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Consensus for the Treatment of Tinea Pedis: A Systematic Review of Randomised Controlled Trials.
OBJECTIVE: To systematically review literature enabling the comparison of the efficacy of pharmaceutical treatments for tinea pedis in adults. DESIGN: Systematic review of randomised controlled trials (RCTs) with mycological cure as the primary outcome. Secondary outcomes did include the clinical assessment of resolving infection or symptoms, duration of treatment, adverse events, adherence, and recurrence. ELIGIBILITY CRITERIA: Study participants suffering from only tinea pedis that were treated with a pharmaceutical treatment. The study must have been conducted using an RCT study design and recording age of the participant > 16 years of age. RESULTS: A total of seven studies met the inclusion criteria, involving 1042 participants. The likelihood of resolution in study participants treated with terbinafine was RR 3.9 (95% CI: 2.0-7.8) times those with a placebo. Similarly, the allylamine butenafine was effective by RR 5.3 (95% CI: 1.4-19.6) compared to a placebo. Butenafine was similarly efficacious to terbinafine RR 1.3 (95% CI: 0.4-4.4). Terbinafine was marginally more efficacious than itraconazole, RR 1.3 (95% CI: 1.1-1.5). SUMMARY/CONCLUSION: Topical terbinafine and butenafine treatments of tinea pedis were more efficacious than placebo. Tableted terbinafine and itraconazole administered orally were efficacious in the drug treatment of tinea pedis fungal infection. We are concerned about how few studies were available that reported the baseline characteristics for each treatment arm and that did not suffer greater than 20% loss to follow-up. We would like to see improved reporting of clinical trials in academic literature. Registration name: Treatment's for athlete's foot-systematic review with meta-analysis [CRD42020162078].
Assessment of fatigue and recovery in sport: narrative review
Fatigue is a phenomenon associated with decreases in both physical and cognitive performances and increases in injury occurrence. Competitive athletes are required to complete demanding training programmes with high workloads to elicit the physiological and musculoskeletal adaptations plus skill acquisition necessary for performance. High workloads, especially sudden rapid increases in training loads, are associated with the occurrence of fatigue. At present, there is limited evidence elucidating the underlying mechanisms associating the fatigue generated by higher workloads and with an increase in injury risk. The multidimensional nature and manifestation of fatigue have led to differing definitions and dichotomies of the term. Consequently, a plethora of physiological, biochemical, psychological and performance markers have been proposed to measure fatigue and recovery. Those include self-reported scales, countermovement jump performance, heart rate variability, and saliva and serum biomarker analyses. The purpose of this review is to provide an overview of the fatigue and recovery plus methods of assessments.
Age- and sex-specific effects of obesity, metabolic syndrome and its components on back pain: The English Longitudinal Study of Ageing.
Objectives We aimed to investigate age- and sex-specific effects of obesity, metabolic syndrome (MetS) and its components on back pain in middle-aged and older English individuals. Methods We used data from the English Longitudinal Study of Ageing, wave 2 (2004-2005). Body mass index (BMI) expressed the obesity, while MetS was defined according to revised Adult Treatment Panel (ATP) III criteria. We assessed associations between obesity, MetS and its components with presence and severity of back pain and provided estimates per strata, middle-aged (50-64 years) and older (65-79 years), women and men. Results The study sample included 3328 participants, 1021 and 835 middle-aged women and men and 773 and 699 older women and men, respectively. We found that BMI (OR=1.07, 95% CI 1.05-1.09), MetS (OR=1.47, 95% CI 1.22-1.77), high waist circumference (WC), high triglycerides (TG), and high fasting blood glucose were associated with the presence of back pain. Effects of BMI were consistent across the strata. However, MetS was associated with back pain only in women, middle-aged (OR=1.59, 95% CI 1.14-2.21) and older (OR=1.43, 95% CI 1.01-2.05). The MetS component driving this association was high WC, supported by high TG in older women. Higher BMI, presence of MetS, high blood pressure and TG were associated with back pain severity. Conclusions We found that obesity was associated with the presence and severity of back pain, irrespective of age and sex. However, we found women-specific effects of MetS driven by high WC, indicating that metabolic dysregulation contributes to back pain pathophysiology in women.
The effect of a hydrolyzed protein diet on the fecal microbiota in cats with chronic enteropathy.
The effect of a hydrolyzed protein diet on the fecal microbiota has not been studied in feline chronic enteropathy (CE). Our study aimed to (1) compare the fecal microbiota of cats with CE to control cats with no gastrointestinal signs and (2) determine the effect of a hydrolyzed protein diet on the fecal microbiota of cats with CE and whether this differs between dietary responders and non-responders. The fecal microbiome of cats with CE (n = 36) showed decreased α-diversity in terms of genus richness (P = 0.04) and increased β-diversity in terms of Bray-Curtis Dissimilarity (P
The bacteriology of pleural infection (TORPIDS): an exploratory metagenomics analysis through next generation sequencing.
BACKGROUND: Pleural infection is a common and severe disease with high morbidity and mortality worldwide. The knowledge of pleural infection bacteriology remains incomplete, as pathogen detection methods based on culture have insufficient sensitivity and are biased to selected microbes. We designed a study with the aim to discover and investigate the total microbiome of pleural infection and assess the correlation between bacterial patterns and 1-year survival of patients. METHODS: We assessed 243 pleural fluid samples from the PILOT study, a prospective observational study on pleural infection, with 16S rRNA next generation sequencing. 20 pleural fluid samples from patients with pleural effusion due to a non-infectious cause and ten PCR-grade water samples were used as controls. Downstream analysis was done with the DADA2 pipeline. We applied multivariate Cox regression analyses to investigate the association between bacterial patterns and 1-year survival of patients with pleural infection. FINDINGS: Pleural infection was predominately polymicrobial (192 [79%] of 243 samples), with diverse bacterial frequencies observed in monomicrobial and polymicrobial disease and in both community-acquired and hospital-acquired infection. Mixed anaerobes and other Gram-negative bacteria predominated in community-acquired polymicrobial infection whereas Streptococcus pneumoniae prevailed in monomicrobial cases. The presence of anaerobes (hazard ratio 0·46, 95% CI 0·24-0·86, p=0·015) or bacteria of the Streptococcus anginosus group (0·43, 0·19-0·97, p=0·043) was associated with better patient survival, whereas the presence (5·80, 2·37-14·21, p<0·0001) or dominance (3·97, 1·20-13·08, p=0·024) of Staphylococcus aureus was linked with lower survival. Moreover, dominance of Enterobacteriaceae was associated with higher risk of death (2·26, 1·03-4·93, p=0·041). INTERPRETATION: Pleural infection is a predominantly polymicrobial infection, explaining the requirement for broad spectrum antibiotic cover in most individuals. High mortality infection associated with S aureus and Enterobacteriaceae favours more aggressive, with a narrower spectrum, antibiotic strategies. FUNDING: UK Medical Research Council, National Institute for Health Research Oxford Biomedical Research Centre, Wellcome Trust, Oxfordshire Health Services Research Committee, Chinese Academy of Medical Sciences, and John Fell Fund.
Pharmacologically induced weight loss is associated with distinct gut microbiome changes in obese rats.
BACKGROUND: Obesity, metabolic disease and some psychiatric conditions are associated with changes to relative abundance of bacterial species and specific genes in the faecal microbiome. Little is known about the impact of pharmacologically induced weight loss on distinct microbiome species and their respective gene programs in obese individuals. METHODOLOGY: Using shotgun metagenomics, the composition of the microbiome was obtained for two cohorts of obese female Wistar rats (n = 10-12, total of 82) maintained on a high fat diet before and after a 42-day treatment with a panel of four investigatory or approved anti-obesity drugs (tacrolimus/FK506, bupropion, naltrexone and sibutramine), alone or in combination. RESULTS: Only sibutramine treatment induced consistent weight loss and improved glycaemic control in the obese rats. Weight loss was associated with reduced food intake and changes to the faecal microbiome in multiple microbial taxa, genes, and pathways. These include increased β-diversity, increased relative abundance of multiple Bacteroides species, increased Bacteroides/Firmicutes ratio and changes to abundance of genes and species associated with obesity-induced inflammation, particularly those encoding components of the flagellum and its assembly. CONCLUSIONS: Sibutramine-induced weight loss in obese rats is associated with improved metabolic health, and changes to the faecal microbiome consistent with a reduction in obesity-induced bacterially-driven inflammation.
UNC45A deficiency causes microvillus inclusion disease-like phenotype by impairing myosin VB-dependent apical trafficking.
Variants in the UNC45A cochaperone have been recently associated with a syndrome combining diarrhea, cholestasis, deafness, and bone fragility. Yet the mechanism underlying intestinal failure in UNC45A deficiency remains unclear. Here, biallelic variants in UNC45A were identified by next-generation sequencing in 6 patients with congenital diarrhea. Corroborating in silico prediction, variants either abolished UNC45A expression or altered protein conformation. Myosin VB was identified by mass spectrometry as client of the UNC45A chaperone and was found misfolded in UNC45AKO Caco-2 cells. In keeping with impaired myosin VB function, UNC45AKO Caco-2 cells showed abnormal epithelial morphogenesis that was restored by full-length UNC45A, but not by mutant alleles. Patients and UNC45AKO 3D organoids displayed altered luminal development and microvillus inclusions, while 2D cultures revealed Rab11 and apical transporter mislocalization as well as sparse and disorganized microvilli. All those features resembled the subcellular abnormalities observed in duodenal biopsies from patients with microvillus inclusion disease. Finally, microvillus inclusions and shortened microvilli were evidenced in enterocytes from unc45a-deficient zebrafish. Taken together, our results provide evidence that UNC45A plays an essential role in epithelial morphogenesis through its cochaperone function of myosin VB and that UNC45A loss causes a variant of microvillus inclusion disease.
Valosin-containing protein-regulated endoplasmic reticulum stress causes NOD2-dependent inflammatory responses.
NOD2 polymorphisms may affect sensing of the bacterial muramyl dipeptide (MDP) and trigger perturbed inflammatory responses. Genetic screening of a patient with immunodeficiency and enteropathy revealed a rare homozygous missense mutation in the first CARD domain of NOD2 (ENST00000300589; c.160G > A, p.E54K). Biochemical assays confirmed impaired NOD2-dependent signaling and proinflammatory cytokine production in patient's cells and heterologous cellular models with overexpression of the NOD2 mutant. Immunoprecipitation-coupled mass spectrometry unveiled the ATPase valosin-containing protein (VCP) as novel interaction partner of wildtype NOD2, while the binding to the NOD2 variant p.E54K was abrogated. Knockdown of VCP in coloncarcinoma cells led to impaired NF-κB activity and IL8 expression upon MDP stimulation. In contrast, tunicamycin-induced ER stress resulted in increased IL8, CXCL1, and CXCL2 production in cells with knockdown of VCP, while enhanced expression of these proinflammatory molecules was abolished upon knockout of NOD2. Taken together, these data suggest that VCP-mediated inflammatory responses upon ER stress are NOD2-dependent.
Humanoid robots to mechanically stress human cells grown in soft bioreactors
AbstractFor more than 20 years, robotic bioreactor systems have facilitated the growth of tissue-engineered constructs using mechanical stimulation. However, we are still unable to produce functional grafts that can translate into clinical use. Humanoid robots offer the prospect of providing physiologically-relevant mechanical stimulation to grafts and implants which may expedite their clinical deployment. To investigate the feasibility of a humanoid bioreactor, we have designed a flexible bioreactor chamber that can be attached to a modified musculoskeletal (MSK) humanoid robot shoulder joint. We demonstrate that fibroblast cells can be grown in this chamber while undergoing physiological adduction-abduction on the robotic arm. A preliminary evaluation of the transcriptome of the cells after 14 days indicated a clear influence of the loading regime on the gene expression profile. These early results will facilitate the exploration of MSK humanoid robots as a biomechanically more realistic platform for tissue engineering and biomaterial testing applications.
Automated Annotator: Capturing Expert Knowledge for Free.
Deep learning enabled medical image analysis is heavily reliant on expert annotations which is costly. We present a simple yet effective automated annotation pipeline that uses autoencoder based heatmaps to exploit high level information that can be extracted from a histology viewer in an unobtrusive fashion. By predicting heatmaps on unseen images the model effectively acts like a robot annotator. The method is demonstrated in the context of coeliac disease histology images in this initial work, but the approach is task agnostic and may be used for other medical image annotation applications. The results are evaluated by a pathologist and also empirically using a deep network for coeliac disease classification. Initial results using this simple but effective approach are encouraging and merit further investigation, specially considering the possibility of scaling this up to a large number of users.
Cessation of exclusive breastfeeding and seasonality, but not small intestinal bacterial overgrowth, are associated with environmental enteric dysfunction: A birth cohort study amongst infants in rural Kenya.
Background: Environmental Enteric Dysfunction (EED) is a chronic intestinal inflammatory disorder of unclear aetiology prevalent amongst children in low-income settings and associated with stunting. We aimed to characterise development of EED and its putative risk factors amongst rural Kenyan infants. Methods: In a birth cohort study in Junju, rural coastal Kenya, between August 2015 and January 2017, 100 infants were each followed for nine months. Breastfeeding status was recorded weekly and anthropometry monthly. Acute illnesses and antibiotics were captured by active and passive surveillance. Intestinal function and small intestinal bacterial overgrowth (SIBO) were assessed by monthly urinary lactulose mannitol (LM) and breath hydrogen tests. Faecal alpha-1-antitrypsin, myeloperoxidase and neopterin were measured as EED biomarkers, and microbiota composition assessed by 16S sequencing. Findings: Twenty nine of the 88 participants (33%) that underwent length measurement at nine months of age were stunted (length-for-age Z score
Myeloid CD40 deficiency reduces atherosclerosis by impairing macrophages' transition into a pro-inflammatory state.
AIMS: CD40 and its ligand, CD40L, play a critical role in driving atherosclerotic plaque development. Disrupted CD40-signaling reduces experimental atherosclerosis and induces a favourable stable plaque phenotype. We recently showed that small molecule-based inhibition of CD40-TNF Receptor Associated Factor-6 interactions attenuates atherosclerosis in hyperlipidaemic mice via macrophage-driven mechanisms. The present study aims to detail the function of myeloid CD40 in atherosclerosis using myeloid-specific CD40-deficient mice. METHOD AND RESULTS: Cd40flox/flox and LysM-cre Cd40flox/flox mice on an Apoe-/- background were generated (CD40wt and CD40mac-/-, respectively). Atherosclerotic lesion size, as well as plaque macrophage content, were reduced in CD40mac-/- compared to CD40wt mice and their plaques displayed a reduction in necrotic core size. Transcriptomics analysis of the CD40mac-/- atherosclerotic aorta revealed downregulated pathways of immune pathways and inflammatory responses.Loss of CD40 in macrophages changed the representation of aortic macrophage subsets. Mass cytometry analysis revealed a higher content of a subset of alternative or resident-like CD206 + CD209b- macrophages in the atherosclerotic aorta of CD40mac-/- compared to CD40wt mice. RNA-sequencing of bone marrow-derived macrophages (BMDMs) of CD40mac-/- mice demonstrated upregulation of genes associated with alternatively activated macrophages (including Folr2, Thbs1, Sdc1 and Tns1). CONCLUSIONS: We here show that absence of CD40 signalling in myeloid cells reduces atherosclerosis and limits systemic inflammation by preventing a shift in macrophage polarization towards pro-inflammatory states. Our study confirms the merit of macrophage-targeted inhibition of CD40 as a valuable therapeutic strategy to combat atherosclerosis.
Anti-TNF (adalimumab) injection for the treatment of adults with frozen shoulder during the pain predominant stage protocol for a multi-centre, randomised, double blind, parallel group, feasibility trial
Objectives: The Anti-Freaze-F trial will assess the feasibility of conducting a large randomised controlled trial to assess whether intra-articular injection of anti-TNF (adalimumab) can reduce pain and improve function in people with pain predominant early stage frozen shoulder. Methods and analysis: We are conducting a multi-centre, randomised feasibility study, with an embedded qualitative sub-study. We will recruit adults ≥18 years with a new episode of shoulder pain attributable to early stage frozen shoulder, recruited from at least five UK NHS musculoskeletal and related physiotherapy services. Participants (n=84) will be randomised (centralised computer generated 1:1 allocation) to receive either: 1) intra-articular injection of anti-TNF (adalimumab 160mg) or 2) placebo injection (saline [0.9% sodium chloride]), both under ultrasound guidance. A second injection of the allocated treatment (adalimumab 80mg) or equivalent volume of placebo will be administered 2-3 weeks later. All participants will receive a physiotherapy advice leaflet providing education and advice about frozen shoulder and pain management. The primary feasibility objectives are: 1) the ability to screen and identify potential participants with pain predominant early stage frozen shoulder; 2) willingness of eligible participants to consent and be randomised to intervention; 3) practicalities of delivering the intervention, including time to first injection and number of participants receiving second injection; 4) standard deviation of the Shoulder Pain and Disability Index (SPADI) score and attrition rate at 3 months from baseline in order to estimate the sample size for a definitive trial. We will also assess follow up rates and viability of patient-reported outcome measures and range of shoulder motion for a definitive trial. Research Ethics Committee approval (REC 21/NE/0214). Trial registration number: ISRCTN 27075727; EudraCT number: 2021-003509-23; ClinicalTrials.gov NCT05299242.
Single-cell multi-omics analysis reveals IFN-driven alterations in T lymphocytes and natural killer cells in systemic lupus erythematosus
Background: The characterisation of the peripheral immune system in the autoimmune disease systemic lupus erythematosus (SLE) at the single-cell level has been limited by the reduced sensitivity of current whole-transcriptomic technologies. Here we employ a targeted single-cell multi-omics approach, combining protein and mRNA quantification, to generate a high-resolution map of the T lymphocyte and natural killer (NK) cell populations in blood from SLE patients. Methods: We designed a custom panel to quantify the transcription of 534 genes in parallel with the expression of 51 surface protein targets using the BD Rhapsody AbSeq single-cell system. We applied this technology to profile 20,656 T and NK cells isolated from peripheral blood from an SLE patient with a type I interferon (IFN)-induced gene expression signature (IFNhi), and an age- and sex- matched IFNlow SLE patient and healthy donor. Results: We confirmed the presence of a rare cytotoxic CD4+ T cell (CTL) subset, which was exclusively present in the IFNhi patient. Furthermore, we identified additional alterations consistent with increased immune activation in this patient, most notably a shift towards terminally differentiated CD57+ CD8+ T cell and CD16+ NKdim phenotypes, and the presence of a subset of recently-activated naïve CD4+ T cells. Conclusions: Our results identify IFN-driven changes in the composition and phenotype of T and NK cells that are consistent with a systemic immune activation within the IFNhi patient, and underscore the added resolving power of this multi-omics approach to identify rare immune subsets. Consequently, we were able to find evidence for novel cellular peripheral biomarkers of SLE disease activity, including a subpopulation of CD57+ CD4+ CTLs.
Germinal center expansion but not plasmablast differentiation is proportional to peptide-MHCII density via CD40-CD40L signaling strength.
T follicular helper (TFH) cells promote expansion of germinal center (GC) B cells and plasma cell differentiation. Whether cognate peptide-MHCII (pMHCII) density instructs selection and cell fate decisions in a quantitative manner remains unclear. Using αDEC205-OVA to differentially deliver OVA peptides to GC B cells on the basis of DEC205 allelic copy number, we find DEC205+/+ B cells take up 2-fold more antigen than DEC205+/- cells, leading to proportional TFH cell help and B cell expansion. To validate these results, we establish a caged OVA peptide, which is readily detected by OVA-specific TFH cells after photo-uncaging. In situ uncaging of peptides leads to multiple serial B-T contacts and cell activation. Differential CD40 signaling, is both necessary and sufficient to mediate 2-fold differences in B cell expansion. While plasmablast numbers are increased, pMHCII density does not directly control the output or quality of plasma cells. Thus, we distinguish the roles TFH cells play in expansion versus differentiation.