Citations

Background Early-life dysbiosis associated with Cesarean section (C-section) delivery is increasingly recognized as a modifiable risk factor influencing short- and long-term health outcomes. This multidisciplinary expert consensus summarizes the clinical implications of C-section on infant gut microbiota. It proposes evidence-based strategies to mitigate these effects, with a focus on the critical window of the first 1,000 days of life. Methods A multidisciplinary panel of 16 pediatricians, neonatologists, pediatric gastroenterologists, and nutrition experts conducted a targeted narrative review of the literature to inform a structured expert consensus process and participated in an online structured consensus process. Seventeen consensus statements were developed and validated through discussion, expert voting, and commentary, supported by a targeted review of current scientific evidence. Results The expert panel reached consensus on the impact of C-section delivery on early microbiota composition and its clinical relevance, emphasizing that the rising prevalence of C-sections worldwide demands urgent attention. Experts unanimously emphasized the importance of exclusive breastfeeding as the primary strategy to support healthy microbiota development in infants born by cesarean section. When exclusive breastfeeding is not possible, evidence-based nutritional approaches, including selected prebiotics and probiotic strains with documented clinical efficacy, are recognized as promising alternatives for supporting microbial balance. Notably, the panel underscored that not all probiotics are equally effective and recommended shifting toward evidence-based strains shown to help restore gut dysbiosis in this population. Also, experts advocated for continuing microbiota-targeted support throughout the first 1,000 days of life, viewing this developmental window as a critical continuum rather than a limited early-life phase, while acknowledging the need for more long-term data. Additionally, education for healthcare professionals and parents about the long-term implications of C-section delivery was emphasized as a key enabler of the broader adoption of eubiosis-targeted strategies. Conclusions Optimizing microbial colonization in infants born by cesarean section requires a multifaceted approach that prioritizes breastfeeding, supports judicious use of evidence-based nutritional interventions when needed, and emphasizes education and continuity of care across early life. By aligning clinical practice with emerging microbiome science, early-life interventions may reduce dysbiosis-associated risks and improve long-term health outcomes.

As an emerging tire wear-derived environmental contaminant, 6PPD-quinone (6PPDQ) has raised significant concerns regarding its neurotoxic potential, particularly for children exposed to recycled tire crumb rubber in playgrounds. However, the molecular mechanisms by which 6PPDQ influences neurological disorders such as epilepsy remain poorly understood. In this study, we employed an integrative framework combining network toxicology, bulk analysis of human epileptic brain tissues, Mendelian randomization, and molecular dynamics simulations to elucidate these mechanisms. Our findings, validated through CETSA-WB and SPR, identify 6PPDQ as a direct ligand that binds to and stabilizes neuronal TP53. Through a synergistic double-hit mechanism, 6PPDQ directly engages the TP53 pathway while simultaneously triggering microglial interleukin-6 secretion. These converging pathways lead to the suppression of the master antioxidant regulator Nrf2, resulting in glutathione depletion, excessive reactive oxygen species accumulation, and exacerbated neuronal damage under excitotoxic stress. Experimental validation using glutamate-induced HT22 cell models and microglia–neuron crosstalk systems confirmed that targeting the TP53/Nrf2 axis or scavenging ROS significantly attenuates 6PPDQ-induced neurotoxicity. Our findings highlight critical risks to pediatric neurological health posed by tire-derived contaminants and identify the TP53/Nrf2 axis as a promising therapeutic target. Furthermore, this work provides a robust scientific basis for refining risk assessment frameworks and developing regulatory strategies to mitigate environmental exposure to 6PPDQ.

Abstract We are interested in artificial gene regulation by exploiting principles learned from lactose repressor (lacI) control of the Escherichia coli lac operon through the formation of tight DNA loops on the order of 100–200 base pairs. We previously showed that appropriately designed DNA target-programmable Transcription Activator-Like Effector dimer (TALED) proteins can produce DNA-looping-dependent gene repression comparable to lacI. Here, we demonstrate regulation of such switches by the principle of controlled repressor autoinhibition. Thus, TALEDs are inhibited by controlled cyclization, dependent on small molecules. Cyclized TALEDs poorly participate in DNA looping. We fit DNA loop length-dependent data with an established thermodynamic model to quantitate these effects. We further demonstrate the ability of small molecules to induce gene expression using this system in actively growing E. coli cells. The resulting designed systems demonstrate regulated gene expression by DNA looping, emulating the lac system but with entirely different molecular components.

Abstract Background Several bispecific antibodies (BsAbs), including mosunetuzumab, glofitamab, and epcoritamab, are approved for non-Hodgkin lymphoma (NHL). However, real-world patient-centered data evaluating treatment-related time burden and preferences are lacking. Methods We conducted an online survey of 120 patients with relapsed/refractory follicular lymphoma (FL; N = 60) and diffuse large B-cell lymphoma (DLBCL; N = 60) receiving BsAbs. Participants reported all-cause healthcare visits and time spent on cancer-related healthcare resource utilization over the past 30 days, including travel, treatment administration, recovery, and impact on daily activities. Participants also evaluated two hypothetical treatment profiles to assess preference for fixed-duration versus treat-to-progression therapy. Results Participants with FL reported a mean of 2.5 healthcare visits in the past 30 days, with significantly fewer visits for mosunetuzumab versus epcoritamab (1.7 vs 3.3, respectively; P < .01). In DLBCL, the mean was 2.6 visits, with fewer visits for glofitamab versus epcoritamab (2.2 vs 3.0; P =.01). Although epcoritamab visits were shorter in FL, more frequent visits and longer recovery time resulted in significantly lower monthly time burden with mosunetuzumab versus epcoritamab (31.2 vs 61.9 hours; P < .05). Similarly, monthly time burden was also lower with glofitamab than epcoritamab in DLBCL (43.0 vs 87.7 hours; P < .05). Most participants reported little to moderate impact on daily activities. Across treatment groups, ≥92% preferred a hypothetical fixed-duration regimen over a treat-to-progression therapy. Conclusion Our real-world data, including novel aspects of time toxicity, demonstrate clinically meaningful differences in time burden associated with BsAbs and emphasize the importance of incorporating patient convenience and preference into shared decision-making in NHL.

Summary Achalasia is a motility condition defined by failure of relaxation of the lower esophageal sphincter and loss of peristalsis in the distal esophagus. Per-oral endoscopic myotomy (POEM) is a technique to reduce lower esophageal sphincter pressure. We performed a systematic review and meta-analysis to assess the association between POEM and the clinical outcomes. We performed a systematic review and a meta-analysis (CRD420251052240). Literature search was done on PubMed and Embase (up to 8 June 2025). Original studies involving achalasia patients who underwent esophageal POEM with impedance planimetry using 8-cm balloon at 30 or 40 mL filling volumes with 325 catheter only (not the 322-N catheter) were included. The outcomes of interest were the clinical response groups (responders’ Eckardt score [ES] < 3 and non-responders’ ES > 3), reflux esophagitis, cross-sectional area (CSA), distensibility index (DI), and diameter. Nineteen studies with 1215 patients were included. The responders (ES < 3) showed a statistically significantly greater increase in DI due to POEM (post-op minus pre-op) (mean difference [MD] = 1.92 mm2/mmHg [0.32, 3.53], P = 0.02) as well as a higher postoperative DI (MD = 1.87 mm2/mmHg [0.04, 3.70], P = 0.05) (40 mL). Reflux esophagitis group had statistically significantly higher CSA and diameter values (CSA MD = 15.68 mm2 [6.91, 24.24], P = 0.0005) (diameter MD = 0.96 mm [0.58, 1.33], P < 0.00001) but no statistically significant difference for DI as compared to the non-reflux esophagitis group (DI MD = 0.19 mm2/mmHg [−0.51, 0.89], P = 0.59). In achalasia patients undergoing esophageal POEM, a greater interval increase in the DI as well as a higher post-procedural DI absolute value predicts a favorable clinical response. Higher postoperative CSA and diameter were linked to reflux esophagitis.

Abstract Background Acute kidney injury (AKI) frequently causes remote organ injury including hepatic steatosis, yet whether lipid accumulation reflects increased synthesis or impaired clearance has not been resolved. Methods We used a murine ischemia-reperfusion AKI model. Unbiased liver proteomics was performed at 24 hours after reperfusion, and dysregulated pathways were identified by Gene Set Enrichment Analysis. Results were validated by Western blotting, qPCR, and immunohistochemistry. These findings were complemented by retrospective analysis of two ICU databases (MIMIC-IV and eICU-CRD). Results AKI significantly increased serum ALT and AST and induced hepatic lipid accumulation. Proteomic analysis revealed that key lipogenic enzymes (Scd1, Fasn, Acly, Acaca) were uniformly suppressed rather than upregulated. Proteins essential for VLDL assembly (ApoB, MTTP, ApoE) were significantly downregulated. Plasma triglycerides were decreased while liver triglycerides were increased, consistent with impaired hepatic lipid export. As in renal tubular cells, AKI also disrupted ER protein folding homeostasis in the liver, triggering ER stress. This was evidenced by upregulated levels of the ER chaperone GRP78, increased XBP1 splicing indicative of UPR activation, and elevated expression of the ER stress-induced pro-apoptotic transcription factor CHOP, suggesting that prolonged ER stress may also promote hepatocyte cell death. TLR4/MyD88 signaling was activated, yet inflammatory cytokines were paradoxically reduced, accompanied by Kupffer cell depletion (decreased F4/80) and monocyte infiltration (increased CD68). In 6,996 propensity-matched ICU patients (MIMIC-IV), AKI independently increased the risk of clinically significant liver injury 4-fold (adjusted OR = 4.41). Analysis of 22,727 patients across 208 hospitals (eICU-CRD) identified a lipid dissociation pattern: elevated triglycerides alongside decreased total cholesterol, HDL, and LDL, with dose-dependent scaling across KDIGO stages. Conclusions These data support ER stress-mediated impairment of VLDL export as a primary driver of AKI-induced hepatic steatosis. Clinical validation across two independent ICU databases identifies a dual metabolic insult: enhanced peripheral lipid delivery compounds impaired hepatic export, amplifying hepatic lipid retention. ER stress and lipid export machinery represent potential therapeutic targets for AKI-associated liver injury.

Objective(s): To (1) report on the long-term recurrence rate of surgically managed pleomorphic adenoma (PA) and (2) assess long-term surgical outcomes after parotidectomy Methods: Cross-sectional survey of all patients with a pathologic diagnosis of PA who underwent surgical management in a tertiary care center from 01/1997 to 12/2023 and had access to an electronic patient portal. Surveys were delivered via electronic patient portal or phone call with 6 questions to assess recurrence and long-term surgical outcomes. Time to first recurrence and recurrence free survival were analyzed using a Kaplan-Meier curve. Results: Seven hundred-forty-five patients met inclusion criteria and received the survey, with a 56% response rate (n = 420). The clinical median follow-up length was 51 days, which extended to a median length of 6.2 years following the survey. The median change in follow-up length was 5.37 years ( P < .001). The recurrence rate was 1% at 5 years, with a median time to first recurrence of 7.54 years. 13% and 9% of responders reported facial asymmetry and incisional cosmetic concerns, respectively. 33% of patients reported experiencing Frey syndrome, which increased from 5.2% of survey responders with documented Frey syndrome at their original post-operative assessment. Conclusion: Long-term assessment of PA outcomes confirms low recurrence rates, suggesting regular surveillance of recurrence is likely unnecessary. Complaints of Frey syndrome increased in frequency with longer term follow-up, which should be considered during patient counseling. Level of Evidence: 3

IgG4-related disease (IgG4-RD) is a relatively recently described condition whose etiology and pathophysiology remain unclear. Histopathological features include dense lymphoplasmacytic tissue infiltration with numerous IgG4-positive plasma cells, storiform fibrosis, and obliterative phlebitis. Most individuals with IgG4-RD are asymptomatic; however, the disease can affect nearly any organ, leading to a wide range of clinical presentations. The four most common patterns are hepatopancreatobiliary disease, systemic disease, head and neck disease, and retroperitoneal disease. Diagnosis is challenging due to diverse organ involvement and is most often confirmed by biopsy. Elevated serum IgG4 concentration can support the diagnosis, though high IgG4 levels are neither highly sensitive nor specific for IgG4-RD. Immunohistochemical IgG4 staining is crucial, especially in patients without elevated serum IgG4. Differential diagnosis is necessary, as IgG4+ plasma cell infiltration is also seen in inflammatory and malignant conditions. First-line treatment consists of glucocorticoids (prednisone), although favorable outcomes have also been achieved with rituximab. Prognosis varies: the disease may resolve spontaneously or follow a relapsing–remitting course. If left untreated or undertreated, IgG4-RD can cause irreversible organ damage and even death. Finally, correlations have been made between IgG4 and different allergic reactions.