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Purpose of Review: Adolescents with haematological malignancies within adult services, in the UK from 16 years old, have unique needs and require developmentally targeted services and approaches to care delivery. High-risk intensive treatments are common for this cohort and a better understanding of what individualised supportive and palliative care means in this context is required., Recent Findings: Being known and understood as an emerging adult, with particular recognition of developmental stage, is an essential component of quality measures and underpins the adolescent, and caregiver, experience when faced with an uncertain or poor cancer prognosis (UPCP). Healthcare professionals (HCPs) can experience increased emotional labour and feelings of professional inadequacy when caring for adolescents with UPCP. Therapeutic alliance improves HCPs understanding of optimum individualised care by improving communication and supported decision making. Access to training and support for HCPs is required to address the emotional impact of therapeutic alliance with teenage/adolescent and young adults (T/AYAs) with advanced cancer., Summary: Investment in therapeutic alliance, alongside robust support mechanisms and targeted training, can improve the skills, confidence and wellbeing for HCPs, and can also ensure optimum individualised care for T/AYAs with UPCP. Evidence for optimum care for adolescents with advanced cancer is relatively scarce, especially for younger T/AYAs (16-24) in the UK who sit within adult services. Further evaluation of the impact of current UK expertise, services and programs are needed to inform future development., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Simple Summary: Neuroendocrine neoplasms (NENs) are occurring more frequently worldwide. Data from the UK cancer database (National Cancer Registration and Analysis Service (NCRAS)) showed that female patients have better survival with neuroendocrine neoplasms. This study used the U.S. cancer database (Surveillance, Epidemiology, and End Results Program (SEER)) to validate and compare these findings. Sixty-months survival for NENs were calculated for both male and female patients from NCRAS and SEER. The findings from NCRAS were confirmed by the findings from SEER that females survive more than males with NENs, mainly with lung and stomach NENs. The reason behind this is unclear and remains unexplained. Background: Neuroendocrine neoplasms (NENs) are increasing in incidence globally. Previous analysis of the UK cancer database (National Cancer Registration and Analysis Service (NCRAS)) showed a notable female survival advantage in most tumour sites. This study aims to compare NCRAS to the Surveillance, Epidemiology, and End Results Program (SEER) to validate these results using the same statistical methods. Methods: A total of 14,834 and 108,399 patients with NENs were extracted from NCRAS and SEER, respectively. Sixty-months survival for both males and females for each anatomical site of NENs were calculated using restricted mean survival time (RMST) and Kaplan–Meier Survival estimates. The sixty-month RMST female survival advantage (FSA) was calculated. Results: FSA was similar in NCRAS and SEER. The highest FSA occurred in lung and stomach NENs. Conclusions: The data from SEER confirm the findings published by NCRAS. Female survival advantage remains unexplained. [ABSTRACT FROM AUTHOR]

A shared decision on the most appropriate agent for the treatment of cancer-associated thrombosis should consider the following factors, which should be reassessed as patients continue along their cancer care pathway: risk of bleeding; tumour site; suitability of oral medications; potential for drug-drug interactions; and patient preference and values regarding choice of drug. Continuing anticoagulation beyond 6 months in patients with cancer-associated venous thromboembolism and active cancer is recommended., (© 2024 British Society for Haematology and John Wiley & Sons Ltd.)

Information about the NMR metabolomics landscape of overall, and common cancers is still limited. Based on a cohort of 83,290 participants from the UK Biobank, we used multivariate Cox regression to assess the associations between each of the 168 metabolites with the risks of overall cancer and 20 specific types of cancer. Then, we applied LASSO to identify important metabolites for overall cancer risk and obtained their associations using multivariate cox regression. We further conducted mediation analysis to evaluate the mediated role of metabolites in the effects of traditional factors on overall cancer risk. Finally, we included the 13 identified metabolites as predictors in prediction models, and compared the accuracies of our traditional models. We found that there were commonalities among the metabolic profiles of overall and specific types of cancer: the top 20 frequently identified metabolites for 20 specific types of cancer were all associated with overall cancer; most of the specific types of cancer had common identified metabolites. Meanwhile, the associations between the same metabolite with different types of cancer can vary based on the site of origin. We identified 13 metabolic biomarkers associated with overall cancer, and found that they mediated the effects of traditional factors. The accuracies of prediction models improved when we added 13 identified metabolites in models. This study is helpful to understand the metabolic mechanisms of overall and a wide range of cancers, and our results also indicate that NMR metabolites are potential biomarkers in cancer diagnosis and prevention., (© 2024 UICC.)

The continuing increase in patient numbers and improvement in healthcare provisions of HIV services in the UK, alongside the effectiveness of combined antiretroviral therapy (cART), has resulted in increasing numbers of the ageing population among people living with HIV (PLWH). It is expected that geriatricians will need to deal with many older people living with HIV (OPLWH) as life expectancy increases. Therefore, geriatric syndromes in OPLWH will be similar to the normal population, such as falls, cognitive decline, frailty, dementia, hypertension, diabetes and polypharmacy. The increase in the long-term use of cART, diabetes, dyslipidaemia and hypertension may lead to high prevalence of cardiovascular disease (CVD). The treatment of such conditions may lead to polypharmacy and may increase the risk of cART drug–drug interactions. In addition, the risk of developing infection and cancer is high. OPLWH may develop an early onset of low bone mineral density (BMD), osteoporosis and fractures. In this review, we have also provided potential psychosocial aspects of an ageing population with HIV, addressing issues such as depression, stigma, isolation and the need for comprehensive medical and psychosocial care through an interdisciplinary team in a hospital or community setting. OPLWH have a relatively high burden of physical, psychological, and spiritual needs and social difficulties, which require palliative care. The holistic type of palliative care that will improve physical, emotional and psychological wellbeing is discussed in this review. [ABSTRACT FROM AUTHOR]

Background: Monte Carlo (MC) simulations are used in nuclear medicine imaging as they provide unparalleled insight into processes that are not directly experimentally measurable, such as scatter and attenuation in an acquisition. Whilst MC is often used to provide a 'ground-truth', this is only the case if the simulation is fully validated against experimental data. This work presents a quantitative validation for a MC simulation of a single-photon emission computed tomography (SPECT) system. Methods: An MC simulation model of the Mediso AnyScan SCP SPECT system installed at the UK National Physical Laboratory was developed in the GATE (Geant4 Application for Tomographic Emission) toolkit. Components of the detector head and two collimator configurations were modelled according to technical specifications and physical measurements. Experimental detection efficiency measurements were collected for a range of energies, permitting an energy-dependent intrinsic camera efficiency correction function to be determined and applied to the simulation on an event-by-event basis. Experimental data were collected in a range of geometries with 99 m Tc for comparison to simulation. The procedure was then repeated with 177 Lu to determine how the validation extended to another isotope and set of collimators. Results: The simulation's spatial resolution, sensitivity, energy spectra and the projection images were compared with experimental measurements. The simulation and experimental uncertainties were determined and propagated to all calculations, permitting the quantitative agreement between simulated and experimental SPECT acquisitions to be determined. Statistical agreement was seen in sinograms and projection images of both 99 m Tc and 177 Lu data. Average simulated and experimental sensitivity ratios of ( 0.991 ± 0.011 ) were seen for emission and scatter windows of 99 m Tc, and ( 0.897 ± 0.014 ) and ( 0.839 ± 0.014 ) for the 113 and 208 keV emissions of 177 Lu, respectively. Conclusions: MC simulations will always be an approximation of a physical system and the level of agreement should be assessed. A validation method is presented to quantify the level of agreement between a simulation model and a physical SPECT system. [ABSTRACT FROM AUTHOR]

While chronological age is the single biggest risk factor for cancer, it is less clear whether frailty, an age-related state of physiological decline, may also predict cancer incidence. We assessed the associations of frailty index (FI) and frailty phenotype (FP) scores with the incidence of any cancer and five common cancers (breast, prostate, lung, colorectal, melanoma) in 453,144 UK Biobank (UKB) and 36,888 Screening Across the Lifespan Twin study (SALT) participants, who aged 38–73 years and had no cancer diagnosis at baseline. During a median follow-up of 10.9 and 10.7 years, 53,049 (11.7%) and 4,362 (11.8%) incident cancers were documented in UKB and SALT, respectively. Using multivariable-adjusted Cox models, we found a higher risk of any cancer in frail vs. non-frail UKB participants, when defined by both FI (hazard ratio [HR] = 1.22; 95% confidence interval [CI] = 1.17–1.28) and FP (HR = 1.16; 95% CI = 1.11–1.21). The FI in SALT similarly predicted risk of any cancer (HR = 1.31; 95% CI = 1.15–1.49). Moreover, frailty was predictive of lung cancer in UKB, although this association was not observed in SALT. Adding frailty scores to models including age, sex, and traditional cancer risk factors resulted in little improvement in C-statistics for most cancers. In a within-twin-pair analysis in SALT, the association between FI and any cancer was attenuated within monozygotic but not dizygotic twins, indicating that it may partly be explained by genetic factors. Our findings suggest that frailty scores are associated with the incidence of any cancer and lung cancer, although their clinical utility for predicting cancers may be limited. [ABSTRACT FROM AUTHOR]

Background: Developmental researchers often use a multi-informant approach to measure adolescent behaviour and adjustment, but informant discrepancies are common. In general population samples, it is often found that parents report more positive and less negative outcomes than adolescents themselves. This study aimed to investigate factors associated with informant discrepancy, including adolescent sex, and parental level of psychological distress and education. Methods: Informant discrepancy on the Strengths and Difficulties Questionnaire was investigated using a Latent Difference Score (LDS) approach, which estimates the true difference between parent and adolescent reports in a structural equation model. The sample were parent-adolescent dyads from the seventh wave of the UK Millennium Cohort Study (N = 6947, 49.3% female, aged 17 years). Results: Parents reported lower levels of difficulties (emotion symptoms, peer problems, conduct problems), and higher levels of pro-social behaviour than adolescents themselves. Conditional effects were found, as discrepancy was greater amongst parent-daughter dyads for emotion and peer problems, and greater amongst parent-son dyads for conduct problems and pro-social behaviour. Parent-adolescent discrepancy was also greater generally if parents had a lower level of psychological distress or a higher level of education. Conclusions: In a large general population sample from the UK, it was found that adolescents tended to report more negative and less positive outcomes than parents reported about them. Conditional effects were found at the parent and adolescent level suggesting that specific informant biases are likely to impact the measurement of adolescent behaviour and adjustment across reporters. [ABSTRACT FROM AUTHOR]

Background and aims: Summarised in polygenic risk scores (PRS), the effect of common, low penetrant genetic variants associated with colorectal cancer (CRC), can be used for risk stratification. Methods: To assess the combined impact of the PRS and other main factors on CRC risk, 163,516 individuals from the UK Biobank were stratified as follows: 1. carriers status for germline pathogenic variants (PV) in CRC susceptibility genes (APC, MLH1, MSH2, MSH6, PMS2), 2. low (< 20%), intermediate (20–80%), or high PRS (> 80%), and 3. family history (FH) of CRC. Multivariable logistic regression and Cox proportional hazards models were applied to compare odds ratios and to compute the lifetime incidence, respectively. Results: Depending on the PRS, the CRC lifetime incidence for non-carriers ranges between 6 and 22%, compared to 40% and 74% for carriers. A suspicious FH is associated with a further increase of the cumulative incidence reaching 26% for non-carriers and 98% for carriers. In non-carriers without FH, but high PRS, the CRC risk is doubled, whereas a low PRS even in the context of a FH results in a decreased risk. The full model including PRS, carrier status, and FH improved the area under the curve in risk prediction (0.704). Conclusion: The findings demonstrate that CRC risks are strongly influenced by the PRS for both a sporadic and monogenic background. FH, PV, and common variants complementary contribute to CRC risk. The implementation of PRS in routine care will likely improve personalized risk stratification, which will in turn guide tailored preventive surveillance strategies in high, intermediate, and low risk groups. [ABSTRACT FROM AUTHOR]

Introduction. Childhood trauma and adversity are common across societies and have strong associations with physical and psychiatric morbidity throughout the life-course. One possible mechanism through which childhood trauma may predispose individuals to poor psychiatric outcomes is via associations with brain structure. This study aimed to elucidate the associations between childhood trauma and brain structure across two large, independent community cohorts. Methods. The two samples comprised (i) a subsample of Generation Scotland (n=1,024); and (ii) individuals from UK Biobank (n=27,202). This comprised n=28,226 for mega-analysis. MRI scans were processed using Free Surfer, providing cortical, subcortical, and global brain metrics. Regression models were used to determine associations between childhood trauma measures and brain metrics and psychiatric phenotypes. Results. Childhood trauma associated with lifetime depression across cohorts (OR 1.06 GS, 1.23 UKB), and related to early onset and recurrent course within both samples. There was evidence for associations between childhood trauma and structural brain metrics. This included reduced global brain volume, and reduced cortical surface area with highest effects in the frontal (β=-0.0385, SE=0.0048, p(FDR)=5.43x10-15) and parietal lobes (β=-0.0387, SE=0.005, p(FDR)=1.56x10-14). At a regional level the ventral diencephalon (VDc) displayed significant associations with childhood trauma measures across both cohorts and at mega-analysis (β=-0.0232, SE=0.0039, p(FDR)=2.91x10-8). There were also associations with reduced hippocampus, thalamus, and nucleus accumbens volumes. Discussion. Associations between childhood trauma and reduced global and regional brain volumes were found, across two independent UK cohorts, and at mega-analysis. This provides robust evidence for a lasting effect of childhood adversity on brain structure. [ABSTRACT FROM AUTHOR]

The increasing prevalence of patients with aortic stenosis worldwide highlights a clinical need for improved and accurate prediction of clinical outcomes following surgery. We investigated patient demographic and cardiovascular magnetic resonance (CMR) characteristics to formulate a dedicated risk score estimating long-term survival following surgery. We recruited consecutive patients undergoing CMR with gadolinium administration prior to surgical aortic valve replacement from 2003 to 2016 in two UK centres. The outcome was overall mortality. A total of 250 patients were included (68 ± 12 years, male 185 (60%), with pre-operative mean aortic valve area 0.93 ± 0.32cm2, LVEF 62 ± 17%) and followed for 6.0 ± 3.3 years. Sixty-one deaths occurred, with 10-year mortality of 23.6%. Multivariable analysis showed that increasing age (HR 1.04, P = 0.005), use of antiplatelet therapy (HR 0.54, P = 0.027), presence of infarction or midwall late gadolinium enhancement (HR 1.52 and HR 2.14 respectively, combined P = 0.12), higher indexed left ventricular stroke volume (HR 0.98, P = 0.043) and higher left atrial ejection fraction (HR 0.98, P = 0.083) associated with mortality and developed a risk score with good discrimination. This is the first dedicated risk prediction score for patients with aortic stenosis undergoing surgical aortic valve replacement providing an individualised estimate for overall mortality. This model can help clinicians individualising medical and surgical care. Trial Registration ClinicalTrials.gov Identifier: NCT00930735 and ClinicalTrials.gov Identifier: NCT01755936. [ABSTRACT FROM AUTHOR]

Key content: Lynch syndrome is an autosomal dominant condition closely associated with colorectal, endometrial and ovarian cancer.Women with Lynch syndrome are at increased risk of both endometrial and ovarian cancer and should be offered personalised counselling regarding family planning, red flag symptoms and risk‐reducing strategies.Surveillance for gynaecological cancer in women with Lynch syndrome remains controversial; more robust data are needed to determine its effectiveness.Universal testing for Lynch syndrome in endometrial cancer is being adopted by centres across Europe and is now recommended by the National Institute for Health and Care Excellence; thus, gynaecologists must become familiar with testing strategies and their results.Testing strategies involve risk stratification of cancers based on phenotypical features and definitive germline testing. Learning objectives: To define the pathogenesis of Lynch syndrome and its associated gynaecological cancers.To understand the testing strategies for Lynch syndrome in women with gynaecological cancer.To learn how best to counsel women with Lynch syndrome regarding gynaecological cancer and risk‐reducing strategies to enable informed decision‐making. Ethical issues: Offering gynaecological surveillance despite a lack of robust evidence for its clinical effectiveness may falsely reassure women and delay risk‐reducing hysterectomy.Genetic testing may yield variants of unknown significance with ill‐defined clinical implications, which can lead to confusion and anxiety.Genetic testing has implications not only for the individual, but also for the whole family, so expert counselling is crucial. [ABSTRACT FROM AUTHOR]

Background Studies estimating excess length of stay (LOS) attributable to nosocomial infections have failed to address time-varying confounding, likely leading to overestimation of their impact. We present a methodology based on inverse probability–weighted survival curves to address this limitation. Methods A case study focusing on intensive care unit–acquired bacteremia using data from 2 general intensive care units (ICUs) from 2 London teaching hospitals were used to illustrate the methodology. The area under the curve of a conventional Kaplan-Meier curve applied to the observed data was compared with that of an inverse probability–weighted Kaplan-Meier curve applied after treating bacteremia as censoring events. Weights were based on the daily probability of acquiring bacteremia. The difference between the observed average LOS and the average LOS that would be observed if all bacteremia cases could be prevented was multiplied by the number of admitted patients to obtain the total excess LOS. Results The estimated total number of extra ICU days caused by 666 bacteremia cases was estimated at 2453 (95% confidence interval [CI], 1803–3103) days. The excess number of days was overestimated when ignoring time-varying confounding (2845 [95% CI, 2276–3415]) or when completely ignoring confounding (2838 [95% CI, 2101–3575]). Conclusions ICU-acquired bacteremia was associated with a substantial excess LOS. Wider adoption of inverse probability–weighted survival curves or alternative techniques that address time-varying confounding could lead to better informed decision making around nosocomial infections and other time-dependent exposures. [ABSTRACT FROM AUTHOR]

Background: Median survival for patients with glioblastoma is less than a year. Standard treatment consists of surgical debulking if feasible followed by temozolomide chemo-radiotherapy. The immune checkpoint inhibitor ipilimumab targets cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and has shown clinical efficacy in preclinical models of glioblastoma. The aim of this study is to explore the addition of ipilimumab to standard therapy in patients with glioblastoma.Methods/design: Ipi-Glio is a phase II, open label, randomised study of ipilimumab with temozolomide (Arm A) versus temozolomide alone (Arm B) after surgery and chemoradiotherapy in patients with recently diagnosed glioblastoma. Planned accrual is 120 patients (Arm A: 80, Arm B: 40). Endpoints include overall survival, 18-month survival, 5-year survival, and adverse events. The trial is currently recruiting in seven centres in the United Kingdom.Trial Registration: ISRCTN84434175. Registered 12 November 2018. [ABSTRACT FROM AUTHOR]

Background: Frail elderly people experience elevated mortality. However, no consensus exists on the definition of frailty, and many frailty scores have been developed. The main aim of this study was to compare the association between 35 frailty scores and incident cardiovascular disease (CVD), incident cancer, and all-cause mortality. Also, we aimed to assess whether frailty scores added predictive value to basic and adjusted models for these outcomes.Methods and Findings: Through a structured literature search, we identified 35 frailty scores that could be calculated at wave 2 of the English Longitudinal Study of Ageing (ELSA), an observational cohort study. We analysed data from 5,294 participants, 44.9% men, aged 60 years and over. We studied the association between each of the scores and the incidence of CVD, cancer, and all-cause mortality during a 7-year follow-up using Cox proportional hazard models at progressive levels of adjustment. We also examined the added predictive performance of each score on top of basic models using Harrell's C statistic. Using age of the participant as a timescale, in sex-adjusted models, hazard ratios (HRs) (95% confidence intervals) for all-cause mortality ranged from 2.4 (95% CI: 1.7-3.3) to 26.2 (95% CI: 15.4-44.5). In further adjusted models including smoking status and alcohol consumption, HR ranged from 2.3 (95% CI: 1.6-3.1) to 20.2 (95% CI: 11.8-34.5). In fully adjusted models including lifestyle and comorbidity, HR ranged from 0.9 (95% CI: 0.5-1.7) to 8.4 (95% CI: 4.9-14.4). HRs for CVD and cancer incidence in sex-adjusted models ranged from 1.2 (95% CI: 0.5-3.2) to 16.5 (95% CI: 7.8-35.0) and from 0.7 (95% CI: 0.4-1.2) to 2.4 (95% CI: 1.0-5.7), respectively. In sex- and age-adjusted models, all frailty scores showed significant added predictive performance for all-cause mortality, increasing the C statistic by up to 3%. None of the scores significantly improved basic prediction models for CVD or cancer. A source of bias could be the differences in mortality follow-up time compared to CVD/cancer, because the existence of informative censoring cannot be excluded.Conclusion: There is high variability in the strength of the association between frailty scores and 7-year all-cause mortality, incident CVD, and cancer. With regard to all-cause mortality, some scores give a modest improvement to the predictive ability. Our results show that certain scores clearly outperform others with regard to three important health outcomes in later life. Finally, we think that despite their limitations, the use of frailty scores to identify the elderly population at risk is still a useful measure, and the choice of a frailty score should balance feasibility with performance. [ABSTRACT FROM AUTHOR]

von Willebrand disease (VWD) is a common autosomally inherited bleeding disorder associated with mucosal or trauma-related bleeding in affected individuals. VWD results from a quantitative or qualitative deficiency of von Willebrand factor (VWF), a glycoprotein that is essential for primary haemostasis and that carries and protects coagulation factor VIII (FVIII) in the circulation. Through characterization of the phenotype and identification of mutations in the VWF gene in patients with VWD, understanding of the genetics and biochemistry of VWF and VWD has advanced considerably. The importance of specific regions of VWF for its interaction with other components of the vasculature has been revealed, and this has facilitated the formal classification of VWD into three subtypes based upon quantitative (types 1 and 3) and qualitative (type 2) deficiency of VWF. The underlying genetic lesions and associated molecular pathology have been identified in many cases of the qualitative type 2 VWD variants (2A, 2B, 2M, 2N) and in the severe quantitative deficiency, type 3 VWD. However in the partial quantitative deficiency, type 1 VWD, the picture is less clear: there is a variable relationship between plasma levels of VWF and bleeding, there is incomplete penetrance and variable expressivity within affected families, the causative molecular defect is unknown in a substantial number of cases, and even in those cases where the causative mutation is known, the associated molecular pathology is not necessarily understood. This guideline aims to provide a framework for best laboratory practice for the genetic diagnosis of VWD, based upon current knowledge and understanding. [ABSTRACT FROM AUTHOR]

Background: Risk prediction models are commonly used in practice to inform decisions on patients' treatment. Uncertainty around risk scores beyond the confidence interval is rarely explored. We conducted an uncertainty analysis of the QRISK prediction tool to evaluate the robustness of individual risk predictions with varying modelling decisions.Methods: We derived a cohort of patients eligible for cardiovascular risk prediction from the Clinical Practice Research Datalink (CPRD) with linked hospitalisation and mortality records (N = 3,792,474). Risk prediction models were developed using the methods reported for QRISK2 and 3, before adjusting for additional risk factors, a secular trend, geographical variation in risk and the method for imputing missing data when generating a risk score (model A-model F). Ten-year risk scores were compared across the different models alongside model performance metrics.Results: We found substantial variation in risk on the individual level across the models. The 95 percentile range of risks in model F for patients with risks between 9 and 10% according to model A was 4.4-16.3% and 4.6-15.8% for females and males respectively. Despite this, the models were difficult to distinguish using common performance metrics (Harrell's C ranged from 0.86 to 0.87). The largest contributing factor to variation in risk was adjusting for a secular trend (HR per calendar year, 0.96 [0.95-0.96] and 0.96 [0.96-0.96]). When extrapolating to the UK population, we found that 3.8 million patients may be reclassified as eligible for statin prescription depending on the model used. A key limitation of this study was that we could not assess the variation in risk that may be caused by risk factors missing from the database (such as diet or physical activity).Conclusions: Risk prediction models that use routinely collected data provide estimates strongly dependent on modelling decisions. Despite this large variability in patient risk, the models appear to perform similarly according to standard performance metrics. Decision-making should be supplemented with clinical judgement and evidence of additional risk factors. The largest source of variability, a secular trend in CVD incidence, can be accounted for and should be explored in more detail. [ABSTRACT FROM AUTHOR]