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Immunoengineering in the field of tendon and bone regeneration: immunomodulatory biomaterials, delivery platforms, and preclinical models for chronic diseases.

Front Bioeng Biotechnol

Wanxue Wang, Pengfei Yan, Junmiao Liu +6 more

The functional and structural reconstruction of the tendon-bone interface (TBI) is a major challenge in orthopedics and sports medicine. Under the influence of chronic degenerative pathologies such as aging, diabetes, and rheumatoid arthritis, the cascading collapse of the local immune-metabolic network disrupts the regenerative microenvironment of the tissue, making the clinical translation of traditional inert physical scaffolds extremely difficult. This review systematically summarizes the latest paradigm shifts in "bone immunoengineering" aimed at overcoming the complex challenges of TBI regeneration. We first decode the core regulatory networks that control interface heterogeneity remodeling, thoroughly analyzing the spatiotemporal polarization dynamics of macrophages, the double-edged effects of the Piezo1-YAP mechanotransduction axis, and the "neuro-immune-skeletal" ternary communication mechanism. Based on this pathological framework, we comprehensively overview next-generation intelligent biophysical and chemical intervention strategies for actively reprogramming extreme microenvironments. These strategies include piezoelectric nanohydrogels for electromechanical-metabolic coupling, Janus asymmetric microfluidic interfaces for multi-ion spatiotemporal rectification, and precise spatial delivery platforms for targeted clearance of senescent cells and engineered exosomes. Furthermore, to overcome the translational barriers between underlying mechanisms and clinical applications, we focus on the cross-scale evolution of preclinical evaluation systems, elaborating on the core value of three-dimensional tendon-bone organoids, microfluidic organ-on-chip systems, and high-resolution spatial transcriptomics. Finally, this review envisions advanced microphysiological systems characterized by closed-loop dynamic adaptive biomaterials, spatiotemporal matching of degradation kinetics, and deep integration with artificial intelligence (AI), highlighting their broad prospects in driving the next-generation of personalized, precise regenerative medicine in orthopedics.

Comparative Utility of B-type Natriuretic Peptide (BNP) and N-terminal Pro-BNP (NT-proBNP) in the Management of Acute Heart Failure: A Study From a Tertiary Care Hospital in Kashmir, India.

Cureus

Javeed A Ganie, Hyder H Lone, Mehraj Ul Islam +4 more

Background Among the various biomarkers, B-type natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP) have proved particularly useful in helping clinicians diagnose acute heart failure (AHF) and evaluate the risk a patient faces at the time of presentation. However, data from the Indian subcontinent, particularly from the Kashmir Valley, with its unique demographic profile and altitude-related cardiovascular burden, remain sparse. This study aimed to compare the utility of these biomarkers in the management of AHF in a tertiary care setting and to evaluate their relationship with disease severity parameters, including New York Heart Association (NYHA) functional class, ejection fraction, and lung ultrasound B-lines. Methods The study was a prospective observational study conducted at the Government Medical College, Srinagar, over a period of 18 months. A total of 223 patients admitted to the hospital with acute heart failure were included. Both BNP and NT-proBNP were measured simultaneously at admission. All patients underwent lung ultrasonography (LUS) for B-line quantification before and after diuretic therapy and echocardiography for ejection fraction assessment. Statistical analyses included Pearson and Spearman correlations, one-way ANOVA, paired t-tests, and receiver operating characteristic (ROC) curve analysis. Results The majority of patients were male, 133 (59.6%), with a mean age of 62.3 ± 10.7 years. Mean BNP and NT-proBNP levels were 581.5 ± 180.1 pg/mL and 1707.5 ± 629.5 pg/mL, respectively. The two biomarkers correlated strongly with each other (Pearson r = 0.750, p < 0.001), and both varied significantly across NYHA functional classes (BNP: F = 6.118, p = 0.001; NT-proBNP: F = 4.405, p = 0.005). Lung ultrasound B-lines showed a significant reduction following diuretic therapy (15.24 ± 1.07 vs 6.77 ± 1.06; p < 0.001). NT-proBNP showed non-significantly higher diagnostic performance over BNP for severe HF (area under the curve (AUC) 0.420 vs. 0.387). No significant difference was noted between the two biomarkers with respect to ejection fraction categories. Conclusion Both BNP and NT-proBNP are comparably effective in reflecting the haemodynamic and clinical severity of acute heart failure in the Kashmiri population. Their strong mutual correlation supports interchangeable use in clinical practice. Integration of lung ultrasound B-line monitoring with natriuretic peptide measurement provides superior assessment of decongestion. These findings have direct implications for resource-limited tertiary care settings, where single-biomarker assay selection is often dictated by cost and availability.

Diagnosing hypocortisolism in disguise: clinical insights from delayed-onset endocrine disorders.

Ann Med Surg (Lond)

Ajith Marimuthu, S Noorul Hidhaya, Vijayalakshmi Gurusamy +4 more

Adrenal insufficiency is characterized by inadequate cortisol production, with or without aldosterone and adrenal androgen precursor deficiencies. This can make it difficult for the body to respond to stress and maintain essential functions. The symptoms of adrenal insufficiency are often non-specific, leading to delayed diagnosis and frequent misinterpretation.

Toward a deeper and more comprehensive understanding of neurological symptoms related to Allgrove syndrome: a case report.

Ann Med Surg (Lond)

Farah Al-Hasani, Hana Diab, Sultaneh Haddad +5 more

Allgrove syndrome (AS) is a rare autosomal recessive disorder caused by triple A syndrome gene mutations, characterized by alacrima, achalasia, and adrenocorticotropic hormone (ACTH)-resistant adrenal insufficiency, with potential neurological complications. Early signs include absent tears, feeding difficulties, vomiting, and growth issues, while adrenal crises and neurological symptoms may appear later. Diagnosis is often delayed when only one feature is present.

Case Report: Challenges in the diagnosis of pseudohypoaldosteronism: insights from a resource-limited setting.

Front Endocrinol (Lausanne)

Salwa A Musa, Nifal S Ariss, Samar S Hassan +4 more

Pseudo-hypoaldosteronism type 1 (PHA1) is a hereditary condition characterized by end-organ resistance to aldosterone, resulting in electrolyte imbalance, metabolic acidosis, and hyperaldosteronism. It is inherited in an autosomal dominant renal or an autosomal recessive systemic form. Here, we report a case series of PHA1, highlighting its challenging diagnosis and underscoring the complexities involved in reaching an accurate diagnosis in a resource-limited setting.

Taste and Smell Disturbances Associated With Secondary Adrenal Insufficiency: A Case Report.

J Gen Fam Med

Takanori Izumi, Eri Doi, Yuki Tsutsui +6 more

Adrenal insufficiency often presents with nonspecific symptoms, impeding early diagnosis. Taste and smell disturbances are rarely recognized as presenting features.

Current treatment landscape of acromegaly.

J Clin Endocrinol Metab

Frederic Castinetti, Adriana G Ioachimescu

Treatment of acromegaly includes surgery followed by chronic medical therapy for persistent growth hormone (GH) excess, and, in some patients, radiation. Treatment is aimed at biochemical normalization, which improves survival and comorbidities. However, many patients experience lifelong burden related to persistent acromegaly manifestations and adverse treatment effects. Long-acting somatostatin receptor ligand (SRL) therapy with octreotide or lanreotide has been the cornerstone of management. Pasireotide long-acting release, a somatostatin receptor multiligand, achieves more favorable biochemical control rates but is associated with an increased risk of hyperglycemia. Pegvisomant, a GH receptor antagonist, can be used as monotherapy or in combination with SRLs. The spectrum of medical therapy has expanded with the advent of oral octreotide capsules; the oral selective somatostatin receptor subtype 2 agonist, paltusotine; and monthly self-administered subcutaneous octreotide. This review outlines the updates to current acromegaly treatment options and their impact on patient outcomes.

GLP-1 Receptor Agonists in Metabolic Dysfunction-Associated Steatotic Liver Disease: Bridging Hepatic and Cardiovascular Outcomes.

Chronic Dis Transl Med

Gabriel Amorim Moreira Alves, Masatoki Teranishi, Rajendranandini Majumdar +6 more

Metabolic dysfunction-associated steatotic liver disease (MASLD) affects over 30% of adults worldwide and represents a systemic cardiometabolic disorder in which cardiovascular disease is the leading cause of death. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are uniquely positioned to address this liver-heart axis by combining hepatic disease-modifying signals with proven cardiovascular risk reduction. This review synthesizes mechanistic, randomized trial, real-world, and cardiovascular outcome evidence for GLP-1RAs in MASLD and metabolic dysfunction-associated steatohepatitis (MASH). In biopsy-based trials, liraglutide (LEAN) increased steatohepatitis resolution without fibrosis worsening (39% vs. 9% with placebo), while semaglutide demonstrated dose-dependent resolution (up to 59% vs. 17% in Phase 2). More recently, semaglutide 2.4 mg weekly met both histologic endpoints at interim analysis in F2-F3 MASH (resolution without fibrosis worsening 62.9% vs. 34.3%; fibrosis improvement ≥ 1 stage 36.8% vs. 22.4%), and tirzepatide (SYNERGY-NASH) achieved high rates of MASH resolution (44%-62% vs. 10%) with concomitant fibrosis improvement signals (up to 51% vs. 30%). Cardiovascular outcome trials demonstrate consistent reductions in major adverse cardiovascular events with GLP-1RAs, including liraglutide (LEADER), semaglutide (SUSTAIN-6 and SELECT), and dulaglutide (REWIND). Mechanistically, GLP-1RAs reduce hepatic lipogenesis and lipotoxicity, attenuate inflammation, improve insulin sensitivity, and modulate gut-brain-liver signaling, with systemic benefits on weight, blood pressure, and atherogenic lipoproteins. Collectively, the evidence supports GLP-1RAs, particularly semaglutide and tirzepatide, as foundational therapies for MASLD patients with obesity, type 2 diabetes, advanced fibrosis, or heart failure phenotypes. Key gaps include treatment duration, durability of fibrosis benefit, and effectiveness in cirrhosis, requiring long-term follow-up.

Liver Fat Is Associated With Elevated FGF21 in Youth With Obesity but Without MASLD.

Pediatr Obes

Emir Tas, Eva C Diaz, Xiawei Ou +2 more

Youth with obesity are at risk for accumulating liver fat, even below the threshold for metabolic dysfunction-associated steatotic liver disease (MASLD), defined as ≥ 5% by MRI. While prior studies suggest that sub-threshold liver fat may carry metabolic risk, the role of fibroblast growth factor-21 (FGF21)-a liver-derived hormone responsive to metabolic stress-has not been well characterised in this context.

Cagrilintide-semaglutide (CagriSema) as an add-on to basal insulin in adults with type 2 diabetes (REIMAGINE 3): a randomised, double-blind, placebo-controlled, multicentre, phase 3 study.

Lancet

Julio Rosenstock, Liana K Billings, Reena Gajria +6 more

Basal insulin treatment for type 2 diabetes often results in inadequate glycaemic control and is associated with weight gain and increased risk of hypoglycaemia. We aimed to compare the efficacy and safety of a once per week combination of cagrilintide with semaglutide (CagriSema) versus placebo as an add-on to basal insulin in individuals with type 2 diabetes.

Cagrilintide-semaglutide: a new option for patients with type 2 diabetes.

Lancet Diabetes Endocrinol

André J Scheen

Cagrilintide-semaglutide (CagriSema) versus semaglutide or cagrilintide in people with type 2 diabetes (REIMAGINE 2): a double-blind, randomised, controlled, phase 3 study.

Lancet Diabetes Endocrinol

John B Buse, Harpreet S Bajaj, Stine-Mathilde Dalskov +8 more

The amylin receptor agonist cagrilintide and the GLP-1 receptor agonist semaglutide have complementary effects on glycaemic control and bodyweight. We aimed to investigate the efficacy and safety of a fixed-dose combination of cagrilintide and semaglutide (cagrilintide-semaglutide; known as CagriSema) versus semaglutide or cagrilintide for glycaemic control in people with type 2 diabetes and overweight or obesity.

Efficacy and safety of once-weekly cagrilintide-semaglutide (CagriSema) in adults with type 2 diabetes inadequately controlled on diet and exercise (REIMAGINE 1): a randomised, double-blind, placebo-controlled, phase 3a study.

Lancet Diabetes Endocrinol

Vanita R Aroda, Raffaella Buzzetti, Stine-Mathilde Dalskov +7 more

Cagrilintide-semaglutide (CagriSema) is a novel, once-weekly combination of the amylin receptor agonist cagrilintide and the GLP-1 receptor agonist semaglutide. We aimed to assess the efficacy and safety of cagrilintide-semaglutide for people with type 2 diabetes inadequately controlled with diet and exercise.

Dose-Response and Clinical Equivalence of Semaglutide and Tirzepatide for Weight Loss in Type 2 Diabetes: A Model-Based Analysis.

Diabetes Ther

Carlos E Builes-Montaño, Andres F Suarez-Rodriguez, Maria A Alzate-Vinasco

Semaglutide and tirzepatide are highly effective incretin-based therapies for weight reduction in individuals with type 2 diabetes (T2DM). However, direct comparisons across the full range of clinically relevant doses in T2DM are limited. This study aimed to evaluate dose-response relationships and clinical equivalence between semaglutide and tirzepatide using a model-based approach.

[Research progress on vascular endothelial growth factor C in meningeal lymphatic vessel-mediated clearance of amyloid β-protein].

Zhejiang Da Xue Xue Bao Yi Xue Ban

Zhaoxie Yu, Yao Wang, Yanan Li +2 more

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the abnormal deposition of amyloid β-protein (Aβ) as a core pathological feature. Meningeal lymphatic vessels are crucial for Aβ clearance, and their dysfunction accelerates AD progression. Vascular endothelial growth factor C (VEGF-C), through activation of vascular endothelial growth factor receptor 3 and downstream pathways, synergistically promotes lymphangiogenesis, enhances lymphatic permeability, and regulates lymphatic fluid flow, thereby improving Aβ clearance efficiency. Genetic factors and aging-related declines in VEGF-C further impair meningeal lymphatic function, creating a vicious cycle. Although VEGF-C intervention has shown cognitive benefits in AD models, clinical translation faces challenges including non-specific activation of signaling pathways and interindividual variability. Future research should focus on precise regulation of VEGF-C and development of individualized AD therapeutic strategies targeting meningeal lymphatic vessels. This review summarizes the molecular mechanisms, influencing factors, and intervention strategies of VEGF-C in regulating meningeal lymphatic vessel function to promote Aβ clearance, aiming to provide insights for AD prevention and treatment.

Long-Term Prognosis and Outcomes in Patients Undergoing His Bundle Pacing Implantation　- A Multicenter, Prospective Observational Study in Japan.

Circ J

Satoshi Yanagisawa, Hiroyuki Kato, Yasunori Kanzaki +15 more

His bundle (HB) pacing (HBP) can achieve an ideal pattern of ventricular activation. The long-term efficacy and clinical outcomes of HBP in Japan remain unclear.

Efficacy and safety of retatrutide, a GIP, GLP-1, and glucagon receptor agonist, in people with type 2 diabetes and inadequate glycaemic control with diet and exercise (TRANSCEND-T2D-1): a double-blind, randomised, phase 3 trial.

Lancet

Harpreet S Bajaj, Michelle Welch, Parag Shah +7 more

Retatrutide is a GIP, GLP-1, and glucagon triple hormone receptor agonist, under clinical development for type 2 diabetes, obesity, and related complications. We aimed to assess the efficacy and safety of retatrutide as a monotherapy in people with type 2 diabetes that is inadequately controlled by diet and exercise alone.

The orexinergic crossroads: Bidirectional links between sleep-wake disturbances and the pathogenesis of Alzheimer's disease in the aging brain.

Sleep Med

Xinxin Tian, Yuqing Shi, Huazhong Xiong +5 more

This review examines the bidirectional relationship between sleep instability and the pathogenesis of Alzheimer's disease, with particular emphasis on the hypothalamic orexinergic system as a key mechanistic link between these processes. Emerging evidence suggests that excessive orexin signaling contributes to insomnia and sleep fragmentation and may accelerate amyloid-β and tau accumulation by impairing glymphatic clearance and activating neurotoxic pathways. Conversely, progressive neurodegeneration can impair sleep-regulatory centers in the brainstem and hypothalamus, thereby creating a vicious cycle that may hasten cognitive decline. We further discuss therapeutic strategies targeting this pathway, with a focus on dual orexin receptor antagonists and complementary medical approaches. Notably, recent preclinical findings suggest that Panax ginseng extracts may inhibit orexin signaling and reactivate autophagy through the mammalian target of rapamycin pathway, thereby attenuating neuronal damage. By synthesizing current mechanistic insights and clinical evidence, this review proposes that modulation of the orexinergic system, through pharmacological and integrative approaches, may represent a promising strategy for delaying disease progression and improving quality of life in older adults.

Pituitary Developmental Gene Defects and Their Contribution to Growth Hormone Deficiency.

Ann Endocrinol (Paris)

Karine Aouchiche, Rachel Reynaud, Theo Charnay +4 more

Growth hormone deficiency (GHD) is a rare endocrine disorder responsible for growth failure. In the absence of an identified secondary cause, a genetic etiology can be identified, affecting genes involved in hypothalamo-pituitary growth hormone (GH) regulation or in pituitary development itself. The anterior pituitary gland arises from the oral ectoderm and is regulated by neuroectodermal signaling and transcription factors that ensure proper differentiation of hormone-producing cells. GH secretion is stimulated by growth-hormone-releasing hormone (GHRH) and ghrelin, with mutations in their respective receptors (GHRHR, GHSR) contributing to isolated GHD (IGHD). Mutations in GH1, encoding GH itself, are the main genetic cause of IGHD. GHD can also arise from mutations in transcription factor genes such as POU1F1, PROP1, IGSF1 or TBX19 or in genes involved in early brain development such as GLI2, LHX3 or HESX1, potentially leading to syndromic presentations with multi-organ involvement. Understanding the genetic basis of GHD is essential to improving diagnostic strategies, genetic counseling and the development of targeted therapies. Although animal models have been fundamental for understanding pituitary ontogenesis, emerging tools such as human pituitary organoids now offer the promise of dissecting human-specific regulatory mechanisms that cannot be fully captured in traditional animal models. This review aims to provide a comprehensive overview of all known genetic causes of GHD, with a particular focus on the underlying molecular mechanisms and their associated phenotypes.

Once-Weekly Subcutaneous Semaglutide 2.4 mg Injection is Cost-Effective for Weight Management in Spain.

Adv Ther

Andreu Altés, Óscar Moreno-Pérez, Miquel Sastre-Belío +6 more

A current major challenge for national health systems (NHS) is the increase of obesity and overweight among populations. Subcutaneous semaglutide 2.4 mg, a glucagon-like peptide 1 analogue, has been approved by the European Medicines Agency as an adjunct to a reduced-calorie diet and increased physical activity (diet and exercise [D&E]) for the treatment of obesity. The aim of this study was to evaluate the cost-effectiveness of semaglutide 2.4 mg in combination with D&E compared with D&E alone in the treatment of patients with obesity in Spain.