Citations

ABSTRACT The enteric nervous system (ENS) is a complex peripheral neural network that coordinates gastrointestinal motility through highly organized synaptic communication. Although tissue-resident muscularis macrophages (MMs) closely associate with enteric neurons, whether they regulate enteric synaptic organization remains unknown. In the central nervous system (CNS), microglia sculpt neural circuits through complement-dependent synaptic remodeling, raising the possibility that analogous neuroimmune mechanisms operate in the gut. Here, we identify a previously unrecognized role for C1qa□ MMs in regulating enteric synaptic homeostasis and gastrointestinal motility. Using macrophage-specific constitutive and inducible C1qa deletion models, single-cell RNA sequencing, enteric synaptosome proteomics, physiology, and advanced imaging, we demonstrate that loss of MMs-derived C1qa increases enteric synaptic density without altering neuronal numbers. C1qa deficiency induced broad transcriptional changes in enteric neurons and macrophages, including altered synapse-associated, lysosomal, and endocytic programs. Proteomic analysis revealed that enteric synapses share a conserved molecular architecture with brain synapses while exhibiting distinct gastrointestinal-specific complement-associated synaptic networks enriched for structural and receptor-localization pathways. Functionally, macrophage-specific C1qa deletion altered excitatory and inhibitory enteric neurotransmission, enhanced cholinergic signaling, reduced nitrergic responses, and accelerated gastrointestinal transit, while smooth muscle responsiveness remained preserved. C1qa□ MMs displayed transcriptional and functional features consistent with a phagocytic synapse-remodeling phenotype, including enrichment of complement, lysosomal, and engulfment pathways. Loss of C1qa impaired macrophage phagocytic activity both in vitro and in vivo and was associated with synapse accumulation and altered macrophage morphology. Importantly, inducible deletion of C1qa in adulthood recapitulated the synaptic and motility phenotypes, demonstrating that C1qa□ MMs continuously regulate enteric synaptic organization beyond development. Together, these findings identify a complement-dependent neuroimmune mechanism that regulates enteric circuit organization and gut motility, establishing MMs as active modulators of adult ENS synaptic homeostasis. Abstract Figure

Neuroplastic changes in phrenic motor neurons that underlie recovery from spinal cord injury may be mediated by perineuronal nets. We show that changes in perineuronal nets around phrenic motor neurons occur within 7 days after cervical spinal cord injury, and that the increase in perineuronal nets around larger phrenic motor neurons was more pronounced. These changes are consistent with substantial reorganization of the neural network onto intact phrenic motor neurons following cervical spinal cord injury.

Background: Overlap between diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS) is associated with significantly higher mortality than either condition alone. While hypertonic (trans locational) hyponatremia is common in hyperglycemic crises, clinically significant hypernatremia in mixed DKA/HHS presents with certain treatment challenges due to rapid osmotic shifts during insulin therapy. Case presentations: A 40-year-old woman with non-significant past medical history presented with vomiting, polyuria, polydipsia, and confusion for two days. Laboratory evaluation revealed serum glucose 1280 mg/dL, arterial pH 7.214, bicarbonate 13.1 mmol/L, anion gap 24, β-hydroxybutyrate 6.0 mmol/L, corrected sodium 152 mmol/L (measured sodium 133 mmol/L), and calculated effective osmolality 337 mOsm/kg. Initial treatment with isotonic saline and intravenous insulin led to improvement in hyperglycemia but worsening corrected hypernatremia to 160 mmol/L after 3 liters of normal saline. Free water deficit was calculated at 6.3 L. Fluid therapy was transitioned to hypotonic solutions with titration to limit sodium correction to ≤10 mmol/L per 24 hours. Sodium levels gradually normalized with resolution of ketoacidosis, and improvement in mental status without significant neurologic complications. Conclusion: In mixed DKA/HHS, early assessment of corrected sodium and effective osmolality is critical. Insulin-mediated intracellular water shifts may unmask or worsen hypernatremia. Prompt reassessment of corrected sodium and individualized fluid management is needed to avoid treatment-related exacerbation of hypertonicity.

Background Acute otitis externa (AOE) is a common condition encountered in primary care. Evidence-based guidelines recommend topical antimicrobial therapy as first-line treatment for uncomplicated disease regardless of diabetes status. However, clinicians may escalate treatment in patients with diabetes because of concern for necrotizing otitis externa (NOE), a rare but potentially life-threatening complication. This study aimed to evaluate whether diabetes status influences systemic antibiotic use in uncomplicated acute otitis externa and to assess factors associated with treatment decisions. Methods A cross-sectional survey was distributed to primary care clinicians participating in a multi-state primary care practice-based research collaborative, comprising physicians, nurse practitioners, and physician associates within the specialties of family medicine, general pediatrics, and general internal medicine. The survey instrument asked clinicians what they would select as first-line treatment for uncomplicated AOE in patients with and without diabetes mellitus (DM). It also assessed factors influencing management decisions as well as confidence in identifying NOE. The primary outcome was whether the clinician reported they would use systemic antibiotics for treatment of AOE, comparing treatment decisions using relative risk (RR) with 95% confidence intervals (CI) for antibiotic exposure given the presence of DM. Results Out of 257 invitations, 58 respondents completed the survey (22.6%). Systemic antibiotics were selected more frequently when DM was present (19.0%) compared with when DM was absent (5.2%), resulting in a significantly increased likelihood of reported systemic antibiotic use (RR = 3.67; 95% CI, 1.08–12.47; p = 0.043). Clinician confidence in identifying NOE varied, with most respondents reporting only slight or moderate confidence. Conclusions Primary care clinicians reported substantially higher use of systemic antibiotics when managing uncomplicated AOE in patients with DM, representing nearly a fourfold increase in antibiotic exposure despite guideline recommendations favoring topical therapy alone. These findings highlight practice variation which may be driven by concern for necrotizing otitis externa, underscoring opportunities to improve antibiotic stewardship and clinician confidence in risk stratification.

ABSTRACT Background While guidelines state that patients with NCCN favorable intermediate risk (FIR) prostate cancer (PCa) may consider active surveillance (AS), there is a relative lack of longer term follow up data informing AS inclusion criteria of patients with Grade Group (GG) 2 prostate cancer in the MRI era. Here we evaluate patient outcomes from a MRI‐screened AS‐eligible cohort of FIR GG2 PCa receiving radical prostatectomy (RP). Methods Patients with prostate MRI, NCCN FIR GG2 PCa (PSA < 10 ng/mL, ≤ cT2a, < 50% core positivity), and no prior treatments who underwent RP from 2015 to 2023 were included from a prospectively maintained prostatectomy registry. Primary outcomes were adverse pathologic features (APF) at RP (GG3‐5, ≥ pT3a, or pN1) and biochemical recurrence (BCR). Logistic regression and Cox regression identified factors associated with APF at RP and time to BCR, respectively. Results Of 522 patients, 110 (21%) had APF at RP and 45 (9%) developed BCR with median follow up 2.4 years (IQR 1.3–2.8). On multivariable logistic regression, % Gleason pattern 4 (%GP4, %GP4 > 25% OR 2.14, 95% CI 1.28–3.58, p = 0.004) was independently associated with APF. On multivariable Cox regression for time to BCR, PSAD (HR 1.06, 95% CI 1.04–1.09, p < 0.001) and positive surgical margins (HR 1.06, 95% CI 1.09–3.78, p = 0.03) were independently associated with BCR. PIRADS, % core positivity, and specimen involvement were associated with neither APF nor BCR. Conclusions % Gleason pattern 4 > 25% and PSAD are the primary factors associated with adverse outcomes and should be considered for patients with FIR GG2 PCa considering active surveillance. PIRADS and measures of biopsy cancer volume were not associated with APF or BCR. These results may inform patient selection for active surveillance among patients with FIR GG2 PCa.

Mechanical ventilation remains a cornerstone of acute respiratory failure management, but ventilator-induced lung injury persists despite lung-protective strategies focused on limiting tidal volume (V T ), plateau pressure, and driving pressure. Mechanical power has emerged as a comprehensive metric that quantifies the total energy delivered to the lungs per unit time by integrating V T , airway pressures, breathing frequency, flow, and PEEP into a single physiologic measure. Observational studies through 2025 show that elevated mechanical power is associated with worse outcomes, including increased mortality, fewer ventilator-free days, and longer ICU stays, with breathing frequency identified as a major contributor even when other settings remain within protective ranges. Although no universal injurious threshold exists because of patient variability, normalization strategies such as indexing mechanical power to predicted body weight or respiratory system compliance have shown promise in improving prognostic value, although consensus on the optimal method is lacking. Currently, mechanical power should be considered a complementary bedside tool that integrates multiple ventilator variables, helps identify key contributors to lung stress and strain, and may support individualized ventilator adjustments to reduce cumulative injury risk as further evidence and technology evolve.

Abstract The lung, one the largest branching organs in our body and vital for survival at first breath, is commonly known as the gas-exchange organ. Recent novel findings on lung sensing cells, molecules, and lung-brain crosstalk in the emerging discipline of interoception have highlighted the consideration of the lung as a sensory organ. Acknowledging the central importance of lung sensing to human health and disease, NHLBI convened a workshop to synthesize the past, current, and future of lung sensing research, with in-person presentations by ∼20 interdisciplinary experts and a large virtual audience. Here, we highlight the key topics discussed and summarize a blueprint for the future in this important field.

Abstract Background Right ventricular (RV) pacing may impair left ventricular function through electromechanical dyssynchrony. Although physiologic pacing is recommended when high ventricular pacing burden is anticipated, many elderly patients with legacy dual-chamber pacemakers may not be good candidates for pacemaker upgrades and undergo programming optimization instead. The acute effects of transitioning from intrinsic left bundle branch block (LBBB) to RV-paced activation remain incompletely understood. Case summary An 85-year-old man with dilated cardiomyopathy, intrinsic LBBB, progressive renal dysfunction, and dual-chamber pacemaker with long programmed atrioventricular delay and &lt;1% RV pacing presented with reduced left ventricular ejection fraction (LVEF) and pedal oedema. Electrocardiogram (ECG) showed left bundle branch block (LBBB) with a QRS width of 166 ms. Baseline echocardiography showed marked AV dyssynchrony with shortened mitral filling time (30% of R–R interval) and impaired global longitudinal strain (GLS −11.0%) and an LVEF of 37% by biplane Simpson’s. Atrioventricular delay (120 ms) optimization induced RV capture and improved filling time (50% of R–R interval), ventricular velocity–time integrals, and interventricular delay. Despite favourable haemodynamic changes, GLS worsened (−8.3% with increased apical rocking, indicating deteriorated myocardial mechanics). Discussion Improved diastolic filling, stroke volume, and interventricular delay during RV pacing may occur at the expense of myocardial efficiency. Strain imaging provided incremental insight beyond conventional Doppler indices and may assist pacing optimization in patients with intrinsic conduction disease.

Abstract Background Geometric uncertainties in high‐dose‐rate brachytherapy, including applicator displacement, catheter deflection, and interstitial needle spread, produce dose deviations that are patient and plan specific. Unlike external beam radiotherapy, where robustness evaluation frameworks are increasingly standardized, high dose rate brachytherapy lacks a normalized aggregate metric for quantifying plan sensitivity to geometric perturbations. Purpose To define a bounded, dimensionless robustness index for per‐fraction evaluation of high dose rate brachytherapy plans that is normalized to clinically meaningful dose‐limit constraints, incorporates dose‐dependent penalty sensitivity, and provides both a full‐scenario severity measure and a dose‐threshold‐filtered variant. Methods Geometric perturbation scenarios (translations, rotations, radial expansion/contraction, catheter deflection, and combined modes) are applied to source dwell positions. For each organ at risk, a convex‐transformed, constraint‐normalized penalty quantifies the fraction of the remaining margin to the dose‐limit constraint consumed per scenario. For target volumes, a prescription‐normalized piecewise penalty captures under‐coverage and excessive dose escalation. The Robustness Index is defined as one minus the mean scenario penalty, yielding a value in [0,1]. Results The framework produces structure‐independent, interpretable indices where a Robustness Index indicates that scenarios consume on average only 10% of the normalized remaining margin to the dose‐limit constraint. A threshold‐filtered variant evaluates robustness among only those scenarios that exceed a clinically specified dose level. Conclusions The proposed robustness index provides a standardized, clinically anchored metric for high dose rate brachytherapy plan evaluation under geometric uncertainty, complementing existing dose volume histogram based reporting with a single interpretable number per structure.