Diagnostic Biomarkers for Alzheimer's Disease Using Non-Invasive Specimens

Studies in the field of Alzheimer's disease (AD) have shown the emergence of biomarkers in biologic fluids that hold great promise for the diagnosis of the disease. A diagnosis of AD at a presymptomatic or early stage may be the key for a successful treatment, with clinical trials currently investigating this. It is anticipated that preventative and therapeutic strategies may be stage-dependent, which means that they have a better chance of success at a very early stage-before critical neurons are lost. Several studies have been investigating the use of cerebrospinal fluid (CSF) and blood as clinical samples for the detection of AD with a number of established core markers, such as amyloid beta (Aβ), total tau (T-tau) and phosphorylated tau ( tau), being at the center of clinical research interest. The use of oral samples-including saliva and buccal mucosal cells-falls under one of the least-investigated areas in AD diagnosis. Such samples have great potential to provide a completely non-invasive alternative to current CSF and blood sampling procedures. The present work is a thorough review of the results and analytical approaches, including proteomics, metabolomics, spectroscopy and microbiome analyses that have been used for the study and detection of AD using salivary samples and buccal cells. With a few exceptions, most of the studies utilizing oral samples were performed in small cohorts, which in combination with the existence of contradictory results render it difficult to come to a definitive conclusion on the value of oral markers. Proteins such as Aβ, T-tau and tau, as well as small metabolites, were detected in saliva and have shown some potential as future AD diagnostics. Future large-cohort studies and standardization of sample preparation and (pre-)analytical factors are necessary to determine the use of these non-invasive samples as a diagnostic tool for AD

Vibrational spectroscopy: a promising approach to discriminate neurodegenerative disorders

Neurodegenerative diseases are a growing burden in modern society, thus crucially calling for the development of accurate diagnostic strategies. These diseases are currently incurable, a fact which has been attributed to their late diagnosis, after brain damage has already become widespread. An earlier and improved diagnosis is necessary for the enrolment of patients into clinical trials and can pave the way for the development of therapeutic tactics. Novel analytical techniques, such as mass spectrometry and vibrational spectroscopy, have been able to successfully detect and characterise neurodegenerative disorders. It is critical to globally support and make use of innovative basic research and techniques, which could ultimately lead to the creation of a cost-effective diagnostic test. Minimally invasive samples, such as biological fluids, have also been shown to reveal information for these diseases; utilising them could simplify sample collection/analysis and be more preferable to patients

Infrared Spectroscopy Coupled with a Dispersion Model for Quantifying the Real-Time Dynamics of Kanamycin Resistance in Artificial Microbiota

Overusage of antibiotics leads to the widespread induction of antibiotic-resistance genes (ARGs). Developing an approach to allow real-time monitoring and fast prediction of ARGs dynamics in clinical or environmental samples has become an urgent matter. Vibrational spectroscopy is potentially an ideal technique toward the characterization of the microbial composition of microbiota as it is nondestructive, high-throughput, and label-free. Herein, we employed attenuated total reflection Fourier transform infrared (ATR-FT-IR) spectroscopy and developed a spectrochemical tool to quantify the static and dynamic composition of kanamycin resistance in artificial microbiota to evaluate microbial antibiotic resistance. Second-order differentiation was introduced in identifying the spectral biomarkers, and principal component analysis followed by linear discriminant analysis (PCA-LDA) was used for the multivariate analysis of the entire spectral features employed. The calculated results of the mathematical dispersion model coupled with PCA-LDA showed high similarity to the designed microbiota structure, with no significant difference (P > 0.05) in the static treatments. Moreover, our model successfully predicted the dynamics of kanamycin resistance within artificial microbiota under kanamycin pressures. This work lends new insights into the potential role of spectrochemical analyses in investigating the existence and trends of antibiotic resistance in microbiota

Underlying role of mitochondrial mutagenesis in the pathogenesis of a disease and current approaches for translational research

Mitochondrial diseases have been extensively investigated over the last three decades but many questions regarding their underlying aetiologies remain unanswered. Mitochondrial dysfunction is not only responsible for a range of neurological and myopathy diseases, but is also considered pivotal in a broader spectrum of common diseases such as epilepsy, autism and bipolar disorder. These disorders are a challenge to diagnose and treat as their aetiology might be multifactorial. In this review, the focus is placed on potential mechanisms capable of introducing defects in mitochondria resulting in disease. Special attention is given to the influence of xenobiotics on mitochondria; environmental factors inducing mutations or epigenetic changes in the mitochondrial genome can alter its expression and impair the whole cell’s functionality. Specifically, we suggest that environmental agents can cause damage by generating abasic sites in mitochondrial DNA, which consequently lead to mutagenesis. Abasic sites are observed in DNA after spontaneous loss of a nucleic base (e.g., “apurinic sites” after loss of purines, adenine or guanine) or through base excision repair; if left unrepaired, they can produce mutagenic DNA lesions. Moreover, we describe current approaches for handling mitochondrial diseases, as well as available prenatal diagnostic tests towards eliminating these maternally-inherited diseases. Undoubtedly, more research is required, as current therapeutic approaches mostly employ palliative therapies rather than targeting primary mechanisms or prophylactic approaches. More effort is needed into further unravelling the relationship between xenobiotics and mitochondria as the extent of influence in mitochondrial pathogenesis is increasingly recognised

Comparative efficacy and complication rates after local treatment for cervical intraepithelial neoplasia and stage 1a1 cervical cancer : protocol for a systematic review and network meta-analysis from the CIRCLE Group

Introduction Local treatments for cervical intraepithelial neoplasia (CIN) and microinvasive disease remove or ablate a cone-shaped part of the uterine cervix containing the abnormal cells. A trend toward less radical techniques has raised concerns that this may adversely impact the rates of precancerous and cancerous recurrence. However, there has been no strong evidence to support such claims. We hereby describe a protocol of a systematic review and network meta-analysis that will update the evidence and compare all relevant treatments in terms of efficacy and complications. Methods and analysis Literature searches in electronic databases (CENTRAL, MEDLINE, EMBASE) or trial registries will identify published and unpublished randomised controlled trials (RCTs) and cohort studies comparing the efficacy and complications among different excisional and ablative techniques. The excisional techniques include cold knife, laser or Fischer cone, large loop or needle excision of the transformation zone and the ablative radical point diathermy, cryotherapy, cold coagulation or laser ablation. The primary outcome will be residual/recurrent disease defined as abnormal histology or cytology of any grade, while secondary outcomes will include treatment failure rates defined as high-grade histology or cytology, histologically confirmed CIN1+ or histologically confirmed CIN2+, human papillomavirus positivity rates, involved margins rates, bleeding and cervical stenosis rates. We will assess the risk of bias in RCTs and observational studies using tools developed by the Cochrane Collaboration. Two authors will independently assess study eligibility, abstract the data and assess the risk of bias. Random-effects meta-analyses and network meta-analyses will be conducted using the OR for dichotomous outcomes and the mean difference for continuous outcomes. The quality of the evidence for the primary outcome will be assessed using the CINeMA (Confidence In Network Meta-Analysis) tool. Ethics and dissemination Ethical approval is not required. We will disseminate findings to clinicians, policy-makers, patients and the public. PROSPERO registration number CRD42018115508.Peer reviewe

Comparative fertility and pregnancy outcomes after local treatment for cervical intraepithelial neoplasia and stage 1a1 cervical cancer : protocol for a systematic review and network meta-analysis from the CIRCLE group

Introduction There are several local treatment methods for cervical intraepithelial neoplasia that remove or ablate a cone-shaped part of the uterine cervix. There is evidence to suggest that these increase the risk of preterm birth (PTB) and that this is higher for techniques that remove larger parts of the cervix, although the data are conflicting. We present a protocol for a systematic review and network meta-analysis (NMA) that will update the evidence and compare all treatments in terms of fertility and pregnancy complications. Methods and analysis We will search electronic databases (CENTRAL, MEDLINE, EMBASE) from inception till October 2019, in order to identify randomised controlled trials (RCTs) and cohort studies comparing the fertility and pregnancy outcomes among different excisional and ablative treatment techniques and/or to untreated controls. The primary outcome will be PTB ( Ethics and dissemination Ethical approval is not required. Results will be disseminated to academic beneficiaries, medical practitioners, patients and the public.Peer reviewe

Laser-assisted rapid evaporative ionisation mass spectrometry (LA-REIMS) as a metabolomics platform in cervical cancer screening

Background The introduction of high-risk human papillomavirus (hrHPV) testing as part of primary cervical screening is anticipated to improve sensitivity, but also the number of women who will screen positive. Reflex cytology is the preferred triage test in most settings but has limitations including moderate diagnostic accuracy, lack of automation, inter-observer variability and the need for clinician-collected sample. Novel, objective and cost-effective approaches are needed. Methods In this study, we assessed the potential use of an automated metabolomic robotic platform, employing the principle of laser-assisted Rapid Evaporative Ionisation Mass Spectrometry (LA-REIMS) in cervical cancer screening. Findings In a population of 130 women, LA-REIMS achieved 94% sensitivity and 83% specificity (AUC: 91.6%) in distinguishing women testing positive (n = 65) or negative (n = 65) for hrHPV. We performed further analysis according to disease severity with LA-REIMS achieving sensitivity and specificity of 91% and 73% respectively (AUC: 86.7%) in discriminating normal from high-grade pre-invasive disease. Interpretation This automated high-throughput technology holds promise as a low-cost and rapid test for cervical cancer screening and triage. The use of platforms like LA-REIMS has the potential to further improve the accuracy and efficiency of the current national screening programme. Funding Work was funded by the MRC Imperial Confidence in Concept Scheme, Imperial College Healthcare Charity, British Society for Colposcopy and Cervical Pathology, National Research Development and Innovation Office of Hungary, Waters corporation and NIHR BRC

Role of human papillomavirus (HPV) vaccination on HPV infection and recurrence of HPV related disease after local surgical treatment : systematic review and meta-analysis

Publisher Copyright: © Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.Objective: To explore the efficacy of human papillomavirus (HPV) vaccination on the risk of HPV infection and recurrent diseases related to HPV infection in individuals undergoing local surgical treatment. Design: Systematic review and meta-analysis Data sources: PubMed (Medline), Scopus, Cochrane, Web of Science, and ClinicalTrials.gov were screened from inception to 31 March 2021. Review methods: Studies reporting on the risk of HPV infection and recurrence of disease related to HPV infection after local surgical treatment of preinvasive genital disease in individuals who were vaccinated were included. The primary outcome measure was risk of recurrence of cervical intraepithelial neoplasia grade 2 or higher (CIN2+) after local surgical treatment, with follow-up as reported by individual studies. Secondary outcome measures were risk of HPV infection or other lesions related to HPV infection. Independent and in duplicate data extraction and quality assessment were performed with ROBINS-I and RoB-2 tools for observational studies and randomised controlled trials, respectively. Grading of Recommendations Assessment, Development, and Evaluation (GRADE) was implemented for the primary outcome. Observational studies and randomised controlled trials were analysed separately from post hoc analyses of randomised controlled trials. Pooled risk ratios and 95% confidence intervals were calculated with a random effects meta-analysis model. The restricted maximum likelihood was used as an estimator for heterogeneity, and the Hartung-Knapp-Sidik-Jonkman method was used to derive confidence intervals. Results: 22 articles met the inclusion criteria of the review; 18 of these studies also reported data from a non-vaccinated group and were included in the meta-analyses (12 observational studies, two randomised controlled trials, and four post hoc analyses of randomised controlled trials). The risk of recurrence of CIN2+ was reduced in individuals who were vaccinated compared with those who were not vaccinated (11 studies, 19 909 participants; risk ratio 0.43, 95% confidence interval 0.30 to 0.60; I2=58%, τ2=0.14, median follow-up 36 months, interquartile range 24-43.5). The effect estimate was even stronger when the risk of recurrence of CIN2+ was assessed for disease related to HPV subtypes HPV16 or HPV18 (six studies, 1879 participants; risk ratio 0.26, 95% confidence interval 0.16 to 0.43; I2=0%, τ2=0). Confidence in the meta-analysis for CIN2+ overall and CIN2+ related to HPV16 or HPV18, assessed by GRADE, ranged from very low to moderate, probably because of publication bias and inconsistency in the studies included in the meta-analysis. The risk of recurrence of CIN3 was also reduced in patients who were vaccinated but uncertainty was large (three studies, 17 757 participants; 0.28, 0.01 to 6.37; I2=71%, τ2=1.23). Evidence of benefit was lacking for recurrence of vulvar, vaginal, and anal intraepithelial neoplasia, genital warts, and persistent and incident HPV infections, although the number of studies and participants in each outcome was low. Conclusion: HPV vaccination might reduce the risk of recurrence of CIN, in particular when related to HPV16 or HPV18, in women treated with local excision. GRADE assessment for the quality of evidence indicated that the data were inconclusive. Large scale, high quality randomised controlled trials are required to establish the level of effectiveness and cost of HPV vaccination in women undergoing treatment for diseases related to HPV infection. Systematic review registration: PROSPERO CRD42021237350.Peer reviewe

Attenuated total reflection Fourier‐transform infrared ( ATR ‐ FTIR ) spectroscopy to diagnose osteoarthritis in equine serum

Background Reliable and validated biomarkers for osteoarthritis (OA) are currently lacking. Objective To develop an accurate and minimally invasive method to assess OA‐affected horses and provide potential spectral markers indicative of disease. Study design Observational, cross‐sectional study. Methods Our cohort consisted of 15 horses with OA and 48 without clinical signs of the disease, which were used as controls. Attenuated total reflection Fourier‐transform infrared (ATR‐FTIR) spectroscopy was used to investigate serum samples (50 μL) collected from these horses. Spectral processing and multivariate analysis revealed differences and similarities, allowing for detection of spectral biomarkers that discriminated between the two cohorts. A supervised classification algorithm, namely principal component analysis coupled with quadratic discriminant analysis (PCA‐QDA), was applied to evaluate the diagnostic accuracy. Results Segregation between the two different cohorts, OA‐affected and controls, was achieved with 100% sensitivity and specificity. The six most discriminatory peaks were attributed to proteins and lipids. Four of the spectral peaks were elevated in OA horses, which could be potentially due to an increase in lipids, protein expression levels and collagen, all of which have been previously reported in OA. Two peaks were found decreased and were tentatively assigned to the reduction of proteoglycan content that is observed during OA. Main limitations The control group had a wide range of ages and breeds. Pre‐symptomatic OA cases were not included. Therefore, it remains unknown whether this test could be also used as an early diagnostic tool. Conclusions This spectrochemical approach could provide an accurate and cost‐effective blood test, facilitating point‐of‐care diagnosis of equine OA