Improved outcomes of large B-cell lymphoma patients treated with CD19 CAR T in the UK over time.

The success of CD19 Chimeric antigen receptor (CAR) T-cell therapy in large B-cell lymphoma (LBCL) has been partially offset by toxicity and logistical challenges, which off-the-shelf agents like CD20xCD3 bispecific antibodies might potentially overcome. However, when using CAR T outcomes as the 'standard-of-care comparator̕ for relapsed/refractory (r/r) LBCL, a potential learning curve with implementing a novel, complex therapy like CAR T needs to be considered. To address this, we analysed 726 UK patients intended to be treated with CD19 CAR T for r/r LBCL and compared outcomes between the first year of the national CAR T programme (Era 1; 2019) and the more recent treatment era (Era 2; 2020-2022). We identified significant improvements for Era 2 versus Era 1 in dropout rate (17% vs. 27%, p = 0.001), progression-free survival (1-year PFS 50% vs. 32%, p < 0.001) and overall survival (1-year OS 60% vs. 40%, p < 0.001). We also observed increased use of bridging therapy, improvement in bridging outcomes, more tocilizumab/corticosteroid use, reduced high-grade cytokine release syndrome (4% vs. 9%, p = 0.01) and intensive care unit admissions (20% vs. 32%, p = 0.001). Our results demonstrate significant improvement in CAR T outcomes over time, highlighting the importance of using up-to-date clinical data when comparing CAR T against new treatment options for r/r LBCL.

Outcome and feasibility of radiotherapy bridging in large B-cell lymphoma patients receiving CD19 CAR T in the UK.

Radiotherapy (RT) has potential synergistic effects with chimeric antigen receptor (CAR) T but is not widely used as bridging therapy due to logistical challenges and lack of standardised protocols. We analysed RT bridging in a multicentre national cohort of large B-cell lymphoma patients approved for 3L axicabtagene ciloleucel or tisagenlecleucel across 12 UK centres. Of 763 approved patients, 722 were leukapheresed, 717 had data available on bridging therapy. 169/717 (24%) received RT bridging, 129 as single modality and 40 as combined modality treatment (CMT). Of 169 patients, 65.7% had advanced stage, 36.9% bulky disease, 86.5% elevated LDH, 41.7% international prognostic index (IPI) ≥3 and 15.2% double/triple hit at the time of approval. Use of RT bridging varied from 11% to 32% between centres and increased over time. Vein-to-vein time and infusion rate did not differ between bridging modalities. RT-bridged patients had favourable outcomes with 1-year progression-free survival (PFS) of 56% for single modality and 47% for CMT (1-year PFS 43% for systemic bridging). This is the largest cohort of LBCL patients receiving RT bridging prior to CAR T reported to date. Our results show that RT bridging can be safely and effectively used even in advanced stage and high-risk disease, with low dropout rates and excellent outcomes.

m2ABQ-a proposed refinement of the modified algorithm-based qualitative classification of osteoporotic vertebral fractures.

Currently, there is no reproducible, widely accepted gold standard to classify osteoporotic vertebral body fractures (OVFs). The purpose of this study is to refine a method with clear rules to classify OVFs for machine learning purposes. The method was found to have moderate interobserver agreement that improved with training. INTRODUCTION: The current methods to classify osteoporotic vertebral body fractures are considered ambiguous; there is no reproducible, accepted gold standard. The purpose of this study is to refine classification methodology by introducing clear, unambiguous rules and a refined flowchart to allow consistent classification of osteoporotic vertebral body fractures. METHODS: We developed a set of rules and refinements that we called m2ABQ to classify vertebrae into five categories. A fracture-enriched database of thoracic and lumbar spine radiographs of patients 65 years of age and older was retrospectively obtained from clinical institutional radiology records using natural language processing. Five raters independently classified each vertebral body using the m2ABQ system. After each annotation round, consensus sessions that included all raters were held to discuss and finalize a consensus annotation for each vertebral body where individual raters' evaluations differed. This process led to further refinement and development of the rules. RESULTS: Each annotation round showed increase in Fleiss kappa both for presence vs absence of fracture 0.62 (0.56-0.68) to 0.70 (0.65-0.75), as well as for the whole m2ABQ scale 0.29 (0.25-0.33) to 0.54 (0.51-0.58). CONCLUSION: The m2ABQ system demonstrates moderate interobserver agreement and practical feasibility for classifying osteoporotic vertebral body fractures. Future studies to compare the method to existing studies are warranted, as well as further development of its use in machine learning purposes.

The top 100 most cited articles on artificial intelligence in radiology: a bibliometric analysis.

AIM: To identify the most influential publications relating to artificial intelligence (AI) in radiology in order to identify current trends in the literature and to highlight areas requiring further research. MATERIALS AND METHODS: A retrospective bibliometric analysis was performed of the top 100 most cited articles on this topic. Data pertaining to year of publication, publishing journal, journal impact factor, authorship, article title, institution, country, type of article, article subject, and keywords were collected. RESULTS: The number of citations per article for the top 100 list ranged from 254 to 3,576 (median 353). The number of citations per year, per article ranged from 10.4 to 894 (median 65.6). The majority of articles (n=62) were published within the last 10 years. The USA was the most common country of origin (n=44). The journal with the greatest number of articles was IEEE Transactions On Medical Imaging (n=38). University Medical Center Utrecht contributed the greatest number of articles (n=6). There were 92 original research articles, 52 of which were clinical studies. The most common clinical subjects were neuroimaging (n=25) and oncology (n=16). The most common keyword used was "deep learning" (n=34). CONCLUSION: This study provides an in-depth analysis of the top 100 most-cited papers on the use of AI in radiology. It also provides researchers with detailed insight into the current influential papers in this field, the characteristics of those studies, as well as potential future trends in this fast-developing area of radiology.

Children's Palliative Care; the identified Learning Needs of Paediatricians.

Aim To determine baseline learning needs of Paediatricians in Ireland when caring for children with palliative care needs. Methods A questionnaire based online survey was conducted. Results One hundred and fourteen paediatricians responded to the survey, the majority were Specialist Registrars but almost half were consultant paediatricians (46% n=52). Most had never had formal education in the paediatric palliative care (57% n=48). Areas of future training that were ranked as important or highly important (percentage of respondents) included: pain management (98% n=81), management of the dying child (96% n=80), palliative care resources (95%n=79), advanced care planning (95% n=79) and communication skills (86% n=71). Those surveyed were asked to comment on the challenges of recent clinical interactions, on analysis three overarching themes emerged; best interests of the child, inadequate training and confidence and co-ordinating care. Conclusion This survey highlights the learning needs of paediatricians and will inform the development of meaningful education sessions for doctors.

A Geospatial Analysis of Adult Major Trauma Transit Time in Dublin

Aims To estimate ambulance transit time of Major Trauma patients from scene to Emergency Department (ED) in order to inform future trauma network design. Methods Dublin Fire Brigade data was analysed and each Major Trauma incident was mapped. Actual distance and time to the receiving ED was measured and estimates of distances and times from each of these incidents to any ED in Dublin (any potential Major Trauma Centre) were formulated using Google Maps in Internet Explorer 11. Results Adult trauma (n=500) was evenly distributed throughout Dublin. The median transit time to each ED varied from 5 to 8 minutes with a longest time of 26 minutes. The calculated median transit time from an incident to any ED was 18 minutes with a maximum estimated transit time of 40 minutes. Conclusion The data demonstrated that all patients could get to any Dublin ED with a median time of 18 minutes and within the internationally recommended transfer time of 45 minutes to a Major Trauma Centre.

Measurement of selected androgens using liquid chromatography-tandem mass spectrometry in reproductive-age women with Type 1 diabetes.

STUDY QUESTION: What information does androgen profiling using liquid chromatography tandem mass spectrometry (LC-MS/MS) provide in reproductive-age women with Type 1 diabetes (T1D)? SUMMARY ANSWER: In T1D women, androstenedione proved most useful of the measured androgens in differentiating subgroups based on clinical phenotypes of hyperandrogenism (HA) and polycystic ovary syndrome (PCOS). WHAT IS KNOWN ALREADY: The prevalence of HA and PCOS are increased in women with T1D. These observations are based on measurement of serum androgens using immunoassays, to-date no studies using LC-MS/MS have been reported in reproductive-age women with T1D. STUDY DESIGN, SIZE, DURATION: This was a cross-sectional study with recruitment of three groups of reproductive-age women: women with T1D (n = 87), non-diabetic women with (N = 97) and without PCOS (N = 101). PARTICIPANTS/MATERIALS, SETTING, METHODS: Using LC-MS/MS, we aimed to characterize androgen profiles and PCOS status in women with T1D, and interpret findings in relation to cohorts of non-diabetic women with and without PCOS. MAIN RESULTS AND THE ROLE OF CHANCE: Compared to non-diabetic women, dehydroepiandrosterone/dehydroepiandrosterone sulphate (DHEA/DHEAS) ratio was lower (P < 0.05) in women with T1D. Testosterone levels were greater in T1D women with clinical HA and anovulation compared to those without clinical HA and with regular cycles, while androstenedione levels were greater in T1D women with HA and anovulation compared to those with HA and regular cycles and also those without HA and with regular cycles (P < 0.05 for all). Compared to T1D women without PCOS, the 18% of T1D women who had PCOS were younger with lower BMI, an older age of menarche, and were more likely to have a positive family history of PCOS (P < 0.05 for all). Androgen levels did not differ between women with T1D and PCOS compared to BMI-matched non-diabetic women with PCOS, but androstenedione levels were greater in T1D women with PCOS compared to obese women with PCOS (P < 0.05). LIMITATIONS, REASONS FOR CAUTION: Relatively small subgroups of patients were studied, reducing the power to detect small differences. Free testosterone levels were not measured using equilibrium dialysis, and were not calculated - commonly used formulae have not been validated in T1D. WIDER IMPLICATIONS OF THE FINDINGS: Androstenedione is a sensitive biochemical marker of clinical hyperandrogenism and PCOS in T1D. T1D women with PCOS are leaner than those without PCOS but are more likely to have a family history of PCOS. Women with T1D and PCOS have a similar biochemical phenotype to lean non-diabetic women with PCOS but differ from obese women with PCOS. The mechanisms underlying PCOS in T1D and its clinical significance require further investigation. STUDY FUNDING/COMPETING INTEREST(S): The study was part-funded by the Meath Foundation. The authors have no competing interests.

Dexamethasone-related adrenal insufficiency in patients with brain and skull base tumours.

PURPOSE: This study aimed to evaluate the prevalence of glucocorticoid-induced adrenal insufficiency in a cohort of patients with brain and skull base tumours and to identify factors which may predict its occurrence. METHODS: Patients with brain or skull base tumours attending for a short synacthen test (SST) (adrenocorticotropin hormone (ACTH) stimulation test) at a single institution over a 3-year period were retrospectively identified. Baseline demographics and dexamethasone exposure were examined. Only patients with dexamethasone exposure were included in the final analysis looking at the primary end point of SST failure. Fisher's exact test, Student's t test, Mann-Whitney test and the Kendall's tau-b test were used to evaluate the influence of age, gender, diagnosis and mean pituitary radiation dose on the primary endpoint. Receiver operating characteristic (ROC) curves were generated to explore the impact of duration and total exposure to dexamethasone on likelihood of SST failure. RESULTS: Thirty-one of 51 patients with previous dexamethasone exposure failed their first SST (61%). No significant relationship was demonstrated between age, gender, diagnosis or mean pituitary radiation dose and SST failure. Duration of and total exposure to dexamethasone were significantly associated with SST failure (p = 0.001 and p = 0.007, respectively). ROC curves generated values of 78 days and 171 mg days to give a sensitivity of 94 and 97%, respectively, to detect SST failure. CONCLUSIONS: Duration of dexamethasone use and total exposure predict for adrenal insufficiency in patients with brain and skull base tumours. Values derived from this study may be useful to identify patients at higher risk of adrenal suppression who require empirical hydrocortisone pending formal testing of the hypothalamic-pituitary-adrenal axis.

Total HDL cholesterol efflux capacity in healthy children - Associations with adiposity and dietary intakes of mother and child.

BACKGROUND AND AIMS: High-density lipoprotein (HDL) cholesterol efflux capacity in adults may be a measure of the atheroprotective property of HDL. Little however, is known about HDL cholesterol efflux capacity in childhood. We aimed to investigate the relationship between HDL cholesterol efflux capacity and childhood anthropometrics in a longitudinal study. METHODS AND RESULTS: Seventy-five children (mean age = 9.4 ± 0.4 years) were followed from birth until the age of 9 years. HDL cholesterol efflux capacity was determined at age 9 by incubating serum-derived HDL-supernatants with 3H-cholesterol labeled J774 macrophages and percentage efflux determined. Mothers provided dietary information by completing food frequency questionnaires in early pregnancy and then 5 years later on behalf of themselves and their children. Pearson's correlations and multiple regression analyses were conducted to confirm independent associations with HDL efflux. There was a negative correlation between HDL cholesterol efflux capacity and waist circumference at age 5 (r = -0.3, p = 0.01) and age 9 (r = -0.24, p = 0.04) and BMI at age 5 (r = -0.45, p = 0.01) and age 9 (r = -0.19, p = 0.1). Multiple regression analysis showed that BMI at age 5 remained significantly associated with reduced HDL cholesterol efflux capacity (r = -0.45, p < 0.001). HDL-C was negatively correlated with energy-adjusted fat intake (r = -0.24, p = 0.04) and positively correlated with energy-adjusted protein (r = 0.24, p = 0.04) and starch (r = 0.29, p = 0.01) intakes during pregnancy. HDL-C was not significantly correlated with children dietary intake at age 5. There were no significant correlations between maternal or children dietary intake and HDL cholesterol efflux capacity. CONCLUSIONS: This novel analysis shows that efflux capacity is negatively associated with adiposity in early childhood independent of HDL-C.

Neuromas as the cause of pain in the residual limbs of amputees. An ultrasound study.

AIM: To explore the morphology of neuromas and to determine the differences, if any, between asymptomatic and symptomatic neuromas using ultrasound. MATERIALS AND METHODS: Eighty patients with symptomatic neuromas were included in this retrospective review. High-resolution ultrasound examination was performed. Transducer pressure allowed real-time analysis of both symptomatic and asymptomatic neuromas. Quantifiable assessment of pain by the patient assigned a pain score of 0, 1, 2, or 3, to each neuroma. RESULTS: One hundred and fifty-nine neuromas were identified in total. Fifty-three neuromas were asymptomatic (pain score=0), very severe pain was recorded in 54 (pain score=3), 16 neuromas were mildly painful (pain score=1) and 36 were moderately painful (pain score=2). The average number of neuromas per patient was 1.98, and the average number of symptomatic neuromas per patient was 1.3. There was no correlation between pain score and patient age, neuroma volume, amputation type, and time since amputation. CONCLUSIONS: High-resolution ultrasound can distinguish between asymptomatic and symptomatic neuromas. Patient age, time since amputation, the type of amputation, and the neuroma volume were not related to the presence of pain.

Pre-Hospital Fast Positive Cases Identified by DFB Ambulance Paramedics: Final Clinical Diagnosis.

Ischaemic stroke clinical outcomes are improved by earlier treatment with intravenous thrombolysis. An existing pathway at the Mater University Hospital for assessment of suspected acute stroke in the Emergency Department was updated, aiming to shorten door-to-needle time. This study examines the final clinical diagnosis of Dublin Fire Brigade Ambulance Paramedic identified Face-Arm-Speech-Test (FAST) positive patients presenting to the Emergency Department over a 7 month period. A retrospective analysis was carried out of 177 consecutive FAST positive patients presenting between March and November 2014. The final clinical diagnosis was acute stroke in 57.1% (n=101) of patients. Of these, 76 were ischaemic strokes of whom 56.5% (n=43) were thrombolysed. In the pre-hospital setting Ambulance Paramedics can identify, with reasonable accuracy, acute stroke using the FAST test. Over half of the ischaemic stroke patients presenting via this pathway can be treated with intravenous thrombolysis.

Gene delivery to the spinal cord using MRI-guided focused ultrasound.

Non-invasive gene delivery across the blood-spinal cord barrier (BSCB) remains a challenge for treatment of spinal cord injury and disease. Here, we demonstrate the use of magnetic resonance image-guided focused ultrasound (MRIgFUS) to mediate non-surgical gene delivery to the spinal cord using self-complementary adeno-associated virus serotype 9 (scAAV9). scAAV9 encoding green fluorescent protein (GFP) was injected intravenously in rats at three dosages: 4 × 10(8), 2 × 10(9) and 7 × 10(9) vector genomes per gram (VG g(-1)). MRIgFUS allowed for transient, targeted permeabilization of the BSCB through the interaction of focused ultrasound (FUS) with systemically injected Definity lipid-shelled microbubbles. Viral delivery at 2 × 10(9) and 7 × 10(9) VG g(-1) leads to robust GFP expression in FUS-targeted regions of the spinal cord. At a dose of 2 × 10(9) VG g(-1), GFP expression was found in 36% of oligodendrocytes, and in 87% of neurons in FUS-treated areas. FUS applications to the spinal cord could address a long-term goal of gene therapy: delivering vectors from the circulation to diseased areas in a non-invasive manner.

Disseminated Mycobacterium haemophilum skeletal disease in a patient with interferon-gamma deficiency.

Disseminated non-tuberculous mycobacterial (NTM) infection is rare in immunocompetent adults. Anti-interferon-gamma (IFN-γ) autoantibodies have recently been associated with NTM infections, particularly in patients of Asian ethnicity. We describe a case of disseminated Mycobacterium haemophilum skeletal infection due to anti IFN-γ autoantibodies in a 71-year-old Cambodian man. He responded to a combination of anti-mycobacterial antibiotics without requirement for immunomodulator therapy. Testing for acquired IFN-γ deficiency due to IFN-γ autoantibodies should be considered when standard tests for immunodeficiency are negative in patients with unusual or severe opportunistic infections, including NTM.

'They're not witches. ' Young children and their parents' perceptions and experiences of Child and Adolescent Mental Health Services.

BACKGROUND: Recent initiatives have emphasized the ongoing need to include children in healthcare research, which is relevant to the development of both paediatric and mental healthcare services. Our aim was to contribute children and their parents' perceptions and experiences of Child and Adolescent Mental Health Services (CAMHS), with the objective of providing guidance for those wishing to improve inclusivity and empowerment. METHOD: We performed a thematic analysis of interview data taken from 11 children (9 boys, 2 girls, aged 8-12) and their parents (12 mothers, 2 fathers), who had recently been referred to CAMHS for mental health and educational problems. RESULTS: Three core themes emerged from the data. Fear of the unknown refers to emotional apprehension due to uncertainty of what happens in CAMHS. However children also provided useful reassurances for future service users. Therapeutic engagement refers to the importance of being listened to and building up good relationships with professionals. Finally making services acceptable was discussed in terms of issues of accessibility, session tolerances and suggestions for the development of child-centred services. CONCLUSIONS: Children were able to provide potentially useful opinions of CAMHS. In a time of limited resources it is imperative that the voices of children and their parents are acknowledged in order to improve accessibility and experiences within CAMHS.