Citations

Problem definition: Coordinated care network (CCN) is a burgeoning paradigm where patients’ diagnosis and treatment plans are developed based on collaboration between multiple, colocated medical specialties to holistically address patients’ health needs. A primary performance metric for CCNs is how quickly patients can complete their itinerary of appointments at multiple medical services in the network. Rapid completion is critical to care delivery but also presents a major operational challenge. Because information about a patient’s condition and treatment options evolves over the course of the itinerary, care paths are not known a priori. Thus, appointments (except for the first one) cannot be reserved in advance, which may result in significant delays if capacity is not allocated properly. Methodology/results: We study capacity allocation for the patient’s first (root) appointment as the primary operational lever to achieve rapid itinerary completion in CCNs. We develop a novel queueing-based analytical framework to optimize this root appointment allocation, maximizing the proportion of patients completing care by prespecified deadlines. Our framework accounts for the complex interactions among all patients in the network through the blocking process, which contrasts with conventional siloed planning. We provide an exact characterization of the itinerary time and develop a mean-field approximation with convergence guarantees that permits tractable solutions for large-scale network problems. In a simulation case study of Mayo Clinic, our solution improves on-time completion from 60% under the current plan to more than 93%. Managerial implications: We demonstrate that root appointment allocation is a multifaceted problem and that ignoring any of those facets can lead to poor performance. Simultaneously accounting for all of these complexities makes manual template design or traditional optimization methods inadequate, highlighting the significance of our integrated approach. Supplemental Material: The online appendix is available at https://doi.org/10.1287/msom.2022.0649 .

AbstractBackgroundThe clinical relevance of cardiac troponin (cTn) elevation in takotsubo syndrome (TTS) remains uncertain. The present study sought to investigate the role of cardiac troponin (cTn) elevations in mortality prediction of patients with Takotsubo syndrome (TTS).MethodsPatients enrolled in the International Takotsubo (InterTAK) Registry from January 2011 to February 2020 with available data on peak cTn levels were included in the analysis. Peak cTn levels during the index hospitalization were used to define clinically relevant myocardial injury. The threshold at which clinically relevant myocardial injury drives mortality at 1 year was identified using restricted cubic spline analysis.ResultsOut of 2′938 patients, 222 (7.6%) patients died during 1‐year follow‐up. A more than 28.8‐fold increase of cTn above the upper reference limit was identified as threshold for clinically relevant myocardial injury. The presence of clinically relevant myocardial injury was significantly associated with an increased risk of mortality at 5 years (adjusted HR 1.58, 95% CI 1.18–2.12, p =.002). Clinically relevant myocardial injury was related to an increased 5‐year mortality risk in patients with apical TTS (adjusted HR 1.57, 95% CI 1.21–2.03, p =.001), in presence of physical stressors (adjusted HR 1.60, 95% CI 1.22–2.11, p =.001), and in absence of emotional stressors (adjusted HR 1.49, 95% CI, 1.17–1.89, p =.001).ConclusionThis study for the first time determined a troponin threshold for the identification of TTS patients at excess risk of mortality. These findings advance risk stratification in TTS and assist in identifying patients in need for close monitoring and follow‐up.

Malignancy has a crucial impact on long-term survival after liver transplantation. There have been enhanced early detection rates with refined cancer screening and improved prognosis for many cancer diagnoses in the general population with the advent of targeted anticancer therapies. Similar advancements have not occurred in the transplant population over this same timeframe. Individualized strategies to reduce the risk of cancer are needed in this high-risk population. Strict adherence to screening and surveillance specific to the transplant population is required. Lifestyle modifications and medication management (both immunosuppressive and non-immunosuppressive) that may impact cancer risk and outcome are highlighted here. As more effective anticancer therapies evolve, transplant recipients’ access to these agents is paramount to truly impact cancer-related outcomes in this population. With adequate immunosuppression, rejection rates with immunotherapy are lower than previously purported. Prospective studies of immunosuppression modifications needed to minimize rejection and maximize cancer response are ongoing and will reduce the fear from oncology and transplant providers alike, allowing utilization of the most optimal therapy available to the individual. This review aims to assess current data to aid in clinical management and identify the need to facilitate further progress in this field.

Abstract Many patients in the emergency department present with signs and symptoms that arouse concern for sepsis; however, other explanations are also possible. There are currently no rapid tests used in clinical practice that reliably distinguish the presence of a bacterial or viral infection vs. a non-infectious etiology and can predict a patient’s likelihood to decompensate. The diagnostic and prognostic uncertainty in “gray zone” patients complicates the decision to begin therapy as clinicians need to balance the risk of withholding therapy vs. the risk of the therapy itself (e.g., overtreatment with antibiotics and hospitalization, which is costly, potentially harmful, and contributes to antibiotic resistance). The TriVerity™ Test uses isothermal amplification and machine-learning algorithms to quantify and interpret mRNA expression levels to determine both likelihood of bacterial infection, viral infection, or no infection, and whether the patient will likely require one or more critical interventions within 7 days. The three scores each fall into one of five interpretation bands ranging from Very high to Very low. Testing takes approximately 30 minutes using the proprietary Myrna™ Instrument with an operator hands-on-time of under one minute. We enrolled 1,222 patients from 22 emergency departments (ED) to validate the performance of the TriVerity Test. Patients were treated as per local standard of care and were followed for 28 days. Bacterial and viral TriVerity results were validated against clinically adjudicated infection status; the illness severity TriVerity result was validated against the need for at least one critical interventions within 7 days. The bacterial TriVerity result had high AUROC for the diagnosis of bacterial infection (0.83; 80% CI 0.81–0.85) and divided bacterial infection likelihood scores into five interpretation bands with increasing likelihood ratios of infection ranging from Very low (LR- 0.08, 80% CI 0.06–0.11) to Very high (LR + 8.04, 80% CI 5.72–11.78). The AUROC for the bacterial TriVerity result was significantly higher compared to AUROCs for C-reactive protein, procalcitonin or white blood cell count. Similarly, the viral TriVerity score showed high AUROC for the diagnosis of viral infection (0.91; 80% CI 0.90–0.93) and likelihood ratios from Very low (LR- 0.09, 80% CI 0.05–0.14) to Very high (LR + 40.93; 80% CI 29.11–79.23). The TriVerity Illness Severity score showed a high AUROC for the prediction of illness severity (0.77; 80% CI 0.77–0.81) with scores divided into five interpretation bands with increasing likelihood ratios ranging from Very low (LR- 0.22; 80% CI 0.14–0.33) to Very high (LR + 11.33; 80% CI 7.31–17.00). TriVerity illness severity results allowed marked re-classification of the risk for “ICU-level care” as compared to clinical assessment (qSOFA scores) alone. In conclusion, TriVerity provides rapid, highly accurate and actionable results for the diagnosis and prognosis of patients with suspected acute infection and/or sepsis, supporting a major unmet medical need. TriVerity may improve personalized management of patients with suspected acute infections and suspected sepsis for improved overall healthcare outcomes.

Abstract Disclosure: A.L. McKenna: None. Y. Huang: None. L. Yang: None. N. Loo: None. C. Ritchie: None. A. Metcalfe: None. R. Nakhleh: None. M. Krishna: None. S. Thota-Kammili: None. J. Eleazer: None. A.Y. Chang: None. Hepatocellular adenomas (HCA) are uncommon, benign epithelial tumors of the liver. Risk factors include exogenous estrogen or androgen use, and genetic and metabolic syndromes. Management of HCA is delineated by sex assigned at birth; Observation is recommended in an HCA less than 5 cm in an individual assigned female at birth, while resection of an HCA in an individual assigned male at birth is recommended no matter the size due to risk of malignant transformation. What is not known is whether risk is different for individuals with gender incongruence on gender affirming hormone therapy (GAHT). There is limited data on the risk of HCA in this population. One case report of a transgender man who continued GAHT after diagnosis of an HCA though no follow-up information was available. We present follow-up on a transgender man assigned female at birth with multiple hemorrhagic HCA that was re-initiated on GAHT after stabilization of adenomas off GAHT. Unlike prior cases, the molecular profile showed ß-catenin negative, estrogen and androgen receptors positive. This is the first case report to our knowledge reporting detailed follow-up after restarting masculinizing GAHT after diagnosis of HCA. A 24-year-old transgender man presented to the emergency department with right upper quadrant pain. Initial labs were notable for ALT of 239 units per liter (U/L) and AST 165 U/L. Magnetic resonance imaging (MRI) of the abdomen and liver elastogram revealed multiple bilobar hepatic masses, the largest measuring 9.9 cm concerning for hemorrhagic HCA which was subsequently confirmed on liver biopsy. Immunostains were positive for estrogen and androgen receptors. The patient had no history of alcohol or illicit drug use, tattoos, or family history of liver disease. The patient had been treated with 100 mg of intramuscular testosterone cypionate weekly for the past six years for gender incongruence locally. No testosterone concentrations were available from prior to or during acute presentation. Discontinuation of hormone therapy was recommended along with conservative management with frequent MRI. Over the next 19 months, monitoring revealed improvement/resolution of the auto infarcting adenomas with the last MRI noting two stable HCA measuring 2.1 cm and 0.8 cm without new or enlarging liver lesions. Due to gender dysphoria off GAHT, reinitiation of hormone therapy with low dose AndroGel 1.62% topically was prescribed at 18 months after presentation. The patient has been monitored with labs monthly and plans to obtain MRI abdomen every three months. To date, the patient has tolerated reinitiation of therapy. This case demonstrates that patients on masculinizing GAHT who develop HCA can be conservatively managed and monitored based on pathology and that testosterone does not necessarily explain sex differences in the presentation/malignant transformation of HCA cisgender men as opposed to cisgender women. Presentation: 6/3/2024

AbstractPatients in delirium require trustful communication and re‐orientation. We developed a flyer with positive, re‐orientating suggestions for families of delirious patients in intensive care units. Suggestions include creating a safe environment, interpreting unusual behaviours positively and fostering mental resilience. Additionally, families are encouraged to prioritize their own well‐being, recognizing their crucial role in supporting their loved ones. This flyer offers practical strategies across four key areas: ensuring security and orientation, reframing noises and body experiences, managing agitation and reshaping perceptions. By equipping families with knowledge and tools, this resource aims to promote understanding, resilience and strength to humanize delirium care.

Background: Ibrutinib, a potent Bruton’s tyrosine kinase inhibitor with marked efficacy against hematological malignancies, is associated with the heightened risk of atrial fibrillation (AF). Although ibrutinib-induced AF is linked to enhanced oxidative stress, the underlying mechanisms remain unclear. Objective: This research aimed to explore the molecular mechanism and regulatory target in ibrutinib-induced AF. Methods: We performed in vivo electrophysiology studies using ibrutinib-treated mice, and then employed proteomic and single-cell transcriptomic analyses to identify the underlying targets and mechanisms. The effects of A-kinase anchoring protein 1 (AKAP1) depletion on mitochondrial quality surveillance (MQS) were evaluated using both in vivo and ex vivo AKAP1 overexpression models. Results: Atrial AKAP1 expression was significantly reduced in ibrutinib-treated mice, leading to inducible AF, atrial fibrosis, and mitochondrial fragmentation. These pathological changes were effectively mitigated in an overexpression model of ibrutinib-treated mice injected with an adeno-associated virus carrying Akap1. In ibrutinib-treated atrial myocytes, AKAP1 down-regulation promoted dynamin-related protein 1 (DRP1) translocation into mitochondria by facilitating DRP1 dephosphorylation at Ser637, thereby mediating excessive mitochondrial fission. Impaired MQS was also suggested by defective mitochondrial respiration, mitochondrial metabolic reprogramming, and suppressed mitochondrial biogenesis, accompanied by excessive oxidative stress and inflammatory activation. The ibrutinib-mediated MQS disturbance can be markedly improved with the inducible expression of the AKAP1 lentiviral system. Conclusions: Our findings emphasize the key role of AKAP1-mediated MQS disruption in ibrutinib-induced AF, which explains the previously observed reactive oxygen species overproduction. Hence, AKAP1 activation can be employed to prevent and treat ibrutinib-induced AF.

Abstract Background Celiac disease (CeD) is a chronic autoimmune disorder triggered by the ingestion of gluten in persons with the genetic risk factors human leukocyte antigens (HLA)-DQ2 and DQ8. Diagnostic evaluation of patients with suspected CeD often includes serology tests for tissue transglutaminase (tTG) antibodies. While the presence of HLA-DQ2 or DQ8 is required for the initiation and development of CeD, the genetic risk associated with the various alleles is not equivalent. Previous studies in patients with normal total IgA demonstrated the risk gradients of various HLA-DQ2 and DQ8 heterodimers in CeD. However, the impact of both gene variants in IgA deficient patients has not been investigated. In this study, HLA-DQ2 and HLA-DQ8 as risk factors for tTG-IgG positivity in IgA deficient patients were evaluated. Methods Retrospective data was collected from a cohort of individuals (n=3,515) with IgA concentrations below the age-dependent reference interval with suspicion for CeD who were tested for HLA-DQ genotyping and tTG-IgG (reference interval < 6 U/mL) at Mayo Clinic Laboratories. Total IgA was measured using quantitative nephelometry (Siemens BN™ II System); HLA typing was performed using the reverse SSO DNA typing assay (LABType SSO kits). tTG-IgG was determined by enzyme-linked immunosorbent assay (QUANTA Lite R h-tTG, Werfen Diagnostics) on the Dynex Agility System. The prevalence and frequency distribution of HLA-DQ2 and DQ8 haplotypes were determined and the odds ratio (OR) was calculated to evaluate the risk gradient for tTG-IgG positivity based on different HLA-DQ variants. Results Among IgA deficient patients, 58% (n=2,041) expressed HLA-DQ2 or DQ8 haplotypes. Relative to patients without permissive alleles, patients homozygous for HLA-DQ2.5 exhibited a significantly increased risk for tTG-IgG positivity (OR = 10.98, 95% CI: 6.56-18.18, p < 0.001) while those homozygous for HLA-DQ2.2 and DQ8 did not (DQ2.2/DQ2.2_OR = 0.72, 95% CI: 0.04-3.44, p = 0.75; DQ8/DQ8_OR = 0.96, 95% CI: 0.05-4.64, p = 0.97). Patients heterozygous for HLA-DQ2.5 (DQ2.5/x) displayed a lower odds ratio relative to homozygous patients (OR = 3.31, 95% CI: 2.29-4.82, p < 0.001); however, the risk for tTG-IgG positivity increased in the presence of HLA-DQ2.2 (DQ2.5/DQ2.2_OR = 7.59, 95% CI: 4.48-12.65, p < 0.001) or HLA-DQ8 (DQ2.5/DQ8_OR = 6.26, 95% CI: 3.55-10.73, p < 0.001) alleles. Conversely, in the absence of HLA-DQ2.5, HLA-DQ2.2 heterozygotes (DQ2.2/x_OR = 2.80, 95% CI: 1.77-4.39, p < 0.001) and HLA-DQ8 heterozygotes (DQ8/x_OR = 0.99, 95% CI: 0.52-1.77, p = 0.99) displayed lower correlations with tTG-IgG positivity, suggesting a potential risk elevation for tTG-IgG positivity is associated with the combination of DQ2.5 and DQ2.2 or DQ8. Conclusions Our study indicates the risk gradient of HLA-DQ genes in IgA deficient patients. Overall, compared to patients without HLA-DQ2 or DQ8 haplotypes, the homozygous HLA-DQ2.5 genotype had the highest correlation with tTG-IgG positivity, followed by HLA-DQ2.5/DQ2.2 and HLA-DQ2.5/DQ8 heterodimers. The results suggest that HLA-DQ2.2 or HLA-DQ8 alone does not confer risk, but when in the presence of HLA-DQ2.5 these alleles may increase the risk for tTG-IgG positivity. Results from this study shed light on the risk of CeD in patients with IgA deficiency.