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Testicular cancer is the most common malignancy in young men. We discuss four cases of germ cell tumours (GCTs) presenting to general practitioners and physicians where there were notable preventable delays in the diagnosis and management. This diagnostic delay is associated with a more advanced stage of disease, and subsequent increased treatment-related morbidity and decreased survival. Our series highlights the variety of ways in which GCTs may present and we discuss the importance of prompt diagnosis through a thorough history and examination, early measurement of serum tumour markers and appropriate multidisciplinary team discussion. GCTs are highly curable cancers in the majority of patients and delays in management can, therefore, have devastating consequences., Competing Interests: No conflict of interests declared

A single-photon CMOS image sensor (CIS) design based on pinned photodiode (PPD) with multiple charge transfers and sampling is described. In the proposed pixel architecture, the photogenerated signal is sampled non-destructively multiple times and the results are averaged. Each signal measurement is statistically independent and by averaging, the electronic readout noise is reduced to a level where single photons can be distinguished reliably. A pixel design using this method was simulated in TCAD and several layouts were generated for a 180-nm CMOS image sensor process. Using simulations, the noise performance of the pixel was determined as a function of the number of samples, sense node capacitance, sampling rate and transistor characteristics. The strengths and limitations of the proposed design are discussed in detail, including the trade-off between noise performance and readout rate and the impact of charge transfer inefficiency (CTI). The projected performance of our first prototype device indicates that single-photon imaging is within reach and could enable ground-breaking performances in many scientific and industrial imaging applications.

Introduction: Differences in microbiota composition in children with autism spectrum disorder (ASD) compared to unaffected siblings and healthy controls have been reported in various studies. This study aims to systematically review the existing literature concerning the role of the gut microbiota in ASD., Methods: An extensive literature search was conducted using MEDLINE and EMBASE databases to identify studies (January 1966 through July 2019)., Results: A total of 28 papers were included. The studies ranged from 12 to 104 participants who were aged between 2 and 18 years from various geographical areas. Majority of studies included faecal samples; however, 4 studies examined mucosal biopsies from different sites. The heterogeneity in ASD diagnostic methodology, gut site sampled and laboratory methods used made meta-analysis inappropriate. Species reported to be significantly higher in abundance in autistic children included Clostridium, Sutterella, Desulfovibrio and Lactobacillus. The findings are however inconsistent across studies. In addition, -potential confounding effects of antimicrobial use, gastrointestinal symptoms and diet on the gut microbiota are unclear due to generally poor assessment of these factors., Conclusion: It is clear that the gut microbiota is altered in ASD, although further exploration is needed on whether this is a cause or an effect of the condition., (© 2020 S. Karger AG, Basel.)

Objective: Barrett's oesophagus is a premalignant condition that occurs in the context of gastro-oesophageal reflux. However, most Barrett's cases are undiagnosed because of reliance on endoscopy. We have developed a non-endoscopic tool: the Cytosponge, which when combined with trefoil factor 3 immunohistochemistry, can diagnose Barrett's oesophagus. We investigated whether a quantitative methylation test that is not reliant on histopathological analysis could be used to diagnose Barrett's oesophagus., Design: Differentially methylated genes between Barrett's and normal squamous oesophageal biopsies were identified from whole methylome data and confirmed using MethyLight PCR in biopsy samples of squamous oesophagus, gastric cardia and Barrett's oesophagus. Selected genes were then tested on Cytosponge BEST2 trial samples comprising a pilot cohort (n=20 cases, n=10 controls) and a validation cohort (n=149 cases, n=129 controls)., Results: Eighteen genes were differentially methylated in patients with Barrett'soesophagus compared with squamous controls. Hypermethylation of TFPI2, TWIST1, ZNF345 and ZNF569 was confirmed in Barrett's biopsies compared with biopsies from squamous oesophagus and gastric cardia (p<0.05). When tested in Cytosponge samples, these four genes were hypermethylated in patients with Barrett's oesophagus compared with patients with reflux symptoms (p<0.001). The optimum biomarker to diagnose Barrett's oesophagus was TFPI2 with a sensitivity and specificity of 82.2% and 95.7%, respectively., Conclusion: TFPI2, TWIST1, ZNF345 and ZNF569 methylation have promise as diagnostic biomarkers for Barrett's oesophagus when used in combination with a simple and cost effective non-endoscopic cell collection device., Competing Interests: Competing interests: Since this study was conducted, the Cytosponge™-TFF3 technology has been licensed to Covidien GI solutions (now owned by Medtronic) by the Medical Research Council. Rebecca Fitzgerald and Maria O’Donovan are named inventors on patents pertaining to the Cytosponge™. Covidien Solutions and Medtronic have not been privy to this manuscript or the data therein. All other authors declare no conflicts of interest., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Little is known about the burden of diabetes mellitus (DM) in pregnancy in low- and middle-income countries despite high prevalence and mortality rates being observed in these countries., Objective: To investigate the prevalence and geographical patterns of DM in pregnancy up to 1 year post-delivery in low- and middle-income countries., Search Strategy: Medline, Embase, Cochrane (Central), Cinahl and CAB databases were searched with no date restrictions., Selection Criteria: Articles assessing the prevalence of gestational diabetes mellitus (GDM), and types 1 and 2 DM were sought., Data Collection and Analysis: Articles were independently screened by at least two reviewers. Forest plots were used to present prevalence rates and linear trends calculated by linear regression where appropriate., Main Results: A total of 45 articles were included. The prevalence of GDM varied. Diagnosis was made by the American Diabetes Association criteria (1.50-15.5%), the Australian Diabetes in Pregnancy Society criteria (20.8%), the Diabetes in Pregnancy Study Group India criteria (13.4%), the European Association for the Study of Diabetes criteria (1.6%), the International Association of Diabetes and Pregnancy Study Groups criteria (8.9-20.4%), the National Diabetes Data Group criteria (0.56-6.30%) and the World Health Organization criteria (0.4-24.3%). Vietnam, India and Cuba had the highest prevalence rates. Types 1 and 2 DM were less often reported. Reports of maternal mortality due to DM were not found. No geographical patterns of the prevalence of GDM could be confirmed but data from Africa is particularly limited., Conclusion: Existing published data are insufficient to build a clear picture of the burden and distribution of DM in pregnancy in low- and middle-income countries. Consensus on a common diagnostic criterion for GDM is needed. Type 1 and 2 DM in pregnancy and postpartum DM are other neglected areas.

Prostaglandin E2 (PGE2) promotes colorectal carcinogenesis. Overall, systemic PGE2 production can be assessed by measuring its major metabolite, PGE-M, in urine. We examined the potential role of PGE-M as a biomarker for colorectal adenoma risk and chemopreventive response to anti-inflammatory drugs. We conducted a prospective case-control study nested within the Nurses' Health Study. Among women who previously provided a urine sample, we identified 420 cases diagnosed with colorectal adenoma during follow-up and matched them to 420 endoscopy-negative controls. We measured urinary PGE-M using an LC/MS assay. Compared with women in the lowest quartile of urinary PGE-M, women in the highest quartile had a multivariate OR of 1.40 (95% confidence interval (CI), 0.92-2.14) for any adenoma; 0.91 (95% CI, 0.48-1.72) for low-risk adenoma (solitary adenoma <1 cm in greatest diameter with tubular/unspecified histology); and 1.66 (95% CI, 1.04-2.67) for high-risk adenoma (adenoma ≥1 cm in greatest diameter and/or tubulovillous, villous or high-grade dysplasia histology or multiple adenomas of any size or histology). Regular use of anti-inflammatory drugs (≥2 standard tablets of aspirin/NSAIDs per week) was associated with a significant reduction in adenoma risk (multivariate OR, 0.61; 95% CI, 0.43-0.87) in women with high baseline PGE-M (quartiles 2-4), but not low PGE-M (quartile 1).Urinary PGE-M is associated with an increased risk of high-risk adenoma. Anti-inflammatory drugs seem to reduce adenoma risk among women with high, but not low PGE-M. Urinary PGE-M may serve as a biomarker to define subsets of the population who may obtain differential chemopreventive benefit from anti-inflammatory drugs., (©2014 American Association for Cancer Research.)

Background: Chronic inflammation plays a role in the development of colorectal cancer (CRC). The novel plasma inflammatory biomarker macrophage inhibitory cytokine-1 (MIC-1, GDF15) may have a direct mechanistic role in colorectal carcinogenesis., Methods: We conducted a prospective, nested, case-control study of incident CRC among men and women who provided a prediagnostic blood specimen. We used an enzyme-linked immunosorbent assay to measure MIC-1 and examined associations between quintiles of MIC-1 and CRC using logistic regression adjusted for matching factors (age and date of blood draw), risk factors, and other plasma inflammatory markers. We also assessed the relationship between MIC-1 levels and prostaglandin-endoperoxide synthase 2 (PTGS2)/cyclooxygenase-2 (COX-2) enzyme status in tumors with available tissue for analysis. All statistical tests were two-sided., Results: Compared with men and women within the lowest quintile of plasma MIC-1, the multivariable relative risk (RR) for CRC was 1.93 (95% confidence interval [CI] = 1.27 to 2.94) for the highest quintile (P linear trend = .004). In an exploratory analysis, we found that among individuals with high plasma MIC-1 levels (quintiles 2-5), compared with nonuse, regular use of aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) was associated with a lower risk of PTGS2-positive CRC (multivariable RR = 0.60; 95% confidence interval = 0.41 to 0.88) but not PTGS2-negative CRC (multivariable RR = 1.21; 95% CI = 0.71 to 2.07). In contrast, among individuals with low MIC-1 levels (quintile 1), aspirin and NSAID use was not associated with a lower risk of PTGS2-positive CRC (multivariable RR = 0.57; 95% CI = 0.21 to 1.54) or PTGS2-negative CRC (multivariable RR = 1.41; 95% CI = 0.47 to 4.23)., Conclusions: Our results support an association between higher levels of circulating MIC-1 (GDF15) and CRC. Aspirin/NSAID use appeared to lower risk of PTGS2-positive cancers, particularly among individuals with high levels of circulating MIC-1.

We present the first report on experimental observation of nonlinear spectral broadening in an all-solid photonic band gap Bragg fiber of relatively large mode area approximately 62 microm(2). The theoretically designed Bragg fiber for this specific application was fabricated by the well known MCVD technique. Nonlinear spectral broadening was observed by launching high power femtosecond pulses of 1067 nm pump wavelength. These first results indicate that fabrication of such Bragg fibers, once perfected, should potentially serve as an alternative route for realization of supercontinuum light.