Inappropriate Responses Research Articles

Duration of delayed diagnosis in HIV/AIDS patients in Iran: a CD4 depletion model analysis

Delayed diagnosis of HIV can lead to an inappropriate response to antiretroviral therapy (ART), rapid progression of the disease, and death. It can also carry harmful effects on public health due to the increment of transmission. This study aimed to estimate the duration of delayed diagnosis (DDD) in HIV patients in Iran. This hybrid cross-sectional cohort study was conducted on the national HIV surveillance system database (HSSD). Linear mixed effect models with random intercept, random slope, and both were used to estimate the parameters required for the CD4 depletion model to determine the best-fitted model for DDD, stratified by the route of transmission, gender, and age group. The DDD was estimated in 11,373 patients including 4,762 (41.87%) injection drug users (IDUs), 512 (4.5%) men who had sexual contact with men (MSM), 3,762 (33.08%) patients with heterosexual contacts, and 2,337 (20.55%) patients who were infected through other routes of HIV transmission. The total mean DDD was 8.41 ± 5.97 years. The mean DDD was 7.24 ± 0.08 and 9.43 ± 6.83 years in male and female IDUs, respectively. In the heterosexual contact group, DDD was obtained as 8.60 ± 6.43 years in male patients and 9.49 ± 7.17 years in female patients. It was also estimated as 9.37 ± 7.30 years in the MSM group. Furthermore, patients infected through other transmission routes were found with a DDD of 7.90 ± 6.74 years for male patients and a DDD of 7.87 ± 5.87 years for female patients. A simple CD4 depletion model analysis is represented, which incorporates a pre-estimation step to determine the best-fitted linear mixed model for calculating the parameters required for the CD4 depletion model. Considering such a noticeably high HIV diagnostic delay, especially in older adults, MSM, and heterosexual contact groups, regular periodic screening is required to reduce the DDD.

Inflation phobia, myths and dogma exacerbate policy responses*

This article offers an alternative narrative on contemporary inflation and policy responses to it. It argues policy responses to inflation have been driven by unfounded beliefs underlying current inflation myths and phobia. These are rooted in neoliberal ideology and dogma, especially influential since the neo-classical counter-revolution against Keynesian macroeconomics. They prevent better understanding of the nature and causes of inflation, leading to inappropriate policy responses exacerbating the situation. Misdiagnoses, policy confusion and anti-labour bias are exposed before offering an alternative narrative and concluding remarks.

Canthin-6-Ones: Potential Drugs for Chronic Inflammatory Diseases by Targeting Multiple Inflammatory Mediators.

Chronic inflammatory disease (CID) is a category of medical conditions that causes recurrent inflammatory attacks in multiple tissues. The occurrence of CID is related to inappropriate immune responses to normal tissue substances and invading microbes due to many factors, such as defects in the immune system and imbalanced regulation of commensal microbes. Thus, effectively keeping the immune-associated cells and their products in check and inhibiting aberrant activation of the immune system is a key strategy for the management of CID. Canthin-6-ones are a subclass of β-carboline alkaloids isolated from a wide range of species. Several emerging studies based on in vitro and in vivo experiments reveal that canthin-6-ones may have potential therapeutic effects on many inflammatory diseases. However, no study has yet summarized the anti-inflammatory functions and the underlying mechanisms of this class of compounds. This review provides an overview of these studies, focusing on the disease entities and the inflammatory mediators that have been shown to be affected by canthin-6-ones. In particular, the major signaling pathways affected by canthin-6-ones, such as the NLR family pyrin domain containing 3 (NLRP3) inflammasome and the NF-κB signaling pathway, and their roles in several CIDs are discussed. Moreover, we discuss the limitations in studies of canthin-6-ones and provide possible solutions. In addition, a perspective that may suggest possible future research directions is provided. This work may be helpful for further mechanistic studies and possible therapeutic applications of canthin-6-ones in the treatment of CID.

Cellular and molecular effects of non-ionizing electromagnetic fields.

The way that living cells respond to non-ionizing electromagnetic fields (EMF), including static/extremely-low frequency and radiofrequency electromagnetic fields, fits the pattern of 'cellular stress response'- a mechanism manifest at the cellular level intended to preserve the entire organism. It is a set pattern of cellular and molecular responses to environmental stressors, such as heat, ionizing radiation, oxidation, etc. It is triggered by cellular macromolecular damage (in proteins, lipids, and DNA) with the goal of repairing and returning cell functions to homeostasis. The pattern is independent of the type of stressor encountered. It involves cell cycle arrest, induction of specific molecular mechanisms for repair, damage removal, cell proliferation, and cell death if damage is too great. This response could be triggered by EMF-induced alternation in oxidative processes in cells. The concept that biological response to EMF is a 'cellular stress response' explains many observed effects of EMF, such as nonlinear dose- and time-dependency, increased and decreased risks of cancer and neurodegenerative diseases, enhanced nerve regeneration, and bone healing. These responses could be either detrimental or beneficial to health, depending on the duration and intensity of the exposure, as well as specific aspects ofthe living organism being exposed. A corollary to electromagnetic hypersensitivity syndrome (EHS) could be an inappropriate response of the hippocampus/limbic system to EMF, involving glucocorticoids on the hypothalamic-pituitary-adrenal axis.

Aldehyde Dehydrogenase 2 Ameliorates LPS-Induced Acute Kidney Injury through Detoxification of 4-HNE and Suppression of the MAPK Pathway.

Lipopolysaccharide (LPS)-induced septic acute kidney injury (AKI) is determined as a devastating organ dysfunction elicited by an inappropriate response to infection with high morbidity and mortality rates. Previous evidence has illustrated an indispensable role of mitochondrial aldehyde dehydrogenase 2 (ALDH2) in the pathogenesis of sepsis-induced multiorgan abnormalities. Specifically, this study investigated the potential role of ALDH2 in sepsis-induced AKI. After LPS administration, we observed a significant decline in renal function, increased inflammatory cytokines, oxidative stress, 4-hydroxy-2-nonenal (4-HNE) accumulation, and apoptosis via MAPK activation in ALDH2-/- mice; in contrast, pretreatment with Alda-1 (an ALDH2 activator) alleviated the LPS-induced dysfunctions in mice. Moreover, in vitro analysis revealed that ALDH2 overexpression in mouse tubular epithelial cells (mTECs) improved the inflammatory response, oxidative stress, 4-HNE accumulation, and apoptosis via MAPK inhibition, whereas ALDH2 knockdown in mTECs aggravated these parameters via MAPK activation. Therefore, ALDH2 may protect against LPS-induced septic AKI by suppressing 4-HNE/MAPK pathway.

Macrophage metabolic profile is altered by hydroxyapatite particle size.

Since the recent observation that immune cells undergo metabolic reprogramming upon activation, there has been immense research in this area to not only understand the basis of such changes, but also to exploit metabolic rewiring for therapeutic benefit. In a resting state, macrophages preferentially utilise oxidative phosphorylation to generate energy; however, in the presence of immune cell activators, glycolytic genes are upregulated, and energy is generated through glycolysis. This facilitates the rapid production of biosynthetic intermediates and a pro-inflammatory macrophage phenotype. While this is essential to mount responses to infectious agents, more evidence is accumulating linking dysregulated metabolism to inappropriate immune responses. Given that certain biomaterials are known to promote an inflammatory macrophage phenotype, this prompted us to investigate if biomaterial particulates can impact on macrophage metabolism. Using micron and nano sized hydroxyapatite (HA), we demonstrate for the first time that these biomaterials can indeed drive changes in metabolism, and that this occurs in a size-dependent manner. We show that micronHA, but not nanoHA, particles upregulate surrogate markets of glycolysis including the glucose transporter (GLUT1), hexokinase 2 (HK2), GAPDH, and PKM2. Furthermore, we demonstrate that micronHA alters mitochondrial morphology and promotes a bioenergetic shift to favour glycolysis. Finally, we demonstrate that glycolytic gene expression is dependent on particle uptake and that targeting glycolysis attenuates the pro-inflammatory profile of micronHA-treated macrophages. These results not only further our understanding of biomaterial-based macrophage activation, but also implicate immunometabolism as a new area for consideration in intelligent biomaterial design and therapeutic targeting. STATEMENT OF SIGNIFICANCE: Several recent studies have reported that immune cell activation occurs concurrently with metabolic reprogramming. Furthermore, metabolic reprogramming of innate immune cells plays a prominent role in determining cellular phenotype and function. In this study we demonstrate that hydroxyapatite particle size alters macrophage metabolism, in turn driving their functional phenotype. Specifically, the pro-inflammatory phenotype promoted by micron-sized HA-particles is accompanied by changes in mitochondrial dynamics and a bioenergetic shift favouring glycolysis. This effect is not seen with nano-HA particles and can be attenuated upon inhibition of glycolysis. This study therefore not only identifies immunometabolism as a useful tool for characterising the immune response to biomaterials, but also highlights immunometabolism as a targetable aspect of the host response for therapeutic benefit.

The Phaedo as an Alternative to Tragedy

This article argues that the Phaedo is written as a new sort of story of how a hero faces death. The opening of the Phaedo makes clear that two features that Plato closely associates with tragedy, pity and lamentation, are inappropriate responses to Socrates’ impending death, and that tuchē (chance) did not affect his happiness. This is the first step in the dialogue’s sustained engagement with tragedy. For Plato, tragedy falls under the category of stories about heroes and gods. Plato wrote the Phaedo so that we would see Socrates as a philosophical hero, a replacement for traditional heroes such as Theseus or Heracles. In fact, I argue that the Phaedo meets every requirement in Republic Books 2–3 for how to tell stories about heroes and gods and so belongs to the same broad category as tragedy. Within this framework, it tells the story of how a true hero saved his companions through philosophy.

Novelty and learning in cognitive control: evidence from the Simon task

While information that is associated with inappropriate responses can interfere with an ongoing task and be detrimental to performance, cognitive control mechanisms and specific contextual conditions can alleviate interference from unwanted information. In the spatial correspondence (Simon) task, interference has been consistently shown to be reduced by spatial non-correspondence in the previous trial (i.e., correspondence sequence effect, CSE); however the mechanisms supporting this sequential effect are not well understood. Here we investigated the role of novelty and trial-to-trial changes in stimulus and response features in a Simon task, observing similar modulation of CSE for novel and non-novel stimulus changes. However, changing the response modality from trial to trial dampened CSE, and this dampening was more pronounced when the probability of switch trials was higher, suggesting a role for long-term learning. The results are consistent with recent accounts, which indicate that spatial interference can be prevented by cognitive control mechanisms triggered by learned bindings.

Is "small quantity lipid nutrition supplement" (SQ-LNS) a sustainable and pragmatic strategy to prevent malnutrition?

Young child malnutrition and food insecurity is the result of many factors including social and economic inequities, disempowerment of women, inadequate support for breastfeeding, degraded environments, poor sanitation, unsafe water, violence and conflict. In this complex context, humanitarian agencies have a responsibility to guard against unintended consequences and ensure that the promotion of “quick fix” interventions do no harm. One such intervention is the Small Quantity Lipid Nutrition Supplement (SQ-LNS), that UNICEF is recommending for introduction into national nutrition programs to reduce mortality. The authors believe this recommendation is based on questionable evidence. They point to a fundamental flaw that trials compared “an intervention (SQ-LNS)” with “no comparable food-based intervention.” In effect, a pre-determined outcome. Also present is a conflict of interest, with support and intellectual input coming from interested food companies. Many other concerns are listed: SQ-LNS is an ultra-processed food (UPF), as defined by Nova Classification; daily feeding to children with poor diets will not improve dietary diversity and may undermine confidence in more culturally appropriate and nutritious family foods; the double burden of malnutrition and the emerging pandemic of overnutrition; the environmental impact of packaging and most importantly the clear potential for commercial exploitation. The widespread use of SQ-LNS in the face of food poverty is viewed as an unsustainable, unsafe and nutritionally inappropriate response. UN and humanitarian agencies should use their considerable diplomatic influence to challenge corporate-led food systems and support governments in their efforts to protect, promote and support breastfeeding and the provision of diverse complementary foods.

Impaired inhibition after delta-9-tetrahydrocannabinol in women not related to circulating estradiol levels

Cannabis and its main psychoactive constituent, delta-9-tetrahydrocannabinol (THC), impair cognitive processes, including the ability to inhibit inappropriate responses. However, responses to cannabinoid drugs vary widely, and little is known about the factors that influence the risk for adverse effects. One potential source of variation in response to cannabinoids in women is circulating ovarian hormones such as estradiol and progesterone. Whereas there is some evidence that estradiol affects responses to cannabinoids in rodents, little is known about such interactions in humans. Here, we investigate whether variations in estradiol levels across the follicular phase of the menstrual cycle modulate the effect of THC on inhibitory control in healthy women. Healthy female occasional cannabis users (N = 60) received THC (7.5 mg and 15 mg, oral) and placebo during either the early follicular phase, when estradiol levels are low, or the late follicular phase, when estradiol levels are higher. They completed a Go/No Go (GNG) task at the time of peak drug effect. We hypothesized that the effects of THC on GNG performance would be greater when estradiol levels were elevated. As expected, THC impaired GNG task performance: it increased response time and errors of commission/false alarms and decreased accuracy, relative to placebo. However, these impairments were not related to estradiol levels. These results suggest that THC-induced impairments in inhibitory control are not affected by cycle-related fluctuations in estradiol levels.

Progression of age-related periodontitis: Literature review

Background: Periodontitis is currently defined as a multifactorial chronic inflammatory disease associated with deregulation of the biofilm with the susceptible host, which can lead to damage the periodontal tissue due to an inappropriate immune response, characterized by a neutrophilic inflammation with subsequent destruction of proteolytic connective tissue. Nowadays, there are arguments that associate the progression of this disease in elderly people, for this reason the objective of this article is to carry out a literature review that links the progression of periodontitis associated with age, in addition to determining if at an older age there is higher prevalence of periodontitis. Methodology: A systematic bibliographic search was carried out in 5 scientific databases: PubMed, Cochrane, Scielo, Science Direct, EBSCO of 45 articles published in English and Spanish in the last 5 years (2018-2022). Results: Evidence suggests that elderly patients (60 years and older) are more likely to develop periodontitis due to a deficient immune response that keep them off from having a correct inflammatory response to various factors, there is also postulated a prolonged exposure to the etiological factor. Conclusions: Evidence reports that older patients have a higher prevalence of periodontitis because aging decreases immune response, which is responsible for protecting the body against different factors. Finally, as patient’s age, nutritional status is altered thereby the digestive process and nutrient absorption from food, which interact with other well-defined risk factors to increase susceptibility to periodontal disease.

Optimal Frequency-Response Corrections for Eddy Covariance Flux Measurements Using the Wiener Deconvolution Method

We describe a new direct correction approach to accurately restore frequency attenuated eddy covariance (EC) measurements. The new approach utilizes the Wiener deconvolution method to optimally estimate the original signal from noisy atmospheric measurements. Key features over conventional EC spectral correction methods include (i) the use of physics-based response functions, (ii) the ability to account for the non-linear phase contributions, and (iii) the direct restoration of the original signal rather than simulating the effect on an ideal reference spectrum. The new correction approach is compared to conventional spectral correction methods in a numerical simulation where the magnitude of the key limitations of conventional methods is explored under conditions relevant to common EC set-ups. The simulation results showed that the spectral correction methods commonly used for calculating EC fluxes introduced systematic error up to 10% to the restored fluxes and substantially increased their random uncertainty. The errors are attributed to the effect of using inappropriate response functions, failing to account for the contribution of the non-linear phase, and due to the assumption of spectral similarity on the scale of averaging intervals. The Wiener deconvolution method is versatile, can be applied under non-ideal conditions, and provides an opportunity to unify analytical and “in-situ” spectral correction methods by applying existing transfer functions to directly restore attenuated spectra. Furthermore, the Wiener deconvolution approach is adaptable for use with various micrometeorological measurement techniques such as eddy accumulation and flux profile measurements.

Loyalty program benefits and their effect on relationship quality and loyalty to the retailer

Loyalty Programs (LPs) aim to increase profit by rewarding, with various benefits, customers who patronize the retailer. This study investigated the benefits LPs provide in the South African Fast-moving consumer goods (FMCG) marketplace and how these influence relationship quality and loyalty between retailer and customer. How the perceived benefits of LPs contribute to relationship quality (satisfaction, trust and commitment), and how they lead to loyalty are examined. To illustrate these relationships, a model showing three independent (perceived benefits, namely altruistic, consumeristic, and egoistic) and three dependent variables (relationship quality, namely trust, satisfaction, and commitment), plus customer loyalty, was developed. A quantitative survey was administered electronically over 11 days to a randomly selected sample of 5000 consumers per day from a commercial database, resulting in 1944 responses. After the deletion of incomplete or inappropriate responses, 479 usable replies remained. Since this sample was self-selected, it should be considered a convenience sample. Structural equation modelling (SEM) with confirmatory factor analysis (CFA) was applied to test the hypotheses and develop the model. SEM indicated that respondents consider egoistic and consumeristic benefits as the same. Furthermore, trust and satisfaction manifest as a single construct. Both consumeristic and altruistic benefits had a significant positive relationship with this unified construct of trust/satisfaction, and the relationship between altruistic benefits and commitment was also positive and significant. Finally, although neither altruistic nor consumeristic benefits appeared to contribute directly to loyalty, a positive relationship existed between the new construct of trust/satisfaction and those of commitment and loyalty. The pathway to loyalty is indirect, and to reach this sought-after goal, relationship quality constructs must first be achieved.

THE ROLE OF DIETARY SUPPLEMENTS IN INFLAMMATORY BOWEL DISEASE: A SYSTEMATIC REVIEW

Recurrent episodes of gastrointestinal inflammation induced by an inappropriate immune response to gut bacteria characterize inflammatory bowel disease (IBD). The phrase "inflammatory bowel disease" refers to two distinct forms of idiopathic intestinal disease distinguished by their location and degree of gut wall involvement. Although Crohn disease is substantially more common in women than in men, ulcerative colitis appears to be equally common in both sexes. IBD is often frequent in affluent countries and cooler regions. It occurs when an excessively powerful immune response is generated in response to a normal stimulus, such as food or intestinal flora, in individuals who are genetically predisposed to developing the disorder. Diet significantly influences intestinal inflammation. Unbalanced meals can result in dysbiosis, which impairs the immune system of the host. The Mediterranean Diet is renowned for being anti-inflammatory and dysbiosis-preventing. Probiotics, butyrate, phosphatidylcholine, lactoferrin, palmitoylethanolamide, silymarin, and omega 3 should be introduced to the diet of the patient in order to stabilize the intestinal microbial population and reinforce the mucosal barrier, hence preventing or alleviating IBD symptoms. Intestinal inflammation is usually associated with vitamin D levels and gut flora. Constant study has demonstrated their link, therefore the prescription of probiotics and vitamin D is beneficial for IBD patients.

Street-connectedness through a COVID-19 lens: Exploring media representations of street-connected children to understand their societal positionality

The 2017 general comment (GC21) to the United Nations Convention on the Rights of the Child (UNCRC) on children in street situations, provides a framework of legal guidance for governments developing policies aimed at protecting street-connected children and sets up the rationale for more awareness raising and public education to counter negative and deficit attitudes towards street-connectedness. Within this framework, the media has a role to play in either challenging conceptualisations of street-connected children as out-of-place within the public and predominantly adult domain described by urban streets, or in reinforcing ideological constructions of citizenship and normalised notions of childhood that result in negative stereotypes of these children. GC21 recommends that interventions targeted at street-connected children should be ethically responsible – adopting child rights approaches aimed at using accurate data/evidence that upholds the dignity of children, their personal integrity, and their right to life. As such, these approaches should also extend to how organisations engage with and utilise the media to represent street-connected children. Focusing on media representations of street-connected children during the six pandemic-affected months of February to July 2020, this paper provides a review of the content of the sources to provide an insight into the structural barriers that face street-connected children because of how they are positioned in society, during the pandemic and in general, and the extent to which the media reinforces or counters the rescue or removal narratives that can lead to inappropriate intervention responses.

Investigation of Effective Drugs in the Treatment of Patients with COVID-19

Background: Due to the lack of definitive treatments for corona disease and the use of various medications in protocols around the world, it is necessary to conduct more epidemiological studies exploring the effect of different available therapeutic regimes; therefore, the present study aimed to explore the current effective drugs for the treatment of hospitalized COVID-19 patients.
 Methods: The present study is a descriptive-analytical study that was conducted between August and September of 2021 at Khalkhal University of Medical Sciences. A convenient sampling method was employed to retrieve the data from the available hospital records, including 252 documents from COVID-19 hospitalized patients. A researcher-made checklist was used to record the data. Data were analyzed using SPSS 26 software.
 Results: The findings showed that Hypertension and Hypotension (n=47,18.7%) are the most common underlying diseases in the study sample. The most therapeutic regimen was the combination of Remdesivir and Dexametason (n=137,54.4%) in hospitalized COVID-19 patients. There are a variety of organ involvements and presentations to the COVID-19; however, most patients experience a mild-to-moderate, self-limited disease; even though, the disease could progress to more fatal cases and lead to death.
 Conclusion: The main pathology exists in the lungs which are caused by an inappropriate immune response that leads to a severe inflammatory response. Therefore, antiviral and anti-inflammatory drugs are currently the first-line therapy for hospitalized patients.

A short history from Karelia study to biodiversity and public health interventions.

Contact with natural environments enriches the human microbiome, promotes immune balance and protects against allergies and inflammatory disorders. In Finland, the allergy & asthma epidemic became slowly visible in mid 1960s. After the World War II, Karelia was split into Finnish and Soviet Union (now Russia) territories. This led to more marked environmental and lifestyle changes in the Finnish compared with Russian Karelia. The Karelia Allergy Study 2002-2022 showed that allergic conditions were much more common on the Finnish side. The Russians had richer gene-microbe network and interaction than the Finns, which associated with better balanced immune regulatory circuits and lower allergy prevalence. In the Finnish adolescents, a biodiverse natural environment around the homes associated with lower occurrence of allergies. Overall, the plausible explanation of the allergy disparity was the prominent change in environment and lifestyle in the Finnish Karelia from 1940s to 1980s. The nationwide Finnish Allergy Programme 2008-2018 implemented the biodiversity hypothesis into practice by endorsing immune tolerance, nature contacts, and allergy health with favorable results. A regional health and environment programme, Nature Step to Health 2022-2032, has been initiated in the City of Lahti, EU Green Capital 2021. The programme integrates prevention of chronic diseases (asthma, diabetes, obesity, depression), nature loss, and climate crisis in the spirit of Planetary Health. Allergic diseases exemplify inappropriate immunological responses to natural environment. Successful management of the epidemics of allergy and other non-communicable diseases may pave the way to improve human and environmental health.

Endogenous Inflammatory Mediators Produced by Injury Activate TRPV1 and TRPA1 Nociceptors to Induce Sexually Dimorphic Cold Pain That Is Dependent on TRPM8 and GFRα3.

The detection of environmental temperatures is critical for survival, yet inappropriate responses to thermal stimuli can have a negative impact on overall health. The physiological effect of cold is distinct among somatosensory modalities in that it is soothing and analgesic, but also agonizing in the context of tissue damage. Inflammatory mediators produced during injury activate nociceptors to release neuropeptides, such as calcitonin gene-related peptide (CGRP) and substance P, inducing neurogenic inflammation, which further exasperates pain. Many inflammatory mediators induce sensitization to heat and mechanical stimuli but, conversely, inhibit cold responsiveness, and the identity of molecules inducing cold pain peripherally is enigmatic, as are the cellular and molecular mechanisms altering cold sensitivity. Here, we asked whether inflammatory mediators that induce neurogenic inflammation via the nociceptive ion channels TRPV1 (vanilloid subfamily of transient receptor potential channel) and TRPA1 (transient receptor potential ankyrin 1) lead to cold pain in mice. Specifically, we tested cold sensitivity in mice after intraplantar injection of lysophosphatidic acid or 4-hydroxy-2-nonenal, finding that each induces cold pain that is dependent on the cold-gated channel transient receptor potential melastatin 8 (TRPM8). Inhibition of CGRP, substance P, or toll-like receptor 4 (TLR4) signaling attenuates this phenotype, and each neuropeptide produces TRPM8-dependent cold pain directly. Further, the inhibition of CGRP or TLR4 signaling alleviates cold allodynia differentially by sex. Last, cold pain induced by both inflammatory mediators and neuropeptides requires TRPM8, as well as the neurotrophin artemin and its receptor GDNF receptor α3 (GFRα3). These results are consistent with artemin-induced cold allodynia requiring TRPM8, demonstrating that neurogenic inflammation alters cold sensitivity via localized artemin release that induces cold pain via GFRα3 and TRPM8.SIGNIFICANCE STATEMENT The cellular and molecular mechanisms that generate pain are complex with a diverse array of pain-producing molecules generated during injury that act to sensitize peripheral sensory neurons, thereby inducing pain. Here we identify a specific neuroinflammatory pathway involving the ion channel TRPM8 (transient receptor potential cation channel subfamily M member 8) and the neurotrophin receptor GFRα3 (GDNF receptor α3) that leads to cold pain, providing select targets for potential therapies for this pain modality.

A274 THE EFFECT OF DIETARY MODULATION ON FUNGAL AND VIRAL COMMUNITIES IN THE GASTROINTESTINAL TRACT: A LITERATURE REVIEW

Abstract Background The human gut microbiome is a complex, dynamic community that has been shown to impact gastrointestinal (GI) diseases, including inflammatory bowel disease (IBD). Particularly, changes in diet quality and composition can influence the composition and function of the gut microbiome, leading to an inappropriate response to inflammation, increasing risk for IBD flare. Currently, our understanding of diet modulation largely revolves around changes in bacterial composition and diversity, despite our knowledge of neighbouring eukaryotes, viruses, and archaea within the GI tract. This literature review serves to bolster our understanding of diet modulation on viral and fungal communities, in an effort to support non-pharmacological therapies in IBD. Purpose To assess current literature investigating the effect of diet modulation on the gut microbiota, with interest in viral and fungal communities. Method We performed a MEDLINE and EMBASE literature review with the following search terms: "microbiome / microbiota / microbe" and "fungi / fungal" or "virus / viral / virome" and "diet composition" or "high fiber/re diet" or "diet therapy" or "diet." Exclusion criteria: - Abstracts - Articles not in English - Expert Review articles - Articles investigating bacterial microbiota communities exclusively Result(s) Our EMBASE and MEDLINE search identified 418 and 343 articles, respectively. After applying our exclusion criteria and removing duplicates, 13 articles were included (5 - fungal communities exclusively, 4 - viral communities exclusively, 4 - both). Novel research directly investigating the impact of diet modulation on fungal and viral communities in the gut microbiota are exceedingly rare. Despite this, both communities in animal and human models showed increases in diversity in response to diet modulation, independent of changes in bacterial composition. Fungal communities in animal studies showed a four-fold increase in diversity with changes in diet composition (standard chow to high-grain/ high fibre /low fat) as soon as 28 days post dietary commencement. In human studies, fungal communities changed in response to short term diet changes, not long-term. Candida was positively correlated with carbohydrate ingestion, while Aspergillus was negatively correlated with short chain fatty acid ingestion. Viral communities in animal models showed a similar increase in diversity in response to diet modulation (standard chow to high-grain/high-fibre). In human studies, virome response to diet increased most significantly in those with lower initial viral diversity. However, viral diversity was impacted most by interpersonal variation, not diet modulation. Conclusion(s) Diet modulation remains a key player in altering the gut microbiome, extending to fungal and viral communities. Further studies are required to elucidate the magnitude and temporal effect on these lesser studied microbial communities, given recent studies showing the importance of fungal/viral microbes in IBD. Please acknowledge all funding agencies by checking the applicable boxes below None Disclosure of Interest None Declared NEUROGASTROENTEROLOGY & MOTILITY

A horse or a zebra? Unusual manifestations of common cutaneous infections in primary immunodeficiency pediatric patients.

Patients with primary immunodeficiency disorders (PIDs) often suffer from recurrent infections because of their inappropriate immune response to both common and less common pathogens. These patients may present with unique and severe cutaneous infectious manifestations that are not common in healthy individuals and may be more challenging to diagnose and treat. To describe a cohort of patients with PIDs with atypical presentations of skin infections, who posed a diagnostic and/or therapeutic challenge. This is a retrospective study of pediatric patients with PID with atypical presentations of infections, who were treated at the immunodeficiency specialty clinic and the pediatric dermatology clinic at the Sheba Medical Center between September 2012 and August 2022. Epidemiologic data, PID diagnosis, infectious etiology, presentation, course, and treatment were recorded. Eight children with a diagnosis of PID were included, five of whom were boys. The average age at PID diagnosis was 1.7 (±SD 3.2) years. The average age of cutaneous infection was 6.9 (±SD 5.9) years. Three patients were born to consanguineous parents. The PIDs included the following: common variable immunodeficiency, severe combined immunodeficiency, DOCK8 deficiency, ataxia telangiectasia, CARD11 deficiency, MALT1 deficiency, chronic granulomatous disease, and a combined cellular and humoral immunodeficiency syndrome of unknown etiology. The infections included the following: ulcerative-hemorrhagic varicella-zoster virus (two cases) atypical fungal and bacterial infections, resistant Norwegian scabies, giant perianal verrucae (two cases), and diffuse molluscum contagiosum. In this case series, we present unusual manifestations of infectious skin diseases in pediatric patients with PID. In some of the cases, recognition of the infectious process prompted life-saving treatment. Increasing familiarity with these dermatological manifestations, as well as keeping a high index of suspicion, is important to enabling early diagnosis of cutaneous infections in PIDs and initiation of prompt suitable treatment.