Abstract: Stimulatory inputs from the brain on CRH and AVP biosynthesis, deficiencies in the negative feedback of cortisol, and insufficient stimulation of β-arrestin-1 by cortisol may all act to increase secretion of ACTH. Cells within the tumor micoenvironment may also contribute to the availability of cortisol to solid tumors. Peripherally, cortisol activity is preserved by 11βHSD type I and is decreased at specific sites by 11βHSD type 2. In metastatic breast cancer, the normal circadian rhythm of serum and salivary cortisol is disrupted, with great hour-to-hour variation and elevated concentrations at the afternoon nadir. Major depression and other chronic illnesses have been associated with increased serum cortisol levels, but breast cancer is unusual in that the opposing steroid DHEA is also elevated. Cortisol increases cancer risk by making glucose available through glycogenolysis and gluconeogenesis, by inhibiting insulin promotion of glucose uptake, and by inhibiting IGF-I promotion of leukocytopoiesis, increasing the synthesis of glutamine synthetase, inhibiting ICAM-I and VCAM-1 for leukocyte recruitment, and increasing the expression of immune checkpoint receptors PD-1 and Tim3 and increasing Treg cells. Cortisol promotes the polarization of macrophages toward the anti-inflammatory M2 phenotype and decreases the M1 phenotype. It also binds to membrane-bound corticosteroid-binding globulin, activating adenylyl cyclase, suppressing T cell proliferation. Overall, elevated cortisol secretion promotes growth of solid tumors, mainly by providing a substrate for growth and by suppression of host defenses. Glucocorticoid agonists may benefit therapies utilizing DNA damage response, retinoid therapy, and PARP1 therapy but may oppose therapies of ER- cancers and immune checkpoint blockade therapy. Cortisol is known to affect several physiological processes. Immunosuppressive activity has been well documented, but how all of the many activities interact to affect the growth of breast cancer has not been reviewed in recent years.

Abstract: Prostate cancer remains a leading cause of male cancer mortality, principally due to the inevitable transition from androgen-sensitive disease to lethal castration-resistant prostate cancer (CRPC). This review synthesizes the multifaceted molecular mechanisms driving this therapeutic failure, moving beyond a catalogue of signaling nodes to a structural and kinetic analysis of resistance networks. We dissect the reactivation of Androgen Receptor (AR) signaling through the lens of key kinase cascades, specifically the PI3K/AKT/mTOR and MAPK axes, and their regulation of the steroidogenic gatekeeper CYP17A1. Special emphasis is placed on the structural determinants of CYP17A1 activity, including the critical Asn202 gating mechanism and the "backdoor" pathway of dihydrotestosterone (DHT) biosynthesis that bypasses canonical testosterone intermediates. Furthermore, we integrate the "hydrophobic spine" hypothesis of kinase activation to explain the efficacy and failure of Type I and Type II kinase inhibitors. In parallel, we unravel the regulatory complexity of non-coding RNAs (ncRNAs), detailing how upregulated transcripts like LINC00675 and Lnc-ZNF30-3 function as dynamic scaffolds and competing endogenous RNAs (ceRNAs) to stabilize AR and promote epithelial-mesenchymal transition (EMT). By converging these insights with emerging therapeutic strategies, such as next-generation lipid nanoparticle (LNP)-mediated RNA interference utilizing hexagonal HII phase endosomal escape, we provide a comprehensive roadmap for dismantling the molecular fortresses of advanced prostate cancer.

Abstract: The role of vitamin D (VD) in cardiovascular health remains controversial. Observational studies have associated low serum 25(OH)D₃ levels with increased cardiovascular risk, whereas interventional and Mendelian randomization trials have failed to demonstrate causality. This discrepancy may reflect unrecognized interindividual variability in VD responsiveness and the weak correlation between circulating VD metabolites and tissue-specific biological effects. This review introduces the emerging concept of variable VD sensitivity, encompassing a continuum from vitamin D resistance (VDRES) to vitamin D hypersensitivity (VDHY). VDRES results from genetic or acquired alterations that impair VD metabolism, transport, or receptor signaling, leading to an insufficient biological response. Conversely, VDHY involves excessive local VD activation, frequently due to CYP24A1 variants or granulomatous activity. The resulting surplus of active VD suppresses parathyroid hormone–related peptide (PTHrP), promoting vascular smooth muscle cell calcification and accelerating atherosclerosis. VD metabolism also appears to intersect with lipid regulation. Patients carrying CYP24A1 mutations, which impair the catabolism of 1,25(OH)₂D₃, exhibit abnormalities in lipid metabolism, including hypercholesterolemia. Dysregulated VD signaling may therefore disrupt cholesterol homeostasis through feedback mechanisms. These opposing phenotypes may help explain the inconsistent cardiovascular outcomes observed in clinical studies. Integrating evidence from endocrinology, vascular biology, and genetics, this review argues for individualized rather than uniform VD supplementation strategies. A deeper understanding of the molecular determinants of VD responsiveness could enhance cardiovascular risk assessment and therapeutic precision. Until assays become available to predict individual responsiveness, clinicians should exercise caution when prescribing VD, particularly in populations at risk for suboptimal response or toxicity.

Abstract: Phosphatidic acid (PA) is increasingly recognized as an important endogenous regulator of cell proliferation and migration, playing relevant roles in physiology and pathology. However, the potential and prominence of extracellular PA in controlling cell functions are not so well established. The present review article has been undertaken to update and discuss the latest findings on extracellular PA as regulator of cell homeostasis, with special attention being paid to its role in the regulation of cell growth and migration. Specifically, exogenous PA potently stimulates myoblast proliferation, and lung cancer cell migration, pointing to a critical role of this glycerophospholipid in the regulation of muscle cell regeneration and lung cancer dissemination. Interestingly, both of these actions are mediated through interaction of PA with lysophosphatidic acid (LPA) receptors and the subsequent activation of different signal transduction pathways. In particular, PA induces mitogen-activated protein kinase kinase (MEK)/extracellularly regulated kinases (ERK) 1 and 2, phosphatidylinositol 3-kinase (PI3K)/Akt, focal adhesion kinase (FAK)/Rac1, and Janus kinase (JAK)/ signal transducer and activator of transcription 3 (STAT3). These findings may contribute to a better understanding of muscle cell biology, and may help to develop new therapeutic strategies to treat lung cancer dissemination.

Abstract:

Background: Older patients with type 2 diabetes mellitus (T2DM) are often undertreated because of concerns regarding hypoglycaemia and clinical heterogeneity. Data on the effectiveness of oral semaglutide in this population remain limited. Methods: This observational study included 81 patients aged ≥65 years with T2DM treated with oral semaglutide for 12 months. Changes in glycaemic, anthropometric and cardiometabolic parameters were evaluated. The primary endpoint was achievement of HbA1c <7% at 12 months. Multivariable logistic regression was performed to identify baseline predictors of response. Results: HbA1c decreased from 7.75 ± 1.01% to 6.80 ± 0.88% after 12 months (p < 0.00001). Significant reductions were observed in body weight (−4.09 ± 4.42 kg, p < 0.00001), BMI (−1.50 ± 1.55 kg/m², p < 0.00001) and waist circumference (−5.83 ± 4.71 cm, p < 0.00001). Improvements were also detected in lipid profile, blood pressure and visceral adiposity indices. No hypoglycaemic events were reported during follow-up. In multivariable analysis, no baseline clinical or metabolic variable independently predicted achievement of HbA1c <7%, indicating a homogeneous glycaemic response across the study population. Greater absolute HbA1c reductions were observed in patients with higher baseline HbA1c. Conclusions: In older patients with T2DM, oral semaglutide is associated with effective glycaemic control without hypoglycaemia and with a response largely independent of baseline clinical characteristics, supporting its use in elderly and clinically heterogeneous populations.

Abstract:

Context: Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is a common autosomal recessive disorder characterized by impaired cortisol and aldosterone synthesis. While genotype-phenotype correlations are well-established for common CYP21A2 mutations, the clinical significance of rare missense variants remains a challenge, often leading to their classification as Variants of Uncertain Significance (VUS) and complicating genetic counseling. Objective: To determine the functional impact and pathogenicity of eleven CYP21A2 variants (p.L10del, p.R76K, p.E162G, p.S274Y, p.L308V, p.S373N, p.P387L, p.H393Q, p.R401G, p.R436C, and p.S494N) utilizing a comprehensive approach integrating population genetics, in silico structural modeling, and in vitro functional assays. Methods: Allele frequencies were analyzed using global databases (gnomAD, 1000G). Evolutionary conservation was assessed via ConSurf, and thermodynamic stability was predicted using FoldX and DUET. Structural dynamics were simulated using Molecular Dynamics (MD) (100 ns). Variants were expressed in HEK293T cells, and enzymatic activity was quantified using radiolabeled progesterone and 17-hydroxyprogesterone (17-OHP) as substrates, normalized to protein expression levels determined by Western blot. Results: Population analysis identified p.L10del and p.S494N as common polymorphisms (allele frequencies >5% in specific populations) with near-normal enzymatic activity (~99% and ~67% for 17-OHP, respectively), supporting a Benign classification. Conversely, p.L308V, p.P387L, and p.R436C were ultra-rare and exhibited severe loss of function, retaining <20% of wild-type activity for 17-OHP. Structural modeling revealed that p.L308V causes steric clashes in the conserved I-helix, while p.P387L induces core destabilization and kinetic instability. p.R436C disrupts the surface hydrogen-bond network essential for P450 Oxidoreductase interaction. These variants are reclassified as Pathogenic, likely associated with Simple Virilizing CAH. Variants p.H393Q and p.R401G showed moderate impairment (~40–45% activity), consistent with a Likely Pathogenic status and Non-Classic CAH phenotype. Conclusions: This study resolves the diagnostic status of eleven CYP21A2 variants. We provide definitive evidence that p.L308V is a severe pathogenic missense mutation distinct from frameshift alleles at the same locus, and that surface mutations like p.R436C can be as deleterious as core mutations due to the disruption of redox partner interfaces. These findings refine the genetic classification of CAH, enabling precise diagnosis and personalized management for affected families.

Abstract: Background/Objectives: Type 2 diabetes (T2D) affects more than 38 million Americans and remains a leading public health challenge. Behavioral self-management is central to glycemic control but is often undermined by dysregulated and addictive-like eating. Continuous glucose monitoring (CGM) offers immediate feedback that may strengthen self-regulation, yet the psychological processes linking CGM use, food addiction (FA), and behavior change are poorly understood. This secondary mixed-methods study examined how CGM-supported group medical visits (GMVs) influence glycemic outcomes and FA symptoms in adults with diabetes. Methods: Adults with T2D participated in a 14-week GMV program integrating CGM review with education on nutrition, physical activity, sleep, stress, and intermittent fasting. Thirteen participants had paired CGM summaries and psychosocial data. Quantitative outcomes included mean glucose, glycemic variability, time-in-range (TIR) and symptoms of food addiction using the modified Yale Food Addiction Scale 2.0 (mYFAS 2.0). Qualitative data came from open-ended surveys analyzed using reflexive thematic analysis. Integration followed a convergent design, merging individual change trajectories with thematic interpretations and case vignettes. Results: Mean glucose decreased by 21 mg/dL and TIR improved by 9 percentage points. Among six participants with baseline FA symptoms, all showed improvement. Four moved from mild to no symptoms, one from moderate to no symptoms, and one from severe to no symptoms. Across the full sample, the mean change was a reduction of 1.2 in the mYFAS 2.0 symptom counts per participant. Thematic analysis identified four interrelated psychological mechanisms: enhanced awareness of food–glucose relationships, increased accountability through shared tracking, motivation via gamified self-monitoring, and relief from cognitive burden associated with dietary uncertainty. Conclusions: Integrating CGM feedback into GMVs may reduce addictive-like eating and promote glycemic improvement by enhancing awareness, accountability, and self-regulatory engagement. These findings position CGM as a behavioral intervention tool that complements its traditional monitoring role and highlight the value of combining real-time biofeedback with group-based support in diabetes care.

Abstract: Diabetic retinopathy (DR) remains one of the most frequent and severe complications in patients with type 2 diabetes (T2DM), with significant implications for vision and quality of life. While classical screening methods are effective, they are not always accessible or systematically used. Sudoscan, a device that evaluates sweat gland function and reflects peripheral autonomic status, has recently attracted attention as a potential tool for early detection of microvascular complications. In this cross-sectional study, we investigated its utility in identifying DR among 271 adults with T2DM. DR was diagnosed in 35.8% of patients, and those affected showed lower Sudoscan scores in the lower limbs and higher scores indicating cardiovascular autonomic neuropathy. Statistical analyses, including ROC curve evaluation and multiple linear regression, revealed moderate diagnostic accuracy and significant correlations between Sudoscan parameters and DR severity. Our results suggest that Sudoscan could serve as a fast, painless, and informative screening tool, particularly valuable in settings with limited access to ophthalmologic services. Although it does not replace fundus examination, it may offer complementary insights and help stratify patients by risk level, guiding more targeted monitoring and intervention strategies.

Abstract:

Background. Both primary hyperparathyroidism (PHPT) and chronic hypoparathyroidism (HypoPT) are associated with the onset and development of cardiovascular diseases (CVDs). Especially PHPT is accompanied by the presence of elevated atherothrombotic risk, while the importance of traditional and new anthropometric indices to reflect the cardiovascular risk remains uncertain in this condition. This study aims to investigate whether novel and traditional anthropometric indices distinguish PHPT and their correlation with atherothrombotic risk. Methods. 40 Subjects with HypoPT, 40 PHPT and 40 age- and sex-matched control subjects were consecutively enrolled for the evaluation of flow-mediated vasodilation (FMD) and carotid intimal-media thickness (IMT). A blood sample was collected for calcium-phosphate metabolism, PTH, TSH and 25-hydroxy vitamin D evaluation. Physical examination was performed to obtain traditional anthropometric parameters and derived indices of adiposity and cardiometabolic risk (waist height ratio (WHtR) and waist hip ratio (WHR) and conicity index (CI)). Results. The PHPT group showed higher central adiposity indices (WHtR p=0.002, and CI p=0.008). Among patients with parathyroid disorders, PHPT subjects display the highest reduction of FMD (p<0.001) and a marked increase of IMT (p<0.001). In the Ctrl group, WHtR showed a weak-to-moderate positive association with IMT (r=0.381, p=0.018). In the PHPT group, no anthropometric index was significantly correlated with IMT or FMD (all p>0.05). Conclusions. WHtR and CI provide evidence of increased central fat adiposity in PHPT but do not account for impaired atherothrombotic risk, indicating that anthropometric indices may lack relevance to cardiovascular risk in this condition and emphasising the importance of a specific assessment profile.

Abstract: Background: Adult growth hormone deficiency (GHD) is linked to increased cardio-vascular and metabolic risk due to oxidative stress (OS), endothelial dysfunction, and adverse body composition. Long-term systemic effects of recombinant human growth hormone (rhGH) therapy remain insufficiently defined. This study assessed the impact of 24-month rhGH replacement on OS, vascular markers, body composition, and bone mineral density (BMD) in adults with severe GHD. Methods: Fifteen adults with confirmed GHD received rhGH for 24 months. Serum insulin-like growth factor -1 (IGF-1), oxidized LDL (Ox-LDL), thioredoxin (Trx), 8-oxoguanine DNA glycosylase (OGG1), E-selectin, ICAM-1, and VCAM-1 were meas-ured at baseline, 12, and 24 months. Body composition and BMD were evaluated by DXA. Results: IGF-1 increased significantly at 12 and 24 months (p < 0.001). Ox-LDL decreased markedly (p < 0.00001), while Trx and OGG1 increased (p < 0.05). Levels of E-selectin, ICAM-1, and VCAM-1 declined, indicating improved endothelial function. Lean body mass and BMD (lumbar spine and femoral neck) increased, whereas body fat percentage decreased. Lipid profiles were unchanged. Significant correlations were observed be-tween vascular markers and adiposity, and between BMD, triglycerides, and IGF-1. Conclusion: A 24-month rhGH therapy improves redox balance, vascular function, and body composition in adults with severe GHD, supporting the use of redox and vascular biomarkers to monitor treatment efficacy.

Abstract:

Introduction: SARS-CoV-2 infection has been increasingly associated with thyroid involvement, likely mediated by post-viral immune–inflammatory mechanisms. However, prospective data on the incidence and medium-term evolution of post-COVID thyroid dysfunction remain limited. Methods: We conducted a prospective, observational, single-center study including adult patients hospitalized for COVID-19 between December 2022 and December 2024. Thyroid function tests, thyroid autoantibodies, inflammatory markers, and thyroid ultrasound were assessed during hospitalization and re-evaluated at 4–6 weeks, 3, 6, and 12 months. Acute disease severity and administered treatments, including corticosteroid therapy, were recorded. Results: A total of 71 patients were enrolled, of whom 67 completed the 12-month follow-up. During follow-up, 6.0% of patients developed subacute thyroiditis and 11.9% developed autoimmune thyroiditis, with most cases showing a mild or self-limited clinical course. Persistence of thyroid autoantibodies at 12 months was observed in a subset of patients. Longitudinal assessment of thyroid hormones revealed an overall trend toward gradual normalization, with marked interindividual variability. Associations between thyroid dysfunction, systemic inflammation, and acute COVID-19 severity were weak. Conclusions: Post-COVID thyroid dysfunction, particularly subacute and autoimmune thyroiditis, was relatively frequent within the first 12 months after SARS-CoV-2 infection, even following mild or moderate acute disease. These findings support the need for risk-adapted thyroid monitoring in the post-COVID period and suggest a triggering role of SARS-CoV-2 for both transient thyroid dysfunction and persistent autoimmune processes.

Abstract: Diabetes is one of the fastest-growing global health emergencies. The International Diabetes Federation (IDF) estimates that in 2024 there were 589 million adults aged 20–79 years living with diabetes worldwide (1 in 9); 43% (252 million) were undiagnosed; diabetes caused 3.4 million deaths; and global health expenditure reached USD 1.015 trillion, with 81% of adults with diabetes living in low- and middle-income countries [1 ]. The downstream burden is driven by preventable complications: diabetic kidney disease affects roughly 30–40% of people with diabetes; diabetic foot ulcers occur in an estimated 19–34% over a lifetime; diabetic peripheral neuropathy affects about 30% of people with diabetes globally; and diabetic retinopathy affects about 22% of adults with diabetes (with ~6% having vision-threatening disease) [2–5]. Saudi Arabia is a high-burden setting within the Middle East and North Africa region: IDF 2024 estimates indicate 5.34 million adults (20–79 years) living with diabetes, an age-standardised prevalence of 23.1% (approximately one in five adults), and 43.6% undiagnosed. This combination of high clinical need and rapidly maturing digital health infrastructure makes Saudi Arabia an ideal implementation testbed for an AI-first, end-to-end care model that can be generalised internationally [1]. This Personal View proposes a fully AI-enabled, clinician-in-the-loop “AI Diabetes Clinic” that synthesises patient-entered data, laboratory and imaging results, and longitudinal records to support diagnosis of type 2 diabetes, personalised pharmacotherapy selection and titration, and continuous complication surveillance. The model combines an AI-assisted pre-visit synthesis, an explainable treatment optimiser aligned with contemporary guidelines, and automated screening workflows for retinopathy, nephropathy, neuropathy, and diabetic foot disease, with escalation to clinicians when risk thresholds are crossed. Because AI-first clinics concentrate clinical, privacy, and cybersecurity risks, deployment must be coupled to robust governance: model transparency, bias and safety testing, audit trails, and human oversight; privacy-by-design and consent aligned with local regulations; and cyber-resilience aligned with national standards. We outline an evaluation strategy spanning usability, clinical effectiveness, equity, safety, and cost-effectiveness, including continuous post-deployment monitoring to ensure sustained performance across populations and care settings.

Abstract: Background: Chronic stress causes disturbances to the physiological responses of the body’s allostatic systems. However, regular physical activity (PA) helps mitigate the accumulation of allostatic load (AL) by enhancing adaptive stress responses and im-proving metabolic health. The current study investigated PA on the primary mediators of AL and metabolic risk markers and metabolic syndrome (MetS) in healthy adults in Germany. Methods: 46 adults (18 - 45 years) were categorized into regular PA (≥ 150 min a week) and non-regular PA (≤ 150 min a week) group. Primary AL mediators were quantified by cortisol (g/12h), epinephrine (g/12h), norepinephrine (g/12h), and dehydroepiandrosterone sulfate (DHEA-S: g/ml). Mann Whitney U-test was used to find the differences between the two groups concerning primary mediators of AL, and metabolic risk markers. Results: Significant differences (p = 0.01) were observed on cortisol between the groups. No significant differences (p > 0.05) were found on metabolic risk markers such as triglycerides, blood pressure, BMI, and HDL-C among the two groups. The MetS diagnosis criteria were met by only n = 2 participants – one from the regular PA and one from the non-regular PA group. Conclusion: Findings show regular PA may support-stress regulatory mechanisms and protection against early metabolic dysregu-lation.

Abstract: Resilience is commonly framed as a psychological trait, yet clinical and experimental evidence demonstrates that resilience failures emerge concurrently across metabolic, endocrine, immune, and cognitive domains. This review examines resilience as a bio-energetic property constrained by how organisms allocate finite metabolic resources under stress. We synthesize evidence from endocrinology, mitochondrial biology, immunometabolism, and stress physiology to propose an integrated Energy Allocation System (EAS) in which the hypothalamic–pituitary–adrenal (HPA), thyroid (HPT), and gonadal (HPG) axes function as a coordinated energy-governance network. Within this framework, mitochondrial reserve capacity serves as the limiting substrate through which hormonal signals regulate mobilization, metabolic pacing, immune tolerance, and recovery. The reviewed literature supports predictable patterns of endocrine reorganization during energetic strain, including prioritization of glucocorticoid-mediated mobilization, constrained thyroid hormone activation, suppression of long-term anabolic investment, and impaired recovery following stress. These configurations reflect adaptive energy-conserving strategies rather than isolated organ dysfunction. We further discuss how routinely available biomarkers and validated psychometric measures can be interpreted as functional readouts of energetic allocation rather than static disease markers. Framing resilience through coordinated energy governance offers a unifying mechanistic lens for interpreting multisystem stress responses and generates testable predictions for future experimental and clinical investigation.

Abstract: Background: Emerging evidence suggests that lipedema may share hormonal, in-flammatory, and genetic mechanisms with gynecologic diseases, particularly endome-triosis. However, the extent and nature of these interrelationships remain poorly cha-racterized, supporting the need for this scoping review. Objectives: To map and synthesize the available evidence on the clinical, pathophysiological, and epidemiolo-gical interrelationships between lipedema in women, endometriosis, and other gyne-cologic diseases. Methods: Searches were conducted in international and regional health databases, including MEDLINE (PubMed), CINAHL, Scopus, Embase, Web of Science, the Cochrane Library, LILACS/VHL, APA PsycInfo, SciELO, Epistemonikos, and La Referencia, as well as grey literature sources and relevant institutional websites. There were no language restrictions. The search period began in 1940, the year in which li-pedema was first described by Allen and Hines. Study selection followed a two-stage process conducted independently by two reviewers, consisting of title and abstract screening followed by full-text review. Data extraction was performed using a pre-developed and peer-reviewed instrument covering participants, concept, context, study methods, and main findings. The review protocol was registered in the Open Science Framework (https://doi.org/10.17605/OSF.IO/D65GS). Results: Twenty-five stu-dies from ten countries were included. Synthesis of the available evidence indicates that lipedema is consistent with a systemic condition involving metabolic and hormonal dimensions, characterized by onset related to reproductive milestones, a high frequency of gynecologic and endocrine comorbidities, and molecular features overlapping with steroid-dependent pathologies. These findings reflect a recent shift from a predominantly lymphovascular paradigm toward a more integrated endocrinometabolic framework. Conclusions: The findings indicate that lipedema clusters with hormone-sensitive gynecologic and endocrine features across reproductive life stages.

Abstract:

Background/Objectives: Accurate preoperative localization of hyperfunctioning parathyroid tissue is essential for minimally invasive parathyroidectomy. Conventional planar dual-phase 99mTc-sestamibi scintigraphy is widely used but shows reduced diagnostic accuracy in patients with thyroid nodules or ectopic glands. Hybrid triple-head SPECT/CT integrates functional and anatomical imaging and may improve lesion detection. This study evaluated the diagnostic performance of triple-head SPECT/CT compared with planar scintigraphy and explored correlations between biochemical markers and imaging positivity. Methods: A retrospective single-center study included 90 adults referred for suspected primary hyperparathyroidism between January 2021 and August 2025. Demographic data, laboratory parameters (PTH, total and ionized calcium, 25-hydroxyvitamin D), and imaging results were collected. Diagnostic accuracy was assessed in patients with surgical confirmation or robust clinical verification. Correlations between biochemical markers and imaging positivity were analyzed using Pearson correlation coefficients. Results: SPECT/CT demonstrated significantly higher sensitivity than planar scintigraphy (62.5% vs. 14.3%) and an excellent negative predictive value (95.1%), whereas planar imaging showed slightly higher specificity (79.5%). Ionized calcium correlated significantly with SPECT/CT positivity (r = 0.39; p = 0.009), while PTH and 25-hydroxyvitamin D showed no significant association. SPECT/CT accurately localized ectopic parathyroid glands and lesions in patients with coexisting thyroid nodularity, overcoming limitations of planar imaging. Several lesions undetected by planar scintigraphy were identified on SPECT/CT, supporting its role in anatomically complex or subtle cases. Conclusions: Triple-head SPECT/CT provided superior diagnostic performance over planar scintigraphy for preoperative localization in primary hyperparathyroidism, particularly in patients with thyroid nodularity or ectopic glands. Ionized calcium may serve as a complementary predictor of lesion detectability. These findings support hybrid SPECT/CT as the preferred first-line imaging modality, facilitating targeted minimally invasive surgery and optimizing surgical planning.

Abstract: Background: Hereditary hypoparathyroidism (hypoPT) is a rare endocrine disorder caused by absent or insufficient parathyroid hormone secretion. Genetic forms are uncommon and frequently underdiagnosed, particularly when clinical onset is atypical.Purpose: We present three cases of genetic hypoPT caused by CASR, GNA11, and GATA3 mutations, highlighting diagnostic challenges and management approaches.Methods: Clinical data, biochemical results, and genetic findings were collected for three female patients with early-onset, nonsurgical hypoPT. Each case was evaluated for presenting symptoms, comorbidities, treatment responses, and outcomes. Relevant literature and guidelines were reviewed for context and management recommendations.Results: All patients exhibited chronic hypocalcemia, hyperphosphatemia, and low PTH without prior neck surgery. Initial manifestations were atypical, delaying diagnosis until adolescence or adulthood. Case 1 (CASR mutation) presented with seizure-like episodes misdiagnosed as epilepsy, and partial response to calcium–vitamin D therapy. Case 2 (GNA11 mutation) showed Raynaud’s phenomenon, dermatologic symptoms, and treatment intolerance without nephrocalcinosis. Case 3 (GATA3 mutation) had early deafness, later renal impairment, and fluctuating calcium levels. Genetic testing confirmed pathogenic variants, and individualized management with active vitamin D analogs achieved partial biochemical control. All patients remain under multidisciplinary follow-up with stabilization of neurological complications and monitoring of renal status. Conclusion: Genetic causes of hypoPT should be suspected in patients with early-onset or atypical presentations in the absence of neck surgery. Timely genetic testing confirms the diagnosis and determines personalized therapy. Management requires careful titration of calcium and active vitamin D to avoid complications and may benefit from emerging treatments (long-acting PTH analogs). Early recognition and tailored interventions can improve patient outcomes and quality of life.

Abstract:

Once-monthly injectable therapies targeting glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and adjacent metabolic pathways are moving from a conceptual goal to a plausible next step for type 2 diabetes (T2D) and obesity. The most clinically advanced program is maridebart cafraglutide (MariTide), a long-acting GLP-1 receptor agonist conjugated to an Fc-containing scaffold that also mediates sustained GIP receptor antagonism. Across phase 2 trials, once-monthly maridebart has produced clinically meaningful weight loss (~12–16% in adults without diabetes; ~8–12% in those with T2D) together with HbA1c reductions of ~1.2–1.6 percentage points, with a safety profile broadly consistent with GLP-1–based therapy. An exploratory every-8-weeks regimen showed attenuated efficacy, suggesting that monthly dosing may represent a practical lower boundary for maintaining therapeutic exposure and metabolic effect in this format. Beyond maridebart, a rapidly expanding pipeline—including ultra–long-acting GLP-1 analogues, dual GLP-1/GIP agonists, long-acting GIPR antagonists, amylin receptor agonists, and emerging thyroid hormone receptor beta (THRβ) agonists—is actively testing monthly regimens or induction-to-monthly maintenance strategies; however, most readouts remain early and are frequently limited to conference presentations or sponsor communications. Key uncertainties include long-term durability, cardiometabolic outcomes, immunogenicity, and interindividual variability in response, which will ultimately determine how once-monthly regimens integrate with established weekly standards in routine care.

Abstract: Background and aim: Recently pre-clinical studies have confirmed that the inhibition of the MAP kinase pathway can induce re-differentiation of radioiodine refractory(RAIR) follicular-cell thyroid cancers (TC). The aim of this trial is to investigate whether the combination of kinase inhibitors (KIs) with myoinositol (MI) can induce or potentiate the re-uptake of RAI in cancer cells Overview and methods: This is an open label, non-pharmacological, multicenter, randomized pilot study. Patients will be divided into 2 groups: a) a control group in which patients are treated with KIs (T plus D or L); b) a group, in which patients are treated with the same KI and in addition with MI. After 30 days of MI treatment, all patient, treated with L-T4 at a semi-suppressive dosage as per clinical practice, will be stimulated with recombinant human TSH (rhTSH) (days 31 and 32). Then at day 35 patients will be submitted to whole-body scintigraphy, with hybrid imaging where possible (SPECT/TC), after administration of the diagnostic activity (185-222 MBq) of 123-I in accordance with the SNMMI/EANM guidelines. Blood samples will be collected before starting MI therapy (day 0), after 30 days of MI therapy and then at days 31, 32, 33, 34 and 35 after MI therapy. QoL will be assessed at beginning of the MI treatment and at the end of its administration. The primary endpoint is to evaluate the restoration of the 123 uptake in RAIR follicular cell-derived TC patients already on KIs therapy alone and on KIs therapy plus MI. Restoration of the 123 uptake will be evaluated in target lesions. Conclusions: The study evaluates the possible re-differentiation of RAIR cell-derived TC in patients treated with KIs plus MI. The re-uptake of iodine will be evaluated as the primary end point, and Tg values and QoL will be evaluated as the secondary end points. The main limitation of the study is that we do not investigate any clinical effects. We will have to post-pone the clinical analysis to a later date after the administration of RAI for therapeutic purposes.

Abstract: Background: Pilgrims with diabetes are at increased risk of acute metabolic complications such as diabetic ketoacidosis (DKA), hyperosmolar hyperglycemic state (HHS), and severe hypo- or hyperglycemia during Hajj, due to extreme heat, prolonged physical exertion, crowding, dehydration, and disruption of daily routines. Recent advances in continuous glucose monitoring (CGM) and artificial intelligence (AI) offer a unique opportunity to predict high-risk glycemic events before clinical deterioration.Objective: To develop and internally validate a machine learning-based predictive model using CGM, physiological, clinical, and environmental data to anticipate acute glycemic crises in pilgrims with diabetes during Hajj, and to evaluate the feasibility and preliminary effectiveness of an AI-assisted alert system in a pilot interventional study.Methods: This two-phase prospective study will be conducted among adult pilgrims with type 1 or type 2 diabetes. In Phase 1 (prospective cohort), approximately 800–1000 pilgrims will be equipped with CGM and wearable devices for continuous monitoring of glucose, heart rate, activity, and other vital signs. Environmental variables and contextual data will be collected. Supervised machine learning models will be trained to predict severe hypoglycemia, severe hyperglycemia, DKA, and HHS over short-term windows (30–60 minutes) and internally validated. In Phase 2 (pilot interventional study), approximately 300–400 pilgrims will be allocated to AI-assisted care with real-time alerts versus standard care. Incidence of acute glycemic events and healthcare utilization will be compared between groups.Expected Results: The AI model is hypothesized to achieve: (1) AUC-ROC ≥0.80 [95% CI] for discrimination, (2) sensitivity ≥80% at the 30–60 minute prediction horizon for severe hypo-/hyperglycemia, (3) calibration slope 0.9–1.1 with intercept near zero, and (4) AI-assisted care will reduce severe hypo-/hyperglycemia incidence by ≥30% compared with standard care.Conclusions: This study aims to provide a practical, scalable framework for AI-enabled risk prediction in high-risk pilgrims with diabetes during Hajj, with potential application to other mass gatherings and hot climates.