The value of plasma metanephrine measurements during adrenal vein sampling.

Objective: The assessment of primary aldosteronism incorporates adrenal vein sampling (AVS) to lateralize aldosterone excess. Current adrenal vein sampling protocols rely on concurrent cortisol measurements to assess successful cannulation and lateralization and may be inaccurate in the setting of autonomous cortisol secretion. We aimed to compare the measurement of plasma cortisol and metanephrine concentrations to assess cannulation and lateralization during AVS. Design: This is a diagnostic accuracy study in a tertiary referral endocrinology department. Methods: Forty-one consecutive patients with confirmed primary aldosteronism undergoing AVS (49 procedures) were included. None had cortisol autonomy. The use of plasma metanephrine-based ratios were compared with standard cortisol-based ratios to assess cannulation and lateralization during ACTH-stimulated AVS. Results: There was strong agreement between a cortisol selectivity index (SI) ≥5.0 and an adrenal vein (AV) to peripheral vein (PV) plasma metanephrine ratio (AVmet-PVmet) of ≥12.0 to indicate successful cannulation of the AV (n = 117, sensitivity 98%, specificity 89%, positive predictive value (PPV) 95%, negative predictive value (NPV) 94%). There was strong agreement between the standard cortisol-based SI and an AV plasma metanephrine-to-normetanephrine ratio (AVmet-AVnormet) of ≥2.0 to indicate successful cannulation (n = 117, sensitivity 93%, specificity 86%, PPV 94%, NPV 84%). There was strong agreement between the cortisol- or metanephrine-derived lateralization index (LI) > 4.0 for determining lateralization (n = 26, sensitivity 100%, specificity 94.1%, PPV 91.6%, NPV 100%). Conclusions: Ratios incorporating plasma metanephrines provide comparable outcomes to standard cortisol-based measurements for interpretation of AVS. Further studies are required to assess the use of metanephrine-derived ratios in the context of confirmed cortisol autonomy. Significance statement: Primary aldosteronism is a common cause of secondary hypertension, and adrenal vein sampling remains the gold standard test to assess lateralization. Cortisol-derived ratios to assess cannulation and lateralization may be affected by concurrent cortisol dysfunction, which is not uncommon in the context of primary aldosteronism. Our study showed comparable outcomes when using accepted cortisol-derived or metanephrine-derived ratios to determine cannulation and lateralization during adrenal vein sampling. Further research is required to validate these findings and to assess the use of metanephrine-derived ratios in the context of confirmed concurrent cortisol dysfunction.

Increasing rates of referrals for investigation of primary aldosteronism at a tertiary centre.

AIM: To describe the frequency and characteristics of patients referred for specialist investigation of primary aldosteronism (PA) in the lower North Island over a 5-year period, and the outcomes of those who received treatment. METHODS: Patients who underwent confirmatory testing or treatment for PA at Wellington Regional Hospital were retrospectively identified and data were collected from electronic clinical records. RESULTS: There has been a five-fold increase in both referrals and confirmatory testing for PA in 2021 compared to 2015. Compared to patients without PA, those eventually diagnosed with PA had a higher ARR, serum sodium, antihypertensive requirement and cardiovascular disease prevalence, as well as lower serum renin, potassium and GFR (all p <0.05), but similar blood pressure. Complete or partial clinical success was achieved in 96% of surgically treated patients compared with 70% of medically treated patients. Thirty-nine percent of patients experienced minor adverse effects with spironolactone and only one significant adverse event was experienced perioperatively. CONCLUSIONS: The rate of referrals and confirmatory testing for PA are increasing in our region. Adrenalectomy and mineralocorticoid antagonist therapy are both safe and effective treatments, although minor adverse effects were common with spironolactone.

The behaviour change behind a successful pilot of hypoglycaemia reduction with HYPO-CHEAT.

Background: Children with hypoglycaemia disorders, such as congenital hyperinsulinism (CHI), are at constant risk of hypoglycaemia (low blood sugars) with the attendant risk of brain injury. Current approaches to hypoglycaemia detection and prevention vary from fingerprick glucose testing to the provision of continuous glucose monitoring (CGM) to machine learning (ML) driven glucose forecasting. Recent trends for ML have had limited success in preventing free-living hypoglycaemia, due to a focus on increasingly accurate glucose forecasts and a failure to acknowledge the human in the loop and the essential step of changing behaviour. The wealth of evidence from the fields of behaviour change and persuasive technology (PT) allows for the creation of a theory-informed and technologically considered approach. Objectives: We aimed to create a PT that would overcome the identified barriers to hypoglycaemia prevention for those with CHI to focus on proactive prevention rather than commonly used reactive approaches. Methods: We used the behaviour change technique taxonomy and persuasive systems design models to create HYPO-CHEAT (HYpoglycaemia-Prevention-thrOugh-Cgm-HEatmap-Assisted-Technology): a novel approach that presents aggregated CGM data in simple visualisations. The resultant ease of data interpretation is intended to facilitate behaviour change and subsequently reduce hypoglycaemia. Results: HYPO-CHEAT was piloted in 10 patients with CHI over 12 weeks and successfully identified weekly patterns of hypoglycaemia. These patterns consistently correlated with identifiable behaviours and were translated into both a change in proximal fingerprick behaviour and ultimately, a significant reduction in aggregated hypoglycaemia from 7.1% to 5.4% with four out of five patients showing clinically meaningful reductions in hypoglycaemia. Conclusions: We have provided pilot data of a new approach to hypoglycaemia prevention that focuses on proactive prevention and behaviour change. This approach is personalised for individual patients with CHI and is a first step in changing our approach to hypoglycaemia prevention in this group.

Oncological outcomes after pancreatoduodenectomy for pancreatic ductal adenocarcinoma in octogenarians: case-control study.

BACKGROUND: By the end of this decade, 70 per cent of all diagnosed pancreatic ductal adenocarcinomas will be in the elderly. Surgical resection is the only curative option. In the elderly perioperative mortality is higher, while controversy still exists as to whether aggressive treatment offers any survival benefit. This study aimed to assess the oncological benefit of pancreatoduodenectomy in octogenarians with pancreatic ductal adenocarcinoma. METHOD: Retrospective multicentre case-control study of octogenarians and younger controls who underwent pancreatoduodenectomy for pancreatic ductal adenocarcinoma between 2008 and 2017. The primary endpoint was overall survival and the secondary endpoint was disease-free survival. RESULTS: Overall, 220 patients were included. Although the Charlson co-morbidity index was higher in octogenerians, Eastern Cooperative Oncology Group performance status, ASA and pathological parameters were comparable. Adjuvant therapy was more frequently delivered in the younger group (n = 80, 73 per cent versus n = 58, 53 per cent, P = 0.006). There was no significant difference between octogenarians and controls in overall survival (20 versus 29 months, P = 0.095) or disease-free survival (19 versus 22 months, P = 0.742). On multivariable analysis, age was not an independent predictor of either oncological outcome measured. CONCLUSION: Octogenarians with pancreatic ductal adenocarcinoma of the head and uncinate process may benefit from comparable oncological outcomes to younger patients with surgical treatment. Due to the age- and disease-related frailty and co-morbidities, careful preoperative assessment and patient selection is of paramount importance.

Surgical outcomes of gallbladder cancer: the OMEGA retrospective, multicentre, international cohort study.

Background: Gallbladder cancer (GBC) is rare but aggressive. The extent of surgical intervention for different GBC stages is non-uniform, ranging from cholecystectomy alone to extended resections including major hepatectomy, resection of adjacent organs and routine extrahepatic bile duct resection (EBDR). Robust evidence here is lacking, however, and survival benefit poorly defined. This study assesses factors associated with recurrence-free survival (RFS), overall survival (OS) and morbidity and mortality following GBC surgery in high income countries (HIC) and low and middle income countries (LMIC). Methods: The multicentre, retrospective Operative Management of Gallbladder Cancer (OMEGA) cohort study included all patients who underwent GBC resection across 133 centres between 1st January 2010 and 31st December 2020. Regression analyses assessed factors associated with OS, RFS and morbidity. Findings: On multivariable analysis of all 3676 patients, wedge resection and segment IVb/V resection failed to improve RFS (HR 1.04 [0.84-1.29], p = 0.711 and HR 1.18 [0.95-1.46], p = 0.13 respectively) or OS (HR 0.96 [0.79-1.17], p = 0.67 and HR 1.48 [1.16-1.88], p = 0.49 respectively), while major hepatectomy was associated with worse RFS (HR 1.33 [1.02-1.74], p = 0.037) and OS (HR 1.26 [1.03-1.53], p = 0.022). Furthermore, EBDR (OR 2.86 [2.3-3.52], p < 0.0010), resection of additional organs (OR 2.22 [1.62-3.02], p < 0.0010) and major hepatectomy (OR 3.81 [2.55-5.73], p < 0.0010) were all associated with increased morbidity and mortality. Compared to LMIC, patients in HIC were associated with poorer RFS (HR 1.18 [1.02-1.37], p = 0.031) but not OS (HR 1.05 [0.91-1.22], p = 0.48). Adjuvant and neoadjuvant treatments were infrequently used. Interpretation: In this large, multicentre analysis of GBC surgical outcomes, liver resection was not conclusively associated with improved survival, and extended resections were associated with greater morbidity and mortality without oncological benefit. Aggressive upfront resections do not benefit higher stage GBC, and international collaborations are needed to develop evidence-based neoadjuvant and adjuvant treatment strategies to minimise surgical morbidity and prioritise prognostic benefit. Funding: Cambridge Hepatopancreatobiliary Department Research Fund.

Continuous glucose monitoring for children with hypoglycaemia: Evidence in 2023.

In 2023, childhood hypoglycaemia remains a major public health problem and significant risk factor for consequent adverse neurodevelopment. Irrespective of the underlying cause, key elements of clinical management include the detection, prediction and prevention of episodes of hypoglycaemia. These tasks are increasingly served by Continuous Glucose Monitoring (CGM) devices that measure subcutaneous glucose at near-continuous frequency. While the use of CGM in type 1 diabetes is well established, the evidence for widespread use in rare hypoglycaemia disorders is less than convincing. However, in the few years since our last review there have been multiple developments and increased user feedback, requiring a review of clinical application. Despite advances in device technology, point accuracy of CGM remains low for children with non-diabetes hypoglycaemia. Simple provision of CGM devices has not replicated the efficacy seen in those with diabetes and is yet to show benefit. Machine learning techniques for hypoglycaemia prevention have so far failed to demonstrate sufficient prediction accuracy for real world use even in those with diabetes. Furthermore, access to CGM globally is restricted by costs kept high by the commercially-driven speed of technical innovation. Nonetheless, the ability of CGM to digitally phenotype disease groups has led to a better understanding of natural history of disease, facilitated diagnoses and informed changes in clinical management. Large CGM datasets have prompted re-evaluation of hypoglycaemia incidence and facilitated improved trial design. Importantly, an individualised approach and focus on the behavioural determinants of hypoglycaemia has led to real world reduction in hypoglycaemia. In this state of the art review, we critically analyse the updated evidence for use of CGM in non-diabetic childhood hypoglycaemia disorders since 2020 and provide suggestions for qualified use.

The hypoglycaemia error grid: A UK-wide consensus on CGM accuracy assessment in hyperinsulinism.

Objective: Continuous Glucose Monitoring (CGM) is gaining in popularity for patients with paediatric hypoglycaemia disorders such as Congenital Hyperinsulinism (CHI), but no standard measures of accuracy or associated clinical risk are available. The small number of prior assessments of CGM accuracy in CHI have thus been incomplete. We aimed to develop a novel Hypoglycaemia Error Grid (HEG) for CGM assessment for those with CHI based on expert consensus opinion applied to a large paired (CGM/blood glucose) dataset. Design and methods: Paediatric endocrinology consultants regularly managing CHI in the two UK centres of excellence were asked to complete a questionnaire regarding glucose cutoffs and associated anticipated risks of CGM errors in a hypothetical model. Collated information was utilised to mathematically generate the HEG which was then approved by expert, consensus opinion. Ten patients with CHI underwent 12 weeks of monitoring with a Dexcom G6 CGM and self-monitored blood glucose (SMBG) with a Contour Next One glucometer to test application of the HEG and provide an assessment of accuracy for those with CHI. Results: CGM performance was suboptimal, based on 1441 paired values of CGM and SMBG showing Mean Absolute Relative Difference (MARD) of 19.3% and hypoglycaemia (glucose <3.5mmol/L (63mg/dL)) sensitivity of only 45%. The HEG provided clinical context to CGM errors with 15% classified as moderate risk by expert consensus when data was restricted to that of practical use. This provides a contrasting risk profile from existing diabetes error grids, reinforcing its utility in the clinical assessment of CGM accuracy in hypoglycaemia. Conclusions: The Hypoglycaemia Error Grid, based on UK expert consensus opinion has demonstrated inadequate accuracy of CGM to recommend as a standalone tool for routine clinical use. However, suboptimal accuracy of CGM relative to SMBG does not detract from alternative uses of CGM in this patient group, such as use as a digital phenotyping tool. The HEG is freely available on GitHub for use by other researchers to assess accuracy in their patient populations and validate these findings.

HYPO-CHEAT's aggregated weekly visualisations of risk reduce real world hypoglycaemia.

Background: Children with congenital hyperinsulinism (CHI) are at constant risk of hypoglycaemia with the attendant risk of brain injury. Current hypoglycaemia prevention methods centre on the prediction of a continuous glucose variable using machine learning (ML) processing of continuous glucose monitoring (CGM). This approach ignores repetitive and predictable behavioural factors and is dependent upon ongoing CGM. Thus, there has been very limited success in reducing real-world hypoglycaemia with a ML approach in any condition. Objectives: We describe the development of HYPO-CHEAT (HYpoglycaemia-Prevention-thrOugh-CGM-HEatmap-Technology), which is designed to overcome these limitations by describing weekly hypoglycaemia risk. We tested HYPO-CHEAT in a real-world setting to evaluate change in hypoglycaemia. Methods: HYPO-CHEAT aggregates individual CGM data to identify weekly hypoglycaemia patterns. These are visualised via a hypoglycaemia heatmap along with actionable interpretations and targets. The algorithm is iterative and reacts to anticipated changing patterns of hypoglycaemia. HYPO-CHEAT was compared with Dexcom Clarity's pattern identification and Facebook Prophet's forecasting algorithm using data from 10 children with CHI using CGM for 12 weeks. HYPO-CHEAT's efficacy was assessed via change in time below range (TBR). Results: HYPO-CHEAT identified hypoglycaemia patterns in all patients. Dexcom Clarity identified no patterns. Predictions from Facebook Prophet were inconsistent and difficult to interpret. Importantly, the patterns identified by HYPO-CHEAT matched the lived experience of all patients, generating new and actionable understanding of the cause of hypos. This facilitated patients to significantly reduce their time in hypoglycaemia from 7.1% to 5.4% even when real-time CGM data was removed. Conclusions: HYPO-CHEAT's personalised hypoglycaemia heatmaps reduced total and targeted TBR even when CGM was reblinded. HYPO-CHEAT offers a highly effective and immediately available personalised approach to prevent hypoglycaemia and empower patients to self-care.

Severe refractory warm autoimmune haemolytic anaemia after the SARS-CoV-2 Pfizer-BioNTech vaccine (BNT162b2 mRNA) managed with emergency splenectomy and complement inhibition with eculizumab.

A male in his teens with a history of liver transplant for biliary atresia (aged 2 years) and autoimmune haemolytic anaemia (AIHA, aged 6 years) presented with jaundice, dark urine, fatigue and chest discomfort that began 48 hours after the first dose of SARS-CoV-2 Pfizer-BioNTech vaccine (BNT162b2 mRNA). Investigations revealed a warm AIHA picture. Over 4 weeks the patient developed life-threatening anaemia culminating in haemoglobin of 35 g/L (after transfusion), lactate dehydrogenase of 1293 units/L and bilirubin of 228 µmol/L, refractory to standard treatment with corticosteroids and rituximab. An emergency splenectomy was performed that slowed haemolysis but did not completely ameliorate it. Eculizumab, a terminal complement pathway inhibitor, was initiated to arrest intravascular haemolysis and showed a favourable response. AIHA is rare but described after the SARS-CoV-2 Pfizer-BioNTech vaccine. This case highlights the rare complication of AIHA, the use of emergency splenectomy for disease control, and the use of eculizumab.

Heterogeneity of management practices surrounding operable gallbladder cancer - results of the OMEGA-S international HPB surgical survey.

BACKGROUND: Gallbladder cancer (GBC) is an aggressive, uncommon malignancy, with variation in operative approaches adopted across centres and few large-scale studies to guide practice. We aimed to identify the extent of heterogeneity in GBC internationally to better inform the need for future multicentre studies. METHODS: A 34-question online survey was disseminated to members of the European-African Hepatopancreatobiliary Association (EAHPBA), American Hepatopancreatobiliary Association (AHPBA) and Asia-Pacific Hepatopancreatobiliary Association (A-PHPBA) regarding practices around diagnostic workup, operative approach, utilization of neoadjuvant and adjuvant therapies and surveillance strategies. RESULTS: Two hundred and three surgeons responded from 51 countries. High liver resection volume units (>50 resections/year) organised HPB multidisciplinary team discussion of GBCs more commonly than those with low volumes (p < 0.0001). Management practices exhibited areas of heterogeneity, particularly around operative extent. Contrary to consensus guidelines, anatomical liver resections were favoured over non-anatomical resections for T3 tumours and above, lymphadenectomy extent was lower than recommended, and a minority of respondents still routinely excised the common bile duct or port sites. CONCLUSION: Our findings suggest some similarities in the management of GBC internationally, but also specific areas of practice which differed from published guidelines. Transcontinental collaborative studies on GBC are necessary to establish evidence-based practice to minimise variation and optimise outcomes.

Families' Experiences of Continuous Glucose Monitoring in the Management of Congenital Hyperinsulinism: A Thematic Analysis.

Background and Aims: In patients with congenital hyperinsulinism (CHI), recurrent hypoglycaemia can lead to longstanding neurological impairments. At present, glycaemic monitoring is with intermittent fingerprick blood glucose testing but this lacks utility to identify patterns and misses hypoglycaemic episodes between tests. Although continuous glucose monitoring (CGM) is well established in type 1 diabetes, its use has only been described in small studies in patients with CHI. In such studies, medical perspectives have been provided without fully considering the views of families using CGM. In this qualitative study, we aimed to explore families' experiences of using CGM in order to inform future clinical strategies for the management of CHI. Methods: Ten patients with CHI in a specialist centre used CGM for twelve weeks. All were invited to participate. Semi-structured interviews were conducted with nine families in whom patient ages ranged between two and seventeen years. Transcripts of the audio-recorded interviews were analysed using an inductive thematic analysis method. Results: Analysis revealed five core themes: CGM's function as an educational tool; behavioural changes; positive experiences; negative experiences; and design improvements. Close monitoring and retrospective analysis of glucose trends allowed for enhanced understanding of factors that influenced glucose levels at various times of the day. Parents noted more hypoglycaemic episodes than previously encountered through fingerprick tests; this new knowledge prompted modification of daily routines to prevent and improve the management of hypoglycaemia. CGM use was viewed favourably as offering parental reassurance, reduced fingerprick tests and predictive warnings. However, families also reported unfavourable aspects of alarms and questionable accuracy at low glucose levels. Adolescents were frustrated by the short proximity range for data transmission resulting in the need to always carry a separate receiver. Overall, families were positive about the use of CGM but expected application to be tailored to their child's medical condition. Conclusions: Patients and families with CHI using CGM noticed trends in glucose levels which motivated behavioural changes to reduce hypoglycaemia with advantages outweighing disadvantages. They expected CHI-specific modifications to enhance utility. Future design of CGM should incorporate end users' opinions and experiences for optimal glycaemic monitoring of CHI.

Primary hyperparathyroidism in adults-(Part II) surgical management and postoperative follow-up: Position statement of the Endocrine Society of Australia, The Australian & New Zealand Endocrine Surgeons, and The Australian & New Zealand Bone and Mineral Society.

OBJECTIVE: To develop evidence-based recommendations to guide the surgical management and postoperative follow-up of adults with primary hyperparathyroidism. METHODS: Representatives from relevant Australian and New Zealand Societies used a systematic approach for adaptation of guidelines (ADAPTE) to derive an evidence-informed position statement addressing eight key questions. RESULTS: Diagnostic imaging does not determine suitability for surgery but can guide the planning of surgery in suitable candidates. First-line imaging includes ultrasound and either parathyroid 4DCT or scintigraphy, depending on local availability and expertise. Minimally invasive parathyroidectomy is appropriate in most patients with concordant imaging. Bilateral neck exploration should be considered in those with discordant/negative imaging findings, multi-gland disease and genetic/familial risk factors. Parathyroid surgery, especially re-operative surgery, has better outcomes in the hands of higher volume surgeons. Neuromonitoring is generally not required for initial surgery but should be considered for re-operative surgery. Following parathyroidectomy, calcium and parathyroid hormone levels should be re-checked in the first 24 h and repeated early if there are risk factors for hypocalcaemia. Eucalcaemia at 6 months is consistent with surgical cure; parathyroid hormone levels do not need to be re-checked in the absence of other clinical indications. Longer-term surveillance of skeletal health is recommended. CONCLUSIONS: This position statement provides up-to-date guidance on evidence-based best practice surgical and postoperative management of adults with primary hyperparathyroidism.

Primary hyperparathyroidism in adults-(Part I) assessment and medical management: Position statement of the endocrine society of Australia, the Australian & New Zealand endocrine surgeons, and the Australian & New Zealand bone and mineral society.

OBJECTIVE: To formulate clinical consensus recommendations on the presentation, assessment, and management of primary hyperparathyroidism (PHPT) in adults. METHODS: Representatives from relevant Australian and New Zealand Societies used a systematic approach for adaptation of guidelines (ADAPTE) to derive an evidence-informed position statement addressing nine key questions. RESULTS: PHPT is a biochemical diagnosis. Serum calcium should be measured in patients with suggestive symptoms, reduced bone mineral density or minimal trauma fractures, and in those with renal stones. Other indications are detailed in the manuscript. In patients with hypercalcaemia, intact parathyroid hormone, 25-hydroxy vitamin D, phosphate, and renal function should be measured. In established PHPT, assessment of bone mineral density, vertebral fractures, urinary tract calculi/nephrocalcinosis and quantification of urinary calcium excretion is warranted. Parathyroidectomy is the only definitive treatment and is warranted for all symptomatic patients and should be considered for asymptomatic patients without contraindications to surgery and with >10 years life expectancy. In patients who do not undergo surgery, we recommend annual evaluation for disease progression. Where the diagnosis is not clear or the risk-benefit ratio is not obvious, multidisciplinary discussion and formulation of a consensus management plan is appropriate. Genetic testing for familial hyperparathyroidism is recommended in selected patients. CONCLUSIONS: These clinical consensus recommendations were developed to provide clinicians with contemporary guidance on the assessment and management of PHPT in adults. It is anticipated that improved health outcomes for individuals and the population will be achieved at a decreased cost to the community.

Short-term outcomes after pancreatoduodenectomy in octogenarians: multicentre case-control study.

BACKGROUND: Pancreatoduodenectomy (PD) is frequently the surgical treatment indicated for a number of pathologies. Elderly patients may be denied surgery because of concerns over poor perioperative outcomes. The aim of this study was to evaluate postoperative clinical outcomes and provide evidence on current UK practice in the elderly population after PD. METHODS: This was a multicentre retrospective case-control study of octogenarians undergoing PD between January 2008 and December 2017, matched with younger controls from seven specialist centres in the UK. The primary endpoint was 90-day mortality. Secondary endpoints were index admission mortality, postoperative complications, and 30-day readmission rates. RESULTS: In total, 235 octogenarians (median age 81 (range 80-90) years) and 235 controls (age 67 (31-79) years) were included in the study. Eastern Cooperative Oncology Group performance status (median 0 (range 0-3) versus 0 (0-2); P = 0.010) and Charlson Co-morbidity Index score (7 (6-11) versus 5 (2-9); P = 0.001) were higher for octogenarians than controls. Postoperative complication and 30-day readmission rates were comparable. The 90-day mortality rate was higher among octogenarians (9 versus 3 per cent; P = 0.030). Index admission mortality rates were comparable (4 versus 2 per cent; P = 0.160), indicating that the difference in mortality was related to deaths after hospital discharge. Despite the higher 90-day mortality rate in the octogenarian population, multivariable Cox regression analysis did not identify age as an independent predictor of postoperative mortality. CONCLUSION: Despite careful patient selection and comparable index admission mortality, 90-day and, particularly, out-of-hospital mortality rates were higher in octogenarians.

Impact of SARS-CoV-2 pandemic on pancreatic cancer services and treatment pathways: United Kingdom experience.

INTRODUCTION: The SARS-CoV-2 pandemic presented healthcare providers with an extreme challenge to provide cancer services. The impact upon the diagnostic and treatment capacity to treat pancreatic cancer is unclear. This study aimed to identify national variation in treatment pathways during the pandemic. METHODS: A survey was distributed to all United Kingdom pancreatic specialist centres, to assess diagnostic, therapeutic and interventional services availability, and alterations in treatment pathways. A repeating methodology enabled assessment over time as the pandemic evolved. RESULTS: Responses were received from all 29 centres. Over the first six weeks of the pandemic, less than a quarter of centres had normal availability of diagnostic pathways and a fifth of centres had no capacity whatsoever to undertake surgery. As the pandemic progressed services have gradually improved though most centres remain constrained to some degree. One third of centres changed their standard resectable pathway from surgery-first to neoadjuvant chemotherapy. Elderly patients, and those with COPD were less likely to be offered treatment during the pandemic. CONCLUSION: The COVID-19 pandemic has affected the capacity of the NHS to provide diagnostic and staging investigations for pancreatic cancer. The impact of revised treatment pathways has yet to be realised.

Clustering of Hypoglycemia Events in Patients With Hyperinsulinism: Extension of the Digital Phenotype Through Retrospective Data Analysis.

BACKGROUND: Hyperinsulinism (HI) due to excess and dysregulated insulin secretion is the most common cause of severe and recurrent hypoglycemia in childhood. High cerebral glucose use in the early hours results in a high risk of hypoglycemia in people with diabetes and carries a significant risk of brain injury. Prevention of hypoglycemia is the cornerstone of the management of HI, but the risk of hypoglycemia at night or the timing of hypoglycemia in children with HI has not been studied; thus, the digital phenotype remains incomplete and management suboptimal. OBJECTIVE: This study aims to quantify the timing of hypoglycemia in patients with HI to describe glycemic variability and to extend the digital phenotype. This will facilitate future work using computational modeling to enable behavior change and reduce exposure of patients with HI to injurious hypoglycemic events. METHODS: Patients underwent continuous glucose monitoring (CGM) with a Dexcom G4 or G6 CGM device as part of their clinical assessment for either HI (N=23) or idiopathic ketotic hypoglycemia (IKH; N=24). The CGM data were analyzed for temporal trends. Hypoglycemia was defined as glucose levels <3.5 mmol/L. RESULTS: A total of 449 hypoglycemic events totaling 15,610 minutes were captured over 237 days from 47 patients (29 males; mean age 70 months, SD 53). The mean length of hypoglycemic events was 35 minutes. There was a clear tendency for hypoglycemia in the early hours (3-7 AM), particularly for patients with HI older than 10 months who experienced hypoglycemia 7.6% (1480/19,370 minutes) of time in this period compared with 2.6% (2405/92,840 minutes) of time outside this period (P<.001). This tendency was less pronounced in patients with HI who were younger than 10 months, patients with a negative genetic test result, and patients with IKH. Despite real-time CGM, there were 42 hypoglycemic events from 13 separate patients with HI lasting >30 minutes. CONCLUSIONS: This is the first study to have taken the first step in extending the digital phenotype of HI by describing the glycemic trends and identifying the timing of hypoglycemia measured by CGM. We have identified the early hours as a time of high hypoglycemia risk for patients with HI and demonstrated that simple provision of CGM data to patients is not sufficient to eliminate hypoglycemia. Future work in HI should concentrate on the early hours as a period of high risk for hypoglycemia and must target personalized hypoglycemia predictions. Focus must move to the human-computer interaction as an aspect of the digital phenotype that is susceptible to change rather than simple mathematical modeling to produce small improvements in hypoglycemia prediction accuracy.

Digital Phenotypes for Understanding Individuals' Compliance With COVID-19 Policies and Personalized Nudges: Longitudinal Observational Study.

BACKGROUND: Governments promote behavioral policies such as social distancing and phased reopening to control the spread of COVID-19. Digital phenotyping helps promote the compliance with these policies through the personalized behavioral knowledge it produces. OBJECTIVE: This study investigated the value of smartphone-derived digital phenotypes in (1) analyzing individuals' compliance with COVID-19 policies through behavioral responses and (2) suggesting ways to personalize communication through those policies. METHODS: We conducted longitudinal experiments that started before the outbreak of COVID-19 and continued during the pandemic. A total of 16 participants were recruited before the pandemic, and a smartphone sensing app was installed for each of them. We then assessed individual compliance with COVID-19 policies and their impact on habitual behaviors. RESULTS: Our results show a significant change in people's mobility (P<.001) as a result of COVID-19 regulations, from an average of 10 visited places every week to approximately 2 places a week. We also discussed our results within the context of nudges used by the National Health Service in the United Kingdom to promote COVID-19 regulations. CONCLUSIONS: Our findings show that digital phenotyping has substantial value in understanding people's behavior during a pandemic. Behavioral features extracted from digital phenotypes can facilitate the personalization of and compliance with behavioral policies. A rule-based messaging system can be implemented to deliver nudges on the basis of digital phenotyping.

Liver regeneration biology: Implications for liver tumour therapies.

The liver has remarkable regenerative potential, with the capacity to regenerate after 75% hepatectomy in humans and up to 90% hepatectomy in some rodent models, enabling it to meet the challenge of diverse injury types, including physical trauma, infection, inflammatory processes, direct toxicity, and immunological insults. Current understanding of liver regeneration is based largely on animal research, historically in large animals, and more recently in rodents and zebrafish, which provide powerful genetic manipulation experimental tools. Whilst immensely valuable, these models have limitations in extrapolation to the human situation. In vitro models have evolved from 2-dimensional culture to complex 3 dimensional organoids, but also have shortcomings in replicating the complex hepatic micro-anatomical and physiological milieu. The process of liver regeneration is only partially understood and characterized by layers of complexity. Liver regeneration is triggered and controlled by a multitude of mitogens acting in autocrine, paracrine, and endocrine ways, with much redundancy and cross-talk between biochemical pathways. The regenerative response is variable, involving both hypertrophy and true proliferative hyperplasia, which is itself variable, including both cellular phenotypic fidelity and cellular trans-differentiation, according to the type of injury. Complex interactions occur between parenchymal and non-parenchymal cells, and regeneration is affected by the status of the liver parenchyma, with differences between healthy and diseased liver. Finally, the process of termination of liver regeneration is even less well understood than its triggers. The complexity of liver regeneration biology combined with limited understanding has restricted specific clinical interventions to enhance liver regeneration. Moreover, manipulating the fundamental biochemical pathways involved would require cautious assessment, for fear of unintended consequences. Nevertheless, current knowledge provides guiding principles for strategies to optimise liver regeneration potential.

Colorectal liver metastases: Current management and future perspectives.

The liver is the commonest site of metastatic disease for patients with colorectal cancer, with at least 25% developing colorectal liver metastases (CRLM) during the course of their illness. The management of CRLM has evolved into a complex field requiring input from experienced members of a multi-disciplinary team involving radiology (cross sectional, nuclear medicine and interventional), Oncology, Liver surgery, Colorectal surgery, and Histopathology. Patient management is based on assessment of sophisticated clinical, radiological and biomarker information. Despite incomplete evidence in this very heterogeneous patient group, maximising resection of CRLM using all available techniques remains a key objective and provides the best chance of long-term survival and cure. To this end, liver resection is maximised by the use of downsizing chemotherapy, optimisation of liver remnant by portal vein embolization, associating liver partition and portal vein ligation for staged hepatectomy, and combining resection with ablation, in the context of improvements in the functional assessment of the future remnant liver. Liver resection may safely be carried out laparoscopically or open, and synchronously with, or before, colorectal surgery in selected patients. For unresectable patients, treatment options including systemic chemotherapy, targeted biological agents, intra-arterial infusion or bead delivered chemotherapy, tumour ablation, stereotactic radiotherapy, and selective internal radiotherapy contribute to improve survival and may convert initially unresectable patients to operability. Currently evolving areas include biomarker characterisation of tumours, the development of novel systemic agents targeting specific oncogenic pathways, and the potential re-emergence of radical surgical options such as liver transplantation.