Citations

Abstract Rationale: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of cancer. They are also associated with life-threatening immune-related adverse events (irAEs), including the rare, poorly understood, and potentially fatal triad of myasthenia gravis, myocarditis, and myositis(triple M syndrome). We aimed to describe the management, intensive care unit (ICU)utilization, and outcomes of patients with irAEs with a specific focus on triple M syndrome. Methods: We conducted a retrospective chart review of patients with irAEs admitted to three quaternary care hospitals between December 2018 and 2023. We aimed to collect data on demographics, cancer type, treatment, ICU resource utilization, and outcomes including mortality. Results: Over this 5-year period, 140 patients were admitted for irAEs. Forty-nine percent were male, median age was 73 (IQR 64-80) years, 7% were of African American or Asian descent, and 32%required ICU admission. Median ICU and hospital length of stay (LOS) were 1.5 (IQR 0.7-2.9)and 7.2 (IQR 4.1-13.4) days, respectively. Among ICU patients, 14/140 (10%) had myositis,22/140 (16%) myocarditis, and 9/140 (6.4%) myasthenia gravis. Triple-M syndrome was diagnosed in 7/140 (5%) patients, including 3 with metastatic melanoma, 2 with genitourinary malignancies, 1 with metastatic lung and 1 with colon cancer. Four had received pembrolizumab and 3 nivolumab. Median ICU and hospital LOS were 3 (IQR 1-6) and 10 (IQR 8-21) days in this group. Three patients required mechanical ventilation, one required tracheostomy, and one required vasopressor support. Triple-M management included corticosteroids, IVIG, pyridostigmine, mycophenolate mofetil, and rituximab. Patients with triple-M syndrome were significantly older than other patients with ICI toxicity (P <0.009) and had higher mortality (57%vs 25%, p = 0.07). Patients discharged from the ICU had a median survival of 67 (IQR 26-201)days. Conclusions: Patients with irAEs frequently require ICU level of support with significant morbidity and mortality, especially with triple M syndrome. Clinicians should always consider the possibility of triple-M syndrome in patients with multiple irAEs as symptoms can be subtle and easily overlooked. Corticosteroids remain the primary treatment of irAEs and can be combined with other immunosuppressive agents such as infliximab, anti-thymocyte globulin, or pyridostigmine. Unfortunately, mortality due to triple-M syndrome remains high underscoring the importance of early recognition and prompt multidisciplinary management of these toxicities.

Abstract Introduction:Hemophagocytic lymphohistiocytosis (HLH) is a severe hyperinflammatory syndrome characterized by excessive immune activation and cytokine release, leading to multi-organ failure and mortality. Despite guideline management to include chemotherapy and transplantation, the characteristics and predictors of critical outcomes in post-transplant-associated hemophagocytic lymphohistiocytosis (PT-HLH) remain poorly understood. Methods:This study is a retrospective cohort analysis of patients admitted to acute care hospitals in the U.S. with HLH between 2016 and 2018. We utilized the National Inpatient Sample, identifying HLH patients using International Classification of Diseases, Tenth Revision-Clinical Modification (ICD-10-CM) codes D76.1, D76.2, and D76.3. Patient demographics, such as age, gender, race, ethnicity, zip code, and insurance status, were obtained from the NIS, while hospital-level characteristics, location and teaching vs. non-teaching status, were considered in the study amongst others. We examined the baseline epidemiology of transplant status, including ICU-related outcomes and resource utilization in patients with and without transplants. Data were analyzed using STATA weighted function, with logistic regression for categorical outcomes. Results:Out of 8,330 adult HLH hospitalizations, 520 (6.2%) were transplant recipients. Among these, 350 (67%) had bone marrow transplants, 90 (17%) had kidney transplants, and 30 (5.8%) had liver transplants. The mean age of HLH patients was 50 ± 19 years; transplant patients were younger (mean age 46 ± 17 years) compared to non-transplant patients (50 ± 18 years), p<0.05. Transplant patients were more likely to be male (72.1% vs. 50.1%, p<0.05), have CMV infection (14.4% vs. 4.1%, p<0.05), be Hispanic (20.8% vs. 14.7%, p<0.05), come from higher median household income areas (38.8% vs. 24.5%, p<0.05), and be treated in teaching hospitals (96.1% vs. 85.8%, p<0.05). Among HLH patients who died in the hospital, 130 (25%) were transplant recipients, compared to 1,180 (15.1%) non-transplant recipients, p<0.05. After adjusting for potential confounders, transplant status was associated with a higher risk of mortality (adjusted odds ratio 1.77, 95% CI 1.11-2.83) and sepsis (adjusted odds ratio o1.78, 95% CI 1.08-2.92). Discussion:In examining a national cohort of PT-HLH cases, our findings review potential risk factors for critical care-related outcomes in post-transplant associated HLH care. PT-HLH patients in our cohort presented with distinct characteristics compared to non-transplant HLH cases. ICU-related outcomes showed statistically significant differences between transplant and non-transplant HLH patients. Specifically, transplant status remained independently associated with a higher risk of mortality and sepsis. Our findings underscore the importance of tailoring treatment plans to each patient's specific risk profile.

Abstract RATIONALE: Critical illness has been shown to disrupt gastrointestinal function, and patients admitted to the intensive care unit (ICU) often experience constipation, aspiration, ileus, and small bowel obstruction. Glucagon-like peptide 1 receptor agonists (GLP-1RA) have become increasingly prevalent in the treatment of type 2 diabetes mellitus and obesity. Pharmacovigilance studies suggest that use of GLP-1RAs may be associated with increased risk of clinically significant gastrointestinal effects. In this study, we assessed whether pre-ICU use of GLP-1RA for either diabetes or obesity was associated with adverse gastrointestinal outcomes. METHODS: This was a retrospective matched cohort study of patients with underlying obesity or diabetes admitted to a Mayo Clinic Medical ICU from 9/1/2018-12/31/2023. Patients who started GLP-1RA within <30 days or stopped them >30 days before admission were excluded. Out of 33,104 eligible patients, we identified 1,549 GLP-1RA exposed patients and matched these to three controls each based on age (±10), sex, body mass index (±5), presence of obesity, diabetes and complications, comorbidities associated with decreased motility, smoking status, alcoholism, abdominal surgeries, Apache score (±20), and Charlson comorbidity index (CCI). Development of gastrointestinal dysfunction (determined by ICD codes) and hospital- and ICU- free days were the outcomes. Conditional logistic regression and mixed linear models were used for the analyses. RESULTS: The final, matched cohort included 6,196 patients. Most patients were male (56.3%), the median age was 66 years (IQR 58-74), 69.9% had a diagnosis of obesity, and 97.5% had a diagnosis of diabetes. Of the patients, 22.9% had a history of abdominal surgery during their lifetime and 30% had surgery within 30 days of admission. When comparing GLP-1RA exposed and non-exposed patients, significant differences were noted in use of motility altering medications (p=0.001, OR 6.75, CI 2.11-21.56), BMI (p<0.001, estimate=0.6, CI 0.47-0.72), and APACHE score (p<0.001, estimate=14.75, CI14.45 – 15.06). Univariable analysis showed that rates of constipation, impaction, and nausea/vomiting were significantly higher among GLP-1RA exposed patients admitted to the ICU, while rates of obstruction were significantly lower (Table 1). After adjusting for APACHE score, only nausea/vomiting remained statistically significant. After controlling for APACHE, GLP-1RA use was associated with an increased number of hospital free days (Table 1). CONCLUSIONS: Our research suggests that in the medical ICU population, GLP-1RA use is unlikely to be associated with adverse GI outcomes. Furthermore, GLP-1RA may be associated with overall hospital length of stay but not ICU length of stay.

Abstract Rationale Hyperchloremia, characterized by elevated chloride levels (>110 mEq/L) in the blood, frequently occurs in critically ill patients following aggressive fluid resuscitation with chloride-rich solutions. It is associated with metabolic acidosis, leading to negative clinical outcomes such as higher morbidity and mortality. However, the impact of hyperchloremia on the duration of mechanical ventilation remains unclear. This study evaluates the correlation between hyperchloremia and the duration of mechanical ventilation in critically ill patients. Methods A retrospective analysis was conducted on intensive care unit patients admitted between 2018 and 2023 who required mechanical ventilation. Patients were categorized into hyperchloremic (serum chloride >110 mEq/L) and non-hyperchloremic groups. The hyperchloremic group was further subdivided into those with metabolic acidosis (pH <7.35) and those without acidosis (pH >7.35). The primary outcome measured was the duration of mechanical ventilation across these groups. Results The study included 7,333 patients, 408 in the hyperchloremic group and 6,926 in the non-hyperchloremic group. Patients with hyperchloremia experienced significantly longer ventilation durations, with an average of 5.9 days compared to 2.6 days in the non-hyperchloremic group (p < 0.01). Among the hyperchloremic subgroups, those with metabolic acidosis had a mean ventilation duration of 4.9 days compared to 6.2 days in those without acidosis (p = 0.7), suggesting no apparent significant influence of acid-base status on ventilation duration. Discussion The study found that hyperchloremia correlates with longer ventilation duration (4.9-6.2 days vs. 2.6 days), independent of pH. While metabolic acidosis might impair respiratory function and increase ventilatory needs, evidence is mixed. Hyperchloremic metabolic acidosis can alter respiratory regulation, causing issues like tachypnea, ventilator dyssynchrony, and the need for sedation, complicating weaning from ventilation. However, hyperchloremia does not always impair respiratory muscle function. The study is limited by its retrospective nature, making causal conclusions difficult. However, the study suggests that better electrolyte management may reduce ventilation duration and improve patient outcomes. Conclusion This study demonstrates a significant association between hyperchloremia and prolonged mechanical ventilation, independent of pH status. The findings suggest that hyperchloremia may either be a marker of severe illness or aggressive resuscitation and directly contribute to prolonged ventilatory support. These findings offer hope for improved patient outcomes, as they suggest that chloride management strategies, including chloride-sparing resuscitation, could potentially reduce mechanical ventilation duration in critically ill patients.

Abstract Introduction: Lactate measurement trends have increased over the last few decades. A study by Chanu et. Al), showed an increase in lactate measurements from 11% (2003) to 48% (2013); associated with an increase in repeating lactate within the first 6 hours (during the “ebb” phase)- (23% to 69%). Despite this, lactate measurement has a low sensitivity (34%) and fails to detect around 35% of severe sepsis cases at onset. This may be explained by clinical reliance on certain prognostic scoring to purse lactate trends. Results: Patients who died had significantly higher measurement frequencies (mean 10.93 ± 12.72) compared to survivors (mean 6.63 ± 11.03). Logistic regression analysis revealed measurement frequency as an independent predictor of mortality (OR = 1.036, 95% CI: 1.031-1.041, p < 0.001), with each additional measurement associated with a 3.6% increase in mortality odds. Age was also significantly associated with mortality (OR = 1.019, 95% CI: 1.015-1.023, p < 0.001), while gender showed no significant effect (OR = 1.065, 95% CI: 0.955-1.187, p = 0.257). Analysis of racial/ethnic disparities revealed significant variations in measurement patterns, though most racial categories showed no independent association with mortality after controlling for other factors. Discussion: Our analysis showed increased testing frequency based on the SOFA score. This may be related to physician's cognitive bias based on the clinical presentation. Increased lactate measurement frequency was associated with increased mortality, which may relate to severity of disease. However it also highlights further investigation to determine if lactate measuring frequency affects outcome. Our analysis also showed age and gender affecting mortality, further pointing towards possible effect of health care inequir=ty and clinical bias

Abstract Rationale: Current guidelines recommend a short course of antibiotic therapy for ventilator-associated pneumonia (VAP) caused by non-fermenting gram-negative bacilli (NF-GNB). However, this approach has been associated with an increased risk of pneumonia recurrence. This meta-analysis aims to address inconsistencies in the literature and evaluate the efficacy of short-course versus long-course antibiotic therapy for VAP, particularly in cases due to NF- GNB. Methods: We systematically searched PubMed, Embase, the Cochrane Library, and ClinicalTrials.gov for randomized controlled trials (RCTs) comparing short versus long courses of antibiotic therapy in patients with VAP. The primary outcomes were the risk of all-cause mortality and pneumonia recurrence. Data were analyzed using RevMan 5.4, with risk ratio (RR) and mean difference (MD) as effect measures. Results: Our pooled analysis included seven RCTs. There was no significant difference in all- cause mortality between short- and long-course antibiotic regimens (RR 1.02; 95% CI: 0.88-1.18; Figure 1). However, a short course of antibiotics increased the incidence ofpneumonia recurrence, particularly in patients with VAP due to NF-GNB (RR 1.64; 95% CI: 1.18-2.29; Figure 1). There were no significant differences between the two regimens regarding the duration of mechanical ventilation (MD 0.01 days; 95% CI: -0.51 to 0.53 days), ICU (MD 0.10 days; 95% CI: -1.00 to 1.20 days) and hospital stay (MD -0.63 days; 95% CI: -3.18 to 1.91 days), or subsequent infection with or acquisition of resistant organisms (RR 0.89; 95% CI: 0.63-1.24). Conclusions: Our meta-analysis suggests that while a short course of antibiotics increases the risk of pneumonia recurrence in NF-GNB VAP, it does not impact mortality compared to a longer course. The clinical significance of the increased recurrence of pneumonia remains uncertain, as it did not result in worse clinical outcomes. A practical approach incorporating validated clinical criteria and biomarker thresholds to guide the duration of antibiotic therapy may be more effective for patients with NF-GNB VAP. Larger RCTs are needed to drawdefinitive conclusions in this population.

Abstract INTRODUCTION Candida auris has emerged as a global pathogenic yeast that disproportionately affects patients in healthcare settings. Infection ranges from localized skin infections to severe bloodstream infections. Multidrug resistance, hardiness on environmental surfaces, and the ability to persist as a colonizer in both sick and healthy patients enables it to spread rapidly in healthcare settings leading to significant morbidity and mortality. Multidrug resistance has led to limited effective therapies and necessitates the need for novel therapeutic options. Here we evaluate the efficacy of ISFP10, an antifungal compound with a novel mechanism of action, against C. auris. ISFP10 inhibits fungal phosphoglucomutase (PGM), an enzyme required for production of substrates for fungal cell wall synthesis (Figure 1). METHODSMIC Testing The compound ISFP10 was submitted to the National Institute of Allergy and Infectious Diseases Therapeutic Development Services for half-maximal and maximal inhibitory concentration (IC50/IC100) testing. C. auris isolates were tested using typical drug-dilution methods. Saccharomyces cerevisiae – C. auris PGM Growth Curve Testing This proof of mechanism assay was instituted to isolate PGM in Saccharomyces for growth curve testing. The Candida auris PGM was cloned into pYES2.1 downstream of an inducible galactose promoter. This plasmid was transformed into S. cerevisiae. C. auris PGM plasmid-containing S. cerevisiae was incubated for 24 hours in 2% glucose minimal media. Using absorbance readings, the inoculum was normalized to 5x105 cells/mL in galactose-containing media. The inoculum was plated onto a 96-well plate in a drug-dilution scheme with ISFP10 at concentrations ranging from 200uM to 6.25uM along with DMSO control wells. Plates were incubated at 30° C for 72 hours in a spectrophotometer with absorbance readings every hour. Growth curves were plotted using GraphPad Prism software. RESULTS The half-maximal inhibitory concentrations (IC50) and maximal inhibitory concentrations (IC100) were consistently low across the three C. auris isolates. The IC50 ranged from 0.5 µg/mL to 1.0 µg/mL, while the IC100 was 1.0 µg/mL for each of the three isolates (Table 1). Growth curves demonstrated concentration-dependent inhibition of C. auris PGM plasmid-containing S. cerevisiae. Figure 2 shows full inhibition of fungal growth at 25µM with dose-dependent delayed growth at lower concentrations. CONCLUSIONS ISFP10 shows promise for inhibiting C. auris PGM in a dose-dependent pattern. It's high in vitro activity and novel mechanism of action necessitates further investigation as a potential therapeutic for C. auris.

Abstract RATIONALE: Community engagement is critical in the conduct of research seeking to address healthcare disparities. Indigenous peoples (American Indians and Alaskan Natives) have the highest prevalence of cigarette smoking and commercial tobacco use among all racial and ethnic groups in the United States. Including Indigenous people as partners in the research process is critical for moving interventions to improve health forward. Engagement in the research process should be considerate of the time, travel, and ease of use for research participants and advisors. Based on feedback from community members, we launched social media pages with deidentified study updates for past participants and any interested community members to receive updates on a prospective mixed methods study designed to inform a pilot smoking cessation intervention. METHODS: Facebook and Instagram were the social media platforms identified for this study. Prior themes identified from the principal investigator's previous work and results of current study informed the development of posts. Institutional Review Board approval was granted for this community engagement method. There were no recruitment activities conducted on these pages, and all information was presented in a deidentified, thematic fashion to protect research participants. There were two social media moderators monitoring interaction with social media pages. An Indigenous artist created accompanying images to enhance engagement with posts. The content covered discussions on smoking cessation identified from the primary study along with profiles highlighting team members and allies. Posts were made at non-fixed, variable intervals from May to September 2024, and were checked bi-weekly to ensure respectful conduct. RESULTS: Between May and September 2024, ten posts were shared, including three highlighting Indigenous team members and allies and seven focused on smoking cessation discussions. Instagram had more engagement when compared to Facebook. Posts that featured Indigenous team members and allies received higher interaction when compared to those on smoking cessation alone, contributing to Instagram's overall success. CONCLUSION: Instagram was the more effective platform demonstrating higher engagement and follower growth when compared to Facebook. Of note, on both platforms, posts that highlighted team members and allies resonated well, and generated the most interaction. This not only emphasizes social media as an effective tool to engage underserved populations in the research process, but also suggests that emphasizing representation and ally-ship among research teams is impactful when engaging Indigenous audiences. This outcome exemplifies the importance of integrating cultural relevance in public health messaging when discussing thoughts and attitudes surrounding smoking cessation.

Abstract Rationale: Effective communication is crucial in healthcare, especially in acute care settings, so that patients/family members can understand treatment options, and share preferences and goals of care. For those with a non-English language preference (NELP), or who have difficulty communicating in English, professional interpreters are recognized as the gold standard in supporting bidirectional communication. However, interpreters are not always readily available for all languages or clinical settings prompting the exploration of other options for translation and interpretation. The recent developments in artificial intelligence (AI), specifically machine translation have enabled more accurate and emotional machine interpretation and translation. Methods: We conducted a systematic review to explore the usability and usefulness of AI-assisted interpretation and translation tools for improving communication between patients and clinicians including verbal and written communication. A comprehensive search of several databases including Ovid MEDLINE(R), Ovid Embase, APA PsycInfo, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews, and Scopus via Elsevier was performed, resulting in 2629 studies. We included studies evaluating tools for direct patient-clinician communication. For verbal communication, we included articles assessing speech interpretation, and for written communication, we focused on discharge instruction translation. Results: A total of 18 studies were included in the final analysis. Among these, 5 assessed the use of speech interpretation and 13 examined text translation of discharge materials. 14 (78%) studies found these novel AI tools beneficial for patient care, whereas 11 (62%) studies highlighted the risks, indicating that these tools can lead to serious mistakes with potential clinical harm. 5 (28%) studies reported participant satisfaction with the use of these tools in their care. Translation and interpretation accuracy varied notably across languages, with lower accuracy scores observed in languages with limited digital resources, such as Haitian Creole and Vietnamese. Conclusion: AI-assisted interpretation and translation in healthcare has several advantages including broader language accessibility than usual resources and potential cost savings for institutions and demonstrates evidence of patient satisfaction. However, these novel tools operate using multiple phases and each stage is prone to errors which may negatively impact patient care and outcomes.. AI-based interpretation and translation show promising potential, however, it is not yet ready for widespread clinical use, so professional language interpreters should be used whenever possible. Future studies should focus on evaluating accuracy as well as how best to integrate these technologies in real-time clinical settings without compromising patient safety and quality of care.

Abstract Introduction Lung involvement is common in ANCA-associated vasculitis (AAV), presenting in various forms: necrotizing granulomatous inflammation, tracheobronchial inflammation, pulmonary capillaritis and diffuse alveolar hemorrhage (DAH), interstitial lung disease (ILD), and asthma.1 Radiologic manifestations are diverse, often complicating diagnosis based on imaging alone. Typical patterns include lung nodules, cavitation, pulmonary hemorrhage, and peripheral consolidation; however, cystic-like lesions are rarely seen.2 We present a case of AAV with bilateral cystic-like lung lesions. Case presentation A 54-year-old male with childhood asthma initially presented to an outside hospital due to progressive exertional dyspnea for 6 years and dysphonia for 1 year. Initial computer tomography (CT) revealed pulmonary cysts (Figure 1), and a CT-guided biopsy of a right upper lobe cystic lesion revealed intra-alveolar hemorrhage, though pathology was non-diagnostic. He received a diagnosis of congenital cystic lung disease and prescribed Trelegy and fluticasone inhalers. He was instructed to take oral prednisone with taper whenever dyspnea recurs for presumed asthma exacerbation. His exertional dyspnea indeed respond to prednisone but not to inhalers, and it would recur a few weeks later, and his dysphonia persisted. He came to our facility for second opinion given being told lung transplantation is the only ultimate treatment in his case. Additional history revealed chronic ear infection, bilateral rupturesd tympanic membrane, chronic rhinosinusitis, and recurrent nasolacrimal duct infection. He had been on oral prednisone for 4 weeks and remained on 10mg daily. Physical exam noted inspiratory wheezing. Further workups were notable for normal eospinophils, normal renal function, positive C-ANCA and PR3, normal pulmonary function test. High-resolution CT deomnstrated numerous areas of parenchymal lucency with circumferential surrounding groundglass opacity (GGO). At this point, the diagnosis of PR3-AAV is made. Patient is subsequently referred to rheumatology for further management. Discussion The diagnosis of AAV relies on clinical, serologic, radiologic, and pathologic data. The atypical presentation may delay diagnosis, especially in cases limited to ear, nose, and throat involvement and the radiological findings are of low specificity.3 While cystic lesions in AAV-related interstitial pneumonia are documented4, this case lacked a defined cyst wall. The central lucency may present partially destroyed lung parenchyma due to GPA-related necrosis (emphysema or pneumatocele) with surrounding areas of blood products deposited from prior peri-lesional hemorrhage. Clinicians should consider a broad differentials when encounter a cystic-like lesion with thorough history-taking being essential.