Risk factors and consequences of wound complications following sartorius flap reconstruction.

OBJECTIVE: Groin wound complications are common following vascular surgery and can lead to significant patient morbidity. Sartorius muscle flap coverage may help to prevent vascular graft infection in the setting of wound dehiscence or infection. However, risk factors and consequences of wound complications following sartorius flap reconstruction remain incompletely investigated. METHODS: We retrospectively queried all patients who underwent sartorius flap reconstruction at a tertiary academic medical center. Data collected included patient demographics, medical comorbidities, surgical indication, index vascular procedure, and postoperative outcomes. The primary outcome was wound complication following sartorius flap procedure, which was defined as groin wound infection, dehiscence, or lymphocutaneous fistula. RESULTS: From 2012 to 2022, a total of 113 patients underwent sartorius flap reconstruction. Of these, 66 (58.4%) were performed after the development of a prior groin complication, and 47 (41.6%) were prophylactic. A total of 88 patients (77.9%) had a prosthetic bypass graft adjacent to the flap. Twenty-nine patients (25.7%) suffered a wound complication following sartorius flap reconstruction, including 14 (12.4%) with wound dehiscence, 13 (11.5%) with wound infection, and two (1.8%) with lymphocutaneous fistula. Patients with wound complications had a higher body mass index (28.8 vs 26.4 kg/m2; P =.03) and more frequently active smokers (86.2% vs 66.7%; P = .04). Additionally, patients with wound complications had a higher unplanned 30-day hospital readmission rates (72.4% vs 15.5%; P < .001), reintervention rates (75.9% vs 8.3%; P < .001), and re-do flap reconstruction rates (13.8% vs 2.4%; P = .02). On multivariable analysis, higher body mass index was independently associated with post-flap wound complications (adjusted odds ratio [aOR], 1.01; 95% confidence interval [CI], 1.001-1.03; P = .037). Consequently, wound complications were associated with both surgical reintervention (aOR, 35.4; 95% CI, 9.9-126.3; P < .001) and unplanned hospital readmission (aOR, 17.8; 95% CI, 5.9-54.1; P < .001). CONCLUSIONS: Sartorius flap reconstruction is an effective adjunct in facilitating wound healing of groin wounds. However, wound complications are common following sartorius flap reconstruction and may be associated with reintervention and unplanned hospital readmission. These data support the judicious and thoughtful utilization of sartorius flap procedures among high-risk patients.

Outcomes Following in Situ Reconstruction for Aortic Infection with the Neo-Aortoiliac System and Aortic Homograft.

BACKGROUND: In situ reconstruction is one of the primary surgical options for primary aortic and graft and endograft infections. One institution's outcomes following aortic reconstruction with femoro-popliteal vein (i.e., the neo-aortoiliac system) and cryopreserved aortic allografts are described. METHODS: A retrospective review was performed of any patient who underwent aortic reconstruction with femoropopliteal vein or cryopreserved aortic allograft from 2013-2022 at a single tertiary-care institution. RESULTS: Twenty four patients underwent in situ reconstruction with the neo-aortoiliac system or with cadaveric allograft for primary or secondary aortic infection from 2013-2022. Short-term (30-day) mortality remains low (3/24 or 12.5%) despite the high incidence of major postoperative complications that necessitated reintervention in 11/24 or 45.8% of the cohort, most often for recurrent intracavitary infection. Gram-negative and drug-resistant pathogens were the most commonly implicated organisms in recurrent intra-abdominal infection. Management of early allograft degeneration is also described with extra-anatomic bypass grafting, conduit/graft embolization, which is then followed by allograft explantation and wide surgical debridement. Despite low short-term (30-day) mortality, all-cause 1-year mortality remains elevated at 38.1% (8/21) in those with an adequate follow-up interval. CONCLUSIONS: In situ reconstruction for primary or secondary aortic infections results in excellent short-term patient outcomes but is characterized by a high incidence of reintervention and an elevated all-cause 1-year mortality.

Preoperative Anemia is Associated with Poorer Postoperative Outcomes in Patients Undergoing Infrainguinal Bypass Surgery.

BACKGROUND: Preoperative anemia is an important, modifiable risk factor among surgical patients. However, data are scarce on the impact of preoperative anemia on postoperative outcomes after infrainguinal bypass. METHODS: In this multi-institutional analysis, data were retrospectively collected on all infrainguinal bypass procedures performed between 2010 and 2020. Patients were grouped by preoperative hemoglobin as per the National Cancer Institute anemia scale (mild, 10 g/dL-lower limit of normal; moderate, 8.0-9.9 g/dL; severe, 6.5-7.9 g/dL). Multivariable comparisons were performed using logistic regression analysis. RESULTS: A total of 492 patients underwent bypass for peripheral artery disease over the 10-year study period. Median preoperative hemoglobin was 11.0 g/dL (interquartile range 9.5-12.7) and median follow-up was 1.7 years. Preoperative anemia was prevalent among bypass patients (mild 52.4% [n = 258], moderate 26.4% [n = 130], and severe 5.1% [n = 25]). Women were more likely to have moderate (49.2% [women] vs. 50.8% [men]) or severe anemia (52.0% [women] vs. 48.0% [men]) compared with normal hemoglobin (17.7% [women] vs. 82.3% [men]) (P < 0.001). Patients with preoperative anemia were more likely to present with tissue loss (22.8% [normal] vs. 47.7% [moderate] vs. 52.0% [severe], P = 0.01). Bypass target and conduit types were similar between groups. Anemic patients had longer median hospital length of stay compared with nonanemic patients (4 days [normal] vs. 5 days [mild] vs. 6 days [moderate] vs. 7 days [severe], P < 0.001). Postoperative mortality at 30 days was similar across anemia groups (2.5% [normal] vs. 4.6% [moderate] vs. 8.0% [severe], P = 0.23). On multivariable analysis, however, postoperative mortality was independently associated with severe anemia (odds ratio 7.5 [1.2-48.8], P = 0.04) and male gender (odds ratio 7.5 [1.2-26.4], P = 0.03). CONCLUSIONS: Preoperative anemia is common among patients undergoing infrainguinal bypass surgery and is an independent risk factor for postoperative mortality. Future investigation is needed to determine whether correction of anemia improves postoperative outcomes in these high-risk patients.

Sarcolipin overexpression impairs myogenic differentiation in Duchenne muscular dystrophy.

Reduction in the expression of sarcolipin (SLN), an inhibitor of sarco(endo)plasmic reticulum (SR) Ca2+-ATPase (SERCA), ameliorates severe muscular dystrophy in mice. However, the mechanism by which SLN inhibition improves muscle structure remains unclear. Here, we describe the previously unknown function of SLN in muscle differentiation in Duchenne muscular dystrophy (DMD). Overexpression of SLN in C2C12 resulted in decreased SERCA pump activity, reduced SR Ca2+ load, and increased intracellular Ca2+ (Cai2+) concentration. In addition, SLN overexpression resulted in altered expression of myogenic markers and poor myogenic differentiation. In dystrophin-deficient dog myoblasts and myotubes, SLN expression was significantly high and associated with defective Cai2+ cycling. The dystrophic dog myotubes were less branched and associated with decreased autophagy and increased expression of mitochondrial fusion and fission proteins. Reduction in SLN expression restored these changes and enhanced dystrophic dog myoblast fusion during differentiation. In summary, our data suggest that SLN upregulation is an intrinsic secondary change in dystrophin-deficient myoblasts and could account for the Cai2+ mishandling, which subsequently contributes to poor myogenic differentiation. Accordingly, reducing SLN expression can improve the Cai2+ cycling and differentiation of dystrophic myoblasts. These findings provide cellular-level supports for targeting SLN expression as a therapeutic strategy for DMD.

Financial Toxicity in Crohn's Disease.

BACKGROUND: A patient-reported outcome measure called Comprehensive Score for Financial Toxicity (COST) was previously developed and validated in patients with cancer. GOALS: We sought to assess the financial toxicity associated with Crohn's disease (CD) by administering the COST questionnaire to patients treated at a tertiary care center. STUDY: Forty-eight patients diagnosed with CD completed questionnaires, which included the COST quality of life instrument as well as questions with regard to sociodemographics and clinical characteristics. Analysis of results was performed with Minitab. RESULTS: Forty-eight completed questionnaires were scored. The mean age of the cohort was 37.6±13.4 years and 58% of patients were women. COST scores had a normal distribution (Anderson-Darling, P=0.31). The median COST score was 22, a result associated with mild negative impact on health-related quality of life. Patients' COST score stratum differed based on their education level (P<0.001), employment status (P=0.037), disability status (P=0.016), household income (P=0.004), and housing arrangement (P=0.006). Disease activity in the past 6 months and more frequent feelings of anxiety and depression also correlated with higher COST score. CONCLUSIONS: In this survey study, we found that the majority of our patients with CD experienced at least mild financial distress. Lower income and education level increased disease activity, and the presence of anxiety and depression increased the financial distress experienced by patients. Further research is needed to develop effective interventions to minimize financial toxicity in this patient population.

Ovarian teratoma-associated anti-NMDA receptor encephalitis with severe features.

Anti-N-methyl-D-aspartame receptor (NMDAR) encephalitis is an uncommon clinical entity for the general intensivist or neurologist. Diagnosis can be made by the presence of cerebrospinal fluid IgG antibody against the GluNR1 and GluNR2 subunits of the NMDAR. We present a case of anti-NMDAR encephalitis in a young woman with an ovarian teratoma treated with surgical resection and multiple immunomodulatory therapies.

Partial Inferior Vena Cava Reconstruction with Cryopreserved Aortic Homograft Following Resection for Malignancy.

Malignant invasion of the inferior vena cava (IVC) often necessitates complete tumor thrombectomy and IVC reconstruction. Bovine pericardial xenografts and prosthetic grafts are frequently used for partial or entire IVC reconstruction with adequate subsequent patency and freedom from thrombosis. Cryopreserved aortic homografts represent an alternative conduit for vena cava replacement with resistance to infection in contaminated fields or following extensive retroperitoneal dissection. Specific reports of aortic homograft use for IVC reconstruction are scarce. Described are 2 cases of cryopreserved aortoiliac artery allograft use for long segment cava patch repair while avoiding extensive caval reconstruction, mobilization and the need for renal vein and hepatic vein re-implantation.

Mechanical thrombectomy of inferior vena cava filter-associated caval thrombosis using FlowTriever and ClotTriever systems.

OBJECTIVE: Chronically indwelling inferior vena cava filters (IVCFs) can have multiple adverse sequelae, including IVCF-associated thrombosis. The Inari ClotTriever and FlowTriever mechanical and aspiration thrombectomy systems (Inari Medical) can be used for acute caval thrombosis associated with IVCFs if appropriate proximal IVCF protection is used intraprocedurally. The present study reports a single institution's outcomes after ClotTriever and FlowTriever thrombectomy of acute IVCF-associated iliocaval thrombus. METHODS: A retrospective review was conducted of all patients who underwent ClotTriever or FlowTriever thrombectomy for IVCF-associated caval thrombosis. The patient demographics, clinical characteristics, and postprocedural outcomes of a 15-patient cohort were compiled and described. RESULTS: A total of 15 patients were identified as presenting with acute IVCF-associated caval thrombosis and having undergone intervention with either the ClotTriever or FlowTriever system from 2019 to 2022. Of the 15 patients in the cohort, 3 (20%) had presented with a threatened extremity (phlegmasia cerulea dolens), and 12 had presented with severe, debilitating, but non-limb-threatening, lower extremity edema. The preprocedural clot burden was significant and involved the cava, iliac veins, and femoropopliteal veins in 7 of 15 patients (47%) in the cohort. The procedure was technically successful in 11 patients (73.33%). Resolution of acute symptoms was noted in 100% of the technically successful procedures. The 30-day mortality rate was 13% (2 of 15 patients). One intraprocedural death occurred from pulmonary embolism, and one patient died of malignancy complications. The surviving patients not lost to follow-up experienced stable or improving venous disease, with only one patient presenting with post-phlebitic syndrome. CONCLUSIONS: Mechanical and aspiration thrombectomy of IVCF-associated thrombus with the FlowTriever and ClotTriever systems have good technical success and resulted in significant improvement in acute symptoms with adequate clot clearance. Proximal embolic protection maneuvers for pulmonary embolism prophylaxis and preexisting filter protection are required intraprocedurally.

Successful Treatment of Acute Limb Ischemia Secondary to Iatrogenic Distal Embolization Using Catheter Directed Aspiration Thrombectomy.

Objective: Acute limb ischemia (ALI) due to thromboembolism is a limb- and life-threatening condition regularly encountered by vascular surgeons. Iatrogenic distal embolization is occasionally seen as a complication of various endovascular procedures. We present a series of four patients who developed ALI due to arterial embolization during cardiovascular procedures that were successfully treated via catheter directed aspiration embolectomy. Methods: Retrospective review of demographics, risk factors, and procedural outcomes was completed for 4 patients who presented with ALI due to distal embolization following cardiovascular procedures. All patients were successfully treated with catheter directed aspiration embolectomy using the Penumbra Indigo System (Penumbra Inc., Alameda, California). All patients had high-quality angiography demonstrating successful embolectomy and end-procedure patency. Results: Three patients presented with Rutherford 2A and one with Rutherford 2B ALI secondary to intraoperative distal embolization. Three patients presented with ALI secondary to distal embolization during peripheral vascular interventions, and one following emergent intra-aortic balloon pump (IABP) placement for myocardial infarction. All emboli were located in the infra-inguinal vasculature. Median post-operative ABIs were 0.94 (n = 4). Median length of stay was 2 days. There were no mortalities and no need for adjunctive fasciotomy, amputation, or bypass for limb salvage. All patients improved clinically after intervention, and returned to their reported pre-hospitalization functional status. Conclusion: All procedures achieved technical success with catheter-directed aspiration thrombectomy with or without adjunctive lysis. Catheter-directed aspiration embolectomy with the Penumbra Indigo System for ALI following an iatrogenic embolic event is a safe, less-invasive treatment option. The use of this technology may reduce the need for traditional open thrombectomy or thrombolytic therapy to address ALI.

mTOR hyperactivity mediates lysosomal dysfunction in Gaucher's disease iPSC-neuronal cells.

Bi-allelic GBA1 mutations cause Gaucher's disease (GD), the most common lysosomal storage disorder. Neuronopathic manifestations in GD include neurodegeneration, which can be severe and rapidly progressive. GBA1 mutations are also the most frequent genetic risk factors for Parkinson's disease. Dysfunction of the autophagy-lysosomal pathway represents a key pathogenic event in GBA1-associated neurodegeneration. Using an induced pluripotent stem cell (iPSC) model of GD, we previously demonstrated that lysosomal alterations in GD neurons are linked to dysfunction of the transcription factor EB (TFEB). TFEB controls the coordinated expression of autophagy and lysosomal genes and is negatively regulated by the mammalian target of rapamycin complex 1 (mTORC1). To further investigate the mechanism of autophagy-lysosomal pathway dysfunction in neuronopathic GD, we examined mTORC1 kinase activity in GD iPSC neuronal progenitors and differentiated neurons. We found that mTORC1 is hyperactive in GD cells as evidenced by increased phosphorylation of its downstream protein substrates. We also found that pharmacological inhibition of glucosylceramide synthase enzyme reversed mTORC1 hyperactivation, suggesting that increased mTORC1 activity is mediated by the abnormal accumulation of glycosphingolipids in the mutant cells. Treatment with the mTOR inhibitor Torin1 upregulated lysosomal biogenesis and enhanced autophagic clearance in GD neurons, confirming that lysosomal dysfunction is mediated by mTOR hyperactivation. Further analysis demonstrated that increased TFEB phosphorylation by mTORC1 results in decreased TFEB stability in GD cells. Our study uncovers a new mechanism contributing to autophagy-lysosomal pathway dysfunction in GD, and identifies the mTOR complex as a potential therapeutic target for treatment of GBA1-associated neurodegeneration.

Altered Differentiation Potential of Gaucher's Disease iPSC Neuronal Progenitors due to Wnt/ß-Catenin Downregulation.

Gaucher's disease (GD) is an autosomal recessive disorder caused by mutations in the GBA1 gene, which encodes acid ß-glucocerebrosidase (GCase). Severe GBA1 mutations cause neuropathology that manifests soon after birth, suggesting that GCase deficiency interferes with neuronal development. We found that neuronopathic GD induced pluripotent stem cell (iPSC)-derived neuronal progenitor cells (NPCs) exhibit developmental defects due to downregulation of canonical Wnt/ß-catenin signaling and that GD iPSCs' ability to differentiate to dopaminergic (DA) neurons was strikingly reduced due to early loss of DA progenitors. Incubation of the mutant cells with the Wnt activator CHIR99021 (CHIR) or with recombinant GCase restored Wnt/ß-catenin signaling and rescued DA differentiation. We also found that GD NPCs exhibit lysosomal dysfunction, which may be involved in Wnt downregulation by mutant GCase. We conclude that neuronopathic mutations in GCase lead to neurodevelopmental abnormalities due to a critical requirement of this enzyme for canonical Wnt/ß-catenin signaling at early stages of neurogenesis.

Reducing sarcolipin expression mitigates Duchenne muscular dystrophy and associated cardiomyopathy in mice.

Sarcolipin (SLN) is an inhibitor of the sarco/endoplasmic reticulum (SR) Ca2+ ATPase (SERCA) and is abnormally elevated in the muscle of Duchenne muscular dystrophy (DMD) patients and animal models. Here we show that reducing SLN levels ameliorates dystrophic pathology in the severe dystrophin/utrophin double mutant (mdx:utr -/-) mouse model of DMD. Germline inactivation of one allele of the SLN gene normalizes SLN expression, restores SERCA function, mitigates skeletal muscle and cardiac pathology, improves muscle regeneration, and extends the lifespan. To translate our findings into a therapeutic strategy, we knock down SLN expression in 1-month old mdx:utr -/- mice via adeno-associated virus (AAV) 9-mediated RNA interference. The AAV treatment markedly reduces SLN expression, attenuates muscle pathology and improves diaphragm, skeletal muscle and cardiac function. Taken together, our findings suggest that SLN reduction is a promising therapeutic approach for DMD.

Cardiac specific expression of threonine 5 to alanine mutant sarcolipin results in structural remodeling and diastolic dysfunction.

The functional importance of threonine 5 (T5) in modulating the activity of sarcolipin (SLN), a key regulator of sarco/endoplasmic reticulum (SR) Ca2+ ATPase (SERCA) pump was studied using a transgenic mouse model with cardiac specific expression of threonine 5 to alanine mutant SLN (SLNT5A). In these transgenic mice, the SLNT5A protein replaces the endogenous SLN in atria, while maintaining the total SLN content. The cardiac specific expression of SLNT5A results in severe cardiac structural remodeling accompanied by bi-atrial enlargement. Biochemical analyses reveal a selective downregulation of SR Ca2+ handling proteins and a reduced SR Ca2+ uptake both in atria and in the ventricles. Optical mapping analysis shows slower action potential propagation in the transgenic mice atria. Doppler echocardiography and hemodynamic measurements demonstrate a reduced atrial contractility and an impaired diastolic function. Together, these findings suggest that threonine 5 plays an important role in modulating SLN function in the heart. Furthermore, our studies suggest that alteration in SLN function can cause abnormal Ca2+ handling and subsequent cardiac remodeling and dysfunction.

Altered active zones, vesicle pools, nerve terminal conductivity, and morphology during experimental MuSK myasthenia gravis.

Recent studies demonstrate reduced motor-nerve function during autoimmune muscle-specific tyrosine kinase (MuSK) myasthenia gravis (MG). To further understand the basis of motor-nerve dysfunction during MuSK-MG, we immunized female C57/B6 mice with purified rat MuSK ectodomain. Nerve-muscle preparations were dissected and neuromuscular junctions (NMJs) studied electrophysiologically, morphologically, and biochemically. While all mice produced antibodies to MuSK, only 40% developed respiratory muscle weakness. In vitro study of respiratory nerve-muscle preparations isolated from these affected mice revealed that 78% of NMJs produced endplate currents (EPCs) with significantly reduced quantal content, although potentiation and depression at 50 Hz remained qualitatively normal. EPC and mEPC amplitude variability indicated significantly reduced number of vesicle-release sites (active zones) and reduced probability of vesicle release. The readily releasable vesicle pool size and the frequency of large amplitude mEPCs also declined. The remaining NMJs had intermittent (4%) or complete (18%) failure of neurotransmitter release in response to 50 Hz nerve stimulation, presumably due to blocked action potential entry into the nerve terminal, which may arise from nerve terminal swelling and thinning. Since MuSK-MG-affected muscles do not express the AChR γ subunit, the observed prolongation of EPC decay time was not due to inactivity-induced expression of embryonic acetylcholine receptor, but rather to reduced catalytic activity of acetylcholinesterase. Muscle protein levels of MuSK did not change. These findings provide novel insight into the pathophysiology of autoimmune MuSK-MG.