Cholinergic modulation of Candida albicans virulence factors and the pathogenesis of candidiasis

Candida albicans is the most prevalent fungal pathogen causing both superficial and invasive fungal infections leading to various challenges on healthcare systems. Normally, C. albicans is a harmless commensal of the human body, but under certain conditions of stress, it can express virulence traits leading to disease. It causes a wide range of infections starting from superficial infections such as oropharyngeal candidiasis to systemic infections such as Candidemia. Biofilm formation is an important feature of C. albicans pathogenesis. There are several factors in C. albicans which contribute to this trait, such as morphological transition, expression of virulence factors, metabolic flexibility, and stress response machinery. Understanding the complexity of the pathways behind the virulence traits of C. albicans is essential for developing effective therapeutic strategies to combat superficial and life threatening systemic infections. In this research, we present a novel antifungal activity of pilocarpine hydrochloride against C. albicans biofilms. We hypothesize that C. albicans may possess muscarinic like receptor(s) that mediate the ability of pilocarpine hydrochloride to inhibit biofilm formation. Pilocarpine hydrochloride reduced filamentation and biofilm formation significantly in a dose dependent manner in both the wild type strain and clinical isolates. The M5 allosteric modulator, similarly, inhibited the biofilm formation significantly in a dose dependent manner. Moreover, pilocarpine hydrochloride reduced the damage and inhibited the innate immune response stimulated by C. albicans infection in both TR146 cells and a three-dimensional human oral tissue model. The transcriptomic profile of C. albicans upon treatment with pilocarpine hydrochloride and acetylcholine revealed differential expression among crucial genes that play a vital role in C. albicans pathogenesis such as downregulation of hyphal specific genes; HWP1, ECE1, and IHD1. RNAseq data also revealed a considerable number of unannotated genes that may play a role in the cholinergic modulation of C. albicans biofilm formation by acetylcholine and pilocarpine hydrochloride. The data generated herein suggest that C. albicans may possess a cholinergic receptor or receptors mediating C. albicans virulence factors. This research provides a foundation to explore further cholinergic pathways in fungal pathogens and their involvement in pathogenicity. It also reveals potential novel effective antifungal therapeutic targets in C. albicans. Furthermore, it emphasizes the feasibility and effectiveness of repurposing known licensed drugs, used for treatment of other conditions, to treat C. albicans infections singularly or as an adjunctive therapy. In the light of the global increased resistance to antifungal and antimicrobial therapies, this work may contribute to the development of more effective therapeutic strategies

Virtual Reality Technology and Speech Analysis for People Who Stutter

Virtual reality (VR) technology provides an interactive computer-generated experience that artificially simulates real-life situations by creating a virtual environment that looks real and stimulates the user’s feelings. During the past few years, the use of VR technology in clinical interventions for assessment, rehabilitation and treatment have received increased attention. Accordingly, many clinical studies and applications have been proposed in the field of mental health, including anxiety disorders. Stuttering is a speech disorder in which affected individuals have a problem with the flow of speech. This can manifest in the repetition and prolongation of words or phrases, as well as in involuntary silent pauses or blocks during which the individual is unable to produce sounds. Stuttering is often accompanied by a social anxiety disorder as a secondary symptom, which requires separate treatment. In this study, we evaluated the effectiveness of using a VR environment as a medium for presenting speech training tasks. In addition, we evaluated the accuracy of a speech analyzer module in detecting stuttering events

Impact of the flavonoid quercetin on beta-amyloid aggregation revealed by intrinsic fluorescence

We report the effects of quercetin, a flavonoid present in human diet, on early stage beta-amyloid (Aβ) aggregation – a seminal event in Alzheimer’s disease. Molecular level changes in Aβ arrangements are monitored by time-resolved emission spectral (TRES) measurements of the fluorescence of Aβ’s single tyrosine intrinsic fluorophore (Tyr). The results suggest that quercetin binds beta-amyloid oligomers at early stages of their aggregation, which leads to the formation of modified oligomers and hinders the creation of beta-sheet structures, potentially preventing the onset of Alzheimer’s disease

Detecting beta-amyloid aggregation from the time-resolved emission spectra

The aggregation of beta-amyloids is one of the key processes responsible for the development of Alzheimer's disease. Early molecular-level detection of beta-amyloid oligomers may help in early diagnosis and in the development of new intervention therapies. Our previous studies on the changes in beta-amyloid's single tyrosine intrinsic fluorescence response during aggregation demonstrated a four-exponential fluorescence intensity decay, and the ratio of the pre-exponential factors indicated the extent of the aggregation in the early stages of the process before the beta-sheets were formed. Here we present a complementary approach based on the time-resolved emission spectra (TRES) of amyloid's tyrosine excited at 279 nmand fluorescent in the window 240–450 nm. TRES has been used to demonstrate sturctural changes occuring on the nanosecond time scale after excitation which has significant advantages over using steady-state spectra.Wedemonstrate this by resolving the fluorescent species and revealing that beta-amyloid's monomers show very fast dielectric relaxation, and its oligomers display a substantial spectral shift due to dielectric relaxation, which gradually decreases when the oligomers become larger

Efficacy of self-designed intraoral appliances in prevention of cheek, lip and tongue bite after local anesthesia administration in pediatric patients

The occurrence of self-inflicted soft tissue injuries following administration of local anesthesia in pediatric patients who have received dental treatment has been reported. Aim: To evaluate the attitudes and knowledge regarding cheek, lip, and tongue bite post administration of local anesthesia among dental practitioners in Saudi Arabia. Additionally, the efficacies of three types of intraoral appliances on the prevention of self-harm were evaluated in pediatric patients. A total of 301 practitioners were provided with a questionnaire consisting of 9 items. In addition, three types of intraoral appliances made of polyethylene terephthalate were designed as follows: design 1 (consisted of an anterior extension with numerous perforations); design 2 (had a buccal flap extension); and design 3 (comprised of serrated borders). The appliances were placed in the oral cavities of 45 children (age, 3?15 years) immediately after the completion of the dental procedure. The patient was asked to retain the appliance for 3 h. After 24 h, both parents and children were required to respond to a checklist to evaluate the effectiveness the appliances. Almost half of the dental practitioners had never encountered self-inflicted soft tissue injury in children after local anesthesia administration. About 60% of the dentists were of the opinion that provision of adequate instructions after treatment could prevent the occurrence of lip, cheek, and tongue biting. Furthermore, among the three appliances used, design 1 was most well accepted. Intraoral appliances used in this study may be considered for use to prevent self-inflicted soft tissue trauma in children following administration of local anesthesia

Molecular and pathological investigation of avian reovirus (ARV) in Egypt with the assessment of the genetic variability of field strains compared to vaccine strains

Avian orthoreovirus (ARV) is among the important viruses that cause drastic economic losses in the Egyptian poultry industry. Despite regular vaccination of breeder birds, a high prevalence of ARV infection in broilers has been noted in recent years. However, no reports have revealed the genetic and antigenic characteristics of Egyptian field ARV and vaccines used against it. Thus, this study was conducted to detect the molecular nature of emerging ARV strains in broiler chickens suffering from arthritis and tenosynovitis in comparison to vaccine strains. Synovial fluid samples (n = 400) were collected from 40 commercial broiler flocks in the Gharbia governorate, Egypt, and then pooled to obtain 40 samples, which were then used to screen ARV using reverse transcriptase polymerase chain reaction (RT-PCR) with the partial amplification of ARV sigma C gene. The obtained RT-PCR products were then sequenced, and their nucleotide and deduced amino acid sequences were analyzed together with other ARV field and vaccine strains from GenBank. RT-PCR successfully amplified the predicted 940 bp PCR products from all tested samples. The phylogenetic tree revealed that the analyzed ARV strains were clustered into six genotypic clusters and six protein clusters, with high antigenic diversity between the genotypic clusters. Surprisingly, our isolates were genetically different from vaccine strains, which aligned in genotypic cluster I/protein cluster I, while our strains were aligned in genotypic cluster V/protein cluster V. More importantly, our strains were highly divergent from vaccine strains used in Egypt, with 55.09–56.23% diversity. Sequence analysis using BioEdit software revealed high genetic and protein diversity between our isolates and vaccine strains (397/797 nucleotide substitutions and 148-149/265 amino acid substitutions). This high genetic diversity explains the vaccination failure and recurrent circulation of ARV in Egypt. The present data highlight the need to formulate a new effective vaccine from locally isolated ARV strains after a thorough screening of the molecular nature of circulating ARV in Egypt

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Surgical site infection after gastrointestinal surgery in high-income, middle-income, and low-income countries: a prospective, international, multicentre cohort study

Background: Surgical site infection (SSI) is one of the most common infections associated with health care, but its importance as a global health priority is not fully understood. We quantified the burden of SSI after gastrointestinal surgery in countries in all parts of the world. Methods: This international, prospective, multicentre cohort study included consecutive patients undergoing elective or emergency gastrointestinal resection within 2-week time periods at any health-care facility in any country. Countries with participating centres were stratified into high-income, middle-income, and low-income groups according to the UN's Human Development Index (HDI). Data variables from the GlobalSurg 1 study and other studies that have been found to affect the likelihood of SSI were entered into risk adjustment models. The primary outcome measure was the 30-day SSI incidence (defined by US Centers for Disease Control and Prevention criteria for superficial and deep incisional SSI). Relationships with explanatory variables were examined using Bayesian multilevel logistic regression models. This trial is registered with ClinicalTrials.gov, number NCT02662231. Findings: Between Jan 4, 2016, and July 31, 2016, 13 265 records were submitted for analysis. 12 539 patients from 343 hospitals in 66 countries were included. 7339 (58·5%) patient were from high-HDI countries (193 hospitals in 30 countries), 3918 (31·2%) patients were from middle-HDI countries (82 hospitals in 18 countries), and 1282 (10·2%) patients were from low-HDI countries (68 hospitals in 18 countries). In total, 1538 (12·3%) patients had SSI within 30 days of surgery. The incidence of SSI varied between countries with high (691 [9·4%] of 7339 patients), middle (549 [14·0%] of 3918 patients), and low (298 [23·2%] of 1282) HDI (p < 0·001). The highest SSI incidence in each HDI group was after dirty surgery (102 [17·8%] of 574 patients in high-HDI countries; 74 [31·4%] of 236 patients in middle-HDI countries; 72 [39·8%] of 181 patients in low-HDI countries). Following risk factor adjustment, patients in low-HDI countries were at greatest risk of SSI (adjusted odds ratio 1·60, 95% credible interval 1·05–2·37; p=0·030). 132 (21·6%) of 610 patients with an SSI and a microbiology culture result had an infection that was resistant to the prophylactic antibiotic used. Resistant infections were detected in 49 (16·6%) of 295 patients in high-HDI countries, in 37 (19·8%) of 187 patients in middle-HDI countries, and in 46 (35·9%) of 128 patients in low-HDI countries (p < 0·001). Interpretation: Countries with a low HDI carry a disproportionately greater burden of SSI than countries with a middle or high HDI and might have higher rates of antibiotic resistance. In view of WHO recommendations on SSI prevention that highlight the absence of high-quality interventional research, urgent, pragmatic, randomised trials based in LMICs are needed to assess measures aiming to reduce this preventable complication

Burnout among surgeons before and during the SARS-CoV-2 pandemic: an international survey

Background: SARS-CoV-2 pandemic has had many significant impacts within the surgical realm, and surgeons have been obligated to reconsider almost every aspect of daily clinical practice. Methods: This is a cross-sectional study reported in compliance with the CHERRIES guidelines and conducted through an online platform from June 14th to July 15th, 2020. The primary outcome was the burden of burnout during the pandemic indicated by the validated Shirom-Melamed Burnout Measure. Results: Nine hundred fifty-four surgeons completed the survey. The median length of practice was 10&nbsp;years; 78.2% included were male with a median age of 37&nbsp;years old, 39.5% were consultants, 68.9% were general surgeons, and 55.7% were affiliated with an academic institution. Overall, there was a significant increase in the mean burnout score during the pandemic; longer years of practice and older age were significantly associated with less burnout. There were significant reductions in the median number of outpatient visits, operated cases, on-call hours, emergency visits, and research work, so, 48.2% of respondents felt that the training resources were insufficient. The majority (81.3%) of respondents reported that their hospitals were included in the management of COVID-19, 66.5% felt their roles had been minimized; 41% were asked to assist in non-surgical medical practices, and 37.6% of respondents were included in COVID-19 management. Conclusions: There was a significant burnout among trainees. Almost all aspects of clinical and research activities were affected with a significant reduction in the volume of research, outpatient clinic visits, surgical procedures, on-call hours, and emergency cases hindering the training. Trial registration: The study was registered on clicaltrials.gov "NCT04433286" on 16/06/2020