Research priorities for children's cancer: a James Lind Alliance Priority Setting Partnership in the UK

OBJECTIVES: To engage children who have experienced cancer, childhood cancer survivors, their families and professionals to systematically identify and prioritise research questions about childhood cancer to inform the future research agenda. DESIGN: James Lind Alliance Priority Setting Partnership. SETTING: UK health service and community. METHODS: A steering group oversaw the initiative. Potential research questions were collected in an online survey, then checked to ensure they were unanswered. Shortlisting via a second online survey identified the highest priority questions. A parallel process with children was undertaken. A final consensus workshop was held to determine the Top 10 priorities. PARTICIPANTS: Children and survivors of childhood cancer, diagnosed before age 16, their families, friends and professionals who work with this population. RESULTS: Four hundred and eighty-eight people submitted 1299 potential questions. These were refined into 108 unique questions; 4 were already answered and 3 were under active study, therefore, removed. Three hundred and twenty-seven respondents completed the shortlisting survey. Seventy-one children submitted questions in the children's surveys, eight children attended a workshop to prioritise these questions. The Top 5 questions from children were taken to the final workshop where 23 questions in total were discussed by 25 participants (young adults, carers and professionals). The top priority was 'can we find effective and kinder (less burdensome, more tolerable, with fewer short and long-term effects) treatments for children with cancer, including relapsed cancer?' CONCLUSIONS: We have identified research priorities for children's cancer from the perspectives of children, survivors, their families and the professionals who care for them. Questions reflect the breadth of the cancer experience, including diagnosis, relapse, hospital experience, support during/after treatment and the long-term impact of cancer. These should inform funding of future research as they are the questions that matter most to the people who could benefit from research.Published version, accepted version, submitted versionThe article is available via Open Access. Click on the 'Additional link' above to access the full-text

Penetrance and expressivity of mitochondrial variants in a large clinically unselected population

BACKGROUND: Whole genome sequencing (WGS) from large clinically unselected cohorts provides a unique opportunity to assess the penetrance and expressivity of rare and/or known pathogenic mitochondrial variants in population. METHOD: Using WGS from 179 862 clinically unselected individuals from the UK Biobank, we performed extensive single and rare variant aggregation association analyses of 15 881 mtDNA variants and 73 known pathogenic variants with 15 mitochondrial disease-relevant phenotypes. RESULTS: We identified 12 homoplasmic and one heteroplasmic variant (m.3243A>G) with genome-wide significant associations in our clinically unselected cohort. Heteroplasmic m.3243A>G (MAF = 0.0002, a known pathogenic variant) was associated with diabetes, deafness and heart failure and 12 homoplasmic variants increased aspartate aminotransferase levels including three low-frequency variants (MAF ~0.002 and beta~0.3 SD). Most pathogenic mitochondrial disease variants (n = 66/74) were rare in the population (G. Multi-system disease risk and penetrance of diabetes, deafness and heart failure greatly increased with m.3243A>G level ≥ 10%. The odds ratio of these traits increased from 5.61, 12.3 and 10.1 to 25.1, 55.0 and 39.5 respectively. Diabetes risk with m.3243A>G was further influenced by type 2 diabetes genetic risk. CONCLUSION: Our study of mitochondrial variation in a large-unselected population identified novel associations and demonstrated that pathogenic mitochondrial variants have lower penetrance in clinically unselected settings. m.3243A>G was an exception at higher heteroplasmy showing a significant impact on health making it a good candidate for incidental reporting.Published version, accepted version (12 month embargo), submitted versionThis article is freely available online. Click on the 'Additional Link' above to access the full-text via the publisher's site

Multiple endocrine neoplasia type 2A syndrome presenting with corneal nerve thickening

Published version, accepted version (12 month embargo), submitted versionThe article is available via Open Access. Click on the 'Additional link' above to access the full-text

Caring for patients with periprosthetic femoral fractures across England and Wales in 2021

AIMS: The aim of this study was to describe services available to patients with periprosthetic femoral fracture (PPFF) in England and Wales, with focus on variation between centres and areas for care improvement. METHODS: This work used data freely available from the National Hip Fracture Database (NHFD) facilities survey in 2021, which asked 21 questions about the care of patients with PPFFs, and nine relating to clinical decision-making around a hypothetical case. RESULTS: Of 174 centres contributing data to the NHFD, 161 provided full responses and 139 submitted data on PPFF. Lack of resources was cited as the main reason for not submitting data. Surgeon (44.6%) and theatre (29.7%) availability were reported as the primary reasons for surgical delay beyond 36 hours. Less than half had a formal process for a specialist surgeon to operate on PPFF at least every other day. The median number of specialist surgeons at each centre was four (interquartile range (IQR) 3 to 6) for PPFF around both hips and knees. Around one-third of centres reported having one dedicated theatre list per week. The routine discussion of patients with PPFF at local and regional multidisciplinary team meetings was lower than that for all-cause revision arthroplasties. Six centres reported transferring all patients with PPFF around a hip joint to another centre for surgery, and this was an occasional practice for a further 34. The management of the hypothetical clinical scenario was varied, with 75 centres proposing ORIF, 35 suggested revision surgery and 48 proposed a combination of both revision and fixation. CONCLUSION: There is considerable variation in both the organization of PPFF services England and Wales, and in the approach taken to an individual case. The rising incidence of PPFF and complexity of these patients highlight the need for pathway development. The adoption of networks may reduce variability and improve outcomes for patients with PPFF.Published versionThe article is available via Open Access. Click on the 'Additional link' above to access the full-text

Characteristics and risk factors of UCS fracture subtypes in periprosthetic fractures around the hip

AIMS: Periprosthetic fractures (PPFs) following hip arthroplasty are complex injuries. This study evaluates patient demographic characteristics, management, outcomes, and risk factors associated with PPF subtypes over a decade. METHODS: Using a multicentre collaborative study design, independent of registry data, we identified adults from 29 centres with PPFs around the hip between January 2010 and December 2019. Radiographs were assessed for the Unified Classification System (UCS) grade. Patient and injury characteristics, management, and outcomes were compared between UCS grades. A multinomial logistic regression was performed to estimate relative risk ratios (RRR) of variables on UCS grade. RESULTS: A total of 1,104 patients were included. The majority were female (57.9%; n = 639), ethnically white (88.5%; n = 977), used mobility aids (67%; n = 743), and had a median age of 82 years (interquartile range (IQR) 74 to 87). A total of 77 (7%) had pain prior to the PPF. The most common UCS grade was B2 (33%; n = 368). UCS type D fractures had the longest length of stay (median 19 days (IQR 11 to 26)), highest readmission to hospital (21%; n = 9), and highest rate of discharge to step-down care (52%; n = 23). Multinomial regression suggests that uncemented femoral stems are associated with a reduced risk of UCS C (RRR 0.36 (95% confidence interval (CI) 0.2 to 0.7); p = 0.002) and increased risk of UCS A (RRR 3.3 (95% CI 1.9 to 5.7); p < 0.001), compared to UCS B fracture. CONCLUSION: The most common PPF type in elderly frail patients is UCS B2. Uncemented stems have a lower risk of UCS C fractures compared to cemented stems. A national PPF database is needed to further identify correlation between implants and fracture subtypes.Published versionThe article is available via Open Access. Click on the 'Additional link' above to access the full-text

Treatment effect heterogeneity following type 2 diabetes treatment with GLP1-receptor agonists and SGLT2-inhibitors: a systematic review

BACKGROUND: A precision medicine approach in type 2 diabetes requires the identification of clinical and biological features that are reproducibly associated with differences in clinical outcomes with specific anti-hyperglycaemic therapies. Robust evidence of such treatment effect heterogeneity could support more individualized clinical decisions on optimal type 2 diabetes therapy. METHODS: We performed a pre-registered systematic review of meta-analysis studies, randomized control trials, and observational studies evaluating clinical and biological features associated with heterogenous treatment effects for SGLT2-inhibitor and GLP1-receptor agonist therapies, considering glycaemic, cardiovascular, and renal outcomes. After screening 5,686 studies, we included 101 studies of SGLT2-inhibitors and 75 studies of GLP1-receptor agonists in the final systematic review. RESULTS: Here we show that the majority of included papers have methodological limitations precluding robust assessment of treatment effect heterogeneity. For SGLT2-inhibitors, multiple observational studies suggest lower renal function as a predictor of lesser glycaemic response, while markers of reduced insulin secretion predict lesser glycaemic response with GLP1-receptor agonists. For both therapies, multiple post-hoc analyses of randomized control trials (including trial meta-analysis) identify minimal clinically relevant treatment effect heterogeneity for cardiovascular and renal outcomes. CONCLUSIONS: Current evidence on treatment effect heterogeneity for SGLT2-inhibitor and GLP1-receptor agonist therapies is limited, likely reflecting the methodological limitations of published studies. Robust and appropriately powered studies are required to understand type 2 diabetes treatment effect heterogeneity and evaluate the potential for precision medicine to inform future clinical care. This study reviews the available evidence on which patient features (such as age, sex, and blood test results) are associated with different outcomes for two recently introduced type 2 diabetes medications: SGLT2-inhibitors and GLP1-receptor agonists. Understanding what individual characteristics are associated with different response patterns may help clinical providers and people living with diabetes make more informed decisions about which type 2 diabetes treatments will work best for an individual. We focus on three outcomes: blood glucose levels (raised blood glucose is the primary symptom of diabetes and a primary aim of diabetes treatment is to lower this), heart disease, and kidney disease. We identified some potential factors that reduce effects on blood glucose levels, including poorer kidney function for SGLT2-inhibitors and lower production of the glucose-lowering hormone insulin for GLP1-receptor agonists. We did not identify clear factors that alter heart and kidney disease outcomes for either medication. Most of the studies had limitations, meaning more research is needed to fully understand the factors that influence treatment outcomes in type 2 diabetes. eng research funding from Eli Lilly and Company, Pfizer, and AstraZeneca. A.G.J. has received research funding from the Novo Nordisk foundation. E.R.P. has received honoraria for speaking from Lilly, Novo Nordisk, and Illumina. All other authors declare no competing interest.Published version, submitted versionRDUH can access the full-text of this article by clicking on the 'Additional Link' above and logging in with NHS OpenAthens if prompted

Machine learning and artificial intelligence in neuroscience: A primer for researchers

Artificial intelligence (AI) is often used to describe the automation of complex tasks that we would attribute intelligence to. Machine learning (ML) is commonly understood as a set of methods used to develop an AI. Both have seen a recent boom in usage, both in scientific and commercial fields. For the scientific community, ML can solve bottle necks created by complex, multi-dimensional data generated, for example, by functional brain imaging or *omics approaches. ML can here identify patterns that could not have been found using traditional statistic approaches. However, ML comes with serious limitations that need to be kept in mind: their tendency to optimise solutions for the input data means it is of crucial importance to externally validate any findings before considering them more than a hypothesis. Their black-box nature implies that their decisions usually cannot be understood, which renders their use in medical decision making problematic and can lead to ethical issues. Here, we present an introduction for the curious to the field of ML/AI. We explain the principles as commonly used methods as well as recent methodological advancements before we discuss risks and what we see as future directions of the field. Finally, we show practical examples of neuroscience to illustrate the use and limitations of ML.Published version, accepted version, submitted versionRDUH can access the full-text of this article by clicking on the 'Additional Link' above and logging in with NHS OpenAthens if prompted

Impact of Frailty on the Development of Proximal Junctional Failure: Does Frailty Supersede Achieving Optimal Realignment?

BACKGROUND: Patients undergoing surgery for adult spinal deformity (ASD) are often elderly, frail, and at elevated risk of adverse events perioperatively, with proximal junctional failure (PJF) occurring relatively frequently. Currently, the specific role of frailty in potentiating this outcome is poorly defined. PURPOSE: To determine if the benefits of optimal realignment in ASD, with respect to the development of PJF, can be offset by increasing frailty. STUDY DESIGN: Retrospective cohort. METHODS: Operative ASD patients (scoliosis >20°, SVA>5 cm, PT>25°, or TK>60°) fused to pelvis or below with available baseline (BL) and 2-year (2Y) radiographic and HRQL data were included. The Miller Frailty Index (FI) was used to stratify patients into 2 categories: Not Frail (FI 3). Proximal Junctional Failure (PJF) was defined using the Lafage criteria. Matched" and "unmatched" refers to ideal age-adjusted alignment post-operatively. Multivariable regression determined impact of frailty on development of PJF. RESULTS: 284 ASD patients met inclusion criteria (62.2yrs±9.9, 81%F, BMI: 27.5 kg/m2±5.3, ASD-FI: 3.4±1.5, CCI: 1.7±1.6). 43% of patients were characterized as Not Frail (NF) and 57% were characterized as Frail (F). PJF development was lower in the NF group compared to the F group, (7% vs. 18%; P=0.002). F patients had 3.2X higher risk of PJF development compared to NF patients (OR: 3.2, 95% CI: 1.3-7.3, P=0.009). Controlling for baseline factors, F unmatched patients had a higher degree of PJF (OR: 1.4, 95% CI:1.02-1.8, P=0.03), however, with prophylaxis there was no increased risk. Adjusted analysis shows F patients when matched post-operatively in PI-LL had no significantly higher risk of PJF. CONCLUSIONS: An increasingly frail state is significantly associated with the development of PJF after corrective surgery for ASD. Optimal realignment may mitigate the impact of frailty on eventual PJF. Prophylaxis should be considered in frail patients who do not reach ideal alignment goals."UnknownNot hel

Diminished Physical Activity in Older Hospitalised Patients with and without COVID-19

Acute viral respiratory infections have proven to be a major health threat, even after the Corona Virus Disease 2019 (COVID-19) pandemic. We aimed to check whether the presence or absence of an acute respiratory infection such as COVID-19 can influence the physical activity of older hospitalised patients. We cross-sectionally studied patients aged ≥60 years, hospitalized during the pandemic in the non-COVID-19 and COVID-19 ward at the University Hospital, Kraków, Poland. Using activPAL3(®) technology, we assessed physical activity for 24 h upon admission and discharge. In addition, we applied the sarcopenia screening tool (SARC-F); measured the hand grip strength and calf circumference; and assessed the Modified Early Warning Score (MEWS), age-adjusted Charlson Index, SpO2%, and length of stay (LoS). Data were analysed using SAS 9.4. The mean (min, max) age of the 31 (58% women, eight with COVID-19) consecutive patients was 79.0 (62, 101, respectively) years. The daily time (activPAL3(®), median [p5, p95], in hours) spent sitting or reclining was 23.7 [17.2, 24] upon admission and 23.5 [17.8, 24] at discharge. The time spent standing was 0.23 [0.0, 5.0] upon admission and 0.4 [0.0, 4.6] at discharge. The corresponding values for walking were 0.0 [0.0, 0.4] and 0.1 [0.0, 0.5]. SARC-F, admission hand grip strength, calf circumference, and LoS were correlated with physical activity upon admission and discharge (all p < 0.04). For every unit increase in SARC-F, there was a 0.07 h shorter walking time upon discharge. None of the above results differed between patients with and without COVID-19. The level of physical activity in older patients hospitalised during the pandemic was low, and was dependent on muscular function upon admission but not on COVID-19 status. This has ramifications for scenarios other than pandemic clinical scenarios.Published version, accepted version, submitted versionThis article is freely available online. Click on the 'Additional Link' above to access the full-text via the publisher's site

Cost-effectiveness of a new ACI technique for the treatment of articular cartilage defects of the knee compared to regularly used ACI technique and microfracture

AIMS: For patients with cartilage defects of the knee, a new biocompatible and in situ cross-linkable albumin-hyaluronan-based hydrogel has been developed for matrix-associated autologous chondrocyte implantation (M-ACI) - NOVOCART® Inject plus (NInject)1. We aimed to estimate the potential cost-effectiveness of NInject, that is not available on the market, yet compared to spheroids of human autologous matrix-associated chondrocytes (Spherox(®))2 and microfracture. MATERIALS AND METHODS: An early Markov model was developed to estimate the cost-effectiveness in the United Kingdom (UK) from the payer perspective. Transition probabilities, response rates, utility values and costs were derived from literature. Since NInject has not yet been launched and no prices are available, its costs were assumed equal to those of Spherox(®). Cycle length was set at one year and the time horizon chosen was notional patients' remaining lifetime. Model robustness was evaluated with deterministic and probabilistic sensitivity analyses (DSA; PSA) and value of information (VOI) analysis. The Markov model was built using TreeAge Pro Healthcare. RESULTS: NInject was cost-effective compared to microfracture (ICER: ₤5,147) while Spherox® was extendedly dominated. In sensitivity analyses, the ICER exceeded conventional WTP threshold of ₤20,000 only when the utility value after successful first treatment with NInject was decreased by 20% (ICER: ₤69,620). PSA corroborated the cost-effectiveness findings of NInject, compared to both alternatives, with probabilities of 60% of NInject undercutting the aforementioned WTP threshold and being the most cost-effective alternative. The VOIA revealed that obtaining additional evidence on the new technology will likely not be cost-effective for the UK National Health Service. LIMITATIONS AND CONCLUSION: This early Markov model showed that NInject is cost-effective for the treatment of articular cartilage defects in the knee, compared to Spherox and microfracture. However, as the final price of NInject has yet to be determined, the cost-effectiveness analysis performed in this study is provisional, assuming equal prices for NInject and Spherox.Published versionSupports Open Acces