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Background: 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.

Methods: 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).

Findings: 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%).

Conclusions: 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.

Funding: This work was funded by Ipsen Biopharmaceuticals, Bristol-Myers Squibb (CA209-8LF), and the University of Michigan Rogel Cancer Center (P30CA046592).

Background: Wild birds are significant vectors in global pathogen transmission, but the diversity and spatial distribution of the pathogens detected in them remain unclear. Understanding the transmission dynamics and hotspots of wild-bird-associated pathogens (WBAPs) is crucial for early disease prevention.

Methods: We compiled an up-to-date dataset encompassing all WBAPs by conducting an extensive search of publications from 1959 to 2022, mapped their diversity and global distribution, and utilized three machine learning algorithms to predict geospatial hotspots where zoonotic and emerging WBAPs were prevalent.

Findings: Based on 1,834 selected studies, a total of 760 pathogens associated with 1,438 wild bird species were identified, including 387 emerging and 212 zoonotic pathogens. Migratory birds exhibited higher pathogen richness (593 species) but a lower proportion of zoonotic pathogens (27.2%) compared to resident birds (303 species and 39.3%, both p < 0.01). When comparing different ecological groups, waterfowl had the highest richness of zoonotic pathogens (128 species), followed by songbirds (76 species). The distribution of WBAPs was significantly influenced by the habitat suitability index of wild birds, mammalian richness, and climatic factors. The potential geographical hotspots of zoonotic and emerging WBAPs were widely distributed in tropical areas of Asia, Africa, and South America, with zoonotic WBAPs having a wider distribution in South America.

Conclusions: Our study illustrates that the geographical hotspots of WBAPs are more widespread than reported, especially in low-income areas, and that the identification, surveillance, and prevention of WBAP infections should be prioritized.

Funding: This work was funded by the National Key Research and Development Program of China.

Background: 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.

Methods: 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.

Findings: 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.

Conclusion: 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.

Funding: No financial funding was received.

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.

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.

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.

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.

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.

Background: 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.

Methods: 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).

Findings: 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.

Conclusions: 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.

Funding: RESC-PainSense, SNSF-MOVE-IT197271.