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The variation of coverage and access to palliative care for cancer patients in eight European countries: an exploratory vignette approach
Abstract Background Palliative care aims to maintain quality of life and offer treatment and person-centred care options for people with serious end-stage illnesses and their families. The purpose of this exploratory study was to compare the statutory coverage and access to palliative care for adult services for people with cancer in 8 European countries using a vignette approach. Methods We used a patient vignette to examine coverage and access to palliative care services across Europe. The palliative care vignette describes a pathway based on guidance for best practices of palliative care patients with incurable cancer. The surveys accompanying the vignette were completed by health services researchers knowledgeable on palliative care, practitioners, government officials, or teams consisting of a health systems expert working together with practitioners. Results Completed vignettes were received from 8 countries: Bulgaria, Estonia, France, Lithuania, the Netherlands, Portugal, Sweden and England. Services provided for palliative care envisioned in the vignette’s pathway are, generally, covered by the statutory health systems. However, in some countries cost sharing exists for hospital stays, certain medicines and medical aids. Furthermore, coverage of social and financial assessments, home equipment and financial advice varied in nearly every country. Travel times to and availability of palliative care specialists were identified as challenges across nearly all countries. Organizational barriers, societal stigmas and knowledge gaps about what palliative care entails were also found to be areas in need of improvement. Conclusions The comparative research presented provides further insight how countries organise palliative care, how services are offered and what levels of access exist around Europe. Our study showed differences in the scope of coverage of and access to the care options in the vignette. While responses showed countries have basic levels of coverage and access to services provided, there were variations, such as availability of specialists or the extent travel and waiting times influence care delivery. Settings where patients receive services also varied. As the need for palliative care grows in the future, health ministries and insurers should be increasingly concerned with how to guarantee coverage of and access to this care, as well as aware of best practices among countries facing similar challenges.
Analysis of airway inflammation demonstrates a mechanism for T2-biologic failure in asthma.
BackgroundTargeted T2 biologics have transformed asthma care, but the clinical response to biologic therapy varies between patients.ObjectiveAssess airways inflammation in T2-high asthma patients treated with anti-IL5 biologics to investigate if differential mechanisms of airway inflammation explains varied response to biologics.MethodsProteomic analysis (Olink®, 1463 protein panel) & high sensitivity cytokine analysis (ELISAs) were performed on induced sputum from T2-high, severe asthma patients in the UK multicentre Mepolizumab EXacerbation (MEX) study. Samples included were pre-mepolizumab (n=28), stable on mepolizumab (n= 43) & at first exacerbation (n=26).ResultsClustering of sputum proteins while stable on mepolizumab identified two clusters. Cluster 1 had increased differentially expressed sputum proteins pre-mepolizumab, stable on mepolizumab & at exacerbation. Cluster 1 were younger at diagnosis, had a longer duration of asthma, lower FEV1% & higher ACQ5 on mepolizumab. Cluster 1 had increased expression of pro-inflammatory cytokines (IL1β, IL6, sIL6R), epithelial alarmins (TSLP, IL 33) and neutrophil activation (MPO, NE & Neutrophil extracellular trap (NET). All patients were T2-high with no difference in FeNO, eosinophil number or activity (EDN) across the two clusters.ConclusionIn a cohort of T2-high severe asthma patients, a subgroup of patients with long duration of disease had worse clinical parameters, increased sputum proteins with increased markers of neutrophil activity, proinflammatory cytokines and epithelial alarmins even when stable on mepolizumab. This suggests the presence of biology not treated by targeted T2-biologics which may contribute to poorer outcomes on biologics and could be a treatable airways trait in severe asthma.
Synovial tissue atlas in juvenile idiopathic arthritis reveals pathogenic niches associated with disease severity
Precision application of targeted therapies is urgently needed to improve long-term clinical outcomes for children affected by inflammatory arthritis, known as juvenile idiopathic arthritis (JIA). Progress has been hampered by our limited understanding of the cellular basis of inflammation in the target tissue of the disease, the synovial membrane. Here, we analyzed biopsies from the inflamed joints of treatment-naïve children with JIA, early in the course of their disease, using single-cell RNA sequencing, multiplexed immunofluorescence, and spatial transcriptomics to establish a cellular atlas of the JIA synovium. We identified distinct spatial tissue niches, composed of specific stromal and immune cell populations. In addition, we localized genes linked to arthritis severity and disease risk to effector cell populations, including tissue resident SPP1 + macrophages and fibrin-associated myeloid cells. Combined analyses of synovial fluid and peripheral blood from matched individuals revealed differences in cellular composition, signaling pathways, and transcriptional programs across these distinct anatomical compartments. Furthermore, our analysis revealed several pathogenic cell populations that are shared with adult-onset inflammatory arthritis, as well as age-associated differences in tissue vascularity, prominence of innate immunity, and enrichment of TGF-β–responsive stromal subsets that up-regulate expression of disease risk–associated genes. Overall, our findings demonstrate the need for age-specific analyses of synovial tissue pathology to guide targeted treatment strategies in JIA.
Distinct neutralization sensitivity between adult and infant transmitted/founder HIV-1 subtype C viruses to broadly neutralizing monoclonal antibodies.
Broadly neutralizing antibodies (bnAbs), passively administered or elicited through vaccination, are a promising strategy for novel HIV prevention, treatment or inducing ART-free remission. However, HIV diversity and evolution are a barrier to the efficacy of bnAbs and there is therefore an urgent need for continuous virus surveillance to identify bnAbs with optimal neutralization breadth and potency against transmitted/founder (TF) viruses, especially in high-burden regions. We determined the neutralization sensitivity of TF viruses isolated within seven days after first detection of heterosexually acquired infection from young women 18-23 years old (n = 39) and within 1 month after birth from in-utero infected infants (n = 21) from FRESH and Baby Cure cohorts respectively, in KwaZulu-Natal, South Africa, where HIV-1 subtype C predominates. Neutralization sensitivities of 47 viruses from FRESH and 21 viruses from Baby Cure were assessed against nine bnAbs targeting different regions on the HIV-1 Env trimer. HIV-1 env sequences within and between bnAb epitopes were compared with database. The bnAbs VRC07-523LS, CAP256-VRC26.25, PGDM1400, 10E8 and PGT151 displayed higher neutralization breadth and potency than other bnAbs against FRESH TF viruses (>70% coverage, starting concentration of 10 μg/ml). Furthermore, VRC07-523LS showed higher neutralization breadth and potency than other bnAbs against Baby Cure TF viruses (p = 0.02). Interestingly, CAP256-VRC26.25 and PGT151 had lower neutralization coverage against infant TF viruses (<60% coverage). Moreover, 40% of infants TF had escape mutations within the V2 loop compared to 28% observed in FRESH and these mutations may explain the observed differences in neutralization sensitivities. However, few mutations were observed in gp120-gp41 interface in both adults and infants. Our findings suggest that intervention studies may have to consider different antibody combinations in adult versus paediatric settings. Moreover, high transmission of escape variants in both vertical and heterosexual transmissions is of concern. This information may be important in the selection of bnAbs that will undergo clinical testing in subtype C settings.
Medullary Thyroid Cancer Risk and Mortality in Carriers of Incidentally Identified MEN2A RET Variants.
ImportanceRET germline pathogenic variants cause multiple endocrine neoplasia type 2 (MEN2), which is associated with medullary thyroid cancer. With increasing incidental identification of these variants in asymptomatic individuals outside family screening, these individuals' risk of medullary thyroid cancer and all-cause mortality without intervention remain unknown in this context.ObjectiveTo evaluate the risk of medullary thyroid cancer and all-cause mortality in clinically unselected individuals with incidentally identified RET variants and assess whether the risk of medullary thyroid cancer differs from those with clinically ascertained RET variants.Design, setting, and participantsThis prospective cohort study of 383 914 unrelated individuals from the clinically unselected UK population (UK Biobank, recruited in 2006-2010, with follow-up to June 2023) and 122 640 unrelated individuals from a US health system (Geisinger MyCode cohort, recruited 2004-2020, with follow-up to October 2023) compared medullary thyroid cancer risk in these cohorts with 1078 individuals who were clinically ascertained with suspicion of MEN2 from a UK routine practice.ExposuresRET germline pathogenic variants causing MEN2.Main outcomes and measuresFrequency and the spectrum of pathogenic RET variants, risk of clinically present medullary thyroid cancer, and all-cause mortality without thyroidectomy were assessed using proportions with exact binomial 95% CIs and survival analysis adjusted for age at recruitment and sex.ResultsIn the UK Biobank, 169 unrelated individuals (mean [SD] age at recruitment, 57.0 [8.1] years; 94 male [55.6%]) had a pathogenic RET variant (prevalence, 0.04% [95% CI, 0.04%-0.05%]). In the US health system-based cohort, 77 unrelated individuals (mean [SD] age at recruitment, 56.2 [17.8] years; 45 female [58.4%]) had a pathogenic RET variant (prevalence, 0.06% [95% CI, 0.05%-0.78%]). The variants were predominantly from the moderate-risk category per American Thyroid Association guidelines (168 individuals [99.4%] and 75 individuals [94.8%], respectively). The Kaplan-Meier estimated medullary thyroid cancer risk by age 75 years in variant carriers in the UK population was 2.2% (95% CI, 0.7%-6.9) and 19.3% (95% CI, 6.4%-30.2%) in US health system cohort. These risks were significantly lower compared with the clinically ascertained cohort with the matched variants (95.7% [95% CI, 82.1%-99.7%]). In the UK Biobank, most variant carriers (166 [98.2%]) did not undergo thyroidectomy, and their all-cause mortality by age 75 years was similar to noncarriers (6.1% [95% CI, 2.7%-13.8%] vs 5.7% [95% CI, 5.6%-5.8%]), with consistent findings in the US health system cohort.Conclusions and relevanceIn this cohort study, moderate-risk RET variants were most common in incidental cases. The variants were associated with a substantially lower medullary thyroid cancer risk than clinically ascertained cases. This evidence addresses a current knowledge gap, enabling more informed clinical decision-making.
Breast cancer germline multigene panel testing in mainstream oncology based on clinical-public health utility: ESMO Precision Oncology Working Group recommendations.
BackgroundWith widening therapeutic indications, germline genetic testing is offered to an increasing proportion of patients with breast cancer (BC) via mainstream oncology services. However, the gene set tested varies widely from just BRCA1/BRCA2 through to 'pan-cancer' panels of nearly 100 genes. If a germline pathogenic variant (GPV) is detected, the BC proband and other family GPV-carriers may be offered interventions such as risk-reducing surgery and intensive surveillance over decades for the various cancers linked to that gene.MethodsThe European Society for Medical Oncology (ESMO) Precision Oncology Working Group established an international expert working group (EWG) in BC germline genetics. This EWG firstly established a framework of criteria by which to evaluate each breast cancer susceptibility gene (BCSG) for potential inclusion on a breast cancer multigene panel test (BC-MGPT) for universal mainstream testing for BC cases. Next, the EWG scored BCSGs for impact regarding (i) BC risk estimation, (ii) clinical actionability and (iii) cancer-related mortality.ResultsThe group agreed that they would constitute a BC-MGPT based on net clinical-public health utility, as quantified by likelihood of impact on cancer-related mortality. Judged as of high or moderate impact on this basis were six BCSGs: BRCA1, BRCA2, PALB2, RAD51C, RAD51D and TP53 (for BC diagnosed <40 years of age), with possible addition of BRIP1. While potentially informative for BC risk estimation, CHEK2 and ATM were judged to offer insufficient evidence for improving cancer-related mortality. The EWG recommended strongly against inclusion of 'syndromic' genes such as STK11, PTEN, NF1 and CDH1.ConclusionsWith expanded germline testing in patients with BC (and cascade testing into families), the number and nature of resultant GPV-carriers identified will be dictated by the genes included on the upfront BC-MGPT. The potential harms, opportunity and economic costs of decades of surveillance of multiple organs and risk-reducing surgeries for GPV-carriers should be justified by strong evidence of meaningful improvement in cancer-related mortality (or health-related quality of life).
Validating data from multiplex assays of variant effect: A CanVIG-UK national survey of NHS clinical scientists.
Advances in technology have made it possible for multiplex assays of variant effect (MAVEs) to systematically generate functional data for thousands of genetic variants. Robust clinical validation and accessible online resources for MAVE data have previously been identified as barriers to the clinical adoption of new MAVEs. We delivered a survey during the November 2024 Cancer Variant Interpretation Group UK (CanVIG-UK) meeting comprising National Health Service (NHS) clinical scientists and clinical geneticists and received 46 responses from individuals regularly performing variant classification for diagnostic reporting. Only 35% reported they would accept clinical validation of the MAVE provided by the authors who conducted the assay; 20% reported they would attempt clinical validation themselves, and 61% would await clinical validation by a trusted central body. 72% reported they would use MAVE data ahead of a formal peer-reviewed publication if reviewed and clinically validated by a trusted central body. When scoring central bodies on a scale of 1-5 for confidence in their review and validation of MAVEs, CanVIG-UK (median = 5), variant curation expert panels (VCEPs; median = 5), and ClinGen SVI Functional Working Group (median = 4) all scored highly. Participants supported making variant-level data accessible via a relevant web resource (although the majority of participants expressed that additional assay-level or variant-level information would have a low likelihood of altering validation scores provided by a trusted central body). These findings, from a comparatively homogeneous clinical diagnostic group operating in a resource-constrained healthcare setting, indicate that clinical application of new MAVEs for variant classification will be delayed unless robust clinical validations are performed by a trusted central body and made readily accessible.
Hepatitis C virus cascade of care among adults in Sindh province, Pakistan: Findings from 2019-2020 household sero-survey.
Pakistan has the largest national burden of hepatitis C virus (HCV) infections (9.8 million). High levels of testing and treatment are needed to achieve HCV elimination, but little data exists on this in Pakistan. A household sero-survey from Sindh province (2019-2020) collected self-reported data from adults on previous HCV testing and treatment, and undertook HCV-antibody (HCV-Ab) testing of participants (2988 children (<18) and 3684 adults) and HCV-RNA testing of HCV-Ab positive individuals. We determined the self-reported HCV cascade-of-care among adults ever eligible for HCV treatment, defined as either having a past infection (HCV-Ab positive and HCV-RNA negative) with self-reported treatment history or current infection (HCV-RNA positive). We assessed factors associated with self-reporting ever being HCV-tested using multi-variable logistic regression. Overall, 10.8% (397/3684) of adults tested HCV Ab-positive in the sero-survey, of which 80.9% (321/397) had a HCV-RNA test result. Of adults defined as ever treatment eligible (n = 232), 40.9% (95/232) reported a previous HCV test and 91.2% (87/95) reported testing positive. Of these, HCV treatment was reported by 69.0% (60/87) and 46.7% (28/60) of treated individuals tested HCV-RNA-negative. Overall, 25.9% (60/232) of treatment-eligible adults reported being treated. The regression analysis suggested that males, older adults (>25 years), and adults with a secondary or higher education level were more likely to have ever been tested for HCV, as were individuals with a family history of hepatitis, received HBV vaccination or that had various risk factors linked to HCV transmission (e.g., blood transfusion, having tattoo/acupuncture, hospitalisation or therapeutic injection (s) history). The cascade-of-care for HCV needs improving to eliminate HCV in Pakistan, especially among younger adults, women and people with low education levels.
Rationale and design of the beta-blocker in heart failure with normal left ventricular ejection fraction (beta-PRESERVE) study.
AimsChronic heart failure with normal left ventricular ejection fraction (HFNEF) is not only common, but also carries a high risk of substantial morbidity and mortality. However, few studies have been conducted in this population and no proven treatment is available. Although beta-blockers are evidence-based first-line therapy in systolic heart failure, they have not been well studied in HFNEF.MethodsThis study is a multicentre, prospective, randomized, open-label, blinded endpoint (PROBE) trial. A total of 1200 patients will be randomized to either beta-blocker (metoprolol succinate) or control (n = 600 per group). The primary endpoint is a composite of hospitalization for heart failure and cardiovascular death. The secondary endpoints include cardiovascular death, heart failure mortality or hospitalization, all-cause mortality, change in New York Heart Association class, change in left ventricular ejection fraction, increase in NT-proBNP (by > or = 50% of the value at randomization), beta-blocker tolerance, and premature termination of beta-blocker therapy due to adverse events. The follow-up period is a minimum of 2 years.ConclusionThis study will provide important evidence, for the first time to our knowledge, of the long-term efficacy of beta-blocker therapy in the management of HFNEF.
Pf8: an open dataset of Plasmodium falciparum genome variation in 33,325 worldwide samples
We describe the Pf8 data resource, the latest MalariaGEN release of curated genome variation data on over 33,000 Plasmodium falciparum samples from 99 partner studies and 122 locations over more than 50 years. This release provides open access to raw sequencing data and genotypes at over 12 million genomic positions. For the first time, it includes copy-number variation (CNV) calls in the drug-resistance associated genes gch1 and crt. As in Pf7, CNV calls are provided for mdr1 and plasmepsin2/3, along with calls for deletion in hrp2 and hrp3, genes associated with rapid diagnostic test failures. This data resource additionally features derived datasets, interactive web applications for exploring patterns of drug resistance and variation in over 5,000 genes, an updated Python package providing methods for accessing and analysing the data, and open access analysis notebooks that can be used as starting points for further analyses. In addition, informative example analyses show contrasting profiles of the decline of chloroquine resistance-associated mutations in Africa, and variation in copy number variation across 10 distinct sub-populations. To the best of our knowledge, Pf8 is the largest open data set of genome variation in any eukaryotic species, making it an invaluable foundational resource for understanding evolution, including that of pathogens.
The Risk-Benefit Balance of Oral Corticosteroid Treatment for Asthma Attacks: A Discrete Choice Experiment of Patients and Healthcare Professionals in the UK and New Zealand.
Background and objectiveOral corticosteroids (OCS) are the guideline recommended treatment for all asthma attacks, but benefits must be considered alongside the potential for cumulative side-effects. There is interest in trialling biomarker-directed management of attacks to rationalise OCS treatment in those with least benefit. Understanding stakeholder perspectives on the risks and benefits associated with OCS treatment can inform trial design and shared decision-making discussions in clinical practice. The aim was to examine patients' and healthcare professionals' preferences for the risks and benefits associated with OCS treatment for asthma attacks.MethodsDiscrete choice experiment (DCE) by patients with asthma and HCPs in the UK and New Zealand. Preferences were analysed using logit models.ResultsEight hundred and twenty-four patients and 171 HCPs completed the DCE. Avoiding the risks of permanent side effects had the greatest impact on treatment preference by patients and HCPs. Avoidance of side effects was weighted higher by patients than HCPs. Patients with uncontrolled asthma were more prepared to trade risk for benefit. Symptom recovery was the most valued clinical benefit to patients and HCPs. Patients preferred 'improving lung function' over 'avoiding additional GP treatment or hospitalisation', whereas HCPs preferred avoidance of further healthcare utilisation. Based on their responses we estimated the minimum clinically important difference for the treatment failure outcome at 20%.ConclusionPatients and HCPs will trade-off treatment benefits to avoid the side-effects associated with OCS. The risk-benefit balance of OCS should feature in shared decision-making discussions with patients experiencing outpatient asthma attacks. The findings support developing trials to personalise acute asthma treatment.
Bowel urgency in ulcerative colitis: effect of baseline urgency and change in urgency in response to mirikizumab.
BackgroundMirikizumab has demonstrated efficacy in moderately to severely active ulcerative colitis. A 1-2-point change in Urgency Numeric Rating Scale (NRS) score can be meaningful for patients. In these post-hoc analyses, we evaluated the efficacy of mirikizumab compared to placebo by baseline Urgency NRS score groups (0-3, 4-6, and 7-10) and its effect on bowel urgency severity over time.MethodologyUrgency NRS was measured as a secondary outcome at baseline, week 12, and week 52. Bowel urgency improvement was assessed for patients who achieved and did not achieve multiple efficacy endpoints. Data were analyzed using Fisher's exact test with nonresponder imputation.ResultsAt weeks 12 and 52, a significantly higher percentage of mirikizumab-treated patients achieved clinical response as well as clinical, endoscopic, and symptomatic remission compared to placebo-treated patients, regardless of baseline Urgency NRS score category (higher proportions versus placebo, delta 9%-45%). Improvement in Urgency NRS score category at weeks 12 and 52 for mirikizumab-treated patients was observed when other efficacy outcomes were achieved (13%-90%) and not achieved (12%-75%).ConclusionsA greater proportion of mirikizumab-treated patients with ulcerative colitis achieved symptomatic, clinical, and endoscopic remission endpoints compared to placebo-treated patients, regardless of baseline bowel urgency severity. After one year, bowel urgency was improved to a greater extent with mirikizumab than with placebo, even for patients who did not achieve other clinical outcomes. Small improvements in bowel urgency are associated with significant health-related quality-of-life improvements. Monitoring shifts in urgency severity over time using the Urgency NRS can aid in understanding patients' treatment outcomes.Trial registrationLUCENT-1 (NCT03518086) Registered 04 May 2018 https://clinicaltrials.gov/study/NCT03518086 . LUCENT-2 (NCT03524092) Registered 10 May 2018 https://clinicaltrials.gov/study/NCT03524092 .
Which first? Surgery or biologic therapy for ileocolic Crohn's disease in the real world.
BackgroundA laparoscopic ileocolic resection could lead to a better outcome to infliximab for ileocolic Crohn's disease. The aim of this study was to explore real world clinical outcomes in biologic-naïve patients with ileocolic Crohn's disease.Research design and methodsAll patients with ileocolic Crohn's disease treated at our institution between January 2011 and December 2018 with biologics or surgical resection were included.ResultsOverall, 222 patients were included, of which 149 (67%) underwent surgery before biologic therapy. Among these, 54 patients (36%) required post-operative biologic therapy. Seventy-three patients were treated with biologics first, of which 29 (40%) subsequently required a surgical resection (p = 0.60). There were 95 patients (43%) who were successfully treated with a surgery-first approach alone. Median follow-up was 73 months (0-406). Characteristics associated on multivariable analysis with change from surgery to biologics were: gender (female) (p = 0.010), presence of obstructive symptoms (p = 0.028), and smoking (p = 0.030). Characteristics associated with changing from biologics to surgery were: isolated terminal ileum disease (p = 0.001) and the presence of obstructive symptoms (p = 0.003).ConclusionsIn our cohort, the risk of recurrent ileocolic Crohn's disease was similar whether patients were treated with a 'surgery first' or 'biologic first' approach.
Development and validation of peripheral blood DNA methylation signatures to predict response to biological therapy in adults with Crohn's disease (EPIC-CD): an epigenome-wide association study.
BackgroundBiological therapeutics are widely used in Crohn's disease, with evidence of efficacy from randomised trials and real-world experience. Primary non-response is a common, poorly understood problem. We aimed to assess blood methylation as a predictor of response to adalimumab, vedolizumab, or ustekinumab in patients with Crohn's disease.MethodsThis epigenome-wide association study used data from two ongoing biobanks (one from the Amsterdam University Medical Centre, University of Amsterdam, Amsterdam, Netherlands [discovery cohort] and the other from the John Radcliffe Hospital, Oxford, UK [validation cohort]) that recruited patients between Oct 1, 2009, and June 17, 2022. Adult participants (age ≥18 years) with active symptomatic and endoscopic Crohn's disease who were scheduled to start adalimumab, vedolizumab, or ustekinumab treatment were included. Patients with ongoing malignancy or serious concomitant inflammatory diseases were excluded. Treatment response was assessed after a median of 28 weeks of treatment (IQR 18-36). Response was defined as a combination of endoscopic criteria (50% or more reduction in the Simple Endoscopic Score for Crohn's Disease) with either clinical or biochemical criteria (corticosteroid-free clinical response: ≥3 point decrease in Harvey-Bradshaw Index [HBI] score or remission [HBI ≤4] and no systemic steroids at follow up; biochemical response: C-reactive protein reduction ≥50% or ≤5 mg/L and faecal calprotectin reduction ≥50% or ≤250 μg/g) compared with baseline. Epigenome-wide DNA methylation and transcriptome-wide gene expression analyses were done on whole peripheral blood leukocyte samples that were collected before the start of treatment. To identify baseline DNA methylation markers associated with response or non-response to treatment, we performed supervised machine learning through stability selected gradient boosting. In a post-hoc analysis, we compared our DNA methylation-based prediction model with clinical decision support tools (CDSTs).FindingsWe profiled the peripheral blood DNA methylome of 273 adults with Crohn's disease scheduled to start adalimumab, vedolizumab, or ustekinumab in the discovery (Amsterdam, n=183; 108 [59·0%] female and 75 [41·0%] male) and the validation cohort (Oxford, n=90; 46 [51·1%] female and 44 [48·9%] male). In the discovery cohort, we defined a panel of DNA methylation biomarkers that were associated with combined endoscopic and clinical or biochemical response to adalimumab (18 markers), vedolizumab (25 markers), or ustekinumab (68 markers), with an area under the curve (AUC) of 0·86 (95% CI 0·58-0·97) for adalimumab, 0·87 (0·67-0·98) for vedolizumab, and 0·89 (0·76-1·00) for ustekinumab. Validation in the Oxford cohort yielded an AUC of 0·25 (0·10-0·35) for adalimumab, 0·75 (0·65-0·85) for vedolizumab, and 0·75 (0·65-0·87) for ustekinumab. In comparison, implementing the CDSTs in the validation cohort yielded an AUC of 0·56 (0·44-0·68) for vedolizumab and 0·66 (0·54-0·77) for ustekinumab. Previous anti-TNF exposure was associated with a reduction in accuracy of the methylation models for vedolizumab (0·66 [0·55-0·73]) and ustekinumab (0·63 [0·52-0·70]) when analysed in the validation cohort.InterpretationOur findings provide evidence for the potential use of DNA methylation as a modality for personalised medicine for Crohn's disease by predicting response to vedolizumab and ustekinumab. The models were more accurate in biologically naive patients and outperform available vedolizumab and ustekinumab CDSTs. We were unable to predict response to adalimumab. The vedolizumab and ustekinumab prediction models are currently being tested in a multicentre randomised clinical trial.FundingThe Leona M and Harry B Helmsley Charitable Trust.
Fecal Calprotectin and C-Reactive Protein Association With Histologic and Endoscopic Endpoints in Mirikizumab-Treated Patients With Ulcerative Colitis.
BackgroundFecal calprotectin (FC) and C-reactive protein (CRP) are noninvasive biomarkers used in ulcerative colitis (UC) clinical trials; however, thresholds defined as "normal" in trials may be higher than "normal" thresholds typically used in clinical practice. We assessed the relationship between FC and CRP improvement in the "normal" range across different cutoff thresholds for patients with moderately to severely active UC treated with mirikizumab.MethodsPatients achieving clinical response to mirikizumab in LUCENT-1 (Weeks 0-12) proceeded to LUCENT-2 (Weeks 12-52 [52 weeks of continuous mirikizumab]). Associations between FC and CRP levels at multiple thresholds and histologic-endoscopic mucosal improvement (HEMI) and histologic-endoscopic mucosal remission (HEMR) at Weeks 12 and 52 were assessed by Fisher's exact test. Least squares means of FC and CRP changes from baseline at Weeks 12 and 52 were calculated using analysis of covariance with HEMI or HEMR status as factors and baseline FC or CRP values as covariates.ResultsAt Weeks 12 and 52, greater proportions of patients with FC thresholds of ≤250, ≤150, ≤100, and ≤50 µg/g, and CRP thresholds of ≤6 and ≤5 mg/L, achieved HEMI and HEMR compared with those not achieving HEMI and HEMR. Changes from baseline in FC and CRP at Week 12 and FC at Week 52 were greater in patients who achieved HEMI and HEMR compared with those not achieving these endpoints.ConclusionsThese results show that FC and CRP analyses may contribute to a noninvasive monitoring strategy in clinical practice.ClinicalTrials.gov numbers: NCT03518086, NCT03524092.
Incidence of discordant pleural fluid exudates and diagnostic patterns - a retrospective cohort study.
BackgroundLight's criteria utilises pleural fluid protein and lactate dehydrogenase (LDH) to differentiate pleural effusions as exudative or transudative. In a subset of exudative pleural effusions, discordance occurs between LDH and protein (protein high, LDH low or vice versa). Research QuestionWhat is the incidence and diagnostic profile associated with discordant pleural fluid biochemistry?Study design and methodsWe conducted a retrospective analysis of 995 pleural fluid samples between 2015-2017 from a UK tertiary centre. Exudates were subdivided into concordant or discordant, with low protein defined as <30g/L and low LDH <170IU/L. Demographics and diagnostic patterns were assessed in both groups. Demographics and diagnostic patterns were assessed in both groups. Chi-squared tests and odds ratios (+/- 95% confidence interval) were calculated for each diagnosis between discordant and concordant pleural effusions, and adjusted ORs calculated using multivariable logistic regression.ResultsIn 715 exudative pleural fluid samples, 229 (32%) were discordant. 85 (37%) of these displayed low protein, with high LDH, and 144 (63%) low LDH with high protein. The median age was higher in the discordant group than the concordant group (75 versus 70 years, p=0.01). The proportion of patients with the following diagnoses were significantly higher in the discordant group compared to concordant: fluid overload (24/229, 10% discordant vs 10/486, 2% concordant, p<0.0001), benign asbestos related pleural effusion (33/229, 14% vs 44/486, 9%, p=0.031) and ICU associated effusion (20/229, 9% vs 15/486, 3%, p=0.001). The following were less frequent in the discordant group: pleural infection (14/229, 6% vs 79/486, 16%, p<0.0001), and malignant pleural effusion (77/229 34% vs 206/486, 42%, p=0.025). These patterns were maintained when adjusting for age and sex.InterpretationDiscordant pleural effusions are common, and represent a biologically distinct entity with different diagnostic patterns compared to concordant effusions. Clinicians should assess for discordance early and tailor investigations accordingly.