Therapeutic Advances in Chronic Disease最新文献

Background: Primary aldosteronism (PA) is the most common endocrine cause of secondary hypertension and can be effectively managed, or even cured, with targeted treatment. Despite this, it remains largely undiagnosed leaving a significant patient population with resistant hypertension and modifiable cardiovascular risk.

Objective: To determine expert consensus on key information about PA that should ideally be taught to medical students as a step toward improving the detection of this common, underdiagnosed, and often easily treated condition.

Design: The study employed a modified Delphi method which consisted of three rounds, the first of which contained an open-ended question about key areas that experts believe to be most important for inclusion in medical teaching resources and then progressing to assessment of individual versus group rankings of consensus items. Experts included both clinician-educator-researchers and patients with lived experience.

Results: Nine critical knowledge areas in epidemiology, diagnostics, and pathophysiology were identified by the Delphi as consensus items, with the highest ranked being: "PA is common but often under-diagnosed - think about it with every hypertensive patient."

Conclusion: Experts reached a consensus, for the first time, on nine critical knowledge areas about PA that should be covered in medical education. Importantly, the consensus accounted for patients' values and decisions. The results of this study could be used to assess medical student knowledge and their learning resources to facilitate curriculum development and medical resource updates to ensure the timely and accurate diagnosis of PA in hypertensive patients.

Background: Increasing evidence suggests that immunophenotypes play a crucial role in Metabolic dysfunction-associated fatty liver disease (MAFLD), but the specific immunophenotypes contributing to its pathogenesis remain unclear.

Objectives: This study aimed to elucidate the causal associations between immunophenotypes and MAFLD and identify the underlying mediation pathways involved.

Design: Mendelian randomization (MR) study.

Methods: This study is a quasi-causal inference analysis using univariable and multivariable MR (UVMR and MVMR). Five MAFLD genome-wide association studies (GWASs) and the largest immunophenotype GWAS were analyzed to assess their causal associations. Two-step MR identified potential mediators and quantified their mediation proportions. Comprehensive MR methods, multiple sensitivity analyses, meta-analyses, and false discovery rate (FDR) further enhanced the robustness of our findings.

Results: Pooled inverse-variance weighted (IVW) estimates in UVMR identified 47 immunophenotypes having a suggestive causal association with MAFLD. After adjusting for FDR, three lymphocyte phenotypes remained significant: CD20 on IgD^-CD24^- B cells (OR: 1.035, p _fdr: 0.006), terminally differentiated CD8⁺ T cells %T cells (OR: 1.052, p _fdr: 0.006), and CD4 on CD39⁺ secreting CD4⁺ regulatory T cells (OR: 1.036, p _fdr: 0.046). Meta-analysis of IVW MVMR estimates with confounders adjustment confirmed that CD20 on IgD^-CD24^- B cells and terminally differentiated CD8⁺ T cells %T cells had significant direct causal associations on MAFLD (p _fdr < 0.05). Additionally, two-step MR analysis identified the waist-to-hip ratio as a mediator, accounting for 42.64% of the causal association between CD20 on IgD^-CD24^- B cells and MAFLD.

Conclusion: The causal associations of three lymphocyte phenotypes with increased MAFLD risk were identified in this study. CD20 on IgD^-CD24^- B cells may both directly and indirectly elevate MAFLD risk, while terminally differentiated CD8⁺ T cells have a direct causal relationship with MAFLD. These findings suggest new possibilities for targeted therapies and underscore the potential for personalized immunotherapy in managing MAFLD.

Background: The application of biologic agents has benefited patients with Behcet's uveitis (BU) who do not respond to conventional treatment regimens. However, there is currently no consensus on the optimal treatment regimen of interferon alpha-2a (IFN-α2a) for refractory BU.

Objectives: To evaluate treatment outcomes and safety of IFN-α2a in a large series of refractory BU patients and to explore whether nonbiologic immunomodulatory agents (cyclosporin A) other than corticosteroids should be concomitantly used.

Design: We conducted a retrospective cohort study, which included 153 BU patients who received IFN-α2a treatment between December 2012 and September 2023 with a minimum duration of 6 months.

Methods: Best-corrected visual acuity (BCVA), the frequency of uveitis relapse, corticosteroid-sparing effect, and side effects were evaluated.

Results: Of the 153 patients enrolled, 87 patients were treated with IFN-α2a plus corticosteroids (IC), and 66 patients were treated with IFN-α2a plus corticosteroids and cyclosporin A (ICC). Both IFN-α2a treatment regimens significantly improved BCVA as early as 2 months following treatment, and the improvement was maintained over at least a 2-year follow-up. At the final visit, 86.8% and 73.1% of the affected eyes in the ICC and IC groups achieved improved or stable vision, respectively. The ICC regimen was more effective at improving vision (p = 0.01). Overall, the frequency of uveitis relapse and the dose of oral prednisolone were significantly reduced in both groups after treatment (all p < 0.0001). However, there were no statistically significant differences in these parameters between the two groups. None of the included patients experienced serious side effects that led to the discontinuation of IFN-α2a therapy.

Conclusion: IFN-α2a treatment is a promising option for patients with refractory BU. Our results showed that cyclosporin A as an adjunct could enhance the therapeutic effect of IFN-α2a.

Background: Patients with primary aldosteronism (PA) exhibit a high prevalence of diabetes mellitus (DM). However, the relationship between visceral adipose tissue (VAT) and new-onset diabetes mellitus (NODM) in PA patients remains unclear.

Objectives: To explore the association between VAT and the risk of NODM in PA patients.

Design: This is a prospective cohort study spanning 10 years (2010-2020).

Methods: A total of 342 PA patients were enrolled prospectively. Abdominal adiposity indexes, including VAT area, VAT ratio, subcutaneous adipose tissue (SAT) area, and SAT ratio, were measured using a computed tomography-based software at diagnosis.

Results: Of 342 PA patients (46.2% male, mean age 50.8 ± 11.2 years), 35 (10.2%) developed NODM over a mean follow-up of 7.4 years. A positive nonlinear association between NODM risk and Log (VAT ratio) ⩾ -0.72 was observed (high-VAT group). High VAT (odds ratio (OR), 6.09; p = 0.005), older age (OR, 1.09; p < 0.001), higher body mass index (OR, 1.24; p < 0.001), higher waist-to-hip ratio (OR, 1.11, p < 0.001), lower baseline aldosterone (OR, 0.99, p = 0.011), higher diastolic blood pressure (OR, 1.05, p = 0.012), and lower systolic blood pressure (OR, 0.98, p = 0.045) as risk factors for high VAT. Adrenalectomy did not significantly associate with reduced NODM risk (OR, 0.49; p = 0.292).

Conclusion: Our findings highlight that 10.2% of PA patients develop NODM over a mean follow-up of 7.4 years, with high VAT increasing the risk. Baseline VAT is a key determinant of NODM development in PA patients, regardless of targeted treatments.

Background: Hepatosteatosis is a common condition that can lead to cirrhosis and liver cancer. Galectin-3 (GAL-3) has been implicated in liver fibrosis and inflammation.

Objectives: The purpose of this study was to investigate the association between GAL-3 and hepatosteatosis.

Design: This study is a retrospective secondary analysis of data from a community health screening program.

Methods: A total of 766 participants were included in the final analysis. Hepatosteatosis was diagnosed using ultrasonography, and GAL-3 levels were measured using enzyme-linked immunosorbent assay. Logistic regression analysis was used to examine the association between GAL-3 levels and the presence of hepatosteatosis, adjusting for age, sex, and other potential confounding factors.

Results: The prevalence of moderate-to-severe hepatosteatosis in the study population was 31.5%. The participants with hepatosteatosis had a significantly higher mean level of GAL-3 compared to those without hepatosteatosis (16.6 ± 7.3 vs 13.5 ± 7.3 ng/ml; p < 0.001). After adjusting for age, sex, body mass index, and other potential confounding factors, a higher level of GAL-3 was significantly associated with an increased risk of moderate-to-severe hepatosteatosis (adjusted odds ratio (aOR) 1.24, 95% confidence interval (CI) 1.05-1.46, p = 0.010). The coexistence of alanine transaminase/aspartate transaminase ratio >1 and GAL-3 >14.4 ng/ml was associated with a significantly increased risk (aOR 3.37, 95% CI: 1.90-5.99, p < 0.001).

Conclusion: Our findings suggest that GAL-3 level is significantly associated with the presence of moderate-to-severe hepatosteatosis, independent of other known cardiometabolic risk factors.

Background: Psoriatic arthritis (PsA) is a chronic systemic inflammatory disease that affects up to 30% of patients with psoriasis. Diagnosis and treatment could be improved by implementing an interdisciplinary dermatological-rheumatological consultation (IDRC).

Objectives: This study aimed to assess the effect of a face-to-face IDRC involving both a dermatologist and a rheumatologist evaluating patients in a single visit, on disease activity and burden in patients with PsA.

Design: Prospective, single-center, cohort study.

Methods: 202 patients with psoriasis were enrolled, among whom 115 individuals with psoriasis and musculoskeletal symptoms underwent an IDRC. Disease manifestations, comorbidities, and both objective and subjective disease activity scores were evaluated.

Results: Out of the participants, 56 were diagnosed with definite PsA, while the remaining 146 had psoriasis. Nail involvement was associated with axial PsA (odds ratio 4.11; 95% CI 1.22-13.82; p = 0.02). Patients with PsA often experienced a prolonged time to diagnosis (mean 187 weeks) and had a significant psychosocial burden (mean Hospital Anxiety and Depression Index Scale [HADS]-Anxiety score of 7.66 and mean HADS-Depression score of 5.63). Post-IDRC, both objective and subjective disease parameters showed improvement, and patients required less time for consultations with healthcare professionals compared to before the IDRC.

Conclusion: These findings suggest that an IDRC approach could effectively expedite and optimize the diagnosis and treatment of patients with psoriasis and musculoskeletal symptoms.

Growth factors were introduced to increase predictability in periodontal regeneration and have since been widely applied in dentistry. This narrative review article highlights histological and latest findings of recombinant human platelet-derived growth factor-BB (rhPDGF-BB) and recombinant human fibroblast growth factor-2 (rhFGF-2) for periodontal regeneration. rhPDGF-BB enhances the proliferation and chemotaxis of periodontal ligament and alveolar bone cells. The optimal dose for rhPDGF-BB, in combination with beta-tricalcium phosphate, is 0.3 mg/ml. It is approved in the United States, Canada, and Taiwan for use in periodontal regeneration and treatment of gingival recession. rhFGF-2 promotes periodontal wound healing through mitogenic and angiogenic effects on mesenchymal cells in the periodontal ligament. It is approved in Japan at an optimal dose of 0.3% for periodontal regeneration in intrabony defects. Both recombinant growth factors show histological evidence of new bone, cementum, and periodontal ligament. Clinical studies demonstrate improved clinical attachment levels and defect resolution for treating intrabony and furcation periodontal defects. Presented clinical cases and consensus reports may serve as a reference for clinicians. rhPDGF-BB and rhFGF-2 are safe and effective biologics that can be applied to improve the outcomes of periodontal regeneration.

Background: Severe upper extremity paresis due to stroke is a significant clinical sequela. Neuromuscular electrical stimulation (NMES)-based rehabilitation has demonstrated promising results along with cortical plasticity. Transcranial alternating current stimulation (tACS) has gained attention due to its unique ability to entrain endogenous oscillatory brain rhythms with injected AC frequency, offering the potential for modifying brain conditions to enhance rehabilitative interventions. Because repetitive motor execution in rehabilitation training requires a smooth transition of the brain state despite often being impaired secondary to stroke, combining NMES and tACS may offer better treatment efficacy.

Aim: This study proposes a phase I/II trial of an outpatient comprehensive rehabilitative treatment combining the integrated volitional-control electrical stimulation (IVES), a closed-loop NMES, and the timing-specified focal tACS in individualized beta frequency (dynamic-precision tACS) targeting severe hand paresis in patients with chronic stroke, aiming to demonstrate the feasibility of combination treatment.

Design: Double-blind randomized cross-over trial.

Methods: The repetitive facilitative finger extension training utilizing closed-loop NMES is combined with dynamic-precision tACS on the primary motor cortex to assist post-movement beta-rebound. Together with regular occupational therapy, we propose a comprehensive outpatient neurorehabilitative regimen. Here, a total of 10 sessions will be conducted using a cross-over design using real and sham tACS.

Analysis: The perception and fatigue from stimulation will be investigated as the primary outcomes. The efficacy of improving sensorimotor function and their background physiological mechanisms will be evaluated as the secondary outcomes.

Discussion: This phase I/II trial will be the first to combine tACS and neurorehabilitation using functional electrical stimulation. A weekly outpatient protocol with cheap devices may offer a new treatment paradigm toward functional recovery for chronic stroke patients with severe upper extremity paresis.

Ethics and trial registration: This study was approved by the Ethics Committee of Kyorin University Faculty of Medicine (814-01). The trial was registered in a public database: UMIN000048274.

Background: Lumbar intervertebral disc and paravertebral muscle degeneration are common causes of chronic low back pain (CLBP). However, the exact etiology of CLBP in young patients remains unclear. Identifying the risk factors for CLBP in young patients could expedite the development of effective preventive recommendations.

Objectives: To identify the factors influencing the presence and severity of CLBP in young patients by analyzing the associations between the fat content of the paravertebral muscles, T2 value of the lumbar intervertebral disc (LIVD), and visual analog scale (VAS) score.

Design: Data for 23 patients diagnosed with CLBP were compared to those of 20 healthy young individuals.

Methods: The T2 values of the LIVD and fat content of the psoas major (PM), multifidus (MF), and erector spinae (ES) muscles for 23 young patients with CLBP and 20 healthy individuals were measured and compared using synthetic magnetic resonance imaging and proton density fat fraction analyses. Moreover, the factors (T2 values and fat content) associated with severe CLBP (assessed using the VAS score) were analyzed.

Results: The fat content of the right MF and ES was higher in patients with CLBP than in healthy individuals (p < 0.05). The T2 values of each LIVD in the CLBP and control groups were not significantly different (p > 0.05). Moreover, the VAS scores did not correlate with the T2 values of the patients (p > 0.05). The fat content of the bilateral MF and ES muscles was positively associated with the VAS score in young patients with CLBP (left MF: r = 0.506, p = 0.01; right MF: r = 0.532, p = 0.01; left ES: r = 0.636, p < 0.01; and right ES: r = 0.716, p < 0.01).

Conclusion: Degeneration of the MF and ES may contribute to CLBP in young patients. In addition, the severity of CLBP is positively correlated with the degree of fat infiltration in the MF and ES.

Background: The association between pyridoxal 5'-phosphate (PLP) and cardiovascular disease (CVD) remains a topic of discussion.

Objectives: This study aimed to explore the relationship between serum PLP levels and the incidence of all-cause mortality, cardiovascular mortality, and the risk of CVD among the US population.

Design: A population-based cohort study.

Methods: This study analyzed data from the National Health and Nutrition Examination Survey. Adjusted hazard ratios (HRs) and their corresponding 95% confidence intervals (CIs) were calculated using weighted Cox proportional hazards regression models to assess the risk associated with all-cause and cardiovascular mortality. Weighted binary logistic regression was utilized to assess the relationship between serum PLP levels and the risk of CVD. Nonlinear associations were evaluated using multivariable-adjusted restricted cubic splines.

Results: There were 2546 cases of all-cause mortality and 867 cases of cardiovascular mortality over a mean follow-up of 11.36 years. In the fully adjusted model, the adjusted HRs with 95% CIs for all-cause mortality associated with increases in serum PLP levels corresponding to the interquartile ranges were 0.83 (0.74-0.93), 0.71 (0.63-0.80), and 0.64 (0.56-0.74), respectively. Similarly, cardiovascular mortality decreased by 0.78 (0.62-0.97), 0.63 (0.49-0.81), and 0.62 (0.50-0.77) with each quartile increase in serum PLP levels. Higher serum PLP levels confer protection against CVD risk (odds ratio: 0.87, 95% CI: 0.79-0.96). Serum PLP levels showed nonlinear relationships with risk of all-cause mortality, cardiovascular mortality, and CVD.

Conclusion: The results of this study provide evidence that serum PLP serves as a protective factor against all-cause mortality, cardiovascular mortality, and CVD in US adults, with dose-response relationships.