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Introduction:Laparotomy is the standard treatment for penetrating abdominal trauma; however, the role of laparoscopy is expanding. We report the case of a penetrating jejunal injury in a patient who initially presented with shock but was successfully managed using a laparoscopic-first approach.Case presentation:A 61-year-old male with a history of distal gastrectomy presented with a self-inflicted abdominal stab wound and had ingested antihypertensive drugs and cigarettes. He was initially diagnosed with hemorrhagic shock (systolic blood pressure, 60–70 mmHg), which stabilized after fluid resuscitation. Computed tomography revealed a hemoperitoneum, free air, and omental herniation. A laparoscopic-first approach identified 1200 mL of hemoperitoneum and a full-thickness jejunal perforation. The small bowel was inspected using the “running the bowel” technique, and the perforation was repaired with a two-layer handsewn technique. Therefore, the hybrid laparoscopic/anterior open approach was deemed useful. The patient recovered uneventfully.Discussion:This case suggests that a laparoscopic-first approach can be safely applied to select patients who initially present with transient hemodynamic instability but stabilize after resuscitation. Careful patient selection and systematic exploration are critical to avoid missed injuries. A pragmatic hybrid approach preserves the benefits of minimal invasion.Conclusion:The laparoscopic-first approach is a safe and feasible option for treating small-bowel injuries in selected patients who achieve hemodynamic stability after resuscitation. This strategy facilitates faster recovery and is particularly beneficial in selected patients requiring rapid postoperative recovery, such as those with psychiatric comorbidities.

Background and Objectives: Pulmonary and mediastinal masses are diagnostic challenges for digestive endosonographers, and patients with these conditions are usually managed in thoracic or pulmonology units. EUS with tissue acquisition can result in adequate samples for histological examination and molecular analysis. Its spread among digestive endosonographers is limited; thus, we aimed to investigate the current management practices among the EUS Italian centers for those patients with mediastinal or pulmonary lesions to identify the principal areas of disagreement and help guide future research towards useful standardization. Methods: A 44‑question survey was sent during a temporal trend of 3 months to the endosonographers in Italian centers performing EUS. The survey includes questions with either a single answer choice or with multiple options exploring different aspects of the EUS done for the evaluation of thoracic lesions. The questions were grouped into specific sections: expertise of the center, periprocedural management, procedural aspects, and future perspectives. Results: Thirty-nine centers completed the survey, 27 (69.2%) from the north of Italy. Only 2 centers among the responders did not perform any mediastinal EUS (5.13%). The majority of centers (22, 59.5%) performed between 0 and 30 mediastinal EUS yearly, and only 3 centers did more than 100 mediastinal EUS per year. Responders were mainly gastroenterologists (34, 87.2%) versus surgeons (5, 12.8%). Only 5 centers performed mediastinal EUS in a shared room with bronchoscopy and endobronchial ultrasound (13.5%). The procedure was considered simple for 20 (54.1%) responders, complex for 5 (13.5%), and needed to be performed in a tertiary thoracic center for 12 (32.4%). Franseen and Fork tips were the most used tips (67.6% and 27%, respectively), and the most common needle diameter was 22 gauge (86.5%). Fifteen centers (40.5%) preferred deep sedation with an anesthesiologist without endotracheal intubation. The main growing indications appear to be local EUS-guided treatments (tumors or collections). Conclusions: This is the first survey assessing an evaluation on mediastinal/pulmonary EUS, which is well represented in Italy. Nonetheless, centers largely have low volumes of these procedures. Our results show heterogeneity in the management of patients affected with mediastinal/pulmonary lesions needing tissue acquisition. More studies also involving pulmonologists, thoracic surgeons, and oncologists are needed to increase data and understanding regarding this procedure.

Dear Editor, We read with great interest the study by Zhou et al[1], which demonstrates that isocucurbitacin B targets STAT3 to induce ferroptosis, reprogram mitochondrial metabolism, and enhance anti–PD-1 immunotherapy responses in triple-negative breast cancer using integrated multi-omics and spatial transcriptomic approaches. In the context of growing interest in ferroptosis-based therapeutic strategies and rational immunotherapy combinations to overcome resistance, this work addresses a timely and clinically relevant question. Nevertheless, several mechanistic and translational considerations warrant further clarification to strengthen causal interpretation and support the broader applicability of these findings. This study complies with the TITAN 2025 framework for transparent and ethical reporting of AI-assisted research[2]. While Zhou et al provide strong evidence that isocucurbitacin B binds STAT3 and suppresses its phosphorylation, whether STAT3 represents the dominant and rate-limiting driver of ferroptosis, mitochondrial rewiring, and anti–PD-1 potentiation remains insufficiently resolved. Their discovery pipeline nominates multiple credible signaling nodes beyond STAT3, yet mechanistic follow-through is largely monocentric, leaving open how much of the observed phenotype reflects on-target STAT3 biology versus scaffold-level polypharmacology typical of cucurbitacin-like compounds[3]. This distinction is consequential for translation, as target primacy directly informs exposure–occupancy relationships, biomarker prioritization, resistance liabilities, and rational combination design. Greater causal stringency could be achieved through orthogonal target validation and epistasis, including restoration with SH2-interface variants engineered to abrogate compound engagement, systematic assessment of activity in STAT3-null contexts with matched rescue, and proteome-scale target engagement demonstrating that STAT3 occupancy tracks with ferroptosis induction and immunotherapy sensitization. The multi-modal integration of transcriptomics, metabolomics, proteomics, and spatial profiling represents a major strength, yet it also concentrates inference risks that bear directly on translational credibility. In spatial analyses, region-of-interest ascertainment and treatment of ROIs as independent replicates can conflate within-tumor heterogeneity with between-subject effects, yielding pseudo-precision unless animals or patients are modeled as the true statistical unit with appropriate nesting[4]. This is not a technical footnote, as conclusions regarding reduced exhaustion, altered PD-1 axis activity, and metabolic reprogramming depend on whether significance is preserved after subject-level aggregation and hierarchical testing. Across modalities, pathway concordance may be further amplified by batch structure, analytic flexibility and multiplicity, and multiplicity when enrichment is repeatedly applied to correlated feature sets[5]. Explicit reporting of pre-specified contrasts, batch adjustment, and family-wise error control, together with subject-level orthogonal validation of key spatial signatures, would strengthen confidence that the reported immune and metabolic shifts reflect robust biological effects rather than analysis-dependent signal. The observed potentiation of anti–PD-1 therapy by isocucurbitacin B is translationally appealing, yet the current evidence remains largely correlative and does not define the minimal causal chain required to justify clinical extrapolation. Increased CD8⁺ T-cell infiltration and reduced exhaustion signatures are consistent with immune reinvigoration, but they do not establish whether ferroptosis constitutes the immunologically productive lesion that gates checkpoint sensitivity or whether both are parallel consequences of broader cellular stress and STAT3 pathway modulation[6]. Discriminating these possibilities requires necessity tests at the levels of both mechanism and effector, including CD8 depletion and targeted interruption of ferroptosis to determine whether the combination advantage is abolished[7]. Moreover, synergy claims in syngeneic models are inherently vulnerable to context dependence driven by baseline inflammation, tumor burden kinetics, and microbiota composition, all of which can shift checkpoint responsiveness across facilities. Demonstration of reproducibility in an additional immunocompetent model, together with reporting of key environmental covariates, would strengthen external validity and help define actionable conditions for isocucurbitacin B–based combinations in future trial design[8]. Collectively, clarifying target primacy, strengthening subject-level robustness of multi-modal inference, and establishing mechanism-based necessity for immunotherapy synergy would materially reinforce the translational foundation of this work. Addressing these issues would not only refine biological interpretation, but also inform biomarker development, patient selection, and rational combination strategies for ferroptosis-based immunotherapy. Such rigor is essential to ensure that promising preclinical synergy can be credibly advanced toward clinical testing and policy-relevant therapeutic decision-making.

To the Editor, We read with interest the randomized trial by Zhang et al[1] entitled “Effect of remimazolam on postoperative delirium in elderly patients undergoing major abdominal surgery: a randomized controlled Trial.” The use of blinded assessors with twice-daily validated assessments and reporting of both intention-to-treat (ITT) and per-protocol (PP) analyses are notable strengths. While postoperative delirium (POD) incidence did not differ significantly between groups [PP: 17.1% vs 19.7%; odds ratio (OR) 1.189, 95% confidence interval (CI) 0.688–2.057], and intraoperative hypotension appeared less frequent with remimazolam, we seek clarification on several points to aid interpretation, particularly given the variability of POD incidence across cohorts (10% reported in elective major abdominal surgery)[2]. First, although the trial was designed as a non-inferiority study (margin 5%, one-sided α = 0.025), the results are largely presented in terms of “no significant difference” based on P-values. For non-inferiority trials, interpretation hinges on the prespecified estimand and its CI relative to the margin. We suggest explicitly reporting the between-group risk difference and its 97.5% confidence interval in both ITT and PP populations, and stating clearly whether the upper confidence bound lies within the 5% margin. A simple figure showing the point estimate and confidence interval against the margin would further aid readers. Second, in the ITT population, baseline imbalances were reported for education level and diabetes – both plausibly related to cognitive reserve and POD risk. Although subsequent analyses identified education, American Society of Anesthesiologists (ASA) grade, age, and Mini-Mental State Examination (MMSE) as prognostic factors, it would be helpful to assess whether these imbalances materially affect the treatment estimate. We therefore suggest a covariate-adjusted sensitivity analysis (e.g., regression including education, diabetes, age, ASA grade, and MMSE) and reporting the adjusted effect alongside the primary analysis, particularly given an overall POD incidence of around 20%. This request is supported by cohort evidence linking education and perioperative vulnerability to POD risk[2–4] (college education: adjusted OR 0.35, 95% CI 0.13–0.91; ASA ≥3: OR 2.0, 95% CI 1.0–3.9). Third, the prespecified subgroup finding in patients aged ≥75 years is notable, with a significant interaction term (P for interaction <0.001) suggesting a higher POD risk with remimazolam. To fully appreciate the clinical relevance of this signal, readers would benefit from seeing the absolute POD rates and the corresponding absolute risk difference within this specific subgroup. Furthermore, as subgroup analyses are inherently sensitive to event counts and multiple testing, cautious interpretation is warranted. Age thresholds show strong associations with POD risk in prospective cohorts; for example, age ≥75 years independently increased POD risk (adjusted risk ratio (RR) 2.54, 95% CI 1.11–5.80) in a noncardiac surgery cohort[5]. Clarifying the interaction in this high-risk demographic is crucial for safe clinical application. Fourth, anesthetic depth was guided by bispectral index (BIS) targets (40–60). The manuscript appropriately acknowledges the uncertainty regarding BIS interpretation under remimazolam. If BIS values do not correspond equivalently to hypnotic depth across different agents, maintaining “similar BIS” may not ensure comparable cortical suppression. This has profound implications for both delirium risk assessment and the interpretation of hemodynamic outcomes. Data on total hypnotic drug doses or alternative depth-of-anesthesia metrics, if available, could provide valuable context. If BIS values under remimazolam reflect a different hypnotic state than under propofol, maintaining “similar BIS” might have resulted in disparate actual anesthesia depths, potentially confounding the comparison of delirium risk. Finally, methodologically, the handling of missing data through last observation carried forward (LOCF) and hot-deck imputation in ITT analyses, along with the exclusion of a notable proportion of patients (22/370) from PP analyses due to additional medications, raises questions about the robustness of the findings. The sensitivity of the primary conclusion to these assumptions, as well as the context of real-world co-interventions, would be valuable to discuss. Additionally, while POD assessment through postoperative day 5 captures most early cases, later-onset delirium associated with complications, ICU transfer, or sleep disruption might be missed, particularly with earlier discharge. This represents a recognized limitation in many POD studies. Moreover, hemodynamic “variability” (not merely the presence of hypotension) has been linked to POD in cohort evidence; for instance, mean arterial pressure variability was associated with POD severity (MAP variance OR 1.038 per 10 units, 95% CI 1.013–1.065) in a prospective cohort[6]. This trial offers valuable prospective evidence on the safety profile of remimazolam in elderly surgical populations. Addressing the aforementioned points would not only clarify the interpretation of the current data but also better guide the design of future trials and the optimization of anesthetic strategies for this novel agent in vulnerable geriatric patients. Ethical approval Not applicable. Consent Not applicable.

Study objective: This systematic review and network meta-analysis aimed to compare the effects of coffee consumption and gum chewing on postoperative bowel function recovery in patients undergoing colorectal surgery. Design: Systematic review and network meta-analysis of randomized controlled trials. Patients: Patients undergoing colorectal surgery. Interventions: Coffee consumption and gum chewing for postoperative bowel function recovery. Measurements: The primary outcomes included the time to first defecation and flatus postoperatively. Secondary outcomes comprised the time to first toleration of food, length of hospital stay, time to first feeling of hunger, postoperative opioid analgesic use, incidence of complications, postoperative ileus, anastomotic leakage, nausea, vomiting, and in-hospital mortality. Main results: Twenty-one studies involving 1536 patients were included. Six studies compared coffee consumption to a control group, while 15 studies compared gum chewing to a control group. Compared with control groups, coffee consumption significantly reduced the time to first defecation [mean difference (95% CI): −10.91 (−16.17, −5.65); I 2 = 43%; P &lt; 0.0001] and flatus [mean difference (95% CI): −6.38 (−11.89, −0.87); I 2 = 0%; P = 0.02]. Similarly, gum chewing demonstrated significant reductions in time to first defecation [mean difference (95% CI): −17.83 (−22.60, −13.07); I 2 = 83%; P &lt; 0.00001] and flatus [mean difference (95% CI): −13.71 (−17.88, −9.54); I 2 = 88%; P &lt; 0.00001]. Network meta-analysis revealed a non-significant trend favoring gum chewing over coffee for these outcomes. Notably, gum chewing provided additional clinical benefits including reduced incidence of postoperative ileus and shorter hospitalization. In contrast, coffee showed superior effects in facilitating earlier oral intake and reducing postoperative opioid requirements. Both interventions exhibited comparable safety profiles with no significant differences in complication rates. Conclusions: This study demonstrates that both chewing gum and coffee consumption can promote postoperative bowel function recovery in patients undergoing colorectal surgery, with chewing gum appearing to yield superior outcomes. Both interventions were significantly more effective than standard care in reducing the time to first flatus and first defecation. Trial registration: PROSPERO identifier: CRD420251114493. The protocol can be accessed at PROSPERO.

Backgrounds: Given the distinct pathogenic mechanisms of early-onset Alzheimer’s disease (EOAD) and late-onset Alzheimer’s disease (LOAD), identifying disease-specific therapeutic targets for each subtype is particularly critical. Methods: We performed proteome-wide Mendelian randomization (MR), colocalization analysis, summary-data-based MR, and Heterogeneity in Dependent Instruments (HEIDI) tests to identify the causal roles of candidate proteins in EOAD and LOAD. Further analyses included protein-protein interaction network analysis, GO/KEGG enrichment analyses, and single-cell RNA sequencing annotation. Druggability evaluation of the target proteins, Phenome-wide association study was conducted to systematically evaluate the potential adverse effects associated with druggable proteins. High-throughput molecular docking and molecular dynamics simulations were conducted to target the top therapeutic targets. Results: Genetically predicted levels of three proteins (APOE, NECTIN2, and PVR) were associated with EOAD risk, nine proteins (APOE, NECTIN2, PVR, EPHB4, SEMA3F, RNASET2, BTN1A1, PSAPL1, and GRN) were associated with LOAD risk, three proteins (APOE, NECTIN2, and PVR) were colocalized with EOAD, and six proteins (APOE, NECTIN2, PVR, SEMA3F, BTN1A1, and EPHB4) were colocalized with LOAD. Three of the proteins (APOE, NECTIN2, and PVR) serve as common targets for both EOAD and LOAD. EPHB4 and BTN1A1 were prioritized for LOAD with the most convincing evidence. The small molecule cucurbit[8]uril exhibits excellent binding affinity with both EPHB4 and BTN1A1 target proteins for the treatment of Alzheimer’s disease. Conclusions: This study pinpointed APOE, NECTIN2, and PVR as shared therapeutic targets for EOAD and LOAD, and EPHB4 and BTN1A1 singled out as a priority target for LOAD.

The Society of Teachers of Family Medicine (STFM) and Stanford University’s Healthcare AI Applied Research Team (HEA3RT) have received a 12-month grant from the Commonwealth Fund to strengthen artificial intelligence (AI) readiness in safety net and rural primary care. The project will focus on

Network modeling is considered an effective method for elucidating the complex relationships between emotional states and their symptoms. This study aimed to investigate the dynamic interaction between interoceptive sensibility and self-management behavior over time in patients with stroke, using longitudinal and cross-lagged network analyses. Data were obtained from three follow-up records of 417 patients with stroke at a tertiary hospital in XX City between July 2024 and June 2025. The Self-Management Behavior Scale and the Multidimensional Intrasensory Awareness Assessment Scale were used to evaluate patients' self-management behavior and interoceptive sensibility, respectively. Symptom-level interactions at each time point were analyzed using network analysis, and cross-lagged panel network analysis was used to investigate the temporal dynamics and bidirectional relationship between interoceptive sensibility and self-management behavior. Network analysis revealed that the number of nonzero connections at time points T1, T2, and T3 was 62, 29, and 17, respectively. The core symptom "attention regulation" (IS4) was consistently and significantly stronger than the other symptoms. The key roles were determined using the cross-lagged symptom network analysis. In T1-T2, "trust" (IS8) was the most predictive variable. "Trust" (IS8) and "body listening" (IS7), "social and interpersonal management" (SEM7), and "daily life management" (SEM6) formed a negative feedback loop. In T2-T3, "Trust" (IS8) is the most predictive, positively associated with "worrying" (IS3), "social and interpersonal management" (SEM7), and "noticing" (IS1). It indirectly affects "disease management" (SEM1) via IS3. In T1-T3, "social and interpersonal management" (SEM7) was the most predictive, associated with "diet management" (SEM3), and indirectly affects "self-regulation" (IS6) and "attention regulation" (IS4) via SEM3. This study identified a dynamic bidirectional association between self-management behavior and interoceptive sensibility in patients with stroke, providing an important reference for the development of targeted interventions and public health strategies to improve self-management behavior in patients with stroke.