tbuckley/cabot-search huggingface dataset:
Targeting histamine receptor 4 in cholinergic urticaria with izuforant (LEO 152020): results from a phase IIa randomized double-blind placebo-controlled multicentre crossover trial
Authors: Eva Grekowitz, Martin Metz, Sabine Altrichter, Andrea Bauer, Knut Brockow, Guido Heine, Leonard Lionnet, Kadriye Kaplan Saday, Thomas Hultsch, Ole E Søerensen, Marcus Maurer
Journal: British Journal of Dermatology (2024)

Abstract Background Cholinergic urticaria (CholU) is a common subtype of chronic inducible urticaria, where signs and symptoms (e.g. pruritic wheals and angioedema) are triggered by sweating due to physical exercise, passive warming and by other sweat-inducing situations. While guidelines recommend treatment with second-generation H1 antihistamines, approximately 90% of patients report uncontrolled disease. Targeting the histamine 4 receptor (H4R) has shown promise in preclinical/clinical studies of allergic/inflammatory diseases. Izuforant (LEO 152020) is a selective oral H4R antagonist with expected dual antipruritic and anti-inflammatory effects. Objectives To assess the effects of izuforant in adults with CholU, a common type of chronic urticaria driven by histamine and characterized by high skin levels of H4R expression. Methods This was a phase IIa randomized double-blind placebo-controlled multicentre crossover trial where patients with CholU with an inadequate response to ≥ 1 standard dose of H1 antihistamine received izuforant 100 mg twice daily or placebo (EUCTR2020-004961-38-DE; NCT04853992). The primary endpoint was change from baseline in Urticaria Activity Score. Exploratory endpoints included CholU activity score over 7 days, urticaria control test, Physician Global Assessment, patient global assessment of severity (PGA-S), provocation tests, Dermatology Life Quality Index and CholU quality of life (CholU-QoL). Pharmacokinetic and pharmacodynamic parameters, and serum biomarkers were assessed, as well as safety and tolerability. Results Nineteen patients were randomized and included in the full analysis set; 18 completed treatment [mean (SD) age 29.5 (9.8) years; mean (SD) CholU duration 8.0 (6.3) years]. The primary and most of prespecified exploratory endpoints were not met; there were significant improvements in PGA-S for izuforant vs. placebo (P = 0.02), and nonsignificant improvements for other endpoints in quality of life and histamine skin prick test. All adverse events (AEs) experienced with izuforant were considered mild. The most frequently reported (&amp;gt; 1 patient) were nausea (three patients) and upper abdominal pain (two patients), occurring more frequently with izuforant vs. placebo (one patient each). There were no treatment-related serious AEs and no patient receiving izuforant discontinued the study. Treatment with izuforant did not cause downregulation of H4R. Conclusions This is the first study to explore the role of H4R as a therapeutic target in urticaria. Targeting H4R with izuforant was well tolerated but did not demonstrate significant improvements vs. placebo in the primary endpoint and all but one prespecified exploratory endpoint in CholU.
Early Life and Childhood Environmental Exposures, More Than Genetic Predisposition, Influence Age of Diagnosis in a Diverse Cohort of 2952 Patients With IBD
Authors: Nidah S. Khakoo, Ashley H. Beecham, Jiangnan Lyu, Maria A. Quintero, Lissette Gomez, Maria T. Abreu, Amar R. Deshpande, David H. Kerman, Jacob L. McCauley, Siobhan Proksell, Oriana M. Damas
Journal: Clinical Gastroenterology and Hepatology (2024)
Living with nodular prurigo
Authors: Oliver Johnson
Journal: British Journal of Dermatology (2024)

Journal Article Corrected proof Living with nodular prurigo Get access Oliver Johnson Oliver Johnson Writing - original draft, Writing - review & editing Department of Dermatology, Wirral University Teaching Hospital NHS Foundation Trust, Wirral, UK Email: oliverross.johnson@nhs.net https://orcid.org/0000-0002-3161-1053 Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, ljae045, https://doi.org/10.1093/bjd/ljae045 Published: 06 February 2024 Article history Received: 05 January 2024 Revision received: 25 January 2024 Accepted: 26 January 2024 Published: 06 February 2024 Corrected and typeset: 04 March 2024
Household concentrations and female and child exposures to air pollution in peri-urban sub-Saharan Africa: measurements from the CLEAN-Air(Africa) study
Authors: Matthew Shupler, Theresa Tawiah, Emily Nix, Miranda Baame, Federico Lorenzetti, Emmanuel Betang, Ryan Chartier, Judith Mangeni, Adithi Upadhya, Rachel Anderson de Cuevas, Edna Sang, Ricardo Piedrahita, Michael Johnson, Daniel Wilson, Seeba Amenga-Etego, Mieks Twumasi, Sara Ronzi, Diana Menya, Elisa Puzzolo, Reginald Quansah, Kwaku Poku Asante, Daniel Pope, Bertrand Hugo Mbatchou Ngahane
Journal: The Lancet Planetary Health (2024)

BackgroundRelatively clean cooking fuels such as liquefied petroleum gas (LPG) emit less fine particulate matter (PM2·5) and carbon monoxide (CO) than polluting fuels (eg, wood, charcoal). Yet, some clean cooking interventions have not achieved substantial exposure reductions. This study evaluates determinants of between-community variability in exposures to household air pollution (HAP) across sub-Saharan Africa.MethodsIn this measurement study, we recruited households cooking primarily with LPG or exclusively with wood or charcoal in peri-urban Cameroon, Ghana, and Kenya from previously surveyed households. In 2019–20, we conducted monitoring of 24 h PM2·5 and CO kitchen concentrations (n=256) and female cook (n=248) and child (n=124) exposures. PM2·5 measurements used gravimetric and light scattering methods. Stove use monitoring and surveys on cooking characteristics and ambient air pollution exposure (eg, walking time to main road) were also administered.FindingsThe mean PM2·5 kitchen concentration was five times higher among households cooking with charcoal than those using LPG in the Kenyan community (297 μg/m3, 95% CI 216–406, vs 61 μg/m3, 49–76), but only 4 μg/m3 higher in the Ghanaian community (56 μg/m3, 45–70, vs 52 μg/m3, 40–68). The mean CO kitchen concentration in charcoal-using households was double the WHO guideline (6·11 parts per million [ppm]) in the Kenyan community (15·81 ppm, 95% CI 8·71–28·72), but below the guideline in the Ghanaian setting (1·77 ppm, 1·04–2·99). In all communities, mean PM2·5 cook exposures only met the WHO interim-1 target (35 μg/m3) among LPG users staying indoors and living more than 10 min walk from a road.InterpretationCommunity-level variation in the relative difference in HAP exposures between LPG and polluting cooking fuel users in peri-urban sub-Saharan Africa might be attributed to differences in ambient air pollution levels. Thus, mitigation of indoor and outdoor PM2·5 sources will probably be critical for obtaining significant exposure reductions in rapidly urbanising settings of sub-Saharan Africa.FundingUK National Institute for Health and Care Research.
Novel lateral flow assay for point-of-care detection of Neisseria gonorrhoeae infection in syndromic management settings: a cross-sectional performance evaluation
Authors: Remco P H Peters, Jeffrey D Klausner, Laura Mazzola, Mandisa M Mdingi, Hyunsul Jung, Ranjana M S Gigi, Jeremie Piton, Joseph Daniels, Lindsey de Vos, Paul C Adamson, Birgitta Gleeson, Cecilia Ferreyra
Journal: The Lancet (2024)
The need for One Health systems-thinking approaches to understand multiscale dissemination of antimicrobial resistance
Authors: Kathryn E Arnold, Gabrielle Laing, Barry J McMahon, Séamus Fanning, Dov J Stekel, Ole Pahl, Lucy Coyne, Sophia M Latham, K Marie McIntyre
Journal: The Lancet Planetary Health (2024)

Although the effects of antimicrobial resistance (AMR) are most obvious at clinical treatment failure, AMR evolution, transmission, and dispersal happen largely in environmental settings, for example within farms, waterways, livestock, and wildlife. We argue that systems-thinking, One Health approaches are crucial for tackling AMR, by understanding and predicting how anthropogenic activities interact within environmental subsystems, to drive AMR emergence and transmission. Innovative computational methods integrating big data streams (eg, from clinical, agricultural, and environmental monitoring) will accelerate our understanding of AMR, supporting decision making. There are challenges to accessing, integrating, synthesising, and interpreting such complex, multidimensional, heterogeneous datasets, including the lack of specific metrics to quantify anthropogenic AMR. Moreover, data confidentiality, geopolitical and cultural variation, surveillance gaps, and science funding cause biases, uncertainty, and gaps in AMR data and metadata. Combining systems-thinking with modelling will allow exploration, scaling-up, and extrapolation of existing data. This combination will provide vital understanding of the dynamic movement and transmission of AMR within and among environmental subsystems, and its effects across the greater system. Consequently, strategies for slowing down AMR dissemination can be modelled and compared for efficacy and cost-effectiveness.
Activity and safety of eltrombopag in combination with cyclosporin A as first‑line treatment of adults with severe aplastic anaemia (SOAR): a phase 2, single-arm study
Authors: Phillip Scheinberg, Carlo Finelli, Efreen H Montaňo-Figueroa, Carlos Vallejo, Lalita Norasetthada, Rodrigo T Calado, Mehmet Turgut, Régis Peffault de Latour, Ulrike Kriemler-Krahn, Jens Haenig, Joan Clark, Junho Jang
Journal: The Lancet Haematology (2024)
Risk of fractures in half a million survivors of 20 cancers: a population-based matched cohort study using linked English electronic health records
Authors: Eva Buzasi, Helena Carreira, Garth Funston, Kathryn E Mansfield, Harriet Forbes, Helen Strongman, Krishnan Bhaskaran
Journal: The Lancet Healthy Longevity (2024)

BackgroundA history of multiple myeloma, prostate cancer, and breast cancer has been associated with adverse bone health, but associations across a broader range of cancers are unclear. We aimed to compare the risk of any bone fracture and major osteoporotic fractures in survivors of a wide range of cancers versus cancer-free individuals.MethodsIn this population-based matched cohort study, we used electronic health records from the UK Clinical Practice Research Datalink linked to hospital data. We included adults (aged ≥18 years) eligible for linkage, and we restricted the study start to Jan 2, 1998, onwards and applied administrative censoring on Jan 31, 2020. The cancer survivor group included survivors of the 20 most common cancers. Each individual with cancer was matched (age, sex, and general practice) to up to five controls (1:5) who were cancer-free. The primary outcomes were any bone fracture and any major osteoporotic fracture (pelvic, hip, wrist, spine, or proximal humeral fractures) occurring more than 1 year after index date (ie, the diagnosis date of the matched individual with cancer). We used Cox regression models, adjusted for shared risk factors, to estimate associations between cancer survivorship and bone fractures.Findings578 160 adults with cancer diagnosed in 1998–2020 were matched to 3 226 404 cancer-free individuals. Crude incidence rates of fractures in cancer survivors ranged between 8·39 cases (95% CI 7·45–9·46) per 1000 person-years for thyroid cancer and 21·62 cases (20·18–23·18) per 1000 person-years for multiple myeloma. Compared with cancer-free individuals, the risk of any bone fracture was increased in 15 of 20 cancers, and of major osteoporotic fractures in 17 of 20 cancers. Effect sizes varied: adjusted hazard ratios (HRs) were largest for multiple myeloma (1·94, 95% CI 1·77–2·13) and prostate cancer (1·43, 1·39–1·47); HRs in the range 1·20–1·50 were seen for stomach, liver, pancreas, lung, breast, kidney, and CNS cancers; smaller associations (HR <1·20) were observed for malignant melanoma, non-Hodgkin lymphoma, leukaemia, and oesophageal, colorectal, and cervical cancers. Increased risks of major osteoporotic fracture were noted most substantially in multiple myeloma (2·25, 1·96–2·58) and CNS (2·12, 1·56–2·87), liver (1·62, 1·01–2·61), prostate (1·60, 1·53–1·67), and lung cancers (1·60, 1·44–1·77). Effect sizes tended to reduce over time since diagnosis but remained elevated for more than 5 years in several cancers, such as multiple myeloma and stomach, lung, breast, prostate, and CNS cancers.InterpretationSurvivors of most types of cancer were at increased risk of bone fracture for several years after cancer, with variation by cancer type. These findings can help to inform mitigation and prevention strategies.FundingWellcome Trust.
Longitudinal Changes in Sex Hormone Binding Globulin (SHBG) and Risk of Incident Diabetes: The Study of Women’s Health Across the Nation (SWAN)
Authors: Monique M. Hedderson, Angela Capra, Catherine Lee, Laurel A. Habel, Jennifer Lee, Ellen B. Gold, Sylvia E. Badon, Susanna D. Mitro, Samar R. El Khoudary
Journal: Diabetes Care (2024)

OBJECTIVE To investigate the associations of longitudinal changes in sex hormone binding globulin (SHBG) and testosterone (T) over the menopause transition with the risk of diabetes. RESEARCH DESIGN AND METHODS We followed 2,952 participants in the Study of Women’s Health Across the Nation (SWAN) who were premenopausal or early perimenopausal and diabetes-free at baseline. SHBG,T, and estradiol (E2) levels were measured at up to 13 follow-up visits (over up to 17 years). We used complementary log-log–based discrete-time survival models anchored at baseline. RESULTS Diabetes developed in 376 women. A 5-unit increase in time-varying SHBG was associated with a 10% reduced risk of diabetes (hazard ratio [HR] 0.91, 95% CI 0.87–0.95), adjusting for covariates, and baseline SHBG,T, and E2 levels. Time-varying T was not associated with diabetes risk. Compared with the lowest quartile for annual rate of change of SHBG since baseline (quartile 1 [Q1] −92.3 to −1.5 nmol/L), all other quartiles were associated with a decreased risk of diabetes adjusting for covariates and baseline SHBG; associations persisted after adjusting for rate of change of T and E2 (Q2 [&amp;gt; −1.5 to −0.2 nmol/L] HR 0.33, 95% CI 0.23–0.48; Q3 [&amp;gt; −0.2 to 1.3 nmol/L] HR 0.37, 95% CI 0.25–0.55; Q4 [&amp;gt;1.3 to 82.0 nmol/L] HR 0.43, 95% CI 0.30–0.63). CONCLUSIONS Increasing levels of SHBG over the menopause transition were associated with a decreased risk of incident diabetes. Stable to increasing rates of change in SHBG were also independently associated with a decreased risk of diabetes compared with decreasing rates of change, suggesting SHBG may affect glucose through a mechanism beyond androgenicity.
Surveillance for Hepatocellular Carcinoma in Patients with Successfully Treated Viral Disease of the Liver: A Systematic Review
Authors: Lorenzo Lani, Benedetta Stefanini, Franco Trevisani
Journal: Liver Cancer (2024)

&lt;b&gt;&lt;i&gt;Background:&lt;/i&gt;&lt;/b&gt; Surveillance for hepatocellular carcinoma (HCC) has been proven to increase the proportion of tumors detected at early stages and the chance of receiving curative therapies, reducing mortality by about 30%. &lt;b&gt;&lt;i&gt;Summary:&lt;/i&gt;&lt;/b&gt; Current recommendations consist of a semi-annual abdominal ultrasound with or without serum alpha-fetoprotein measurement in patients with cirrhosis and specific subgroups of populations with chronic viral hepatitis. Antiviral therapies, such as nucleot(s)ide analogs that efficiently suppress the replication of hepatitis B virus (HBV) and direct-acting antiviral drugs able to eliminate the hepatitis C virus (HCV) in &amp;gt;90% of patients, have radically changed the outcomes of viral liver disease and decreased, but not eliminated, the risk of HCC in both cirrhotic and non-cirrhotic patients. HCC risk is a key starting point for implementing a cost-effective surveillance and should also guide the decision-making process concerning its modality. As the global number of effectively treated viral patients continues to rise, there is a pressing need to identify those for whom the benefit-to-harm ratio of surveillance is favorable and to determine how to conduct cost-effective screening on such patients. &lt;b&gt;&lt;i&gt;Key Messages:&lt;/i&gt;&lt;/b&gt; This article addresses this topic and attempts to determine which patients should continue HCC surveillance after HBV suppression or HCV eradication, based on cost-effectiveness principles and the fact that HCC risk declines over time. We also formulate a proposal for a surveillance algorithm that switches the use of surveillance for HCC from the “one-size-fits-all” approach to individualized programs based on oncologic risk (&lt;i&gt;precision surveillance&lt;/i&gt;).
Prophylactic Radiation Therapy for High-Risk Asymptomatic Bone Metastases: A New Standard of Care or Need for More Data?
Authors: Adrian Wai Chan, Charles B. Simone, Yvette van der Linden, Peter Hoskin, Jay Detsky, J. Isabelle Choi, S.F. Lee, Henry CY Wong, Emily J. Martin, Srinivas Raman, Dirk Rades, Agata Rembielak, Joanna Kazmierska, Vassilios Vassiliou, Sara Alcorn, Pierluigi Bonomo, Eva Oldenburger
Journal: Journal of Clinical Oncology (2024)
Association of Major Adverse Financial Events and Later-Stage Cancer Diagnosis in the United States
Authors: Joan L. Warren, Angela B. Mariotto, Jennifer Stevens, Amy J. Davidoff, Veena Shankaran, Kevin C. Ward, Xiao-Cheng Wu, Stephen M. Schwartz, Lynne Penberthy, K. Robin Yabroff
Journal: Journal of Clinical Oncology (2024)

This study assessed the prevalence of specific major adverse financial events (AFEs)-bankruptcies, liens, and evictions-before a cancer diagnosis and their association with later-stage cancer at diagnosis.
Metabolic reprogramming directed by super-enhancers in tumors: An emerging landscape
Authors: Zongjiang Zhou, Jinghe Li, Diabate Ousmane, Li Peng, Xiaoqing Yuan, Junpu Wang
Journal: Molecular Therapy (2024)

Metabolic reprogramming is an essential hallmark of tumors, and metabolic abnormalities are strongly associated with the malignant phenotype of tumor cells. This is closely related to transcriptional dysregulation. Super-enhancers are extremely active cis-regulatory regions in the genome, and can amalgamate a complex set of transcriptional regulatory components that are crucial for establishing tumor cell identity, promoting tumorigenesis, and enhancing aggressiveness. In addition, alterations in metabolic signaling pathways are often accompanied by changes in super-enhancers. Presently, there is a surge in interest in the potential pathogenesis of various tumors through the transcriptional regulation of super-enhancers and oncogenic mutations in super-enhancers. In this review, we summarize the functions of super-enhancers, oncogenic signaling pathways, and tumor metabolic reprogramming. In particular, we focus on the role of the super-enhancer in tumor metabolism and its impact on metabolic reprogramming. This review also discusses the prospects and directions in the field of super-enhancer and metabolic reprogramming. Metabolic reprogramming is an essential hallmark of tumors, and metabolic abnormalities are strongly associated with the malignant phenotype of tumor cells. This is closely related to transcriptional dysregulation. Super-enhancers are extremely active cis-regulatory regions in the genome, and can amalgamate a complex set of transcriptional regulatory components that are crucial for establishing tumor cell identity, promoting tumorigenesis, and enhancing aggressiveness. In addition, alterations in metabolic signaling pathways are often accompanied by changes in super-enhancers. Presently, there is a surge in interest in the potential pathogenesis of various tumors through the transcriptional regulation of super-enhancers and oncogenic mutations in super-enhancers. In this review, we summarize the functions of super-enhancers, oncogenic signaling pathways, and tumor metabolic reprogramming. In particular, we focus on the role of the super-enhancer in tumor metabolism and its impact on metabolic reprogramming. This review also discusses the prospects and directions in the field of super-enhancer and metabolic reprogramming.
Results from the randomized phase III DREAMM-7 study of belantamab mafodotin (belamaf) + bortezomib, and dexamethasone (BVd) vs daratumumab, bortezomib, and dexamethasone (DVd) in relapsed/refractory multiple myeloma (RRMM).
Authors: Maria-Victoria Mateos, Pawel Robak, Marek Hus, Zhongjun Xia, Vera Zherebtsova, Christopher Ward, P. Joy Ho, Roman Hajek, Kihyun Kim, Meletios A. Dimopoulos, Claudio Cerchione, Antonio Riccio, Astrid McKeown, Rachel Rogers, Hena Baig, Lydia Eccersley, Sumita Roy-Ghanta, Joanna Opalinska, Vania Hungria
Journal: Journal of Clinical Oncology (2024)

439572 Background: Belamaf, a BCMA-targeted antibody drug conjugate, has previously demonstrated clinical activity and a manageable safety profile, supporting its use in combination with standard-of-care (SoC) therapies in RRMM. DREAMM-7 (NCT04246047) is a global, randomized, open-label, phase III head-to-head trial evaluating the efficacy and safety of BVd triplet vs SoC triplet, DVd, in patients (pts) with RRMM with ≥1 prior line of therapy (LOT). Methods: Pts with ≥1 prior LOT were randomized (1:1) to BVd: B 2.5 mg/kg IV Q3W + V 1.3 mg/m 2 (D1, 4, 8, 11 of 21-day cycles (C); up to 8 C) + d 20 mg (D1, 2, 4, 5, 8, 9, 11, 12; up to 8 C) or DVd: D 16 mg/kg (21-day C), C1-3, Q1W, C4-8, Q3W, and Q4W from C 9 on); V and d schedules were the same. The primary endpoint was independent review committee-assessed progression free survival (PFS). Secondary endpoints available include overall survival (OS), duration of response (DOR), overall response rate (ORR). Results: 494 pts were randomized (BVd n = 243, DVd n = 251). With a median (range) follow-up of 28.2 mo (0.10-40 mo), the median PFS (mPFS) in the BVd arm was 36.6 mo (95% CI, 28.4 mo-NR) vs 13.4 mo (11.1-17.5 mo) with DVd; hazard ratio (HR) 0.41 (95% CI, 0.31-0.53; p &lt; 0.00001). OS data was 29% mature; median OS was not reached in either arm; HR, 0.57 (95% CI, 0.40-0.80; nominal p &lt; 0.0005). ORR was 82.7% (95% CI, 77.4-87.3%) with BVd and 71.3% (65.3-76.8%) with DVd. Median DOR (mDOR) was 35.6 mo (95% CI, 30.5 mo-NR) for BVd vs 17.8 mo (13.8-23.6 mo) for DVd. All pts in both arms experienced ≥1 AE (Table). Grade 3/4 treatment-related AEs (TRAE) were reported in 90% of pts in the BVd arm and 67% with DVd. Serious AEs (SAE) were reported in 50% of pts in BVd vs 37% in DVd arm. Ocular AEs were more frequent on BVd vs DVd (79% vs 29%) and were manageable. Conclusions: The DREAMM-7 head-to-head study of BVd vs DVd demonstrated statistically significant PFS benefit of BVd with a mPFS improvement of 23 mo in pts with RRMM with ≥1 prior LOT. A strong and clinically meaningful OS benefit (nominal p &lt; 0.0005) was observed. Additionally, BVd led to greater depth of response and doubling of mDOR vs DVd and had a manageable safety profile. These results support BVd as a potential new SoC in this setting. Clinical trial information: NCT04246047 . [Table: see text]
Clinical Features and Long-Term Outcomes of a Pan-Canadian Cohort of Adolescents and Young Adults with Myeloproliferative Neoplasms: A Canadian MPN Group Study
Authors: James T. England, Natasha Szuber, Shireen Sirhan, Tom Dunne, Sonia Cerquozzi, Madeleine Hill, Pierre J. A. Villeneuve, Jenny M. Ho, Bekim Sadikovic, Pratibha Bhai, Nupur Krishnan, Sebastian Dowhanik, Chris Hillis, Jose-Mario Capo-Chichi, Hubert Tsui, Verna Cheung, Karine Gauthier, Hassan Sibai, Marta B. Davidson, Aniket Bankar, Rouslan Kotchetkov, Vikas Gupta, Dawn Maze
Journal: Leukemia (2024)