Treatment methods for cervical intraepithelial neoplasia in England: A cost-effectiveness analysis.

OBJECTIVE: To compare the cost-effectiveness of different treatments for cervical intraepithelial neoplasia (CIN). DESIGN: A cost-effectiveness analysis based on data available in the literature and expert opinion. SETTING: England. POPULATION: Women treated for CIN. METHODS: We developed a decision-analytic model to simulate the clinical course of 1000 women who received local treatment for CIN and were followed up for 10 years after treatment. In the model we considered surgical complications as well as oncological and reproductive outcomes over the 10-year period. The costs calculated were those incurred by the National Health Service (NHS) of England. MAIN OUTCOME MEASURES: Cost per one CIN2+ recurrence averted (oncological outcome); cost per one preterm birth averted (reproductive outcome); overall cost per one adverse oncological or reproductive outcome averted. RESULTS: For young women of reproductive age, large loop excision of the transformation zone (LLETZ) was the most cost-effective treatment overall at all willingness-to-pay thresholds. For postmenopausal women, LLETZ remained the most cost-effective treatment up to a threshold of £31,500, but laser conisation became the most cost-effective treatment above that threshold. CONCLUSIONS: LLETZ is the most cost-effective treatment for both younger and older women. However, for older women, more radical excision with laser conisation could also be considered if the NHS is willing to spend more than £31,500 to avert one CIN2+ recurrence.

Protocol for a systematic review and meta-analysis of the diagnostic test accuracy of host and HPV DNA methylation in cervical cancer screening and management.

INTRODUCTION: Human papillomavirus (HPV) is necessary but not sufficient for cervical cancer development. During cervical carcinogenesis, methylation levels increase across host and HPV DNA. DNA methylation has been proposed as a test to diagnose cervical intraepithelial neoplasia (CIN); we present a protocol to evaluate the accuracy of methylation markers to detect high-grade CIN and cervical cancer. METHODS AND ANALYSIS: We will search electronic databases (Medline, Embase and Cochrane Library), from inception, to identify studies examining DNA methylation as a diagnostic marker for CIN or cervical cancer, in a cervical screening population. The primary outcome will be to assess the diagnostic test accuracy of host and HPV DNA methylation for high-grade CIN; the secondary outcomes will be to examine the accuracy of different methylation cut-off thresholds, and accuracy in high-risk HPV positive women. Our reference standard will be histology. We will perform meta-analyses using Cochrane guidelines for diagnostic test accuracy. We will use the number of true positives, false negatives, true negatives and false positives from individual studies. We will use the bivariate mixed effect model to estimate sensitivity and specificity with 95% CIs; we will employ different bivariate models to estimate sensitivity and specificity at different thresholds if sufficient data per threshold. For insufficient data, the hierarchical summary receiver operating curve model will be used to calculate a summary curve across thresholds. If there is interstudy and intrastudy variation in thresholds, we will use a linear mixed effects model to calculate the optimum threshold. If few studies are available, we will simplify models by assuming no correlation between sensitivity and specificity and perform univariate, random-effects meta-analysis. We will assess the quality of studies using QUADAS-2 and QUADAS-C. ETHICS AND DISSEMINATION: Ethical approval is not required. Results will be disseminated to academic beneficiaries, medical practitioners, patients and the public. PROSPERO REGISTRATION NUMBER: CRD42022299760.

Primary Melanoma of the Cervix Uteri: A Systematic Review and Meta-Analysis of the Reported Cases.

Primary malignant melanoma (MM) of the cervix uteri is a rare and aggressive malignancy of the female reproductive tract. Considering that clinical data on this cancer are scarce, we aimed to comprehensively examine the currently available literature and provide an overview of the reported cases of cervical MM focusing on the clinical characteristics, diagnosis and therapeutic management. We conducted a systematic review of the literature by screening three electronic databases until June 2022. The critical appraisal checklist provided by the Joanna Briggs Institute was employed to evaluate the overall quality of the studies. We included 96 reports, which comprised 137 patients diagnosed with MM of the cervix. The mean age of the patients was 56.5 (median: 58, age range: 33-88). Data regarding menopausal status were provided for 98 patients with 15 being premenopausal and 83 being postmenopausal. The most common presenting symptom was vaginal bleeding (83%, 100/121). Biopsy (either excisional or punch biopsy) was used as the first diagnostic modality in most of the patients (67%, 64/95), followed by cytology (18%, 17/95). In 74 cases, the FIGO staging system for cervical cancer was used with the most common stage being FIGO stage I (38%, 28/74), followed by FIGO stage II (36%, 27/74), FIGO stage III (19%, 14/74) and FIGO stage IV (7%, 5/74). Most of the patients were managed surgically (90%, 119/131) with a hysterectomy (either radical or total), and a salpingo-oophorectomy with/without lymphadenectomy was the most common approach utilized (40%, 48/119). The data of clinical outcomes were provided for 105 patients, of whom 61 died (58%, 61/105) and 44 survived (42%, 44/105). Knowledge regarding the rare occurrence of MM in the cervix and the increased awareness of clinicians can prevent clinical misdiagnosis and ultimately improve further the clinical outcomes of patients developing this rare malignancy.

Female Dynamics in Authorship of Scientific Publications in the Public Library of Science: A 10-year Bibliometric Analysis of Biomedical Research.

Women are generally underrepresented in science, technology, engineering, and mathematics (STEM). As scientific production reflects scholarly impact and participation in the scientific process, the number of journal publications forms a pertinent measure of academic productivity. This study examined the prevalence and evolution of female representation in prominent author positions across multidisciplinary biomedical research. Publications from seven exemplar cross-specialty journals of the Public Library of Science (PLoS Medicine, PLoS Biology, PLoS One, PLoS Computational Biology, PLoS Genetics, PLoS Pathogens, and PLoS Neglected Tropical Diseases) between January 2010 and December 2020 were extracted from Web of Science. Using Genderize.io, the gender of authors from their first names was estimated using a 75% threshold. The association between female prevalence in first and last authorship and journal was evaluated using a binary logistic regression, and odds ratios were estimated against a 50:50 reference on gender. In 266,739 publications, 43.3% of first authors and 26.7% of last authors were females. Across the ten-year period, female first authorship increased by 19.6% and last authorship by 3.2%. Among all journals, PLoS Neglected Tropical Diseases had the greatest total proportion of female first authors (45.7%) and PLoS Medicine of female last authors (32%), while PLoS Computational Biology had the lowest proportion in these categories (23.7% and 17.2%). First authors were less likely to be females in all PLoS journals (p < 0.05) except for PLoS Neglected Tropical Diseases (odds ratio: 0.84, 95% confidence interval: 0.71-1.00), where the odds of female authorship were not significantly different (p = 0.054). Last authors were not more likely to be females in all PLoS journals (p < 0.001). Overall, women still appear underrepresented as first authors in biomedical publications and their representation as last authors has severely lagged. Efforts towards gender equality in scholarly authorship will contribute to the representation of women in biomedical research and ensure that their potential is not lost.

Diverticulitis during pregnancy: A review of the reported cases.

Background: Diverticular disease of the colon represents a common clinical condition in the western world. Its prevalence increases with age and only 5% of cases occur in adults younger than 40 years of age, making it a rare condition during pregnancy. The aim of this review was to provide an overview of the reported cases of diverticulitis during pregnancy. Methods: We conducted a systematic review of the literature based on preferred reporting items for systematic review and meta-analysis (PRISMA) guidelines. We searched three different electronic databases namely PubMed, Scopus and Web of Science from inception to December 2021. Literature search and data extraction were completed in duplicates. Results: The initial search yielded 564 articles from which 12 were finally included in our review. Ten articles were case reports and two were observational studies. The mean age of the cases was 34 years. The presenting complain was provided for 11 cases. The majority of the patients (10/11, 91%) presented with abdominal pain located mainly on the left (6/11, 55%) or right (4/11, 36%) iliac fossa. The most common diagnostic modality used for the diagnosis of the condition was ultrasonography in nine cases (9/12, 75%) followed by magnetic resonance imaging (MRI) in two cases (2/12, 17%). In spite of clinical and radiological evaluation, the initial diagnosis was inaccurate in seven cases (7/12, 58%). The therapeutic approach was available for 11 cases and it was based on the administration of intravenous antibiotics in six cases (6/11, 55%) and surgical management in five cases (5/11, 45%). Data for the type of delivery was provided in nine studies with five patients (5/9, 56%) delivering vaginally and four patients (4/9, 44%) delivering with cesarean section. Conclusion: As advanced maternal age becomes more common, the frequency of diverticulitis in pregnancy may increase. Although available guidelines do not exist, the clinical awareness, early recognition of the disorder, using diagnostic modalities such as ultrasound and MRI, and rapid therapeutic approach with antibiotics, may improve maternal and neonatal outcomes.

Infrared Spectroscopy of Urine for the Non-Invasive Detection of Endometrial Cancer.

Current triage for women with post-menopausal bleeding (PMB) to diagnose endometrial cancer rely on specialist referral for intimate tests to sequentially image, visualise and sample the endometrium. A point-of-care non-invasive triage tool with an instant readout could provide immediate reassurance for low-risk symptomatic women, whilst fast-tracking high-risk women for urgent intrauterine investigations. This study assessed the potential for infrared (IR) spectroscopy and attenuated total reflection (ATR) technology coupled with chemometric analysis of the resulting spectra for endometrial cancer detection in urine samples. Standardised urine collection and processing protocols were developed to ensure spectroscopic differences between cases and controls reflected cancer status. Urine spectroscopy distinguished endometrial cancer (n = 109) from benign gynaecological conditions (n = 110) with a sensitivity of 98% and specificity of 97%. If confirmed in subsequent low prevalence studies embedded in PMB clinics, this novel endometrial cancer detection tool could transform clinical practice by accurately selecting women with malignant pathology for urgent diagnostic work up whilst safely reassuring those without.

Alzheimer's disease diagnosis by blood plasma molecular fluorescence spectroscopy (EEM).

Despite tremendous research advances in detecting Alzheimer's disease (AD), traditional diagnostic tests remain expensive, time-consuming or invasive. The search for a low-cost, rapid, and minimally invasive test has marked a new era of research and technological developments toward establishing blood-based AD biomarkers. The current study has employed excitation-emission matrices (EEM) of fluorescence spectroscopy combined with machine learning to diagnose AD using blood plasma samples from 230 individuals (83 AD patients from 147 healthy controls). To evaluate the performance of the classification algorithms, we calculated the commonly used figures of merit (accuracy, sensitivity and specificity) and figures of merit that take into account the samples unbalance and the discrimination power of the models, as F2-score (F2), Matthews correlation coefficient (MCC) and test effectiveness ([Formula: see text]). The classification models achieved satisfactory results: Parallel Factor Analysis with Quadratic Discriminant Analysis (PARAFAC-QDA) with 83.33% sensitivity, 100% specificity, 86.21% F2; and Tucker3-QDA with 91.67% sensitivity, 95.45% specificity and 91.67% F2. In addition, the classifiers show high overall performance with 94.12% accuracy and 0.87 MCC. Regarding the discrimination power between healthy and AD patients, the classification algorithms showed high effectiveness with the mean scores separated by three or more standard deviations. The PARAFAC's spectral profiles and the wavelength values from both models loading profiles can be used in future research to relate this information to plasma AD biomarkers. Our results point to a rapid, low-cost and minimally invasive blood-based method for AD diagnosis.

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

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.

Comparative effectiveness and risk of preterm birth of local treatments for cervical intraepithelial neoplasia and stage IA1 cervical cancer: a systematic review and network meta-analysis.

BACKGROUND: The trade-off between comparative effectiveness and reproductive morbidity of different treatment methods for cervical intraepithelial neoplasia (CIN) remains unclear. We aimed to determine the risks of treatment failure and preterm birth associated with various treatment techniques. METHODS: In this systematic review and network meta-analysis, we searched MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials database for randomised and non-randomised studies reporting on oncological or reproductive outcomes after CIN treatments from database inception until March 9, 2022, without language restrictions. We included studies of women with CIN, glandular intraepithelial neoplasia, or stage IA1 cervical cancer treated with excision (cold knife conisation [CKC], laser conisation, and large loop excision of the transformation zone [LLETZ]) or ablation (radical diathermy, laser ablation, cold coagulation, and cryotherapy). We excluded women treated with hysterectomy. The primary outcomes were any treatment failure (defined as any abnormal histology or cytology) and preterm birth (<37 weeks of gestation). The network for preterm birth also included women with untreated CIN (untreated colposcopy group). The main reference group was LLETZ for treatment failure and the untreated colposcopy group for preterm birth. For randomised controlled trials, we extracted group-level summary data, and for observational studies, we extracted relative treatment effect estimates adjusted for potential confounders, when available, and we did random-effects network meta-analyses to obtain odds ratios (ORs) with 95% CIs. We assessed within-study and across-study risk of bias using Cochrane tools. This systematic review is registered with PROSPERO, CRD42018115495 and CRD42018115508. FINDINGS: 7880 potential citations were identified for the outcome of treatment failure and 4107 for the outcome of preterm birth. After screening and removal of duplicates, the network for treatment failure included 19 240 participants across 71 studies (25 randomised) and the network for preterm birth included 68 817 participants across 29 studies (two randomised). Compared with LLETZ, risk of treatment failure was reduced for other excisional methods (laser conisation: OR 0·59 [95% CI 0·44-0·79] and CKC: 0·63 [0·50-0·81]) and increased for laser ablation (1·69 [1·27-2·24]) and cryotherapy (1·84 [1·33-2·56]). No differences were found for the comparison of cold coagulation versus LLETZ (1·09 [0·68-1·74]) but direct data were based on two small studies only. Compared with the untreated colposcopy group, risk of preterm birth was increased for all excisional techniques (CKC: 2·27 [1·70-3·02]; laser conisation: 1·77 [1·29-2·43]; and LLETZ: 1·37 [1·16-1·62]), whereas no differences were found for ablative methods (laser ablation: 1·05 [0·78-1·41]; cryotherapy: 1·01 [0·35-2·92]; and cold coagulation: 0·67 [0·02-29·15]). The evidence was based mostly on observational studies with their inherent risks of bias, and the credibility of many comparisons was low. INTERPRETATION: More radical excisional techniques reduce the risk of treatment failure but increase the risk of subsequent preterm birth. Although there is uncertainty, ablative treatments probably do not increase risk of preterm birth, but are associated with higher failure rates than excisional techniques. Although we found LLETZ to have balanced effectiveness and reproductive morbidity, treatment choice should rely on a woman's age, size and location of lesion, and future family planning. FUNDING: National Institute for Health and Care Research: Research for Patient Benefit.

Is Hysteroscopy Prior to IVF Associated with an Increased Probability of Live Births in Patients with Normal Transvaginal Scan Findings after Their First Failed IVF Trial?

(1) Background: Nowadays, pregnancy can be achieved by in vitro fertilisation (IVF) or by intracytoplasmic sperm injection (ICSI) for many infertile couples. However, implantation failure still remains a significant problem and it can be stressful for both patients and doctors. One of the key players for pregnancy achievement is the uterine environment. Hysteroscopy is the most reliable method to evaluate the uterine cavity and to identify any intauterine pathology. The aim of this retrospective study was to compare live birth ranges in between women who after a first failed IVF/ICSI attempt underwent a hysteroscopy and those who were evaluated by a transvaginal scan. (2) The retrospective study took place at the Assisted Reproductive Unit of the University Hospital of Ioannina, Greece, from 2017 to 2020. It included 334 women with normal findings in a repeat ultrasound scan after a failed IVF/ICSI trial, 137 of whom underwent in turn diagnostic hysteroscopy before the next IVF/ICSI. (3) Results: Live birth rates were higher in the study group (58/137 vs. 52/197 p = 0.0025). Abnormal endometrial findings were identified in 30% of the patients of the study group. (4) Conclusions: The addition of hysteroscopy as an additional investigation to those patients with a first failed IVF/ICSI could improve the rates of live births. A properly conducted RCT could lead to a robust answer.

The role of T-cells in neurobehavioural development: Insights from the immunodeficient nude mice.

Mice homozygous for the nude mutation (Foxn1nu) are hairless and exhibit congenital dysgenesis of the thymic epithelium, resulting in a primary immunodeficiency of mature T-cells, and have been used for decades in research with tumour grafts. Early studies have already demonstrated social behaviour impairments and central nervous system (CNS) alterations in these animals, but did not address the complex interplay between CNS, immune system and behavioural alterations. Here we investigate the impact of T-cell immunodeficiency on behaviours relevant to the study of neurodevelopmental and neuropsychiatric disorders. Moreover, we aimed to characterise in a multidisciplinary manner the alterations related to those findings, through evaluation of the excitatory/inhibitory synaptic proteins, cytokines expression and biological spectrum signature of different biomolecules in nude mice CNS. We demonstrate that BALB/c nude mice display sociability impairments, a complex pattern of repetitive behaviours and higher sensitivity to thermal nociception. These animals also have a reduced IFN-γ gene expression in the prefrontal cortex and an absence of T-cells in meningeal tissue, both known modulators of social behaviour. Furthermore, excitatory synaptic protein PSD-95 immunoreactivity was also reduced in the prefrontal cortex, suggesting an intricate involvement of social behaviour related mechanisms. Lastly, employing biospectroscopy analysis, we have demonstrated that BALB/c nude mice have a different CNS spectrochemical signature compared to their heterozygous littermates. Altogether, our results show a comprehensive behavioural analysis of BALB/c nude mice and potential neuroimmunological influences involved with the observed alterations.

PCNA in Cervical Intraepithelial Neoplasia and Cervical Cancer: An Interaction Network Analysis of Differentially Expressed Genes.

The investigation of differentially expressed genes (DEGs) and their interactome could provide valuable insights for the development of markers to optimize cervical intraepithelial neoplasia (CIN) screening and treatment. This study investigated patients with cervical disease to identify gene markers whose dysregulated expression and protein interaction interface were linked with CIN and cervical cancer (CC). Literature search of microarray datasets containing cervical epithelial samples was conducted in Gene Expression Omnibus and Pubmed/Medline from inception until March 2021. Retrieved DEGs were used to construct two protein-protein interaction (PPI) networks. Module DEGs that overlapped between CIN and CC samples, were ranked based on 11 topological algorithms. The highest-ranked hub gene was retrieved and its correlation with prognosis, tissue expression and tumor purity in patients with CC, was evaluated. Screening of the literature yielded 9 microarray datasets (GSE7803, GSE27678, GSE63514, GSE6791, GSE9750, GSE29570, GSE39001, GSE63678, GSE67522). Two PPI networks from CIN and CC samples were constructed and consisted of 1704 and 3748 DEGs along 21393 and 79828 interactions, respectively. Two gene clusters were retrieved in the CIN network and three in the CC network. Multi-algorithmic topological analysis revealed PCNA as the highest ranked hub gene between the two networks, both in terms of expression and interactions. Further analysis revealed that while PCNA was overexpressed in CC tissues, it was correlated with favorable prognosis (log-rank P=0.022, HR=0.58) and tumor purity (P=9.86 × 10-4, partial rho=0.197) in CC patients. This study identified that cervical PCNA exhibited multi-algorithmic topological significance among DEGs from CIN and CC samples. Overall, PCNA may serve as a potential gene marker of CIN progression. Experimental validation is necessary to examine its value in patients with cervical disease.

The vaginal microbiota and innate immunity after local excisional treatment for cervical intraepithelial neoplasia.

BACKGROUND: Vaginal microbiota (VMB) composition is altered in women with cervical intra-epithelial neoplasia (CIN) compared to healthy controls and is associated with disease progression. However, the impact of CIN excision on the VMB and innate immunity is not known. This observational study aims to explore the impact of CIN excision on the VMB, antimicrobial peptides (AMP) and proinflammatory cytokines. METHODS: We sampled 103 non-pregnant, premenopausal women at the time of excisional treatment for CIN and at their 6-month follow-up visit. A further 39 untreated controls with normal cytology were also sampled. We used metataxonomics to group vaginal swab samples into community state types (CSTs) and ELISA to quantify cytokine and AMP levels in matched vaginal secretions. Analyses were performed to compare the bacterial composition and immune analyte levels before and after CIN excision and in healthy controls. RESULTS: Women with CIN had significantly higher rates of Lactobacillus species depletion pre-treatment compared to healthy controls (CST IV 21/103, 20% vs 1/39, 3%, p = 0.0081). Excision did not change the VMB composition, with CST IV remaining significantly more prevalent after excision compared to untreated, healthy controls (CST IV 19/103, 20% vs 1/39, 3%, p = 0.0142). Prevotella bivia and Sneathia amnii were significantly higher in samples before treatment compared to untreated controls, and Prevotella bivia remained significantly higher amongst the treated, with less Lactobacillus crispatus compared to untreated controls. IL-1ß and IL-8 remained significantly elevated pre- (p < 0.0001 and p = 0.0014, respectively) and post-treatment (p < 0.0001 and p = 0.0035, respectively) compared to untreated controls. Levels of human beta-defensin-1 and secretory leukocyte protease inhibitor were both significantly reduced following CIN excision (p < 0.0001); however, their levels remained lower than controls post-treatment. CONCLUSIONS: Women with CIN have an increased prevalence of Lactobacillus sp. depletion, high-diversity VMB composition, and higher levels of proinflammatory cytokines and AMPs compared to normal controls. Surgical excision of the disease reduces levels of vaginal AMPs but does not alter VMB composition or cytokine levels. These findings suggest that women with CIN have an inherent predisposition to a high-diversity proinflammatory environment that is not corrected by disease excision. The failure to re-establish a Lactobacillus-enriched CST may explain why women remain at high risk of pre-invasive and invasive disease recurrence.

The Relation between Caffeine Consumption and Endometriosis: An Updated Systematic Review and Meta-Analysis.

While the contributing factors leading to endometriosis remain unclear, its clinical heterogeneity suggests a multifactorial causal background. Amongst others, caffeine has been studied extensively during the last decade as a putative contributing factor. In this systematic review and meta-analysis, we provide an overview/critical appraisal of studies that report on the association between caffeine consumption and the presence of endometriosis. In our search strategy, we screened PubMed and Scopus for human studies examining the above association. The main outcome was the relative risk of endometriosis in caffeine users versus women consuming little or no caffeine (<100 mg/day). Subgroup analyses were conducted for different levels of caffeine intake: high (>300 mg/day) or moderate (100-300 mg/day). Ten studies were included in the meta-analysis (five cohort and five case-control studies). No statistically significant association was observed between overall caffeine consumption and risk for endometriosis (RR 1.12, 95% confidence interval (CI) 0.97-1.28, I2 = 70%) when compared to little or no (<100 mg/day) caffeine intake. When stratified according to level of consumption, high intake was associated with increased risk of endometriosis (RR 1.30, 95%CI 1.04-1.63, I2 = 56%), whereas moderate intake did not reach nominal statistical significance (RR 1.18, 95%CI 0.99-1.40, I2 = 37%). In conclusion, caffeine consumption does not appear to be associated with increased risk for endometriosis. However, further research is needed to elucidate the potential dose-dependent link between caffeine and endometriosis or the probable role of caffeine intake as a measurement of other unidentified biases.

Invasive cervical cancer following treatment of pre-invasive lesions: A potential theory based on a small case series.

PURPOSE: The aim of this study is to present a single department's experience on cervical cancer cases following previous excision of cervical intraepithelial neoplasia (CIN) and to discuss potential pathogenesis. METHODS: Nine cervical cancer cases meeting the inclusion criteria, with available pathological and follow-up data, were considered eligible for this study. RESULTS: The majority (7/9) have had clear excisional margins. The interval between initial treatment and cancer diagnosis ranged from 7 to 17 years. In all cases cancer diagnosis was "unexpected", as the prior cytological and/or colposcopic evaluation was not suggestive of significant cervical pathology. All cancers were squamous, and 5/9 at stage I. CONCLUSION: The long interval between initial CIN treatment and final diagnosis as well as the normal post-treatment follow-up may suggest a 'de novo' underlying but 'hidden' carcinogenesis process. It might be that dysplastic cells entrapped within crypts (or normal metaplastic affected by the same predisposing factors) continue undergoing their evolution, undetectable by cytology and colposcopy until they invade stroma and surfaces (endo- and/or ectocervical) approximately a decade later. Heavy cauterisation of cervical crater produced post excision might be a potential culprit of this entrapment.

Diagnostic segregation of human breast tumours using Fourier-transform infrared spectroscopy coupled with multivariate analysis: Classifying cancer subtypes.

The present study aimed to investigate whether attenuated total reflection Fourier-transform infrared (ATR-FTIR) spectroscopy coupled with multivariate analysis could be applied to discriminate and classify among breast tumour molecular subtypes based on the unique spectral "fingerprints" of their biochemical composition. The different breast cancer tissues and normal breast tissues were collected and identified by pathology and ATR-FTIR spectroscopy respectively. The study indicates that the levels of the lipid-to-protein, nucleic acid-to-lipid, phosphate-to-carbohydrate and their secondary structure ratio, including RNA-to-DNA, Amide I-to-Amide II, and RNA-to-lipid ratios were significantly altered among the molecular subtype of breast tumour compared with normal breast tissues, which helps explain the changes in the biochemical structure of different molecular phenotypes of breast cancer. Tentatively-assigned characteristic peak ratios of infrared (IR) spectra reflect the changes of the macromolecule structure in different issues to a great extent and can be used as a potential biomarker to predict the molecular subtype of breast tumour. The present study acts as the first case study to show the successful application of IR spectroscopy in classifying subtypes of breast cancer with biochemical alterations. Therefore, the present study is likely to help to provide a new diagnostic approach for the accurate diagnosis of breast tumours and differential molecular subtypes and has the potential to be used for further intraoperative management.

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.

Bisphenol-A and polycystic ovary syndrome: a review of the literature.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among women of reproductive age with reproductive, metabolic and endocrine implications. While the exact pathophysiological mechanisms of the syndrome are unknown, its heterogeneity suggests a multifactorial causal background. In the last two decades, numerous environmental chemicals, including Bisphenol-A (BPA) that is used in the synthesis of polycarbonate plastics, have been proposed as potential contributors to the aetiology of PCOS. This review provides a holistic overview of the available data regarding the possible relation of PCOS with BPA exposure. We have included a total number of 24 studies. Eleven human case-control and 13 animal studies provided data regarding this potential relation. Accumulating evidence suggests that a correlation between high levels of BPA and the presence of PCOS may exist. Contradicting results from human and animal studies, however, render it difficult to conclude on the exact role of BPA in the pathogenesis of PCOS. BPA may constitute a consequence of the syndrome rather than a cause, but further research is still needed to clarify this. Continued efforts to study the early origins of PCOS, using prospective-designed studies, are required to identify the exact effect of BPA on women with PCOS.

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 (Aß), total tau (T-tau) and phosphorylated tau (P-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 Aß, T-tau and P-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.

Detecting Endometrial Cancer by Blood Spectroscopy: A Diagnostic Cross-Sectional Study.

Endometrial cancer is the sixth most common cancer in women, with a rising incidence worldwide. Current approaches for the diagnosis and screening of endometrial cancer are invasive, expensive or of moderate diagnostic accuracy, limiting their clinical utility. There is a need for cost-effective and minimally invasive approaches to facilitate the early detection and timely management of endometrial cancer. We analysed blood plasma samples in a cross-sectional diagnostic accuracy study of women with endometrial cancer (n = 342), its precursor lesion atypical hyperplasia (n = 68) and healthy controls (n = 242, total n = 652) using attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectroscopy and machine learning algorithms. We show that blood-based infrared spectroscopy has the potential to detect endometrial cancer with 87% sensitivity and 78% specificity. Its accuracy is highest for Type I endometrial cancer, the most common subtype, and for atypical hyperplasia, with sensitivities of 91% and 100%, and specificities of 81% and 88%, respectively. Our large-cohort study shows that a simple blood test could enable the early detection of endometrial cancer of all stages in symptomatic women and provide the basis of a screening tool in high-risk groups. Such a test has the potential not only to differentially diagnose endometrial cancer but also to detect its precursor lesion atypical hyperplasia-the early recognition of which may allow fertility sparing management and cancer prevention.