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'Treat-to-target': a call for earlier targeted intervention in asthma.
The treat-to-target (TTT) approach is a concept that has been successfully implemented in many disease areas, such as rheumatoid arthritis (RA) and cardiovascular disease, and is more recently being discussed in asthma. Currently, asthma management is focused on severity of symptoms and disease control, with treatment approaches tailored to these symptoms versus the underlying disease activity. Although successful in many patients, there are limitations to this approach, as treatments targeting the underlying pathophysiology of disease may not be initiated until later on a patient's disease trajectory. This can leave patients with uncontrolled asthma despite high treatment doses, or initiating these treatments after long-term lung-function decline has already occurred. Implementing a TTT approach in asthma that focuses on remission as a treatment goal advocates for a more personalised treatment approach whereby the remission target offers patients and clinicians a clear benchmark for the best possible outcomes, and treatments that target the underlying pathophysiology of disease are initiated earlier in the disease course, to optimise long-term outcomes and prevent irreversible lung-function decline.
ESMO Precision Oncology Working Group recommendations on the structure and quality indicators for molecular tumour boards in clinical practice.
BackgroundWith an increased uptake of genomic profiling in clinical practice and the evolving complexity of diagnostic modalities, vast amounts of complex data need to be properly interpreted and integrated into an individualised care plan. To address these challenges, molecular tumour boards (MTBs) have been widely established. As of today, no international recommendations regulating the composition and workflows of MTBs have been defined.MethodsESMO's Precision Oncology Working Group (POWG) established an international expert panel in precision oncology and defined core areas of interest. After several consultations and through an expert consensus process, the group reached a consensus level for each recommendation.ResultsThe group defined five components in the MTB process that are critical to its function and clinical use: (i) the primary task of MTBs consists in providing genomic-informed clinical recommendations, particularly for cases exhibiting complex genomic alterations; (ii) to achieve this, MTBs should encompass interdisciplinary expertise, with key roles for oncologists with genomic expertise, pathologists with molecular training and clinical geneticists; (iii) MTBs' recommendations should be documented in a structured report that includes genomic-informed treatment strategies, management plans for potential tumour-detected germline alterations and guidance for additional genomic testing; (iv) structured follow-up processes should be implemented for monitoring the clinical effectiveness of MTBs recommendations and (v) finally, the panel proposed quality indicators for operating MTBs, including turnaround times for cases discussion and the proportion of cases for which actionable recommendations and clinical trial enrolments were successfully implemented.ConclusionsThese ESMO's POWG recommendations can serve as a guidance and help to define quality standards for MTBs to allow for harmonisation and to further expedite the integration of precision oncology into clinical practice.
Identification of genes associated with testicular germ cell tumor susceptibility through a transcriptome-wide association study.
Transcriptome-wide association studies (TWASs) have the potential to identify susceptibility genes associated with testicular germ cell tumors (TGCTs). We conducted a comprehensive TGCT TWAS by integrating genome-wide association study (GWAS) summary data with predicted expression models from normal testis, TGCT tissues, and a cross-tissue panel that encompasses shared regulatory features across 22 normal tissues, including the testis. Gene associations were evaluated while accounting for variant-level effects from GWASs, followed by fine-mapping analyses in regions exhibiting multiple TWAS signals, and finally supplemented by colocalization analysis. Expression and protein patterns of identified TWAS genes were further examined in relevant tissues. Our analysis tested 19,805 gene-disease links, revealing 165 TGCT-associated genes with a false discovery rate of less than 0.01. We prioritized 46 candidate genes by considering GWAS-inflated signals, correlations between neighboring genes, and evidence of colocalization. Among these, 23 genes overlap with 22 GWAS loci, with 7 being associations not previously implicated in TGCT risk. Additionally, 23 genes located within 21 loci are at least 1 Mb away from published GWAS index variants. The 46 prioritized genes display expression levels consistent with expected expression levels in human gonadal cell types and precursor tumor cells and significant enrichment in TGCTs. Additionally, immunohistochemistry revealed protein-level accumulation of two candidate genes, ARID3B and GINM1, in both precursor and tumor cells. These findings enhance our understanding of the genetic predisposition to TGCTs and underscore the importance of further functional investigations into these candidate genes.
Small-molecule dissolution of stress granules by redox modulation benefits ALS models.
Neurodegenerative diseases, such as amyotrophic lateral sclerosis, are often associated with mutations in stress granule proteins. Aberrant stress granule condensate formation is associated with disease, making it a potential target for pharmacological intervention. Here, we identified lipoamide, a small molecule that specifically prevents cytoplasmic condensation of stress granule proteins. Thermal proteome profiling showed that lipoamide stabilizes intrinsically disordered domain-containing proteins, including SRSF1 and SFPQ, which are stress granule proteins necessary for lipoamide activity. SFPQ has redox-state-specific condensate dissolving behavior, which is modulated by the redox-active lipoamide dithiolane ring. In animals, lipoamide ameliorates aging-associated aggregation of a stress granule reporter protein, improves neuronal morphology and recovers motor defects caused by amyotrophic lateral sclerosis-associated FUS and TDP-43 mutants. Thus, lipoamide is a well-tolerated small-molecule modulator of stress granule condensation, and dissection of its molecular mechanism identified a cellular pathway for redox regulation of stress granule formation.
Readability and complexity of written information presented to hospitalised patients for trial consent during the COVID-19 pandemic in the UK: a retrospective document analysis
ObjectivesPatient information sheets (PISs) and informed consent forms (ICFs) are essential tools to communicate and document informed consent for clinical trial participation. These documents need to be easily understandable, especially when used to take informed consent from acutely unwell patients. Health literacy guidance recommends written information should be at a level between reading ages 9–11. We aimed to assess the readability and complexity of PISs/ICFs used for clinical trials of acute therapies during the COVID-19 pandemic.DesignRetrospective document analysis.SettingPISs/ICFs used in trials involving pharmaceutical interventions recruiting hospitalised patients with COVID-19 during the first year of the pandemic were sourced from hospitals across the UK.Primary and secondary outcome measuresPISs/ICFs were assessed for length, approximate reading time and subsection content. Readability and language complexity were assessed using Flesch-Kincaid Grade Level (FKGL) (range 1–18; higher is more complex), Gunning-Fog (GFOG) (range 1–20; higher is more complex) and Flesch Reading Ease Score (FRES) (range 0–100; below 60 is ‘difficult’ for comprehension).Results13 documents were analysed with a median length of 5139 words (range 1559–7026), equating to a median reading time of 21.4 min (range 6.5–29.3 min) at 240 words per minute. Median FKGL was 9.8 (9.1–10.8), GFOG 11.8 (10.4–13) and FRES was 54.6 (47.0–58.3). All documents were classified as ‘difficult’ for comprehension and had a reading age of 14 years old or higher.ConclusionsAll PISs/ICFs analysed contained literary complexity beyond both recommendations and the reading level of many in the UK population. Researchers should seek to improve communications to improve trial volunteer comprehension and recruitment.
Elevated basophil count is associated with increased odds of endometriosis
Graphical abstract Abstract Immunological dysregulation plays a fundamental role in the inflammatory aspects of endometriosis. Circulating blood leukocytes, one of the most abundant immune cell populations in the human body, have been shown diagnostic significance in some diseases. Nevertheless, the association between peripheral blood leukocyte counts and endometriosis remains unexplored to date. We analyzed two targeted study cohorts: a tertiary center cohort (Endometriosis at Oxford University (ENDOX) Study: 325 cases/177 controls) and a large-scale population study (UK Biobank (UKBB): 1537 cases/6331 controls). In both datasets, peripheral venous blood sample results were retrieved, and counts of leukocyte subpopulations, including neutrophils, lymphocytes, monocytes, eosinophils, and basophils, were analyzed. Logistic regression models were used to investigate the association of leukocyte subtype alterations with endometriosis status, adjusting for confounding factors. We demonstrate that a higher blood basophil level is associated with increased odds of endometriosis. This association was first discovered in the ENDOX cohort (basophils >0.04 × 109/L: OR 1.65 (95% CI: 1.06–2.57), Ptrend = 0.025) and replicated in the UKBB dataset (basophils >0.04 × 109/L: OR 1.26 (95% CI: 1.09–1.45), Ptrend = 0.001). Notably, women with basophil counts in the upper tercile had significantly increased odds of having stage III/IV endometriosis (ENDOX study: OR = 2.30, 95% CI (1.25–4.22), Ptrend = 0.007; UKBB study (OR = 1.40, 95% CI (1.07–1.85), Ptrend = 0.015). None of the other leukocyte subtypes showed an association. Our findings suggest an association between inflammatory responses and the pathogenesis of endometriosis; future studies are warranted to investigate whether the association is causal. Lay summary Endometriosis is a long-term disease affecting approximately 10% of women during their fertile age. It happens when the tissue similar to the lining of the womb grows in other parts of the body, commonly causing pelvic pain and subfertility. Most diagnostic tests for endometriosis are neither accurate nor reliable, leading to a long wait before a correct diagnosis. Looking for changes in blood cell counts could guide doctors for further testing to confirm diagnosis. Our study shows that a higher number of basophils, a specialized type of white cells, commonly measured in a simple blood test, are positively linked with a higher likelihood of endometriosis. The link becomes stronger in severe endometriosis cases. Although we are showing a robust link, whether this can be used to find endometriosis sooner needs to be tested in future studies.
Development and validation of a new algorithm for improved cardiovascular risk prediction
AbstractQRISK algorithms use data from millions of people to help clinicians identify individuals at high risk of cardiovascular disease (CVD). Here, we derive and externally validate a new algorithm, which we have named QR4, that incorporates novel risk factors to estimate 10-year CVD risk separately for men and women. Health data from 9.98 million and 6.79 million adults from the United Kingdom were used for derivation and validation of the algorithm, respectively. Cause-specific Cox models were used to develop models to predict CVD risk, and the performance of QR4 was compared with version 3 of QRISK, Systematic Coronary Risk Evaluation 2 (SCORE2) and atherosclerotic cardiovascular disease (ASCVD) risk scores. We identified seven novel risk factors in models for both men and women (brain cancer, lung cancer, Down syndrome, blood cancer, chronic obstructive pulmonary disease, oral cancer and learning disability) and two additional novel risk factors in women (pre-eclampsia and postnatal depression). On external validation, QR4 had a higher C statistic than QRISK3 in both women (0.835 (95% confidence interval (CI), 0.833–0.837) and 0.831 (95% CI, 0.829–0.832) for QR4 and QRISK3, respectively) and men (0.814 (95% CI, 0.812–0.816) and 0.812 (95% CI, 0.810–0.814) for QR4 and QRISK3, respectively). QR4 was also more accurate than the ASCVD and SCORE2 risk scores in both men and women. The QR4 risk score identifies new risk groups and provides superior CVD risk prediction in the United Kingdom compared with other international scoring systems for CVD risk.