Vertical maxillary excess (VME) often presents with excessive gingival display, deep bite, and occlusal plane discrepancies that significantly impact smile esthetics. The management of VME in adult patients with compromised dentition poses unique challenges requiring comprehensive treatment planning and precise biomechanical execution. This case report describes the diagnosis and orthodontic management of a 19-year-old female presenting with a VME-induced gummy smile, occlusal cant, increased overjet, and a decayed mandibular molar requiring extraction. The patient exhibited a skeletal Class II maxillomandibular relationship with end-on canine and molar relations bilaterally, excessive gingival display exceeding 4 mm, and a mutilated mandibular first molar (tooth 36) with a mesioangularly erupting third molar (tooth 38). The patient was diagnosed with VME, excessive gingival display, occlusal cant on the right side, a deep bite of 4 mm, increased overjet of 5 mm, Class II molar and canine relations on the left side, a non-restorable mandibular molar requiring extraction, and midline discrepancy. Following the extraction of the compromised mandibular first molar, space was successfully managed through orthodontic molar protraction. The mandibular second molar (tooth 37) was protracted into the extraction space of tooth 36, achieving a bilateral Class I molar relationship. Bilateral premolar extractions in the upper arch created space for simultaneous whole arch intrusion assisted by temporary anchorage devices in the maxillary anterior region and infrazygomatic crest implants in the maxillary posterior region. Comprehensive fixed mechanotherapy corrected vertical and sagittal discrepancies, re-established symmetry, improved smile esthetics, and resolved the occlusal cant. This report highlights the importance of carefully planned biomechanics and vertical smile management in addressing esthetic imbalances without surgical intervention.
Ocean-atmosphere CO2 exchange is key in modulating global climate, but the Arctic Ocean's anthropogenic carbon (Cant) uptake is poorly constrained. Most studies in the Canada Basin using the Transit Time Distribution (TTD) relied on two years of paired gas tracers, CFC-12 and SF6. Here we use nuclear reprocessing products 129I, 236U, and 137Cs to estimate Cant in the Atlantic Water layer by the TTD. We present the evolution of Cant in the Canada Basin from 1993 to 2023, and a high-resolution distribution of Cant across the basin in 2022. We observe a basin-wide inventory increase in the Atlantic Layer (400-1000 m) of 5.5  ± 0.9 Tg C yr-1. Cant content in water entering the Canada Basin tracks increasing atmospheric input, time-lagged by 15-20 years; we anticipate Cant content of up to 65 μmol kg-1 in core Atlantic Water entering the basin by 2050.
Proprioception, our internal awareness of limb position and movement, is essential for shoulder stability through neuromuscular control. Following traumatic anterior instability (TAI), proprioceptive impairments may develop, potentially affecting upper limb function. These deficits vary across individuals. Previous studies have focused primarily on joint position sense and kinesthesia, while sense of force (SoF) deficits in chronic TAI remain largely unexplored. Moreover, clinical assessments are multifactorial and time-limited, and little is known about how SoF relates to common clinical measures. This cross-sectional study aimed to (1) determine whether chronic TAI is associated with shoulder SoF deficits compared with the contralateral side and a control group (CG) and (2) explore potential associations between SoF, maximal voluntary isometric strength (MVIC), and clinical questionnaires used in shoulder instability assessment. Participants aged 18-40 with TAI underwent SoF assessment in both shoulders. A matched CG (n = 37) was tested only on the dominant arm. Proprioceptive accuracy (PA) during SoF testing, MVIC, and shoulder questionnaires (Western Ontario Shoulder Instability Index, Shoulder Instability-Return to Sport after Injury, Disabilities of the Arm, Shoulder and Hand (short version)) were collected for analysis. The TAI group included 37 participants (27% female, n = 10; 73% male, n = 27), subdivided into non-surgical (TAINS, n = 18) and surgical (TAIS, n = 19) subgroups. Analysis revealed a significant main effect of intensity on PA, F(1,36) = 26.835, P < .001, η2 P = .427, but no significant main effect of group, F(1,36) = 0.545, P > .05, η2 P = .015, nor intensity × group interaction, F(1,36) = 0.131, P > .05, η2 P = .004. A significant main effect of side was observed, F(1,35) = 4.18, P < .05, η2 P = .107, with higher PA score on the affected side (10% ± 7.6) than the unaffected side (8.5% ± 6.8; Cohen's d = 0.196). Only the model for the 20% external rotation condition was statistically significant (adjusted R2 = 0.383; F(2,33) = 11.884,P < .001), with Disabilities of the Arm, Shoulder and Hand (short version) (β = 0.763, P < .001) and Shoulder Instability-Return to Sport after Injury score (β = -0.519, P = .002) emerging as significant predictors. Chronic TAI subjects showed no difference in SoF performance compared with the CG. Associations between SoF, MVIC, and clinical questionnaire outcomes were minimal, emphasizing the importance of interpreting clinical assessments collectively rather than in isolation.
Background and Objectives: Mid-term skeletal stability after bimaxillary orthognathic surgery in patients with facial asymmetry and a relatively normal sagittal skeletal relationship (ANB ≈ 1-4°) remains underreported. This study aimed to determine the three-dimensional characteristics and temporal changes in postoperative skeletal remodeling and symmetry maintenance in such patients. Materials and Methods: This retrospective case series included 25 patients (ANB ≈ 1-4°) undergoing bimaxillary orthognathic surgery. Three-dimensional computed tomography was performed preoperatively (T0), immediately postoperatively (T1), and at 6-12 months postoperatively (T2) to quantify bilateral condylar, ramus, mandibular body, maxillary parameters, and occlusal cant. Statistical analyses were performed using appropriate statistical methods for paired and repeated-measures designs. Results: Preoperatively, the long side exhibited significantly greater condylar volume, ramus height, and mandibular body length than the short side (all p < 0.05). Postoperatively, a "long-side reduction and short-side augmentation" strategy significantly reduced or reversed most bilateral differences, with a marked improvement in occlusal plane cant (p < 0.01). At T2, only mild bone remodeling was observed, with no significant loss of postoperative skeletal symmetry. The occlusal plane remained stable. Conclusions: In patients without marked sagittal discrepancies, bimaxillary orthognathic surgery effectively restores transverse and vertical skeletal symmetry. Mid-term stability is well maintained over 6-12 months, with only mild condylar and ramus remodeling, suggesting adaptive remodeling rather than relapse.
Rare neuromuscular diseases pose significant diagnostic challenges due to their genetic complexity and varied clinical presentations. Current diagnostic methods are often costly and inefficient, with primary care physician slacking adequate knowledge and effective diagnostic algorithms needed for accurate identification. This study addresses these challenges by developing PhenoRareAI, a model designed to improve the diagnosis of rare neuromuscular diseases such as Glycogen Storage Disease II and Spinal Muscular Atrophy. A total of 109 electronic health records from Huashan Hospital and external centers were used to develop and validate PhenoRareAI. The model integrates phenotype recognition algorithms and disease priority ranking models, which were rigorously tested against baseline models and validated with external datasets. The key outcome measures included the accuracy of phenotype recognition and disease diagnosis. PhenoRareAI demonstrated signifi cant improvement in phenotype recognition, achieving a micro F1-score and a macro F1-score of 27.40% and 25.16%, compared to the baseline PhenoPro model's scores of 11.44% and 14.65%. In terms of disease prioritization, the model achieved a top 1 ranking for 15 cases of Glycogen Storage Disease II and 17 cases of Spinal Muscular Atrophy after phenotype enhancement, with a mean reciprocal rank (MRR) of 37.37 and 57.21, respectively, significantly outperforming existing methods. PhenoRareAI signifi cantly enhances the diagnosis process for rare neuromuscular diseases, demonstrating strong potential for clinical application. These findings highlight the importance of integrating AI-driven diagnostic tools into healthcare to better navigate the complexities of rare disease diagnosis. The online version contains supplementary material available at 10.1007/s13755-026-00455-w.
Smile esthetics are crucial in orthodontics; however, orthodontists, general dentists, and laypersons perceive deviations differently, prompting the need for comparative evaluation. This study explored how these groups assess upper midline discrepancies, gingival display, maxillary cant, reduced upper teeth show, asymmetric upper lip elevation, and chin deviation, aiming to determine their combined impact on smile attractiveness and treatment needs while identifying thresholds for clinical intervention to enhance patient-focused care. This cross-sectional study was conducted in the Department of Orthodontics from August 2023 to October 2024. A frontal smile photograph was digitally manipulated to create six series of images (54 images), each with nine variations of upper midline displacement with respect to facial midline (-2 to +2 mm in 0.5 mm increments). Modifications included increased gingival exposure (gumminess), a 5° maxillary cant, reduced upper teeth show, 2 mm asymmetric upper lip elevation, and 2 mm chin deviation. Ninety evaluators (30 orthodontists, 30 general dentists, 30 laypersons) assessed the images using a visual analog scale (VAS) for attractiveness and indicated the need for treatment. Data were analyzed using one-way analysis of variance (ANOVA) for VAS scores and chi-square tests for treatment need, with intra-evaluator reliability assessed using intraclass correlation coefficients. Orthodontists demonstrated significantly higher sensitivity to minor upper midline deviations (-1.0 mm to 0.0 mm), maxillary cant, and asymmetric upper lip elevation compared to general dentists and laypersons (P < 0.05), with significant intergroup differences in perceived treatment need for all conditions except chin deviation at the ideal midline (0.0 mm). As deviations increased beyond 0.5 mm, perceptions converged, becoming statistically indistinguishable (P > 0.05). Orthodontists recommended treatment most frequently (>90% for 1.5-2.0 mm deviations), particularly for chin deviation and upper lip asymmetry, while laypersons showed the lowest treatment need perception (40%-60% No for minor deviations). Increased gingival display and chin deviation amplified the treatment need across groups, with same-side chin and midline deviations less noticeable than opposite-side deviations. Professional expertise significantly influenced the detection of subtle smile deviations, with orthodontists advocating treatment more often than laypersons. These findings emphasize the need for tailored patient communication to align clinical interventions with patient expectations and enhance patient-centered orthodontic outcomes.
Cytomegalovirus (CMV) infection is a significant complication in pediatric liver transplant recipients. This study aimed to assess the incidence, risk factors, and suspected effects of CMV infection in children undergoing liver transplantation and compared acyclovir and ganciclovir-based preventive therapy. The study included 92 patients who had liver transplants at Ege University Transplantation Unit between 2011 and 2021. Sixty-four pediatric patients with preoperative CMV immunoglobulin G (IgG) positivity were analyzed. Patients with early mortality, re-transplantation within 6 months, and CMV IgG negativity were excluded. The study consisted of 39 females (61%) and 25 males (39%), with a median age of 5.3 years at transplantation. Cytomegalovirus viremia occurred in 42 patients (65%), and CMV disease developed in 7 patients (10%). The median duration of CMV viremia was 40 days, and CMV disease was 105 days. Age was significantly associated with CMV disease development, with younger patients at higher risk (P = .007). The choice of antiviral treatment (acyclovir vs. valganciclovir) did not significantly impact the development of CMV vire mia or disease. Cytomegalovirus viremia and disease are common in pediatric liver transplant recipients, with younger age being a signifi cant risk factor for CMV disease. However, CMV viremia and disease did not significantly impact this cohort's graft loss, acute cellular rejection, or mortality. The choice of antiviral treatment and immunosuppression protocols did not influence CMV outcomes. These find ings highlight the need for vigilant monitoring and tailored management strategies for CMV in pediatric liver transplantation.   Cite this article as: Barut D, Kunay B, Yıldırım Arslan S, et al. CMV infection in pediatric liver transplantation and comparison of prophylaxis methods depending on donor serostatus. Turk J Gastroenterol. 2026;37(2):242-250.
Epicardial adipose tissue (EAT) is a component of visceral adiposity and mediates cardiac function and atherosclerosis via expression of several bioactive molecules. To evaluate the significance and relationship between epicardial fat thickness (EFT) and familial dyslipidemia and left ventricular function. This prospective case-control study was conducted at Assiut University Children's Hospital between September 2023 and August 2025. Twenty-one children with familial dyslipidemia and twenty-one age-, sex-, and BMI-matched healthy controls underwent clinical evaluation, lipid profile assessment, and transthoracic echocardiography, including measurement of epicardial fat thickness and left ventricular systolic and diastolic function according to American Society of Echocardiography guidelines. Dyslipidemic patients showed significantly higher total cholesterol (332.9 ± 222.3 mg/dL), triglycerides (391.4 ± 251.6 mg/dL), and LDL (154.3 ± 130.4 mg/dL) than controls (p < 0.001). Mixed hyperlipidemia was the most common type (47.6%). Echocardiography revealed increased epicardial fat thickness (2.88 ± 0.94 mm vs. 2.29 ± 0.57 mm; p = 0.018), larger left atrial (21.45 ± 3.86 mm; p = 0.031) and aortic diameters (17.54 ± 3.12 mm; p = 0.013). Triglyceride level was the only independent predictor of epicardial fat thickness (β = 0.437, p = 0.028).  Echocardiography revealed increased epicardial fat thickness and early cardiac remodeling. Serum triglycerides were the only independent predictor of EFT, suggesting its key role in subclinical cardiovascular risk among dyslipidemic children. • Epicardial adipose tissue is associated with cardiovascular risk factors in adults. • Children with primary dyslipidemia may develop early cardiac dysfunction. • This study demonstrates a signifi cant association between epicardial adipose tissue thickness and left ventricular function in children. • It highlights the potential role of epicardial fat as an early marker of cardiac involvement in pediatric dyslipidemia.
This study examined the relationship between smile aesthetics perception and personality factors among individuals with varying dental education backgrounds. This cross-sectional study included 412 participants categorized into four groups: pre-clinical dental students, clinical dental students, practicing dentists, and laypeople. Participants rated 20 photographs depicting variations in maxillary midline diastema, central incisor crown length, smile arc, gingival display, and incisal plane cant on a ten-point attractiveness scale. Personality factors were assessed using the NEO-FFI questionnaire, measuring Neuroticism, Extraversion, Openness, Agreeableness, and Conscientiousness. Dental professionals assigned significantly lower aesthetic scores to smiles with a 2.0 mm central incisor crown reduction, a 4.0 mm gingival display increase, and an incisal plane cant compared to non-dental raters (P < .05). Higher Agreeableness and Conscientiousness scores were associated with a preference for smiles without midline diastema (r = .118, 0.112; P = .017, 0.023). Higher Extraversion and Openness scores were associated with a preference for no gingival display (r = .147, 0.123; P = .003, 0.012). Perceptions of smile aesthetics varied significantly between dental and non-dental raters. Severity of smile discrepancy has a predictive role in aesthetic preferences, influencing the perceived attractiveness of specific smile characteristics. Personality factors had some associations with the perceived attractiveness of specific smile characteristics. Understanding how severity of smile discrepancy, personality traits and dental training influence esthetic preferences can help clinicians better tailor smile design and treatment communication to individual patient expectations.
Cervical cancer continues to pose a significant global health chal-lenge, with relatively high incidence and mortality rates among gynecological malignancies, particularly in developing countries. Complex etiological factors, including genetic predispo-sition, environmental influences, and biological mechanisms, regulate the progression of cer-vical cancer. Recent advances in understanding RNA splicing have contributed to a more de-tailed elucidation of these complexities, presenting a promising avenue for cervical cancer research. Here, we elucidate how alternative splicing events promote the synthesis of diverse protein isoforms that modulate tumorigenesis, progression, and metastasis. A PubMed and Google Scholar-based literature search was performed to identify genes involved in splicing mechanisms as biomarkers for cervical cancer. The search covered studies published between 2000 and 2024. The following keywords were used: "splicing," "splicing factors/genes," "gene regulation," "spliceosomes," "splicing as cancer hallmark," and "splicing mechanisms," in combination with "cervical cancer." We included only English-language publications related specifically to splicing in cervical cancer. We consolidated major splicing factors identified across genomic studies, clinical research, and mechanistic evaluations related to cervical cancer, which may serve as signifi-cant prognostic and diagnostic biomarkers. These consolidated findings highlight the potential impact of splicing on clinical decision-making, various therapeutic modalities, and personalized medicine. Furthermore, therapeutic strategies targeting splicing mechanisms could lead to novel interventions that im-prove clinical outcomes in cervical cancer patients.
This study aimed to evaluate the accuracy of maxillary repositioning using patient-specific implants (PSI) adapted for minimally invasive orthognathic surgery (MIOS), employing a simplified two-plate fixation protocol. Although all patients underwent bimaxillary orthognathic surgery, quantitative accuracy analysis was limited to the maxilla. This retrospective study included 20 patients treated with PSI tailored for MIOS. The surgical protocol involved limited soft tissue dissection and maxillary fixation using only two plates. Postoperative accuracy was assessed through computed tomography and voxel-based comparison with the virtual surgical plan. Discrepancies were measured in three linear axes and cant correction. Statistical analysis included Bland-Altman plots, effect sizes, and intraclass correlation coefficients (ICCs). All procedures were completed without intraoperative complications. Discrepancies between planned and postoperative positions ranged from 0.02 mm to 0.31 mm. ICCs exceeded 0.82 across all variables, with cant correction ICCs of 0.98 and 0.99. Effect sizes were negligible to small, and Bland-Altman analysis revealed no systematic bias. Customized PSI can be effectively adapted for use in MIOS protocols. Despite a reduced fixation strategy, high accuracy and reproducibility were achieved. These findings support the use of simplified PSI workflows as a precise and less invasive alternative in modern orthognathic surgery.
The 2023 Kahramanmaraş (M7.8) and Elbistan (M7.6) earthquakes in Türkiye provide a profound case study in multi-fault rupture dynamics. We update a pre-existing Coulomb stress model¹ to analyse the historical and immediatestress conditions that caused this doublet. Our fi ndings indicate the Pazarcık segment of the Kahramanmaraşearthquake source rupture failed under high historical loading (12 bars since 1822) and immediate Coulomb stresstransfer (~2.5 bars) from the initial Narlı rupture. The pattern of stress changes is consistent with the observations ofsuper-shear rupture to the Northeast of the Pazarcık segment and sub-shear rupture speeds to the south-west.Conversely, the Elbistan earthquake was primarily triggered by signifi cant normal stress reduction (unclamping; ~11bars) from the mainshock, which overcame an initially negative stress state, and creating favourable conditions forthe observed super-shear rupture. This sequence underscores the critical role of combined coseismic and long-termstress transfer in driving complex, cascading fault ruptures.
Herbal medicines have gained remarkable popularity due to their natural origins and potential medicinal value. Nevertheless, they are chemically complex and pose signifi-cant pharmacological challenges. This review focuses on the key aspects influencing their clinical use: their variable bioavailability, complex pharmacokinetics (ADME), and potential for interactions. A primary concern is herb-drug interactions, with special emphasis on the modulation of drug-metabolizing enzymes by specific phytoconstituents, which can alter drug concentrations to an extent that may be life-threatening, causing either increased toxicity or therapeutic failure. The pharmacological profile is further complicated by the complex effects of constituents, such as synergistic or antagonistic actions, which make predicting therapeutic response and safety difficult. A critical challenge in this field is the frequent dis-connect between in vitro findings and in vivo outcomes, underscoring the importance of phar-macokinetic data, particularly bioavailability, for accurate clinical risk assessment. Safety is a paramount concern, as it is often compromised by inconsistent standardization and quality control, leading to batch-to-batch variability, potential adulteration, and contamination. The absence of stringent regulation impairs therapeutic consistency and introduces health risks. To address these issues, advanced approaches are being employed to improve bioavailability, including novel drug delivery systems that enhance solubility and stability. This review em-phasizes that a rigorous, phytoconstituent-centric approach is essential for navigating the complexities of herbal medicine. By addressing challenges in pharmacokinetics, interactions, safety, standardization, and bioavailability through rigorous scientific investigation and em-bracing future perspectives, such as in silico modeling and improved regulatory frameworks, the quality, safety, and effectiveness of herbal treatments can be ensured, supporting their responsible integration into modern, evidence-based medical systems.
Patellofemoral pain (PFP) is a chronic knee pain disorder that has high recurrence rates after treatment. While longer pain duration (>4 months) is one of the primary mediators for poor PFP prognosis, there are no clinical studies testing patients' response to early physiotherapy. This study aims to determine the effectiveness of an early physiotherapy programme compared with a delayed-delivery programme for people with PFP at short-term, medium-term and long-term follow-up. Young adults (18-35 years old) with PFP will be recruited in Brazil, the USA and Belgium. 152 eligible participants will be assessed at baseline and allocated to early (treatment initiated between 4 and 12 weeks after pain onset) or delayed (treatment initiated after ≥6 months after pain onset) intervention groups. The programme (education plus exercise therapy) will be similar for both groups and consists of a 12-week online programme with individual supervised and unsupervised sessions performed three times a week. Primary (self-reported pain, function, recovery and treatment response) and secondary (psychosocial features) outcomes will be reassessed immediately and at 3, 6 and 12 months after treatment completion. Regression models with generalised estimating equations or χ² tests will determine group*time interactions (intention-to-treat analyses). The timing of physiotherapy may have a significant effect on patient outcomes with PFP. This study can provide relevant clinical messages about early management of PFP.
Complete androgen insensitivity syndrome (CAIS) is a rare X-linked recessive disorder due to androgenreceptor mutations, characterised by a 46,XY karyotype, female phenotype, and undescended testes. This reportaims to illustrate the clinical management and the rare synchronous pathology of multiple gonadal tumors in a 60-year-old phenotypic female with long-standing CAIS. A 60-year-old patient presented following the incidental detection of bilateral adnexal masses. Diagnosticevaluation included imaging (USG/MRI) to assess internal reproductive organs and gonadal morphology, alongsidehormonal analysis (LH, testosterone, and estradiol). A laparoscopic bilateral gonadectomy was performed to managethe suspected neoplasia. Imaging demonstrated the absence of the uterus and ovaries, confi rming bilateral solid gonadal lesions.Hormonal analysis showed elevated LH with normal testosterone and estradiol levels. Histopathology of the excisedtissues revealed a complex and heterogeneous presentation: the left gonad contained a Sertoli cell tumor, a Leydigcell tumor, and sclerotic seminiferous tubules; the right gonad showed a Sertoli cell adenoma. This rare synchronous pathology illustrates the signifi cant heterogeneity of neoplasia associated withCAIS. Current evidence supports individualized postpubertal gonadectomy to balance the risk of malignancy againstthe benefi ts of endogenous hormonal production. The fi ndings emphasize that long-term follow-up and tailoredsurgical timing are essential components in the clinical management of CAIS.
A 28-year-old woman with facial asymmetry after aligner treatment visited our hospital. She complained of an asymmetric gummy smile and a deviated mental area developed after clear aligner treatment. On CT examination, occlusal cant was found, leading to facial asymmetry. We made a clinical diagnosis of jaw deformity with an asymmetric face, and recommended her orthognathic surgery using wire orthodontics. She accepted jaw surgery; however, she refused wire orthodontic treatment. Therefore, we selected bimaxillary osteotomy with a surgical-first approach using her clear aligner to correct the inclined occlusal plane and improve the deviated jaw. The functional occlusion could be established, and improvement of facial form could be gained with a proper occlusal plane. This case report is a rare case, in which retreatment of the surgical approach for bimaxillary osteotomy for marked facial asymmetry developed after aligner treatment. We must be aware of the necessity of thorough and careful examination to avoid misdiagnosis.
Primary care providers (PCPs) play a key role in addressing sleep-related issues such as insomnia but often lack training in sleep medicine. The UCI Train New Trainers (TNT) Primary Care Psychiatry Fellowship includes training on sleep disorder assessment and management. We evaluated the programs' ability to enhance PCPs' skills in identifying and managing behavioral sleep disorders. Case assessments were administered twice to fellows, at the start and end of an educational conference. Fellows selected four of ten listed psychiatric and sleep diagnoses for each case. Fellows also underwent pre-, mid-, and post-fellowship surveys to determine whether training was associated with changes in comfort diagnosing and treating sleep disorders. Fellows showed a significant improvement in sleep disorder identification after training compared to before. They also reported significant improvement in comfort diagnosing insomnia, accuracy identifying circadian rhythm disorders, and comfortability administering CBT-I. Use of structured sleep assessments increased but remained less frequent than mood disorder screening tools. Fellows exhibited increased comfort and competence in managing behavioral sleep medicine, particularly insomnia and circadian rhythm sleep disorders with brief didactic training. Further training in non-pharmacological treatments and greater use of standardized sleep assessments is warranted to optimize patient outcomes in primary care settings.
Immune dysregulation, including autoimmunity, autoinflammation, allergy, and malignancy predisposition, adds significant disease burden in primary immune disorders (PID) and inborn errors of immunity (IEIs). We evaluated whether the 5-graded immune deficiency and dysregulation activity (IDDA2.1) score, encompassing 21 organ involvement and disease burden parameters, supports diagnosis across a wide spectrum of IEIs. From April 2022 to November 2024, collaborators from 84 centers collected 1,043 IDDA score datasets from 825 patients across 89 IEIs (17 disorders with ≥10 patients each; range, 1-196 per IEI), including 177 scores from 141 treated patients. Supervised machine learning models (k-nearest neighbors, support vector machine, logistic regression, random forest) classified patients into disease groups and ranked corresponding predictive features, while unsupervised uniform manifold approximation and projection (UMAP) visualized disease-specific clustering. Feature analysis reflected clinicians' recognition of IEI patterns and confirmed internal IDDA score consistency. Phenotype profiles in treated patients remained informative, inversely reflecting anticipated treatment-dependent phenotype amelioration. UMAP effectively distinguished IEIs by IDDA2.1 profiles. Genetic disorder prediction achieved 73% overall accuracy, 70% for the correct monogenic IEI, and 93% within the top 3 predictions; classification reached 43% for IEI-International Union of Immunological Society categories and 59% for 12 "cardinal" IEIs (25 genes). Random forest feature importance analysis can inform targeted clinical screening for key disease manifestations. The top 3 prediction approach demonstrates diagnostic potential, but improved accuracy will require larger, globally shared datasets. Small sample sizes for rare diseases highlight the necessity of broader collaboration to enhance AI-assisted clinical decision-making in the future.
Malnutrition among older hospitalized adults with chronic heart failure (CHF) is associated with adverse clinical outcomes, yet reliable early risk stratification tools remain lacking. This study aimed to develop and validate a machine learning (ML) model for malnutrition risk stratification in this population. Malnutrition among older hospitalized adults with chronic heart failure (CHF) is associated with adverse clinical outcomes, yet reliable early risk stratification tools remain lacking. This study aimed to develop and validate a machine learning (ML) model for malnutrition risk stratification in this population. Malnutrition prevalence was 44.1% (348/790). In the internal testing, CatBoost (CAT) achieved superior performance with an AUC of 0.901 (95% confidence interval [CI]: 0.858-0.943), accuracy of 0.840, recall of 0.753, and the lowest Brier score of 0.113. This model demonstrated strong calibration, clinical utility, and the highest composite score (62/64). External validation confirmed CAT's generalizability (AUC: 0.916, 95% CI: 0.887-0.945). SHAP analysis identified body mass index (BMI), calf circumference, New York Heart Association (NYHA) classification, age, and diabetes as signifi-cant contributors to malnutrition risk. The CAT-based model effectively stratifies malnutrition risk in older hospitalized CHF patients, offering a tool for early intervention to improve outcomes. Further multicenter prospective studies are needed to validate its real-world applicability.
Dipeptidyl peptidase-1 (DPP1) inhibitors prevent the activation of neutrophil serine proteases and reduce exacerbations in people with bronchiectasis. We previously identified a novel effect of DPP1 inhibitors in reducing the neutrophil pseudoenzyme azurocidin-1 (AZU1). The aim of this study was to investigate the role of AZU1 in the pathophysiology of bronchiectasis. Sputum AZU1 concentrations were analysed in multiple cohorts. These consisted of two observational cohorts of patients with bronchiectasis (EMBARC BRIDGE cohort 1 and cohort 2) and a cohort of patients with chronic obstructive pulmonary disease (COPD; TARDIS COPD cohort) to correlate AZU1 with disease severity and exacerbations. A rhinovirus challenge study was used to investigate AZU1 concentrations during experimental exacerbation in COPD, people who smoke, and controls. A post-hoc analysis of the phase 2 WILLOW trial of brensocatib versus placebo was used to assess the effect of DPP1 inhibition on airway AZU1. Higher AZU1 sputum concentration was associated with increased bronchiectasis disease severity index (p<0·0001), decreased percentage predicted forced expiratory volume in 1 second (r=-0·4662, p<0·001), and increased exacerbation frequency (p<0·0019; EMBARC cohort 1, n=197). AZU1 was associated with radiological severity (Reiff score), symptoms (quality of life bronchiectasis respiratory symptom score), and bacterial infection (sputum microbiology and 16S microbiome alpha diversity; highest levels of AZU1 were found in airway samples with Pseudomonas aeruginosa; p<0·0001; EMBARC cohort 2, n=144). Bronchiectasis patients with bacterial and viral exacerbations had increased concentrations of AZU1 (p=0·0003; n=96). These findings were extended to COPD, in which AZU1 was related to COPD severity (COPD cohort, n=101), and in patients with COPD challenged with rhinovirus A16, AZU1 was increased at day 9 post-challenge (p<0·001; n=9). In-vitro AZU1 impaired ciliary function and epithelial integrity, suggesting a mechanism by which AZU1 drives disease pathogenesis. In a post-hoc analysis of the WILLOW trial, AZU1 was the most downregulated protein with brensocatib treatment (brensocatib 10 mg, n=71; brensocatib 25 mg, n=73; and placebo, n=71). Over 24 weeks, AZU1 was significantly reduced by DPP1 inhibition (p<0·0001). AZU1 was identified as a novel marker of disease severity in bronchiectasis, associated with bacterial infection and exacerbation, and targeted by DPP1 inhibition. EMBARC3 and Insmed.