Cancer Trial Impact:Understanding implementation of the SCOT trial findings at a national level

Aims: The Short Course Oncology Treatment (SCOT) trial indicated that 3 months of adjuvant doublet chemotherapy was non-inferior to 6 months of treatment for patients with colorectal cancer, with considerably less toxicity. The SCOT trial results were disseminated in June 2017. The aim of this study was to understand if SCOT trial findings were implemented in Scotland. Materials and methods: A retrospective analysis was carried out on a dataset derived from a source population of 5.4 million people. Eligible patients were those with stage II or III colorectal cancer who received adjuvant chemotherapy. Logistic regression was applied to understand the extent of practice change to a 3-month adjuvant chemotherapy duration after the SCOT trial results were disseminated. Interrupted time series analysis was used to visualise differences in prescribing trends before and after June 2017 for the overall cohort, and by SCOT trial eligibility. Results: In total, 2310 patients were included in the study; 1957 and 353 treated pre- and post-June 2017, respectively. The median treatment duration decreased from 21 weeks (interquartile range 14–24) prior to June 2017 to 12 weeks (interquartile range 12–21 weeks) after June 2017 (P < 0.001). The proportion of patients receiving over 3 months of adjuvant treatment decreased from 75% to 42% (P < 0.001). This change was most noticeable for patients who met the SCOT trial eligibility criteria, and specifically for those with low-risk stage III disease and those treated with capecitabine and oxaliplatin (CAPOX). Although practice change occurred in all locations, there were differences between regions that could be explained by pre-SCOT trial prescribing trends. Discussion: A significant change in chemotherapy prescribing occurred after dissemination of the SCOT trial results. National, real-world data can be used to capture the extent of implementation of clinical trial results. In this case, implementation was aligned with clinical trial subgroup findings. This type of analysis could be conducted to evaluate the impact of other clinical trials

Local delivery of tacrolimus using electrospun poly-ε-caprolactone nanofibres suppresses the T-cell response to peripheral nerve allografts

OBJECTIVE: Repair of nerve gap injuries can be achieved through nerve autografting, but this approach is restricted by limited tissue supply and donor site morbidity. The use of living nerve allografts would provide an abundant tissue source, improving outcomes following peripheral nerve injury. Currently this approach is not used due to the requirement for systemic immunosuppression, to prevent donor-derived cells within the transplanted nerve causing an immune response, which is associated with severe adverse effects. The aim of this study was to develop a method for delivering immunosuppression locally, then to test its effectiveness in reducing the immune response to transplanted tissue in a rat model of nerve allograft repair. APPROACH: A coaxial electrospinning approach was used to produce poly-ε-caprolactone fibre sheets loaded with the immunosuppressant tacrolimus. The material was characterised in terms of structure and tacrolimus release, then tested in vivo through implantation in a rat sciatic nerve allograft model with immunologically mismatched host and donor tissue. MAIN RESULTS: Following successful drug encapsulation, the fibre sheets showed nanofibrous structure and controlled release of tacrolimus over several weeks. Materials containing tacrolimus (and blank material controls) were implanted around the nerve graft at the time of allograft or autograft repair. The fibre sheets were well tolerated by the animals and tacrolimus release resulted in a significant reduction in lymphocyte infiltration at three weeks post-transplantation. SIGNIFICANCE: These findings demonstrate proof of concept for a novel nanofibrous biomaterial-based targeted drug delivery strategy for immunosuppression in peripheral nerve allografting

Botulinum toxin treatment of spasticity in diplegic cerebral palsy : a randomised, double-blind, placebo-controlled, dose-ranging study

This study evaluated the efficacy and safety of three doses of botulinum toxin A (BTX-A; Dysport®) in 125 patients (mean age 5.2 years, SD 2; 54% male)with dynamic equinus spasticity during walking. Participants were randomized to receive Dysport (10, 20, or 30 units/kg) or placebo to the gastrocnemius muscle of both legs. Muscle length was calculated from electrogoniometric measurements and the change in the dynamic component of gastrocnemius shortening at four weeks was prospectively identified as the primary outcome measure. All treatment groups showed statistically significant decreases in dynamic component compared with placebo at 4 weeks. Mean improvement in dynamic component was most pronounced in the 20 units/kg group, being equivalent to an increase in dorsiflexion with the knee extended at 19°, and was still present at 16 weeks. The safety profile of the toxin appears satisfactory

Children and Young People with Long COVID—Comparing Those Seen in Post-COVID Services with a Non-Hospitalised National Cohort: A Descriptive Study

Background: Post-COVID services have been set up in England to treat children with ongoing symptoms of Long COVID. To date, the characteristics of children seeking treatment from these services has not been described. / Purpose: (1) to describe the characteristics of children aged 11–17 referred to the Pan-London Post-COVID service and (2) to compare characteristics of these children with those taking part in the United Kingdom’s largest research study of Long COVID in children (CLoCk). / Design: Data from 95 children seeking treatment from the Post-COVID service between May 2021 and August 2022 were included in the study. Their demographic characteristics, symptom burden and the impact of infection are described and compared to children from CLoCk. / Results: A high proportion of children from the Post-COVID service and CLoCk reported experiencing health problems prior to the pandemic. Almost all Post-COVID service children met the research Delphi definition of Long COVID (94.6%), having multiple symptoms that impacted their lives. Symptoms were notably more severe than the participants in CLoCk. / Conclusions: This study describes the characteristics of children seeking treatment for Long COVID compared to those identified in the largest longitudinal observational study to date. Post-COVID service children have more symptoms and are more severely affected by their symptoms following infection with COVID-19 than children in the CLoCk study. Research to understand predisposing factors for severity and prognostic indicators is essential to prevent this debilitating condition. Evaluation of short- and long-term outcomes of interventions by clinical services can help direct future therapy for this group

Children and Young People with Long COVID:comparing those seen in Post-COVID services with a non-hospitalised national cohort: a descriptive study

Background: Post-COVID services have been set up in England to treat children with ongoing symptoms of Long COVID. To date, the characteristics of children seeking treatment from these services has not been described.Purpose: (1) To describe the characteristics of children aged 11-17 referred to the Pan London Post-COVID service and (2) To compare characteristics of these children with those taking part in the UK’s largest research study of Long COVID in children (CLoCk).Design: Data from 95 children seeking treatment from the Post-COVID service between May 2021 and August 2022 were included in the study. Their demographic characteristics, symptom burden and the impact of infection are described and compared to children from CLoCk.Results: A high proportion of children from the Post-COVID service and CLoCk reported experiencing health problems prior to the pan-demic. Almost all Post-COVID service children met the research Delphi definition of Long COVID (94.6%), having multiple symptoms that impacted their lives. Symptoms were notably more severe than the participants in CLoCk.Conclusions: This study describes the characteristics of children seeking treatment for Long COVID compared to those identified in the largest longitudinal observational study to date. Post-COVID service children have more symptoms and are more severely affected by their symptoms following infection with COVID-19 than children in the CLoCk study. Research to understand predisposing factors for severity and prognostic indicators is essential to prevent this debilitating condition. Evaluation of short and long-term outcomes of interventions by clinical services can help direct future therapy for this group.<br/

Assessing the role of insulin-like growth factors and binding proteins in prostate cancer using Mendelian randomization:genetic variants as instruments for circulating levels

Circulating insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) are associated with prostate cancer. Using genetic variants as instruments for IGF peptides, we investigated whether these associations are likely to be causal. We identified from the literature 56 single nucleotide polymorphisms (SNPs) in the IGF axis previously associated with biomarker levels (8 from a genome-wide association study [GWAS] and 48 in reported candidate genes). In ∼700 men without prostate cancer and two replication cohorts (N∼900 and ∼9,000), we examined the properties of these SNPS as instrumental variables (IVs) for IGF-I, IGF-II, IGFBP-2 and IGFBP-3. Those confirmed as strong IVs were tested for association with prostate cancer risk, low (< 7) vs high (≥ 7) Gleason grade, localised vs advanced stage, and mortality, in 22,936 controls and 22,992 cases. IV analysis was used in an attempt to estimate the causal effect of circulating IGF peptides on prostate cancer. Published SNPs in the IGFBP1/IGFBP3 gene region, particularly rs11977526, were strong instruments for IGF-II and IGFBP-3, less so for IGF-I. Rs11977526 was associated with high (vs low) Gleason grade (OR per IGF-II/IGFBP-3 level-raising allele 1.05; 95% CI 1.00, 1.10). Using rs11977526 as an IV we estimated the causal effect of a one SD increase in IGF-II (∼265 ng/ml) on risk of high vs low grade disease as 1.14 (95% CI 1.00, 1.31). Because of the potential for pleiotropy of the genetic instruments, these findings can only causally implicate the IGF pathway in general, not any one specific biomarker. This article is protected by copyright. All rights reserved

Frailty, prefrailty and employment outcomes in Health and Employment After Fifty (HEAF) Study

Objectives Demographic changes are requiring people to work longer. No previous studies, however, have focused on whether the ‘frailty’ phenotype (which predicts adverse events in the elderly) is associated with employment difficulties. To provide information, we assessed associations in the Health and Employment After Fifty Study, a population-based cohort of 50–65-year olds.Methods Subjects, who were recruited from 24 English general practices, completed a baseline questionnaire on ‘prefrailty’ and ‘frailty’ (adapted Fried criteria) and several work outcomes, including health-related job loss (HRJL), prolonged sickness absence (&gt;20 days vs less, past 12 months), having to cut down substantially at work and difficulty coping with work's demands. Associations were assessed using logistic regression and population attributable fractions (PAFs) were calculated.Results In all, 3.9% of 8095 respondents were classed as ‘frail’ and 31.6% as ‘prefrail’. Three-quarters of the former were not in work, while 60% had left their last job on health grounds (OR for HRJL vs non-frail subjects, 30.0 (95% CI 23.0 to 39.2)). Among those in work, ORs for prolonged sickness absence, cutting down substantially at work and struggling with work's physical demands ranged from 10.7 to 17.2. The PAF for HRJL when any frailty marker was present was 51.8% and that for prolonged sickness absence was 32.5%. Associations were strongest with slow reported walking speed. Several associations were stronger in manual workers than in managers.Conclusions Fried frailty symptoms are not uncommon in mid-life and are strongly linked with economically important adverse employment outcomes. Frailty could represent an important target for prevention.</p

Sex steroids, growth factors and mammographic density: a cross-sectional study of UK postmenopausal Caucasian and Afro-Caribbean women

INTRODUCTION: Sex steroids, insulin-like growth factors (IGFs) and prolactin are breast cancer risk factors but whether their effects are mediated through mammographic density, one of the strongest risk factors for breast cancer, is unknown. If such a hormonal basis of mammographic density exists, hormones may underlie ethnic differences in both mammographic density and breast cancer incidence rates. METHODS: In a cross-sectional study of 270 postmenopausal Caucasian and Afro-Caribbean women attending a population-based breast screening service in London, UK, we investigated whether plasma biomarkers (oestradiol, oestrone, sex hormone binding globulin (SHBG), testosterone, prolactin, leptin, IGF-I, IGF-II and IGF binding protein 3 (IGFBP3)) were related to and explained ethnic differences in mammographic percent density, dense area and nondense area, measured in Cumulus using the threshold method. RESULTS: Mean levels of oestrogens, leptin and IGF-I:IGFBP3 were higher whereas SHBG and IGF-II:IGFBP3 were lower in Afro-Caribbean women compared with Caucasian women after adjustment for higher mean body mass index (BMI) in the former group (by 3.2 kg/m(2) (95% confidence interval (CI): 1.8, 4.5)). Age-adjusted percent density was lower in Afro-Caribbean compared with Caucasian women by 5.4% (absolute difference), but was attenuated to 2.5% (95% CI: -0.2, 5.1) upon BMI adjustment. Despite ethnic differences in biomarkers and in percent density, strong ethnic-age-adjusted inverse associations of oestradiol, leptin and testosterone with percent density were completely attenuated upon adjustment for BMI. There were no associations of IGF-I, IGF-II or IGFBP3 with percent density or dense area. We found weak evidence that a twofold increase in prolactin and oestrone levels were associated, respectively, with an increase (by 1.7% (95% CI: -0.3, 3.7)) and a decrease (by 2.0% (95% CI: 0, 4.1)) in density after adjustment for BMI. CONCLUSIONS: These findings suggest that sex hormone and IGF levels are not associated with BMI-adjusted percent mammographic density in cross-sectional analyses of postmenopausal women and thus do not explain ethnic differences in density. Mammographic density may still, however, be influenced by much higher premenopausal hormone levels

Predictors of depressive symptoms in older adults living in care homes in Thailand

Background: Thai culture traditionally abhors elders living in care homes due to the belief that this represents a dereliction of filial piety by their children, thus care homes are stigmatized as the domain of poor older adults with no family. This may impact negatively on psychological wellbeing of residents, although little is known about the key factors influencing depressive symptoms. Therefore, this study explores factors associated with depressive symptoms, internalised stigma, self-esteem, social support and coping strategies among older adults residing in care homes in Thailand. Method/Design: A cross-sectional questionnaire study was conducted with 128 older residents recruited from two care homes in Northeast Thailand. Data were collected using the 15-Item Thai Geriatric Depression Scale, Internalised Stigma of Living in a Care Home Scale, Thai Version of Rosenberg Self-Esteem Scale, Thai Version of Multidimensional Scale of Perceived Social Support and the Coping Strategies Inventory Short-Form. Results: Depressive symptoms were significantly correlated with internalised stigma, self-esteem and social support (r= 0.563, -0.574 and -0.333) (p< 0.001), respectively. Perceived internalised stigma of living in a care home was the strongest predictor of care home residents reporting depressive symptoms (odds ratio=9.165). Discussion: Older adults who perceived high internalised stigma of living in a care home were over nine times as likely to report experiencing depressive symptoms. Efforts to decrease or prevent perceived internalised stigma might help to reduce depressive symptoms. Interventions might include media collaboration, educational interventions in the care home setting and organising social activities for residents and their families

SYT1-associated neurodevelopmental disorder: a case series.

Synaptotagmin 1 (SYT1) is a critical mediator of fast, synchronous, calcium-dependent neurotransmitter release and also modulates synaptic vesicle endocytosis. This paper describes 11 patients with de novo heterozygous missense mutations in SYT1. All mutations alter highly conserved residues, and cluster in two regions of the SYT1 C2B domain at positions Met303 (M303K), Asp304 (D304G), Asp366 (D366E), Ile368 (I368T) and Asn371 (N371K). Phenotypic features include infantile hypotonia, congenital ophthalmic abnormalities, childhood-onset hyperkinetic movement disorders, motor stereotypies, and developmental delay varying in severity from moderate to profound. Behavioural characteristics include sleep disturbance and episodic agitation. Absence of epileptic seizures and normal orbitofrontal head circumference are important negative features. Structural MRI is unremarkable but EEG disturbance is universal, characterized by intermittent low frequency high amplitude oscillations. The functional impact of these five de novo SYT1 mutations has been assessed by expressing rat SYT1 protein containing the equivalent human variants in wild-type mouse primary hippocampal cultures. All mutant forms of SYT1 were expressed at levels approximately equal to endogenous wild-type protein, and correctly localized to nerve terminals at rest, except for SYT1M303K, which was expressed at a lower level and failed to localize at nerve terminals. Following stimulation, SYT1I368T and SYT1N371K relocalized to nerve terminals at least as efficiently as wild-type SYT1. However, SYT1D304G and SYT1D366E failed to relocalize to nerve terminals following stimulation, indicative of impairments in endocytic retrieval and trafficking of SYT1. In addition, the presence of SYT1 variants at nerve terminals induced a slowing of exocytic rate following sustained action potential stimulation. The extent of disturbance to synaptic vesicle kinetics is mirrored by the severity of the affected individuals' phenotypes, suggesting that the efficiency of SYT1-mediated neurotransmitter release is critical to cognitive development. In summary, de novo dominant SYT1 missense mutations are associated with a recognizable neurodevelopmental syndrome, and further cases can now be diagnosed based on clinical features, electrophysiological signature and mutation characteristics. Variation in phenotype severity may reflect mutation-specific impact on the diverse physiological functions of SYT1