ctDNA whole exome sequencing in pancreatic ductal adenocarcinoma unveils organ-dependent metastatic mechanisms and identifies actionable alterations in fast progressing patients.

Understanding progression mechanisms and developing new targeted therapies is imperative in pancreatic ductal adenocarcinoma (PDAC). In this study, 80 metastatic PDAC patients were prospectively recruited and divided into discovery (n=37) and validation (n=43) cohorts. Tumor and plasma samples taken at diagnosis were pair analyzed using whole exome sequencing (WES) in patients belonging to the discovery cohort alone. The variant allele frequency (VAF) of KRAS mutations was measured by ddPCR in plasma at baseline and response assessment in all patients. Plasma WES identified at least one pathogenic variant across the cohort, uncovering oncogenic mechanisms, DNA repair, microsatellite instability, and alterations in the TGFb pathway. Interestingly, actionable mutations were mostly found in plasma rather than tissue. Patients with shorter survival showed enrichment in cellular organization regulatory pathways. Through WES we could identify a specific molecular profile of patients with liver metastasis, which exhibited exclusive mutations in genes related to the adaptive immune response pathway, highlighting the importance of the immune system in liver metastasis development. Moreover, KRAS mutations in plasma (both at diagnosis and persistent at follow-up) correlated with shorter progression free survival (PFS). Patients presenting a reduction of over 84.75% in KRAS VAF at response assessment had similar PFS to KRAS-negative patients. Overall, plasma WES reveals molecular profiles indicative of rapid progression, potentially actionable targets, and associations between adaptive immune response pathway alterations and liver tropism.

COVID-19 cluster surveillance using exposure data collected from routine contact tracing: The genomic validation of a novel informatics-based approach to outbreak detection in England.

Contact tracing was used globally to prevent onwards transmission of COVID-19. Tracing contacts alone is unlikely to be sufficient in controlling community transmission, due to the pre-symptomatic, overdispersed and airborne nature of COVID-19 transmission. We describe and demonstrate the validity of a national enhanced contact tracing programme for COVID-19 cluster surveillance in England. Data on cases occurring between October 2020 and September 2021 were extracted from the national contact tracing system. Exposure clusters were identified algorithmically by matching ≥2 cases attending the same event, identified by matching postcode and event category within a 7-day rolling window. Genetic validity was defined as exposure clusters with ≥2 cases from different households with identical viral sequences. Exposure clusters were fuzzy matched to the national incident management system (HPZone) by postcode and setting description. Multivariable logistic regression modelling was used to determine cluster characteristics associated with genetic validity. Over a quarter of a million (269,470) exposure clusters were identified. Of the eligible clusters, 25% (3,306/13,008) were genetically valid. 81% (2684/3306) of these were not recorded on HPZone and were identified on average of one day earlier than incidents recorded on HPZone. Multivariable analysis demonstrated that exposure clusters occurring in workplaces (aOR = 5·10, 95% CI 4·23-6·17) and education (aOR = 3·72, 95% CI 3·08-4·49) settings were those most strongly associated with genetic validity. Cluster surveillance using enhanced contact tracing in England was a timely, comprehensive and systematic approach to the detection of transmission events occurring in community settings. Cluster surveillance can provide intelligence to stakeholders to support the assessment and management of clusters of COVID-19 at a local, regional, and national level. Future systems should include predictive modelling and network analysis to support risk assessment of exposure clusters to improve the effectiveness of enhanced contract tracing for outbreak detection.

Risk of transmission of SARS-CoV-2 on international flights, a retrospective cohort study using national surveillance data in England.

BACKGROUND: It is not yet fully understood to what extent in-flight transmission contributed to the spread of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). This study aimed to determine the occurrence and extent of SARS-CoV-2 transmission in-flight and assess factors associated with transmission risk to inform future control strategies. METHODS: Retrospective cohort study using data obtained from contact tracing of international flights arriving in England between 02/08/2021-15/10/2021. Transmission risk was estimated by calculating the secondary attack rate (SAR). Univariable and multivariable analyses of the SAR by specific risk factors was undertaken, including: number of in-flight index cases; number of symptomatic index cases; contact vaccination status; flight duration; proximity to the index case(s); contact age. RESULTS: 11,307 index cases linked to 667,849 contacts with 5,289 secondary cases reported. In-flight SAR was 0.79% (95% CI: 0.77-0.81). Increasing numbers of symptomatic cases (when > 4 index cases compared to one index case aOR 1.85; 95% CI: 1.40-2.44) and seating proximity to an index case (seated within compared to outside of two rows OR 1.82; 95% CI: 1.50-2.22) were associated with increased risk of secondary cases. Full vaccination history was protective (aOR 0.52; 95% CI: 0.47-0.57). CONCLUSIONS: This study confirms that in-flight transmission of SARS-CoV-2 occurred. There are factors associated with increased risk of infection. Contact tracing identified exposed persons who subsequently developed infection. A targeted approach to contact tracing passengers with the highest exposure risk could be an effective use of limited public health resources.

Solid pseudopapillary neoplasms of the pancreas: Multicenter Vasepa study.

INTRODUCTION: Solid pseudopapillary tumors (SPT) of the pancreas are rare exocrine neoplasms of the pancreas. Correct preoperative diagnosis is not always feasible. The treatment of choice is surgical excision. These tumors have a good prognosis with a high disease-free survival rate. OBJECTIVE: To describe the clinicopathological and radiological characteristics as well as short- and long-term follow-up results of patients who have undergone SPT resection. METHODS: Multicenter retrospective observational study in patients with SPT who had undergone surgery from January 2000-January 2022. We have studied preoperative, intraoperative, and postoperative variables as well as the follow-up results (mean 28 months). RESULTS: 20 patients with histological diagnosis of SPT in the surgical specimen were included. 90% were women; mean age was 33.5 years (13-67); 50% were asymptomatic. CT was the most used diagnostic test (90%). The most frequent location was body-tail (60%). Preoperative biopsy was performed in 13 patients (65%), which was correct in 8 patients. Surgeries performed: 7 distal pancreatectomies, 6 pancreaticoduodenectomies, 4 central pancreatectomies, 2 enucleations, and 1 total pancreatectomy. The R0 rate was 95%. Four patients presented major postoperative complications (Clavien-Dindo > II). Mean tumor size was 81 mm. Only one patient received adjuvant chemotherapy. With a mean follow-up of 28 months, 5-year disease-free survival was 95%. CONCLUSION: SPT are large, usually located in the body-tail of the pancreas, and more frequent in women. The R0 rate obtained in our series is very high (95%). The oncological results are excellent.

A case of swine influenza A(H1N2)v in England, November 2023.

Under International Health Regulations from 2005, a human infection caused by a novel influenza A virus variant is considered an event that has potential for high public health impact and is immediately notifiable to the World Health Organisation. We here describe the clinical, epidemiological and virological features of a confirmed human case of swine influenza A(H1N2)v in England detected through community respiratory virus surveillance. Swabbing and contact tracing helped refine public health risk assessment, following this unusual and unexpected finding.

Tailoring the Use of Central Pancreatectomy Through Prediction Models for Major Morbidity and Postoperative Diabetes: International Retrospective Multicenter Study.

OBJECTIVE: To develop a prediction model for major morbidity and endocrine dysfunction after CP which could help in tailoring the use of this procedure. SUMMARY BACKGROUND DATA: Central pancreatectomy (CP) is a parenchyma-sparing alternative to distal pancreatectomy for symptomatic benign and pre-malignant tumors in body and neck of the pancreas CP lowers the risk of new-onset diabetes and exocrine pancreatic insufficiency compared to distal pancreatectomy but it is thought to increase the risk of short-term complications including postoperative pancreatic fistula (POPF). METHODS: International multicenter retrospective cohort study including patients from 51 centers in 19 countries (2010-2021). Primary endpoint was major morbidity. Secondary endpoints included POPF grade B/C, endocrine dysfunction, and the use of pancreatic enzymes. Two risk model were designed for major morbidity and endocrine dysfunction utilizing multivariable logistic regression and internal and external validation. RESULTS: 838 patients after CP were included (301 (36%) minimally invasive) and major morbidity occurred in 248 (30%) patients, POPF B/C in 365 (44%), and 30-day mortality in 4 (1%). Endocrine dysfunction in 91 patients (11%) and use of pancreatic enzymes in 108 (12%). The risk model for major morbidity included male sex, age, BMI, and ASA score≥3. The model performed acceptable with an area under curve (AUC) of 0.72(CI:0.68-0.76). The risk model for endocrine dysfunction included higher BMI and male sex and performed well (AUC:0.83 (CI:0.77-0.89)). CONCLUSIONS: The proposed risk models help in tailoring the use of CP in patients with symptomatic benign and premalignant lesions in the body and neck of the pancreas and are readily available via www.pancreascalculator.com.

A Bayesian multivariate factor analysis model for causal inference using time-series observational data on mixed outcomes.

Assessing the impact of an intervention by using time-series observational data on multiple units and outcomes is a frequent problem in many fields of scientific research. Here, we propose a novel Bayesian multivariate factor analysis model for estimating intervention effects in such settings and develop an efficient Markov chain Monte Carlo algorithm to sample from the high-dimensional and nontractable posterior of interest. The proposed method is one of the few that can simultaneously deal with outcomes of mixed type (continuous, binomial, count), increase efficiency in the estimates of the causal effects by jointly modeling multiple outcomes affected by the intervention, and easily provide uncertainty quantification for all causal estimands of interest. Using the proposed approach, we evaluate the impact that Local Tracing Partnerships had on the effectiveness of England's Test and Trace programme for COVID-19.

Mpox knowledge, behaviours and barriers to public health measures among gay, bisexual and other men who have sex with men in the UK: a qualitative study to inform public health guidance and messaging.

BACKGROUND: The 2022-23 mpox epidemic is the first-time sustained community transmission had been reported in countries without epidemiological links to endemic areas. During that period, the outbreak almost exclusively affected sexual networks of gay, bisexual, or other men who have sex with men (GBMSM) and people living with HIV. In efforts to control transmission, multiple public health measures were implemented, including vaccination, contact tracing and isolation. This study examines knowledge, attitudes, and perceptions of mpox among a sample of GBMSM during the 2022-23 outbreak in the UK, including facilitators for and barriers to the uptake of public health measures. METHODS: Interviews were conducted with 44 GBMSM between May and December 2022. Data were analysed using reflexive thematic analysis. Positive and negative comments pertaining to public health measures were collated in a modified version of a 'table of changes' to inform optimisations to public health messages and guidance. RESULTS: Most interviewees were well informed about mpox transmission mechanisms and were either willing to or currently adhering to public health measures, despite low perceptions of mpox severity. Measures that aligned with existing sexual health practices and norms were considered most acceptable. Connections to GBMSM networks and social media channels were found to increase exposure to sexual health information and norms influencing protective behaviours. Those excluded or marginalized from these networks found some measures challenging to perform or adhere to. Although social media was a key mode of information sharing, there were preferences for timely information from official sources to dispel exaggerated or misleading information. CONCLUSIONS: There are differential needs, preferences, and experiences of GBMSM that limit the acceptability of some mitigation and prevention measures. Future public health interventions and campaigns should be co-designed in consultation with key groups and communities to ensure greater acceptability and credibility in different contexts and communities.

Understanding adherence to self-isolation in the first phase of the COVID-19 pandemic in England: a cross-sectional mixed-methods study.

BACKGROUND: During the early "containment" phase of the COVID-19 response in England (January-March 2020), contact tracing was managed by Public Health England (PHE). Adherence to self-isolation during this phase and how people were making those decisions has not previously been determined. The aim of this study was to gain a better understanding of decisions around adherence to self-isolation during the first phase of the COVID-19 response in England. METHODS: A mixed-methods cross sectional study was conducted, including an online survey and qualitative interviews. The overall pattern of adherence was described as never leaving home, leaving home for lower-contact reasons and leaving home for higher-contact reasons. Fisher's exact test was used to test associations between adherence and potentially predictive binary factors. Factors showing evidence of association overall were then considered in relation to the three aspects of adherence individually. Qualitative data were analysed using inductive thematic analysis. RESULTS: Of 250 respondents who were advised to self-isolate, 63% reported not leaving home at all during their isolation period, 20% reported leaving only for lower-contact activities (dog walking or exercise) and 16% reported leaving for higher-contact, and therefore higher-risk, reasons. Factors associated with adherence to never going out included: the belief that following isolation advice would save lives, experiencing COVID-19 symptoms, being advised to stay in their room, having help from outside and having regular contact by text message from PHE. Factors associated with non-adherence included being angry about the advice to isolate, being unable to get groceries delivered and concerns about losing touch with friends and family. Interviews highlighted that a sense of duty motivated people to adhere to isolation guidance and where people did leave their homes, these decisions were based on rational calculations of the risk of transmission - people would only leave their homes when they thought they were unlikely to come into contact with others. CONCLUSIONS: Understanding adherence to isolation and associated reasoning during the early stages of the pandemic is essential to pandemic preparedness for future emerging infectious disease outbreaks. Individuals make complex decisions around adherence by calibrating transmission risks, therefore treating adherence as binary should be avoided.

Evaluating the impact on health outcomes of an event that resulted in a delay in contact tracing of COVID-19 cases in England, September 2020: an observational study.

OBJECTIVE: In September 2020, 15 861 SARS-CoV-2 case records failed to upload from the Second Generation Surveillance System (SGSS) to the Contact Tracing Advisory Service (CTAS) tool, delaying the contact tracing of these cases. This study used CTAS data to determine the impact of this delay on population health outcomes: transmission events, hospitalisations and mortality. Previously, a modelling study suggested a substantial impact. DESIGN: Observational study. SETTING: England. POPULATION: Individuals testing positive for SARS-CoV-2 and their reported contacts. MAIN OUTCOME MEASURES: Secondary attack rates (SARs), hospitalisations and deaths among primary and secondary contacts were calculated, compared with all other concurrent, unaffected cases. Affected SGSS records were matched to CTAS records. Successive contacts and cases were identified and matched to hospital episode and mortality outcomes. RESULTS: Initiation of contact tracing was delayed by 3 days on average in the primary cases in the delay group (6 days) compared with the control group (3 days). This was associated with lower completion of contact tracing: 80% (95% CI: 79% to 81%) in delay group and 83% (95% CI: 83% to 84%) in control group. There was some evidence to suggest increased transmission to non-household contacts among those affected by the delay. The SAR for non-household contacts was higher among secondary contacts in the delay group than the control group (delay group: 7.9%, 95% CI: 6.5% to 9.2%; control group: 5.9%, 95% CI: 5.3% to 6.6%). There did not appear to be a significant difference between the delay and control groups in the odds of hospitalisation (crude OR: 1.1 (95% CI: 0.9 to 1.2)) or death (crude OR: 0.7 (95% CI: 0.1 to 4.0)) among secondary contacts. CONCLUSIONS: Our analysis suggests that the delay in contact tracing had a limited impact on population health outcomes; however, contact tracing was not completed for all individuals, so some transmission events might not be captured.

Did mpox knowledge, attitudes and beliefs affect intended behaviour in the general population and men who are gay, bisexual and who have sex with men? An online cross-sectional survey in the UK.

OBJECTIVES: To investigate rates of mpox beliefs, knowledge and intended behaviours in the general population and in gay, bisexual or other men who have sex with men (GBMSM), and factors associated with intended behaviours. To test the impact of motivational messages (vs a factual control) on intended behaviours. DESIGN: Cross-sectional online survey including a nested randomised controlled trial. SETTING: Data collected from 5 September 2022 to 6 October 2022. PARTICIPANTS: Participants were aged 18 years or over and lived in the UK (general population). In addition, GBMSM were male, and gay, bisexual or had sex with men. The general population sample was recruited through a market research company. GBMSM were recruited through a market research company, the dating app Grindr and targeted adverts on Meta (Facebook and Instagram). MAIN OUTCOME MEASURES: Intention to self-isolate, seek medical help, stop all sexual contact, share details of recent sexual contacts and accept vaccination. RESULTS: Sociodemographic characteristics differed by sample. There was no effect of very brief motivational messaging on behavioural intentions. Respondents from Grindr and Meta were more likely to intend to seek help immediately, completely stop sexual behaviour and be vaccinated or intend to be vaccinated, but being less likely to intend to self-isolate (ps<0.001). In the general population sample, intending to carry out protective behaviours was generally associated with being female, older, having less financial hardship, greater worry, higher perceived risk to others and higher perceived susceptibility to and severity of mpox (ps<0.001). There were fewer associations with behaviours in the Grindr sample, possibly due to reduced power. CONCLUSIONS: GBMSM were more likely to intend to enact protective behaviours, except for self-isolation. This may reflect targeted public health efforts and engagement with this group. Associations with socioeconomic factors suggest that providing financial support may encourage people to engage with protective behaviours.

Pilot of asymptomatic swabbing of humans following exposures to confirmed avian influenza A(H5) in avian species in England, 2021/2022.

A programme of asymptomatic swabbing was piloted in 2021/2022 in England to further understand the risk of human infection with avian influenza in exposed individuals and to evaluate this surveillance approach as a public health measure. There were challenges in deploying this pilot that will need to be addressed for future seasons. However, there was one detection of avian influenza A(H5N1) in a human despite low uptake in eligible exposed persons. Future use of asymptomatic swabbing could help provide an evidence base to quantify asymptomatic infection, quickly identify signals of increased animal to human transmission and improve public health preparedness.

Understanding the impact of the COVID-19 pandemic response on GI infection surveillance trends in England, January 2020-April 2022.

Stepwise non-pharmaceutical interventions and health system changes implemented as part of the COVID-19 response have had implications on the incidence, diagnosis, and reporting of other communicable diseases. Here, we established the impact of the COVID-19 outbreak response on gastrointestinal (GI) infection trends using routinely collected surveillance data from six national English laboratory, outbreak, and syndromic surveillance systems using key dates of governmental policy to assign phases for comparison between pandemic and historic data. Following decreases across all indicators during the first lockdown (March-May 2020), bacterial and parasitic pathogens associated with foodborne or environmental transmission routes recovered rapidly between June and September 2020, while those associated with travel and/or person-to-person transmission remained lower than expected for 2021. High out-of-season norovirus activity was observed with the easing of lockdown measures between June and October 2021, with this trend reflected in laboratory and outbreak systems and syndromic surveillance indicators. Above expected increases in emergency department (ED) attendances may have reflected changes in health-seeking behaviour and provision. Differential reductions across specific GI pathogens are indicative of the underlying routes of transmission. These results provide further insight into the drivers for transmission, which can help inform control measures for GI infections.

The Agile Co-production and Evaluation framework for developing public health interventions, messaging and guidance.

A lesson identified from the COVID-19 pandemic is that we need to extend existing best practice for intervention development. In particular, we need to integrate (a) state-of-the-art methods of rapidly coproducing public health interventions and messaging to support all population groups to protect themselves and their communities with (b) methods of rapidly evaluating co-produced interventions to determine which are acceptable and effective. This paper describes the Agile Co-production and Evaluation (ACE) framework, which is intended to provide a focus for investigating new ways of rapidly developing effective interventions and messaging by combining co-production methods with large-scale testing and/or real-world evaluation. We briefly review some of the participatory, qualitative and quantitative methods that could potentially be combined and propose a research agenda to further develop, refine and validate packages of methods in a variety of public health contexts to determine which combinations are feasible, cost-effective and achieve the goal of improving health and reducing health inequalities.

Duodenal diastatic perforation due to double gastric and jejunal trichobezoar in a patient with Rapunzel syndrome.

Rapunzel syndrome is a rare clinical entity in which a trichobezoar is produced by the ingestion of hair at the gastric level, extending in the form of a tail towards the duodenum. It occurs in young patients with trichotillomania and trichophagia. We present the case of a 24-year-old woman with a history of anxiety without treatment, who for 10 years presented trichotillomania and trichophagia, producing a picture of intestinal obstruction that required surgical intervention, evidencing a giant Trichobezoar throughout the gastric cavity and one jejunum associated with diastatic perforation. duodenal.

Laboratory diagnosed microbial infection in English UK Biobank participants in comparison to the general population.

Understanding the genetic and environmental risk factors for serious bacterial infections in ageing populations remains incomplete. Utilising the UK Biobank (UKB), a prospective cohort study of 500,000 adults aged 40-69 years at recruitment (2006-2010), can help address this. Partial implementation of such a system helped groups around the world make rapid progress understanding risk factors for SARS-CoV-2 infection and COVID-19, with insights appearing as early as May 2020. In principle, such approaches could also to be used for bacterial isolations. Here we report feasibility testing of linking an England-wide dataset of microbial reporting to UKB participants, to enable characterisation of microbial infections within the UKB Cohort. These records pertain mainly to bacterial isolations; SARS-CoV-2 isolations were not included. Microbiological infections occurring in patients in England, as recorded in the Public Health England second generation surveillance system (SGSS), were linked to UKB participants using pseudonymised identifiers. By January 2015, ascertainment of laboratory reports from UKB participants by SGSS was estimated at 98%. 4.5% of English UKB participants had a positive microbiological isolate in 2015. Half of UKB isolates came from 12 laboratories, and 70% from 21 laboratories. Incidence rate ratios for microbial isolation, which is indicative of serious infection, from the UKB cohort relative to the comparably aged general population ranged from 0.6 to 1, compatible with the previously described healthy participant bias in UKB. Data on microbial isolations can be linked to UKB participants from January 2015 onwards. This linked data would offer new opportunities for research into the role of bacterial agents on health and disease in middle to-old age.

Exploring the impact of shielding advice on the wellbeing of individuals identified as clinically extremely vulnerable amid the COVID-19 pandemic: a mixed-methods evaluation.

BACKGROUND: The national shielding programme was introduced by UK Government at the beginning of the COVID-19 pandemic, with individuals identified as clinically extremely vulnerable (CEV) offered advice and support to stay at home and avoid all non-essential contact. This study aimed to explore the impact and responses of "shielding" on the health and wellbeing of CEV individuals in Southwest England during the first COVID-19 lockdown. METHODS: A two-stage mixed methods study, including a structured survey (7 August-23 October 2020) and semi-structured telephone interviews (26 August-30 September 2020) with a sample of individuals who had been identified as CEV and advised to "shield" by Bristol, North Somerset & South Gloucestershire (BNSSG) Clinical Commissioning Group (CCG). RESULTS: The survey was completed by 203 people (57% female, 54% > 69 years, 94% White British, 64% retired) in Southwest England identified as CEV by BNSSG CCG. Thirteen survey respondents participated in follow-up interviews (53% female, 40% > 69 years, 100% White British, 61% retired). Receipt of 'official' communication from NHS England or General Practitioner (GP) was considered by participants as the legitimate start of shielding. 80% of survey responders felt they received all relevant advice needed to shield, yet interviewees criticised the timing of advice and often sought supplementary information. Shielding behaviours were nuanced, adapted to suit personal circumstances, and waned over time. Few interviewees received community support, although food boxes and informal social support were obtained by some. Worrying about COVID-19 was common for survey responders (90%). Since shielding had begun, physical and mental health reportedly worsened for 35% and 42% of survey responders respectively. 21% of survey responders scored ≥ 10 on the PHQ-9 questionnaire indicating possible depression and 15% scored ≥ 10 on the GAD-7 questionnaire indicating possible anxiety. CONCLUSIONS: This research highlights the difficulties in providing generic messaging that is applicable and appropriate given the diversity of individuals identified as CEV and the importance of sharing tailored and timely advice to inform shielding decisions. Providing messages that reinforce self-determined action and assistance from support services could reduce the negative impact of shielding on mental health and feelings of social isolation.