Risk factors for leg wound infection after conventional and no-touch vein harvesting: insights from a multicentre randomised trial.
ClinicalTrials.gov: ID NCT03501303.
Humans↗
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Ifebemtinib plus garsorasib in previously treated metastatic colorectal cancer with KRASG12C mutation: a multicentre, randomised, phase 1b/2 trial.
BACKGROUND: Ifebemtinib is a potent oral focal adhesion kinase inhibitor. Preclinical evidence supports combining ifebemtinib with the KRASG12C inhibitor garsorasib. This study aimed to evaluate this combination in KRASG12C-mutated solid tumours. METHODS: This multicentre, phase 1b/2 study had a phase 1b component to establish the recommended phase 2 dose and a phase 2 multitumour expansion component. In phase 1b, the safety and tolerability of ifebemtinib combined with garsorasib was assessed using a 3 + 3 design in KRASG12C-mutated solid tumours. No dose-limiting toxic effects were observed, and the recommended phase 2 dose was established as ifebemtinib 100 mg orally once daily plus garsorasib 600 mg orally twice daily. Here, we report the results of the cohort of previously treated KRASG12C-mutated metastatic colorectal cancer from phase 2 expansion. Eligible patients (aged ≥18 years) who had histologically confirmed locally advanced or metastatic colorectal cancer harbouring the KRASG12C mutation, an Eastern Cooperative Oncology Group performance-status score of 0 or 1, and had disease progression after previous irinotecan-based or oxaliplatin-based combination therapy, were recruited from seven of nine participating tertiary hospitals in China. On the basis of the recommended phase 2 dose, phase 2 comprised a single-arm study to evaluate the safety and efficacy of ifebemtinib combined with garsorasib and an open-label, randomised study in which patients were randomly assigned (1:1) to receive ifebemtinib plus garsorasib or garsorasib alone, by use of centralised computer-generated block randomisation with no stratification. Investigators were masked to the block size. The primary efficacy endpoint of phase 2 was investigator-assessed objective response rate (Response Evaluation Criteria in Solid Tumours, version 1.1), assessed in the safety analysis set in the single-arm study and in all randomly assigned patients (intention-to-treat population) in the randomised study. At least six objective responses (safety analysis set) were required in the single-arm study to proceed to the randomised study. This study is registered with ClinicalTrials.gov, NCT06166836 and NCT05379946, and is active but not recruiting. FINDINGS: Between April 7, 2023 and Dec 13, 2024, 51 patients were enrolled in phase 2 (15 in the single-arm study and 36 in the randomised study). In the single-arm study, the median age was 53 years (IQR 39 to 63), nine (60%) patients were female, six (40%) were male, and all were Asian. In the randomised study, the median age was 51 years (IQR 42 to 59) in the combination group and 63 years (IQR 54 to 66) in the monotherapy group, 24 (67%) were female, 12 (33%) were male, and all patients were Asian. In the single-arm part, the confirmed objective response rate was 46·7% (95% CI 21·3 to 73·4). Seven patients had partial responses, triggering progression to the randomised study. In the randomised study, the confirmed objective response rate was 38·9% (95% CI 17·3 to 64·3) with the combination therapy versus 16·7% (95% CI 3·6 to 41·4) with garsorasib alone (between-group difference 22·2%, 95% CI -7·7 to 49·1; one-sided p=0·068). In the single-arm study, grade 3 treatment-related adverse events occurred in four (27%) of 15 patients, and in the randomised study, grade 3 treatment-related adverse events occurred in six (33%) of 18 patients in the combination group and five (28%) of 18 in the garsorasib group. Grade 3 treatment-related adverse events occurring in at least two patients were diarrhoea (six [18%]), proteinuria (two [6%]), and intestinal obstruction (two [6%]) in patients treated with combination therapy (combined), and increased alanine aminotransferase and γ-glutamyltransferase (two [11%] each) in patients treated with garsorasib alone. Serious adverse events occurred in ten (30%) patients in the combination group and in four (22%) patients in the monotherapy group. One patient in the garsorasib monotherapy group died due to the underlying malignancy within 30 days after completing study treatment, which was reported as a serious adverse event. The death was assessed by the investigators as not related to garsorasib. No grade 4 treatment-related adverse events or treatment-related deaths were reported across all cohorts. INTERPRETATION: The combination of ifebemtinib and garsorasib showed promising anticancer activity and manageable safety profile in previously treated patients with KRASG12C-mutated metastatic colorectal cancer. Although the improvement in response rate did not reach statistical significance in the randomised study, these findings support further evaluation of ifebemtinib plus garsorasib in this population. FUNDING: InxMed, InventisBio, National Natural Science Foundation of China, the Jian Bing Ling Yan + X Research and Development Program of Zhejiang Province, and the Zhejiang Province Medical and Health Science and Technology Plan Project.
Humans↗
Noncombustible Nicotine or Tobacco Product Use After Smoking Cessation and Major Vision-Impairing Diseases: A Nationwide Cohort Study.
OBJECTIVE: We assessed the risk of major vision-impairing eye diseases among smokers who quit combustible cigarettes (CC) and switch to noncombustible nicotine or tobacco products (NNTPs) compared with those who completely quit using tobacco. DESIGN: Retrospective cohort study. PARTICIPANTS: About 179 273 adults from the Korean National Health Insurance Service who smoked CC in 2011 to 2012 and reported cessation in 2018 to 2019, classified into complete quitters and NNTP switchers. METHODS: This nationwide longitudinal cohort study followed participants for up to 6 years and identified incident major vision-impairing eye diseases (cataract, glaucoma, age-related macular degeneration, diabetic retinopathy, and refractive and accommodation disorders) using standardized diagnostic codes. Propensity score matching was applied to emulate a pseudo-randomized comparison, balanced on key demographic, clinical, comorbidity, and lifestyle characteristics. Subdistribution hazard ratios (SHRs) were evaluated using the Fine-Gray subdistribution hazards model accounting for all-cause mortality as a competing risk. MAIN OUTCOME MEASURES: Adjusted SHRs for incident major vision-impairing eye diseases. RESULTS: Among 32 316 matched participants followed for a mean of 4.6 years, 6328 incident major vision-impairing eye disease events occurred. The incidence was 41.1 and 44.0 per 1000 person-years for complete quitters and NNTP switchers, respectively. Switching to NNTPs was associated with an increased risk of major vision-impairing eye disease (SHR, 1.07; 95% CI, 1.02-1.13). The risk elevation was most pronounced for diabetic retinopathy (SHR, 1.24; 95% CI, 1.00-1.53) and refractive and accommodation disorders (SHR, 1.07; 95% CI, 1.01-1.12). These findings were robust across inverse probability-weighted and Cox proportional hazards models. The association remained consistent in sensitivity analyses and across clinical subgroups. CONCLUSIONS: Transitioning from CC to NNTPs is associated with a modest but consistent increase in the risk of major vision-impairing eye diseases compared with complete nicotine abstinence. These findings challenge the assumption that substituting NNTPs for CCs is visually harmless and indicate that, from an ophthalmic perspective, complete cessation of all nicotine products should remain the preferred cessation goal.
Humans↗
HSK21542 for Postoperative Analgesia in Gynecological Surgery: A Pooled Post-Hoc Analysis of Two Phase III Randomized Controlled Trials.
BACKGROUND: Effective postoperative pain management in gynecological surgery is challenging because of complex visceral-somatic pain interactions and the adverse effects of conventional analgesics. HSK21542, a novel peripherally restricted kappa-opioid receptor (KOR) agonist that selectively targets visceral pain pathways enriched with KORs, may provide adequate analgesia without systemic adverse events. METHODS: We conducted a pooled post-hoc analysis of data from two phase III, multicenter, triple-blinded, randomized controlled trials (Study 301, HSK21542 vs placebo; Study 303, HSK21542 vs tramadol vs placebo). Eligible patients undergoing elective gynecological surgery were included. The primary outcome was the summed pain-intensity difference over 12 and 24 hours (SPID 12h and SPID 24h ). Secondary outcomes were pain-relief quality (proportion of patients relieved from severe pain with a pain numerical rating score ≤ 3 between 0 and 24 hours) and rescue-analgesic requirements (number of doses and time to first rescue analgesic). Adverse events were also assessed. RESULTS: A total of 370 patients were analyzed: 150 received HSK21542, 139 received a placebo, and 81 received tramadol. After inverse probability of treatment weighting (IPTW) adjustment, baseline characteristics were well-balanced across treatment groups (all standardized mean differences [SMD] <0.1; see Table 1 for 95% CIs). HSK21542 produced greater reductions in pain intensity over 12 and 24 hours than placebo (least-squares mean differences -8.1 and -16.3 for SPID 12h and SPID 24h , respectively. Both P < .001) and no statistically significant difference was observed between HSK21542 and tramadol ( P > .05). Significantly more patients in the HSK21542 group were relieved from severe pain at 0 to 12 hours (92.7% vs 82.7%, P < .001) and required fewer rescue doses at 0 to 12 hours (0.00 [IQR 0.00-1.00] vs 1.00 [IQR 0.00-2.00], P < .001) and 0 to 24 hours (0.00 [IQR 0.00-1.00] vs 1.00 [IQR 0.00-2.00], P < .001) than those in the placebo group, whereas no significant differences with tramadol both in 0 to 12 and 0 to 24 hours. HSK21542 was also associated with significantly lower incidences of nausea (24.7% vs 66.7%) and vomiting (21.3% vs 60.5%) than tramadol. Only one case of dizziness occurred in the tramadol group. CONCLUSIONS: HSK21542 could provide adequate postoperative analgesia with few adverse events in patients undergoing gynecological surgery.
Humans↗
Immunogenicity and safety of prophylactic HPV vaccines in people living with HIV: A systematic review and meta-analysis.
Human papillomavirus (HPV) is a major global public health concern, causing genital warts and cancers of the cervix, anus, oropharynx, vulva, and penis. People living with HIV (PLWH) face a disproportionately elevated burden of HPV infection and HPV-related malignancies due to chronic immunosuppression. We conducted a systematic review and meta-analysis searching six databases from January 2006 to June 2026 without language restrictions. Twenty-five studies were included in the systematic review; 12 independent studies (N = 1,493 for HPV16) were included in the quantitative meta-analysis. Using a DerSimonian-Laird random-effects model with logit transformation, pooled seroconversion rates were: HPV16 97.8% (95% CI: 94.9-99.1%; I2 = 89.6%; 15 datasets), HPV18 94.2% (95% CI: 86.1-97.7%; I2 = 95.8%; 13 datasets), HPV6 97.0% (95% CI: 93.7-98.6%; I2 = 66.1%; 10 studies), and HPV11 97.1% (95% CI: 90.5-99.1%; I2 = 95.5%; 10 studies). CD4 count was the most consistently reported modifier of immunogenic response: HPV16 seroconversion was 98.5% in PLWH with CD4 > 350 cells/μL vs. 71.1% in those with CD4 ≤ 200 cells/μL (ACTG A5240). All three vaccine generations demonstrated high immunogenicity. Two doses of the nonavalent vaccine were non-inferior to three doses in virologically suppressed women (Papillon RCT). No vaccine-related serious adverse events were reported. GRADE certainty of evidence was moderate for HPV16, HPV6, and HPV11, and low for HPV18. Prophylactic HPV vaccination achieves high seroconversion rates across all vaccine generations in PLWH. CD4 count significantly modifies vaccine response, underscoring the importance of vaccination before severe immunosuppression develops. These findings support current international recommendations advocating HPV vaccination for all PLWH.
Humans↗
Obinutuzumab or Tacrolimus in Primary Membranous Nephropathy.
BACKGROUND: Studies of obinutuzumab, a type II anti-CD20 antibody, have shown efficacy in the treatment of hematologic cancers and autoimmune diseases. An evaluation of the efficacy and safety of obinutuzumab in patients with primary membranous nephropathy is needed. METHODS: In a phase 3 trial, we randomly assigned adults with primary membranous nephropathy in a 1:1 ratio to receive intravenous obinutuzumab or oral tacrolimus. The primary end point was complete remission (defined as a urinary protein-to-creatinine ratio of 0.3 or lower and a stable estimated glomerular filtration rate [eGFR]) at week 104. Key secondary end points were complete or partial remission at week 104, complete remission at week 76, a sustained reduction in the eGFR of at least 30%, duration of complete remission, and change in the Patient-Reported Outcomes Measurement Information System Fatigue T score from baseline to week 104. Fixed-sequence hierarchical testing was performed. Safety was assessed. RESULTS: A total of 142 patients underwent randomization. At week 104, complete remission was observed in 26 of 71 patients in the obinutuzumab group and in 4 of 70 patients in the tacrolimus group (37% vs. 6% with multiple imputation for missing data; adjusted difference, 31 percentage points; 95% CI, 18 to 44; P<0.001). The analyses of complete or partial remission at week 104 and complete remission at week 76 also showed a significant treatment effect. The analysis of a sustained eGFR reduction did not show a significant treatment effect; thus, subsequent end points in the hierarchy were not formally tested for significance. Adverse events of grade 3 or higher were reported in 16 patients (22%) in the obinutuzumab group and in 13 patients (19%) in the tacrolimus group; serious adverse events occurred in 12 (17%) and 10 (14%), respectively. There were 61 and 57 infections per 100 patient-years in the obinutuzumab and tacrolimus groups, respectively; 3 and 4 serious infections per 100 patient-years; and 11 and 14 serious adverse events per 100 patient-years. Adverse drug reactions with obinutuzumab included infusion-related reactions, respiratory tract infections, and neutropenia. One patient in each group died during escape therapy. CONCLUSIONS: Obinutuzumab was superior to tacrolimus in inducing complete remission in patients with primary membranous nephropathy. (Funded by F. Hoffmann-La Roche; MAJESTY ClinicalTrials.gov number, NCT04629248.).
Adult↗
Pharmacokinetics and safety of TBAJ-587, a novel antimycobacterial diarylquinoline, in healthy participants.
TBAJ-587 is a second-generation diarylquinoline with greater antimycobacterial activity and a potentially better safety profile than the first-generation bedaquiline. It is currently under development for the treatment of drug-susceptible and drug-resistant tuberculosis. A first-in-human trial of TBAJ-587, including single and multiple ascending oral doses and a dedicated food-effect cohort, was conducted in 92 healthy adults. Plasma exposures of TBAJ-587 were generally linear for AUCtau and slightly subproportional for Cmax, with the major circulating active metabolite, M3, remaining low relative to the parent. A high-fat meal increased the mean Cmax and AUClast 3.46- and 2.26-fold, respectively. TBAJ-587 accumulated with multiple dosing over the 28-day period, with mean accumulation ratios across the three tested doses ranging from 1.69 to 2.32 for Cmax and from 2.74 to 3.73 for AUCtau. However, steady-state conditions were not yet reached on day 28. Mean terminal half-lives after 28-day dosing of TBAJ-587 ranged from approximately 80 to 111 days. There were no deaths or serious adverse events, and TBAJ-587 was generally safe and well tolerated at single doses of 25-800 mg under fasting conditions and multiple doses of 50-200 mg once daily for 28 days after a standard breakfast. In addition, no dose- or time-dependent effects were noted for any of the other safety and tolerability parameters, including no clinically significant effects on the QTc interval. These results support further investigation of TBAJ-587 for the treatment of tuberculosis.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT04890535.
Humans↗
Retinoid dynamics in immune cells during age-related diseases.
Retinoids comprise vitamin A and its structurally related natural and synthetic derivatives. Retinoid dynamics involves multiple retinoid forms, carrier proteins, and enzymes that orchestrate the absorption, transport, storage and biotransformation of dietary vitamin A. Beyond their canonical metabolic functions, metabolites and proteins involved in retinoid metabolism also play distinct roles in signal transduction and transcriptome reprogramming, broadening the mechanisms that influence immune cell fate decisions. Age‑related changes in retinoid bioavailability and signaling intensity alter immune cell polarization and function, thereby contributing to the pathogenesis of chronic inflammation in neurodegenerative diseases, cardiovascular diseases, osteoarthritis, and other age-related diseases. In this review, we focus on age-related alterations in the retinoid metabolic pathway and their impact on inflammation and the progression of age-related diseases. This review highlights the pivotal role of retinoid metabolism in anti-ageing interventions and considers future directions and challenges in this field.
Humans↗
Adjuvant alectinib versus chemotherapy in resected ALK-positive non-small-cell lung cancer (ALINA): health-related quality-of-life and safety outcomes from a randomised, open-label, phase 3 trial.
BACKGROUND: For patients with resected, ALK-positive non-small-cell lung cancer (NSCLC), adjuvant alectinib significantly improved disease-free survival versus platinum-based chemotherapy in the global, phase 3, open-label, randomised ALINA trial. We report safety and health-related quality-of-life (HRQoL) outcomes from the ALINA trial. METHODS: Eligible patients aged 18 years or older with resected, ALK-positive, stage IB (≥4 cm)-IIIA NSCLC (per the American Joint Committee on Cancer and the Union for International Cancer Control Cancer Staging Manual 7th edition) and an Eastern Cooperative Oncology Group performance status of 0-1 were randomly assigned (1:1) via a block-stratified randomisation method to receive oral alectinib (600 mg twice daily) for 24 months or intravenous platinum-based chemotherapy for four 3-week cycles. Randomisation was stratified according to disease stage and race. The primary endpoint, previously reported, was disease-free survival. Safety was a secondary endpoint and HRQoL was an exploratory endpoint. Safety was assessed by the investigator as per the National Cancer Institute Common Terminology Criteria for Adverse Events version 5·0 until 28 days after the last alectinib dose or chemotherapy cycle. HRQoL was assessed via the Short-Form 36-item health survey version 2 (SF-36v2) questionnaire at baseline, every 3 weeks to week 12, then every 12 weeks until disease recurrence, consent withdrawal, death, or week 96. Norm-based scoring was applied; clinically meaningful changes were defined using the SF-36v2 manual. Safety was assessed in the safety-evaluable population and HRQoL in the intention-to-treat population. This study is registered with ClinicalTrials.gov (NCT03456076) and is ongoing. FINDINGS: Between Aug 16, 2018, and Dec 8, 2021, 257 patients were assigned to receive alectinib (n=130) or chemotherapy (n=127). 123 (48%) patients were male and 134 (52%) were female; 143 (56%) were Asian. The safety-evaluable population comprised 128 patients who received alectinib and 120 patients who received chemotherapy; median duration of safety follow-up was 24·8 months (IQR 22·0-24·9) in the alectinib group and 3·7 months (IQR 3·7-3·8) in the chemotherapy group. The safety of adjuvant alectinib was generally consistent with its known profile. The most common grade 3-4 adverse events were blood creatine phosphokinase increased (eight [6%] of 128), alanine aminotransferase increased (two [2%] of 128), and blood bilirubin increased (two [2%] of 128) in the alectinib group, and neutrophil count decreased (12 [10%] of 120), neutropenia (ten [8%] of 120), and nausea (five [4%] of 120) in the chemotherapy group. Serious treatment-related adverse events occurred in two (2%; one each with appendicitis and pneumonitis) of 128 patients in the alectinib group and eight (7%) of 120 patients in the chemotherapy group ( most common were gastrointestinal disorders in three [3%] patients). No deaths due to adverse events were reported in either group. There were fewer discontinuations due to adverse events with alectinib (seven [5%]) versus chemotherapy (15 [13%]). A clinically meaningful difference in improvement from baseline was seen at week 12 for bodily pain, role physical, mental health, social functioning, and vitality SF-36v2 domains with alectinib; improvements in physical and mental HRQoL were maintained over 2 years of active treatment (at week 96, mean Mental Component Summary score: 49·9 [SD 10·4]; mean Physical Component Summary score: 48·8 [SD 7·2]) and reached levels similar to the general population (population norm: 50). INTERPRETATION: For patients with resected ALK-positive NSCLC, adjuvant alectinib had a manageable safety profile; HRQoL improved and was maintained over 2 years of active treatment. Together with the disease-free survival benefit seen in ALINA, these data support adjuvant alectinib as an important new standard-of-care for patients with resected ALK-positive NSCLC. FUNDING: F Hoffmann-La Roche.
Adult↗
Adaptive proteomic remodeling and eNOS upregulation in luminal endothelium and perivascular adipose tissue of patent saphenous vein grafts after CABG.
OBJECTIVE: Long-term patency of saphenous vein grafts (SVGs) remains a significant challenge in coronary artery bypass grafting (CABG). The biological factors underlying successful human grafts are poorly understood. We aimed to characterize the structural and molecular features associated with successful graft function. METHODS: Patent and occluded SVG and internal thoracic artery (ITA) grafts were obtained from explanted hearts of CABG patients undergoing heart transplantation for end-stage heart failure not attributable to graft failure, along with freshly harvested ITA and SVG controls. Samples underwent histomorphological analysis, immunohistochemistry (IHC), and liquid chromatography-tandem mass spectrometry (LC-MS/MS) proteomics. RESULTS: Patent ITA (ITA-P) showed minimal intimal hyperplasia with medial reinforcement, whereas patent SVGs (SVG-P) had organized, α-smooth muscle actin (αSMA)-positive myofibroblast-rich neointima. Endothelial nitric oxide synthase (eNOS) was markedly upregulated in patent grafts at two sites-the luminal endothelium and adventitial microvessels within perivascular adipose tissue (PVAT)-and lost at both sites in occluded SVG (SVG-O). Adventitial CD31-positive microvessels were significantly increased in patent grafts. Proteomically, ITA-P and SVG-P shared a largely common adaptive proteome enriched in translation, RNA processing, and extracellular matrix (ECM) organization, with shared upstream activation of NR4A3, EGFR, and STAT1, and conduit-specific signatures (IGF-1/RUNX2 in ITA-P; RETN/SRC/PTGES in SVG-P). PTGES was strongly expressed in the adventitia of SVG-P. CONCLUSIONS: Patent arterial and venous bypass grafts exhibited a shared adaptive phenotype characterized by dual-site upregulation of eNOS in both the luminal endothelium and the perivascular microvessels/PVAT. In SVG-P, PTGES was co-upregulated alongside eNOS, indicating a mechanistic link between the proteomic and IHC findings. These findings highlight the perivascular compartment as a site of adaptive, eNOS-associated changes in patent vein grafts.
Humans↗
Older adults with resectable gastric cancer undergoing perioperative chemotherapy or preoperative chemoradiotherapy plus perioperative chemotherapy: A secondary analysis of the AGITG TOPGEAR phase III trial.
PURPOSE: To evaluate treatment adherence, adverse events, and survival in older (≥70 years) adults undergoing perioperative treatment for gastric cancer. METHODS: Patients with resectable gastric/gastro-esophageal junction adenocarcinoma (ECOG 0-1) enrolled in the phase III TOPGEAR trial were randomized to perioperative chemotherapy (ECF/ECX or FLOT) alone or perioperative chemotherapy plus preoperative chemoradiotherapy (45 Gy in 25 fractions with concurrent fluoropyrimidine). In this exploratory analysis, treatment completion, grade ≥ 3 adverse events (CTCAE v3.0), surgical outcomes, overall survival (OS) and progression-free survival (PFS) were compared between older and younger adults. RESULTS: Of the 574 patients enrolled, 135 (24%) were ≥ 70 years. Older adults more frequently required preoperative chemotherapy dose reductions, omissions, or delays (chemoradiotherapy: 55% vs 35%, p = 0.004; chemotherapy: 60% vs 48%, p = 0.087). Rates of grade ≥ 3 adverse events were comparable between older and younger patients (chemoradiotherapy: 66% vs 67%, p = 0.874; chemotherapy: 68% vs 59%, p = 0.220), but older adults more often had hematologic toxicity and grade ≥ 3 diarrhea in the chemotherapy group (56% vs 37%, p = 0.006; 21% vs 6%, p < 0.001). Resection rates, grade 3/4 surgical complications, number of removed lymph nodes, and 30-/90-day mortality were similar by age. OS and PFS were comparable across age groups, with numerically favorable outcomes for older adults (OS: HR 0.86, 95% CI 0.58-1.26 [chemoradiotherapy]; HR 0.75, 95% CI 0.51-1.11 [chemotherapy]; PFS: HR 0.78, 95% CI 0.53-1.15 [chemoradiotherapy]; HR 0.70, 95% CI 0.47-1.03 [chemotherapy]). CONCLUSIONS: Older adults with gastric cancer achieved comparable oncologic outcomes to younger patients, despite more frequent treatment modifications and higher hematologic toxicity.
Humans↗
Safety, tolerability, pharmacokinetics, and pharmacodynamics of oral JMKX003002 in Chinese healthy participants: a randomized, double-blind, placebo-controlled, single- and multiple-ascending dose, and food-effect phase I clinical trial.
OBJECTIVE: To evaluate the safety, tolerability, pharmacokinetics (PK), and pharma-codynamics (PD) of the sodium-hydrogen exchanger 3 (NHE3) inhibitor JMKX003002 in Chinese healthy participants. PATIENTS AND METHODS: This phase I, randomized, double-blind, placebo-controlled study included a single-ascending dose (SAD) study with seven cohorts (1 mg [n = 4] and 5, 20, 50, 75, 100, or 125 mg [n = 8]), a food-effect (FE) study with six sequence groups (25 mg twice daily, n = 4), and a multiple-ascending dose (MAD) study with two cohorts (10 mg or 20 mg twice daily, n = 10). RESULTS: JMKX003002 was well-tolerated, with mostly mild treatment-related adverse events. One Grade 3 diarrhoea occurred in each of the 50 mg and 125 mg groups. No serious adverse events were reported, and no participants discontinued or withdrew due to treatment-emergent adverse events. Most plasma samples were below the limit of quantification (0.2 ng/mL), with only transient detection of low concentrations, indicating low systemic exposure. JMKX003002 was primarily excreted in stool (79.9% recovered) and was undetectable in urine. The PD results consistently showed decreased urinary sodium and phosphorus, along with increased stool sodium and phosphorus, compared to baseline across all three studies. One day after discontinuation, stool sodium and phosphorus remained elevated relative to baseline in the MAD study. Mixed-effects model analysis in the FE study demonstrated significant food effect on stool sodium and phosphorus excretion. CONCLUSION: JMKX003002 exhibited favorable safety and tolerability with minimal systemic exposure. It effectively increased sodium and phosphorus excretion in stool. These promising findings warrant further investigation of JMKX003002 to evaluate its clinical benefits. TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR2300070473). Registered on April 13, 2023; prospectively registered.
Adult↗
Mechanistic Insights Into the Association Between Gut Microbiota Diversity and Atherosclerosis, Acute Coronary Syndrome, and Peripheral Arterial Disease Progression.
BACKGROUND: The gut microbiome has emerged as a potential contributor to cardiovascular diseases (CVDs), including atherosclerosis, acute coronary syndrome (ACS), and peripheral arterial disease (PAD). While observational studies link dysbiosis to CVD, causal relationships remain uncertain. METHODS: This narrative review synthesizes evidence from human observational studies, clinical interventions, and experimental models to distinguish association from mechanistic plausibility and clinical causality. Literature was searched through July 2026 in PubMed/MEDLINE, Web of Science, and Scopus. RESULTS: Microbial metabolites-including trimethylamine N-oxide (TMAO), short-chain fatty acids (SCFAs), bile acids, and lipopolysaccharide (LPS)-modulate endothelial function, immune cell programming, platelet activity, and plaque stability through receptor-mediated signaling and epigenetic regulation. SCFAs demonstrate potentially protective effects via GPCR and HDAC pathways, while TMAO is associated with atherothrombotic risk. However, much mechanistic evidence derives from preclinical studies. Heterogeneity from diet, geography, host characteristics, renal function, and medications substantially influences microbiota-CVD associations. CONCLUSION: The gut-vascular connection is biologically plausible, but definitive clinical causality remains unproven. Microbiome-directed therapies (dietary modulation, pre/pro/synbiotics, targeted metabolite inhibition) are investigational. Prospective, standardized, adequately powered human studies with clinically meaningful outcomes are essential before routine cardiovascular application.
Gastrointestinal Microbiome↗
Ketamine assisted psychotherapy to reduce chronic neuropathic pain: A mixed-methods randomized pilot trial.
BACKGROUND: Intravenous ketamine can provide short-term analgesia in chronic neuropathic pain but benefits often wane after treatment. We conducted a randomized pilot trial to assess the feasibility of combining ketamine infusions with psychotherapy to inform future efficacy trials. METHODS: In this single-center, randomized, outcome-assessor-blinded pilot trial at a Canadian tertiary pain clinic, adults with moderate-to-severe chronic neuropathic pain were randomly assigned in 1:1:1 ratio to the ketamine, psychotherapy, or combined ketamine plus psychotherapy arm. Ketamine was delivered as three intravenous infusions over 16 weeks; psychotherapy consisted of 16 weekly cognitive behavioral therapy and mindfulness-based meditation sessions. The primary outcome was feasibility, assessed using prespecified progression criteria. Exploratory outcomes included changes in pain interference (PROMIS 6a T-score), pain intensity, mood, and qualitative interview findings at week 20 (ClinicalTrials.gov: NCT05639322). FINDINGS: Between October 23, 2023, and March 31, 2025, 30 participants were randomized, and 26 (87%) completed 20-week follow-up. Most feasibility criteria, including consent, retention, data completeness, and absence of study-related serious adverse events, were met; adherence targets were partially met. Exploratory pain outcomes showed numerical improvement across groups, with clinically meaningful reductions observed for pain interference and pain intensity. Sixty-four adverse events were recorded, mostly mild and in ketamine-containing groups; no serious study-related adverse events occurred. CONCLUSIONS: Combined ketamine and psychotherapy was feasible and acceptably safe in this pilot trial, supporting evaluation in a larger efficacy-powered study. FUNDING: The study was funded by the St. Michael's Hospital Innovation Fund, The Canadian Pain Society Early Investigator Award and the Physician Services Incorporation Early Career Researcher Award.
Humans↗
Efficacy and safety of microwave ablation for the treatment of pulmonary osteosarcoma oligometastases.
PURPOSE: Evaluate efficacy and safety of microwave ablation (MWA) for pulmonary osteosarcoma oligometastases. METHODS: Twenty-two patients (median age, 16 years [range, 9-41 years]; 15 male) with pulmonary osteosarcoma oligometastases who underwent MWA from January 2018 to December 2023 were included, with 27 MWA sessions for 36 lung metastases. Technical success and complications were evaluated in all 22 patients, while efficacy and survival were evaluated in 19 patients with 24 MWA sessions in treatment of 32 tumors. Technical success was assessed for each tumor. Local tumor control, progression-free survival (PFS) and overall survival (OS) were estimated using Kaplan-Meier method. Complications were classified using Common Terminology Criteria for Adverse Events version 5.0. RESULTS: Technical success was achieved in all 36 tumors (100.0%). Local tumor progression occurred in five of 32 tumors (15.6%). The estimated local tumor control rates at 12, 24 and 36 months were 96.9%, 86.1% and 81.5%, respectively. No significant difference in local control was found between tumors ≤ 10 mm and > 10 mm (p = .470). Twelve of 19 patients (63.2%) developed new lung metastases outside the ablation area, including one with concurrent newly developed bone metastases and one with recurrence of primary osteosarcoma. The median PFS was 21.5 months. The estimated OS rates at 12, 24 and 60 months were 100.0%, 94.4% and 94.4%, respectively. Major complications occurred in five of 27 sessions (18.5%). CONCLUSIONS: MWA preliminarily demonstrates a high technical success rate, notable local tumor control, promising overall survival and acceptable safety for pulmonary osteosarcoma oligometastases.
Adolescent↗
Bioepidemiology of cardiac amyloidosis.
BACKGROUND: Cardiac amyloidosis, primarily due to immunoglobulin light chain (AL) or transthyretin (ATTR) amyloid, is an increasingly recognized cause of heart failure. Modern diagnostic advances suggest that ATTR, particularly in older adults, may be more prevalent than historically reported. METHODS: All Olmsted County decedents aged ≥40 years from 1970 to 1976 were identified. Available ventricular myocardium from retained paraffin blocks was screened histologically for amyloid using sulfated Alcian blue staining; positive cases underwent grading and proteomic typing by laser microdissection coupled with liquid chromatography-tandem mass spectrometry (LC-MS/MS). Beyond prevalence estimation, this analysis characterizes amyloid type, deposition grade and distribution, associated comorbidities, and cause-of-death patterns, comparing amyloid-positive decedents with age- and sex-matched controls. RESULTS: Of 2,566 eligible deaths, 1,028 autopsy cases with evaluable myocardium formed the study cohort (mean age 70.5 years; 61.1% male; 97% White). Cardiac amyloid was present in 52 cases giving an overall prevalence of 5.1% (95% CI: 3.8-6.6, which rose from 0% under age 60 to 37.5% (95% CI: 21.1-56.3) in those ≥90 years (p < 0.001). While prevalence estimates were higher in men above age 80 compared to women, there was no evidence of an interaction of age and sex (p = 0.90). The quantity of amyloid was sufficient for typing in 38 cases: ATTR (84.2%), AL (7.9%), serum amyloid A (5.3%), and apolipoprotein A-IV (2.6%). Adjusted estimates assuming untyped mild cases were ATTR-type increased ATTR prevalence to 4.5% (95% CI: 3.3-5.9) overall. Comorbidity profiles were similar between amyloid-positive and negative groups, though syncope and leg weakness were more common in amyloid-positive decedents. CONCLUSIONS: In an unselected autopsy cohort, cardiac amyloid was common, particularly ATTR in older adults. Prevalence increased steeply after age 80. These findings suggest that ATTR amyloidosis is not rare and is likely underdiagnosed and has similar prevalence in women and men, despite the male predominance reported in the literature.
Humans↗
Morbidity and mortality from local anesthetics: localized and systemic toxicity.
PURPOSE OF THE REVIEW: Local anesthetics remain vital to modern medicine, yet their narrow therapeutic window continues to result in complications. This review synthesizes recent literature to define the current landscape of local anesthetic-associated adverse events. RECENT FINDINGS: Perioperative mortality attributable to local anesthetics persists despite sustained safety initiatives and professional society recommendations. Pharmacovigilance and case data identify lidocaine (oropharyngeal, topical, and via local infiltration) as the predominant contributor to adverse outcomes, including death. Local anesthetic systemic toxicity remains an issue, with a recent shift in epidemiology: an increasing proportion of toxic events originates from surgeon- and proceduralist-administered analgesia. Anesthesiologist-controlled methods also cause toxicity via catheter-based delivery and nerve blocks in highly vascular regions. Localized toxicity in the form of high neuraxial contributes to morbidity, with recent reviews reinforcing known risk factors; whereas localized neurotoxicity appears less troublesome when managed appropriately. SUMMARY: The cumulative evidence identifies shifts in the patterns of systemic and localized toxicities. Bupivacaine-based peripheral nerve blocks no longer represent the principal cause of complications because of the advent of ultrasound guidance and lipid emulsion therapy. In contrast, high neuraxial techniques persist as a cause of morbidity, accompanied by intravenous/oropharyngeal lidocaine, proceduralist-administered local infiltration analgesia, and catheter-based delivery.
Humans↗
Baseline Computed Tomography Coronary Angiography and Polygenic Risk Profiles in Adults With Type 2 Diabetes: A Cross-Sectional Analysis From the VOLTAIRE Study.
AIMS: To characterise baseline clinical, anatomical, and genetic cardiovascular risk profiles in participants enrolled in the VOLTAIRE (Evaluation of Polygenic Scores and CT Imaging in Risk Factor Modification in Patients with Type 2 Diabetes) study and examine concordance across these domains. METHODS: This analysis included adults with T2D who completed baseline computed tomography coronary angiography (CTCA) and polygenic risk score (PRS) assessment prior to randomisation in the VOLTAIRE study. Coronary atherosclerosis was evaluated using coronary artery calcium (CAC) score and CTCA-derived stenosis severity. Clinical risk was assessed using the New Zealand Society for the Study of Diabetes 5-year cardiovascular risk calculator. Polygenic risk for coronary artery disease was assessed using a genome-wide PRS and categorised into tertiles. RESULTS: Among 126 participants with T2D (mean age 57.5 ± 8.7 years; 62.7% male), coronary atherosclerotic burden was highly heterogeneous: 34.9% had CAC = 0, whereas 19.8% had CAC ≥ 400. Moderate-to-severe coronary stenosis (≥ 50%) was present in 40.5% of participants overall, including 20.4% of those classified as low clinical risk. PRS distribution was variable (low 37.3%, intermediate 35.7%, high 27.0%). Overlap between anatomical, genetic, and clinical domains was limited, with only 8.7% of participants classified as high risk across all three. CONCLUSIONS: Substantial heterogeneity and limited overlap exist between anatomical, genetic, and clinical cardiovascular risk measures in T2D. These findings support a multimodal approach to risk assessment integrating imaging and genetic profiling. TRIAL REGISTRATION: https://www. CLINICALTRIALS: gov; ID: NCT07091162.
Aged↗