Clinical Outcome Variables Research Articles

Arthroscopic Superior Capsular Reconstruction with Acellular Human Dermal Allograft for Irreparable Rotator Cuff Tears: Outcomes, Complications, and Reoperations at 2-Year Minimum Follow-up

BackgroundManagement of posterosuperior irreparable rotator cuff tears (IRCTs) remains challenging without clear consensus amongst shoulder surgeons. Arthroscopic superior capsular reconstruction (SCR) with dermal allograft has been proposed as a promising treatment option. However, current investigations are limited to short term studies and recent data has suggested variable clinical outcomes. Therefore, the purpose of this investigation was to report intermediate-term clinical outcomes in patients who underwent arthroscopic SCR with a dermal allograft for IRCTs. MethodsOver a four-year period (2016 to 2020), all patients who underwent an arthroscopic dermal allograft SCR with a minimum two-year follow-up period were identified. SCR with dermal allograft was performed for patients with an IRCT utilizing a 3mm acellular dermal allograft. Collected clinical outcomes included range of motion (ROM), strength, Numeric Rating Scale (NRS) for pain, American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form (ASES) score, Single Assessment Numeric Evaluation (SANE) score, complications, and reoperations. ResultsThe final cohort included 41 dermal allograft SCR performed in 40 patients (one bilateral) with a majority male cohort (n = 29; 72%), a mean age of 67 ± 7 years, BMI of 28.4 ± 5.0, and follow-up of 5.3 ± 1.4 years. Clinically, there was a significant improvement in pre- and post-operative NRS pain scores from 5.0 to 1.8 (P < .001), but no differences in pre- and post-operative forward flexion (P = .268), abduction (P = .822), external rotation (P = .323), or internal rotation (P = .995). The final post-operative ASES and SANE scores were 66 ± 28 and 59 ± 30, respectively. There were 8 (19.5%) complications, which consisted primarily of symptomatic graft failure in 6 (14.6%) shoulders and progression of rotator cuff arthropathy in 2 (4.9%) shoulders. Reoperations occurred in 6 (14.3%) shoulders: 4 (9.8%) were conversion to rTSA and 2 (4.9%) were arthroscopic revision dermal allograft SCR with partial repair and reattachment of the torn graft. ConclusionAt a cohort mean of five years after arthroscopic superior capsular reconstruction with dermal allograft for irreparable rotator cuff tears, patients experienced sustained pain relief but no significant improvement in shoulder function. Additionally, 20% sustained a postoperative complication with a 14% reoperation rate. These findings should be considered when counseling patients about the challenges of managing IRCTs and the possible outcomes of utilizing dermal allograft SCR as a surgical modality.

Bone-marrow-based augmentation in rotator cuff repair—from microfracture to bone marrow aspirate concentrate

AbstractRotator cuff tears are a major cause of shoulder dysfunction, and relatively high rates of rotator cuff re-tear persist despite surgical advancements, particularly in patients with poor biological healing potential. Bone-marrow-based augmentation techniques, specifically bone marrow stimulation (BMS) and bone marrow aspirate concentrate (BMAC), have been introduced to enhance the biological environment at the repair site, potentially improving outcomes. Bone marrow stimulation, commonly achieved through microfracture, stimulates the release of growth factors and mesenchymal stem cells (MSCs) from the bone marrow to promote tendon-to-bone integration. Although simple and cost-effective, clinical results for BMS augmentation in rotator cuff repair (RCR) are mixed, with most recent meta-analyses not demonstrating a clinically significant superiority over conventional RCR. Augmentation with BMAC offers a more sophisticated approach, concentrating MSCs and anti-inflammatory cytokines to directly enhance the healing process. Preclinical studies have shown promising results with BMAC augmentation, demonstrating improved tendon integrity and biomechanical strength. The existing clinical studies suggest BMAC may reduce re-tear rates and enhance tendon healing, although outcomes are not yet universally optimal. The current evidence highlights the potential of these techniques, particularly as a potential treatment option in biologically challenging cases. However, the variability in clinical outcomes underscores the need for further research to refine these methods and establish their role in routine clinical practice.

Impact of knee geometry on joint contact mechanics after meniscectomy.

Finite element modeling has served as a cornerstone in understanding knee joint mechanics post-meniscectomy, yet the influence of varying knee geometries remains unknown. The present study aimed to fill that gap by employing statistical shape modeling to generate knee models from MRI data of 31 human knees, capturing the population's knee size and shape variations. Finite element simulations were conducted to replicate intact, partial, and total medial meniscectomy conditions during standing. The results revealed a substantial shift in load distribution from the medial to lateral compartment following medial meniscectomy with its magnitude depending on knee geometry. Cartilages experienced variable degrees of pressure changes at different sites, which could also be different for fluid and contact pressures. While changes in joint size led to somewhat predictable alterations in contact pressure, variations in joint shape resulted in unexpected changes in contact and fluid pressures, emphasizing the need for computational simulations. The average knee geometry exhibited the lowest contact and fluid pressures under the given loading and boundary conditions, in contrast to knees with shapes deviating from the average. This study highlights the significance of individual knee shape in the biomechanical outcome of meniscectomy, potentially explaining the variability in clinical outcomes observed post-surgery.

Abstract A027: Acceleration of drug metabolism mediated by CYP3A4 enzyme activation provides a bona fide environmental resistance mechanism to targeted therapies

Abstract Background: Targeted therapies against oncogenic signaling addictions, including one resulting from EML4-ALK fusions, can induce strong and durable clinical responses. However, these therapies are not curative in advanced cancers, as a subset of tumor cells avoid elimination, and these persisting populations evolve resistance that drives tumor relapse. Using a drug screen, we found that the evolving ALK inhibitor (ALKi) persisters display exquisite sensitivity to the histone demethylase inhibitor, JIB04 in vitro. Paradoxically, validation studies in mice revealed that instead of enhancing tumor sensitivity, JIB04 desensitizes tumors to ALKi, alectinib and lorlatinib, suggesting that it activates an unknown environmental modifier. While JIB04 is not used in the clinics, we reasoned that deciphering the underlying mechanism could uncover environment-mediated resistance to ALKi that might be triggered by clinically relevant factors. Results: We found that the resistance-promoting effect of JIB04 in mice is mediated by reducing systemic ALKi concentrations. This reduction is attributable to accelerated pharmacokinetics, due to the hyperactivation of the P450 family member, CYP3A4. Higher CYP3A4 activity leads to faster drug clearance and reduced drug exposure to tumors. Importantly, JIB04 triggers a similar resistance to other clinically relevant CYP3A4 substrates, the frontline EGFR inhibitor, osimertinib and the recently introduced KRASG12C inhibitor, sotorasib. Finally, the resistance- promoting effects of JIB04 could be phenocopied by chemically unrelated activators of CYP3A4, indicating a wide generalizability of this macro-environmental therapy resistance mechanism. Conclusions: Our study uncovered that acceleration of drug metabolism, triggered by CYP3A4 enzyme activators is a bona fide environmental resistance mechanism. Since P450 family liver detoxifying enzymes mediate the metabolism of many drugs, this resistance mechanism is likely to be relevant to a broad range of therapeutic contexts. Significance: While the importance of pharmacokinetic considerations is widely appreciated, modulation of drug metabolism is not typically considered as a candidate mechanism when therapy resistance is encountered in research and clinical settings. Multiple dietary, pharmacological and genetic modifiers are known to modulate P450 family enzymes. Moreover, substantial variability in drug plasma concentrations was documented in patients treated with identical doses of targeted therapies, and this variability strongly correlated with variability in clinical responses. While the direct link between variability in CYP3A4 activity and clinical outcomes in human patients has yet to be established, the mechanism uncovered in our study might represent a substantial but entirely overlooked contributor to resistance. Consequently, consideration of this mechanism and monitoring of CYP3A4 activity and systemic drug levels might improve our understanding of the biology of therapy resistance and enable an actionable path to improve clinical outcomes. Citation Format: Pragya Kumar, Robert Vander Velde, Malgorzata Weh, Andriy Marusyk. Acceleration of drug metabolism mediated by CYP3A4 enzyme activation provides a bona fide environmental resistance mechanism to targeted therapies [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr A027.

Abstract C028: Decreased heterogeneity in immune interactions in oral cavity squamous cell carcinoma patients with recurrence

Abstract There have been improvements in clinical risk stratifications for oral cavity squamous cell carcinoma (OSCC) with the AJCC 8th edition staging system. Other studies suggest the addition of a metric of specific immune interactions in and around the tumor may be helpful to further stratify patients, with mixed findings. The advent of spatial imaging has allowed a global view for assessing tumor features in the context of all surrounding cell interactions. We hypothesize that the lack of architectural information could contribute to varied clinical outcomes in previous studies, such as tumor recurrence. This highlights how spatial technologies could aid in understanding the role of tissue architecture and its influence on biology and medicine. To study tissue remodeling spatially, we focused on multiplexed-ion beam imaging (MIBI), a spatial proteomics platform to visualize 40 immuno-onco proteins simultaneously. Our banked patient cohort consists of 20 recurrent and 49 non-recurrent OSCC primary surgery samples. Clinical metadata capturing pathologic stage, alcohol use, smoking history, survival data, and more were also collected. With our pathologist, we curated 290 field-of-views (FOVs) of matched primary tumors, uninvolved lymph nodes, and metastatic lymph nodes (if any). Downstream computational analysis using existing MIBI codebases augmented with in-house spatial analytics has revealed a robust spatial dataset. After using machine-learning algorithms to cell segment our images, we validated these assigned cells and marker staining to further annotate cell populations. When we analyzed direct cell interactions, there was a decrease in heterogeneity in immune interactions within recurrent patients compared to non-recurrent patients. To ascertain how the loss of these interactions affected recurrence prognosis, we investigated their prevalence within the tumor border vicinity. We hypothesize that the proximity and cell-cell interactions near the border will promote a tumor-suppressive environment. Utilizing centroid-to-centroid distance measurements, we distilled the top 30 cell-cell interactions within a 100-micron distance from the tumor border. Cell pairs involving macrophage tissue-resident memory cells and CD8 T memory resident cells were more abundant in recurrent patients, while pairs involving CD4 T regulatory and CD8 cells were found in non-recurrent patients. Reassuringly, cell pairings involving myeloid cells were upregulated in the recurrent cohort as expected. Interestingly, cancer-associated fibroblast cell pairings were upregulated indiscriminately in both patient sub- cohorts. This suggests that the impact of certain known immunosuppressive changes may contribute in varying amounts to disease control. Our data demonstrates differences in the architecture of tumors with known divergent outcomes, which suggests global tissue-level changes could be a predictive factor. Clinically, interrogating these interactions of interest could guide treatment escalation or de-escalation in the future. Citation Format: Connie J. Zhou, Jane Lee, Rebecca Jaszczak, Steven R. Long, Patrick K. Ha, Matthew H. Spitzer. Decreased heterogeneity in immune interactions in oral cavity squamous cell carcinoma patients with recurrence [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr C028.

EPCO-02. HIGH CELLULAR PLASTICITY STATE OF HUMAN MEDULLOBLASTOMA LOCAL RECURRENCE AND DISTANT DISSEMINATION

Abstract Medulloblastoma (MB) is a heterogeneous pediatric brain tumor with variable clinical outcomes. Since current treatments facing limitations due to tumor resistance, less than 10% of relapsed patients survive beyond five years, with poorly understood recurrence mechanisms. To obtain cellular diversity and genetic characters in primary and recurrent MB, we conducted comprehensive analyses utilizing the single-cell/nucleus RNA sequencing (sc/snRNA-seq), snATAC-seq and spatial transcriptomics, complemented with bulk RNA sequencing and matched primary-recurrent whole exon profiles. SHH and Group_3 subgroups revealed distinct cellular subsets, including cycling, differentiated and quiescent tumor cells. Recurrent or disseminated MB displayed a dramatically different cellular ecosystem compared to primary tumors, with varying proportions of shared cell types. Local recurrence exhibited a higher enrichment of cycling tumor cells, while differentiated subset was notably present in disseminated lesions, indicating that local recurrences harbored the stronger proliferative capacity, whereas disseminations relatively well differentiated. Additionally, chromosomal alterations were assessed, reflecting distinct genetic subclones, such as chr7q gain and chr11 loss in Group_3 disseminations. Notably, the emergence of a subpopulation termed “high cellular plasticity (HCP)” during MB progression was noted, characterized by dynamic adaptability and stemness properties. As validated, HCP state was associated with increased chromatin accessibility, contributing to tumor recurrence and immune microenvironment remodeling. Functionally, inhibiting markers associated with HCP cells, such as PTPRZ1, efficiently suppressed MB metastasis in preclinical models. In conclusion, our findings fill the critical knowledge gaps in understanding the cellular diversity, chromosomal alterations and biological dynamics in MB recurrence and dissemination, offering potential therapeutic interventions.

DISP-10. RACIAL AND SOCIOECONOMIC DIFFERENCES IN CLINICAL AND ACCESS TO CARE OUTCOMES IN NEUROSURGICAL-ONCOLOGY PATIENTS

Abstract BACKGROUND Large database studies have identified racial and socioeconomic differences in neurosurgical-oncologic outcomes. For clearer insights and understanding, more detailed and prospective evaluation is needed. METHODS We retrospectively analyzed a database of 1475 patients undergoing surgery for CNS tumors over 5 years. Multivariate analysis, specific to various pathologies, was conducted to identify demographic and socioeconomic factors (including age, sex, racial identity, primary language, insurance status, and income estimate) associated with access to care and clinical outcomes. Additionally, prospective patient-centered interviews were conducted on neuro- oncology patients to qualitatively explore reasons for disparities in healthcare. RESULTS Significant associations were found between racial identities (White n=911; Hispanic n=285; Asian n=206; Black n=74) and sex (ANOVA p 0.0043), age (p&amp;lt;0.0001), income estimate (p&amp;lt;0.0001), primary language (p&amp;lt;0.0001), and insurance status (p&amp;lt;0.0001). Among different pathologies, presentation to the ED, rather than outpatient setting, was consistently associated with a non- English primary language (p=0.0312) and Medi-Cal insurance (p=0.0029). Time from imaging diagnosis to neurosurgical consultation was associated with non- English primary language (p=0.0262) and Medi-Cal (p=0.0030). Delay between recommendation for surgery and date of surgery was significant in Black patients (p=0.0112). A non- English primary language was negatively associated with having a gross total resection (p=0.0087). Notably, adjuvant treatments were less likely for those with non-English primary language (p=0.0203), Black race (p=0.0049), and Medi-Cal coverage (p=0.0014). Cox regression analysis identified only age (p&amp;lt;0.0001) as a predictor of poorer overall survival in oncologic cases. Prospective interviews identified cultural, economic (work- related), and healthcare navigation issues as reasons for differences in access to care. CONCLUSIONS Across the spectrum of neurosurgical oncology diagnoses, racial and socioeconomic factors independently associate with access to care but not clinical outcome variables. Further investigation is needed, particularly in patients with non- English primary languages and cultural attitudes towards chemotherapy and radiation therapy.

Human iPSC-derived MSCs induce neurotrophic effects and improve metabolic activity in acute neuronal injury models.

Mesenchymal stromal cell (MSC) therapy has regenerative potentials to treat various pathological conditions including neurological diseases. MSCs isolated from various organs can differentiate into specific cell types to repair organ damages. However, their paracrine mechanisms are predicted to predominantly mediate their immunomodulatory, pro-angiogenic, and regenerative properties. While preclinical studies highlight the significant potential of MSC therapy in mitigating neurological damage from stroke and traumatic brain injury, the variability in clinical trial outcomes may stem from the inherent heterogeneity of somatic MSCs. Accumulating evidence has demonstrated that induced pluripotent stem cells (iPSCs) are an ideal alternative resource for the unlimited expansion and biomanufacturing of MSCs. Thus, we investigated how iPSC-derived MSCs (iMSCs) influence properties of iPSC-derived neurons. Our findings demonstrate that the secretome from iMSCs possesses neurotrophic effects, improving neuronal survival and promoting neuronal outgrowth and synaptic activity in vitro Additionally, the iMSCs enhance metabolic activity via mitochondrial respiration in neurons, both in vitro and in mouse models. Glycolytic pathways also increased following the administration of iMSC secretome to iPSC-derived neurons. Consistently, in vivo experiments showed that intravenous administration of iMSCs compensated for the elevated energetic demand in male mice with irradiation-induced brain injury by restoring synaptic metabolic activity during acute brain damage. 18F-FDG PET imaging also detected an increase in brain glucose uptake following iMSC administration. Together, our results highlight the potential of iMSC-based therapy in treating neuronal damage in various neurological disorders, while paving the way for future research and potential clinical applications of iMSCs in regenerative medicine.Significance Statement Regenerative biotherapeutics using MSCs have emerged as a promising intervention for treating various neurological diseases. Our study explored the potential beneficial effects of human iPSC-derived MSCs (iMSCs) on neurons. We demonstrated that molecules secreted into the culture medium by iMSCs enhance regenerative capabilities by improving neuronal survival, growth, and metabolic activity, as well as synaptic functions, in human iPSC-derived neurons. Mouse experiments also suggested the potential of iMSC therapy to mitigate synaptic mitochondrial dysfunction and enhance brain glucose uptake during acute radiation-induced brain injury, steps that contribute to restoring normal neuronal function. Our results highlight that iMSCs may be a promising alternative cell product for treating neuronal damage, overcoming the inconsistent efficacy of somatic MSCs due to cell variability.

Trends in All-cause Mortality among U.S. Veterans with Sarcoidosis, 2004–2022

BACKGROUNDSarcoidosis is an idiopathic multiorgan disease with variable clinical outcomes. Comprehensive analysis of sarcoidosis mortality in U.S. Veterans is lacking. RESEARCH QUESTIONSWhat are the trends in all-cause mortality among U.S. Veterans with sarcoidosis, and how are these trends influenced by demographics, Black vs. White racial disparities, and geographic variability in relation to mortality? STUDY DESIGN AND METHODSUsing Veterans Health Administration (VHA) electronic health records (EHR), we conducted a population-based, retrospective cohort study of adjusted all-cause mortality 2004–2022 among Veterans diagnosed with sarcoidosis who received care through the VHA. Demographics, region of residence, service branch, tobacco use, and comorbidities were extracted from EHR. Annual trends in all-cause mortality and patient-level characteristics associated with mortality were examined with multivariable ungrouped Poisson regression. We visualized trends and analyzed state-by-state mortality using the marginal means procedure. In subgroup analysis (2015–2022), we considered the impact of neighborhood-level socioeconomic disparities using the area deprivation index (ADI). RESULTSIn all, 23,745 Veterans were diagnosed with sarcoidosis between 2004 and 2019 and followed through 2022. After adjustment, including age and sex, all-cause mortality increased annually by 4.7% (P<0.0001) and was 6.4% higher in Black than White Veterans (mortality rate ratio=1.064, P=0.02). A subgroup analysis comparing models with and without ADI adjustment showed no meaningful change in mortality trends. Risk factors for increased all-cause mortality included older age, male sex, Black race, and Northeast residence, and lower risk with “Other” service branches. Despite distinct geographical variations in mortality rates, no clear patterns emerged. INTERPRETATIONMortality among Veterans with sarcoidosis is rising. Differences identified by service branch and higher risk among male Veterans raise questions about differences in environmental exposures. The narrower racial disparities and smaller impact of ADI than in other studies may highlight the role of universal healthcare access in achieving equitable outcomes.

Artificial Intelligence Applications in Lymphoma Diagnosis and Management: Opportunities, Challenges, and Future Directions.

Lymphoma, a heterogeneous group of blood cancers, presents significant diagnostic and therapeutic challenges due to its complex subtypes and variable clinical outcomes. Artificial intelligence (AI) has emerged as a promising tool to enhance the accuracy and efficiency of lymphoma pathology. This review explores the potential of AI in lymphoma diagnosis, classification, prognosis prediction, and treatment planning, as well as addressing the challenges and future directions in this rapidly evolving field.

Addressing Semantic Variability in Clinical Outcome Reporting Using Large Language Models

Background/Objectives: Clinical trials frequently employ diverse terminologies and definitions to describe similar outcomes, leading to ambiguity and inconsistency in data interpretation. Addressing the variability in clinical outcome reports and integrating semantically similar outcomes is important in healthcare and clinical research. Variability in outcome reporting not only hinders the comparability of clinical trial results but also poses significant challenges in evidence synthesis, meta-analysis, and evidence-based decision-making. Methods: This study investigates variability reduction in outcome measures reporting using rule-based and large language-based models. It aims to mitigate the challenges associated with variability in outcome reporting by comparing these two models. The first approach, which is rule-based, will leverage well-known ontologies, and the second approach exploits sentence-bidirectional encoder representations from transformers (SBERT) to identify semantically similar outcomes along with Generative Pre-training Transformer (GPT) to refine the results. Results: The results show that the relatively low percentages of outcomes are linked to established rule-based ontologies. Analysis of outcomes by word count highlighted the absence of ontological linkage for three-word outcomes, which indicates potential gaps in semantic representation. Conclusions: Employing large language models (LLMs), this study demonstrates its ability to identify similar outcomes, even with more than three words, suggesting a crucial role in outcome harmonization efforts, potentially reducing redundancy and enhancing data interoperability.

Implications of a new clinical classification of acute myocardial infarction

Abstract Background The Universal Definition of Myocardial Infarction has provided standardisation of the diagnostic criteria for myocardial infarction. However, there remain significant challenges in adopting some of the current recommendations in practice. The diagnostic criteria for type 2 myocardial infarction identify a heterogenous group of patients with variable clinical outcomes and no clear treatment implications to date. Purpose To determine the implications of a new clinical classification for myocardial infarction with more objective diagnostic criteria using cardiac imaging.(1) Methods In a prospective cohort study,(2) patients with type 2 myocardial infarction underwent coronary angiography and cardiac magnetic resonance imaging or echocardiography. The new classification was applied to identify (a) spontaneous myocardial infarction due to acute coronary pathology, (b) secondary myocardial infarction precipitated by acute illness in the presence of obstructive coronary artery disease, a new regional wall motion abnormality or infarct pattern scarring, and (c) no myocardial infarction in the absence of obstructive disease or new myocardial abnormality. The diagnostic outcome was the proportion of patients with type 2 myocardial infarction reclassified as having spontaneous, secondary or no myocardial infarction by the new clinical classification. The prognostic outcome was a composite of all-cause death, any recurrent myocardial infarction, or heart failure hospitalisation during follow up. Results In 100 patients (65 years, 43% women) with type 2 myocardial infarction, the new classification identified 25 and 31 patients with spontaneous and secondary myocardial infarction, respectively, and 44 without myocardial infarction (Figure 1). Compared to patients without myocardial infarction, those with secondary myocardial infarction were older, had more risk factors, and higher troponin concentrations (P&amp;lt;0.05 for all). In patients who underwent cardiac magnetic resonance imaging, there was evidence of infarct-pattern late gadolinium enhancement in 95% (19/20) and 60% (15/25) of patients with spontaneous and secondary myocardial infarction, respectively, which was more likely to be transmural in the former. In patients reclassified as secondary myocardial infarction, just 45% and 58% were established on aspirin or a lipid lowering therapy. During a median follow up of 4.4 years, death, myocardial infarction or heart failure hospitalization was more common in secondary myocardial infarction compared to those without myocardial infarction (55% [17/31] versus 16% [7/44], P&amp;lt;0.001; Figure 2). Conclusions A new clinical classification of myocardial infarction informed by cardiac imaging would reduce the diagnosis of myocardial infarction in acute illness and identify those patients at highest risk who are most likely to benefit from treatment.Figure 1:Alluvial plotFigure 2:Kaplan Meier curve

Translational strategies to uncover the etiology of congenital anomalies of the kidney and urinary tract.

While up to 50% of children requiring kidney replacement therapy have congenital anomalies of the kidney and urinary tract (CAKUT), they represent only a fraction of the total patient population with CAKUT. The extreme variability in clinical outcome underlines the fundamental need to devise personalized clinical management strategies for individuals with CAKUT. Better understanding of the pathophysiology of abnormal kidney and urinary tract development provides a framework for precise diagnoses and prognostication of patients, the identification of biomarkers and disease modifiers, and, thus, the development of personalized strategies for treatment. In this review, we provide a state-of-the-art overview of the currently known genetic causes, including rare variants in kidney and urinary tract development genes, genomic disorders, and common variants that have been attributed to CAKUT. Furthermore, we discuss the impact of environmental factors and their interactions with developmental genes in kidney and urinary tract malformations. Finally, we present multi-angle translational modalities to validate candidate genes and environmental factors and shed light on future strategies to better understand the molecular underpinnings of CAKUT.

Short-term morbidity and mortality after right hemicolectomy: an update of national performance in the Netherlands.

The purpose of this Dutch retrospective population-based study was to evaluate how short-term outcomes and inter-hospital variability after right hemicolectomy for colon cancer have evolved between 2012 and 2020. Patients who underwent right hemicolectomy for primary solitary colon cancer between 1 January 2012 and 31 December 2020 and were registered in the Dutch Colorectal Audit were included. Surgical characteristics and outcomes were assessed during three time periods (2012-2014, 2015-2017, 2018-2020). Complications and mortality were the primary outcomes, and reintervention, readmission and length of stay secondary outcomes. In total, 29 274 patients were included. Significant increase in minimally invasive surgery (51.1% 2012-2014, 73.2% 2015-2017, 85.0% 2018-2020), increase in conversion (6.6%, 7.8%, 9.1%, P < 0.001) and decrease in acute/urgent resections (15.9%, 11.7%, 10.9%, P < 0.001) were found. The overall complication rate was slightly lower in the third period (30.9%, 30.6%, 28.8%, P = 0.004), primarily because of decreasing non-surgical complications (19.7%, 20.6%, 17.6%, P < 0.001), while surgical complications remained unchanged (17.5%, 18.3%, 18.2%, P = 0.277). Postoperative mortality was 3.4%, 2.3% and 3.5%, respectively. Reintervention rate slightly decreased (9.4%, 8.3%, 8.6%, P < 0.001). The proportion of patients admitted for more than 6 days decreased over time (54.3%, 42.4%, 34.3%, P < 0.001), with an increase in readmission rate (7.4%, 6.8%, 9.3%, P < 0.001). Inter-hospital variability decreased over time for complications, length of stay and conversion. This study shows a national decreasing inter-hospital variability in clinical outcomes after right hemicolectomy and a decrease in postoperative complications. Despite increasing use of laparoscopy, surgical complications and mortality remained stable over time.

The epigenetic state of the cell of origin defines mechanisms of leukemogenesis.

Acute myeloid leukemia (AML) shows variable clinical outcome. The normal hematopoietic cell of origin impacts the clinical behavior of AML, with AML from hematopoietic stem cells (HSCs) prone to chemotherapy resistance in model systems. However, the mechanisms by which HSC programs are transmitted to AML are not known. Here, we introduce the leukemogenic MLL-AF9 translocation into defined human hematopoietic populations, finding that AML from HSCs is enriched for leukemic stem cells (LSCs) compared to AML from progenitors. By epigenetic profiling, we identify a putative inherited program from the normal HSC that collaborates with oncogene-driven programs to confer aggressive behavior in HSC-AML. We find that components of this program are required for HSC-AML growth and survival and identify RNA polymerase (RNAP) II-mediated transcription as a therapeutic vulnerability. Overall, we propose a mechanism as to how epigenetic programs from the leukemic cell of origin are inherited through transformation to impart the clinical heterogeneity of AML.

Clinical outcome-guided deep temporal clustering for disease progression subtyping

ObjectiveComplex diseases exhibit heterogeneous progression patterns, necessitating effective capture and clustering of longitudinal changes to identify disease subtypes for personalized treatments. However, existing studies often fail to design clustering-specific representations or neglect clinical outcomes, thereby limiting the interpretability and clinical utility. MethodWe design a unified framework for subtyping longitudinal progressive diseases. We focus on effectively integrating all data from disease progressions and improving patient representation for downstream clustering. Specifically, we propose a clinical Outcome-Guided Deep Temporal Clustering (OG-DTC) that generates representations informed by clustering and clinical outcomes. A GRU-based seq2seq architecture captures the temporal dynamics, and the model integrates k-means clustering and outcome regression to facilitate the formation of clustering structures and the integration of clinical outcomes. The learned representations are clustered using a Gaussian mixture model to identify distinct subtypes. The clustering results are extensively validated through reproducibility, stability, and significance tests. ResultsWe demonstrated the efficacy of our framework by applying it to three Alzheimer’s Disease (AD) clinical trials. Through the AD case study, we identified three distinct subtypes with unique patterns associated with differentiated clinical declines across multiple measures. The ablation study revealed the contributions of each component in the model and showed that jointly optimizing the full model improved patient representations for clustering. Extensive validations showed that the derived clustering is reproducible, stable, and significant. ConclusionOur temporal clustering framework can derive robust clustering applicable for subtyping longitudinal progressive diseases and has the potential to account for subtype variability in clinical outcomes.

Investigating the pathophysiology and evolution of internal carotid dissection: a fluid-structure interaction simulation study.

Arterial dissection, a condition marked by the tearing of the carotid artery's inner layers, can result in varied clinical outcomes, including progression, stability, or spontaneous regression. Understanding these outcomes' underlying mechanisms is crucial for enhancing patient care, particularly with the increasing use of computer simulations in medical diagnostics and treatment planning. The aim of this study is to utilize computational analysis of blood flow and vascular wall to: (1) understand the pathophysiology of stroke-like episodes in patients with carotid artery dissection; and (2) assess the effectiveness of this method in predicting the evolution of carotid dissection. Utilizing contrast-enhanced magnetic resonance angiography (MRA), we segmented images of the patient's right internal carotid artery. These images were transformed into 3D solids for simulation in Ansys multifisic software, employing a two-way fluid structure interaction (FSI) analysis. Simulations were conducted across two wall conditions (atherosclerotic and normal) and three pressure states (hypotension, normotension, hypertension). The simulations indicated a significant pressure discrepancy between the true and false lumens of the artery. This suggests that flap motion and functional occlusion under hypertensive conditions could be the cause of the clinical episodes. Thrombotic risk and potential for dissection extension were not found to be critical concerns. However, a non-negligible risk of vessel dilation was assessed, aligning with the patient's clinical follow-up data. This study highlights specific hemodynamic parameters that could elucidate carotid artery dissection's mechanisms, offering a potential predictive tool for assessing dissection progression and informing personalized patient care strategies.

Sarcomatoid Morphology in Pediatric Langerhans Cell Neoplasm Does Not Always Predict Aggressive Clinical Course.

Langerhans cell sarcoma (LCS), a rare malignant neoplasm in the general category of myeloid neoplasms characterized by overtly malignant Langerhans cells (LC) with conspicuous mitotic activity including atypical forms. Although most cases occur in adults, rare examples of LCS have been reported in children with variable clinical outcome. We present 2 childhood cases of Langerhans cell neoplasm with high grade sarcomatous features and OSBPL9::BRAF fusion and BRAF V600E mutation.

Hospital Heart Failure Medical Therapy Score and Associated Clinical Outcomes and Costs

A composite score for guideline-directed medical therapy (GDMT) for patients with heart failure (HF) is associated with increased survival. Whether hospital performance according to a GDMT score is associated with a broader array of clinical outcomes at lower costs is unknown. To evaluate hospital variability in GDMT score at discharge, 90-day risk-standardized clinical outcomes and costs, and associations between hospital GDMT score and clinical outcomes and costs. This was a retrospective cohort study conducted from January 2015 to September 2019. Included for analysis were patients hospitalized for HF with reduced ejection fraction (HFrEF) in the Get With the Guidelines-Heart Failure Registry, a national hospital-based quality improvement registry. Study data were analyzed from July 2022 to April 2023. GDMT score at discharge. Hospital variability in GDMT score, a weighted index from 0 to 1 of GDMT prescribed divided by the number of medications eligible, at discharge was evaluated using a generalized linear mixed model using the hospital as a random effect and quantified with the adjusted median odds ratio (AMOR). Parallel analyses centering on 90-day mortality, HF rehospitalization, mortality or HF rehospitalization, home time, and costs were performed. Costs were assessed from the perspective of the Centers of Medicare & Medicaid Services. Associations between hospital GDMT score and clinical outcomes and costs were evaluated using Spearman coefficients. Among 41 161 patients (median [IQR] age, 78 [71-85] years; 25 546 male [62.1%]) across 360 hospitals, there was significant hospital variability in GDMT score at discharge (AMOR, 1.23; 95% CI, 1.21-1.26), clinical outcomes (mortality AMOR, 1.17; 95% CI, 1.14-1.24; HF rehospitalization AMOR, 1.22; 95% CI, 1.18-1.27; mortality or HF rehospitalization AMOR, 1.21; 95% CI, 1.18-1.26; home time AMOR, 1.07; 95% CI, 1.06-1.10) and costs (AMOR, 1.23; 95% CI, 1.21-1.26). Higher hospital GDMT score was associated with lower hospital mortality (Spearman ρ, -0.22; 95% CI, -0.32 to -0.12; P < .001), lower mortality or HF rehospitalization (Spearman ρ, -0.17; 95% CI, -0.26 to -0.06; P = .002), more home time (Spearman ρ, 0.14; 95% CI, 0.03-0.24; P = .01), and lower cost (Spearman ρ, -0.11; 95% CI, -0.21 to 0; P = .047) but not with HF rehospitalization (Spearman ρ, -0.10; 95% CI, -0.20 to 0; P = .06). Results of this cohort study reveal that hospital variability in GDMT score, clinical outcomes, and costs was significant. Higher GDMT score at discharge was associated with lower mortality, lower mortality or hospitalization, more home time, and lower cost. Efforts to increase health care value should include GDMT optimization.

The Desmoplakin Phenotype Spectrum: Is the Inflammation the "Fil Rouge" Linking Myocarditis, Arrhythmogenic Cardiomyopathy, and Uncommon Autoinflammatory Systemic Disease?

Myocarditis is an inflammatory condition of cardiac tissue presenting significant variability in clinical manifestations and outcomes. Its etiology is diverse, encompassing infectious agents (primarily viruses, but also bacteria, protozoa, and helminths) and non-infectious factors (autoimmune responses, toxins, and drugs), though often the specific cause remains unidentified. Recent research has highlighted the potential role of genetic susceptibility in the development of myocarditis (and in some cases the development of inflammatory dilated cardiomyopathy, i.e., the condition in which there is chronic inflammation (>3 months) and left ventricular dysfunction\dilatation), with several studies indicating a correlation between myocarditis and genetic backgrounds. Notably, pathogenic genetic variants linked to dilated or arrhythmic cardiomyopathy are found in 8-16% of myocarditis patients. Genetic predispositions can lead to recurrent myocarditis and a higher incidence of ventricular arrhythmias and heart failure. Moreover, the presence of DSP mutations has been associated with distinct pathological patterns and clinical outcomes in arrhythmogenic cardiomyopathy (hot phases). The interplay between genetic factors and environmental triggers, such as viral infections and physical stress, is crucial in understanding the pathogenesis of myocarditis. Identifying these genetic markers can improve the diagnosis, risk stratification, and management of patients with myocarditis, potentially guiding tailored therapeutic interventions. This review aims to synthesize current knowledge on the genetic underpinnings of myocarditis, with an emphasis on desmoplakin-related arrhythmogenic cardiomyopathy, to enhance clinical understanding and inform future research directions.