Maintaining Clinical Freedom Whilst Achieving Value in Biologics Prescribing: An Integrated Cross-Specialty Consensus of UK Dermatologists, Rheumatologists and Gastroenterologists.

Funder: Janssen UKBACKGROUND: Biologics are now key drugs in the management of immune-mediated inflammatory diseases. However, the increasingly complex biologics environment and growing cost pressures in the UK have led to variability in drug commissioning and inequity of patient access across regions. OBJECTIVES: Our objectives were to provide consensus recommendations for enhancing the current situation in biologic prescribing in the UK by balancing clinical freedom with equitable distribution of biologics given the limited availability of resources. METHODS: A modified Delphi approach was used to reach integrated, cross-specialty consensus among dermatologists, rheumatologists and gastroenterologists practising within the English National Health Service (NHS). RESULTS: We describe the concepts of clinical freedom and clinical judgement and demonstrate how, together with patient choice, they can be exercised in the context of biologic prescribing in the NHS. We highlight that in England, local variations occur that are at odds with National Institute for Health and Care Excellence (NICE) guidance; these variably limit the degree to which clinicians can exercise clinical freedom and impact on equity of patient access to treatments. We define factors encompassing a drug's value and identify challenges to the measurement and interpretation of this concept, which can raise barriers to the freedom of clinical choice and appropriate prescribing decisions allowing practices of holistic and personalised medicine. Cross-specialty consensus recommendations on ensuring equitable access to biologics in the NHS while protecting appropriate and individualised drug selection for patients are provided. We have also provided strategies for improving physician-commissioner communication to harmonise equity of patient access to biologics across England and improve patient outcomes. Commentary from patient advisory groups indicates that they welcome our exploration that value does not equal cost and agree that there should be an emphasis on shared decision making, which requires the clinician to practice clinical freedom by aligning the patient's needs and preferences with available treatment choices. CONCLUSIONS: This consensus highlights the need to strike a balance between clinical freedom and short-term cost restrictions to support equitable resource distribution within the English NHS. Consideration of these recommendations may help to harmonise local, regional and national services and balance equity of patient access to biologic treatments with excellence in the NHS

Maintaining Clinical Freedom Whilst Achieving Value in Biologics Prescribing: An Integrated Cross-Specialty Consensus of UK Dermatologists, Rheumatologists and Gastroenterologists.

Funder: Janssen UKBACKGROUND: Biologics are now key drugs in the management of immune-mediated inflammatory diseases. However, the increasingly complex biologics environment and growing cost pressures in the UK have led to variability in drug commissioning and inequity of patient access across regions. OBJECTIVES: Our objectives were to provide consensus recommendations for enhancing the current situation in biologic prescribing in the UK by balancing clinical freedom with equitable distribution of biologics given the limited availability of resources. METHODS: A modified Delphi approach was used to reach integrated, cross-specialty consensus among dermatologists, rheumatologists and gastroenterologists practising within the English National Health Service (NHS). RESULTS: We describe the concepts of clinical freedom and clinical judgement and demonstrate how, together with patient choice, they can be exercised in the context of biologic prescribing in the NHS. We highlight that in England, local variations occur that are at odds with National Institute for Health and Care Excellence (NICE) guidance; these variably limit the degree to which clinicians can exercise clinical freedom and impact on equity of patient access to treatments. We define factors encompassing a drug's value and identify challenges to the measurement and interpretation of this concept, which can raise barriers to the freedom of clinical choice and appropriate prescribing decisions allowing practices of holistic and personalised medicine. Cross-specialty consensus recommendations on ensuring equitable access to biologics in the NHS while protecting appropriate and individualised drug selection for patients are provided. We have also provided strategies for improving physician-commissioner communication to harmonise equity of patient access to biologics across England and improve patient outcomes. Commentary from patient advisory groups indicates that they welcome our exploration that value does not equal cost and agree that there should be an emphasis on shared decision making, which requires the clinician to practice clinical freedom by aligning the patient's needs and preferences with available treatment choices. CONCLUSIONS: This consensus highlights the need to strike a balance between clinical freedom and short-term cost restrictions to support equitable resource distribution within the English NHS. Consideration of these recommendations may help to harmonise local, regional and national services and balance equity of patient access to biologic treatments with excellence in the NHS

A Framework for Multi-Omic Prediction of Treatment Response to Biologic Therapy for Psoriasis.

Biologic therapies have shown high efficacy in psoriasis, but individual response varies and is poorly understood. To inform biomarker discovery in the Psoriasis Stratification to Optimise Relevant Therapy (i.e., PSORT) study, we evaluated a comprehensive array of omics platforms across three time points and multiple tissues in a pilot investigation of 10 patients with severe psoriasis, treated with the tumor necrosis factor (TNF) inhibitor, etanercept. We used RNA sequencing to analyze mRNA and small RNA transcriptome in blood, lesional and nonlesional skin, and the SOMAscan platform to investigate the serum proteome. Using an integrative systems biology approach, we identified signals of treatment response in genes and pathways associated with TNF signaling, psoriasis pathology, and the major histocompatibility complex region. We found association between clinical response and TNF-regulated genes in blood and skin. Using a combination of differential expression testing, upstream regulator analysis, clustering techniques, and predictive modeling, we show that baseline samples are indicative of patient response to biologic therapies, including signals in blood, which have traditionally been considered unreliable for inference in dermatology. In conclusion, our pilot study provides both an analytical framework and empirical basis to estimate power for larger studies, specifically the ongoing PSORT study, which we show as powered for biomarker discovery and patient stratification

Characterizing Long COVID in Children and Adolescents

ImportanceMost research to understand postacute sequelae of SARS-CoV-2 infection (PASC), or long COVID, has focused on adults, with less known about this complex condition in children. Research is needed to characterize pediatric PASC to enable studies of underlying mechanisms that will guide future treatment.ObjectiveTo identify the most common prolonged symptoms experienced by children (aged 6 to 17 years) after SARS-CoV-2 infection, how these symptoms differ by age (school-age [6-11 years] vs adolescents [12-17 years]), how they cluster into distinct phenotypes, and what symptoms in combination could be used as an empirically derived index to assist researchers to study the likely presence of PASC.Design, setting, and participantsMulticenter longitudinal observational cohort study with participants recruited from more than 60 US health care and community settings between March 2022 and December 2023, including school-age children and adolescents with and without SARS-CoV-2 infection history.ExposureSARS-CoV-2 infection.Main outcomes and measuresPASC and 89 prolonged symptoms across 9 symptom domains.ResultsA total of 898 school-age children (751 with previous SARS-CoV-2 infection [referred to as infected] and 147 without [referred to as uninfected]; mean age, 8.6 years; 49% female; 11% were Black or African American, 34% were Hispanic, Latino, or Spanish, and 60% were White) and 4469 adolescents (3109 infected and 1360 uninfected; mean age, 14.8 years; 48% female; 13% were Black or African American, 21% were Hispanic, Latino, or Spanish, and 73% were White) were included. Median time between first infection and symptom survey was 506 days for school-age children and 556 days for adolescents. In models adjusted for sex and race and ethnicity, 14 symptoms in both school-age children and adolescents were more common in those with SARS-CoV-2 infection history compared with those without infection history, with 4 additional symptoms in school-age children only and 3 in adolescents only. These symptoms affected almost every organ system. Combinations of symptoms most associated with infection history were identified to form a PASC research index for each age group; these indices correlated with poorer overall health and quality of life. The index emphasizes neurocognitive, pain, and gastrointestinal symptoms in school-age children but change or loss in smell or taste, pain, and fatigue/malaise-related symptoms in adolescents. Clustering analyses identified 4 PASC symptom phenotypes in school-age children and 3 in adolescents.Conclusions and relevanceThis study developed research indices for characterizing PASC in children and adolescents. Symptom patterns were similar but distinguishable between the 2 groups, highlighting the importance of characterizing PASC separately for these age ranges

SARS-CoV-2 lineage B.1.1.7 is associated with greater disease severity among hospitalised women but not men: multicentre cohort study.

BACKGROUND: SARS-CoV-2 lineage B.1.1.7 has been associated with an increased rate of transmission and disease severity among subjects testing positive in the community. Its impact on hospitalised patients is less well documented. METHODS: We collected viral sequences and clinical data of patients admitted with SARS-CoV-2 and hospital-onset COVID-19 infections (HOCIs), sampled 16 November 2020 to 10 January 2021, from eight hospitals participating in the COG-UK-HOCI study. Associations between the variant and the outcomes of all-cause mortality and intensive therapy unit (ITU) admission were evaluated using mixed effects Cox models adjusted by age, sex, comorbidities, care home residence, pregnancy and ethnicity. FINDINGS: Sequences were obtained from 2341 inpatients (HOCI cases=786) and analysis of clinical outcomes was carried out in 2147 inpatients with all data available. The HR for mortality of B.1.1.7 compared with other lineages was 1.01 (95% CI 0.79 to 1.28, p=0.94) and for ITU admission was 1.01 (95% CI 0.75 to 1.37, p=0.96). Analysis of sex-specific effects of B.1.1.7 identified increased risk of mortality (HR 1.30, 95% CI 0.95 to 1.78, p=0.096) and ITU admission (HR 1.82, 95% CI 1.15 to 2.90, p=0.011) in females infected with the variant but not males (mortality HR 0.82, 95% CI 0.61 to 1.10, p=0.177; ITU HR 0.74, 95% CI 0.52 to 1.04, p=0.086). INTERPRETATION: In common with smaller studies of patients hospitalised with SARS-CoV-2, we did not find an overall increase in mortality or ITU admission associated with B.1.1.7 compared with other lineages. However, women with B.1.1.7 may be at an increased risk of admission to intensive care and at modestly increased risk of mortality.This report was produced by members of the COG-UK-HOCI Variant substudy consortium. COG-UK-HOCI is part of COG-UK. COG-UK is supported by funding from the Medical Research Council (MRC) part of UK Research & Innovation (UKRI), the National Institute of Health Research (NIHR) and Genome Research Limited, operating as the Wellcome Sanger Institute

Psychosocial impact of undergoing prostate cancer screening for men with BRCA1 or BRCA2 mutations.

OBJECTIVES: To report the baseline results of a longitudinal psychosocial study that forms part of the IMPACT study, a multi-national investigation of targeted prostate cancer (PCa) screening among men with a known pathogenic germline mutation in the BRCA1 or BRCA2 genes. PARTICPANTS AND METHODS: Men enrolled in the IMPACT study were invited to complete a questionnaire at collaborating sites prior to each annual screening visit. The questionnaire included sociodemographic characteristics and the following measures: the Hospital Anxiety and Depression Scale (HADS), Impact of Event Scale (IES), 36-item short-form health survey (SF-36), Memorial Anxiety Scale for Prostate Cancer, Cancer Worry Scale-Revised, risk perception and knowledge. The results of the baseline questionnaire are presented. RESULTS: A total of 432 men completed questionnaires: 98 and 160 had mutations in BRCA1 and BRCA2 genes, respectively, and 174 were controls (familial mutation negative). Participants' perception of PCa risk was influenced by genetic status. Knowledge levels were high and unrelated to genetic status. Mean scores for the HADS and SF-36 were within reported general population norms and mean IES scores were within normal range. IES mean intrusion and avoidance scores were significantly higher in BRCA1/BRCA2 carriers than in controls and were higher in men with increased PCa risk perception. At the multivariate level, risk perception contributed more significantly to variance in IES scores than genetic status. CONCLUSION: This is the first study to report the psychosocial profile of men with BRCA1/BRCA2 mutations undergoing PCa screening. No clinically concerning levels of general or cancer-specific distress or poor quality of life were detected in the cohort as a whole. A small subset of participants reported higher levels of distress, suggesting the need for healthcare professionals offering PCa screening to identify these risk factors and offer additional information and support to men seeking PCa screening

An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers

Introduction: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. Methods: We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. Results: We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. Conclusions: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.Peer reviewe