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{"title":"Depemokimab, the first ultra-long-acting anti-IL-5 monoclonal antibody for severe eosinophilic asthma.","authors":"Santi Nolasco, Claudia Crimi","doi":"10.1016/j.medj.2024.10.022","DOIUrl":"https://doi.org/10.1016/j.medj.2024.10.022","url":null,"abstract":"<p><p>Depemokimab, the first ultra-long-acting anti-IL-5 monoclonal antibody, significantly reduced exacerbation rates in patients with severe eosinophilic asthma when administered biannually.¹ While it offers potential benefits for patient adherence and convenience, the trials showed no improvement in symptoms and lung function. Further research is needed to determine its optimal place in therapy and identify patients who will benefit the most.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":"5 12","pages":"1452-1455"},"PeriodicalIF":12.8,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142824525","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ticagrelor monotherapy after short DAPT in ACS: Time to turn theory into practice.","authors":"Mattia Galli, Sebastiano Sciarretta","doi":"10.1016/j.medj.2024.08.006","DOIUrl":"https://doi.org/10.1016/j.medj.2024.08.006","url":null,"abstract":"<p><p>Guidelines still recommend 12-month DAPT after acute coronary syndrome (ACS). This is possibly due to the insufficient power of most trials to detect hard ischemic endpoints, particularly in the subgroup of high ischemic-risk patients, such as those with ST-elevation ACS. Individual patient data meta-analyses play an important role in overcoming these limitations.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":"5 12","pages":"1443-1445"},"PeriodicalIF":12.8,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142824530","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel agents for treating severe hypertriglyceridemia.","authors":"Anthony S Wierzbicki","doi":"10.1016/j.medj.2024.10.019","DOIUrl":"10.1016/j.medj.2024.10.019","url":null,"abstract":"<p><p>The PALISADE trial extended the data available for inhibition of apolipoprotein (apo) C3 inhibition for treating severe hypertriglyceridemia.¹ 75 patients with persistent chylomicronemia were allocated to 2 doses of plozasiran or placebo. Triglycerides were reduced by a net 53%-58%, and a borderline significant 17% reduction was seen in pancreatitis events. These results offer potential treatments for familial or multifactorial chylomicronemia syndromes.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":"5 12","pages":"1446-1448"},"PeriodicalIF":12.8,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142824526","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bilirubin metabolism in early life and respiratory health during preschool age: A combined analysis of two independent birth cohorts.","authors":"Min Kim, Nicklas Brustad, Anders U Eliasen, Mina Ali, Tingting Wang, Morten A Rasmussen, Madeleine Ernst, David Hougaard, Augusto A Litonjua, Craig E Wheelock, Rachel S Kelly, Yulu Chen, Nicole Prince, Paul A Townsend, Jakob Stokholm, Scott T Weiss, Klaus Bønnelykke, Jessica Lasky-Su, Bo Chawes","doi":"10.1016/j.medj.2024.07.021","DOIUrl":"10.1016/j.medj.2024.07.021","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Bilirubin has antioxidant properties, and elevated levels within the normal range have been associated with improved lung function and decreased risk of asthma in adults, but studies of young children are scarce. Here, we investigate associations between bilirubin in early life and respiratory health endpoints during preschool age in two independent birth cohorts.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Bilirubin metabolites were assessed at ages 0.5, 1.5, and 6 years in COPSAC&lt;sub&gt;2010&lt;/sub&gt; (Copenhagen Prospective Studies on Asthma in Childhood 2010) and ages 1, 3, and 6 years in the VDAART (The Vitamin D Antenatal Asthma Reduction Trial) cohort. Meta-analyses were done to summarize the relationship between levels of bilirubin metabolites and asthma, infections, lung function, and allergic sensitization until age 6 across the cohorts. Interaction with the glucuronosyltransferase family 1 member A1 (UGT1A) genotype encoding for an enzyme in the bilirubin metabolism was explored, and metabolomics data were integrated to study underlying mechanisms.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Findings: &lt;/strong&gt;Increasing bilirubin (Z,Z) at ages 1.5-3 years was associated with an increased risk of allergic sensitization (adjusted relative risk [aRR] = 1.85 [1.20-2.85], p = 0.005), and age 6 bilirubin (Z,Z) also showed a trend of association with allergic sensitization at age 6 (aRR = 1.31 [0.97-1.77], p = 0.08), which showed significant interaction for the age 6 bilirubin (Z,Z)xUGT1A genotype. Further, increasing bilirubin (E,E), bilirubin (Z,Z), and biliverdin at ages 1.5-3 years was associated with a lower forced expiratory volume at age 6 (aRR range = 0.81-0.91, p &lt; 0.049) but without a significant interaction with the UGT1A genotype (p interactions &gt; 0.05). Network analysis showed a significant correlation between bilirubin metabolism and acyl carnitines. There were no associations between bilirubin metabolites and the risk of asthma and infections.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;Bilirubin metabolism in early life may play a role in childhood respiratory health, particularly in children with specific UGT1A genotypes.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Funding: &lt;/strong&gt;The Lundbeck Foundation (Grant no R16-A1694), The Ministry of Health (Grant no 903516), Danish Council for Strategic Research (Grant no 0603-00280B), and The Capital Region Research Foundation have provided core support to the COPSAC research center. This project has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (grant agreement No. 946228). The Vitamin D Antenatal Asthma Reduction Trial (VDDART, ClinicalTrials.gov identifier: NCT00920621) was supported by grant U01HL091528 from NHLBI, U54TR001012 from the National Centers for Advancing Translational Sciences (NCATS). Metabolomics work by VDAART was supported by the National Heart, Lung, and Blood Institute (NHLBI) grant R01HL123915 and R01HL141826. S.T.W. was suppo","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"1485-1494.e3"},"PeriodicalIF":12.8,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141996585","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unraveling the physiological and psychosocial signatures of pain by machine learning.","authors":"Noemi Gozzi, Greta Preatoni, Federico Ciotti, Michèle Hubli, Petra Schweinhardt, Armin Curt, Stanisa Raspopovic","doi":"10.1016/j.medj.2024.07.016","DOIUrl":"10.1016/j.medj.2024.07.016","url":null,"abstract":"<p><strong>Background: </strong>Pain is a complex subjective experience, strongly impacting health and quality of life. Despite many attempts to find effective solutions, present treatments are generic, often unsuccessful, and present significant side effects. Designing individualized therapies requires understanding of multidimensional pain experience, considering physical and emotional aspects. Current clinical pain assessments, relying on subjective one-dimensional numeric self-reports, fail to capture this complexity.</p><p><strong>Methods: </strong>To this aim, we exploited machine learning to disentangle physiological and psychosocial components shaping the pain experience. Clinical, psychosocial, and physiological data were collected from 118 chronic pain and healthy participants undergoing 40 pain trials (4,697 trials).</p><p><strong>Findings: </strong>To understand the objective response to nociception, we classified pain from the physiological signals (accuracy >0.87), extracting the most important biomarkers. Then, using multilevel mixed-effects models, we predicted the reported pain, quantifying the mismatch between subjective level and measured physiological response. From these models, we introduced two metrics: TIP (subjective index of pain) and Φ (physiological index). These represent possible added value in the clinical process, capturing psychosocial and physiological pain dimensions, respectively. Patients with high TIP are characterized by frequent sick leave from work and increased clinical depression and anxiety, factors associated with long-term disability and poor recovery, and are indicated for alternative treatments, such as psychological ones. By contrast, patients with high Φ show strong nociceptive pain components and could benefit more from pharmacotherapy.</p><p><strong>Conclusions: </strong>TIP and Φ, explaining the multidimensionality of pain, might provide a new tool potentially leading to targeted treatments, thereby reducing the costs of inefficient generic therapies.</p><p><strong>Funding: </strong>RESC-PainSense, SNSF-MOVE-IT197271.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"1495-1509.e5"},"PeriodicalIF":12.8,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141907821","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ticagrelor monotherapy in ST-elevation myocardial infarction: An individual patient-level meta-analysis from TICO and T-PASS trials.","authors":"Yong-Joon Lee, Deok-Kyu Cho, Jun-Won Lee, Sanghoon Shin, Sung Woo Kwon, Yongsung Suh, Tae Soo Kang, Jong-Kwan Park, Jang-Whan Bae, Woong Cheol Kang, Seunghwan Kim, Seung-Jun Lee, Sung-Jin Hong, Chul-Min Ahn, Jung-Sun Kim, Byeong-Keuk Kim, Young-Guk Ko, Donghoon Choi, Yangsoo Jang, Kyeong Ho Yun, Myeong-Ki Hong","doi":"10.1016/j.medj.2024.07.019","DOIUrl":"10.1016/j.medj.2024.07.019","url":null,"abstract":"<p><strong>Background: </strong>Patients with ST-elevation myocardial infarction (STEMI) tend to be excluded or under-represented in randomized clinical trials evaluating the effects of potent P2Y12 inhibitor monotherapy after short-term dual antiplatelet therapy (DAPT).</p><p><strong>Methods: </strong>Individual patient data were pooled from randomized clinical trials that included STEMI patients undergoing drug-eluting stent (DES) implantation and compared ticagrelor monotherapy after short-term (≤3 months) DAPT versus ticagrelor-based 12-month DAPT in terms of centrally adjudicated clinical outcomes. The co-primary outcomes were efficacy outcome (composite of all-cause death, myocardial infarction, or stroke) and safety outcome (Bleeding Academic Research Consortium type 3 or 5 bleeding) at 1 year.</p><p><strong>Findings: </strong>The pooled cohort contained 2,253 patients with STEMI. The incidence of the primary efficacy outcome did not differ between the ticagrelor monotherapy group and the ticagrelor-based DAPT group (1.8% versus 2.0%; hazard ratio [HR] = 0.88; 95% confidence interval [CI] = 0.49-1.61; p = 0.684). There was no difference in cardiac death between the groups (0.6% versus 0.7%; HR = 0.89; 95% CI = 0.32-2.46; p = 0.822). The incidence of the primary safety outcome was significantly lower in the ticagrelor monotherapy group (2.3% versus 4.0%; HR = 0.56; 95% CI = 0.35-0.92; p = 0.020). No heterogeneity of treatment effects was observed for the primary outcomes across subgroups.</p><p><strong>Conclusions: </strong>In patients with STEMI treated with DES implantation, ticagrelor monotherapy after short-term DAPT was associated with lower major bleeding without an increase in the risk of ischemic events compared with ticagrelor-based 12-month DAPT. Further research is necessary to extend these findings to non-Asian patients.</p><p><strong>Funding: </strong>This study was funded by Biotronik (Bülach, Switzerland).</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"1466-1474.e2"},"PeriodicalIF":12.8,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141996589","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transformative or transitional? Deciphering the role of NIAGARA in shaping future practice.","authors":"Daniele Raggi, Robert A Huddart","doi":"10.1016/j.medj.2024.11.004","DOIUrl":"https://doi.org/10.1016/j.medj.2024.11.004","url":null,"abstract":"<p><p>The phase 3 NIAGARA trial¹ demonstrated a statistically significant improvement in event-free and overall survival in cisplatin-eligible patients with muscle-invasive bladder cancer treated with perioperative durvalumab in combination with neoadjuvant chemotherapy, compared to neoadjuvant chemotherapy alone. The combination was manageable and did not adversely impact surgery. NIAGARA positions perioperative durvalumab with chemotherapy as a potential new standard of care.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":"5 12","pages":"1456-1458"},"PeriodicalIF":12.8,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142824576","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"At the right time: Moving precision therapy to newly diagnosed cancer.","authors":"Adam Wahida, Ben George, Razelle Kurzrock","doi":"10.1016/j.medj.2024.10.017","DOIUrl":"https://doi.org/10.1016/j.medj.2024.10.017","url":null,"abstract":"<p><p>Precision oncology aims to match the right drug(s) to the right patient. Equally important is ensuring that precision therapies are offered at the right time. Transformative, rather than incremental, outcome improvement may require treatment at diagnosis rather than in the advanced/metastatic setting after genomic evolution.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":"5 12","pages":"1463-1465"},"PeriodicalIF":12.8,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142824524","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Homoharringtonine synergizes with venetoclax in early T cell progenitor acute lymphoblastic leukemia: Bench and bed.","authors":"Shanshan Suo, Shu Sun, Le Xuan Truong Nguyen, Jiejing Qian, Fenglin Li, Dandan Zhao, Wenjuan Yu, Yinjun Lou, Honghu Zhu, Hongyan Tong, Min Yang, Xin Huang, Shuqi Zhao, Junjing Qiao, Chen Liang, Huafeng Wang, Yi Zhang, Xiang Zhang, Dinh Hoa Hoang, Fang Chen, Hyunjun Kang, Melissa Valerio, Jie Sun, Lucy Ghoda, Ling Li, Guido Marcucci, Bin Zhang, Jie Jin","doi":"10.1016/j.medj.2024.07.018","DOIUrl":"10.1016/j.medj.2024.07.018","url":null,"abstract":"<p><strong>Background: </strong>Early T cell precursor acute lymphoblastic leukemia (ETP-ALL) is a distinct subtype of T-ALL with a poor prognosis. To find a cure, we examined the synergistic effect of homoharringtonine (HHT) in combination with the BCL-2 inhibitor venetoclax (VEN) in ETP-ALL.</p><p><strong>Methods: </strong>Using in vitro cellular assays and ETP-ALL xenograft models, we first investigated the synergistic activity of HHT and VEN in ETP-ALL. Next, to explore the underlying mechanism, we employed single-cell RNA sequencing of primary ETP-ALL cells treated with HHT or VEN alone or in combination and validated the results with western blot assays. Based on the promising preclinical results and given that both drugs have been approved for clinical use, we then assessed this combination in clinical practice.</p><p><strong>Findings: </strong>Our results showed that HHT synergizes strongly with VEN both in vitro and in vivo in ETP-ALL. Mechanistic studies demonstrated that the HHT/VEN combination concurrently downregulated key anti-apoptotic proteins, i.e., MCL1, leading to enhanced apoptosis. Importantly, the clinical results were very promising. Six patients with ETP-ALL with either refractory/relapsed (R/R) or newly diagnosed disease were treated with an HHT/VEN-based regimen. All patients achieved complete remission (CR) after only one cycle of treatment.</p><p><strong>Conclusions: </strong>Our findings demonstrate that a combination of HHT/VEN is effective on ETP-ALL and represents the \"backbone\" of a promising and safe regimen for newly diagnosed and R/R patients with ETP-ALL.</p><p><strong>Funding: </strong>This work was funded by the National Cancer Institute, Gehr Family Foundation, George Hoag Family Foundation, National Natural Science Foundation of China, and Key Research and Development Program of Zhejiang Province of China.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"1510-1524.e4"},"PeriodicalIF":12.8,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141996586","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interlesional response heterogeneity is associated with the prognosis of abiraterone treatment in metastatic castration-resistant prostate cancer.","authors":"Jian Pan, Junlong Wu, Beihe Wang, Bin Zhu, Xiaohang Liu, Hualei Gan, Yu Wei, Shengming Jin, Xiaoxin Hu, Qifeng Wang, Shaoli Song, Chang Liu, Dingwei Ye, Yao Zhu","doi":"10.1016/j.medj.2024.07.020","DOIUrl":"10.1016/j.medj.2024.07.020","url":null,"abstract":"<p><strong>Background: </strong>Interlesional response heterogeneity (ILRH) poses challenges to the treatment of metastatic castration-resistant prostate cancer (mCRPC). Currently, there are no prospective clinical trials exploring the prognostic significance of ILRH on paired positron emission tomography/computed tomography (PET/CT) in the context of abiraterone therapy.</p><p><strong>Methods: </strong>In this prospective study, we enrolled patients with mCRPC treated with abiraterone (ClinicalTrials.gov: NCT05188911; ChiCTR.org.cn: ChiCTR2000034708). ⁶⁸Ga-prostate-specific membrane antigen (PSMA)+¹⁸F-fluorodeoxyglucose (FDG) PET/CT and circulating tumor DNA (ctDNA) monitoring were performed at baseline and week 13. Patients were grouped by their early ILRH measurement. The primary endpoint was to evaluate the predictive role of ILRH for conventional progression-free survival (PFS) through the concordance index (C-index) assessment. Conventional PFS was defined as the time from medication to conventional radiographic progression, clinical progression, or death.</p><p><strong>Findings: </strong>Ultimately, 33 patients were included with a median follow-up of 28.7 months. Baseline+week 13 PSMA PET/CT revealed that 33.3% of patients showed ILRH. Those patients with hetero-responding disease had significantly different PFS compared to the responding and non-responding groups (hazard ratio: responding group = reference, hetero-responding group = 4.0, non-responding group = 5.8; p < 0.0001). The C-index of ILRH on paired PSMA PET/CT (0.742 vs. 0.660) and FDG PET/CT (0.736 vs. 0.668) for conventional PFS was higher than that of PSA response. In an exploratory analysis, PSMA-/FDG+ lesions at week 13 were identified as a strong surrogate for poor conventional PFS (p = 0.039).</p><p><strong>Conclusions: </strong>ILRH on both baseline+week 13 PSMA and FDG PET/CT strongly associated with conventional PFS.</p><p><strong>Funding: </strong>This study was funded by the Ministry of Science and Technology of China and Shanghai.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"1475-1484.e3"},"PeriodicalIF":12.8,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141996587","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}