Citations

Introduction: Cryoablation of intercostal nerves is performed for pain control after minimally invasive repair of pectus excavatum (MIRPE). Cryoablation affects both sensory and motor neurons, resulting in temporary anesthesia to the chest wall and loss of intercostal motor function. The study objective is to determine the effect of cryoablation on incentive spirometry (IS) volumes, as a measure of pulmonary function, after MIRPE. Materials and Methods: A single-institution retrospective review of pediatric patients undergoing MIRPE was performed. All patients received a multimodal regimen (MMR) of analgesics postoperatively. Three groups were compared—cryoablation (CRYO), elastomeric pain pump (EPP), and MMR alone. The primary outcomes were postoperative IS volumes and IS volumes as a ratio of preoperative forced vital capacity (FVC). Secondary outcomes included pain scores, opioid use, length of stay (LOS), and infectious complications. Results: MIRPE was performed in 115 patients: 50 CRYO, 50 EPP, and 15 MMR alone. Groups were similar for demographics and pectus excavatum severity. Postoperative spirometry measurements were similar across groups: IS (CRYO 750 mL [500,961] versus EPP 750 mL [590,1019] versus MMR 696 mL [500,1037], P = .77); IS/FVC (CRYO 0.19 [0.14,0.26] versus EPP 0.20 [0.16,0.26] versus MMR 0.16 [0.15,0.24], P = .69). Although pain scores were also similar across groups, CRYO patients used less opioid ( P < .05) and had shorter LOS ( P < .05). Postoperative pneumonia was rare and similar across groups ( P = 1.00). Conclusion: Intercostal nerve cryoablation during MIRPE does not adversely affect postoperative IS volumes or increase pneumonia rate, despite the temporary loss of motor innervation to intercostal muscles. Cryoablation provides effective pain control with less opioid use.

Abstract Neuromyelitis optica spectrum disorder (NMOSD) is a severe inflammatory autoimmune disease of the central nervous system that is manifested as secondary myelin loss. Oligodendrocyte progenitor cells (OPCs) are the principal source of myelinating oligodendrocytes (OLs) and are abundant in demyelinated regions of NMOSD patients, thus possibly representing a cellular target for pharmacological intervention. To explore the therapeutic compounds that enhance myelination due to endogenous OPCs, we screened the candidate drugs in mouse neural progenitor cell (NPC)‐derived OPCs. We identified drug edaravone, which is approved by the Food and Drug Administration (FDA), as a promoter of OPC differentiation into mature OLs. Edaravone enhanced remyelination in organotypic slice cultures and in mice, even when edaravone was administered following NMO‐IgG‐induced demyelination, and ameliorated motor impairment in a systemic mouse model of NMOSD. The results of mechanistic studies in NMO‐IgG‐treated mice and the biopsy samples of the brain tissues of NMOSD patients indicated that the mTORC1 signaling pathway was significantly inhibited, and edaravone promoted OPC maturation and remyelination by activating mTORC1 signaling. Furthermore, pharmacological activation of mTORC1 signaling significantly enhanced myelin regeneration in NMOSD. Thus, edaravone is a potential therapeutic agent that promotes lesion repair in NMOSD patients by enhancing OPC maturation.

Abstract Cirrhosis is complicated by a high rate of nosocomial infections (NIs), which result in poor outcomes and are challenging to predict using clinical variables alone. Our aim was to determine predictors of NI using admission serum metabolomics and gut microbiota in inpatients with cirrhosis. In this multicenter inpatient cirrhosis study, serum was collected on admission for liquid chromatography–mass spectrometry metabolomics, and a subset provided stool for 16SrRNA analysis. Hospital course, including NI development and death, were analyzed. Metabolomic analysis using analysis of covariance (ANCOVA) (demographics, Model for End‐Stage Liver Disease [MELD] admission score, white blood count [WBC], rifaximin, and infection status adjusted) and random forest analyses for NI development were performed. Additional values of serum metabolites over clinical variables toward NI were evaluated using logistic regression. Stool microbiota and metabolomic correlations were compared in patients with and without NI development. A total of 602 patients (231 infection admissions) were included; 101 (17%) developed NIs, which resulted in worse inpatient outcomes, including intensive care unit transfer, organ failure, and death. A total of 127 patients also gave stool samples, and 20 of these patients developed NIs. The most common NIs were spontaneous bacterial peritonitis followed by urinary tract infection, Clostridioides difficile, and pneumonia. A total of 247 metabolites were significantly altered on ANCOVA. Higher MELD scores (odds ratio, 1.05; p < 0.0001), admission infection (odds ratio, 3.54; p < 0.0001), and admission WBC (odds ratio, 1.05; p = 0.04) predicted NI (area under the curve, 0.74), which increased to 0.77 (p = 0.05) with lower 1‐linolenoyl‐glycerolphosphocholine (GPC) and 1‐stearoyl‐GPC and higher N‐acetyltryptophan and N‐acetyl isoputreanine. Commensal microbiota were lower and pathobionts were higher in those who developed NIs. Microbial–metabolite correlation networks were complex and dense in patients with NIs, especially sub‐networks centered on Ruminococcaceae and Pseudomonadaceae. NIs are common and associated with poor outcomes in cirrhosis. Admission gut microbiota in patients with NIs showed higher pathobionts and lower commensal microbiota. Microbial–metabolomic correlations were more complex, dense, and homogeneous among those who developed NIs, indicating greater linkage strength. Serum metabolites and gut microbiota on admission are associated with NI development in cirrhosis.

Background: Despite efforts to improve access to Medications for Opioid Use Disorder (MOUD), such as buprenorphine, the number of opioid overdoses in the United States continues to rise. In April 2021, the Department of Health and Human Services removed the mandatory training requirement to obtain a buprenorphine waiver; the goal was to encourage more providers to prescribe buprenorphine, thus improving access. Little is known about the attitudes on buprenorphine prescribing after this policy change. Objective: The primary objective was to assess attitudes among primary care providers toward the removal of the buprenorphine waiver training requirement. A secondary objective was to identify other barriers to prescribing buprenorphine. Methods: We conducted a survey between September 15 and October 13, 2021 to assess the overall beliefs on the effectiveness of MOUD and attitudes toward the removal of the waiver training, current knowledge of buprenorphine, current practice styles related to screening for and treating OUD, and attitudes toward prescribing buprenorphine in the future. This survey was sent to 890 Mayo Clinic primary care providers in 5 US states. Results: One hundred twenty-three respondents (13.8%) completed the survey; 35.8% respondents agreed that the removal of the waiver training was a positive step. These respondents expressed a greater familiarity with the different formulations, pharmacology, and titration of buprenorphine. This group was also more likely to prescribe (or continue to prescribe) buprenorphine in the future. Approximately one-third (34.4%) of respondents reported perceived institutional support in prescribing buprenorphine. This group expressed greater confidence in diagnosing OUD, had greater familiarity with the different formulations, pharmacology, and titration of buprenorphine, and was more likely to prescribe (or continue to prescribe) buprenorphine in the future. Respondents who have been in practice for 11 to 20 years since completion of training were most likely to refer all OUD patients to specialists. Conclusions: Results of our survey suggests that simply removing the mandatory waiver training requirement is insufficient in positively changing attitudes toward buprenorphine prescribing. A key barrier is the perceived lack of institutional support. Future studies investigating effective ways to provide such support may help improve providers’ willingness to prescribe buprenorphine.

Objective: Even with our best practices, we are frequently unable to prevent slow and stalled wound healing—particularly in people with impaired circulation and conditions such as diabetes. As a result, greater insight into the nature of wound healing and alternative treatment approaches is needed. An avenue that may be of particular promise is increasing understanding of the role of secretory leukocyte protease inhibitor (SLPI) as there is evidence that it enhances wound healing, its expression increases in response to inflammation and infection, and it exhibits anti-protease, anti-inflammatory, antiviral antibacterial and antifungal activities. Method: The response of SLPI levels to wounding and skin injury was assessed by taking punch skin biopsies from healthy volunteers and assessing the levels of SLPI at the site of injury at the time of wounding (baseline) as well as one, two, three, four, seven, nine and 12 weeks later. Results: A total of 35 volunteers took part in the study. Significant elevations were found: levels of SLPI were greatly increased, 12 times that at baseline, and remained elevated at three weeks despite re-epithelialisation having occurred. Conclusion: These findings not only suggest that levels of SLPI rise rapidly following wounding, but that these elevations are sustained, and continue to increase even when re-epithelialisation has occurred. These results suggest that the role and potential benefits of this protease inhibitor deserve further exploration.

Suicidality is increased in autism spectrum disorder (ASD), yet effective interventions are lacking. Developing biologically based approaches for preventing and treating suicidality in ASD hinges on the identification of biomarkers of suicidal ideation (SI). Here, we assessed magnetic resonance spectroscopy (MRS) markers of glutamatergic neurotransmission in ASD youth and young adults. Twenty-eight ASD participants (16–33 years) underwent 1H-MRS, and metabolites were quantified using LCModel. N-acetylaspartate (NAA), glutamate (Glu), and the NAA/Glu ratio from the left dorsolateral prefrontal cortex were compared between ASD SI+ (n = 13) and ASD SI− (n = 15) participants. We found that ASD SI+ participants had a higher NAA/Glu ratio compared ASD SI- participants. The NAA/Glu ratio also predicted SI and significantly discriminated between ASD SI+/SI− participants. All analyses including NAA and Glu alone were non-significant. Here, we provide preliminary evidence for the importance of NAA/Glu in ASD with SI, with implications for biomarker discovery. Further mechanistic research into risk and interventional approaches to address SI in ASD are needed.

12040 Background: Novel strategies are needed to assess frailty in the context of therapy decisions for older adults with acute myeloid leukemia (AML). Our objectives were to describe pre-treatment DAFI scores for older AML patients treated on clinical trials and explore their relationship with treatment outcomes. Methods: We conducted a exploratory analysis utilizing data from two clinical trials of adults aged ≥60 years with newly diagnosed AML (Alliance/CALGB 11001 [intensive therapy] and Alliance/CALGB 11002 [non-intensive therapy]). We included the subset of patients in each trial enrolled on geriatric assessment companion studies (Alliance/CALGB 361006, 361101). A DAFI score was calculated for each patient using 51 variables including demographic, geriatric assessment, and laboratory data derived from the geriatric assessment. Individuals with ≥90% items were included (consistent with other studies); DAFI scores ranged from 0 to 1 and were evaluated using established categories (0- <.2 [robust]; 0.2-<.35 [pre-frail]; 0.35+ [frail]) and as a continuous score. Associations between DAFI scores and toxicity and overall survival (OS) were evaluated with Fisher’s exact-testing and Kaplan Meier/cox proportional hazards, respectively. Results: The median age was 68 years (range 61, 82) and 72 years (range 61, 92) for those getting intensive (N=31) and less intensive therapy (N= 75), respectively. Individuals in the intensive study had a median pre-treatment DAFI score of 0.15 (range 0.05, 0.31) and were all categorized as robust (75%) or pre-frail (25%). There was no significant difference in median OS (14.6 vs. 14.7 months) or non-hematological grade 3+ adverse events (AEs; 85% vs. 89%) between robust vs. pre-frail individuals in this trial, respectively. However, pre-frail adults experienced a trend towards greater grade 4 non-hematological toxicity than robust individuals (67% vs 26%, p=0.05). In the non-intensive trial, the median DAFI score was 0.24 (range 0.04, 0.48) and most individuals were pre-frail (49.3%) or frail (17.3%). Non-hematologic grade 3+ AEs did not vary by DAFI group, 88% robust, 95% pre-frail, and 77% frail (p=0.15). Median OS was 7.4, 10.8, and 6.3 months for robust, pre-frail, and frail respectively (p=0.17). Adjusting for age, each 0.1 increase in DAFI score was associated with increased mortality hazard (HR 1.8, 95% CI 1.0-3.2). Conclusions: DAFI score calculation provides a potential novel strategy for categorization of frailty in AML. In our assessment, higher DAFI scores were associated with toxicity during intensive induction and mortality in the less intensive setting. This method should be studied in larger samples randomized by treatment intensity. Support: UG1CA189823; Bayer Healthcare/Berlex (CALGB 11001); NCT01253070 (CALGB 11001). Clinical trial information: NCT01253070, NCT01420926.