Rodis D. PaparodisMD

Paricalcitol (19-nor-1,25-dihydroxyvitamin D₂) is a synthetic vitamin D receptor (VDR) agonist used for the treatment of secondary hyperparathyroidism mainly in chronic kidney disease (CKD), with a 10-times lower calcemic potential and 3-times less potent to the VDR than calcitriol. This narrative review examines the available preclinical and clinical evidence on the immunomodulatory actions of paricalcitol beyond mineral metabolism. Experimental studies show that paricalcitol can modulate immune-cell function, inflammatory signaling, oxidative stress and fibrosis through VDR-dependent pathways. Human evidence is derived mainly from patients with CKD and kidney transplantation, where reductions in inflammatory and oxidative stress markers have been reported; however, findings are not consistent across all studies. Evidence in other immune-mediated conditions, including IgA nephropathy, psoriasis, atopic dermatitis, autoimmune alopecia, and type 1 diabetes (T1D), remains limited and is based largely on case series and reports and non-RCTs. The PRECAL study (ISRCTN17354692) provides preliminary evidence that timely VDR activation may influence the course of T1D, requiring controlled confirmation. No dosing regimen has yet been established for immunomodulatory use, while the calcitriol replacement daily dose × 3/day (given the relevant potency) has been proven reasonably safe and effective in the PRECAL study. Predictive biomarkers of response are lacking, warranting further basic research.

Thyroid nodules are detected in a large proportion of adults undergoing high-resolution ultrasonography, yet only a minority harbor clinically significant cancer. The clinical problem is therefore not only cancer detection but calibrated risk stratification: avoiding delayed diagnosis of aggressive disease while limiting unnecessary biopsies, molecular testing and diagnostic surgery. Artificial intelligence (AI) has moved rapidly from experimental image classification to clinically deployed decision support. This invited review synthesizes current evidence for AI applications in the evaluation and management of thyroid nodules and differentiated thyroid cancer, emphasizing ultrasound-based computer-aided diagnosis, indeterminate cytology, molecular integration, cytopathology and histopathology, lymph node assessment, report quality control, surveillance and emerging multimodal large language models. Commercial and near-commercial systems, including S-Detect, AmCAD-UT, Koios DS Thyroid, AIBx and newer deep-learning systems, show that AI can improve consistency, support less experienced readers and, in selected settings, reduce low-yield fine-needle aspiration without unacceptable loss of sensitivity. A particularly important future role may be AI-enabled de-escalation, in which image-derived estimates of benignity help support surveillance when clinical, sonographic, cytologic or molecular risk signals are concordantly low. However, performance varies by case mix, cancer prevalence, scanner platform, operator experience, geographic cohort, reference standard and whether the model is used as a stand-alone classifier or second reader. The strongest evidence supports AI as an adjunct to standardized ultrasound risk stratification and shared decision-making, not as a replacement for expert clinical judgment. Future progress will depend on prospective multicenter validation, transparent reporting, local calibration, workflow design, regulation, post-market surveillance and assessment of patient-centered outcomes.

Introduction: Thyroglobulin antibodies (Tg-Abs) are often thought to be associated with thyroid autoimmunity, and as such, a link with thyroid cancer has been found in some, but not all, studies. Tg-Abs are also found in non-autoimmune thyroid-follicular destruction. Given these contradictory results, we designed the present study. Methods: We reviewed data from patients undergoing thyroidectomy for different indications in multiple centers across Greece and the US over 10 years. We compared the incidence of thyroid cancer and its features of tumor aggressiveness among patients with positive (≥30 IU/mL) and negative (p < 0.05. Tumor size was larger, and capsular invasion and lymph node involvement were significantly more common in Tg-Abs+ subjects. Mean Tg-Abs were higher in subjects with tumors with extrathyroidal extension, capsular invasion, and lymph node involvement. On regression, Tg-Abs positivity was not associated with thyroid cancer incidence or aggressiveness, though, with the important exception of lymph node involvement (p < 0.001). Conclusions: Elevated preoperative thyroglobulin-antibody titers do not seem to affect the likelihood of developing thyroid cancer, even though they seem to be a surrogate for lymph node metastasis (as opposed to thyroid peroxidase antibodies, TPO-Abs). Further work is needed to clarify the interplay of this immune response on thyroid cancer metastatic behavior.

Introduction: Vitamin D deficiency [25(OH)D < 30 ng/mL] is widely prevalent globally and the efforts to tackle it have been rather unsuccessful to date. Despite different cutoffs used to define it, many clinicians adhere to the 2011 Endocrine Society definition. We present a special treat-to-target protocol aiming to restore and maintain vitamin D sufficiency. Methods: We reviewed the efficacy and safety of our vitamin D supplementation protocol over 5 years, and compared it to a group of patients who self-reported never taking vitamin D supplements. We recorded the baseline, 2-month, and annual 25(OH)D (D) measurements, along with subjects’ age, sex, BMI, history of osteoporosis, nephrolithiasis, nephrocalcinosis, and renal colics. According to our supplementation protocol, replenishment of vitamin D involves cholecalciferol dosing in two steps: a loading dose (LD) for 2 months and a maintenance dose (MD) thereafter. Please refer to the main text for loading and maintenance dose titration. Results: Of 8329 cases with vitamin D measurements, 2248 had adequate follow up data of 3524.5 patient-years and were included in the study: a total of 1575 intervention subjects and 673 controls, with an average follow-up of 18.8 months. Baseline vitamin D concentrations of 22.6 ng/mL (controls) did not change significantly (2 months: 22.2; 1 year: 21.7; 2 years: 22.0; 3 years: 23.8; 4 years: 21.8; and 5 years: 22.1 ng/mL), while concentrations of 21.9 ng/mL (intervention group) reached and remained 40 ng/mL (2 months: 41.0; 1 year: 39.4; 2 years: 39.0; 3 years: 39.3; 4 years: 40.4; and 5 years: 39.4 ng/mL). Vitamin D adequacy was achieved in 91.6% of patients in the intervention arm compared to only 16.9% in controls (p < 0.0001). Mean D and rates of adequacy were significantly higher over time in the intervention arm (p < 0.0001). The incidence of renal adverse events or hypervitaminosis did not differ between groups (p > 0.05). Conclusions: Our intervention protocol appears highly efficient in achieving and maintaining vitamin D adequacy over 5 years, with no increase in adverse events compared with controls, presenting it as an effective long-term strategy.

Atherosclerotic cardiovascular diseases continue to be a leading cause of death globally. Although statin medications remain the cornerstone of treatment for lowering low‐density lipoprotein cholesterol and reducing cardiovascular risk, there is a proportion of patients in whom treatment with statins may not achieve the guideline recommended low‐density lipoprotein cholesterol targets despite using maximally tolerated doses, or for various reasons, patients are unable or unwilling to intensify or continue statins. In these instances, use of nonstatin medications like ezetimibe, bempedoic acid, or PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors (alirocumab, evolocumab, inclisiran) in addition to maximally tolerated statin therapy can lead to additional lowering of low‐density lipoprotein cholesterol and beneficial reductions in cardiovascular events. This review provides an overview of the evidence supporting the use of nonstatin low‐density lipoprotein cholesterol lowering medications for cardiovascular risk reduction and practical considerations for the use of these agents.

Background and Objectives: To identify clinical, ultrasound (US) and real-time elastography (RTE) characteristics indicative of malignancy in small thyroid lesions. Materials and Methods: 141 consecutive patients with incidentally discovered solid thyroid nodules (diameter ≤ 10 mm) by neck US were assessed, and RTE was performed. The nodules were classified per American (ACR-TIRADS) and European (EU-TIRADS) criteria; US-guided FNA was conducted on EU-TIRADS 5 nodules. The US and RTE features of nodules classified as benign (Bethesda II) or malignant (Bethesda V and VI) were compared. Results: 41 nodules were classified as EU-TIRADS 5. Their Fine Needle Aspiration (FNA) cytology was Bethesda II (n = 11), III-IV (n = 3), V (n = 10) or VI (n = 17). Bethesda V–VI patients had a higher rate of autoimmune thyroiditis (p = 0.015) and higher ACR-scoring points (p < 0.001) compared with Bethesda II. The elastography ratio was equal between the groups (p = 0.584). In logistic regression analysis, ACR-scoring points predicted FNA results, with an area under the curve (AUC) of 0.993 (sensitivity 92.6% and specificity of 100%). The clinical model (age, body mass index, sex, autoimmunity, L-thyroxine treatment, nodule diameter, elastography ratio) achieved an AUC of 0.744. A “mixed” model, combining clinical characteristics with the ACR scoring points, achieved perfect performance (AUC = 1.000), predicting FNA results with 100% sensitivity and specificity. Conclusions: The proposed “mixed model” can predict Bethesda V–VI in thyroid nodules <10 mm, allowing for the selection of those needing further evaluation.