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PubMed2026

Development of a cell-based nanoluciferase reporter system for high-throughput screening of HBV cccDNA inhibitors.

Hepatitis B virus (HBV) persistence is sustained by the viral covalently closed circular DNA (cccDNA) minichromosome, which remains a major barrier to curative antiviral therapies. The lack of reliable quantitative cccDNA detection methods and surrogate markers has hindered efforts to target cccDNA in antiviral high-throughput screening (HTS). Here, we established a novel inducible cccDNA-dependent nanoluciferase (NLuc) reporter cell line, designated HepBLE12, by inserting an in-frame 11-amino acid split-NLuc HiBiT tag into the precore (pC) coding region of an HBV transgene. The resulting 1.3-kDa HiBiT tag on pC serves as the detection module of the split NLuc system, generating quantitative luminescence upon high-affinity complementation with the cognate 18-kDa LgBiT subunit in cell lysates. Notably, the HiBiT assay enables direct detection of intracellular HiBiT-pC protein rather than secreted HBeAg, providing a reporter signal more closely linked to cccDNA activity. HepBLE12 cells exhibited inducible and robust viral DNA replication, and the cccDNA-dependent HiBiT signal was validated under diverse experimental conditions that modulate cccDNA formation or transcription. We further miniaturized the assay to a 384-well format and optimized key parameters following standard HTS assay development practices. The assay was successfully automated and demonstrated excellent performance in a multi-day variability study and a pilot screen, with signal-to-background (S/B) ≈ 9, coefficient of variance (CV) < 10%, and average Z-factor value of 0.74, exceeding canonical HTS quality benchmarks. Together, the HepBLE12 cell-based HTS platform provides a robust and practical tool for identifying inhibitors targeting HBV cccDNA.

Hepatitis B virus↗

PubMed2026

The role of adjunctive aqueous suppressants for anti-vascular endothelial growth factor therapy: A systematic review.

Our goal is to determine whether adjunctive aqueous suppressants (topical β-blockers, carbonic anhydrase inhibitors, or oral acetazolamide) enhance outcomes of anti-vascular endothelial growth factor (anti-VEGF) therapy for diabetic macular edema (DME), retinal vein occlusion (RVO), and neovascular age-related macular degeneration (nAMD), focusing on retinal thickness, visual acuity, injection burden, intraocular pressure (IOP), and safety. DME, RVO, and nAMD are leading causes of vision loss treated with repeated intravitreal injections, yet many eyes show persistent fluid. Aqueous suppressants are inexpensive and widely available, with potential to prolong intravitreal drug residence and improve outcomes, but their clinical value remains uncertain. Following a registered protocol, we searched 4 databases (January, 2000 toMay, 2025) for randomized and comparative studies evaluating adjunct aqueous suppressants with anti-VEGF therapy. Primary outcome was change in retinal thickness; secondary outcomes included visual acuity, injection burden, IOP, and adverse events. Risk of bias was assessed and findings synthesized narratively. Twelve studies (7 randomized trials; 495 eyes) met inclusion criteria. In DME, 3 of 4 trials showed greater thickness reduction with adjunctive dorzolamide (±timolol), although visual gains were inconsistent. In RVO, 1 trial suggested transient anatomical benefit, whereas oral acetazolamide showed no added effect. In nAMD, adjunctive dorzolamide-timolol reduced residual fluid in refractory cases without visual or treatment-sparing benefit. Topical therapy produced modest IOP reductions without serious adverse events. Adjunct aqueous suppressants may provide limited short-term anatomical benefit, particularly in DME and refractory nAMD, but consistent functional or durability effects are not found in this study. Larger, longer-term randomized studies are needed.

Humans↗

PubMed2026

Development and validation of an LC-MS/MS method for the quantification of the KRASG12C inhibitor divarasib.

Divarasib is a newly developed covalent KRASG12C inhibitor, currently under clinical investigation in a phase 3 trial in patients with non-small cell lung cancer (NSCLC). At the moment, very limited pharmacokinetic data are publicly known. However, obtaining more insight into the pharmacokinetic properties of divarasib is important, since this may provide a better understanding of its efficacy and safety risks. Pre-clinical studies have been performed in mouse models to evaluate the effect of drug transporters and drug-metabolizing enzymes on the plasma exposure and tissue distribution of divarasib. Therefore, a reliable quantification method is required. To our knowledge, no bioanalytical assay of divarasib has been published yet. Therefore, in this study we developed and validated an assay to quantify divarasib in human plasma and in eight different mouse-related matrices, and partially in mouse plasma, using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The method was initially evaluated over a concentration range of 1-10,000 nM. However, due to carry-over observed at 10,000 nM, the validated calibration range was established at 1-2000 nM, with matrix-dependent LLOQs of 1-10 nM. Erlotinib was used as an internal standard and acetonitrile was utilized to perform protein precipitation as sample pretreatment. Divarasib demonstrated stability in human plasma and in mouse plasma and tissue homogenates under various experimental conditions. A pilot in vivo study showed the applicability of our validated LC-MS/MS method. Ongoing clinical trials may collect plasma samples, and this developed method enables quantification of divarasib in both mouse and human plasma samples.

Animals↗

PubMed2026

Response-adapted surgical de-escalation following neoadjuvant immunotherapy in resectable mucosal HNSCC A systematic review and meta-analysis.

INTRODUCTION: Recent encouraging outcomes with neoadjuvant immune checkpoint inhibitors (ICIs) in mucosal head and neck squamous cell carcinoma (HNSCC) have generated interest in surgical de-escalation. However, the oncologic safety of response-adapted surgery (RAS) and its ability to achieve survival outcomes comparable to baseline-planned surgery (BPS) remain uncertain. METHODS: A systematic search of the PubMed, EMBASE, Cochrane Library, and the Clinical Trials Registry for studies of neoadjuvant ICIs, with or without chemotherapy, in resectable mucosal HNSCC, that explicitly report surgical extent, between 2020-2025 was performed. Two independent reviewers extracted data following PRISMA guidelines. Main outcomes included major pathologic response (MPR), pathologic complete response (pCR), event-free survival (EFS), and overall survival (OS). Study-level proportions were pooled by random effects models. Heterogeneity was assessed by the I2 statistic. RESULTS: The comparative analysis consisted of 4 RAS studies (involving 202 patients) and 11 BPS studies (403 patients). The pooled overall EFS was 83.3% (76.9-88.2) for the former and 82% (75.2-87.2) for the latter (P=.751), and the respective pooled OS was 92.3% (87.5-95.3) and 91.4% (80.3-96.5) (P=.839). The pooled pCR rate was 41.7% (95% CI 5.4-48.4; I2=.0) for RAS and 19.8% (95%CI 13.3-29.6; I2=.62) for BPS (P=.001), while the MPR was not significantly different (59.6%, versus 48.5%, P=.245). RAS was associated with greater organ preservation and reduced need for mandibulectomy and free-flap reconstruction. CONCLUSIONS: RAS following neoadjuvant ICIs in mucosal HNSCC may enable surgical de-escalation with preserved oncologic outcomes and improved function in selected patients. Larger prospective studies are warranted.

Humans↗

PubMed2026

Effects of CPAP on endothelial activation and fibrinolytic balance in coronary artery disease with obstructive sleep apnea: The RICCADSA randomized controlled trial.

BACKGROUND: Obstructive sleep apnea (OSA) promotes endothelial activation and a prothrombotic milieu through intermittent hypoxia, oxidative stress, and systemic inflammation, mechanisms closely linked to atherosclerosis progression. The vascular effects of continuous positive airway pressure (CPAP) therapy in patients with established coronary artery disease (CAD) remain incompletely understood. OBJECTIVE: To evaluate the longitudinal effects of CPAP treatment on endothelial adhesion molecules and fibrinolytic balance in patients with CAD and OSA. METHODS: In this randomized controlled analysis from the RICCADSA trial, 210 revascularized CAD patients with moderate-to-severe OSA were assigned to CPAP (n = 104) or no-CPAP (n = 106) and had available biomarker measurements at baseline and 12 months. Circulating intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and plasminogen activator inhibitor-1 (PAI-1) were assessed. Linear mixed-effects models were used to examine longitudinal changes and time-by-treatment interactions adjusted for cardiometabolic covariates. RESULTS: For ICAM-1, no significant time-by-treatment interaction was observed. For PAI-1, a borderline time-by-treatment interaction suggested a numerically smaller increase in the CPAP group compared with no-CPAP (p = 0.09). CPAP treatment was associated with a significantly greater reduction in VCAM-1 over time compared with no-CPAP (time-by-treatment interaction p = 0.045 in adjusted models). CONCLUSIONS: CPAP treatment was associated with selective modulation of vascular biomarkers in patients with CAD and OSA, characterized by attenuation of endothelial activation reflected by reduced VCAM-1 levels, while fibrinolytic imbalance appeared largely resistant to intervention. These findings support pathway-specific vascular responses to CPAP and provide mechanistic insight into residual atherosclerotic risk in this high-risk population.

Aged↗

PubMed2026

Efficacy of dapagliflozin on hepatic steatosis and fibrosis in patients with type 2 diabetes mellitus and metabolic dysfunction-associated steatotic liver disease: a pre-specified single-arm analysis from a randomized controlled trial.

AIM: To evaluate the association of dapagliflozin therapy with changes in hepatic steatosis and non-invasive fibrosis surrogate markers in patients with type 2 diabetes mellitus (T2DM) and Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) over 12 months. METHODS: This is a pre-specified single-arm analysis from a randomised, open-label, parallel-group trial. Of 54 participants randomised to dapagliflozin 10 mg daily, 50 (92.6%) completed the 12-month follow-up and were included in the per-protocol analysis. Assessments at baseline, 3, 6, and 12 months included transient elastography (CAP and LSM), ultrasonography, and biochemical tests. Primary endpoints were changes in hepatic steatosis (CAP) and non-invasive fibrosis surrogates (LSM). RESULTS: Significant reductions were observed in hepatic steatosis (CAP: 316.7 to 245.7 dB/m; mean change - 71.02 dB/m, 95% CI: -63.4 to - 78.6; p < 0.001) and in liver stiffness as a non-invasive fibrosis surrogate (LSM: 8.59 to 7.28 kPa; mean change - 1.31 kPa, 95% CI: -0.92 to - 1.70; p < 0.001). Improvements were also observed in glycaemic control, body weight, lipid profile, liver enzymes, ultrasonographic steatosis grading, and serum fibrosis markers. Genitourinary infections were the most frequently reported adverse events (32%); no serious adverse events were recorded. CONCLUSIONS: Dapagliflozin was associated with significant improvements in hepatic steatosis, non-invasive fibrosis surrogate markers, metabolic parameters, and liver function in T2DM patients with MASLD over 12 months. These findings provide region-specific evidence for an Indian population and support further controlled investigation. However, these findings should be interpreted in light of the pre-specified single-arm design of this analysis, the open-label methodology, relatively small sample size, and the absence of liver biopsy confirmation.

Humans↗

PubMed2026

Efficacy and Safety of Rivaroxaban in Patients with Peripheral Artery Disease: A GRADE-assessed Systematic Review and Meta-Analysis.

BACKGROUND: Peripheral artery disease (PAD) is a common atherosclerotic disorder characterized by progressive arterial narrowing in the limbs. This study aims to determine the efficacy and safety of rivaroxaban, focusing on major cardiovascular events, limb outcomes, and bleeding risks. METHODS: PubMed, Cochrane, and EMBASE were searched for randomized controlled trials (RCTs) and nonrandomized comparative studies that compared rivaroxaban, either alone or in combination with aspirin, to placebo or standard care such as antiplatelet therapy. Risk ratios and hazard ratios with 95% confidence intervals were pooled using R v4.5.1 with an appropriate random-effects model applied. Subgroup analyses were performed according to rivaroxaban plus aspirin versus rivaroxaban alone. RESULTS: A total of 39,991 participants across 6 studies were included. Compared with control, use of rivaroxaban was linked to a significant reduction in composite efficacy outcomes (relative risk [RR] = 0.84, 95% confidence interval [CI] 0.78-0.91, P < 0.001), risk of acute limb ischemia (RR = 0.65, 95% CI 0.55-0.78, P < 0.001), and thromboembolism (RR = 0.60, 95% CI 0.38-0.97, P = 0.037). Although rivaroxaban plus aspirin failed to show a significant reduction in the risk of amputation, rivaroxaban alone reported a significant risk reduction (RR = 0.50, 95% CI 0.30-0.85, P = 0.003). However, its use was associated with a significantly higher risk of major bleeding (hazard ratio [HR] = 1.54, 95% CI 1.38-1.72, P < 0.001) and International Society on Thrombosis and Hemostasis-defined bleeding (RR = 1.45, 95% CI 1.19-1.76, P < 0.001). No significant differences were observed for stroke, myocardial infarction, major adverse limb events, fatal bleeding, mortality, or cardiovascular mortality. CONCLUSION: Rivaroxaban-based therapy reduced the trial-defined composite efficacy outcome, acute limb ischemia, and thromboembolism in patients with PAD, but increased the risk of major bleeding. These findings support individualized use of rivaroxaban-based therapy in carefully selected patients, balancing ischemic and limb-protective benefits against bleeding risk.

Humans↗

PubMed2026

Ultrashort vs Standard-Duration Dual Antiplatelet Therapy in Acute Coronary Syndrome Patients Undergoing PCI: A Meta-Analysis.

BACKGROUND: The efficacy and safety of ultrashort (≤1-month) dual antiplatelet therapy (DAPT) followed by antiplatelet monotherapy remain uncertain in acute coronary syndrome (ACS) patients. OBJECTIVES: This study sought to compare ultrashort vs standard-duration DAPT in patients with ACS undergoing percutaneous coronary intervention (PCI). METHODS: We conducted a systematic review and meta-analysis of randomized controlled trials until February 15, 2026. Primary outcomes were major adverse cardiac and cerebrovascular events (MACCE), major bleeding, and net adverse clinical event (NACE). Prespecified subgroup analyses examined by ethnicity (East Asian vs non-East Asian) and abbreviation strategy (intensive: ≤1-week DAPT or clopidogrel/aspirin monotherapy vs moderate: ≥2-week DAPT, followed by ticagrelor/prasugrel monotherapy). RESULTS: Across 10 trials (n = 29,232), ultrashort DAPT did not increase MACCE risk (HR: 1.06; 95% CI: 0.93-1.20; P = 0.38; I2 = 24%), with higher MACCE risk observed in ST-segment elevation myocardial infarction (STEMI) but not non-ST-segment elevation ACS (NSTE-ACS), and significantly reduced major bleeding (HR: 0.47; 95% CI: 0.35-0.64; P < 0.00001; I2 = 44%), resulting in a net clinical benefit (HR: 0.83; 95% CI: 0.72-0.97; P = 0.02; I2 = 61%). Bleeding reduction was more pronounced in East Asians (HR: 0.35; 95% CI: 0.25-0.49; P < 0.00001; I2 = 0%) than non-East Asians (HR: 0.63; 95% CI: 0.43-0.93; P = 0.02; I2 = 44%), with a significant interaction (P = 0.02). The abbreviation strategy significantly modified outcomes (P for interaction = 0.003): intensive abbreviation raised MACCE risk (HR: 1.37; 95% CI: 1.11-1.69; P = 0.003; I2 = 0%), while moderate abbreviation had no statistically significant difference (HR: 0.96; 95% CI: 0.85-1.08; P = 0.47; I2 = 0%). CONCLUSIONS: In patients with ACS undergoing PCI, ultrashort DAPT reduced bleeding without increasing ischemic events overall, although a signal of increased MACCE was observed in STEMI but not in NSTE-ACS. Bleeding reduction was greater in East Asians, while ≤1-week DAPT or clopidogrel/aspirin monotherapy may increase ischemic risk.

Humans↗

PubMed2026

Symptoms and treatment response to florensocatib and inhaled tobramycin in bronchiectasis: Post hoc analysis of two randomized trials.

Inhaled antibiotics and DPP-1 inhibitors improve clinical outcomes in bronchiectasis, but whether baseline symptom burden predicts differential treatment responses remains unclear. In this post hoc analysis of two multicenter randomized trials (SAVE-BE, n = 224; TORNASOL, n = 357), we evaluate the association between baseline Quality of Life-Bronchiectasis Respiratory Symptom Scale (QoL-B-RSS) and treatment effects of florensocatib and inhaled tobramycin. In SAVE-BE, florensocatib reduces exacerbation rates versus placebo (relative risk [RR], 0.47; 95% confidence interval [CI], 0.33-0.67; p < 0.0001), with RRs of 0.53 and 0.40 observed in patients with high and low symptom burdens, respectively, but no significant symptomatic improvement. In TORNASOL, tobramycin produces clinically meaningful QoL-B-RSS improvements (exceeding the 8-point cutoff in high-symptom patients) and ameliorates bronchitic symptoms, with greater benefits in those with higher baseline symptom burden. These hypothesis-generating findings suggest that baseline symptom burden may identify differential responses to anti-inflammatory versus anti-infective therapies in bronchiectasis and support its potential as a simple, practical stratification tool to guide personalized treatment.

Humans↗

PubMed2026

Effects of semaglutide and empagliflozin on markers of endothelial function in persons with type 2 diabetes: A post hoc analysis of a randomized clinical trial.

AIMS: The endothelium maintains vascular health by regulating blood flow and protecting against inflammatory damage. In type 2 diabetes (T2DM), however, hyperglycemia, hypertension, and hyperlipidemia place a significant burden on the endothelium, potentially leading to atherosclerosis and cardiovascular disease (CVD). While semaglutide and empagliflozin have been shown to reduce CVD risk in T2DM, it remains unclear whether these benefits are mediated by improved endothelial function. This post-hoc analysis explores the effects of these agents on markers of endothelial function, i.e. the reactive hyperaemic index (RHI) and the endothelial-derived cell adhesion molecules (CAMs) E-Selectin, ICAM-1, P-Selectin, and VCAM-1. METHODS: This was a post-hoc analysis of a 32-week randomized trial evaluating the separate and combined effects of semaglutide and empagliflozin on cardio-renal organ damage. One hundred and twenty participants with type 2 diabetes, age ≥ 50 were randomized to four groups (semaglutide, empagliflozin, the combination or placebo). An increase in RHI and/or a decrease in CAMs were considered beneficial. RESULTS: RHI increased compared to baseline (0.11, 95%CI [0.008;0.21], p = 0.03) but not compared to placebo in the semaglutide group (0.11, 95%CI [-0.04;0.24], p = 0.16). There was no effect on RHI in the empagliflozin group. Compared to placebo, E-Selectin decreased significantly in the semaglutide and combination groups (-9, 95%CI [-14.1;-5.1] p < 0.01 and - 9, 95%CI [-14.3; -5.2] p < 0.01, respectively). VCAM-1 increased in the same groups, compared to placebo (12.3, 95%CI[2.8;20.8] p = 0.01 and 16.2, 95%CI [7.2;24.3], p < 0.01, respectively).P-Selectin and ICAM-1 was not significantly affected in any of the groups, compared to placebo (p ≥ 0.11 and p ≥ 0.09, respectively). CONCLUSION: Semaglutide improved endothelial function compared to baseline, but not significantly versus placebo, which likely is due to limited power. CAM responses were heterogeneous, suggesting distinct roles in endothelial dysfunction and atherosclerosis. ClinicalTrialsRegister.eu: EudraCT 2019-000781-38.

Aged↗

PubMed2026

Seed-derived mucilage polysaccharides as biomaterials for in vivo tissue regeneration: A systematic review.

Chronic wounds, bone defects, and cartilage injuries represent persistent clinical challenges requiring biomaterial platforms that actively regulate inflammation, oxidative stress, angiogenesis, and extracellular matrix remodeling. Conventional synthetic dressings often provide limited biological activity in these contexts. Seed-derived mucilages - polysaccharide-rich hydrocolloids obtained from chia (Salvia hispanica), flaxseed (Linum usitatissimum), fenugreek (Trigonella foenum-graecum), psyllium (Plantago ovata), guar (Cyamopsis tetragonoloba), quince (Cydonia oblonga) etc. - have emerged as biocompatible, biodegradable, and chemically versatile platforms for tissue engineering. This systematic review, conducted according to PRISMA 2020 guidelines, synthesized in vivo evidence on seed-derived mucilage-based biomaterials across wound healing, bone repair, cartilage regeneration, and related applications. PubMed, Scopus, and Web of Science Core Collection were searched for original in vivo experimental studies published in English between 2020 and 2026. Eligible studies reported at least one measurable regenerative outcome. Data were extracted independently by two reviewers, and methodological quality was assessed using the SYRCLE Risk of Bias tool. Forty-three studies were included. Hydrogels were the dominant biomaterial format, followed by films, scaffolds, sponges, nanoparticle systems, and bilayer or Janus composites. Included systems generally improved wound closure, re-epithelialization, collagen deposition, angiogenesis, antioxidant defense, and inflammatory regulation. However, most studies used small animals with short follow-up periods, and many incorporated nanoparticles or bioactive agents, limiting attribution of efficacy to the mucilage matrix alone. Risk of bias was predominantly unclear due to insufficient reporting of randomization and blinding. Blank mucilage controls, standardized characterization, long-term biosafety data, and clinically relevant models are essential prerequisites for translational progress.

Humans↗

PubMed2026

Safety, tolerability, and efficacy of RIPK1 inhibitor, SAR443820, in amyotrophic lateral sclerosis (HIMALAYA): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial.

BACKGROUND: RIPK1, a protein regulating inflammatory signalling and cell death, is implicated in amyotrophic lateral sclerosis (ALS) pathophysiology. SAR443820 is a selective, oral, CNS-penetrant, reversible RIPK1 inhibitor. We aimed to evaluate the safety, tolerability, and efficacy of SAR443820 in participants with ALS. METHODS: This multicentre, randomised, double-blind, placebo-controlled, phase 2 trial was conducted at 63 clinical sites in 13 countries (Belgium, Canada, China, France, Germany, Italy, Japan, the Netherlands, Poland, Spain, Sweden, the UK, and the USA). Adults (aged 18-80 years) with a diagnosis of possible ALS, clinically probable ALS, clinically probable laboratory-supported ALS, or clinically definite ALS, in accordance with the revised El Escorial World Federation of Neurology criteria, were randomly assigned (2:1) by use of a stratified block design (blocks of three) to receive either 20 mg SAR443820 orally twice per day or matching placebo in the 24-week double-blind period. Randomisation was done centrally using interactive response technology and stratified by geographical region of trial site, region of ALS onset, use of riluzole, use of edaravone, and use of the combination of sodium phenylbutyrate and taurursodiol. Participants, care providers, investigators, and outcomes assessors were masked to trial intervention. The primary outcome was a change in ALS Functional Rating Scale Revised (ALSFRS-R) total score from baseline to week 24 and was calculated for all participants who had an ALSFRS-R total score available at baseline and at week 24. Safety analyses included all randomly assigned participants receiving one dose or more of trial intervention. This trial is registered with ClinicalTrials.gov (NCT05237284) and was terminated early. FINDINGS: Between April 13, 2022, and July 17, 2023, 397 participants were screened and 305 randomly assigned to SAR443820 (n=203) or placebo (n=102); six were excluded from the primary analysis due to missing baseline ALSFRS-R values. Mean age was 56·9 years (SD 11·5); 183 (60%) participants were male and 122 (40%) were female. Least squares mean change in ALSFRS-R from baseline to week 24 was -6·73 (95% CI -7·48 to -5·98) for SAR443820 group (n=169) and -6·32 (-7·36 to -5·27) for placebo group (n=87). There was no statistically significant difference between the study groups (least squares mean difference -0·41 [95% CI -1·71 to 0·88]). Participants in the SAR443820 group had higher incidence of adverse events (171 [85%] of 202 vs placebo 80 [78%] of 102) and treatment discontinuations (28 [14%] of 202 vs placebo five [5%] of 102), with elevated hepatic enzymes being the most common cause. Nine deaths occurred in the double-blind period (seven [3%] of 202 in the SAR443820 group and two [2%] of 102 in the placebo group); none was attributed to SAR443820. INTERPRETATION: SAR443820 did not show clinical benefit and was associated with higher hepatic enzyme increase, indicating that further clinical development of SAR443820 in ALS is not warranted. FUNDING: Sanofi.

Humans↗

PubMed2026

Catecholaminergic Contributions to Inhibitory Control Following Physical Fatigue: Behavioral and Neurophysiological Findings.

Acute physical fatigue can impair cognitive control, yet its underlying neurochemical mechanisms remain unclear. This study investigated whether catecholaminergic modulation influences behavioral and neural markers of inhibitory control following physical fatigue. Eighteen healthy, recreationally active adults (9 males, 9 females; 23.4 ± 2.2 years) completed a randomized, triple-blind, placebo-controlled crossover study. On separate visits, participants received methylphenidate (MPH; 20 mg; a dopamine and noradrenaline reuptake inhibitor), reboxetine (REB; 8 mg; a noradrenaline reuptake inhibitor), or placebo. Physical fatigue was induced by repeated bilateral leg extensions to task failure. Cognitive performance was assessed before and after physical fatigue using a Go/No-Go task with electroencephalographic recording. Behavioral outcomes included reaction time and accuracy, while event-related potentials measured neural stages of response execution and inhibition (N2 and P3). Mixed-effects models were used for statistical analysis. For No-Go trials, a significant MPH × Time interaction was observed for accuracy (p = 0.008), with improved post-fatigue performance following MPH administration (p = 0.048). At the neural level, MPH was associated with shorter fronto-central No-Go N2 latency (p = 0.038) and altered fatigue-related changes in No-Go P3 latency (p = 0.047). REB did not produce comparable behavioral or neural effects. These findings provide pharmacological evidence that catecholaminergic mechanisms contribute to inhibitory control following physical fatigue. The differential effects of MPH and REB suggest that selective noradrenergic enhancement alone is insufficient to maintain inhibitory control following physical fatigue. Instead, the findings implicate broader dopaminergic and noradrenergic mechanisms, potentially involving alterations in the temporal dynamics of inhibitory processing. TRIAL REGISTRATION: (G095422N and identifier NCT05880342).

Adult↗

PubMed2026

Safety and outcomes of dapagliflozin initiation in critically ill patients with acute kidney injury: A post-hoc analysis of the defender trial.

BACKGROUND: SGLT2 inhibitor use in acute kidney injury (AKI) is controversial due to concerns about hemodynamic instability. We evaluated dapagliflozin initiation in critically ill patients with AKI enrolled in the DEFENDER trial. METHODS: Among 212 patients with AKI at enrollment (100 dapagliflozin, 112 control), we compared 28-day mortality, kidney replacement therapy (KRT), and composite death/KRT. Adjusted risk differences were estimated controlling for age, sepsis, baseline vasopressor use, and creatinine. Physiological trajectories (creatinine, urine output, fluid balance, acid-base parameters) over days 1-5 were analyzed using mixed models. Likelihood ratios quantified compatibility with clinically meaningful harm or benefit. RESULTS: Event rates were similar: 28-day mortality 38% vs 40%, KRT 12% vs 18%, composite 41% vs 42% (dapagliflozin vs control). Adjusted risk differences were - 1.9% (95% CI -14.5 to 10.7) for death, -7.4% (-16.2 to 1.5) for KRT, and - 0.9% (-13.6 to 11.8) for the composite. Physiological trajectories showed no divergence suggestive of hemodynamic or metabolic instability. Likelihood ratios provided limited separation: at 5% absolute effect threshold, LR against harm was 1.47 and against benefit 1.19. CONCLUSIONS: Dapagliflozin initiation in critically ill patients with AKI was not associated with excess mortality, KRT, or physiological derangement. The near-neutral evidential profile indicates neither moderate harm nor benefit can be excluded, supporting feasibility of dedicated trials of SGLT2 inhibitors in AKI.

Humans↗

PubMed2026

Examining early-phase symptom trajectories in interpersonal psychotherapy versus antidepressant medication for adults with depression: A dynamic time warp network analysis.

BACKGROUND: Depression is characterized by substantial symptom heterogeneity, which is often concealed when examining total severity scores. Analyzing symptom-level change can improve our understanding of treatment effects and recovery processes. This study, therefore, examined dynamic symptom networks during early-phase interpersonal psychotherapy (IPT) and selective serotonin reuptake inhibitor (SSRI) antidepressant treatment, assessing patterns of symptom change across as well as differences between treatments. METHODS: Using weekly item-level Hamilton Depression Rating Scale (HAM-D) data from a randomized clinical trial comparing IPT and SSRIs for adults with depression, this preregistered study examined symptom trajectories in the first six weeks of treatment with Dynamic Time Warping (DTW). RESULTS: Depressive symptom trajectories and DTW-based symptom networks were largely similar for IPT and SSRI. In both conditions, changes in somatic symptoms of anxiety and middle insomnia tended to precede improvements in depressed mood. CONCLUSIONS: Early symptom change may occur outside the core affective domain, underscoring the importance of monitoring symptoms broadly. Symptom-level patterns may reflect patients' stage of recovery and provide clinically relevant information beyond total severity scores. The absence of differences in improvement patterns between IPT and SSRI suggest few indications for treatment selection based on baseline symptom profiles. Future research should replicate and extend these findings to subsequent treatment phases using more frequent assessments and a broader range of interventions.

Humans↗

PubMed2026

EZH1/2 inhibition selectively targets SMARCA4/2 co-deficient lung cancer cells by suppressing stemness and proliferation.

SMARCA4-deficient thoracic malignancies comprise biologically heterogeneous tumors, ranging from conventional non-small cell lung cancer with SMARCA4 alterations to thoracic SMARCA4-deficient undifferentiated tumor (SMARCA4-UT), an aggressive entity frequently associated with concomitant SMARCA2 loss. However, the extent to which SMARCA4-deficient lung cancer cell lines recapitulate SMARCA4-UT-like biology remains incompletely defined. Here, we characterized lung cancer cell lines across distinct SMARCA4 and SMARCA2 states and identified a subgroup with SMARCA4/2 co-deficiency that exhibited reduced expression of epithelial lineage markers and transcriptional similarity to SMARCA4-UT and other SWI/SNF-deficient malignancies. The EZH1/2 inhibitor HM97662 selectively suppressed growth in SMARCA4/2-deficient cells, with limited effects in SMARCA2-proficient cells. EZH1/2 inhibition broadly reduced H3K27me3 and induced derepression of PRC2 targets regardless of drug sensitivity. However, its biological effects were most pronounced in SMARCA4/2-deficient cells, where it promoted apoptosis, reduced stemness marker expression, attenuated the SMARCA4-UT-associated transcriptional signature, and suppressed proliferative and mTORC1-related programs. Chromatin accessibility analysis further revealed cell-line-specific patterns of accessibility loss, with reduced accessibility at stemness-associated transcription factor motif-enriched regions coupled with transcriptional repression of nearby genes in SMARCA4/2-deficient cells. These findings support dual EZH1/2 inhibition as a potential therapeutic vulnerability in SMARCA4/2-deficient, SMARCA4-UT-like lung cancer cells.

Humans↗

PubMed2026

Atomoxetine Versus Placebo for Cognitive Deficits in Stimulant Use Disorder: A Systematic Review.

BACKGROUND: Stimulant use disorder (StUD), particularly involving cocaine and amphetamines, is associated with significant cognitive impairments that impede recovery and increase relapse risk. Atomoxetine, a selective norepinephrine reuptake inhibitor, has been proposed as a potential treatment given its role in enhancing executive function and its established efficacy in attention-deficit/hyperactivity disorder (ADHD). This systematic review aimed to evaluate the efficacy, cognitive, and mood effects of atomoxetine compared with placebo in individuals with StUD. METHODS: A comprehensive literature search of PubMed, Cochrane CENTRAL, and Embase databases was conducted to identify randomized controlled trials (RCTs) evaluating atomoxetine for StUD. Eligible studies compared atomoxetine with placebo and assessed outcomes related to cognition (attention and response inhibition), stimulant use or abstinence, mood symptoms, and safety. Data were extracted and synthesized qualitatively due to methodological heterogeneity across studies. RESULTS: Nine RCTs met the inclusion criteria. Findings on cognitive outcomes were inconsistent: Some studies reported improvements in attentional bias and inhibitory control, while others showed no significant effects. Atomoxetine did not significantly reduce stimulant use, craving, or sustain abstinence compared with placebo. Limited mood-related benefits were observed, particularly among male participants, although results were variable. Across studies, atomoxetine was well tolerated, with most adverse events mild and transient. CONCLUSION: Despite a compelling neurobiological rationale and evidence of modest cognitive and mood benefits, atomoxetine has not demonstrated consistent efficacy as a monotherapy for StUD. Its favorable safety profile may warrant further investigation in carefully defined populations, such as individuals with comorbid ADHD or in combination with behavioral interventions.

Atomoxetine Hydrochloride↗

PubMed2026

Utility of monocyte-derived cells to investigate immune-mediated drug-induced liver injury.

Immune-mediated drug-induced liver injury (DILI) is triggered or exacerbated by the immune system mounting an attack against the drug or its metabolites. The array of in vitro assays for evaluating drug immune liability is limited, highlighting a significant gap in effectively predicting and understanding immune-mediated hepatotoxicity. We aimed to investigate whether monocytes differentiated with the Metaheps (MH) protocol could provide insights into the molecular mechanisms of immune-mediated DILI. MH were generated from monocytes of healthy volunteers (HV) and DILI patients. MH phenotypic characterization was performed by proteomics and qPCR. MH sensitivity to drugs associated with immune-mediated DILI was assessed by lactate dehydrogenase (LDH) assay. Drug-induced LDH release by DILI-derived MH was compared to the upper limit of the 95% CI calculated from HV-derived MH cells treated with the same drug. The 95% CI determined in HV-derived MH was set as the sensitivity threshold for the specific drug. MH cells retain the expression of several immune-related proteins of the parental monocytes and activate a pro-inflammatory response upon exposure to lipopolysaccharide. For all MH (6 out of 6) generated from patients with penicillin-induced DILI, the LDH release upon re-challenge was above the threshold. The sensitivity of MH generated from seven patients with immune checkpoint inhibitor (ICI)-induced hepatotoxicity was ICI-dependent, responding to nivolumab and/or ipilimumab (4 out of 5), but not to pembrolizumab (0 out of 2). Additionally, DILI-derived MH were not sensitive to non-DILI drugs. In conclusion, monocyte-derived cells may serve as an additional tool for drug-specific mechanistic studies of immune-mediated DILI.

Humans↗