Using saliva epigenetic data to develop and validate a multivariable predictor of esophageal cancer status.

Background: Salivary epigenetic biomarkers may detect esophageal cancer. Methods: A total of 256 saliva samples from esophageal adenocarcinoma patients and matched volunteers were analyzed with Illumina EPIC methylation arrays. Three datasets were created, using 64% for discovery, 16% for testing and 20% for validation. Modules of gene-based methylation probes were created using weighted gene coexpression network analysis. Module significance to disease and gene importance to module were determined and a random forest classifier generated using best-scoring gene-related epigenetic probes. A cost-sensitive wrapper algorithm maximized cancer diagnosis. Results: Using age, sex and seven probes, esophageal adenocarcinoma was detected with area under the curve of 0.72 in discovery, 0.73 in testing and 0.75 in validation datasets. Cancer sensitivity was 88% with specificity of 31%. Conclusion: We have demonstrated a potentially clinically viable classifier of esophageal cancer based on saliva methylation.

Development and validation of a multivariable risk factor questionnaire to detect oesophageal cancer in 2-week wait patients.

INTRODUCTION: Oesophageal cancer is associated with poor health outcomes. Upper GI (UGI) endoscopy is the gold standard for diagnosis but is associated with patient discomfort and low yield for cancer. We used a machine learning approach to create a model which predicted oesophageal cancer based on questionnaire responses. METHODS: We used data from 2 separate prospective cross-sectional studies: the Saliva to Predict rIsk of disease using Transcriptomics and epigenetics (SPIT) study and predicting RIsk of diSease using detailed Questionnaires (RISQ) study. We recruited patients from National Health Service (NHS) suspected cancer pathways as well as patients with known cancer. We identified patient characteristics and questionnaire responses which were most associated with the development of oesophageal cancer. Using the SPIT dataset, we trained seven different machine learning models, selecting the best area under the receiver operator curve (AUC) to create our final model. We further applied a cost function to maximise cancer detection. We then independently validated the model using the RISQ dataset. RESULTS: 807 patients were included in model training and testing, split in a 70:30 ratio. 294 patients were included in model validation. The best model during training was regularised logistic regression using 17 features (median AUC: 0.81, interquartile range (IQR): 0.69-0.85). For testing and validation datasets, the model achieved an AUC of 0.71 (95% CI: 0.61-0.81) and 0.92 (95% CI: 0.88-0.96) respectively. At a set cut off, our model achieved a sensitivity of 97.6% and specificity of 59.1%. We additionally piloted the model in 12 patients with gastric cancer; 9/12 (75%) of patients were correctly classified. CONCLUSIONS: We have developed and validated a risk stratification tool using a questionnaire approach. This could aid prioritising patients at high risk of having oesophageal cancer for endoscopy. Our tool could help address endoscopic backlogs caused by the COVID-19 pandemic.

Face Mask Acceptability for Communal Religious Worship During the COVID-19 Pandemic in the United Kingdom: Results from the CONFESS Study.

The COVID-19 pandemic has led to restrictions such as social distancing and mandatory wearing of face masks. Singing and religious gatherings have been linked to infection clusters, and between 2020 and 2021 indoor congregational singing and chanting were prohibited in the United Kingdom. We evaluated attitudes to face mask use and their acceptability as well as changes within places of worship since their reopening in July up to autumn 2020. In this cross-sectional study, participants were recruited using convenience sampling through selective targeting of religious organisations and social media. Participants self-enrolled and completed an online questionnaire, which included open and closed questions. We used multivariable logistic regression to identify factors associated with face mask acceptability. We performed thematic analysis to evaluate responses to open questions. A total of 939 participants were included in the analysis. Median age was 52.7 years and 66.1% were female, while 80.7% identified as Christian. A majority (672/861; 78.0%) of participants would find it acceptable to wear a face mask and reduce their singing or chanting volume if required, even though 428/681 (49.1%) found face masks to be uncomfortable. Multivariable regression found that younger age was associated with a higher acceptability of face masks (adjusted OR (aOR): 0.98 (95% confidence interval (95% CI) 0.96-1.00), p = 0.0218). The majority of respondents stated that religious services had become shorter, attended by fewer people and with reduced singing or chanting. Most (869/893, 97.3%) stated their place of worship complied with government guidelines, with 803/887 (90.5%) reported that their place of worship enforced face mask wearing and 793/887 (89.4%) at least moderately happy with precaution measures. Our study demonstrates the significant impact of COVID-19 in places of worship but a high degree of compliance with guidelines. Face masks, despite practical difficulties, appeared to be more acceptable if there was an incentive of being able to sing and chant.

Novel epigenetic network biomarkers for early detection of esophageal cancer.

BACKGROUND: Early detection of esophageal cancer is critical to improve survival. Whilst studies have identified biomarkers, their interpretation and validity is often confounded by cell-type heterogeneity. RESULTS: Here we applied systems-epigenomic and cell-type deconvolution algorithms to a discovery set encompassing RNA-Seq and DNA methylation data from esophageal adenocarcinoma (EAC) patients and matched normal-adjacent tissue, in order to identify robust biomarkers, free from the confounding effect posed by cell-type heterogeneity. We identify 12 gene-modules that are epigenetically deregulated in EAC, and are able to validate all 12 modules in 4 independent EAC cohorts. We demonstrate that the epigenetic deregulation is present in the epithelial compartment of EAC-tissue. Using single-cell RNA-Seq data we show that one of these modules, a proto-cadherin module centered around CTNND2, is inactivated in Barrett's Esophagus, a precursor lesion to EAC. By measuring DNA methylation in saliva from EAC cases and controls, we identify a chemokine module centered around CCL20, whose methylation patterns in saliva correlate with EAC status. CONCLUSIONS: Given our observations that a CCL20 chemokine network is overactivated in EAC tissue and saliva from EAC patients, and that in independent studies CCL20 has been found to be overactivated in EAC tissue infected with the bacterium F. nucleatum, a bacterium that normally inhabits the oral cavity, our results highlight the possibility of using DNAm measurements in saliva as a proxy for changes occurring in the esophageal epithelium. Both the CTNND2/CCL20 modules represent novel promising network biomarkers for EAC that merit further investigation.

Endoscopic eradication therapy for Barrett's esophagus-related neoplasia: a final 10-year report from the UK National HALO Radiofrequency Ablation Registry.

BACKGROUND AND AIMS: Long-term durability data for effectiveness of radiofrequency ablation (RFA) to prevent esophageal adenocarcinoma in patients with dysplastic Barrett's esophagus (BE) are lacking. METHODS: We prospectively collected data from 2535 patients with BE (mean length, 5.2 cm; range, 1-20) and neoplasia (20% low-grade dysplasia, 54% high-grade dysplasia, 26% intramucosal carcinoma) who underwent RFA therapy across 28 UK hospitals. We assessed rates of invasive cancer and performed detailed analyses of 1175 patients to assess clearance rates of dysplasia (CR-D) and intestinal metaplasia (CR-IM) within 2 years of starting RFA therapy. We assessed relapses and rates of return to CR-D (CR-D2) and CR-IM (CR-IM2) after further therapy. CR-D and CR-IM were confirmed by an absence of dysplasia and intestinal metaplasia on biopsy samples taken at 2 consecutive endoscopies. RESULTS: Ten years after starting treatment, the Kaplan-Meier (KM) cancer rate was 4.1% with a crude incidence rate of .52 per 100 patient-years. CR-D and CR-IM after 2 years of therapy were 88% and 62.6%, respectively. KM relapse rates were 5.9% from CR-D and 18.7% from CR-IM at 8 years, with most occurring in the first 2 years. Both were successfully retreated with rates of CR-D2 of 63.4% and CR-IM2 of 70.0% 2 years after retreatment. EMR before RFA increased the likelihood of rescue EMR from 17.2% to 41.7% but did not affect the rate of CR-D, whereas rescue EMR after RFA commenced reduced CR-D from 91.4% to 79.7% (χ2P < .001). CONCLUSIONS: RFA treatment is effective and durable to prevent esophageal adenocarcinoma. Most treatment relapses occur early and can be successfully retreated.

Spatiotemporal droplet dispersion measurements demonstrate face masks reduce risks from singing.

COVID-19 has restricted singing in communal worship. We sought to understand variations in droplet transmission and the impact of wearing face masks. Using rapid laser planar imaging, we measured droplets while participants exhaled, said 'hello' or 'snake', sang a note or 'Happy Birthday', with and without surgical face masks. We measured mean velocity magnitude (MVM), time averaged droplet number (TADN) and maximum droplet number (MDN). Multilevel regression models were used. In 20 participants, sound intensity was 71 dB for speaking and 85 dB for singing (p < 0.001). MVM was similar for all tasks with no clear hierarchy between vocal tasks or people and > 85% reduction wearing face masks. Droplet transmission varied widely, particularly for singing. Masks decreased TADN by 99% (p < 0.001) and MDN by 98% (p < 0.001) for singing and 86-97% for other tasks. Masks reduced variance by up to 48%. When wearing a mask, neither singing task transmitted more droplets than exhaling. In conclusion, wide variation exists for droplet production. This significantly reduced when wearing face masks. Singing during religious worship wearing a face mask appears as safe as exhaling or talking. This has implications for UK public health guidance during the COVID-19 pandemic.

Predicting endoscopic activity recovery in England after COVID-19: a national analysis.

BACKGROUND: The COVID-19 pandemic has led to a substantial reduction in gastrointestinal endoscopies, creating a backlog of procedures. We aimed to quantify this backlog nationally for England and assess how various interventions might mitigate the backlog. METHODS: We did a national analysis of data for colonoscopies, flexible sigmoidoscopies, and gastroscopies from National Health Service (NHS) trusts in NHS England's Monthly Diagnostic Waiting Times and Activity dataset. Trusts were excluded if monthly data were incomplete. To estimate the potential backlog, we used linear logistic regression to project the cumulative deficit between actual procedures performed and expected procedures, based on historical pre-pandemic trends. We then made further estimations of the change to the backlog under three scenarios: recovery to a set level of capacity, ranging from 90% to 130%; further disruption to activity (eg, second pandemic wave); or introduction of faecal immunochemical testing (FIT) triaging. FINDINGS: We included data from Jan 1, 2018, to Oct 31, 2020, from 125 NHS trusts. 10 476 endoscopy procedures were done in April, 2020, representing 9·5% of those done in April, 2019 (n=110 584), before recovering to 105 716 by October, 2020 (84·5% of those done in October, 2019 [n=125 072]). Recovering to 100% capacity on the current trajectory would lead to a projected backlog of 162 735 (95% CI 143 775-181 695) colonoscopies, 119 025 (107 398-130 651) flexible sigmoidoscopies, and 194 087 (172 564-215 611) gastroscopies in January, 2021, attributable to the pandemic. Increasing capacity to 130% would still take up to June, 2022, to eliminate the backlog. A further 2-month interruption would add an extra 15·4%, a 4-month interruption would add an extra 43·8%, and a 6-month interruption would add an extra 82·5% to the potential backlog. FIT triaging of cases that are found to have greater than 10 µg haemoglobin per g would reduce colonoscopy referrals to around 75% of usual levels, with the backlog cleared in early 2022. INTERPRETATION: Our work highlights the impact of the pandemic on endoscopy services nationally. Even with mitigation measures, it could take much longer than a year to eliminate the pandemic-related backlog. Urgent action is required by key stakeholders (ie, individual NHS trusts, Clinical Commissioning Groups, British Society of Gastroenterology, and NHS England) to tackle the backlog and prevent delays to patient management. FUNDING: Wellcome/EPSRC Centre for Interventional and Surgical Sciences (WEISS) at University College London, National Institute for Health Research University College London Hospitals Biomedical Research Centre, and DATA-CAN, Health Data Research UK.

Accuracy of clinical staging for T2N0 oesophageal cancer: systematic review and meta-analysis.

Oesophageal cancer is the sixth commonest cause of overall cancer mortality. Clinical staging utilizes multiple imaging modalities to guide treatment and prognostication. T2N0 oesophageal cancer is a treatment threshold for neoadjuvant therapy. Data on accuracy of current clinical staging tests for this disease subgroup are conflicting. We performed a meta-analysis of all primary studies comparing clinical staging accuracy using multiple imaging modalities (index test) to histopathological staging following oesophagectomy (reference standard) in T2N0 oesophageal cancer. Patients that underwent neoadjuvant therapy were excluded. Electronic databases (MEDLINE, Embase, Cochrane Library) were searched up to September 2019. The primary outcome was diagnostic accuracy of combined T&N clinical staging. Publication date, first recruitment date, number of centers, sample size and geographical location main histological subtype were evaluated as potential sources of heterogeneity. The search strategy identified 1,199 studies. Twenty studies containing 5,213 patients met the inclusion criteria. Combined T&N staging accuracy was 19% (95% CI, 15-24); T staging accuracy was 29% (95% CI, 24-35); percentage of patients with T downstaging was 41% (95% CI, 33-50); percentage of patients with T upstaging was 28% (95% CI, 24-32) and percentage of patients with N upstaging was 34% (95% CI, 30-39). Significant sources of heterogeneity included the number of centers, sample size and study region. T2N0 oesophageal cancer staging remains inaccurate. A significant proportion of patients were downstaged (could have received endotherapy) or upstaged (should have received neoadjuvant chemotherapy). These findings were largely unchanged over the past two decades highlighting an urgent need for more accurate staging tests for this subgroup of patients.

How COVID-19 has changed the unselected medical take: an observational study.

INTRODUCTION: COVID-19 has had a profound effect on the NHS. Little information has been published as to how the unselected medical take has been affected. METHODS: We retrospectively reviewed patients who were referred to general medicine during March 2020. We compared clinical outcomes of patients with and without COVID-19. RESULTS: 814 patients were included, comprising 777 unique patients. On average, 26 patients were admitted per day. 38% of admitted patients were suspected of COVID-19, with greater numbers of COVID-19 patients in the second half compared to the first half of the month (p<0.001). Logistic regression analyses showed suspected COVID-19 was an independent predictor for inpatient mortality (odds ratio [OR] = 6.09, p<0.001) and 30-day mortality (OR = 4.66, p<0.001). CONCLUSIONS: COVID-19 patients had worse clinical outcomes and increased healthcare use compared to non-COVID-19 patients. Our study highlights some of the challenges in healthcare provision faced during this pandemic.

Incorporation of information diffusion model for enhancing analyses in HIV molecular surveillance.

Molecular surveillance of infections is essential in monitoring their transmission in the population. In this study, newly diagnosed HIV patients' phylogenetic, clinical and behavioural data were integrated, and an information diffusion model was incorporated in analysing transmission dynamics. A genetic network was constructed from HIV sequences, from which transmission cascades were extracted. From the transmission cascades, CRF01_AE had higher values of information diffusion metrics, including scale, speed and range, than that of B, signifying the distinct transmission patterns of two circulating subtypes in Hong Kong. Patients connected in the network, were more likely male, younger, of main circulating subtypes, to have acquired HIV infection locally, and a higher CD4 level at diagnosis. Genetic connections varied among men who have sex with men (MSM) who used different channels of sex networking and varied in their engagement in risk behaviours. MSM using recreational drugs for sex held positions of greater importance within the network. Significant differences in network metrics were observed among MSM as differentiated by their mobile apps usage patterns, evidencing the impact of social network on transmission networks. The applied model in the presence of consistently collected longitudinal data could enhance HIV molecular epidemiologic surveillance for informing future intervention planning.

Pre-exposure prophylaxis (PrEP) for MSM in low HIV incidence places: should high risk individuals be targeted?

Pre-exposure prophylaxis (PrEP) targeting high-risk men who have sex with men (MSM) has been shown to be a cost-effective HIV control measure. However, the approach could be a challenge in low HIV incidence places with a low proportion of high-risk MSM. To examine the impact of PrEP in such setting in Asia, we developed an epidemic model and conducted cost-effectiveness analysis using empirical multicentre clinical and HIV sequence data from HIV-infected MSM in Hong Kong, in conjunction with behavioural data of local MSM. Without PrEP, the HIV incidence (per 100 person-years) would increase from 1.1 to 1.6 between 2011 and 2021. PrEP could avert 3-63% of total new infections in a five-year period (2017-2021), the variability of which depends on the implementation strategies and combination with test-and-treat. However, under current market drug price in 2016, the incremental cost per quality-adjusted life-year gained (QALYG) of PrEP (USD1583136/QALYG) is almost 3 times higher than test-and-treat intervention alone (USD396874/QALYG). Assuming 93% fall of PrEP drug price and in combination with test-and-treat, putting 30% of MSM on non-targeting PrEP would be more feasible, cost-effective (USD268915/QALYG), and could avert more new infections (40%). PrEP could contribute to HIV epidemic control in a low incidence place.

An unusual presentation of cardiac tamponade associated with Epstein-Barr virus infection.

We present a case of an 80-year-old woman who presented with a dry cough, shortness of breath and general malaise. She had presented 5 days previously with a sore throat, feeling feverish and with non-specific symptoms. Her background included paroxysmal atrial fibrillation and hypertension. She was initially thought to have decompensated heart failure secondary to atrial fibrillation and was initiated on diuretic therapy. However, a transthoracic echocardiogram performed revealed collapse of the right ventricle and a swinging heart, suggestive of cardiac tamponade. The patient underwent therapeutic pericardiocentesis where 700 mL of exudative, blood-stained fluid was drained. Subsequent testing of the pericardial fluid revealed the presence of Epstein-Barr virus DNA. Serial follow-up transthoracic echocardiograms revealed resolution of the pericardial effusion and the patient remained asymptomatic.