Search Results (10,879)

Background: Hepatitis B and C viral infections remain a significant global health challenge, despite the implementation of an effective direct-acting antiviral (DAAs) and nucleos(t)ide analogues (NAs). Current HBV therapy is not curative as stopping therapy usually leads to active disease in most patients requiring long-term treatment. Although current HCV-DAAs are highly effective they fall short due to arising drug-resistance and have limited ability to avert re-infections. Furthermore, current HCV DAA treatments lead to the reactivation of occult HBV infection, compromising the effectiveness of current antiviral therapies, and increasing the risk of severe liver complications like cirrhosis and hepatocellular carcinoma. In addition, current treatments do not restore the immune dysfunction, a characteristic of chronic HBV infection. Given the global burden of disease, there is an urgent need for more effective therapy that can shorten the duration of treatment and achieve high rates of HBsAg reduction. Combining an antiviral to reduce viral antigen burden and an immunomodulator to boost the immune response could provide an effective treatment for HBV/HCV infections. Methods: In this study, we explored the potential of a novel bacterial therapeutic agent, heat-killed Caulobacter crescentus (HKCC), as an alternative and/or adjunct host-based therapy for HCV and HBV infections. Here, we have investigated the antiviral effects of the HKCC-stimulated human PBMCs using in vitro HCV and HBV infection models to assess viral replication, viral relapse responses, protein expression, and cytotoxicity. Results: Our findings reveal that HKCC induced a multi-functional cytokine response (IFN, TNF, IL-2, IL-10, IL-6, IL-17A, and IL-22) in PBMCs obtained from multiple healthy donors. Supernatants collected from these HKCC-stimulated human PBMCs, alone and in combination with antivirals, strikingly inhibited HCV replication and viral relapse responses without inducing any cytotoxic effects on HCV-1a replicon cells. In addition, these PBMC supernatants, with or without antivirals, led to the suppression of HBV DNA replication and inhibited HBsAg and HBeAg production in HepG 2.2.15 cells. Conclusions: In conclusion, HKCC is a promising candidate for eliminating HBV and HCV infections, and warrants further investigation to potentially contribute to the development of a novel host-based immunotherapy. Full article

Atrial fibrillation (AF) and diabetes mellitus frequently coexist and together define a high-risk cardiometabolic phenotype. Diabetes is associated with an increased incidence of AF, although this relationship is strongly influenced by obesity, hypertension, chronic kidney disease (CKD), heart failure (HF), sleep-disordered breathing, and broader metabolic risk clustering. Once AF develops, diabetes is associated with greater thromboembolic and HF risk, impaired quality of life, cognitive vulnerability, and excess mortality. These adverse outcomes may be partly explained by a multidimensional atrial substrate, described here within the conceptual framework of diabetic atrial cardiomyopathy, in which hyperglycaemia, insulin resistance, glycaemic variability, oxidative stress, inflammation, autonomic dysfunction, microvascular disease, lipotoxicity, and epicardial adipose tissue dysfunction may contribute to atrial fibrosis, electrical heterogeneity, impaired calcium handling, mitochondrial injury, and mechanical dysfunction. Collectively, these abnormalities may facilitate AF initiation, persistence, progression, and recurrence after rhythm-control interventions. Management should therefore extend beyond rhythm control and anticoagulation alone. In individuals at increased risk of AF, priorities include cardiometabolic optimization, treatment of obesity, hypertension, CKD, HF, and sleep apnoea, lifestyle intervention, and selective rhythm surveillance. In subclinical AF, decisions regarding anticoagulation should account for AF burden, thromboembolic and bleeding risk, renal function, frailty, and patient preference. In established AF, stroke prevention, symptom-directed rate or rhythm control, cardiometabolic therapy, and longitudinal reassessment remain central. This narrative review integrates the epidemiology, mechanisms, and management of AF in diabetes across the continuum from AF risk to subclinical and clinical disease. Full article

Background/Objectives: Adalimumab (ADM) is a recombinant, fully human monoclonal antibody that exhibits pronounced inter- and intra-individual pharmacokinetic variability attributed to several factors. This study aims to externally evaluate the published ADM population pharmacokinetic models and their potential use in clinical practice, as well as to develop novel population pharmacokinetic model. Methods: Literature search was conducted using PubMed to identify ADM population pharmacokinetic models. Data from 195 patients with Crohn’s disease treated at the University Medical Center “Zvezdara”, Serbia, were used for the external evaluation of previously published models. In addition, the development of the new population pharmacokinetic model incorporated informative priors derived from the best-performing published model. Nonlinear mixed-effects modeling was performed in NONMEM^® (versions 7.6) for both prediction- and simulation-based diagnostics of existing models, as well as for the development of a new model. Results: Eight published pharmacokinetic models of ADM were included in the external evaluation. Although none of the models satisfied both population-level and normalized prediction distribution error (NPDE) diagnostic criteria, individual-level performance was acceptable: median prediction errors (MDPEs) were within ±20% across all studies, and median absolute prediction errors (MDAPEs) were below 30% in most cases (7 of 8 studies). The best-performing model was identified and implemented as a priori information in subsequent model development. A one-compartment model using with first-order absorption and elimination best described the data. The apparent clearance (CL/F) was estimated at 0.334 L/day, while informative priors were used for V/F and the effect of anti-drug antibodies (ADAs) on CL/F. Covariate analysis on CL/F identified C-reactive protein (CRP) and dosing regimen as statistically significant predictors (p < 0.01). Conclusions: The previous pharmacokinetic models of ADM exhibited suboptimal performance in population-level metrics and simulation-based diagnostics, while individual-level metrics showed substantial improvement. The newly developed model of ADM highlights associations among immunogenicity, drug pharmacokinetics, and inflammatory burden. Full article

Cutaneous leishmaniasis (CL) is highly prevalent in northern Ethiopia but data on community knowledge, attitudes, and health-seeking behaviours remain limited. A cross-sectional survey was conducted between November and December 2022 in CL-endemic areas of Tigray using mixed sampling and a structured questionnaire administered to 512 households. Knowledge of CL transmission was poor: only 1% correctly identified sand flies as the vector, while 25% believed the disease was genetically acquired. Approximately 67% of participants perceived CL as stigmatizing, and 63.3% reported a preference for traditional or local treatments over biomedical care. Knowledge levels were higher among rural residents and in households with prior CL experience. Gender and education were significantly associated with treatment-seeking and prevention practices, and participants from households with previous CL episodes reported better practices overall. Despite this, most participants demonstrated limited knowledge, unfavourable attitudes and suboptimal treatment-seeking and prevention behaviours. These findings highlight a disconnect between high disease burden, perceived seriousness and stigma, and limited understanding of transmission and prevention. Targeted, community-based health education interventions are needed to improve awareness of transmission, reduce stigma, and enhance access to effective treatment in CL-endemic settings. Full article

Background/Objectives: Hepatic glycogen storage diseases (GSDs) are rare inherited metabolic disorders requiring lifelong nutritional management and strict metabolic control, which may adversely affect the health-related quality of life (HRQoL). This study aimed to evaluate the HRQoL in children with hepatic GSD using both child and parent reports, compare findings with normative data, and explore associations with biochemical, anthropometric, and nutritional management-related parameters. Methods: The study included 23 children with hepatic GSD and their parents. HRQoL was assessed using the Pediatric Quality of Life Inventory (PedsQL) Generic Core Scale. Child and parent reports were compared with normative data for healthy and chronically ill children. Agreement between child and parent reports was evaluated with intraclass correlation coefficients, and exploratory associations between variables were assessed using partial Spearman correlation analyses. Results: Total and most subscale PedsQL scores reported by both children and parents were significantly lower than those of healthy peers and children with chronic diseases (p < 0.05). Parents reported lower HRQoL scores than children, particularly in psychosocial, social, and school functioning domains, with low to moderate agreement between reports. Exploratory analyses suggested that body composition and nutritional treatment burden indicators were correlated with selected HRQoL domains. Conclusions: Children with hepatic GSD experience impaired HRQoL from both child and parent perspectives. Integrating HRQoL assessment into routine clinical and nutritional follow-up may help identify unmet psychosocial and dietary support needs and support more individualized nutritional management in children with hepatic GSD. Full article

Background/Objectives: Severe asthma and chronic rhinosinusitis with nasal polyps (CRSwNP) frequently coexist and are associated with type 2 inflammation, leading to poor symptom control and high healthcare burden. Biologic therapies targeting IL-4Rα and IL-5/IL-5R have shown efficacy in type 2 inflammatory asthma and CRSwNP, but comprehensive evidence on their efficacy, safety, and research trends is limited. Methods: We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) evaluating dupilumab, mepolizumab, benralizumab, or reslizumab in patients with type 2 inflammatory asthma and/or CRSwNP. Primary outcomes included lung function (FEV1), symptom control (ACQ, SNOT-22, nasal polyp score), and serious adverse events (SAEs). Risk of bias was assessed using the Cochrane RoB 2.0 tool. Publication bias was evaluated with funnel plots and Trim-and-Fill analysis. Bibliometric analysis was performed to identify publication trends and emerging research directions. Results: A total of 23 RCTs involving 8758 participants were included. Biologic therapy was not associated with a significant increase in serious adverse events (RR = 1.15, 95% CI: 0.89–1.50). Compared with control treatment, biologics significantly improved FEV1 (MD = 100.67 mL, 95% CI: 65.94–135.40) and ACQ scores (MD = −0.40, 95% CI: −0.54 to −0.25). In patients with CRSwNP and comorbid asthma, biologics also improved SNOT-22 scores (MD = −13.16, 95% CI: −24.85 to −1.47) and nasal polyp scores (MD = −1.31, 95% CI: −1.95 to −0.68). Dupilumab trials showed larger reductions in nasal polyp score than IL-5/IL-5R-targeted trials, although this indirect comparison should be interpreted cautiously. Bibliometric analysis indicated increasing research attention to upstream epithelial targets such as TSLP. Conclusions: Both IL-4Rα and IL-5/IL-5R-targeted biologics are effective and well-tolerated in type 2 inflammatory airway diseases. IL-4Rα inhibition shows favorable upper-airway outcomes in CRSwNP with asthma, but head-to-head trials are needed to clarify its comparative efficacy relative to IL-5/IL-5R-targeted therapies. Emerging research directions are shifting toward upstream epithelial alarmin antibodies. Full article

Background: β-haemoglobinopathies, including sickle cell disease and transfusion-dependent β-thalassaemia, are among the most common monogenic disorders worldwide and represent a major global health burden. Conventional treatments, such as blood transfusions, iron chelation, fetal haemoglobin induction, and allogeneic haematopoietic stem cell transplantation, have improved outcomes but remain limited by treatment-related toxicity, donor availability, and incomplete curative potential. Methods: A narrative literature review was conducted using PubMed up to 2025. Search terms included “sickle cell disease,” “sickle cell anemia,” “β-thalassemia,” “transfusion-dependent beta-thalassemia,” “gene therapy,” “gene addition,” “gene editing,” “CRISPR-Cas9,” “lentiviral vector,” “children,” “paediatric,” and “pediatric.” Relevant clinical trials, reviews, consensus statements, and guidelines were selected and qualitatively analysed. Results: Gene therapy for β-haemoglobinopathies is based mainly on two strategies: gene addition and gene editing. Gene addition uses lentiviral vectors to introduce functional or modified β-globin genes into autologous haematopoietic stem cells, whereas gene editing targets regulatory pathways, particularly BCL11A, to reactivate fetal haemoglobin synthesis or correct disease-causing mutations. Clinical studies have shown encouraging outcomes, including transfusion independence in many patients with β-thalassaemia and marked reduction or elimination of vaso-occlusive crises in sickle cell disease. Paediatric and adolescent data are increasingly promising, although still limited. Conclusions: Gene therapy is reshaping the treatment landscape of β-haemoglobinopathies by offering a personalised and potentially curative approach. However, long-term safety, conditioning toxicity, fertility preservation, accessibility, costs, and implementation in high-prevalence regions remain critical challenges. Further studies are needed to optimise patient selection and expand equitable access. Full article

Background/Objectives: Chronic kidney disease and hemodialysis have a significant impact on patients’ lives. Social and clinical factors may influence perceived disease burden and the availability of social support, both of which are relevant for adherence and well-being. This study aimed to determine the relationship between perceived disease burden and social support among adults on hemodialysis in northern Colombia. Methods: A cross-sectional study was conducted on 183 patients receiving hemodialysis in northern Colombia. Disease burden was assessed using the GCPC-UN instrument and perceived social support using the Medical Outcomes Study Social Support Survey (MOS-SSS). Data were analyzed using descriptive statistics, nonparametric tests (Mann–Whitney U and Kruskal–Wallis), Spearman’s correlation, and a multivariate linear regression model with HC3 robust errors. Results: The mean age was 52.2 years (SD: 12.1), and 63.4% of participants were male. The overall disease burden score was 45.72 (SD: 16.47) out of a theoretical maximum of 144, with physical distress being the factor that contributed most to it (mean: 20.03; SD: 6.83). Functional social support was moderate (median: 72; IQR: 63–80). A significant inverse correlation was found between social support and disease burden (Spearman’s rho = −0.160; p = 0.03). In the multivariate model, time on hemodialysis was associated with a higher burden (a 0.628-point increase per 12 months; 95% CI: 0.022–1.234; p = 0.04), while age showed a non-significant inverse trend. Conclusions: When assessing the burden of disease, patients on hemodialysis primarily experience physical distress and perceive a moderate level of social support. A longer duration of dialysis is associated with an increase in the perceived burden, while social support showed a weak inverse correlation with the burden of disease in the unadjusted analysis; however, this association was not confirmed as statistically significant in the multivariable model. Full article

Background/Objectives: Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease associated with psychiatric burden, but longitudinal data on incident psychiatric outcomes remain limited. This study aimed to evaluate incident psychiatric disorders in adults with HS compared with matched non-HS controls and to assess sex-specific risk. Methods: We conducted a retrospective propensity score–matched cohort study using the TriNetX Global Collaborative Network. Adults with at least two HS diagnoses and no prior psychiatric diagnosis were compared with non-HS controls with repeated general health examination encounters and no psychiatric history. Time-to-event analyses estimated hazard ratios (HRs) with 95% confidence intervals (CIs). Sensitivity analyses used a 30-day lag and restriction to the most recent 5-year period. Results: After matching, 37,964 pairs were retained for the primary individual-outcome analysis. Median follow-up was shorter in the HS cohort than in matched controls (844 vs. 1505 days). HS was associated with increased risk of any psychiatric disorder (12.3% vs. 5.8%; HR 3.17, 95% CI 3.01–3.34) and severe psychiatric illness (0.6% vs. 0.1%; HR 6.70, 95% CI 4.77–9.41). Elevated risks were observed for bipolar/manic disorders, personality disorders, substance use disorders, psychotic disorders, suicidal ideation, depression, eating disorders, anxiety, and insomnia/parasomnia. Women had higher hazards of depression and anxiety, whereas men had higher hazards of substance use disorders; insomnia/parasomnia showed a nominal association with higher hazard in men. Conclusions: In this observational EHR-based study, HS was associated with broad incident psychiatric morbidity. These findings support consideration of proactive mental health assessment and integrated dermatologic–psychiatric care in patients with HS. Full article

Background/Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) highlights the central role of metabolic dysregulation in hepatic steatosis. Patients with inflammatory bowel disease (IBD) are increasingly recognized to have an adverse cardiometabolic risk profile; however, data regarding MASLD prevalence and associated factors in this population remain limited, particularly in regions with a high metabolic burden such as Türkiye. This study aimed to determine the prevalence of MASLD in patients with IBD and to identify the metabolic and disease-related factors associated with its development. Methods: In this retrospective cross-sectional study, adult patients with IBD followed at a tertiary referral center in Türkiye were included. Hepatic steatosis was assessed using routine abdominal imaging, and MASLD was defined according to the 2023 Delphi Consensus criteria. Clinical, demographic, and metabolic variables were analyzed. Multivariable logistic regression analysis was performed to identify factors independently associated with MASLD. Results: A total of 194 IBD patients who had abdominal imaging available within the previous 6 months were included, of whom 61.3% had MASLD. MASLD was more prevalent in patients with UC than in those with CD (70.7% vs. 55.5%, p = 0.036). However, UC diagnosis was not independently associated with MASLD after multivariable adjustment. Patients with MASLD were older and had higher body mass index and less favorable metabolic profiles. In multivariable analysis, age (OR 1.055, 95% CI 1.022–1.089; p < 0.001), body mass index (OR 1.199, 95% CI 1.092–1.316; p < 0.001), and triglyceride levels (OR 1.012, 95% CI 1.004–1.020; p = 0.005) were independently associated with MASLD. In contrast, disease-related factors, including disease activity, biologic therapy, and prior surgery, were not independently associated with MASLD. Conclusions: MASLD prevalence was high among selected IBD patients with available abdominal imaging and appears to be more strongly associated with metabolic risk factors than with disease-specific characteristics. In populations with a high background cardiometabolic burden, MASLD in IBD may largely reflect the underlying regional metabolic milieu. These findings support the integration of metabolic risk assessment and proactive MASLD screening into routine IBD care. Prospective longitudinal studies are needed to clarify the causal relationship between metabolic dysfunction, IBD-related factors, and MASLD progression. Full article

Heart failure (HF)—a highly prevalent condition among older adults—is characterized by recurrent exacerbations and progressive symptom burden, significantly affecting functional autonomy and quality of life. Palliative care may alleviate symptoms and improve quality of life for patients and their families, promoting personalized care aligned with individual preferences. Although international guidelines recommend the early integration of palliative care into standard HF management, its implementation in real-world practice remains limited. Improving awareness and competencies in identifying end-of-life needs and in advance care planning may facilitate earlier integration of palliative care into HF clinical pathways. This paper presents a case of advanced HF in which palliative care was introduced only during the final hospitalization, highlighting the importance of the earlier integration of palliative care throughout the disease trajectory. This paper results from a collaboration between young members of the Italian Society of Palliative Care and the Italian Society of Gerontology and Geriatrics. The case serves as a practical training model for healthcare professionals in applying a palliative care approach to advanced HF. It illustrates key strategies and tools employed across different stages of care, including patient identification, multidimensional assessment, shared decision-making, advance care planning, symptom management, medication review, and palliative sedation. Full article

Background: Influenza infections have reached an approximate number of one billion cases annually in the general population. Hospitalization due to this infection is associated with high morbidity, and a proportion of hospitalized children may require ICU admission. In the United States of America, one in five children hospitalized due to influenza requires transfer to the intensive care unit (ICU). The real burden of this disease is not accurately known, especially for the pediatric population. Objective: The objective of this study was to define the characteristics of influenza-associated complications in pediatric patients hospitalized at a tertiary hospital in Brasov, Romania. Methods: This was an observational, retrospective study that gathered 258 influenza-infected patients aged from 0 up to 18 years old, hospitalized during the period from 1 January 2020 to 31 December 2025 at the Children’s Hospital of Brasov (a single-center study, but in a tertiary unit). The complications from this disease were categorized into respiratory, hematological, musculoskeletal, renal, ENT, cutaneous, rheumatological, and bacterial superinfections. Results: The patients were stratified according to their influenza type (A or B) and length of hospital stay. The length of stay was categorized as 0–4 days, 5–10 days, or >10 days. No significant association was observed between the influenza type and admission duration (χ² = 2.185, df = 2, p = 0.3354). The most frequent complications were respiratory—bronchiolitis and pneumonia (22.8%)—followed by hematological (13.5%). Conclusions: The length of stay did not differ significantly between patients with influenza A and those with influenza B in the selected sample. The most common complications were respiratory, hematological, ENT, and neurological. Full article

Background/Objectives: Identifying aggressive tumor biology within early-stage hepatocellular carcinoma (HCC) remains challenging. Scores based on liver function, systemic inflammation, and HCC biomarkers have been linked to overall survival prognosis; however, the combined ability of these scores to assess tumor-specific prognosis in early-stage disease is unclear. In this single-center, prospective study, biomarker profiling with AFP, AFP-L3, and DCP, along with modified albumin–bilirubin (mALBI), and neutrophil–lymphocyte ratio (NLR)/platelet–lymphocyte ratios (PLRs) were evaluated to determine their prognostic role in assessing clinical manifestations of aggressive biology by stratifying HCC progression risk. Methods: Indices and biomarkers were assessed at BCLC-A-stage HCC diagnosis and prior to liver-directed therapy (LDT). The primary prospective study endpoint was time-to-advanced-stage tumor progression (TTP). Results: The cohort included 232 patients diagnosed with early-stage HCC who underwent treatment with LDT. A multivariate model revealed that mALBI grade (p = 0.021), cumulative lesion size (p = 0.005), and elevations in HCC biomarkers (p < 0.001) were associated with TTP. Biomarker profile stratified TTP (p < 0.001) in which patients with complex profiles (3+) had 1-year progression risks of 69%. The biomarker system retained the ability to stratify TTP within small (≤3 cm) and large (>3 cm) cumulative tumor burden (p < 0.001, p = 0.005). While PLR was not prognostic for TTP, NLR disappeared from the multivariate model and mALBI stratified long-term progression risk (p = 0.003). In low-complex biomarker patients (0–1+), mALBI stratified progression risk (p = 0.001). Conclusions: Multi-positive biomarker profiling in early-stage HCC identifies a population with clinical manifestations of aggressive tumor biology at high risk of rapid post-treatment disease progression that may benefit from more aggressive treatment approaches. In patients with low-risk biomarker profiles (0–1+), mALBI can assess longer-term (>1-year) post-treatment disease progression risk, while scores based on systemic inflammation were not associated with tumor-restricted outcomes. Full article

Background: Pancreatic resection (Pancreatoduodenectomy, PD, distal pancreatectomy, DP, or total pancreatectomy, TP) is the standard of care for resectable pancreatic adenocarcinoma (PDAC). Despite advances in multimodal therapy, recurrence rates remain high, approaching 80%, and continue to drive poor overall survival. Objective: This review evaluates the burden and clinical significance of localized recurrence in PDAC and critically examines the potential role of intraoperative radiation therapy (IORT) in improving locoregional disease control. Results: Distant recurrence remains the predominant pattern of failure, occurring in 55–75% of patients, most commonly involving the liver, lungs, and peritoneum. However, isolated local recurrence, observed in approximately 17–32% of patients, represents a clinically meaningful subset associated with significant morbidity and potential for subsequent metastatic progression. IORT, delivered as a single high-dose radiation treatment to the tumor bed at the time of surgery, enables precise targeting of areas at highest risk for residual microscopic disease while minimizing radiation exposure to adjacent radiosensitive structures. Retrospective and meta-analytic data, while limited, suggest that IORT is associated with improved local control and modest survival benefit without a significant increase in perioperative morbidity, though interpretation is limited by study heterogeneity and lack of randomized control trials. Conclusion: IORT represents a rational adjunct in the multimodal management of PDAC, particularly for patients at high risk of locoregional failure, including those with borderline resectable or locally advanced disease, nodal involvement, perineural invasion, or concern for margin positivity. Prospective studies are needed to better define optimal patient selection and to clarify the role of IORT in the modern treatment paradigm. Full article

The glymphatic system has been proposed as a brain-wide pathway that promotes the exchange between cerebrospinal and interstitial fluids and facilitates the clearance of metabolic waste products, including amyloid-β and tau proteins. Diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) has emerged as a non-invasive magnetic resonance imaging technique proposed to indirectly assess glymphatic-related fluid dynamics. This systematic review evaluated the methodological consistency and clinical applicability of the ALPS index in neurodegenerative diseases. A structured search of PubMed (MEDLINE) and Web of Science identified human studies published up to January 2026 investigating DTI-ALPS in neurodegenerative conditions. Data regarding study populations, MRI acquisition parameters, image-processing methods, statistical approaches, and clinical associations were extracted and synthesized. Ten studies met the inclusion criteria. Across studies, lower ALPS index values were generally associated with cognitive impairment, amyloid burden, and disease severity, particularly in Alzheimer’s disease. Several studies incorporated multimodal biomarkers, including amyloid positron emission tomography and cerebrospinal fluid markers, thereby improving the biological interpretation of DTI-ALPS findings. However, substantial methodological heterogeneity was identified across studies, including variability in region-of-interest placement, diffusion acquisition protocols, and image-processing pipelines. Furthermore, the interpretation of diffusivity metrics as direct measures of glymphatic flow remains controversial. Current evidence suggests that DTI-ALPS may represent a promising non-invasive imaging marker of glymphatic-related alterations; however, its biological specificity and clinical applicability remain insufficiently established. Standardized acquisition protocols, harmonized analytical pipelines, and longitudinal multicenter studies are required to clarify its role in neurodegenerative disease research. Full article