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Malcolm Begg,1 J Nicole Hamblin,1 Emily Jarvis,2 Glyn Bradley,3 Stephen Mark,4 David Michalovich,5 Mark Lennon,6 Hannah E Wajdner,5 Augustin Amour,5 Robert Wilson,1 Ken Saunders,5 Rikako Tanaka,7 Saki Arai,7 Teresa Tang,8 Cedric Van Holsbeke,9 Jan De Backer,9 Wim Vos,9 Ingrid L Titlestad,10 J Mark FitzGerald,11 Kieran Killian,12 Jean Bourbeau,13 Claude Poirier,14 François Maltais,15 Anthony Cahn,1 Edith M Hessel1 1Refractory Respiratory Inflammation Discovery Performance Unit, GlaxoSmithKline, Stevenage, UK; 2Biostatistics, GlaxoSmithKline R&D, Stevenage, UK; 3Computational Biology, Medicinal Science and Technology, GlaxoSmithKline, Stevenage, UK; 4Study Management, Clinical Development, GlaxoSmithKline, Mississauga, ON, Canada; 5Adaptive Immunity Research Unit, GlaxoSmithKline, Stevenage, UK; 6Nonclinical and Translational Statistics, GlaxoSmithKline, Stevenage, UK; 7Data Management & Strategy, Clinical Development, GlaxoSmithKline, Tokyo, Japan; 8Pharma Safety, Clinical Development, GlaxoSmithKline, Brentford, Middlesex, UK; 9FLUIDDA nv, Kontich, 2550, Belgium; 10Department of Respiratory Medicine, Odense University Hospital and University of Southern Denmark, Odense, Denmark; 11Centre for Heart and Lung Health, University of British Columbia, Vancouver, BC, Canada; 12Cardiorespiratory Research Laboratory, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada; 13Department of Medicine, Division of Experimental Medicine, McGill University, Montreal, QC, Canada; 14Department of Medicine, Respiratory Medicine Division, University of Montreal, Montreal, QC, Canada; 15Institut Universitaire de Cardiologie et de Pneumologie de Québe, Université Laval, Quebec City, QC, CanadaCorrespondence: Malcolm BeggRefractory Respiratory Inflammation Discovery Performance Unit, GlaxoSmithKline, Stevenage, Herts, UKEmail malcolm.5.begg@gsk.comBackground: Inhibition of phosphoinositide 3-kinase δ (PI3Kδ) exerts corrective effects on the dysregulated migration characteristics of neutrophils isolated from patients with chronic obstructive pulmonary disease (COPD).Objective: To develop novel, induced sputum endpoints to demonstrate changes in neutrophil phenotype in the lung by administering nemiralisib, a potent and selective inhaled PI3Kδ inhibitor, to patients with stable COPD or patients with acute exacerbation (AE) of COPD.Methods: In two randomized, double-blind, placebo-controlled clinical trials patients with A) stable COPD (N=28, randomized 3:1) or B) AECOPD (N=44, randomized 1:1) received treatment with inhaled nemiralisib (1mg). Endpoints included induced sputum at various time points before and during treatment for the measurement of transcriptomics (primary endpoint), inflammatory mediators, functional respiratory imaging (FRI), and spirometry.Results: In stable COPD patients, the use of nemiralisib was associated with alterations in sputum neutrophil transcriptomics suggestive of an improvement in migration phenotype; however, the same nemiralisib-evoked effects were not observed in AECOPD. Inhibition of sputum inflammatory mediators was also observed in stable but not AECOPD patients. In contrast, a placebo-corrected improvement in forced expiratory volume in 1 sec of 136 mL (95% Credible Intervals − 46, 315mL) with a probability that the true treatment ratio was > 0% (Pr(θ> 0)) of 93% was observed in AECOPD. However, FRI endpoints remained unchanged.Conclusion: We provide evidence for nemiralisib-evoked changes in neutrophil migration phenotype in stable COPD but not AECOPD, despite improving lung function in the latter group. We conclude that induced sputum can be used for measuring evidence of alteration of neutrophil phenotype in stable patients, and our study provides a data set of the sputum transcriptomic changes during recovery from AECOPD.Keywords: nemiralisib, sputum, transcriptomics, COPD exacerbations, PI3Kdelta

Anthony Cahn,1 J Nicole Hamblin,2 Jon Robertson,3 Malcolm Begg,2 Emily Jarvis,3 Robert Wilson,1 Gordon Dear,4 Claudia Leemereise,5 Yi Cui,6 Maki Mizuma,7 Mickael Montembault,8 Cedric Van Holsbeke,9 Wim Vos,9 Wilfried De Backer,10 Jan De Backer,9 Edith M Hessel2 1Discovery Medicine, GlaxoSmithKline, Stevenage, UK; 2Refractory Respiratory Inflammation Discovery Performance Unit, GlaxoSmithKline, Stevenage, UK; 3Biostatistics, GlaxoSmithKline, Stevenage, UK; 4Mechanistic Safety & Disposition, GlaxoSmithKline, Ware, UK; 5Global Clinical Sciences & Delivery, GlaxoSmithKline, Amersfoort, the Netherlands; 6Pharma Safety, GlaxoSmithKline, Brentford, Middlesex, UK; 7Data Management & Strategy, GlaxoSmithKline, Tokyo, Japan; 8Global Clinical Sciences & Delivery, GlaxoSmithKline, Brentford, Middlesex, UK; 9FLUIDDA nv, Kontich, 2550, Belgium; 10Pulmonary Medicine & Pulmonary Rehabilitation, University of Antwerp, Antwerp, BelgiumCorrespondence: Anthony CahnDiscovery Medicine, GlaxoSmithKline, Stevenage, UKTel +44 1438766374Email tony.x.cahn@gsk.comPurpose: This study evaluated the safety and efficacy of inhaled nemiralisib, a phosphoinositide 3-kinase δ (PI3Kδ) inhibitor, in patients with an acute exacerbation of chronic obstructive pulmonary disease (COPD).Methods: In this double-blind, placebo-controlled study, 126 patients (40– 80 years with a post-bronchodilator forced expiratory volume in 1 sec (FEV1) ≤ 80% of predicted (previously documented)) were randomized 1:1 to once daily inhaled nemiralisib (1 mg) or placebo for 84 days, added to standard of care. The primary endpoint was specific imaging airway volume (siVaw) after 28 treatment days and was analyzed using a Bayesian repeated measures model (clintrials.gov: NCT02294734).Results: A total of 126 patients were randomized to treatment; 55 on active treatment and 49 on placebo completed the study. When comparing nemiralisib and placebo-treated patients, an 18% placebo-corrected increase from baseline in distal siVaw (95% credible intervals (Cr I) (− 1%, 42%)) was observed on Day 28. The probability that the true treatment ratio was > 0% (Pr(θ> 0)) was 96%, suggestive of a real treatment effect. Improvements were observed across all lung lobes. Patients treated with nemiralisib experienced a 107.3 mL improvement in posterior median FEV1 (change from baseline, 95% Cr I (− 2.1, 215.5)) at day 84, compared with placebo. Adverse events were reported by 41 patients on placebo and 49 on nemiralisib, the most common being post-inhalation cough on nemiralisib (35%) vs placebo (3%).Conclusion: These data show that addition of nemiralisib to usual care delivers more effective recovery from an acute exacerbation and improves lung function parameters including siVaw and FEV1. Although post-inhalation cough was identified, nemiralisib was otherwise well tolerated, providing a promising novel therapy for this acutely ill patient group.Keywords: acute exacerbation, COPD, nemiralisib

The development of online virtual patients has proved to be an effective vehicle for pedagogical and technological skills transfer and capacity building for medical and healthcare educators in Malawi. A project between the University of Edinburgh and the University of Malawi has delivered more than 20 collaboratively developed, virtual patients, contextualised for in-country medical and healthcare education and, more significantly, a cadre of healthcare professionals skilled in developing digital resources and integrating these into their emerging curricula. The process of engaging with new approaches to teaching and delivering personalised, context sensitive content via a game-informed, technology-supported process has contributed to the ability of healthcare educators in Malawi to drive pedagogical change, meet the substantial challenges of delivering new curricula, cope with increasing student numbers and promote teacher professional development. This initial phase of the project has laid the foundation for a broader second phase that focuses on promoting curriculum change, developing educational infrastructure and in-country capacity to create, and integrate digital resources into education and training across multi-professional groups and across educational levels. [ABSTRACT FROM AUTHOR]

Objective This study aimed to establish whether medical students from 2 different cultures can learn effectively from a shared web-based learning environment. Methods Students from the College of Medicine, Edinburgh, UK and the Medical School, Gifu, Japan shared 2 weeks of teaching and learning in clinical genetics, using problem-based learning in a web-based application (WBA). Questions about language, time zone, agreement about the curriculum (learning outcomes, tutor activity and assessment) and specific pedagogical issues about the educational effectiveness of students' learning were considered. Results and Conclusions The evidence indicates that a shared WBA is practical where the learning outcomes and problem scenarios are common and students are fluent in the same language. Problem-based learning transfers itself best to online discussion boards when the numbers in the group are 16 or more. Students do not use the WBA as a primary source of resource material, and they augment the discussion boards with face-to-face meetings with peers and tutors. [ABSTRACT FROM AUTHOR]

There is widespread concern regarding the safety of silver-mercury amalgam dental restorations, yet little evidence to support their harm or safety. We examined whether mercury dental amalgams are adversely associated with cognitive functioning in a cross-sectional sample of healthy working adults. We studied 550 adults, 30-49 years of age, who were not occupationally exposed to mercury. Participants were representative of employees at a major urban medical center. Each participant underwent a neuropsychologic test battery, a structured questionnaire, a modified dental examination, and collection of blood and urine samples. Mercury exposure was assessed using a) urinary mercury concentration (UHg); b) the total number of amalgam surfaces; and c) the number of occlusal amalgam surfaces. Linear regression analysis was used to estimate associations between each marker of mercury exposure and each neuropsychologic test, adjusting for potential confounding variables. Exposure levels were relatively low. The mean UHg was 1.7 microg/g creatinine (range, 0.09-17.8); the mean total number of amalgam surfaces was 10.6 (range, 0-46) and the mean number of occlusal amalgam surfaces was 6.1 (range, 0-19). No measure of exposure was significantly associated with the scores on any neuropsychologic test in analyses that adjusted for the sampling design and other covariates. In a sample of healthy working adults, mercury exposure derived from dental amalgam restorations was not associated with any detectable deficits in cognitive or fine motor functioning. [ABSTRACT FROM AUTHOR]

1 Interactions between the cannabinoid system and the adenosine system were investigated in the myenteric plexus-longitudinal muscle (MPLM) of the guinea-pig ileum. 2 Electrically-evoked contractions of the MPLM were inhibited in a concentration dependent manner by exogenous adenosine and the adenosine receptor agonist 2-chloroadenosine. These inhibitory effect were reversed by the selective A[SUB1] receptor antagonist DPCPX (20 nM). 3 Preincubation of the MPLM with the cannabinoid receptor agonist CP55,940 (1 nM) or the endogenous cannabinoid ligand anandamide caused a significant leftward shift in the concentration-effect curves to adenosine and 2-chloroadenosine. 4 Electrically-evoked contractions of the MPLM were inhibited in a concentration dependent manner by the adenosine uptake inhibitor dipyridamole. The inhibition was reversed by DPCPX (20 nM). 5 Pretreatment with CP55,940 (1 nM) or anandamide (10 μM) significantly reduced the inhibition produced by dipyridamole, an effect which was completely reversed by the selective CB[SUB1] receptor ligand SR 141716 (100 nM). 6 Electrically evoked adenosine release, measured in real time by means of adenosine-specific biosensors, was inhibited by CP55,940 (10 nM). This inhibition was blocked when CP55,940 was applied in the presence of SR141716 (100 nM). 7 These results confirm the presence of presynaptic CB[SUB1] and A[SUB1] receptors in the guinea-pig MPLM, and suggest that CB[SUB1] receptor stimulation reduces electrically-evoked adenosine release. Overall the date raise the possibility that the cannabinoid system plays a role in the modulation of adenosine transmission in the MPLM. [ABSTRACT FROM AUTHOR]

The objectives of this study were to compare the relationship of oral candidiasis to HIV status, cohort and CD4+ lymphocyte values in injecting drug users and homosexual men and to examine its impact on prognosis. An oral examination was added to an ongoing longitudinal study of HIV infection. Data obtained at 6-month intervals included smoking, illicit drug use, medication use, symptoms and medical diagnoses, physical examination findings and laboratory data. In this study HIV+ subjects were much more likely to present with oral candidiasis than were HIV- subjects (OR = 6.3, P < 0.01). Injecting drug users, regardless of serostatus, were more likely than homosexual men to present with oral candidiasis (OR = 3.0, P = 0.001). In both cohorts oral candidiasis was associated with low CD4+ lymphocyte counts and percent ages, and Kaplan-Meier survival estimates showed that subjects with oral candidiasis had a poorer prognosis than those without candidiasis, even after controlling for CD4+ lymphocyte count. [ABSTRACT FROM AUTHOR]

Presents a case of a family affected by a mild form of xeroderma pigmentosum with the pedigree of four generations. Information on the disease as an incompletely sex-linked recessive character; Description of parents of xerodermatous children; Implications of exposure to sunshine in late spring or early summer for the family; Age of onset of the first tumors in the affected members of the generation.

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The purpose of this research was to establish the level of importance attached to competitive intelligence (CI) at a mass import retail organization in South Africa. The rationale of CI is to alert an organization about the current situation as it relates to its business environment and competitors, and how these aspects affect the competitive situation. In this article, the value and significance that CI presents to organizations upon implementation are discussed by focusing upon the need for a competitive strategy, the significance of institutionalizing CI, various organizational structure options and the establishment of a CI culture. A survey was conducted at a mass import retail organization to determine the level of importance attached to CI. A total of 107 employees were randomly selected to participate in the completion of a questionnaire. Based on the results, it was found that this organization practised CI, albeit in an informal manner, and it was concluded that there was a relatively high level of importance attached to CI within this organization. However, areas for improvement were identified and a recommendation was made of implementing a formal CI function within the organization. [ABSTRACT FROM AUTHOR]

Kidney stone formation is an intricate process that involves a disruption in the interplay of the multiple organs and systems involved in regulating the concentration of specific ions in the body. Women who have gone through menopause are susceptible to kidney stone disease. This systematic review aims to investigate the potential influence of estrogen on kidney function and oxalate homeostasis, notably through the anion transporter SLC26A6 (also known as putative anion transporter 1 or PAT1) in females. In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 checklist, a systematic search of online databases included Pubmed, ScienceDirect Journals, and Ingenta Connect Journals. Predetermined criteria to include and exclude papers, gathering articles published between 2012 and 2022, were determined. After a thorough analysis, eight articles (three cohorts, one case-control, one in vivo, one in vitro, and two cross-sectional studies) were identified for the final quality assessment review.  The eight selected and quality-assessed articles provided evidence of a directly proportional connection between estrogen and kidney function. A correlation between serum estrogen levels and the development of kidney stone disease was confirmed. Administration of β-estradiol was shown to effectively inhibit the function of the anion transporter PAT1 in a tissue-specific manner. In the case of the kidney, estrogen was observed to down-regulate PAT1, which led to a reduction in oxalate transporting activity and, consequently, a decrease in kidney stone formation. Consensus suggests that serum estrogen levels and optimal kidney functioning are interrelated. Furthermore, analysis of the quality-assessed articles and a comprehensive literature review revealed estrogen's tissue-specific regulation of the PAT1 anion transporter aids in maintaining kidney function and anion homeostasis. Additional research is needed to solidify estrogen's role in kidney stone disease to determine its therapeutic value in clinical practice., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Tarhuni et al.)

Achalasia, a neurodegenerative disease caused by the progressive destruction of ganglion cells in the myenteric plexus, is accompanied by incomplete relaxation of the lower esophageal sphincter. Laparoscopic Heller's myotomy (LHM) coupled with fundoplication has been the gold standard procedure for achalasia. Peroral esophageal myotomy (POEM) has recently gained popularity as it is minimally invasive, has fewer adverse events, and has excellent short-term outcomes. So, we aimed to compare the clinical efficacy, safety, and postoperative outcomes between LHM and POEM. We did a systematic review by following the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines for 2020 and exploring research databases such as PUBMED and PMC Central, Google Scholar, and Research Gate. After appropriate screenings, articles relevant to the review were scrutinized based on the eligibility criteria. Quality assessment tools such as the Newcastle-Ottawa Scale (NOS) and the assessment of multiple systematic reviews (AMSTAR) were used to finalize the articles. A total of 11 articles (seven observational studies, two RCTs, and two systematic reviews) were included in the review after a quality check. The study included 2127 patients, classified into 981 for POEM and 1146 for LHM, who had undergone treatment for achalasia. Most of the studies had a follow-up of ≤ two years. Comparing efficacy, POEM had similar results to LHM in terms of Eckardt scores. However, abnormal DeMeester scores were found in POEM. Adverse events were significantly higher in LHM when compared to POEM in terms of safety. Peroral esophageal myotomy also stood out as having a shorter procedure time, a shorter hospital stay, and lesser odds of being a clinical failure. As for postoperative outcomes, despite treatment with proton pump inhibitors, LHM was more effective in preventing the development of esophagitis compared to POEM due to partial fundoplication.   Postoperative reflux and the development of esophagitis remain certain with POEM and need to be followed up with more studies with longer follow-ups. However, POEM still stands as a better choice compared to LHM in terms of efficacy and safety., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Latha Kumar et al.)

The benefits of physical activity during pregnancy or postpartum are auspicious, especially in preventing and treating postpartum depression. This review aimed to examine the relationship between exercise and postpartum depression in terms of prevention and treatment. The goals were to determine if exercise alone is sufficient for this purpose and to attract attention to the kind, intensity, and duration needed to achieve this purpose. A literature review was conducted in PubMed, PubMed Central, MEDLINE, and Cochrane libraries. The search terms were "physical activity," "postpartum depression," "postnatal depression," and "exercise." Physical activity can be a preventative measure and a treatment aid for pregnant or postpartum women with depressive disorders. However, the exercise protocol should include a support/wellness program to achieve better and more remarkable results., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, N. Fotso et al.)

Peptic ulcer disease (PUD) refers to the occurrence of an open erosion in the inner lining of the stomach, duodenum, or sometimes lower esophagus. Treatments like proton pump inhibitors (PPIs) or histamine 2 receptor antagonists (H2RAs) are available on the market to efficiently treat the break in the mucosal lining. However, there is little evidence about the effects of the medication on the type and location of the ulcer and the epigastric pain caused by disintegration and increased acidity in the stomach. Given the above, we conducted a systematic review comparing the safety and efficacy of PPIs and H2RAs in various ulcer locations (gastric, duodenal, and pre-pyloric) and the effect of prolonging the treatment with the same medication or changing into a drug from another class in treatment-resistant ulcers. We employed major research literature databases and search engines such as PubMed, Medical Literature Analysis and Retrieval System Online (MEDLINE), Science Direct, and Google Scholar to find relevant articles. After a thorough screening, a quality check using various tools, and applying filters that suited our eligibility criteria, we identified eight articles, of which five were random clinical trials (RCTs), two review articles, and one meta-analysis. This study compares the different side effects of PPIs and H2RAs. Most studies concluded that omeprazole is superior in healing ulcers and bringing pain relief and that patients resistant to H2RAs can be treated better when switched to a PPI. This study also discusses the adverse effects of chronic use, such as diarrhea, constipation, headaches, and gastrointestinal infections. Patients on long-term PPI therapy are required to take calcium supplements to prevent the risk of fractures in older adults. Regarding long-term outcomes, PPIs remain the mainstay of treatment for peptic ulcer disease, based on the papers we reviewed., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Begg et al.)

Cerebral palsy is a group of disorders affecting individuals already from birth. It enormously impacts an individual's physical and emotional life and can bring many challenges to the individual, caregivers, and families. Therefore, it is crucial to investigate interventions that could improve various symptoms in children with cerebral palsy. Our systematic review intends to assess the effect of different exercise and physical therapy interventions in children with cerebral palsy. We used three databases for our article search: PubMed, Medical Literature Analysis and Retrieval System Online (MEDLINE), and PubMed Central (PMC). The combined number of papers found in all databases was 65,412. We then applied our inclusion and exclusion criteria, filters, key terms, and Medical Subheadings (MeSH). After applying our quality assessment tools, we included nine papers in our systematic review. The studies included in our review used various interventions to assess for improvement in symptoms in individuals with cerebral palsy. Interventions included stretching and resistance exercises, horse riding, biking, core stability exercises, slackline training, a home exercise program using an online tool, sit-to-stand exercise program, and functional training. Many studies have shown that interventions improved symptoms like balance, coordination, gait, and cardiovascular endurance in cerebral palsy. This review suggests that some of the included interventions have great potential to improve the symptoms of cerebral palsy and, therefore, can be a great addition to existing training and rehabilitation programs. Given that studies included a relatively small number of participants and were conducted over a short time, more research with a more significant number of participants over a longer time is necessary., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Gonzalez et al.)

Inflammatory bowel diseases (IBDs), including Crohn's disease and ulcerative colitis, are immune-mediated chronic inflammatory diseases that target the gastrointestinal tract and other distant organs. The incidence of IBDs has been rising and is more prevailing in Western communities. The etiology has been vague, but different theories include environmental factors that elicit an uncontrolled immune response, which damages internal organs. Treatment of either Crohn's disease or ulcerative colitis has witnessed significant advances; however, pharmacological drugs' side effects limit their use. Research about microbiota and its influence on IBDs has gained fame, and multiple studies correlate microbiota diversity positively with IBD treatment. Many factors contribute to the microbiota's health, including different diets, antibiotics, prebiotics, probiotics, synbiotics, and postbiotics. Specific immune responses lie behind the pathogenesis of IBDs and microbiota dysbiosis, and different studies have postulated new ways to control this abnormal response. Physical activity, sun exposure, efficient sleep, intermittent fasting, and supplementation of probiotics and vitamins are natural ways that help modulate this immune response, do not cost money as IBD pharmacological drugs, and do not come with deleterious side effects that are sometimes more harmful than IBDs. Our article proposes a comprehensive natural approach that can benefit IBD patients enormously. This approach does not replace the medications currently used in treating IBDs. The suggested approach can be used in combination with medications and might aid in reducing the doses of those medications., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Mahmoud et al.)

Irritable bowel syndrome (IBS) is a gut-brain disorder involving alterations in intestinal sensitivity and motility. Currently, IBS has no cure, and treatment focuses on the management of symptoms. The diverse, and sometimes contradictory, collections of symptoms reported across the different subtypes of IBS make treatment, as well as diagnosis, difficult for physicians. All subtypes of IBS have one symptom in common: abdominal pain caused by differences in the level of visceral sensitivity. Though current research on this topic is in its infancy, some researchers have proven, through experimental studies, that 5-hydroxytryptamine (serotonin) receptor type 7 (5-HT7) affects both visceral sensitivity and smooth muscle tone in the bowel. Therefore, this review will be discussing the future possibility of alleviating abdominal pain in patients with IBS and related disorders by modulating the 5-HT7 receptor., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Osman et al.)

The gut microbiota has been studied and continues to be a developing area in the pathognomic development of metabolic diseases like diabetes. Treatment with diet changes, the addition of supplements like prebiotics/probiotics, and the impact of fecal microbial transplantation can be correlated to targeting changes in dysbiosis. Understanding the impacts of various anti-hyperglycemic agents such as metformin and the implications of post-bariatric surgery on the gut microbiota diversity has emerged. These areas of study are crucial to understanding the pathognomic aspects of diabetes disease progression at the microbial level of metabolic and inflammatory mechanisms, which may give more insight into focusing on the role of diet prebiotic/probiotic supplements as potential forms of prospective management in diabetes and the development of more agents that target gut microbiota, which harbors low-grade inflammation. Intestinal dysbiosis was consistently observed in the mechanism of gut microbial change in diabetic individuals, contributing to reduced insulin sensitivity and poor glycemic control. This systematic review was carried out using the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) 2020 checklist. We performed a literature search using the PubMed, Google Scholar and Science Direct databases in accordance with the eligibility criteria and ultimately selected 14 articles for final analysis. The Scale for the Assessment of Narrative Review Articles (SANRA) and the PRISMA 2020 checklist were used to assess the quality of selected articles for cross-sectional studies, traditional literature reviews, and systematic reviews, respectively. We collected papers from 2012 to 2022 for this review. We gathered articles from databases, such as this study, which show there is a strong connection between microbiota and diabetes that appears to exist. The objective is to assess and identify any dietary and therapeutic agents that may alter the microbiota and potentially target and modulate insulin sensitivity. This review article will discuss the pathophysiological effects of gut microbiota in diabetes management and the impact of various gut biodiversity therapeutics that can aid in reversing insulin sensitivity., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Sadagopan et al.)

Activated PI3Kδ Syndrome (APDS) is a rare inherited inborn error of immunity caused by mutations that constitutively activate the p110 delta isoform of phosphoinositide 3-kinase (PI3Kδ), resulting in recurring pulmonary infections. Currently no licensed therapies are available. Here we report the results of an open-label trial in which five subjects were treated for 12 weeks with nemiralisib, an inhaled inhibitor of PI3Kδ, to determine safety, systemic exposure, together with lung and systemic biomarker profiles (Clinicaltrial.gov: NCT02593539). Induced sputum was captured to measure changes in phospholipids and inflammatory mediators, and blood samples were collected to assess pharmacokinetics of nemiralisib, and systemic biomarkers. Nemiralisib was shown to have an acceptable safety and tolerability profile, with cough being the most common adverse event, and no severe adverse events reported during the study. No meaningful changes in phosphatidylinositol (3,4,5)-trisphosphate (PIP3; the enzyme product of PI3Kδ) or downstream inflammatory markers in induced sputum, were observed following nemiralisib treatment. Similarly, there were no meaningful changes in blood inflammatory markers, or lymphocytes subsets. Systemic levels of nemiralisib were higher in subjects in this study compared to previous observations. While nemiralisib had an acceptable safety profile, there was no convincing evidence of target engagement in the lung following inhaled dosing and no downstream effects observed in either the lung or blood compartments. We speculate that this could be explained by nemiralisib not being retained in the lung for sufficient duration, suggested by the increased systemic exposure, perhaps due to pre-existing structural lung damage. In this study investigating a small number of subjects with APDS, nemiralisib appeared to be safe and well-tolerated. However, data from this study do not support the hypothesis that inhaled treatment with nemiralisib would benefit patients with APDS., Competing Interests: Declaration of competing interest MBegg, AA, EJ, TT, SSF, AW, MBeerahee, DF, YK, Aca, and EBH were all employees and share holders in GlaxoSmithKline at the time of this trial. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Respiratory viral infections are typically more severe in older adults. Older adults are more vulnerable to infection and do not respond effectively to vaccines due to a combination of immunosenescence, so-called inflamm-ageing, and accumulation of comorbidities. Although age-related changes in immune responses have been described, the causes of this enhanced respiratory disease in older adults remain poorly understood. We therefore performed volunteer challenge with respiratory syncytial virus (RSV) in groups of younger and older adult volunteers. The aim of this study was to establish the safety and tolerability of this model and define age-related clinical, virological, and immunological outcomes., Methods: In this human infection challenge pilot study, adults aged 18-55 years and 60-75 years were assessed for enrolment using protocol-defined inclusion and exclusion criteria. Symptoms were documented by self-completed diaries and viral load determined by quantitative PCR of nasal lavage. Peripheral blood B cell frequencies were measured by enzyme-linked immunospot and antibodies against pre-fusion and post-fusion, NP, and G proteins in the blood and upper respiratory tract were measured. The study was registered with ClinicalTrials.gov, NCT03728413., Findings: 381 adults aged 60-75 years (older cohort) and 19 adults aged 18-55 years (young cohort) were assessed for enrolment using protocol-defined inclusion and exclusion criteria between Nov 12, 2018, and Feb 26, 2020. 12 healthy volunteers aged 60-75 years and 21 aged 18-55 years were inoculated intranasally with RSV Memphis-37. Nine (67%) of the 12 older volunteers became infected, developing mild-to-moderate upper respiratory tract symptoms that resolved without serious adverse events or sequelae. Viral load peaked on day 6 post-inoculation and symptoms peaked between days 6 and 8. Increases in circulating IgG-positive and IgA-positive antigen-specific plasmablasts, serum neutralising antibodies, and pre-F specific IgG were similar younger and older adults. However, in contrast to young participants, secretory IgA titres in older volunteers failed to increase during infection and, unlike serum IgG, did not correlate with protection., Interpretation: Better understanding of age-related differences in clinical outcomes and immune correlates of protection can overcome reduction in vaccine efficacy with advancing age. We identify correlates of protection in older adults, revealing previously unrecognised factors which might have implications for targeted vaccine discovery and drug development in this vulnerable group., Funding: Medical Research Council and GlaxoSmithKline EMINENT Consortium., Competing Interests: Declaration of interests BSG reports patents for pre-fusion RSV F antigen design. These are for products undergoing clinical evaluation and no royalty payments have been made. EH was, at the time of this work, a full-time employee of GSK, and GlaxoSmithKline provided in kind support to the work described in the Article. PO reports funding from Medical Research Council UK and GlaxoSmithKline; the programme was co-funded by a collaborative award under the EMINENT programme, under the award INFLAMMAGE. PO also participated in the scientific advisory board and sponsored educational events by Janssen and Seqrius. MB is a full-time employee of GSK and stockholder of GlaxoSmithKline. All other authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Wounding induces a calcium wave and disrupts the calcium gradient across the epidermis but mechanisms mediating calcium and downstream signalling, and longer-term wound healing responses are incompletely understood. As expected, live-cell confocal imaging of Fluo-4-loaded normal human keratinocytes showed an immediate increase in [Ca 2+ ] i at the wound edge that spread as a calcium wave (8.3 µm/s) away from the wound edge with gradually diminishing rate of rise and amplitude. The amplitude and area under the curve of [Ca 2+ ] i flux was increased in high (1.2 mM) [Ca 2+ ] o media. 18α-glycyrrhetinic acid (18αGA), a gap-junction inhibitor or hexokinase, an ATP scavenger, blocked the wound-induced calcium wave, dependent in part on [Ca 2+ ] o . Wounding in a high [Ca 2+ ] o increased nuclear factor of activated T-cells (NFAT) but not NFkB activation, assessed by dual-luciferase receptor assays compared to unwounded cells. Treatment with 18αGA or the store-operated channel blocker GSK-7975A inhibited wound-induced NFAT activation, whereas treatment with hexokinase did not. Real-time cell migration analysis, measuring wound closure rates over 24 h, revealed that 18αGA essentially blocked wound closure whereas hexokinase and GSK-7975A showed relatively minimal effects. Together these data indicate that while both gap-junction communication and ATP release from damaged cells are important in regulating the wound-induced calcium wave, long-term transcriptional and functional responses are dominantly regulated by gap-junction communication., (© 2021 The Authors. Journal of Cellular Physiology Published by Wiley Periodicals LLC.)

The airway epithelium represents a fragile environmental interface potentially disturbed by cigarette smoke (CS), the major risk factor for developing chronic obstructive pulmonary disease (COPD). CS leads to bronchial epithelial damage on ciliated, goblet, and club cells, which could involve calcium (Ca 2+ ) signaling. Ca 2+ is a key messenger involved in virtually all fundamental physiological functions, including mucus and cytokine secretion, cilia beating, and epithelial repair. In this study, we analyzed Ca 2+ signaling in air-liquid interface-reconstituted bronchial epithelium from control subjects and smokers (with and without COPD). We further aimed to determine how smoking impaired Ca 2+ signaling. First, we showed that the endoplasmic reticulum (ER) depletion of Ca 2+ stores was decreased in patients with COPD and that the Ca 2+ influx was decreased in epithelial cells from smokers (regardless of COPD status). In addition, acute CS exposure led to a decrease in ER Ca 2+ release, significant in smoker subjects, and to a decrease in Ca 2+ influx only in control subjects. Furthermore, the differential expression of 55 genes involved in Ca 2+ signaling highlighted that only ORAI3 expression was significantly altered in smokers (regardless of COPD status). Finally, we incubated epithelial cells with an ORAI antagonist (GSK-7975A). GSK-7975A altered Ca 2+ influx and ciliary beating, but not mucus and cytokine secretion or epithelial repair, in control subjects. Our data suggest that Ca 2+ signaling is impaired in smoker epithelia (regardless of COPD status) and involves ORAI3. Moreover, ORAI3 is additionally involved in ciliary beating.

Rationale: There is a need to develop imaging protocols which assess neutrophilic inflammation in the lung., Aim: To quantify whole lung neutrophil accumulation in (1) healthy volunteers (HV) following inhaled lipopolysaccharide (LPS) or saline and (2) patients with COPD using radiolabelled autologous neutrophils and single-photon emission computed tomography/CT (SPECT/CT)., Methods: 20 patients with COPD (Global initiative for chronic obstructive lung disease (GOLD) stages 2-3) and 18 HVs were studied. HVs received inhaled saline (n=6) or LPS (50 µg, n=12) prior to the injection of radiolabelled cells. Neutrophils were isolated using dextran sedimentation and Percoll plasma gradients and labelled with 99m Technetium (Tc)-hexamethylpropyleneamine oxime. SPECT was performed over the thorax/upper abdomen at 45 min, 2 hours, 4 hours and 6 hours. Circulating biomarkers were measured prechallenge and post challenge. Blood neutrophil clearance in the lung was determined using Patlak-Rutland graphical analysis., Results: There was increased accumulation of 99m Tc-neutrophils in the lungs of patients with COPD and LPS-challenged subjects compared with saline-challenged subjects (saline: 0.0006±0.0003 mL/min/mL lung blood distribution volume [mean ±1 SD]; COPD: 0.0022±0.0010 mL/min/mL [p<0.001]; LPS: 0.0025±0.0008 mL/min/mL [p<0.001]). The accumulation of labelled neutrophils in 10 patients with COPD who underwent repeat radiolabelling/imaging 7-10 days later was highly reproducible (0.0022±0.0010 mL/min/mL vs 0.0023±0.0009 mL/min/mL). Baseline interleukin (IL)-6 levels in patients with COPD were elevated compared with HVs (1.5±1.06 pg/mL [mean ±1 SD] vs 0.4±0.24 pg/mL). LPS challenge increased the circulating IL-6 levels (7.5±2.72 pg/mL) 9 hours post challenge., Conclusions: This study shows the ability to quantify 'whole lung' neutrophil accumulation in HVs following LPS inhalation and in subjects with COPD using autologous radiolabelled neutrophils and SPECT/CT imaging. Moreover, the reproducibility observed supports the feasibility of using this approach to determine the efficacy of therapeutic agents aimed at altering neutrophil migration to the lungs., Competing Interests: Competing interests: MB, AC, KP, SM, JM, ML, GB, EJ, MdG, FW and EMH are employees of GSK. NT, NF, RS, DG, CS, AW, JB, AMP and ERC have no competing interests to declare., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.)

Nemiralisib (GSK2269557), a potent inhaled inhibitor of phosphoinositide 3-kinase δ (PI3K δ ), is being developed for the treatment of respiratory disorders including chronic obstructive pulmonary disease. Determining the pharmacokinetic (PK) and pharmacodynamic (PD) responses of inhaled drugs early during drug development is key to informing the appropriate dose and preferred dose regimen in patients. We set out to measure PD changes in induced sputum in combination with drug concentrations in plasma and bronchoalveolar lavage (BAL) taken from healthy smokers ( n = 56) treated for up to 14 days with increasing doses of inhaled nemiralisib (0.1-6.4 mg). Induced sputum analysis demonstrated a dose-dependent reduction in phosphatidylinositol-(4,5)-trisphosphate (PIP3, the product of PI3K activation), with a maximum placebo-corrected reduction of 23% (90% confidence interval [CI], 11%-34%) and 36% (90% CI, 11%-64%) after a single dose or after 14 days of treatment with nemiralisib, respectively (2 mg, once daily). Plasma analysis suggested a linear PK relationship with an observed accumulation of ∼3- to 4.5-fold (peak vs. trough) in plasma exposure after 14 days of nemiralisib treatment. The BAL analysis at trough confirmed higher levels of the drug in the lungs versus plasma (32-fold in the BAL fluid component, and 214-fold in the BAL cellular fraction). A comparison of the drug levels in plasma and the reductions in sputum PIP3 showed a direct relationship between exposure and PIP3 reduction. These results demonstrated target engagement upon treatment with inhaled nemiralisib and provide confidence for a once-daily dosing regimen., (Copyright © 2019 The Author(s).)

This study describes the pharmacokinetic (PK) and pharmaco-dynamic (PD) profile of N -(5-(4-(5-(((2 R ,6 S )-2,6-dimethylmorpholino)methyl)oxazol-2-yl)-1 H -indazol-6-yl)-2-methoxypyridin-3-yl)methanesulfonamide (GSK2292767A), a novel low-solubility inhaled phosphoinositide 3-kinase delta (PI3K δ ) inhibitor developed as an alternative to 2-(6-(1H-indol-4-yl)-1H-indazol-4-yl)-5-((4-isopropylpiperazin-1-yl)methyl)oxazole (nemiralisib), which is a highly soluble inhaled inhibitor of PI3K δ with a lung profile consistent with once-daily dosing. GSK2292767A has a similar in vitro cellular profile to nemiralisib and reduces eosinophilia in a murine PD model by 63% ( n = 5, P < 0.05). To explore whether a low-soluble compound results in effective PI3K δ inhibition in humans, a first time in human study was conducted with GSK2292767A in healthy volunteers who smoke. GSK2292767A was generally well tolerated, with headache being the most common reported adverse event. PD changes in induced sputum were measured in combination with drug concentrations in plasma from single (0.05-2 mg, n = 37), and 14-day repeat (2 mg, n = 12) doses of GSK2292767A. Trough bronchoalveolar lavage (BAL) for PK was taken after 14 days of repeat dosing. GSK2292767A displayed a linear increase in plasma exposure with dose, with marginal accumulation after 14 days. Induced sputum showed a 27% (90% confidence interval 15%, 37%) reduction in phosphatidylinositol-trisphosphate (the product of phosphoinositide 3-kinase activation) 3 hours after a single dose. Reduction was not maintained 24 hours after single or repeat dosing. BAL analysis confirmed the presence of GSK2292767A in lung at 24 hours, consistent with the preclinical lung retention profile. Despite good lung retention, target engagement was only present at 3 hours. This exposure-response disconnect is an important observation for future inhaled drug design strategies considering low solubility to drive lung retention., (Copyright © 2019 The Author(s).)

Phosphoinositide 3-kinase δ (PI3K δ ) is a lipid kinase involved in leukocyte recruitment and activation. Activation of PI3K δ has been linked to airway inflammation and asthma pathogenesis. This randomized, double-blind, placebo-controlled, crossover study investigated the efficacy, safety, tolerability, and pharmacokinetics of a PI3K δ inhibitor, nemiralisib (GSK2269557), in patients with persistent, uncontrolled asthma. Patients ( n = 50) received once-daily inhaled nemiralisib (1000 µ g) or placebo for 28 days, with a crossover to the alternative treatment following a 4-week washout period. Spirometry demonstrated no discernible difference in trough forced expiratory volume in 1 second (FEV 1 ) from baseline (adjusted posterior median 7 ml; 95% credible interval -83, 102 ml) between nemiralisib and placebo treatment at day 28 (primary endpoint). These results were supported by most secondary endpoints, including weighted mean FEV 1 (0-4 hours) and change in trough forced vital capacity at day 28. Nemiralisib was generally well-tolerated, with few side effects except for post-inhalation cough (nemiralisib: 35%; placebo: 9%). At day 14, sputum interleukin (IL)-5, IL-13, IL-6, and IL-8 levels were reduced by a median of 17%, 7%, 15%, and 8%, respectively, when comparing nemiralisib with placebo [ n = 15 (IL-5, IL-8) or 16 (IL-6, IL-13); posterior probability of a true ratio >0%: 78%, 64%, 76%, and 63%, respectively]. These results suggest that nemiralisib inhibited PI3K δ locally; however, this did not translate into meaningful clinical improvement. Further studies will investigate the potential efficacy of nemiralisib in patients with asthma with other specific more severe phenotypes, including those who are colonized with bacteria and frequently exacerbate., (Copyright © 2018 The Author(s).)

Background It has been seen that despite the increasing incidence of benign testicular disorders (BTDs), little work has been done towards its awareness among the male populace. Also, the trend of not seeking help in this regard is concerning. In this study, we aim to better perceive the level of understanding and common practices regarding BTDs among educated young men. Methods A cross-sectional study was carried out among two groups of ages 14-20 and 21-28 years. The inclusion criterion was that of educated males in an urban setting. Data were collected through a standardized questionnaire using cluster sampling by independent interviewers. The questionnaire consisted of four parts dealing with demographics, knowledge, attitudes and practices. Chi-square and Mann-Whitney U test were used as the primary statistical tests. Results The sample population consisted of an equal number of participants between the ages of 14 and 20, and between 21 and 28 years (n = 200, 50%). About half the participants (n = 215, 53.8%) were not familiar with the term BTDs. The majority (n = 324, 78.8%) of participants were not aware of symptoms of BTDs. Three-fourth of the participants believed that the subject is considered taboo in Pakistan (n = 307, 73.6%) while a majority of participants (n = 340, 85%) believed media coverage can help spread awareness of BTDs. A huge number (n = 268, 67%) thought that BTDs can cause fertility problems while one-third of them would not perform testicular self-examination (TSE) in case of pain or swelling in the scrotal region (n = 119, 29.8). The level of education and age were significantly associated with the knowledge regarding symptoms and types of BTDs. Conclusion Knowledge of BTDs and practices of TSE in the young educated men of Karachi are alarmingly poor. Therefore, there is an urgent need to create awareness at all levels using different strategies and platforms., Competing Interests: The authors have declared that no competing interests exist.

Inappropriate activation of mast cells via the Fc ε RI receptor leads to the release of inflammatory mediators and symptoms of allergic disease. Calcium influx is a critical regulator of mast cell signaling and is required for exocytosis of preformed mediators and for synthesis of eicosanoids, cytokines and chemokines. Studies in rodent and human mast cells have identified Orai calcium channels as key contributors to Fc ε RI-initiated mediator release. However, until now the role of TRPC calcium channels in Fc ε RI-mediated human mast cell signaling has not been published. Here, we show evidence for the expression of Orai 1,2, and 3 and TRPC1 and 6 in primary human lung mast cells and the LAD2 human mast cell line but, we only find evidence of functional contribution of Orai and not TRPC channels to Fc ε RI-mediated calcium entry. Calcium imaging experiments, utilizing an Orai selective antagonist (Synta66) showed the contribution of Orai to Fc ε RI-mediated signaling in human mast cells. Although, the use of a TRPC3/6 selective antagonist and agonist (GSK-3503A and GSK-2934A, respectively) did not reveal evidence for TRPC6 contribution to Fc ε RI-mediated calcium signaling in human mast cells. Similarly, inactivation of STIM1-regulated TRPC1 in human mast cells (as tested by transfecting cells with STIM1-KK 684-685 EE - TRPC1 gating mutant) failed to alter Fc ε RI-mediated calcium signaling in LAD2 human mast cells. Mediator release assays confirm that Fc ε RI-mediated calcium influx through Orai is necessary for histamine and TNF α release but is differentially involved in the generation of cytokines and eicosanoids., (© 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

Rationale: Acute respiratory distress syndrome is refractory to pharmacological intervention. Inappropriate activation of alveolar neutrophils is believed to underpin this disease's complex pathophysiology, yet these cells have been little studied., Objectives: To examine the functional and transcriptional profiles of patient blood and alveolar neutrophils compared with healthy volunteer cells, and to define their sensitivity to phosphoinositide 3-kinase inhibition., Methods: Twenty-three ventilated patients underwent bronchoalveolar lavage. Alveolar and blood neutrophil apoptosis, phagocytosis, and adhesion molecules were quantified by flow cytometry, and oxidase responses were quantified by chemiluminescence. Cytokine and transcriptional profiling were used in multiplex and GeneChip arrays., Measurements and Main Results: Patient blood and alveolar neutrophils were distinct from healthy circulating cells, with increased CD11b and reduced CD62L expression, delayed constitutive apoptosis, and primed oxidase responses. Incubating control cells with disease bronchoalveolar lavage recapitulated the aberrant functional phenotype, and this could be reversed by phosphoinositide 3-kinase inhibitors. In contrast, the prosurvival phenotype of patient cells was resistant to phosphoinositide 3-kinase inhibition. RNA transcriptomic analysis revealed modified immune, cytoskeletal, and cell death pathways in patient cells, aligning closely to sepsis and burns datasets but not to phosphoinositide 3-kinase signatures., Conclusions: Acute respiratory distress syndrome blood and alveolar neutrophils display a distinct primed prosurvival profile and transcriptional signature. The enhanced respiratory burst was phosphoinositide 3-kinase-dependent but delayed apoptosis and the altered transcriptional profile were not. These unexpected findings cast doubt over the utility of phosphoinositide 3-kinase inhibition in acute respiratory distress syndrome and highlight the importance of evaluating novel therapeutic strategies in patient-derived cells.