Anesthesiology - Papers

In this multicenter, double-blind randomized clinical trial of 784 adults undergoing elective cardiac surgery, four perioperative doses of dapagliflozin reduced postoperative AKI from 52% to 28% compared with placebo (relative risk 0.54, 95% CI 0.45-0.65; P<.001). Follow-up testing was completed in 99% of participants, and atrial fibrillation and reoperation rates were similar between groups.

This study demonstrates that cold exposure increases platelet production through adipose thermogenesis and circulating free fatty acids. The mechanistic pathway involves fatty-acid β-oxidation, acetyl-CoA, p300/SIRT1-dependent regulation of C/EBPα, and downstream GATA-1/NF-E2 activation in megakaryocytes. Genetic or pharmacological interruption of this pathway reduced deep venous thrombosis and retinal vein occlusion in mice, while human observations showed increased platelet counts during cold exposure and cold seasons.

Latent class analysis identified hyperinflammatory and hypoinflammatory phenotypes among 548 critically ill patients with pulmonary sepsis; the hyperinflammatory phenotype was associated with greater lung injury and mortality. A pneumococcal pneumonia mouse model reproduced divergent inflammatory trajectories despite uniform pathogen exposure, and dexamethasone or IL-6 receptor blockade benefited only the more inflamed phenotype. This provides a clinically anchored framework for phenotype-targeted therapy in severe pneumonia.

This mechanistic study identifies EGFR as a neutrophil-intrinsic driver of NETosis in sepsis via an EGFR–MAPK14–CEBPβ–PGLYRP1–TREM1 axis. Neutrophil-specific EGFR deletion improves survival and reduces cytokine storm and NETs; rescue with recombinant PGLYRP1 confirms pathway centrality.

Using the MIA model and human samples, the authors show that B cell–derived IgM autoantibodies drive nociceptive sensitization in osteoarthritic joints, with complement C5a upregulation. Passive transfer of IgM from MIA mice or OA patients induced sensitization, and intra-articular C5aR blockade reduced it.

This translational study identifies early lipid peroxidation as a therapeutic target in human liver transplants and demonstrates that ferroptosis inhibition (FXT-001) preserves graft viability in porcine liver/lung perfusion and split ex vivo perfusion of declined human lungs. Next-generation inhibitors (FXT-002/003) showed improved pharmacokinetics and safety profiles, supporting ferroptosis blockade as a strategy against ischemia-reperfusion injury.

In a double-blind crossover phase 1 study in 13 healthy men under remifentanil-induced respiratory depression, danavorexton (orexin-2 agonist) significantly increased minute ventilation, tidal volume, and respiratory rate, and reduced sedation without altering pain tolerance. Effects persisted beyond infusion with only mild adverse events (one transient insomnia).

Using fMRI across humans and three non-human species, the authors demonstrate that reduced integrated information under anesthesia is a convergent phenomenon linked to regional PVALB/Pvalb gene expression gradients. Brain dynamics become harder to control during disintegration, and thalamic deep brain stimulation reverses both the loss of integration and controllability in macaques.

In a 26-week, single-centre, double-blind RCT (n=108), once-weekly semaglutide 2.4 mg significantly reduced heavy drinking days versus placebo (estimated treatment difference −13.7 percentage points; 95% CI −22.0 to −5.4; p=0.0015). Benefits extended to multiple secondary alcohol-related and somatic outcomes, with mostly mild-to-moderate transient gastrointestinal adverse events occurring more often with semaglutide.

In a double-blind randomized trial of 38 older adults undergoing joint replacement, perioperative infusions of a young donor plasma protein fraction significantly modulated proteomic and single-cell immune signaling responses to surgical trauma. Key inflammatory pathways (JAK-STAT, NF-κB, MAPK) were attenuated with corresponding cellular signaling changes, providing first-in-human proof of anti-inflammatory immunomodulation by young plasma components.

Using rocuronium-conjugates and single-cell antibody sequencing, the authors identified oligoclonal, high-affinity anti-rocuronium antibodies that, when expressed as human IgE, activated human mast cells/basophils and caused severe anaphylaxis in FcεRI-humanized mice. Cocrystal structures mapped distinct epitopes involving the ammonium group, establishing mechanistic foundations and the first murine model of NMBA anaphylaxis.

Across multiple cohorts, a three-biomarker tool (procalcitonin, soluble TREM-1, IL-6) accurately quantified immune dysregulation in CAP/sepsis and was independently associated with mortality and secondary infection risk. Post-hoc reanalysis of a hydrocortisone RCT (CAPE COD) suggested survival benefit only in patients with severe dysregulation by this model, supporting biomarker-guided immunomodulation.

In 984 obese adults undergoing sedated gastrointestinal endoscopy, HFNC oxygenation reduced hypoxia from 21.2% to 2.0% and eliminated severe hypoxia, without increasing adverse events. Subclinical respiratory depression also declined markedly with HFNC.

This cryo-EM study resolves THIK1 in a closed state, identifies a central pore gate formed by TM4 tyrosines, and maps a volatile anesthetic binding site required for inhibition. Multimodal validation links structural gating to anesthetic action on microglial K2P channels.

In a multicenter RCT of 418 adults undergoing GI endoscopy, an RL-based automated system for ciprofol delivery achieved non-inferior hypoxemia rates to clinician-managed anesthesia and significantly shortened induction time without increasing drug use or recovery time. More intraoperative movement occurred under the automated system, consistent with lighter anesthetic depth.

Using cryo-EM structures of human TRPM3, the authors identified a compact binding pocket that enabled virtual screening and lead optimization to a picomolar antagonist with favorable drug-like properties. The compound produced strong, dose-dependent analgesia in rodent neuropathic and migraine pain models, validating TRPM3 as a non-opioid analgesic target.

In IIH patients, dural venous sinus stenoses correlated with altered perivenous fluid patterns and brain edema. In mice, jugular vein ligation induced transient intracerebral hypertension, edema, and impaired clearance, worsened by meningeal lymphatic vessel (MLV) depletion; only MLV-intact animals restored clearance. These data implicate venous flow–MLV coupling as a controller of intracerebral pressure and brain clearance.

In high-risk major surgical patients identified by clinical factors and urinary tubular stress biomarkers, a KDIGO-aligned preventive bundle reduced moderate-to-severe AKI within 72 hours (14.4% vs 22.3%; OR 0.57; NNT ≈12) without increasing adverse events. The pragmatic strategy focused on hemodynamic optimization, nephrotoxin avoidance, and glycemic control.

In a multicenter phase 3 RCT (n=820), a full-spectrum cannabis extract (VER-01) produced a statistically significant, modest reduction in chronic low back pain versus placebo over 12 weeks and improved neuropathic pain symptoms in a predefined subgroup. Adverse events were more frequent but mainly mild-to-moderate, and no dependence or withdrawal was observed.

Using Patch-seq and cross-species transcriptomics, the authors identify OSMR and SST as molecular markers of human mechano-insensitive C-fiber nociceptors and demonstrate selective modulation by oncostatin M in human volunteers. This defines a long-sought human targetable nociceptor subtype and provides translational evidence for neuromodulatory strategies in neuropathic pain.

In mouse models of neuropathic pain, dynamic microvascular movements within injured dorsal root ganglia trigger episodic spontaneous pain via Piezo2 mechanotransduction in sensory neurons. Angiogenesis amplifies this phenomenon, and anti-VEGF therapy or targeting Piezo2 suppresses spontaneous pain and clustered neuronal firing.

This study demonstrates that nociceptive thresholds oscillate across the day in a mouse neuropathic pain model and identifies a rhythmic circuit from the hypothalamic suprachiasmatic nucleus (SCN) to descending analgesia that drives this pattern. Elevated daytime VIP neuron activity in SCN is implicated, linking the central circadian clock to pain modulation.

Protectin DX provided superior and resolution-promoting analgesia in a fracture-induced postoperative pain model, dependent on GPR37. It enhanced macrophage efferocytosis via calcium signaling and rapidly dampened nociceptor activity, outperforming PD1/DHA, steroids, and meloxicam and shortening pain duration.

Using clinical data and mechanistic mouse experiments, the authors show that bortezomib-associated neuropathic pain manifests earlier in females via ICAM-1–driven perivascular monocyte/macrophage accumulation in the spinal cord and CCL1-mediated neuronal activation. This sex-specific pathway provides actionable targets for prevention or early intervention in female patients.