Search Results (7,206)

Background and Clinical Significance: Multiligamentous knee injuries (MLKIs) are uncommon but severe injuries associated with instability, neurovascular compromise, and long-term functional impairment. Irreducible knee dislocations are a distinct subgroup requiring urgent intervention because soft-tissue interposition may prevent closed reduction and place the limb at risk of skin necrosis and vascular compromise. This report reviews current concepts in MLKI management and presents a complex KD-IV irreducible knee dislocation treated with a staged surgical strategy. Case Presentation: A 56-year-old woman presented 24 h after a skiing injury with a grossly deformed knee, multidirectional instability, and an anteromedial “pucker sign”. Magnetic resonance imaging demonstrated a KD-IV injury with complete rupture of the anterior cruciate ligament, posterior cruciate ligament, and medial collateral ligament, associated with capsular disruption and intra-articular soft-tissue interposition causing irreducibility. Urgent open reduction was performed. The first stage included reduction of the incarcerated capsule, capsular repair, and reconstruction of the posteromedial corner and medial collateral ligament using a semitendinosus autograft. Delayed reassessment at 6 months demonstrated satisfactory stability, minimal residual anterior laxity, and no subjective instability; therefore, anterior cruciate ligament reconstruction was not performed. At final follow-up, the patient had near-full range of motion, no significant valgus instability, and no arthrofibrosis or vascular complications. Conclusions: Management of MLKIs should be individualized according to reducibility, soft-tissue condition, neurovascular status, and functional demands. Irreducible KD-IV dislocations with a pucker sign require urgent open reduction. In selected patients, staged reconstruction may reduce postoperative stiffness and allow selective omission of cruciate ligament reconstruction when satisfactory functional stability is achieved. Full article

Background: Tirzepatide is a novel therapeutic option for the management of metabolic disorders which has started to be implemented in routine practice. The study aimed to analyze the effectiveness of tirzepatide use and patient education in the field of healthy eating and weight loss, based on real-life data from the practice of a primary care physician, in metabolic syndrome (MetSyn) patients during a one-year follow-up period. Methods: This is a retrospective study based on real-life data of 118 MetSyn patients who were under the supervision of a general practitioner (GP). Analysis was conducted on 62 patients supported by trizepatide (2.5 mg for 4 weeks, then 5 mg for 4 weeks and 7 mg for 46 weeks) with dietary education and 56 patients that underwent dietary education with motivation only. Lipid profile, glucose level and blood pressure were assessed. Body Mass Index (BMI), waist-to-height ratio (WHtR), A Body Shape Index (ABSI), Lipid Accumulation Product (LAP), Visceral Adiposity Index (VAI) and Body Roundness Index (BRI) were calculated. The KomPAN^® questionnaire was used for dietary assessment and WHO Quality of Life-BREF for the quality of life assessment at 52 weeks. Results: Patients from both groups significantly reduced their body weight and WC and the values of the following indices: BMI, WHtR, ABSI, LAP and BRI. A significant increase in LDL cholesterol and triglyceride values was observed in both groups and a significant decrease in glucose level only in the group with tirzepatide combined with dietary modification. Energy value, energy density of food and nutrient intake did not differ between groups, while the intensity of beneficial nutritional features (pHDI-10) was low. Significant differences in patients’ QoL were observed, especially in the domain related to mental health (higher in trizepatide + diet group). Conclusions: Support in primary care by a physician was successful from a long-term perspective in the group using tirzepatide in combination with diet modification as well as in the group based on dietary modification only. The data do not indicate a significant advantage of any one approach for patients, prioritizing an individualized approach to treatment. Full article

Background/Objectives: Lung cancer (LC) remains the leading cause of cancer-related death worldwide, despite advances in systemic and targeted therapies. A mechanism of survival of tumor cells is metabolic reprogramming, characterized by increased glucose uptake, aerobic glycolysis, and alterations in mitochondrial function. These adaptations seem to support tumor growth, immune evasion, and therapeutic resistance. In parallel, supportive care and specifically nutritional interventions have become essential components of modern oncology. The interplay between metabolic reprogramming and targeted nutritional strategies represents a promising area of investigation that bridges tumor biology with supportive care, aiming to enhance both therapeutic efficacy and patient quality of life. Methods: This narrative review explores the biological and pathophysiological rationale for the ketogenic diet (KD) as a possible complementary intervention in LC management and summarizes the published preclinical and clinical data supporting this rationale. Results: We discuss key aspects of tumor metabolism, including the Warburg effect, glucose dependency, oxidative stress regulation, fatty acid metabolism, lactate cycling and tumor microenvironment interactions, with particular emphasis on how carbohydrate restriction and ketosis may exacerbate mitochondrial dysfunction in cancer cells and modulate inflammatory pathways. Furthermore, we summarize available preclinical and clinical evidence evaluating the KD in oncology and, more specifically, in LC, focusing on feasibility, safety, metabolic effects, and potential synergy with chemotherapy, radiotherapy, and immunotherapy. Conclusions: While preclinical models suggest enhanced treatment efficacy, clinical data remain limited and heterogeneous, with patient adherence representing a major challenge. Further well-designed longitudinal studies are required to clarify the therapeutic role of the ketogenic diet in lung cancer. Full article

Systemic sclerosis (SSc) is a complex autoimmune connective tissue disease characterized by microvascular dysfunction, immune activation, and progressive fibrosis affecting multiple organs, including the heart. Myocardial involvement represents an important but frequently underrecognized manifestation of SSc and may develop even in the absence of overt clinical symptoms. Cardiac manifestations include ventricular dysfunction, arrhythmias, conduction abnormalities, and heart failure, contributing substantially to morbidity and mortality. The underlying pathophysiology involves coronary microvascular dysfunction, immune-mediated myocardial inflammation, and progressive myocardial fibrosis, which often precede clinically apparent cardiac disease. This review aims to summarize the current understanding of myocardial involvement in SSc and to provide a comprehensive overview of contemporary multimodality cardiovascular imaging techniques for its detection, characterization, and risk stratification. A comprehensive overview of the current literature was conducted focusing on established and emerging cardiovascular imaging modalities for the evaluation of myocardial involvement in SSc. Particular attention was given to echocardiography, cardiac magnetic resonance (CMR), nuclear imaging techniques including positron emission tomography (PET) and single-photon emission computed tomography (SPECT), and cardiac computed tomography (CT). Recent advances in imaging biomarkers, parametric mapping, myocardial strain analysis, and emerging technologies such as artificial intelligence (AI), radiomics, and molecular imaging were also considered. Multimodality cardiovascular imaging plays a central role in the early detection and comprehensive assessment of myocardial involvement in SSc. Advanced imaging techniques enable improved identification of subclinical myocardial dysfunction, microvascular impairment, inflammation, and fibrosis. An integrated imaging approach combining echocardiography, CMR, nuclear imaging, and CT may facilitate earlier diagnosis, enhance risk stratification, and ultimately improve cardiovascular outcomes in patients with SSc. Full article

Background: Discrepancies are frequently observed between liver steatosis grading assessed by conventional B-mode ultrasonography and vibration-controlled transient elastography (VCTE) with controlled attenuation parameter (CAP). This study aimed to identify factors associated with these differences and to evaluate whether the two imaging methods provide comparable steatosis classifications. Methods: We conducted a retrospective cross-sectional observational study including 130 hospitalized patients evaluated over a two-year period who underwent laboratory testing, abdominal ultrasonography, and transient elastography. The analyzed variables included demographic characteristics, nutritional status, comorbidities, and biochemical parameters such as alanine aminotransferase (ALAT), total cholesterol, triglycerides, gamma-glutamyl transferase (GGT), and the fibrosis-4 index (FIB-4). Patients were classified into two groups: concordant steatosis grading between the two methods (n = 61) and discordant results (n = 69). Results: Concordant steatosis grading was more frequently observed in patients with serum total cholesterol > 200 mg/dL (45.9%) and FIB-4 values between 1.45–3.25 (44.2%). A trend toward higher concordance was also observed in patients with elevated triglycerides. In contrast, viral liver disease was significantly associated with discordant results (26.2%). Higher fibrosis stages assessed by VCTE (F ≥ 2) and FIB-4 values > 3.25 showed a non-significant trend toward discordance. Conclusions: Several clinical and biochemical factors influence the agreement between ultrasound and VCTE-based CAP in the assessment of hepatic steatosis. Elevated cholesterol and intermediate FIB-4 values were associated with concordant results, whereas viral liver disease was associated with discordance between the two imaging modalities. Full article

Background/Objectives: Autophagy plays a role in systemic lupus erythematosus (SLE) pathogenesis. Nevertheless, the specific genetic determinants underpinning this process remain poorly characterized. Summary data-based Mendelian randomization (SMR) analysis was therefore utilized to pinpoint autophagy-related genes associated with SLE risk. Methods: We analyzed 700 autophagy-related genes, integrating methylation quantitative trait loci (mQTL), expression QTL (eQTL) from blood and relevant tissue, and protein QTL (pQTL) data with genome-wide association studies (GWAS) data on SLE from the IEU dataset (discovery). GWAS data from FinnGen and the GWAS Catalog were used as replication datasets. Colocalization analysis identified shared genetic variants. Blood samples from 10 healthy control and 20 SLE patients were collected and analyzed for the expression of candidate genes. Results: Our SMR analysis identified suggestive associations between NLRP6 expression (OR = 0.528, 95%CI = 0.291–0.96) and p27Kip1 protein abundance (OR = 0.269, 95%CI = 0.08–0.904) with SLE susceptibility in the discovery cohort, supported by colocalization evidence. Additionally, we found that the methylation of the NLRP6 promoter (cg06432119) was significantly increased, while NLRP6 expression and p27Kip1 level were significantly decreased in SLE patients compared to controls. Furthermore, NLRP6 mRNA expression was significantly negatively correlated with the SLE severity (SLEDAI-2000). Conclusions: These findings not only prioritized candidate genes via SMR analysis but also provided evidence of epigenetic dysregulation of NLRP6 and its correlation with disease activity in SLE, thereby offering novel insights into the underlying mechanisms. Full article

Research into effective predictive markers and therapeutic interventions for COVID-19 remains of considerable interest. Vitamin D may be relevant, especially in frail populations in whom deficiency is more prevalent. In this prospective observational cohort study, 139 patients with moderate-to-severe COVID-19 who were hospitalized during the third wave of the pandemic in Italy were enrolled. Plasma vitamin D concentrations (both 25-hydroxyvitamin D-25(OH)D and 1,25-dihydroxyvitamin D-1,25(OH)₂D) together with parathyroid hormone levels were measured using a chemiluminescent assay validated for clinical use on automated laboratory platforms. Plasma vitamin D levels were below the sufficiency threshold. Notably, 25(OH)D concentrations were significantly lower in patients who experienced a negative outcome (11.10 [8.80–16.20] vs. 15.25 [9.90–24.80] ng/mL, p = 0.0450) and significantly higher in patients with rapid clinical recovery (15.25 [10.70–24.80] vs. 13.30 [7.47–19.60] ng/mL, p = 0.0446) compared with all other patients. Through multivariable logistic regression analysis, higher 25(OH)D levels at the time of hospitalization were confirmed as an independent predictor of favorable outcome. A plasma 25(OH)D concentration above 11.10 ng/mL predicted favorable disease resolution, with a positive likelihood ratio of 1.40 (IQR: 1.05–1.87). In conclusion, our findings support plasma vitamin D levels as an independent predictor of clinical outcomes in patients hospitalized with COVID-19 pneumonia. Full article

Juvenile idiopathic arthritis (JIA) represents the most common cause of chronic arthritis in childhood; however, not all early-onset arthropathies are inflammatory in origin. We report the case of a 4-year-old girl initially diagnosed with oligoarticular JIA and treated with methotrexate followed by a tumor necrosis factor inhibitor, without significant clinical improvement and despite persistently normal inflammatory markers. Clinical reassessment raised suspicion of a non-inflammatory arthropathy, supported by characteristic radiographic findings including metaphyseal flaring of the distal femora and proximal tibiae. Genetic analysis identified compound heterozygous pathogenic variants in the PRG4 gene, confirming the diagnosis of camptodactyly–arthropathy–coxa vara–pericarditis (CACP) syndrome (OMIM #208250). PRG4 encodes lubricin, a mucin-like glycoprotein essential for boundary lubrication of articular cartilage and maintenance of synovial joint homeostasis. Loss-of-function variants disrupt joint lubrication, leading to mechanical synovial hyperplasia and chronic non-inflammatory joint effusion. This case highlights common diagnostic pitfalls in pediatric rheumatology and underscores the importance of considering genetic causes of chronic arthropathy when clinical and laboratory features are atypical for inflammatory disease. Early molecular diagnosis prevents unnecessary immunosuppressive therapy and enables appropriate multidisciplinary management. Full article

Background and Objectives: Patients with rheumatoid arthritis (RA) are found to have a higher risk of dental diseases. Although herbal medicines (HMs) have long been used to treat various conditions, few studies focus on its impact on dental diseases. In this longitudinal cohort study, we assessed the correlation between HM use and risk of dental diseases in RA groups. Materials and Methods: A total of 2359 persons with RA aged 20–80 who were free of dental diseases between 2001 and 2010 were retrospectively enrolled from nationwide register-based data. They were then classified into HMs and non-HMs groups based on whether they ever used combined HMs after RA onset. Incidence rate and hazard ratios (HRs) of dental diseases were estimated for both groups by the end of 2013 via fitting Cox proportional hazards model. Results: Incidence rate of dental disease was reported to be lower in the HMs group than in the non-HMs group (90.21 per 1000 person-years versus 106.94 per 1000 person-years, respectively). RA individuals treated with HMs showed a significantly lower risk of dental diseases, especially dental caries, pulpitis, periodontitis, and stomatitis. Among commonly prescribed formulas, eleven herbal products significantly associated with a lower risk of dental diseases, such as Hai-Piao-Xiao, Yan-Hu-Suo, Chuan-Niu-Xi, Mo-Yao, Olibanum, Bei-Mu, Mu-Gua, Gui-Zhi-Shao-Yao-Zhi-Mu-Tang, Shao-Yao-Gan-Cao-Tang, Xue-Fu-Zhu-Yu-Tang, and Ping-Wei-San. Conclusions: The addition of HMs treatment may have advantages to proactively prevent sequent risk of dental disorders for persons with rheumatic diseases. A deeper exploration focusing on pharmacological action is needed to provide more reliable evidence for the improvement of susceptible individuals’ oral hygiene. Full article

Background: Early postoperative changes in creatinine-based estimated glomerular filtration rate (eGFR) after bariatric surgery can be misread as a kidney injury. During rapid weight loss, indexing eGFR to a fixed body surface area (BSA) of 1.73 m² may alter apparent trajectories. We compared absolute (mL/min) and BSA-indexed (mL/min/1.73 m²) eGFR changes after sleeve gastrectomy, stratified by baseline glomerular hyperfiltration (GH). Methods: In this retrospective cohort of 145 adults undergoing laparoscopic sleeve gastrectomy, serum creatinine was obtained at baseline (≤30 days pre-op) and 3 months (post-op days 75–105). Indexed eGFR was calculated with the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 2021 creatinine equation; BSA with the Mosteller formula; and absolute eGFR as indexed eGFR × (BSA/1.73). GH was defined as indexed eGFR ≥ 120 mL/min/1.73 m². A REML mixed-effects model (Group, Time, Group × Time) with patient-cluster bootstrap inference was used. An age-adjusted sensitivity model including Age and Age × Time was also fitted. Results: Fifty-four participants (37%) met the GH criteria. Absolute eGFR declined by −26.6 mL/min in GH versus −17.3 mL/min in non-GH (difference-in-differences [DiD] −9.3 mL/min; 95% CI −13.9 to −4.7; p < 0.001). The indexed eGFR changes were smaller (−4.2 vs. −0.5 mL/min/1.73 m²; DiD −3.7; 95% CI −7.3 to −0.03; p = 0.048; bootstrap p_sign = 0.052). In the age-adjusted sensitivity model, the Group × Time interaction for absolute eGFR attenuated but remained statistically significant (−6.57 mL/min; 95% CI, −13.09 to −0.06; p = 0.048), whereas the corresponding interaction for indexed eGFR was attenuated and no longer statistically significant (−3.99 mL/min/1.73 m²; 95% CI −9.15 to 1.16; p = 0.129). Conclusions: Within three months after sleeve gastrectomy, participants with higher baseline indexed filtration showed a larger decline in absolute eGFR but only a small change in indexed eGFR. These results show that early postoperative creatinine-based eGFR trajectories are scale dependent and should be interpreted cautiously during rapid weight loss. Because postoperative acute kidney injury (AKI) was not adjudicated and direct kidney function markers were unavailable, this study does not distinguish physiological hemodynamic change from structural kidney injury. Reporting both absolute and indexed eGFR may improve early postoperative interpretation and help align dosing decisions with rapid changes in body size. Full article

Background/Objectives: Pulmonary vein isolation (PVI) is the gold standard for atrial fibrillation (AF) ablation. Recently, a randomized study showed that adding voltage-guided ablation (VGA) in persistent AF cases was beneficial. The aim of the present study was to evaluate the safety, efficacy and predictors of success of redo procedures after VGA in an exclusively persistent AF cohort. Methods: Data are derived from the prospective Erfurt AF ablation registry. Starting in 2015, ablation procedures were performed using CARTO3D and VGA. Patients receiving their first redo procedure between 01/2015 and 08/2022 were included. Follow-up included 72 h Holter ECG or device interrogation, ECG, symptom-triggered event recording, and questioning at 3 and 12 months after the redo procedure. The primary endpoint was freedom of recurrence of AF or atrial tachycardia (AT) without drugs between 3 and 12 months. Results: Altogether, 683 patients received a first VGA between January 2015 and May 2022, and 77 patients had their first redo procedure occurring 20 ± 17 months after the first procedure. During the first redo procedure, reconnected PVs were found in 44%, reconnected lines in 23% and new or progressive LVZs in 57% of patients. Complications occurred in two patients (2.6%). During follow-up one patient died, and one did not participate due to aphasia. It was found that 69% were free of recurrence and 61% were free of recurrence off drugs. Patients with recurrence were older than those without recurrence off drugs (73 ± 6 versus 69 ± 9 years, p = 0.049). Conclusions: Redo procedures after VGA in persistent AF have comparatively good results; although, many patients have progressive fibrosis. Full article

In rheumatoid arthritis (RA), activated synovial tissue-derived mesenchymal stem cells (MSC) acquire a pathogenic phenotype and produce pro-inflammatory cytokines, chemokines, metalloproteinases, pro-osteoclastic and pro-angiogenic factors. The acquisition of this aggressive phenotype might be due to modified expression of micro-RNAs. We aimed to clarify the role of specific micro-RNAs (miR-146a-5p, miR-221-3p, miR-34a-3p, miR-150, miR-203a-3p and miR-155-3p) in an in vitro model of RA. Methods: Micro-RNA expression was determined in RA patient plasma and in commercial human synovial tissue-derived MSC-like cells stimulated with a panel of pro-inflammatory mediators (poly I:C, TNF-α, IL-1β, IFN-γ) to mimic the rheumatoid arthritis pathogenic setting. Next, unstimulated cells or TNF-α stimulated cells were transfected with miR-146a-5p mimic or miR-221-3p mimic. Protein and/or mRNA expressions of chemokines, cytokines, VEGF, MMPs and RANKL were determined by ELISA or qRT-PCR. MiR-34a-3p, miR-146a-5p, miR-150, miR-221-3p and miR-203a-5p were upregulated in RA patient plasma versus healthy controls. Moreover, synovial tissue-derived MSC-like cells expressed miR-146a-5p and miR-221-3p in response to pro-inflammatory mediators. Overexpression of miR-146a-5p increased CCL2 and CXCL8 expression and miR-221-3p increased IL-1β and IL-6 expression in synovial tissue-derived MSC-like cells stimulated with TNF-α. Conclusion: Overexpression of miR-146a-5p and miR-221-3p might favour inflammation and participate in rheumatoid arthritis pathogenesis. Full article

Background and Objectives: Angiogenesis plays an important role in many types of cancers, including melanoma. Mast cells are among the most important cellular partners involved in the angiogenic process. The purpose of the present study is to establish the interrelations between microvessels and mast cell density, and to describe the prognostic role of mast cells in malignant melanoma. Materials and Methods: A total of 92 cases of melanoma were evaluated. Hematoxylin–eosin staining and CD34/mast cell tryptase double immunostaining were performed. Results: Of the cases, 28 were classified as T1 (30.43%), 31 as T2 (33.69%), 21 as T3 (22.82%), and 12 as T4 (13.04%). Mast cells were mainly located in the infiltrate area in cases with inflammatory infiltrate. Few mast cells were observed in the absence of infiltrate. A granular type was observed in intratumoral areas with an isolated and perivascular distribution of mast cells. A significant correlation was found between intratumoral MVD and intratumoral MCD (mast cell density) in T1 and T4 melanoma cases (p = 0.0001 and p = 0.0029, respectively). In T2 cases, significant correlations were found between intratumoral and peritumoral MVD and G (p = 0.0169, p = 0.0003), between intratumoral MCD and MVD (p = 0.0041), and between peritumoral MVD and the number of peritumoral mast cells (p = 0.0011). T3 cases showed a significant correlation between the density of intratumoral mast cells and peritumoral ones (p = 0.001); between the MVD and mast cell density of the intratumoral area (p = 0.0001); between the intratumoral MVD and peritumoral mast cell density (p = 0.0001); between the MVD and mast cell density of the peritumoral area (p = 0.0325); and between the peritumoral MVD and intratumoral mast cell density (p = 0.0458). Conclusions: Both intratumoral and peritumoral mast cells were found to participate in melanoma progression, and they showed greater involvement in the early phases of angiogenesis in malignant melanoma. Full article

Plasma circular RNAs (circRNAs) are stable RNA molecules found in blood, which makes them potential noninvasive biomarkers for acute myocardial infarction (MI). The aim of this study was to describe the plasma circRNA profile in patients with acute MI and to identify circRNA markers that may help detect heart injury and reflect the biological processes involved. We compared plasma samples from patients with acute MI and healthy controls using total RNA sequencing with unique molecular identifiers (UMIs). After sequencing, reads were processed through quality control, alignment, duplicate removal, and circRNA detection. Differential expression was analyzed after adjusting for age, sex, smoking, and technical factors. Several circRNAs were significantly different between MI cases and controls and were able to separate the two groups in principal component and receiver operating characteristic analyses. Among the most increased circRNAs were hsa-PASK_0004, hsa-STXBP3_0002, hsa-RCAN3_0002, and hsa-RANBP9_0044, while hsa-HIF1A_0002, hsa-SUZ12_0049, hsa-PNRC1_0001, and hsa-RAB2A_0002 were decreased. Several candidates showed AUC values above 0.7. Pathway analysis linked the host genes of these circRNAs to inflammation, platelet activation, coagulation, and cardiomyocyte stress responses. Overall, these findings suggest that circulating circRNAs may serve as useful blood-based markers of MI and provide insight into the molecular changes that accompany acute MI. Full article

Objective: The objective of this study was to characterize real-world distributions of C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) across major rheumatic diagnoses and to quantify concordance/discordance patterns and combined CRP-ESR inflammatory phenotypes. Methods: We retrospectively extracted all CRP and ESR tests performed in a tertiary university rheumatology hospital (January 2018–December 2023), including ICD-10-coded diagnoses. Analyses were conducted at the measurement level and patient level (medians across repeated tests). CRP and ESR were expressed as raw values and multiples of ULN and categorized into severity strata. CRP and ESR datasets were merged by patient identifier and calendar date to define same-day pairs; paired analyses used Spearman correlations and ULN-based phenotype classes. Sensitivity analyses tested alternative pairing windows, first-pair-only analyses, phenotype persistence rules, and tertile/quartile discordance definitions. Results: Among 16,921 patients with ≥1 CRP and 17,126 with ≥1 ESR, CRP was more disease-discriminative and only negligibly age-related, whereas ESR increased modestly with age and showed marked sex shifts across severity categories. Inflammatory burden was highest in gout and rheumatoid arthritis, intermediate in psoriatic arthritis and ankylosing spondylitis, and lower in connective tissue diseases (systemic lupus erythematosus, mixed connective tissue disease, Sjogren’s disease, systemic sclerosis, and dermato/polymyositis) and osteoarthritis; CRP distributions were more strongly right-tailed than ESR. Merging yielded 44,427 same-day CRP-ESR pairs from 16,824 patients (99.1% match). CRP and ESR were moderately correlated at measurement and patient levels, yet discordance was common: 27.3% of pairs showed isolated elevation of a single marker. Conclusions: In routine rheumatology care, CRP and ESR provide complementary information. CRP-ESR dissociation is frequent, persists at the patient level, and follows diagnosis-dependent phenotype patterns. Full article