Unique model of chronic hypoxia in fetal lambs demonstrates abnormal contrast-enhanced ultrasound brain perfusion.

BACKGROUND: Children with congenital heart disease (CHD) demonstrate long-term neurodevelopmental impairments. We investigated contrast-enhanced ultrasound (CEUS) cerebral perfusion in a fetal animal model exposed to sub-physiologic oxygen at equivalent levels observed in human fetuses with CHD. METHODS: Fifteen fetal lambs [hypoxic animals (n = 9) and normoxic controls (n = 6)] maintained in an extrauterine environment underwent periodic brain CEUS. Perfusion parameters including microvascular flow velocity (MFV), transit time, and microvascular blood flow (MBF) were extrapolated from a standardized plane; regions of interest (ROI) included whole brain, central/thalami, and peripheral parenchymal analyses. Daily echocardiographic parameters and middle cerebral artery (MCA) pulsatility indices (PIs) were obtained. RESULTS: Hypoxic lambs demonstrated decreased MFV, increased transit time, and decreased MBF (p = 0.026, p = 0.016, and p < 0.001, respectively) by whole brain analyses. MFV and transit time were relatively preserved in the central/thalami (p = 0.11, p = 0.08, p = 0.012, respectively) with differences in the peripheral parenchyma (all p < 0.001). In general, cardiac variables did not correlate with cerebral CEUS perfusion parameters. Hypoxic animals demonstrated decreased MCA PI compared to controls (0.65 vs. 0.78, respectively; p = 0.027). CONCLUSION: Aberrations in CEUS perfusion parameters suggest that in environments of prolonged hypoxia, there are regional microvascular differences incompletely characterized by MCA interrogation offering insights into fetal conditions which may contribute to patient outcomes. IMPACT: This work utilizes CEUS to study cerebral microvascular perfusion in a unique fetal animal model subjected to chronic hypoxic conditions equal to fetuses with congenital heart disease. CEUS demonstrates altered parameters with regional differences that are incompletely characterized by MCA Doppler values. These findings show that routine MCA Doppler interrogation may be inadequate in assessing microvascular perfusion differences. To our knowledge, this study is the first to utilize CEUS to assess microvascular perfusion in this model. The results offer insight into underlying conditions and physiological changes which may contribute to known neurodevelopmental impairments in those with congenital heart disease.

Accuracy of Conflicts in Interest in General Surgical Journals.

OBJECTIVE: To evaluate the accuracy of self-reported conflicts of interest (COIs) for articles published in prominent minimally invasive and general surgical journals. BACKGROUND: Accurate reporting of industry relationships and COIs is crucial for unbiased assessment of a particular study. Despite the enactment of COI laws, such as the Physician Payments Sunshine Act in 2010, prior work suggests that 40-70% of self-reported COIs have discrepancies. METHODS: We utilized three public databases -- Open Payments (USA), Disclosure UK, and Disclosure Australia -- to assess the accuracy of COI disclosures among authors of 918 published articles from these respective countries. Seven journals were utilized to review the COIs for authors of manuscripts published in 2022 - JAMA Surgery, Annals of Surgery, British Journal of Surgery (BJS), Journal of American College of Surgeons (JACS), Surgical Endoscopy, Obesity Surgery, and Surgery for Obesity and Related Diseases (SOARD). RESULTS: Among the analyzed 6206 authors, 5675 belonged to countries of interest: USA (4282), UK (718), and Australia (213). Of these, 774 authors (12.5%) self-reported a conflict of interest in their papers. Overall, only 4055 researchers (69.1%) reported COIs accurately. Authors from the US had the lowest accuracy of reporting COI at 69% as opposed to UK (93%) and Australia (96%). Inaccurate COI reporting was most common in corresponding/senior authors (39%) and least common amongst first authors (18%). Most payments in excess of $50,000 made to authors by an industry sponsor were not disclosed appropriately. CONCLUSIONS: Our study shows that inaccuracy of self-reported COIs in general surgery journals remains high at 31%. While our findings should encourage authors to overreport any possible COI, journals should consider verifying the authors' COI to facilitate more accurate reporting.

A second chance for a new heart? The role of metabolic and bariatric surgery in patients with end-stage heart failure.

BACKGROUND: Obesity is an independent risk factor for heart failure (HF). Substantial weight loss has been shown to reverse obesity-related cardiomyopathy. This study aimed to report our institution's experience with laparoscopic sleeve gastrectomy (LSG) in patients with morbid obesity and end-stage HF. METHODS: Between 2018 and 2022, 26 patients with end-stage HF were referred for LSG. Of 26 patients, 16 underwent an operation, and 10 did not. After institutional review board approval, a retrospective electronic medical record review was performed to evaluate (i) age, (ii) preoperative weight, (iii) decrease in body mass index (BMI) score, (iv) whether the patient underwent heart transplantation, and (v) mortality. Data analysis was performed using Stata/SE (version 17.0; StataCorp). The Wilcoxon rank-sum test was used to compare continuous variables between the cohorts, and the Pearson chi-square test was used for binary variables with Bonferroni correction applied. RESULTS: The LSG and non-LSG cohorts had comparable ages (P = .088) and starting BMI score (P = .918), and a proportion of patients had a ventricular assist device (P = .191). Patients who underwent LSG lost significantly more weight than the patients who did not, with an average decrease in BMI score of 8.9 kg/m2 (SD, ±6.13) and 1.1 kg/m2 (SD, ±4.10), respectively (P = .040). Of note, 6 patients (37.5%) who underwent LSG eventually underwent transplantation, compared with 2 patients (20.0%) from the matched cohort (P = .884). Of the 26 patients, there were 6 deaths: 2 (12.5%) in the LSG cohort and 4 (40.0%) in the non-LSG cohort (P = .525). CONCLUSION: LSG may be safe and effective for weight loss in patients with HF. This operation may provide patients affected by obesity with end-stage HF the lifesaving opportunity to achieve transplant candidacy.

Safety and cost of performing laparoscopic sleeve gastrectomy with same day discharge at a large academic hospital.

BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) is the most common surgical treatment for morbid obesity. While certain specialized ambulatory surgery centers offer LSG on an outpatient basis, patients undergoing LSG at most academic centers are admitted to hospital for initial postoperative convalescence and monitoring. Our institution has begun to offer LSG with same-day discharge (SDD) in select patients. We aimed to compare the perioperative outcomes and costs for patients undergoing LSG with inpatient admission versus SDD. METHODS: All patients enrolled in the SDD program from December 2020 through July 2022 were identified from a prospectively maintained database. Patients enrolled in this pathway were analyzed on an intention-to-treat basis even if ultimately admitted postoperatively. Propensity scoring was used to match these patients 1:1 to those with planned inpatient recovery based on age, BMI, and ASA classification. RESULTS: Seventy-five patients were enrolled in the LSG with SDD program during the study period. Among these, 62 patients (82.7%) had successful immediate postoperative discharge. Reasons for cancelation of planned SDD included anxiety (n = 5), pain (n = 3), nausea (n = 2), and one patient each with hypotension, urinary retention, and bleeding. After matching, there were no differences in age, BMI, or ASA classification in a comparison group of patients with planned inpatient recovery. There were no differences in perioperative complications. There were no readmissions or requirements for outpatient intravenous fluids among patients with SDD, compared to n = 3 (4.0%) and n = 2 (2.7%) in the inpatient cohort, respectively. The total perioperative cost for patients undergoing LSG with planned SDD was 6.8% less than those with inpatient recovery. CONCLUSION: With appropriate protocols, LSG with same-day discharge can safely be performed at large academic surgery centers without increased morbidity or need for additional services in the perioperative period. SDD may be associated with decreased costs and allows for more efficient hospital bed allocation.

Circulating T cell specific extracellular vesicle profiles in cardiac allograft acute cellular rejection.

There is a critical need for biomarkers of acute cellular rejection (ACR) in organ transplantation. We hypothesized that ACR leads to changes in donor-reactive T cell small extracellular vesicle (sEV) profiles in transplant recipient circulation that match the kinetics of alloreactive T cell activation. In rodent heart transplantation, circulating T cell sEV quantities (P < .0001) and their protein and mRNA cargoes showed time-specific expression of alloreactive and regulatory markers heralding early ACR in allogeneic transplant recipients but not in syngeneic transplant recipients. Next generation sequencing of their microRNA cargoes identified novel candidate biomarkers of ACR, which were validated by stem loop quantitative reverse transcription polymerase chain reaction (n = 10). Circulating T cell sEVs enriched from allogeneic transplant recipients mediated targeted cytotoxicity of donor cardiomyocytes by apoptosis assay (P < .0001). Translation of the concept and EV methodologies to clinical heart transplantation demonstrated similar upregulation of circulating T cell sEV profiles at time points of grade 2 ACR (n = 3 patients). Furthermore, T cell receptor sequencing of T cell sEV mRNA cargo demonstrated expression of T cell clones with intact complementarity determining region 3 signals. These data support the diagnostic potential of T cell sEVs as noninvasive biomarker of ACR and suggest their potential functional roles.

Adaptation of HLA testing to characterize the cynomolgus macaque MHC polymorphisms and alloantibody signatures.

Nonhuman primates are the closest animal models to humans with respect to genetics and physiology. Consequently, a critical component of immunogenetics research relies on drawing inferences from the cynomolgus macaque to inform human trials. Despite the conserved organization of the Major Histocompatibility Complex (MHC) between cynomolgus macaques and humans, MHC genotyping of cynomolgus macaques is challenging due to high rates of copy number variants, duplications, and rearrangements, particularly at the MHC class I loci. Furthermore, the limited availability of commercial reagents specific to cynomolgus macaques that can be used to characterize anti-MHC class I and class II antibody (Ab) specificities in cynomolgus macaques presents a major bottleneck in translational research. Here we successfully characterized cynomolgus macaque Mafa class I and class II serologic specificities in 86 animals originating from various geographical regions using the complement dependent cytotoxicity (CDC) assay with human HLA class I and class II monoclonal antibody (mAb) typing trays. Further, we successfully induced and characterized anti-Mafa class I and class II alloantibody specificity using HLA single antigen bead assays. We also subsequently tracked the alloAb burden in the animals during treatment with anti-B lymphocyte stimulator (BLyS) treatment. Altogether, these methods can be easily used in translational research to serotype MHC class I and class II specificity in macaques, characterize their alloAb specificity, and evaluate the efficacy of novel therapeutic modalities in depleting circulating alloAbs in these animals.

Open preperitoneal inguinal hernia repair has superior 1-year patient-reported outcomes compared to Shouldice non-mesh repair.

INTRODUCTION: The Shouldice method for inguinal hernia repair remains the gold standard for prosthesis-free repairs. Nonetheless, international guidelines have favored posterior mesh reinforcement as the standard of care for inguinal hernia repair due to lower risk of recurrence and chronic pain, avoidance of general anesthesia, and favorable biomechanical properties. Recent publications have shown the benefits of an open approach to posterior repairs. Herein, we use the Abdominal Core Health Quality Collaborative (ACHQC) registry to compare patient-reported outcomes after a Shouldice no-mesh repair versus open preperitoneal (OPP) mesh repair. METHODS: We performed a propensity score matched analysis to compare patient-reported quality of life (QoL) and peri/postoperative outcomes after a Shouldice repair versus OPP. Data from 2012 to 2022 were obtained from the ACHQC, and 1:1 optimal matching was performed. EuraHS scores were used to estimate QoL, and further analysis on the EuraHS domains of pain, aesthetics, and activity restriction were performed between the two cohorts. RESULTS: Matching resulted in 257 participants in each, Shouldice and OPP cohorts. OPP was associated with a better QoL score compared to Shouldice at 30 days after surgery (Median (IQR) 7.75 (2.0-17.0) vs 13.0 (4.0-26.1); OR 0.559 [0.37, 0.84]; p = 0.003). This difference persisted at 6 months and 1 year postoperatively (OR 0.447 [0.26, 0.75] and 0.492 [0.26, 0.93], respectively). We did not observe any significant differences in hernia recurrence risk at 1-year, or rates of 30-day SSOs/SSIs, postoperative bleeding, peripheral nerve injury, DVTs, or UTIs. CONCLUSION: Our data suggest that OPP is associated with significantly better patient-reported QoL, in the first month after surgery and up to 1 year postoperatively, especially with respect to lesser pain, when compared to the Shouldice repair. In specialized inguinal hernia practices, open posterior mesh repairs may lead to better outcomes than non-mesh repairs. We encourage more training in both repairs to facilitate larger prospective studies and evaluation of the generalizability of these results to all surgeons performing IHR.

Immunotherapy targeting B cells and long-lived plasma cells effectively eliminates pre-existing donor-specific allo-antibodies.

Pre-existing anti-human leukocyte antigen (HLA) allo-antibodies constitute a major barrier to transplantation. Current desensitization approaches fail due to ineffective depletion of allo-specific memory B cells (Bmems) and long-lived plasma cells (LLPCs). We evaluate the efficacy of chimeric antigen receptor (CAR) T cells targeting CD19 and B cell maturation antigen (BCMA) to eliminate allo-antibodies in a skin pre-sensitized murine model of islet allo-transplantation. We find that treatment of allo-sensitized hosts with CAR T cells targeting Bmems and LLPCs eliminates donor-specific allo-antibodies (DSAs) and mitigates hyperacute rejection of subsequent islet allografts. We then assess the clinical efficacy of the CAR T therapy for desensitization in patients with multiple myeloma (MM) with pre-existing HLA allo-antibodies who were treated with the combination of CART-BCMA and CART-19 (ClinicalTrials.gov: NCT03549442) and observe clinically meaningful allo-antibody reduction. These findings provide logical rationale for clinical evaluation of CAR T-based immunotherapy in highly sensitized candidates to promote successful transplantation.

Personalized Scrub Caps for Identification of Surgical Trainees.

This survey study investigates whether personalized scrub caps for surgical trainees can help decrease role and name misidentification, microaggressions, and miscommunication-related delays in patient care.

Reusable scrub caps are cost-effective and help reduce the climate footprint of surgery.

BACKGROUND: As the US healthcare sector contributes to 5-10% of national CO2 emissions, with a substantial contribution from surgical services, a collective effort is important to minimize the climate footprint of surgery. Solid plastic waste generated from single-use items in operating rooms is a major contributor to greenhouse gas emissions. To address this problem, we implemented a pilot study to replace single-use scrub caps with reusable caps. METHODS: Ninety-two surgical trainees at the Massachusetts General Hospital, Boston, were provided reusable personalized scrub caps. Over 6 months, their use of the reusable cap was compared with corresponding use of disposable single-use caps. We then used the cost of raw materials, fabric and cap manufacturing, transportation, and end-of-life/waste treatment to perform an economic and environmental burden analysis. RESULTS: After 6 months of reusable scrub cap use, 33 participants (51.6%) reported that due to their use of a reusable scrub cap, their utilization of disposable bouffant or caps had decreased by 76-100%. This was associated with a significant reduction in the use of single-use caps after adjusting for surgical case volume. The carbon footprint of single-use scrub caps was significantly higher than reusable caps during the study period. Reusable scrub cap usage also strongly correlated with substantial reductions in energy consumption and freshwater toxicity. CONCLUSIONS: Reusable personalized cloth scrub caps are cost-effective and can help reduce surgery's carbon footprint by reducing waste generated from disposable scrub cap use. More programs should consider replacing single-use polypropylene caps with reusable scrub caps for their operating room staff.

Primary Tissue Repair for Inguinal Hernias: The Shouldice Repair Technique and Patient Selection.

It is estimated that approximately one in four men and one in 20 women will develop an inguinal hernia over the course of their lifetime. A non-mesh inguinal hernia repair via the Shouldice technique is a unique approach that necessitates dissection of the entire groin region as well as careful assessment for any secondary hernias. Subsequently, a pure tissue laminated closure allows the repair to be performed without tension. Herein, the authors describe a brief overview of inguinal hernias and discuss the relevant patient evaluation, operative steps of the Shouldice procedure, and postoperative considerations.

Impact of Portable Normothermic Machine Perfusion for Liver Transplantation From Adult Deceased Donors.

OBJECTIVE: To assess how liver allografts preserved using portable normothermic machine perfusion (NMP) compare against those that underwent ischemic cold storage (ICS) in the setting of donation after brain death (DBD) and donation after circulatory death (DCD) liver transplantation (LT). BACKGROUND: Compared with conventional ICS, NMP may offer more homeostatic preservation, permit physiological assessment of organ function, and provide opportunities for graft improvement/modification. We report a single-center US experience of liver NMP. METHODS: A single-center, retrospective analysis of collected data on 541 adult whole LTs from 469 DBD donors [NMP (n = 58) vs ICS (n = 411)] and 72 DCD donors [NMP (n = 52) vs ICS (n = 20)] between January 2016 and December 2022. RESULTS: In DBD LT, male sex [odds ratio (95% CI): 1.83 (1.08-3.09)] and >10% macrosteatosis of the donor liver [1.85 (1.10-3.10)] were statistically significant independent risk factors of early allograft dysfunction (EAD). Donor age >40 years and cold ischemia time >7 hours were independent risk factors of reperfusion syndrome (RPS). One-year, 3-year, and 5-year incidences of ischemic cholangiopathy (IC) did not differ significantly in DBD cases between the NMP and ICS cohorts. In DCD LT, NMP was an independent protective factor against EAD [0.11 (0.03-0.46)] and RPS [0.04 (0.01-0.25)]. The incidence of IC in the DCD cases at 1-year and 3-year time points was significantly lower in the NMP cohort (1.9% compared with 20% in the ICS group). CONCLUSIONS: Compared with conventional ICS, NMP can significantly reduce the incidence of EAD, RPS, and IC after DCD LT.

Improved patient-reported outcomes after open preperitoneal inguinal hernia repair compared to anterior Lichtenstein repair: 10-year ACHQC analysis.

INTRODUCTION: The Lichtenstein repair has been synonymous with "open" inguinal hernia repair (IHR) for 40 years. However, international guidelines have suggested that posterior mesh placement results in advantageous biomechanics and reduced risk of nerve-related chronic pain. Additionally, the use of local anesthetics has been shown to reduce postoperative pain and complication risks. An open transrectus preperitoneal/open preperitoneal (TREPP/OPP) repair combines posterior mesh placement with the use of local anesthetic and as such could be the ideal repair for primary inguinal hernia. Using the Abdominal Core Health Quality Collaborative (ACHQC) registry, we compared open anterior mesh with open posterior mesh repairs. METHODS: We performed a propensity score matched analysis of patients undergoing open IHR between 2012 and 2022 in the ACHQC. After 1:1 optimal matching, both the TREPP/OPP and Lichtenstein cohorts were balanced with 451 participants in each group. Outcomes included patient-reported quality of life (QoL), hernia recurrence, and postoperative opioid use. RESULTS: Improvement was seen after TREPP/OPP in EuraHS QoL score at 30 days (OR 0.558 [0.408, 0.761]; p = 0.001), and the difference persisted at 1 year (OR 0.588 [0.346, 0.994]; p = 0.047). Patient-reported opioid use at 30-day follow-up was significantly lower in the TREPP/OPP cohort (OR 0.31 [0.20, 0.48]; p < 0.001). 30-day frequency of surgical-site occurrences was significantly higher in the Lichtenstein repair cohort (OR 0.22 [0.06-0.61]; p = 0.007). There were no statistically significant differences in hernia recurrence risk at 1 year, or rates of postoperative bleeding, peripheral nerve injury, DVTs, or UTIs. CONCLUSION: Our analysis demonstrates a benefit of posterior mesh placement (TREPP/OPP) over anterior mesh placement (Lichtenstein) in open inguinal hernia repair in patient-reported QoL and reduced opioid use.

Contrast-enhanced subharmonic aided pressure estimation for assessment of intracranial pressure in vivo.

BACKGROUND: Intracranial pressure (ICP) monitoring in children currently requires invasive techniques. Subharmonic aided pressure estimation (SHAPE) uses contrast-enhanced ultrasound (CEUS) to measure intravascular and interstitial pressure, but utility in ICP measurements has yet to be explored. OBJECTIVE: The objective of this study was to investigate SHAPE as a novel tool for noninvasive ICP measurements in fetal lambs. MATERIALS AND METHODS: Eighteen fetal lambs at 107-139 days gestational age (term = 145 days) underwent subdural ICP catheter placement. The brain was imaged in the coronal plane in CEUS mode optimized for SHAPE, while infusing an US contrast agent into the fetal circulation. After SHAPE calibration, saline was infused via the subdural catheter to increase ICP. Five-second SHAPE cine clips were obtained at various ICPs. Subharmonic intensity values of the whole brain and thalami were correlated with ICP values using mixed effects linear regression analyses and the strength of the relationship was evaluated by Spearman's rank-order correlation. RESULTS: Forty-nine experiments produced 723 datapoints, including SHAPE intensity values and mean ICP measurements. There was a statistically significant inverse relationship between SHAPE intensity values and ICP measurements in the whole brain and thalami (median rho value - 0.58 and - 0.56, respectively). CONCLUSION: SHAPE intensity values of the brain demonstrate an inverse and statistically significant correlation with in vivo ICP measurements in an animal model.

Modulation of the gut microbiota engages antigen cross-presentation to enhance antitumor effects of CAR T cell immunotherapy.

Several studies have shown the influence of commensal microbes on T cell function, specifically in the setting of checkpoint immunotherapy for cancer. In this study, we investigated how vancomycin-induced gut microbiota dysbiosis affects chimeric antigen receptor (CAR) T immunotherapy using multiple preclinical models as well as clinical correlates. In two murine tumor models, hematopoietic CD19+-A20 lymphoma and CD19+-B16 melanoma, mice receiving vancomycin in combination with CD19-directed CAR T cell (CART-19) therapy displayed increased tumor control and tumor-associated antigens (TAAs) cross-presentation compared with CART-19 alone. Fecal microbiota transplant from human healthy donors to pre-conditioned mice recapitulated the results obtained in naive gut microbiota mice. Last, B cell acute lymphoblastic leukemia patients treated with CART-19 and exposed to oral vancomycin showed higher CART-19 peak expansion compared with unexposed patients. These results substantiate the role of the gut microbiota on CAR T cell therapy and suggest that modulation of the gut microbiota using vancomycin may improve outcomes after CAR T cell therapy across tumor types.

A 3D atlas of functional human brain energetic connectome based on neuropil distribution.

The human brain is energetically expensive, yet the key factors governing its heterogeneous energy distributions across cortical regions to support its diversity of functions remain unexplored. Here, we built up a 3D digital cortical energy atlas based on the energetic costs of all neuropil activities into a high-resolution stereological map of the human cortex with cellular and synaptic densities derived, respectively, from ex vivo histological staining and in vivo PET imaging. The atlas was validated with PET-measured glucose oxidation at the voxel level. A 3D cortical activity map was calculated to predict the heterogeneous activity rates across all cortical regions, which revealed that resting brain is indeed active with heterogeneous neuronal activity rates averaging around 1.2 Hz, comprising around 70% of the glucose oxidation of the cortex. Additionally, synaptic density dominates spatial patterns of energetics, suggesting that the cortical energetics rely heavily on the distribution of synaptic connections. Recent evidence from functional imaging studies suggests that some cortical areas act as hubs (i.e., interconnecting distinct and functionally active regions). An inverse allometric relationship was observed between hub metabolic rates versus hub volumes. Hubs with smaller volumes have higher synapse density, metabolic rate, and activity rates compared to nonhubs. The open-source BrainEnergyAtlas provides a granular framework for exploring revealing design principles in energy-constrained human cortical circuits across multiple spatial scales.

Systematic single-cell pathway analysis to characterize early T cell activation.

Pathway analysis is a key analytical stage in the interpretation of omics data, providing a powerful method for detecting alterations in cellular processes. We recently developed a sensitive and distribution-free statistical framework for multisample distribution testing, which we implement here in the open-source R package single-cell pathway analysis (SCPA). We demonstrate the effectiveness of SCPA over commonly used methods, generate a scRNA-seq T cell dataset, and characterize pathway activity over early cellular activation. This reveals regulatory pathways in T cells, including an intrinsic type I interferon system regulating T cell survival and a reliance on arachidonic acid metabolism throughout T cell activation. A systems-level characterization of pathway activity in T cells across multiple tissues also identifies alpha-defensin expression as a hallmark of bone-marrow-derived T cells. Overall, this work provides a widely applicable tool for single-cell pathway analysis and highlights regulatory mechanisms of T cells.