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Diagnosis, treatment and survival from bladder, upper urinary tract, and urethral cancers: real-world findings from NHS England between 2013 and 2019
No full textOBJECTIVE: We report NHS England data for patients with bladder cancer (BC), upper tract urothelial cancer (UTUC: renal pelvic and ureteric), and urethral cancers from 2013 to 2019. MATERIALS AND METHODS: Hospital episode statistics, waiting times, and cancer registrations were extracted from NHS Digital. RESULTS: Registrations included 128 823 individuals with BC, 16 018 with UTUC, and 2533 with urethral cancer. In 2019, 150 816 persons were living with a diagnosis of BC, of whom 113 067 (75.0%) were men, 85 117 (56.5%) were aged >75 years, and 95 553 (91.7%) were Caucasian. Incidence rates were stable (32.7-34.3 for BC, 3.9-4.2 for UTUC and 0.6-0.7 for urethral cancer per 100 000 population). Most patients 52 097 (mean [range] 41.3% [40.7-42.0%]) were referred outside the 2-week-wait pathway and 15 340 (mean [range] 12.2% [11.7-12.6%]) presented as emergencies. Surgery, radiotherapy, chemotherapy, or multimodal treatment use varied with disease stage, patient factors and Cancer Alliance. Between 27% and 29% (n = 6616) of muscle-invasive BCs did not receive radical treatment. Survival rates reflected stage, grade, location, and tumour histology. Overall survival rates did not improve over time (relative change: 0.97, 95% confidence interval 0.97-0.97) at 2 years in contrast to other cancers. CONCLUSION: The diagnostic pathway for BC needs improvement. Increases in survival might be delivered through greater use of radical treatment. NHS Digital data offers a population-wide picture of this disease but does not allow individual outcomes to be matched with disease or patient features and key parameters can be missing or incomplete.Published version, accepted version (12 month embargo), submitted versionRD&E staff can access the full-text of this article by clicking on the 'Additional Link' above and logging in with NHS OpenAthens if prompted
TSH and FT4 reference interval recommendations and prevalence of gestational thyroid dysfunction: quantification of current diagnostic approaches
No full textCONTEXT: Guidelines recommend use of population- and trimester-specific TSH and FT4 reference intervals (RIs) in pregnancy. Since these are often unavailable, clinicians frequently rely on alternative diagnostic strategies. We sought to quantify the diagnostic consequences of current recommendations. METHODS: We included cohorts participating in the Consortium on Thyroid and Pregnancy. Different approaches were used to define RIs: a TSH fixed upper limit of 4.0 mU/L (fixed limit approach), a fixed subtraction from the upper limit for TSH of 0.5 mU/L (subtraction approach) and using non-pregnancy RIs. Outcome measures were sensitivity and false discovery rate (FDR) of women for whom levothyroxine treatment was indicated and those for whom treatment would be considered according to international guidelines. RESULTS: The study population comprised 52,496 participants from 18 cohorts. Compared to the use of trimester-specific reference intervals, alternative approaches had a low sensitivity (0.63-0.82) and high FDR (0.11-0.35) to detect women with a treatment indication or consideration. Sensitivity and FDR to detect a treatment indication in the first trimester were similar between the fixed limit, subtraction and non-pregnancy approach (0.77-0.11 vs 0.74-0.16 vs 0.60-0.11). The diagnostic performance to detect overt hypothyroidism, isolated hypothyroxinemia and (sub)clinical hyperthyroidism mainly varied between FT4 RI approaches, while the diagnostic performance to detect subclinical hypothyroidism varied between the applied TSH RI approaches. CONCLUSION: Alternative approaches to define RIs for TSH and FT4 in pregnancy result in considerable over- and underdiagnosis compared with population- and trimester-specific RIs. Additional strategies need to be explored to optimize identification of thyroid dysfunction during pregnancy.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
Treatable traits: a comprehensive precision medicine approach in interstitial lung disease
No full textInterstitial lung disease (ILD) is a diverse group of inflammatory and fibrotic lung conditions causing significant morbidity and mortality. A multitude of factors beyond the lungs influence symptoms, health-related quality of life, disease progression and survival in patients with ILD. Despite an increasing emphasis on multidisciplinary management in ILD, the absence of a framework for assessment and delivery of comprehensive patient care poses challenges in clinical practice. The treatable traits approach is a precision medicine care model that operates on the premise of individualised multidimensional assessment for distinct traits that can be targeted by specific interventions. The potential utility of this approach has been described in airway diseases, but has not been adequately considered in ILD. Given the similar disease heterogeneity and complexity between ILD and airway diseases, we explore the concept and potential application of the treatable traits approach in ILD. A framework of aetiological, pulmonary, extrapulmonary and behavioural and lifestyle treatable traits relevant to clinical care and outcomes for patients with ILD is proposed. We further describe key research directions to evaluate the application of the treatable traits approach towards advancing patient care and health outcomes in ILD.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
Pathogenic variants in SMARCA1 cause an X-linked neurodevelopmental disorder modulated by NURF complex composition
No full textPathogenic variants in ATP-dependent chromatin remodeling proteins are a recurrent cause of neurodevelopmental disorders (NDDs). The NURF complex consists of BPTF and either the SNF2H (SMARCA5) or SNF2L (SMARCA1) ISWI-chromatin remodeling enzyme. Pathogenic variants in BPTF and SMARCA5 were previously implicated in NDDs. Here, we describe 40 individuals from 30 families with de novo or maternally inherited pathogenic variants in SMARCA1. This novel NDD was associated with mild to severe ID/DD, delayed or regressive speech development, and some recurrent facial dysmorphisms. Individuals carrying SMARCA1 loss-of-function variants exhibited a mild genome-wide DNA methylation profile and a high penetrance of macrocephaly. Genetic dissection of the NURF complex using Smarca1, Smarca5, and Bptfsingle and double mouse knockouts revealed the importance of NURF composition and dosage for proper forebrain development. Finally, we propose that genetic alterations affecting different NURF components result in a NDD with a broad clinical spectrum.UnknownNot hel
Genomic Diagnosis of Rare Pediatric Disease in the United Kingdom and Ireland
No full textBACKGROUND: Pediatric disorders include a range of highly penetrant, genetically heterogeneous conditions amenable to genomewide diagnostic approaches. Finding a molecular diagnosis is challenging but can have profound lifelong benefits. METHODS: We conducted a large-scale sequencing study involving more than 13,500 families with probands with severe, probably monogenic, difficult-to-diagnose developmental disorders from 24 regional genetics services in the United Kingdom and Ireland. Standardized phenotypic data were collected, and exome sequencing and microarray analyses were performed to investigate novel genetic causes. We developed an iterative variant analysis pipeline and reported candidate variants to clinical teams for validation and diagnostic interpretation to inform communication with families. Multiple regression analyses were performed to evaluate factors affecting the probability of diagnosis. RESULTS: A total of 13,449 probands were included in the analyses. On average, we reported 1.0 candidate variant per parent-offspring trio and 2.5 variants per singleton proband. Using clinical and computational approaches to variant classification, we made a diagnosis in approximately 41% of probands (5502 of 13,449). Of 3599 probands in trios who received a diagnosis by clinical assertion, approximately 76% had a pathogenic de novo variant. Another 22% of probands (2997 of 13,449) had variants of uncertain significance in genes that were strongly linked to monogenic developmental disorders. Recruitment in a parent-offspring trio had the largest effect on the probability of diagnosis (odds ratio, 4.70; 95% confidence interval [CI], 4.16 to 5.31). Probands were less likely to receive a diagnosis if they were born extremely prematurely (i.e., 22 to 27 weeks' gestation; odds ratio, 0.39; 95% CI, 0.22 to 0.68), had in utero exposure to antiepileptic medications (odds ratio, 0.44; 95% CI, 0.29 to 0.67), had mothers with diabetes (odds ratio, 0.52; 95% CI, 0.41 to 0.67), or were of African ancestry (odds ratio, 0.51; 95% CI, 0.31 to 0.78). CONCLUSIONS: Among probands with severe, probably monogenic, difficult-to-diagnose developmental disorders, multimodal analysis of genomewide data had good diagnostic power, even after previous attempts at diagnosis. (Funded by the Health Innovation Challenge Fund and Wellcome Sanger Institute.).Published version (6 month embargo)RD&E staff can access the full-text of this article by clicking on the 'Additional Link' above and logging in with NHS OpenAthens if prompted
Estimating the rate of severe visual loss (wipe-out) following cataract surgery, a British Ophthalmological Surveillance Unit (BOSU) study
No full textBACKGROUND: A sudden, irreversible reduction in visual acuity ('wipe-out') is a feared complication of cataract surgery. Current literature on wipe-out is limited in quantity and quality, and largely predates modern cataract surgery and imaging techniques. The objectives of our study were to estimate the incidence of wipe-out and to identify potential risk factors. METHODS: We prospectively collated cases of wipe-out occurring in the UK during a 25-month study period using the British Ophthalmic Surveillance Unit reporting system. A total of 21 potential cases of wipe-out were reported, 5 of which met all inclusion and exclusion criteria. RESULTS: The estimated incidence of wipe-out during the study period was 0.00000298, or approximately 3 cases per million cataract operations. All cases of wipe-out occurred exclusively in patients with advanced glaucoma (mean deviation -21.0 decibels or worse in the operated eye), with an over-representation of black people (40%) in our case series. A prior diagnosis of retinal vein occlusion (60%) and elevated post-operative IOP (40%) were more common among individuals suffering from wipe-out compared to the general population, suggesting these factors may contribute to the pathogenesis of wipe-out. CONCLUSIONS: Our study shows that wipe-out is a rare complication, affecting approximately 3 per million undergoing cataract surgery. Patients with advanced glaucoma, black patients, and those with previous retinal vein occlusions may be at greater risk of wipe-out. We hope that the findings of our study will be used to help inform treatment decision-making and the cataract surgery consent process.Accepted version (6 month embargo), submitted versionThe article is available via Open Access. Click on the 'Additional link' above to access the full-text
Nitrofurantoin: what is the evidence for current UK guidance?
No full textThree days of nitrofurantoin at 100 mg twice daily is recommended as first-line treatment for uncomplicated urinary tract infection (UTI) in evidence-based guidelines across the UK. A review of international guidelines shows that the evidence base has been interpreted in very different ways. UK guidelines are unusual in promoting short (3 day) courses, and we find little direct evidence to support this. Although 'short' courses of antibiotics for other agents may provide optimum balance between providing effective treatment whilst reducing selective pressure driving resistance amongst colonizing microbial flora, it remains unclear that course lengths can be extrapolated to nitrofurantoin. Three days of nitrofurantoin may indeed be a useful intervention in a large group of patients. However, without supporting evidence and because clinical response should be expected to vary widely, it is unclear that establishing and promoting an antibiotic duration for UTI is the best approach to optimizing prescribing in this important area.0
Predictors and prognosis of population-based subjective cognitive decline: longitudinal evidence from the Caerphilly Prospective Study (CaPS)
No full textOBJECTIVES: To understand associations between the subjective experience of cognitive decline and objective cognition. This subjective experience is often conceptualised as an early step towards neurodegeneration, but this has not been scrutinised at the population level. An alternative explanation is poor meta-cognition, the extreme of which is seen in functional cognitive disorder (FCD). DESIGN: Prospective cohort (Caerphilly Prospective Study). SETTING: Population-based, South Wales, UK. PARTICIPANTS: This men-only study began in 1979; 1225 men participated at an average age of 73 in 2002-2004, including assessments of simple subjective cognitive decline (sSCD, defined as a subjective report of worsening memory or concentration). Dementia outcomes were followed up to 2012-2014. Data on non-completers was additionally obtained from death certificates and local health records. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome measure was incident dementia over 10 years. Secondary outcome measures included prospective change in objective cognition and cross-sectional cognitive internal inconsistency (the existence of a cognitive ability at some times, and its absence at other times, with no intervening explanatory factors except for focus of attention). RESULTS: sSCD was common (30%) and only weakly associated with prior objective cognitive decline (sensitivity 36% (95% CI 30 to 42) and specificity 72% (95% CI 68 to 75)). Independent predictors of sSCD were older age, poor sleep quality and higher trait anxiety. Those with sSCD did not have excess cognitive internal inconsistency, but results suggested a mild attentional deficit. sSCD did not predict objective cognitive change (linear regression coefficient -0.01 (95% CI -0.13 to 0.15)) nor dementia (odds ratio 1.35 (0.61 to 2.99)) 10 years later. CONCLUSIONS: sSCD is weakly associated with prior objective cognitive decline and does not predict future cognition. Prior sleep difficulties and anxiety were the most robust predictors of sSCD. sSCD in the absence of objective decline appears to be a highly prevalent example of poor meta-cognition (ie, poor self-awareness of cognitive performance), which could be a driver for later FCD.Published version, accepted version, submitted versionThe article is available via Open Access. Click on the 'Additional link' above to access the full-text
Sarcoidosis and frailty: recognizing factors that foster holistic resilience
No full textPURPOSE OF REVIEW: Sarcoidosis is a multiorgan system disease exerting significant impact on biophysical, social, psychological and emotional well-being. Mortality and disability correlate to accessible, timely, expert care for sarcoidosis and its related complications. Across health conditions, positive healthcare interactions and interventions can rehabilitate unfavourable factors tied to concepts of ' frailty' . Here, we set out to introduce concepts related to frailty and their impact in the context of sarcoidosis. RECENT FINDINGS: Studies examining frailty across other multiorgan and single organ-based diseases that mirror organ involvement in sarcoidosis demonstrate findings that bear relevance in sarcoidosis. Namely, factors predisposing a person to frailty are a multifactorial phenomenon which are also reflected in the lived experience of sarcoidosis; and that early diagnosis, intervention and prevention may alter a course towards more favourable health outcomes. SUMMARY: Factors predisposing to frailty in other health conditions may also signal a risk in sarcoidosis. In turn, proactive health preservation - regardless of age - may lead to improved biopsychosocial reserve and health-related quality of life. Fortifying holistic resilience in sarcoidosis is anticipated to reduce risk of the occurrence and prolongation of health-related complications, and facilitate swifter recovery from biophysical complications as well as from psychosocial and emotional stressors.Published version, accepted version (12 months embrago)Not hel
Pretreatment Vitamin D Concentrations Do Not Predict Therapeutic Outcome to Anti-TNF Therapies in Biologic-Naïve Patients With Active Luminal Crohn's Disease
No full textBACKGROUND AND AIMS: Vitamin D has a regulatory role in innate and adaptive immune processes. Previous studies have reported that low pretreatment vitamin D concentrations are associated with primary non-response (PNR) and non-remission to anti-TNF therapy. This study aimed to assess whether pretreatment 25-hydroxyvitamin D concentrations predicted PNR and non-remission to infliximab and adalimumab in patients with active luminal Crohn's disease. METHODS: 25-Hydroxyvitamin D concentrations were measured in stored baseline samples from 659 infliximab- and 448 adalimumab-treated patients in the Personalised Anti-TNF Therapy in Crohn's disease (PANTS) study. Cut-offs for vitamin D were deficiency 50 nmol/L. RESULTS: About 17.1% (189/1107; 95% CI, 15.0-19.4) and 47.7% (528/1107; 95% CI, 44.8-50.6) of patients had vitamin D deficiency and insufficiency, respectively. 22.2% (246/1107) of patients were receiving vitamin D supplementation. Multivariable analysis confirmed that sampling during non-summer months, South Asian ethnicity, lower serum albumin concentrations, and non-treatment with vitamin D supplementation were independently associated with lower vitamin D concentrations. Pretreatment vitamin D status did not predict response or remission to anti-TNF therapy at week 14 (infliximab P(pnr) = .89, adalimumab P(pnr) = .18) or non-remission at week 54 (infliximab P = .13, adalimumab P = .58). Vitamin D deficiency was, however, associated with a longer time to immunogenicity in patients treated with infliximab, but not adalimumab. CONCLUSIONS: Vitamin D deficiency is common in patients with active Crohn's disease. Unlike previous studies, pretreatment vitamin D concentration did not predict PNR to anti-TNF treatment at week 14 or nonremission at week 54.Published version, accepted version, submitted versionThe article is available via Open Access. Click on the 'Additional link' above to access the full-text