Clinical Outcome Variables Research Articles

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<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<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.

Patients carrying pathogenic SCN8A variants with loss‐ and gain‐of‐function effects can be classified into five subgroups exhibiting varying developmental and epileptic components of encephalopathy

AbstractObjectivePhenotypic heterogeneity presents challenges in providing clinical care to patients with pathogenic SCN8A variants, which underly a wide disease spectrum ranging from neurodevelopmental delays without seizures to a continuum of mild to severe developmental and epileptic encephalopathies (DEEs). An important unanswered question is whether there are clinically important subgroups within this wide spectrum. Using both supervised and unsupervised machine learning (ML) approaches, we previously found statistical support for two and three subgroups associated with loss‐ and gain‐ of‐ function vari‐ants, respectively. Here, we test the hypothesis that the unsupervised subgroups (U1–U3) are distinguished by differential contributions of developmental and epileptic components.MethodsWe predicted that patients in the U1 and U2 subgroups would differ in timing of developmental delay and seizure onset, with earlier and concurrent onset of both features for the U3 subgroup. Standard statistical procedures were used to test these predictions, as well as to investigate clinically relevant associations among all five subgroups.ResultsTwo‐population proportion and Kruskal–Wallis tests supported the hypothesis of a reversed order of developmental delay and seizure onset for patients in U1 and U2, and nearly synchronous developmental delay/seizure onset for the U3 (termed DEE) subgroup. Association testing identified subgroup variation in treatment response, frequency of initial seizure type, and comorbidities, as well as different median ages of developmental delay onset for all five subgroups.SignificanceUnsupervised ML approaches discern differential developmental and epileptic components among patients with SCN8A‐related epilepsy. Patients in U1 (termed developmental encephalopathy) typically gain seizure control yet rarely experience improvements in development, whereas those in U2 (termed epileptic encephalopathy) have fewer if any developmental impairments despite difficulty in achieving seizure control. This understanding improves prognosis and clinical management and provides a framework to discover mechanisms underlying variability in clinical outcome of patients with SCN8A‐related disorders.

Translation and validation of the Czech Partner version of the Birth Satisfaction Scale-Revised (BSS-R)

ABSTRACT Background The Birth Satisfaction Scale-Revised (BSS-R) is a widely used, psychometrically robust and brief self-report measure of birth experience from the mothers perspective. The current study sought to adapt and validate the BSS-R for partners, evaluating key psychometric properties, including the underlying tri-dimensional factor structure of stress experienced, personal attributes and quality of care. Aim To translate and validate a Czech speaking partner version of the Birth Satisfaction Scale-Revised (BSS-R) and examine key measurement characteristics and association with fundamental clinical outcome variables. Method Following translation of the UK partner BSS-R into Czech, the Czech Partner BSS-R (CZP-BSS-R) was administered to 225 partners of women who had given birth within the past 5-years. Key psychometric characteristics were examined, including factor structure, divergent and known-groups discriminant validity and internal reliability, Results Established measurement models of the BSS-R observed in mothers were found to offer an excellent fit to partner data. The CZP-BSS-R also demonstrated excellent validity and reliability characteristics. Conclusions The CZP-BSS-R was found to be valid and reliable, with results from Czech partners ‘mirroring’ factor structure and key validity characteristics previously established in Czech mothers. The BSS-R validated for completion by Czech speaking mothers now has a matched version available for use with Czech speaking partners.

Understanding and Overcoming Resistance to Selective FGFR Inhibitors across FGFR2-Driven Malignancies.

Understanding resistance to selective FGFR inhibitors is crucial to improve the clinical outcomes of patients with FGFR2-driven malignancies. We analyzed sequential ctDNA, ± whole-exome sequencing, or targeted next-generation sequencing on tissue biopsies from patients with tumors harboring activating FGFR2 alterations progressing on pan-FGFR-selective inhibitors, collected in the prospective UNLOCK program. FGFR2::BICC1 Ba/F3 and patient-derived xenograft models were used for functional studies. Thirty-six patients were included. In cholangiocarcinoma, at resistance to both reversible inhibitors (e.g., pemigatinib and erdafitinib) and the irreversible inhibitor futibatinib, polyclonal FGFR2 kinase domain mutations were frequent (14/27 patients). Tumors other than cholangiocarcinoma shared the same mutated FGFR2 residues, but polyclonality was rare (1/9 patients). At resistance to reversible inhibitors, 14 residues in the FGFR2 kinase domain were mutated-after futibatinib, only the molecular brake N550 and the gatekeeper V565. Off-target alterations in PI3K/mTOR and MAPK pathways were found in 11 patients, often together with on-target mutations. At progression to a first FGFR inhibitor, 12 patients received futibatinib or lirafugratinib (irreversible inhibitors), with variable clinical outcomes depending on previous resistance mechanisms. Two patients with TSC1 or PIK3CA mutations benefited from everolimus. In cell viability assays on Ba/F3 and in pharmacologic studies on patient-derived xenografts, irreversible inhibitors retained better activity against FGFR2 kinase domain mutations, with lirafugratinib active against the recalcitrant V565L/F/Y. At progression to FGFR inhibitors, FGFR2-driven malignancies are characterized by high intra- and interpatient molecular heterogeneity, particularly in cholangiocarcinoma. Resistance to FGFR inhibitors can be overcome by sequential, molecularly oriented treatment strategies across FGFR2-driven tumors.

Diagnostic challenges and outcome of fatty acid oxidation defects in a tertiary care center in Lebanon

BackgroundFatty acid oxidation defects are rare autosomal recessive disorders with variable clinical manifestations and outcome. Early detection by systematic neonatal screening may improve their prognosis. Long-term outcome studies of these disorders in the Middle East and North Africa region are limited. The purpose of this study is to report the diagnostic challenges and outcome of fatty acid oxidation defects in a major tertiary care center in Lebanon, a resource-constrained country in the Middle East.MethodsA retrospective review of charts of all fatty acid oxidation defects sequential patients diagnosed and followed at our center was conducted. Collected data included: parental consanguinity, age at diagnosis, clinical presentation, biochemical profile, confirmatory diagnosis, treatment and outcome. A genotype–phenotype correlation was also performed, when available.ResultsSeven types of fatty acid oxidation defects were identified in a total of 34 patients from 21 families. Most families (79%) were consanguineous (first-degree cousins). The majority were diagnosed when clinically symptomatic (78%), at various ages between 10 days and 19 years (average: 2 years). Follow-up duration spanned between 2 months and 15 years (average: 5 years). The remainder of the patients were detected while still asymptomatic by systematic neonatal screening (9%) or due to positive family history (9%). The most common defect was carnitine transporter deficiency (50%) with an exclusive cardiac presentation related to a founder variant c.981C > T, (p.Arg254*) in the SLC22A5 gene. Medium chain acyl-CoA dehydrogenase deficiency was found in 13% only, which could be explained by the absence of systematic neonatal screening. Rare gene variants were detected in very long chain and multiple acyl-CoA dehydrogenase deficiency. The worse prognosis was observed in very long chain acyl-CoA dehydrogenase deficiency. The overall survival at last follow-up reached 75% with a complete reversal of symptoms with treatment in most patients (63%), despite their late diagnosis.ConclusionsOur experience highlights the diagnostic challenges and outcome of fatty acid oxidation defects in a resource-constrained country with high consanguinity rates. Physicians’ awareness and systematic neonatal screening are key for diagnosis. Larger genotype–phenotype studies are still needed to understand the natural history of these rare diseases and possibly improve their outcome.

Ischemia time in partial nephrectomy: to rush really matters?

Aim: The growth in the incidence of small renal masses has led the implementation of laparoscopic partial nephrectomy to become the technique of choice. However, arterial clamping and secondary renal ischemia still mean a controversial issue due to the risk of renal failure. Our objective is to evaluate the existing literature and its relationship to our experience. Methods: We performed a retrospective study of our series over six years. We analyzed different clinical, perioperative and postoperative functional outcome variables and compared the relationship between tumor complexity and the need for ischemia as well as the relation between ischemia time and renal function over a follow-up time of 6 months. For the discussion, we led a review of the literature on the subject and the paradigm shift that has taken place over the years. Results: A total of 148 patients, most of them male (68.2%) with an average age of 62.4 [standard deviation (SD) 1.7] years, had a Charlson index of 3 [interquartile range (IQR) 1-4]. The average R.E.N.A.L. score was 6 (IQR 5-8). Intraoperative complications were observed in 8.1% of the cases, most of which involved bleeding from a major artery or vein (7.4%). Postoperative complications occurred in 23.6% of the patients, the majority being classified as Clavien 2. Arterial clamping was carried out in 52.7% of the interventions, with a median ischemia time of 8 min (IQR 0-18). The average hospital stay was three days (IQR 2-5). Previous median glomerular filtration rate (GFR) was 83 mL/min/1.73 m2 (IQR 66.2-93.6). On the first postoperative day, the median GFR was 78.4 (SD 21.8), and at 6 months, it was 75.2 (SD 22). We found no statistically significant differences between having hypertension or diabetes mellitus and GFR after surgery, but we found differences in the correlation of a Charlson index ≥ 3 and deterioration of renal function, being the P values 0.01, 0.08 and 0.00 for the first postoperative day, after three and 6 months, respectively. No statistically significant differences were found in whether having a previous chronic kidney disease influenced the decision to perform arterial clamping or not, with a P value of 0.104. Statistically significant differences were found in the relationship between R.E.N.A.L. score and ischemia time. Conclusion: Renal tumors with a higher R.E.N.A.L. score involve the need to accomplish a longer arterial clamping, but its relationship with the deterioration of renal function is unclear, since there are other risk factors, such as patient’s comorbidities.

Correlates of disease severity in bluetongue as a model of acute arbovirus infection.

Most viral diseases display a variable clinical outcome due to differences in virus strain virulence and/or individual host susceptibility to infection. Understanding the biological mechanisms differentiating a viral infection displaying severe clinical manifestations from its milder forms can provide the intellectual framework toward therapies and early prognostic markers. This is especially true in arbovirus infections, where most clinical cases are present as mild febrile illness. Here, we used a naturally occurring vector-borne viral disease of ruminants, bluetongue, as an experimental system to uncover the fundamental mechanisms of virus-host interactions resulting in distinct clinical outcomes. As with most viral diseases, clinical symptoms in bluetongue can vary dramatically. We reproduced experimentally distinct clinical forms of bluetongue infection in sheep using three bluetongue virus (BTV) strains (BTV-1IT2006, BTV-1IT2013 and BTV-8FRA2017). Infected animals displayed clinical signs varying from clinically unapparent, to mild and severe disease. We collected and integrated clinical, haematological, virological, and histopathological data resulting in the analyses of 332 individual parameters from each infected and uninfected control animal. We subsequently used machine learning to select the key viral and host processes associated with disease pathogenesis. We identified and experimentally validated five different fundamental processes affecting the severity of bluetongue: (i) virus load and replication in target organs, (ii) modulation of the host type-I IFN response, (iii) pro-inflammatory responses, (iv) vascular damage, and (v) immunosuppression. Overall, we showed that an agnostic machine learning approach can be used to prioritise the different pathogenetic mechanisms affecting the disease outcome of an arbovirus infection.

Medial Closing Wedge High Tibial Osteotomy Accurately Corrects Genu Valgum without Iatrogenic Deformity or Complications: A Consecutive Series of Thirty-one Procedures.

Angular deformities of the tibia and femur lead to mechanical axis deviation (MAD) of the lower limb and malorientation of the joints adjacent to the deformity. The current study analyses the outcomes of using a medial closing wedge high tibial osteotomy (MCWHTO) for the management of genu valgum with high medial proximal tibial angle (MPTA), and combined MCWHTO with lateral opening-wedge distal femoral osteotomy (LOWDFO) in the setting of concomitant genu varum with low lateral distal femoral angle (LDFA). There were 18 high tibial osteotomy (HTO)-only and 13 combined HTO + distal femoral osteotomy (DFO) procedures performed. The primary radiographic outcome variables included postoperative MPTA and MAD (in mm). The accuracy of MAD correction was expressed as a percentage. The postoperative posterior proximal tibial angle (PPTA) and limb length discrepancy (LLD) were also measured as secondary radiographic outcome variables. The clinical outcome variables included intraoperative surgical complications (e.g., hinge fracture), all-causes for revision, union rate, time to union, and postoperative knee range of motion. Functional outcomes used included the LDSRS, PROMIS, and EuroQOL scores. The mean preoperative MPTA was 92.9° (SD = 1.81, range: 88-96). After surgical correction, the mean MPTA was 86.0° (SD = 1.80, range: 83-90) (p < 0.0001). The mean preoperative MAD was 32.5 mm (SD = 20.16, range: 10-77) lateral to the centre of the knee joint. The mean postoperative MAD was 2.44 mm medial to the centre of the joint (SD = 7.13, range: 13 medial - 15 lateral) (p < 0.0001). The mean change in MAD achieved through surgical correction was 38.16 mm (SD = 17.94, range: 13-77). The accuracy of MAD correction was 96.1% (SD = 0.06%, range: 81.25-100%). The time to unassisted WB was a mean of 75 days (SD = 44.5, range: 44-242).There was a single stable hinge fracture and one case of chronic regional pain syndrome diagnosed. There were no cases of non-union and no indications for revision surgery in any case. Medial closing wedge high tibial osteotomy is an effective surgical procedure for the management of genu valgum deformity. The MPTA, LDFA, and MAD can be accurately corrected without significantly altering PPTA or limb length. It may be combined with open lateral distal femoral osteotomy for cases with femoral and tibial contributions to deformity without significantly impacting clinical outcomes. Functional outcomes, specifically relating to self-image are significantly improved after the MCWHTO has been performed. Sheridan GA, Page BJ, Greenstein MD, et al. Medial Closing Wedge High Tibial Osteotomy Accurately Corrects Genu Valgum without Iatrogenic Deformity or Complications: A Consecutive Series of Thirty-one Procedures. Strategies Trauma Limb Reconstr 2024;19(2):82-86.

Genomic profiles and clinical presentation of chordoma

Chordoma is a rare bone cancer with variable clinical outcomes. Here, we recruited 184 sporadic chordoma patients from the US and Canada and collected their clinical and treatment data. The average age at diagnosis was 45.5 years (Range 5–78) and the chordoma site distribution was 49.2% clivus, 26.2% spinal, and 24.0% sacral. Most patients (97.5%) received surgery as the primary treatment, among whom 85.3% also received additional treatment. Except for the most prevalent cancers like prostate, lung, breast, and skin cancer, there was no discernible enrichment for any specific cancer type among patients or their family members. Among a subset of patients (N = 70) with tumor materials, we conducted omics analyses and obtained targeted panel sequencing and SNP array genotyping data for 51 and 49 patients, respectively. The most recurrent somatic driver mutations included PIK3CA (12%), followed by chromatin remodeling genes PBRM1 and SETD2. Amplification of the 6q27 region, containing the chordoma susceptibility gene TBXT, was detected in eight patients (16.3%). Clival patients appeared to be less likely to carry driver gene mutations, chromosome arm level deletion events (e.g., 5p, 5p, and 9p), or 6q27 amplification compared to sacral patients. After adjusting for age, sex, tumor site, and additional treatment, patients with somatic deletions of 14q (OR = 13.73, 95% CI 1.96–96.02, P = 0.008) and 18p (OR = 13.68, 95% CI 1.77–105.89, P = 0.012) were more likely to have persistent chordoma. The study highlights genomic heterogeneity in chordoma, potentially linked to location and clinical progression.

Unveiling the Quest: Crafting an Enzyme-Linked Immunosorbent Assay (ELISA) Technique to Uncover COVID-19 Antibodies.

The COVID-19 pandemic, caused by the novel coronavirus SARS-CoV-2, has had a profound impact on global health. Rapid and accurate diagnostic tools are crucial for effective disease control and management. The enzyme-linked immunosorbent assay (ELISA) has emerged as a reliable and widely used method for detecting COVID-19 antibodies in patients, which develop in response to SARS-CoV-2 infection. While the ELISA technique is effective in identifying the presence of antibodies and thus confirming exposure to the virus, its role in predicting the clinical course and severity of the disease is limited. ELISA primarily confirms prior exposure to the virus or vaccination status, but it does not directly correlate antibody levels with the severity or progression of the disease. The variability in clinical outcomes is influenced by factors such as viral load, patient co-morbidities, genetic predispositions, and the timing of the immune response. ELISA has diverse applications in epidemiology, vaccination assessment, and therapeutic development. It determines antibody prevalence, aids in surveillance, and evaluates vaccine effectiveness and antibody protection duration. ELISA quantitatively measures antibody levels, providing insights into the immune response and treatment efficacy. Challenges include specialized facilities and personnel, cross-reactivity, and false results. Multiplex assays and integration with other diagnostics are future directions. In summary, ELISA is an essential tool in COVID-19 diagnostics, enabling precise assessment of the immune response and contributing to effective strategies. The development of point-of-care devices that integrate ELISA technology could enable rapid and accessible testing in various settings. Additionally, integrating ELISA with other diagnostic platforms could enhance the overall diagnostic capabilities for COVID-19. Despite challenges, ongoing advancements in ELISA technology, and its integration with other diagnostic approaches, hold promise for further improving COVID-19 diagnostics and management strategies.

Probabilistic Refinement of Focused Ultrasound Thalamotomy Targeting for Parkinson's Disease Tremor.

There remains high variability in clinical outcomes when the same magnetic resonance image-guided focused ultrasound (MRgFUS) thalamotomy target is used for both essential tremor (ET) and tremor-dominant Parkinson's disease (TDPD). Our goal is to refine the MRgFUS thalamotomy target for TDPD versus ET. We retrospectively performed voxel-wise efficacy and structural connectivity mapping using 3-12-month post-procedure hand tremor scores for a multicenter cohort of 32 TDPD patients and a previously published cohort of 79 ET patients, and 24-hour T1-weighted post-MRgFUS brain images. We validated our findings using Unified Parkinson's Disease Rating Scale part III scores for an independent cohort of nine TDPD patients. The post-MRgFUS clinical improvements were 45.9% ± 35.9%, 55.5% ± 36%, and 46.1% ± 18.6% for ET, multicenter TDPD and validation TDPD cohorts, respectively. The TDPD and ET efficacy maps differed significantly (ppermute < 0.05), with peak TDPD improvement (87%) at x = -13.5; y = -15.0; z = 1.5, ~3.5 mm anterior and 3 mm dorsal to the ET target. Discriminative connectivity projections were to the motor and premotor regions in TDPD, and to the motor and somatosensory regions in ET. The disorder-specific voxel-wise efficacy map could be used to estimate outcome in TDPD patients with high accuracy (R = 0.8; R2 = 0.64; P < 0.0001). The model was validated using the independent cohort of nine TDPD patients (R = 0.73; R2 = 0.53; P = 0.025-voxel analysis). We demonstrated that the most effective MRgFUS thalamotomy target in TDPD is in the ventral intermediate nucleus/ventralis oralis posterior border region. This finding offers new insights into the thalamic regions instrumental in tremor control, with pivotal implications for improving treatment outcomes. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.