanced pain control.

Estrogen receptor beta in astrocytes modulates cognitive function in mid-age female mice.

Menopause is associated with cognitive deficits and brain atrophy, but the brain region and cell-specific mechanisms are not fully understood. Here, we identify a sex hormone by age interaction whereby loss of ovarian hormones in female mice at midlife, but not young age, induced hippocampal-dependent cognitive impairment, dorsal hippocampal atrophy, and astrocyte and microglia activation with synaptic loss. Selective deletion of estrogen receptor beta (ERß) in astrocytes, but not neurons, in gonadally intact female mice induced the same brain effects. RNA sequencing and pathway analyses of gene expression in hippocampal astrocytes from midlife female astrocyte-ERß conditional knock out (cKO) mice revealed Gluconeogenesis I and Glycolysis I as the most differentially expressed pathways. Enolase 1 gene expression was increased in hippocampi from both astrocyte-ERß cKO female mice at midlife and from postmenopausal women. Gain of function studies showed that ERß ligand treatment of midlife female mice reversed dorsal hippocampal neuropathology.

Neuroprotection in Cerebral Cortex Induced by the Pregnancy Hormone Estriol.

In multiple sclerosis (MS), demyelination occurs in the cerebral cortex, and cerebral cortex atrophy correlates with clinical disabilities. Treatments are needed in MS to induce remyelination. Pregnancy is protective in MS. Estriol is made by the fetoplacental unit, and maternal serum estriol levels temporally align with fetal myelination. Here, we determined the effect of estriol treatment on the cerebral cortex in the preclinical model of MS, experimental autoimmune encephalomyelitis (EAE). Estriol treatment initiated after disease onset decreased cerebral cortex atrophy. Neuropathology of the cerebral cortex showed increased cholesterol synthesis proteins in oligodendrocytes, more newly formed remyelinating oligodendrocytes, and increased myelin in estriol-treated EAE mice. Estriol treatment also decreased the loss of cortical layer V pyramidal neurons and their apical dendrites and preserved synapses. Together, estriol treatment after EAE onset reduced atrophy and was neuroprotective in the cerebral cortex.

Overexpression of VIPR2 in mice results in microencephaly with paradoxical increased white matter volume.

Large scale studies in populations of European and Han Chinese ancestry found a series of rare gain-of-function microduplications in VIPR2, encoding VPAC2, a receptor that binds vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide with high affinity, that were associated with an up to 13-fold increased risk for schizophrenia. To address how VPAC2 receptor overactivity might affect brain development, we used a well-characterized Nestin-Cre mouse strain and a knock-in approach to overexpress human VPAC2 in the central nervous system. Mice that overexpressed VPAC2 were found to exhibit a significant reduction in brain weight. Magnetic resonance imaging analysis confirmed a decrease in brain size, a specific reduction in the hippocampus grey matter volume and a paradoxical increase in whole-brain white matter volume. Sex-specific changes in behavior such as impaired prepulse inhibition and contextual fear memory were observed in VPAC2 overexpressing mice. The data indicate that the VPAC2 receptor may play a critical role in brain morphogenesis and suggest that overactive VPAC2 signaling during development plays a mechanistic role in some forms of schizophrenia.

A Cross-Species Neuroimaging Study of Sex Chromosome Dosage Effects on Human and Mouse Brain Anatomy.

All eutherian mammals show chromosomal sex determination with contrasting sex chromosome dosages (SCDs) between males (XY) and females (XX). Studies in transgenic mice and humans with sex chromosome trisomy (SCT) have revealed direct SCD effects on regional mammalian brain anatomy, but we lack a formal test for cross-species conservation of these effects. Here, we develop a harmonized framework for comparative structural neuroimaging and apply this to systematically profile SCD effects on regional brain anatomy in both humans and mice by contrasting groups with SCT (XXY and XYY) versus XY controls. Total brain size was substantially altered by SCT in humans (significantly decreased by XXY and increased by XYY), but not in mice. Robust and spatially convergent effects of XXY and XYY on regional brain volume were observed in humans, but not mice, when controlling for global volume differences. However, mice do show subtle effects of XXY and XYY on regional volume, although there is not a general spatial convergence in these effects within mice or between species. Notwithstanding this general lack of conservation in SCT effects, we detect several brain regions that show overlapping effects of XXY and XYY both within and between species (cerebellar, parietal, and orbitofrontal cortex), thereby nominating high priority targets for future translational dissection of SCD effects on the mammalian brain. Our study introduces a generalizable framework for comparative neuroimaging in humans and mice and applies this to achieve a cross-species comparison of SCD effects on the mammalian brain through the lens of SCT.SIGNIFICANCE STATEMENT Sex chromosome dosage (SCD) affects neuroanatomy and risk for psychopathology in humans. Performing mechanistic studies in the human brain is challenging but possible in mouse models. Here, we develop a framework for cross-species neuroimaging analysis and use this to show that an added X- or Y-chromosome significantly alters human brain anatomy but has muted effects in the mouse brain. However, we do find evidence for conserved cross-species impact of an added chromosome in the fronto-parietal cortices and cerebellum, which point to regions for future mechanistic dissection of sex chromosome dosage effects on brain development.

Chronic experimental autoimmune encephalomyelitis is an excellent model to study neuroaxonal degeneration in multiple sclerosis.

Animal models of multiple sclerosis (MS), specifically experimental autoimmune encephalomyelitis (EAE), have been used extensively to develop anti-inflammatory treatments. However, the similarity between MS and one particular EAE model does not end at inflammation. MS and chronic EAE induced in C57BL/6 mice using myelin oligodendrocyte glycoprotein (MOG) peptide 35-55 share many neuropathologies. Beyond both having white matter lesions in spinal cord, both also have widespread neuropathology in the cerebral cortex, hippocampus, thalamus, striatum, cerebellum, and retina/optic nerve. In this review, we compare neuropathologies in each of these structures in MS with chronic EAE in C57BL/6 mice, and find evidence that this EAE model is well suited to study neuroaxonal degeneration in MS.

Decreased neurofilament light chain levels in estriol-treated multiple sclerosis.

Estrogens have neuroprotective actions depending on estrogen type, dose, and timing in both preclinical models and in women during health and disease. Serum neurofilament light chain is a putative biomarker of neurodegeneration in multiple sclerosis, aging, and other neurodegenerative diseases. Here, oral treatment with an estrogen unique to pregnancy (estriol) using an 8 mg dose to induce a mid-pregnancy blood estriol level reduced serum neurofilament light chain in nonpregnant MS women at mean age of 37 years. This is consistent with estriol-mediated protection from neuro-axonal injury and supports the use of serum neurofilament light chain as a biomarker in MS.

Targeted deletion of PAC1 receptors in retinal neurons enhances neuron loss and axonopathy in a model of multiple sclerosis and optic neuritis.

Chronic inflammation drives synaptic loss in multiple sclerosis (MS) and is also commonly observed in other neurodegenerative diseases. Clinically approved treatments for MS provide symptomatic relief but fail to halt neurodegeneration and neurological decline. Studies in animal disease models have demonstrated that the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP, ADCYAP1) exhibits anti-inflammatory, neuroprotective and regenerative properties. Anti-inflammatory actions appear to be mediated primarily by two receptors, VPAC1 and VPAC2, which also bind vasoactive intestinal peptide (VIP). Pharmacological experiments indicate that another receptor, PAC1 (ADCYAP1R1), which is highly selective for PACAP, provides protection to neurons, although genetic evidence and other mechanistic information is lacking. To determine if PAC1 receptors protect neurons in a cell-autonomous manner, we used adeno-associated virus (AAV2) to deliver Cre recombinase to the retina of mice harboring floxed PAC1 alleles. Mice were then subjected to chronic experimental autoimmune encephalomyelitis (EAE), a disease model that recapitulates major clinical and pathological features of MS and associated optic neuritis. Unexpectedly, deletion of PAC1 in naïve mice resulted in a deficit of retinal ganglionic neurons (RGNs) and their dendrites, suggesting a homeostatic role of PAC1. Moreover, deletion of PAC1 resulted in increased EAE-induced loss of a subpopulation of RGNs purported to be vulnerable in animal models of glaucoma. Increased axonal pathology and increased secondary presence of microglia/macrophages was also prominently seen in the optic nerve. These findings demonstrate that neuronal PAC1 receptors play a homeostatic role in protecting RGNs and directly protects neurons and their axons against neuroinflammatory challenge. SIGNIFICANCE STATEMENT: Chronic inflammation is a major component of neurodegenerative diseases and plays a central role in multiple sclerosis (MS). Current treatments for MS do not prevent neurodegeneration and/or neurological decline. The neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) has been shown to have anti-inflammatory, neuroprotective and regenerative properties but the cell type- and receptor-specific mechanisms are not clear. To test whether the protective effects of PACAP are direct on the PAC1 receptor subtype on neurons, we delete PAC1 receptors from neurons and investigate neuropathologigical changes in an animal model of MS. The findings demonstrate that PAC1 receptors on neurons play a homeostatic role in maintaining neuron health and can directly protect neurons and their axons during neuroinflammatory disease.

Social Media for the Hepato-Pancreato-Biliary community (#SoMe4HPB): connecting a specialized online group for scientific and clinical knowledge dissemination.

BACKGROUND: Social media has an increasingly important role in scientific communication, clinical discussions and knowledge distribution. While several surgical disciplines have taken to internet for increased connectivity, there is currently little knowledge about the social media activity in the field of hepatopancreatobiliary surgery. We aimed to evaluate the implementation and use of a specific HPB hashtag and Twitter handle. METHODS: The hashtag and Twitter handle (#SoMe4HPB; @hpb_so) were initiated on February 2019. We evaluated the response during the initial 15 months by applying NodeXL to trace activity. RESULTS: The Twitter handle had 1388 followers (by May 7, 2020) and had generated 855 tweets and retweets. A total of 1120 mentions of 182 accounts were recorded in original tweets by @hpb_so. The largest global reach was recorded in December 2019 (254.000 people). Pancreatic cancer was the subject of 15% of all posts, liver malignancies of 12% of all posts and minimally invasive surgery of 8%. CONCLUSION: The Social Media for the Hepato-Pancreato-Biliary community (#SoMe4HPB) and its associated Twitter handle @hpb_so had a well-built inception followed by a progressive development connecting individuals interested in HPB Surgery internationally. The involvement of more actors is required in order to fully attain its scientific dissemination role.

Patient-Reported Outcome Measures in Colorectal Surgery: Construction of Core Measures Using Open-Source Research Method.

Purpose. The primary aim of the study was to review the existing literature about patient-reported outcome measures (PROMs) in colorectal cancer and IBD. The secondary aim was to present a road map to develop a core outcome set via opinion gathering using social media. Method. This study is the first step of a three-step project aimed at constructing simple, applicable PROMs in colorectal surgery. This article was written in a collaborative manner with authors invited both through Twitter via the #OpenSourceResearch hashtag. The 5 most used PROMs were presented and discussed as slides/images on Twitter. Inputs from a wide spectrum of participants including researchers, surgeons, physicians, nurses, patients, and patients' organizations were collected and analyzed. The final draft was emailed to all contributors and 6 patients' representatives for proofreading and approval. Results. Five PROM sets were identified and discussed: EORTC QLQ-CR29, IBDQ short health questionnaire, EORTC QLQ-C30, ED-Q5-5L, and Short Form-36. There were 315 tweets posted by 50 tweeters with 1458 retweets. Awareness about PROMs was generally limited. The general psycho-physical well-being score (GPP) was suggested and discussed, and then a survey was conducted in which more than 2/3 of voters agreed that GPP covers the most important aspects in PROMs. Conclusion. Despite the limitations of this exploratory study, it offered a new method to conduct clinical research with opportunity to engage patients. The general psycho-physical well-being score suggested as simple, applicable PROMs to be eventually combined procedure-specific, disease-specific, or symptom-specific PROMs if needed.

Enhancing engagement beyond the conference walls: analysis of Twitter use at #ICPIC2019 infection prevention and control conference.

BACKGROUND: Social media may provide a tool, when coupled with a patient-included™ conference, to enhance the engagement among the general public. We describe authors and potential readers of Twitter content surrounding a patient-included™ scientific congress, the International Consortium for Prevention and Infection Control (ICPIC) 2019. METHODS: Retrospective observational analysis of Twitter users posting with the #ICPIC2019 hashtag during the conference. Tweet authors, overall followers, and active followers were categorized according to their Twitter biographies using unsupervised learning. Diversity of professional backgrounds of Tweet authors and their followers was explored. Network analysis explored connectedness between the reach of authors. RESULTS: In total, 1264 participants attended ICPIC 2019, of which 28 were patients. From September 7 to 16, 2019, we were able to categorize 235'620 (41%) followers linked to 474 (76%) authors. Among authors and followers, respectively 34% and 14% were healthcare workers, 11% and 15% were from industry representatives, 8% and 7% were academic researchers. On average, 23% (range 9-39%) followers belonged to the same categories as authors. Among all followers categorized, only 582/235 620 (0.25%) interacted with original messages, including healthcare workers (37%), global and public health (12%), academic research (11%) and those from industry (11%). Though the similarity between Tweet authors and followers was supported by network analysis, we also observed that non-healthcare workers (including patients) appeared to have more diverse followers. CONCLUSIONS: We observed the participation of numerous Tweet authors and followers from diverse professional backgrounds potentially supporting the benefit of including patients in conferences to reach a more general, non-specialized public.

Twitter Analytics to Inform Provisional Guidance for COVID-19 Challenges in the Meatpacking Industry.

The COVID-19 pandemic raised considerable challenges to obtain reliable guidance to help occupational health practitioners, workers, and stakeholders building up efficient prevention strategies at the workplace, between the constant increase of publications in the domain, the time required to run high-quality research and systematic reviews, and the urgent need to identify areas for prevention at the workplace. Social Media and Twitter, in particular, have already been used in research and constitute a useful source of information to identify community needs and topics of interest for prevention in the meatpacking industry. In this commentary, we introduce the methods and tools we used to screen relevant posts on Twitter. Twitter analytics is a way to capture real-time concerns of the community and help ensure compliance with the notion of social accountability. As such research has limitations in terms of exhaustiveness and level of evidence, it should be considered as provisional guidance to direct both actions at the workplace and further conventional research projects.

Sex differences in brain atrophy in multiple sclerosis.

BACKGROUND: Women are more susceptible to multiple sclerosis (MS) than men by a ratio of approximately 3:1. However, being male is a risk factor for worse disability progression. Inflammatory genes have been linked to susceptibility, while neurodegeneration underlies disability progression. Thus, there appears to be a differential effect of sex on inflammation versus neurodegeneration. Further, gray matter (GM) atrophy is not uniform across the brain in MS, but instead shows regional variation. Here, we study sex differences in neurodegeneration by comparing regional GM atrophy in a cohort of men and women with MS versus their respective age- and sex-matched healthy controls. METHODS: Voxel-based morphometry (VBM), deep GM substructure volumetry, and cortical thinning were used to examine regional GM atrophy. RESULTS: VBM analysis showed deep GM atrophy in the thalamic area in both men and women with MS, whereas men had additional atrophy in the putamen as well as in localized cortical regions. Volumetry confirmed deep GM loss, while localized cortical thinning confirmed GM loss in the cerebral cortex. Further, MS males exhibited worse performance on the 9-hole peg test (9HPT) than MS females. We observed a strong correlation between thalamic volume and 9HPT performance in MS males, but not in MS females. CONCLUSION: More regional GM atrophy was observed in men with MS than women with MS, consistent with previous observations that male sex is a risk factor for worse disease progression.

ACC.20: Impact of social media at the virtual scientific sessions during the COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic led to the American College of Cardiology (ACC) Annual Scientific Session 2020 (ACC.20) being held as a virtual event. HYPOTHESIS: Social media activity around a virtual event might be quite different to that of a physical meeting. The goal of this study was to assess impact of ACC.20 through Twitter and compare it to ACC.19. METHODS: Data were extracted using NodeXL, with analysis in Excel. RESULTS: ACC.20-related tweeting was demonstrated globally. However tweeting and participants fell substantially for ACC.20. Tweeting, participation and tweet views were overestimated by the most widely used social media analysis tool used at medical conferences (Symplur). CONCLUSION: Comparing the 2019 and 2020 Scientific Sessions, the global cardiology community continued to communicate despite COVID-19, but with reduced social media activity potentially due to the briefer format, no physical interaction and private virtual chatroom during live sessions, reducing visibility of new cardiology research findings.

Beyond the hashtag - An exploration of tweeting and replies at the European Society of Surgical Oncology 39th clinical conference (ESSO39).

INTRODUCTION: Previous studies of conference tweeting have focused on tweets that used the conference hashtag. The aim of this study was to document responses beyond a specific conference hashtag. METHODS: Observational study exploring replies to tweets for the 39th meeting of ESSO (ESSO39), Rotterdam, 9-11 October 2019. An extract of #ESSO39 tweets was obtained using NodeXL. Replies to these tweets were identified by viewing the tweets via Twitter.com. RESULTS: There were 210 tweets posted using the #ESSO39 hashtag by 64 tweeters. However, extending the analysis to include responses that did not use the hashtag, tweets using the hashtag only represent 54% of all tweets posted or quoted at the conference, and only 49% of the tweeters posting content or quoted in tweets. Based on this study of ESSO39 therefore roughly half of tweets and contributors to conference tweeting were not captured by focusing simply on the conference hashtag (#ESSO39). Mentioning another tweeter(s) in a tweet or response was associated with more retweets, as was including the hashtag in replies. CONCLUSIONS: Twitter activity at medical conferences extends beyond the conference hashtag. Almost half of the tweeting was beyond the hashtag. To increase visibility of tweets, conference delegates should include the conference hashtag and mention other tweeters in their tweets and responses. Searching for tweets is an active process requiring users to click into replies. Twitter and third-party social media tools should improve identification and display of responses, showing the branching structure of replies and quoting tweets in real time.

European Society for Medical Oncology (ESMO) 2018 Congress Twitter analysis: from ethics to results through the understanding of communication and interaction flows.

BACKGROUND: Twitter is a microblogging service providing a platform for social networking. For medical information, Twitter is an interesting channel for sharing and spreading information and as an engagement platform for different stakeholders. Benefits and caveats of uncontrolled medical information must be carefully pondered, considering the possible intended and unintended adverse outcomes of uncontrolled influencing. The aim of this study was to describe the non-commercial content shared on Twitter and to analyse the level of influence of commercial tweeters during the European Society of Medical Oncology (ESMO) 2018 annual meeting held in Munich. DESIGN/METHODOLOGY: A retrospective analysis of the tweets shared in the period 19-23 October 2018 indexed with the hashtag #ESMO18 or #ESMO2018 was performed; methodology of systematic reviews was mirrored. Commercial tweeters (pharmaceutical and biotechnology companies, device manufacturers and spam tweeters) were excluded from the primary analysis, and only non-commercial tweets from and about the congress were included. Tweets were analysed using a network analytical tool (NodeXL). RESULTS: A total of 7100 tweets posted by 1334 tweeters were identified for the period of interest. Less than 10% of tweeters were identified as commercial, posting 15.7% of tweets and receiving almost one-quarter of retweets. However, pharmaceutical and biotech tweeters were substantially less likely to be mentioned by other tweeters. All of the top 10 retweeters of non-commercial content were clinicians and/or professional organisations, in stark contrast with the commercial content. CONCLUSIONS: The use of social networks in medical meetings, including oncology, is increasing for real-time communication and informed opinion-making. The uncontrolled spread of information on Twitter can both stimulate discussions on non-official and non-canonical channels of communication and provide uncontrolled influencing of diverse stakeholders. The disclosure of financial declarations of interest on Twitter could enhance the transparency of the information, as is already happening in medical journals.

Social Media Analytics: What You Need to Know as a Urologist.

In this digital era there has been increasing use of social media in the field of urology. Although we can often feel the impact of social media in our daily encounters, we need more quantifiable measures to evaluate and monitor social media activities. By gathering and analyzing data from different social media platforms, we will be able to understand how we can engage our audience more successfully in the dissemination of urological information. In this mini-review we discuss the fundamentals of social media analytics with a special focus on social media metrics and social network analysis. We also discuss the implications of social media analytics with the aim of fostering a better understanding of this important aspect of social media. PATIENT SUMMARY: By gathering and analyzing data from social media platforms, we will be able to understand how we can engage our audience more successfully in the dissemination of urological information.

Understanding the Composition of a Successful Tweet in Urology.

BACKGROUND: Little is known about the key composition of a successful tweet in urology. OBJECTIVE: To investigate for predictors of engagement with urology content on Twitter. DESIGN, SETTING, AND PARTICIPANTS: This was a cross-sectional study based on 2-wk Twitter data surrounding a major international urology conference. INTERVENTION: We examined the engagement for all original tweets containing the hashtags for the European Association of Urology conference ("#EAU19" and/or "#EAU2019"). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Study outcomes included engagement with tweets, as measured by the number of "likes" and "retweets." Tweet- and Twitter user-related parameters of each individual tweet were recorded. Multiple linear regression analyses were performed to investigate for predictors of likes and retweets. RESULTS AND LIMITATIONS: From March 9 to 22, 2019, there were a total of 37 222 tweets. Among them, 3534 were "original tweets" that had 31 889 likes and 10 031 retweets. On multivariable analysis, the word count, number of mentions, and presence of a photo were predictors of likes and retweets. An increasing number of hashtags were associated with fewer likes. The number of "followings" and "followers" of the contributor, and their time since joining Twitter did not have any associations with the number of likes or retweets. The major limitation of the study is the lack of assessment about the quality of the tweet content. CONCLUSIONS: Based on the Twitter data from a urology conference, we concluded that the word count, number of mentions, and presence of a photo within the tweet were associated with audience engagement. PATIENT SUMMARY: We could engage the audience more successfully by increasing the number of words and mentions, and including a photo within a tweet. The results formulated the basic principles in creating successful tweets for sharing urological knowledge.

Axonal damage in spinal cord is associated with gray matter atrophy in sensorimotor cortex in experimental autoimmune encephalomyelitis.

BACKGROUND: Gray matter (GM) atrophy in brain is one of the best predictors of long-term disability in multiple sclerosis (MS), and recent findings have revealed that localized GM atrophy is associated with clinical disabilities. GM atrophy associated with each disability mapped to a distinct brain region, revealing a disability-specific atlas (DSA) of GM loss. OBJECTIVE: To uncover the mechanisms underlying the development of localized GM atrophy. METHODS: We used voxel-based morphometry (VBM) to evaluate localized GM atrophy and Clear Lipid-exchanged Acrylamide-hybridized Rigid Imaging-compatible Tissue-hYdrogel (CLARITY) to evaluate specific pathologies in mice with experimental autoimmune encephalomyelitis (EAE). RESULTS: We observed extensive GM atrophy throughout the cerebral cortex, with additional foci in the thalamus and caudoputamen, in mice with EAE compared to normal controls. Next, we generated pathology-specific atlases (PSAs), voxelwise mappings of the correlation between specific pathologies and localized GM atrophy. Interestingly, axonal damage (end-bulbs and ovoids) in the spinal cord strongly correlated with GM atrophy in the sensorimotor cortex of the brain. CONCLUSION: The combination of VBM with CLARITY in EAE can localize GM atrophy in brain that is associated with a specific pathology in spinal cord, revealing a PSA of GM loss.