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{"title":"Hb Monza: A novel extensive HBB duplication with preserved α-β subunit interaction and unstable hemoglobin phenotype.","authors":"Ivan Civettini, Arianna Zappaterra, Paola Corti, Amedeo Messina, Andrea Aroldi, Andrea Biondi, Fabrizio Cavalca, Valentina Crippa, Francesca Crosti, Giulia Maria Ferrari, Federica Malighetti, Luca Mologni, Alberto Piperno, Daniele Ramazzotti, Chiara Scollo, Alfonso Zambon, Fabio Rossi, Carlo Gambacorti-Passerini","doi":"10.1016/j.medj.2024.11.007","DOIUrl":"https://doi.org/10.1016/j.medj.2024.11.007","url":null,"abstract":"<p><strong>Background: </strong>Unstable hemoglobins are caused by single amino acid substitutions in the HBB gene, often affecting key histidine residues, leading to protein destabilization and hemolytic crises. In contrast, long HBB variants, exceeding 20 bp, are rare and associated with a β-thalassemia phenotype due to disrupted α-β chain interactions. We describe a family wherein four of six members carry a novel 23-amino-acid in-frame duplication of HBB (c.176_244dup), named hemoglobin (Hb) Monza. Despite its length, this duplication manifests as an unstable hemoglobin variant rather than a β-thalassemia phenotype.</p><p><strong>Methods: </strong>A static 3D model of the Hb Monza β chain was generated using AlphaFold and SWISS-MODEL. Molecular dynamics (MD) simulations were performed with the Generalized Born implicit solvent model. After energy minimization and heating to 311 K (38°C), a 40 ns production run was conducted.</p><p><strong>Findings: </strong>3D modeling of Hb Monza revealed minimal structural changes in the Hb β chain, particularly in the key histidine residues and their interaction with the iron atom. Additionally, the static 3D model showed a preserved α-β interaction, explaining the absence of a β-thalassemia clinical phenotype. MD simulations under thermal stress revealed a notable increase in root-mean-square deviation compared to the wild-type β subunit, along with a loss of contacts with the heme, explaining the hemolytic crises during febrile episodes.</p><p><strong>Conclusion: </strong>Despite the long duplication in HBB, Hb Monza retains functional α-β interaction while demonstrating instability under stressful conditions. This unique variant presents with an unstable Hb phenotype rather than a β-thalassemia phenotype.</p><p><strong>Funding: </strong>No financial funding was received.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":""},"PeriodicalIF":12.8,"publicationDate":"2024-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142865602","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":"Single-pill combination therapy is the standard of care for hypertension, but it is time for the next step: Implementation.","authors":"Jose P Lopez-Lopez, Patricio Lopez-Jaramillo","doi":"10.1016/j.medj.2024.11.010","DOIUrl":"https://doi.org/10.1016/j.medj.2024.11.010","url":null,"abstract":"<p><p>The GMRx2 trial¹ in adults with high blood pressure (BP) demonstrated that after 12 weeks, a low-dose single-pill combination of telmisartan, amlodipine, and indapamide significantly reduced BP levels compared to several dual combinations (telmisartan with amlodipine, telmisartan with indapamide, or amlodipine with indapamide). Adverse events did not differ between the groups. This novel therapeutic option could improve high BP control.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":"5 12","pages":"1461-1462"},"PeriodicalIF":12.8,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142824529","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":"Perioperative immunotherapy in urothelial carcinoma: AMBASSADOR charts the path forward.","authors":"Kriti Mittal, Monika Joshi","doi":"10.1016/j.medj.2024.10.018","DOIUrl":"https://doi.org/10.1016/j.medj.2024.10.018","url":null,"abstract":"<p><p>The AMBASSADOR trial revealed improvement in disease-free survival with adjuvant pembrolizumab in patients with high-risk muscle-invasive urothelial carcinoma compared to observation.¹ In this Viewpoint, we discuss the clinical implications of these findings in the context of prior data from the CheckMate-274 and the recently published NIAGARA trial, envisioning the path forward for perioperative immunotherapy.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":"5 12","pages":"1449-1451"},"PeriodicalIF":12.8,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142824527","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":"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":"https://doi.org/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":"BilT03: Phase 1b/2 multicenter trial of nivolumab with 5-fluorouracil and liposomal irinotecan for previously treated advanced biliary tract cancer.","authors":"Vaibhav Sahai, Kent A Griffith, Bruce S Lin, Heloisa P Soares, Sreenivasa R Chandana, Oxana Crysler, Chandan Kumar-Sinha, Thomas Enzler, Dominique Dippman, Valerie Gunchick, Mark M Zalupski","doi":"10.1016/j.medj.2024.10.024","DOIUrl":"https://doi.org/10.1016/j.medj.2024.10.024","url":null,"abstract":"<p><strong>Background: </strong>Second-line chemotherapy with 5-fluorouracil/leucovorin (5FULV) and liposomal irinotecan improves survival in advanced biliary tract cancer (BTC). In this phase 1b/2 trial, we investigated the combination of 5FULV and liposomal irinotecan with nivolumab following progression on first-line chemotherapy for advanced BTC.</p><p><strong>Methods: </strong>Patients received 2,400 mg/m² 5-fluorouracil, leucovorin (dose level: 0:400 or -1:200 mg/m²), 70 mg/m² liposomal irinotecan, and 240 mg nivolumab every 2 weeks (ClinicalTrials.gov: NCT03785873). The phase 1b and 2 primary objectives included recommended phase 2 dose (RP2D) and median progression-free survival (PFS; null and alternative hypotheses of 2.9 and 5.0 months) with a two-sided alpha of 0.05 and >80% power. Secondary objectives were safety, objective response rate (ORR), and overall survival (OS).</p><p><strong>Findings: </strong>Of 30 patients with a median age of 63.5 years, 18 (60%) were men, 25 (83%) were White, 16 (53%) had an ECOG performance status of 0, and 19 (63.3%) had intrahepatic cholangiocarcinoma. In phase 1b, the RP2D was dose level 0 after a dose-limiting toxicity event of enterocolitis (n = 1). Median PFS was 4.1 months (95% confidence interval [CI], 1.9-9.9). The ORR was 16.7% (5 partial responses) per irRECIST, the median OS was 7.4 months (95% CI, 5.7-15.9), and the 24-month survival rate was 23.3%. The most common grade ≥3 treatment-related adverse events were diarrhea (5; 16.7%), fatigue (4; 13.3%), and neutropenia (3; 10%).</p><p><strong>Conclusions: </strong>Treatment was well tolerated, but the primary endpoint was not met. The median OS was similar to prior trials with this drug combination, but the 24-month survival rate was higher than expected.</p><p><strong>Funding: </strong>This work was funded by Ipsen Biopharmaceuticals, Bristol-Myers Squibb (CA209-8LF), and the University of Michigan Rogel Cancer Center (P30CA046592).</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":""},"PeriodicalIF":12.8,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142865599","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":"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}