Medicine and Pharmacology

Abstract: Background: Regional citrate anticoagulation (RCA) is the recommended anticoagulation strategy for continuous kidney replacement therapy (CKRT) because it prolongs circuit lifespan and reduces bleeding risk compared with systemic heparin. However, systemic citrate accumulation may occur when citrate delivery exceeds metabolic or extracorporeal clearance, potentially leading to severe metabolic disturbances. Summary: Citrate is normally metabolized through mitochondrial oxidative pathways in the liver, skeletal muscle, and kidneys, generating bicarbonate and releasing bound calcium. Conditions associated with impaired oxidative metabolism—most notably circulatory shock, but also severe hypoperfusion, hyperlactatemia, hypothermia, or excessive citrate load—predispose to systemic citrate accumulation. Severe hepatic dysfunction alone is rarely sufficient in the absence of circulatory failure. Citrate accumulation produces a characteristic biochemical profile including ionized hypocalcemia, elevated total calcium, an increased total-to-ionized calcium ratio, high anion-gap metabolic acidosis, ionized hypomagnesemia, and hypernatremia. Clinical manifestations typically occur late and include hypotension, arrhythmias, neuromuscular irritability, and progressive metabolic acidosis. Early recognition relies on structured biochemical monitoring rather than clinical signs alone. Key Messages: Systemic citrate toxicity reflects impaired mitochondrial oxidative metabolism and reduced systemic metabolic reserve rather than isolated hepatic dysfunction. Circulatory shock is the principal risk factor. Early biochemical surveillance allows timely intervention and renders citrate accumulation largely reversible. When applied within protocolized monitoring strategies, RCA remains a safe and effective anticoagulation method for CKRT.

Abstract: Thoracoabdominal aortic aneurysm (TAAA) is a complex vascular disorder involving both thoracic and abdominal segments of the aorta and remains associated with substantial morbidity and mortality. One of the most serious complications after thoracoabdominal aortic aneurysm (TAAA) repair is spinal cord ischemia (SCI), which may progress to spinal cord infarction and result in irreversible neurologic deficits including paraplegia, neurogenic bladder dysfunction, and bowel dysfunction. The incidence of SCI after TAAA repair varies with the extent of aneurysmal involvement, operative duration, and patient comorbidities. The primary pathophysiologic mechanism involves interruption of radiculomedullary arterial flow, compounded by systemic hypotension, and limited collateral circulation. Because SCI profoundly affects functional recovery and long-term quality of life, prevention and early recognition are central to perioperative management. Established neuroprotective strategies emphasize maintenance of spinal cord perfusion through meticulous hemodynamic optimization, cerebrospinal fluid (CSF) drainage, and temperature modulation. Intraoperative neuromonitoring using motor- and somatosensory-evoked potentials facilitate early detection, while newer modalities such as near-infrared spectroscopy and CSF lactate monitoring may offer additional insight. When SCI occurs despite prophylaxis, rapid initiation of rescue measures including CSF drainage, hemodynamic augmentation, and other discussed treatments may improve neurologic outcomes. Long-term care focuses on rehabilitation, symptom management, and psychological support. Therefore, this review aims to consolidate medical evidence to improve the prevention, detection, and treatment of spinal cord infarction associated with thoracoabdominal aortic aneurysm repair.

Abstract: Skull base pneumatization is anatomically variable and clinically relevant for temporal bone and transsphenoidal surgical corridors, but manual volumetric segmentation is time-consuming. This retrospective pilot study evaluated a clinician-guided deep learning workflow for computed tomography segmentation of temporal bone/mastoid and sphenoid sinus pneumatization. Bone-window computed tomography (CT) datasets were curated, converted to NIfTI format, and segmented using 3D Slicer, MONAI Label, and a three-dimensional SegResNet-based model. The mastoid workflow used side-specific temporal bone crops, while the sphenoid workflow used full-head CT volumes. The final mastoid development dataset included 122 side-cases, with an independent 28 side-case expert-validation cohort. The sphenoid arm included 117 expert-submitted development labels and a separate 17-case expert-validation cohort. The mastoid model achieved strong expert agreement, with mean Dice 0.9691 and median Dice 0.9794 on the independent validation set. The sphenoid workflow achieved a best internal validation Dice of 0.8750, while expert comparison of saved automatic masks showed mean Dice 0.9426 and median Dice 0.9408. Exploratory mask analysis enabled volumetric, densitometric, and extension-pattern assessment of pneumatized skull base compartments. This research supports clinician-guided deep learning as a feasible approach for reproducible CT-based skull base pneumatization segmentation and radiomic analysis.

Abstract: Backgound/Objectives: to assess the efficacy of a product containing Diosmine, Cumarin and Arbutin (Linfadren®) in reducing edema and pain and improving specific symptomatology in patients undergoing rehabilitation treatment after hip or knee arthroplasty. Methods: in this monocentric prospective study, fifty consecutive patients, hospitalized for rehabilitation, were administered Linfadren® twice a day for 20 days. Limb circumference, pain and specific symptomatology were assessed at baseline and at the end of the treatment; the specific symptomatology was evaluated by means of Western Ontario and McMaster Universities Arthritis Index (WOMAC), self-administered. Results: baseline and final limb circumference showed a statistically significant difference with 60.42 ± 6.77 cm vs 53.7 ± 6.37 cm; P < 0.0001. Baseline and final pain showed a statistically significant difference with NRS 4.0 ± 1.01 vs 0.4 ± 0.70 – P < 0.0001. Baseline and final specific symptomatology differed in statistically significant manner being the respective scores 37.1 ± 14.4 vs 18.1 ± 11.4; P < 0.0001. No deep venous thrombosis event occurred. Conclusions: the product containing Diosmine, Cumarine and Arbitin demonstrates being efficacy in reducing edema and pain and in improving specific symptomatology in patients undergoing rehabilitation treatment after hip or knee arthroplasty. This is relevant for clinical rehabilitation as improves patients’ specific conditions thus making them able to better perform intensive physiotherapy protocols, enhancing the recovery; moreover, it could also play a role in preventing deep venous thrombosis.

Abstract: The development of functional staple foods with improved metabolic properties represents a practical dietary strategy for the prevention of type 2 diabetes. This study investigated the effects of incorporating sprouted fenugreek (Trigonella foenum-graecum L.) into wheat-based flatbread (chapatti) on postprandial glycemic and insulinemic responses in healthy adults. Wheat (cv. Galaxy 2013) and fenugreek seeds were germinated for up to 96 h and analyzed for nutritional composition and antioxidant activity. Composite flours containing 0%, 2.5%, 5%, and 7.5% sprouted fenugreek were formulated and evaluated for sensory acceptability. Eighteen healthy participants (18–25 years; BMI 21–22.5 kg/m²) consumed chapattis containing 7.5% sprouted fenugreek or control white flour in a ran-domized crossover design. Blood glucose and serum insulin were measured at 0, 30, 60, and 120 min postprandially. Sprouting significantly increased protein, dietary fiber, and antioxidant capacity in both wheat and fenugreek (p < 0.001). Total phenolic content in wheat increased from 55.82 to 110.17 mg GAE/100 g after 96 h of germination, accompa-nied by a significant rise in DPPH radical scavenging activity. The formulation containing 7.5% sprouted fenugreek showed the highest sensory acceptability (7.52/9). Fenu-greek-supplemented chapattis significantly reduced postprandial glucose and insulin re-sponses (p < 0.05) compared with control. Incorporation of 7.5% sprouted fenugreek into wheat flatbread improves nutritional quality while attenuating glycemic and insulinemic responses, suggesting a practical dietary strategy for metabolic health and diabetes pre-vention.

Abstract: Background/Objectives. Human voices convey critical socio-affective information, including emotional states. Although autistic individuals are often reported to show difficulties in processing vocal emotional cues, behavioral findings remain inconsistent. This study aimed to assess neural and behavioral sensitivity to vocal emotion expressions in autistic adults using a sensitive, individual-level EEG approach. Methods. We compared autistic adult men (N = 25) with a non-autistic control group (N = 25), matched for age, sex, and IQ. Neural responses were measured using an auditory frequency-tagging EEG paradigm, in which streams of neutral vocal utterances were presented at 4 Hz, interspersed with emotional utterances (fear, anger, sadness, happiness) every third stimulus, yielding an oddball frequency of 1.333 Hz. Participants also completed a multimodal behavioral emotion recognition task. Results. No significant group differences were observed in either behavioral performance or EEG responses. Both groups showed greater difficulty in auditory emotion recognition compared to visual and audiovisual modalities. Robust oddball EEG responses were found in both groups, indicating automatic neural discrimination of vocal emotions. Higher response amplitudes were observed for fear and anger across groups. Conclusions. These findings indicate intact neural and behavioral processing of vocal emotions in autistic adult men, supporting the notion of developmental delay rather than persistent deficit in socio-affective auditory processing.

Abstract: Background: Identifying biomarkers in prodromal Parkinson's disease (PD) remains critical for early therapeutic interventions. In addition to genetic predisposition, non-motor symptoms, such as REM sleep behavior disorder (RBD) and anosmia, have been associated with an increased risk for developing PD. This systematic review focuses on assessing gait abnormalities through kinematic assessments in individuals at increased PD risk.Methods: A Boolean phrase was applied to search for gait kinematic studies in cohorts with preclinical PD state. Thirty-seven studies were extracted from PubMed: 13 were deemed relevant by abstract screening, 9 met the inclusion criteria while 4 were excluded due to established PD diagnosis in participants.Results: In individuals with RBD, reduced gait velocity and cadence, increased stride and double-support times, impaired trunk kinematics, and greater gait variability under dual-task conditions were observed. Genetic carriers of PD-related mutations (GCPDM) demonstrated increased arm swing asymmetry and variability, increased stride time variability, and reduced lower-limb excursion. Longitudinal assessments of individuals with idiopathic hyposmia (IH) showed progressive motor deterioration which later turned into overt PD using dopaminergic challenge tests and imaging. When machine learning was applied to sensor assessments, it was capable of distinguishing healthy individuals from those with risk factors for PD or overt PD.Conclusion: Sensor-based gait analysis is a promising tool for detecting early subclinical gait abnormalities in individuals at increased risk for developing PD. Kinematic assessments not only can assist in identifying at-risk individuals for PD but potentially support disease modifying clinical trials.

Abstract: The rapid development of pharmacotherapy has progressed from using single GLP-1 receptor agonists, such as semaglutide, to more complex options like dual incretin agonism with GLP-1/GIP (tirzepatide) and GLP-1/glucagon co-agonism (survodutide). Other combinations include GLP-1/amylin (CagriSema) and triple agonism (retatrutide). This evolution highlights that metabolic disease is not a uniform biological condition, and we are observing distinct clinical metabolic outcomes associated with each specific agonist. Yet the choice of therapy is still primarily influenced by the amount of weight loss rather than by understanding the primary physiological defect driving each patient's disease. We propose a “liver-centred network” failure model in which obesity and metabolic liver disease arise from dysregulation of coordinated hormonal signalling networks governing energy intake, hepatic lipid handling, oxidative metabolism, and adipose tissue function. Within this framework, patients can be classified into five clinically distinguishable metabolic phenotypes, each characterised by a dominant biological defect and a corresponding preferred multi-agonist therapeutic strategy: hyperphagic obesity with preserved metabolic flexibility, hepatic insulin resistance and MASLD/MASH-dominant disease, the energy-conservation phenotype, sarcopenic obesity, and the cardio-renal-metabolic vulnerability phenotype. If validated by prospective outcome studies, treatment selection based on phenotype and suitable biomarkers of dominant pathophysiology, rather than BMI alone, may signify a shift from obesity pharmacotherapy to genuine precision metabolic medicine.

Abstract: Background: Hemophagocytic lymphohistiocytosis is a life-threatening hyperinflammatory syndrome that can mimic sepsis in adults, delaying diagnosis and treatment. Methods: We reviewed three adult patients admitted to a high-complexity referral hospital in Colombia, all initially managed as sepsis, analyzing clinical findings, laboratory results, bone marrow studies, diagnostic approach, and outcomes. Results: All patients had persistent fever, cytopenias, organomegaly, hyperferritinemia, and hypertriglyceridemia, with ongoing inflammation despite appropriate antimicrobial therapy. Bone marrow examination showed hemophagocytosis in all cases. One case was associated with acute myeloid leukemia and had a poor outcome, while two infection-related cases, triggered by disseminated histoplasmosis and visceral leishmaniasis, improved with targeted therapy and supportive care. Conclusions: Persistent inflammation, cytopenias, and markedly elevated ferritin despite standard sepsis treatment should prompt early consideration of hemophagocytic lymphohistiocytosis and investigation of the underlying trigger.

Abstract: X-linked hypophosphatemia (XLH) is one of the most common inherited phosphate-wasting disorders, caused by pathogenic variants in the PHEX gene that result in excess fibroblast growth factor 23 (FGF23) and chronic hypophosphatemia. Historically considered a pediatric disease characterized by rickets and growth impairment, XLH is now recognized as a lifelong condition with substantial adult morbidity including osteomalacia, fractures, enthesopathy, osteoarthritis, and reduced quality of life. The discovery of FGF23 as the central mediator of phosphate wasting transformed understanding of disease pathophysiology and enabled development of burosumab, a monoclonal antibody that neutralizes FGF23 and restores phosphate homeostasis. While burosumab represents a paradigm shift in therapy, accumulating evidence indicates that XLH involves FGF23-independent mechanisms, including osteopontin accumulation, ASARM peptide generation, and pyrophosphate dysregulation, which contribute to persistent skeletal abnormalities despite biochemical correction. This review integrates current insights into the molecular genetics, pathophysiology, and lifelong clinical features of XLH, with particular attention to emerging concepts involving local bone matrix abnormalities and their impact on therapeutic innovation. We trace the transition from conventional phosphate and active vitamin D supplementation to targeted FGF23 inhibition, highlight the limitations of existing treatment strategies, and explore future directions such as small‑molecule inhibitors, anti‑sclerostin therapy, gene-based approaches, and ultimately PHEX‑focused repair. A comprehensive understanding of XLH as both a systemic endocrine disorder and an intrinsic defect of osteocyte biology is critical for optimizing patient care and steering the development of curative therapies.

Abstract: Background/Objectives: New-onset atrial fibrillation is a common complication of acute myocardial infarction and is associated with increased mortality, heart failure, and recurrent cardiovascular events. Prediction models for the occurrence of atrial fibrillation may facilitate early risk stratification, improve patient monitoring, and support personalized therapeutic decision-making in clinical practice. Methods: A prospective study included 150 patients with acute myocardial infarction admitted within 24 hours of symptom onset. Clinical, laboratory, electrocardiographic, and echocardiographic data were collected, and a machine learning model was developed to predict new-onset atrial fibrillation. Model performance was evaluated using ROC-AUC, while SHAP analysis was applied to identify and quantify the contribution of individual predictors. Results: The machine learning model demonstrated excellent predictive performance, achieving an accuracy of 97.0%, ROC-AUC of 0.991, and precision–recall AUC of 0.991 in the independent test set. SHapley Additive Explanations (SHAP) and permutation importance analyses identified the E/e′ ratio, left ventricular mass index, left ventricular ejection fraction, left atrial volume index, oxidative stress markers (malondialdehyde and superoxide dismutase), NT-proBNP, and complete revascularization as the most influential predictors of new-onset atrial fibrillation after acute myocardial infarction. Conclusions: Machine learning combined with SHAP-based explainability showed high potential for predicting new-onset atrial fibrillation after acute myocardial infarction. This approach may improve individualized risk assessment and clinical decision-making, pending validation in larger multicenter cohorts.

Abstract: Background. Hyperbaric oxygen therapy (HBOT) delivers 100% oxygen at supra-atmospheric pressure, producing tissue hyperoxygenation, enhanced phagocytic killing, neoangiogenesis, and immunomodulation. Although HBOT is well established in head-and-neck practice, its specific role in sinonasal disease remains poorly systematised. Objective. To reappraise the rationale, evidence, and practical implementation of HBOT in two cardinal sinonasal indications—acute invasive fungal rhinosinusitis (AIFRS) and post-radiotherapy sinonasal damage—through a rhinology-centred, multidisciplinary lens. Methods. Narrative review of articles published in PubMed/MEDLINE, Scopus, Embase, and the Cochrane Library between 1 January 1980 and 31 March 2026, conducted following the SANRA framework and combining MeSH terms for HBOT with sinonasal, mucormycosis, osteoradionecrosis, and skull-base keywords. Results. In AIFRS, HBOT addresses the angioinvasive ischaemic core, restores oxidative neutrophil killing, and potentiates amphotericin B; observational data—including the recent COVID-19-associated mucormycosis (CAM) experience—suggest a survival benefit when HBOT is added early to surgical and antifungal therapy. In post-radiotherapy injury, HBOT reverses Marx's hypoxic–hypocellular–hypovascular triad, supporting healing of osteoradionecrosis (maxillary and skull-base), soft-tissue radionecrosis, and reconstructive procedures in the irradiated bed. Sinus barotrauma, the most frequent rhinological complication, is largely preventable with structured pre-treatment ENT assessment. Conclusions. HBOT is a mechanistically well-founded, well-tolerated adjunct with a favourable safety profile when delivered by a multidisciplinary team. Sinonasal-specific prospective registries and pragmatic randomised trials are urgently needed.

Abstract: Allergen-specific IgE multiplex serology enables the molecular characterization of sensitizations in large populations. This study analyzed results from 21,121 canine sera collected in the USA during 2024–2025 using the Pet Allergy Xplorer (PAX) 238-allergen platform to determine sensitization prevalence and profiles. Sensitization to at least one allergen and to at least one environmental allergen was detected in 90.7% and 86.2% of dogs, respectively. House dust mites (HDM) were the predominant allergens (79.5%), followed by Hymenoptera venoms (39.8%), meats (21.9%), weeds (21.5%), and tree pollens (18.6%). Sensitization to the Dermatophagoides farinae HDM was the most prevalent (76.7%). Unsupervised clustering of 16,366 sensitized dogs identified six biologically coherent profiles centered on flea saliva, mammalian serum albumins/IgGs, honeybee venom, HDM group-2 allergens, storage mites, and PR-10-family allergens. A second, pollen/plant-food-focused analysis found clusters associated with Parietaria Par j 2, ragweed, granule-bound starch synthases, and PR-10 allergens, as well as a minor Phl p 6-associated grass pollen profile. Altogether, these results define the molecular sensitization repertoire of allergic dogs in the US and provide the background for interpreting IgE serological results and optimizing allergen selection for immunotherapy.

Abstract: Background and Objectives: High-risk pregnancy is associated with increased vulnerability to psychological distress, yet the protective mechanisms that may buffer this vulnerability remain insufficiently understood. This study examined differences in emotional distress and coping strategies between women with high-risk and low-risk pregnancies and investigated whether active coping and marital satisfaction attenuate associations between negative pregnancy experiences, prenatal depression and perceived stress. Materials and Methods: A cross-sectional study was conducted among 195 pregnant women aged 18–51 years (M = 31.76, SD = 5.32), including 102 women with high-risk pregnancies and 93 women with low-risk pregnancies. Participants completed measures of prenatal depression (EPDS), state anxiety (STAI), perceived stress (PSS-10), pregnancy-related anxiety (PRAS), pregnancy experiences (PES), coping strategies (COPE), and marital satisfaction (CSI). Independent-samples t tests, correlation analyses, partial correlations and moderation analyses were conducted. Results: Women with high-risk pregnancies reported significantly higher levels of prenatal depression (p = 0.032) and pregnancy-related anxiety (p < 0.001) than women with low-risk pregnancies. They also reported lower use of socio-emotional support (p = 0.036) and mental disengagement coping strategies (p = 0.022). Negative pregnancy experiences were positively associated with state anxiety, pregnancy-related anxiety, prenatal depression, and perceived stress after controlling for pregnancy risk status (all p < 0.001). Maladaptive coping strategies were generally associated with higher emotional distress, whereas adaptive coping strategies, particularly positive reinterpretation and planning, were associated with lower levels of prenatal depression and anxiety. Active coping moderated the association between negative pregnancy experiences and perceived stress (β = −0.16, p = 0.016). Marital satisfaction moderated the association between prenatal depression and perceived stress among women with high-risk pregnancies (β = −0.21, p = 0.016). Conclusions: Active coping and marital satisfaction emerged as modifiable protective factors that may attenuate psychological distress during pregnancy. These findings support the integration of psychological screening, coping-focused interventions, and partner involvement into prenatal care, particularly for women experiencing high-risk pregnancies.

Abstract: Epidermal growth factor receptor (EGFR)-targeted therapy represents the first and most successful example of precision oncology in non–small cell lung cancer (NSCLC), with more than 10 approved agents, including tyrosine kinase inhibitors, bispecific antibodies and antibody–drug conjugates. Over the past two decades, the diagnostic and therapeutic landscape of EGFR-mutant NSCLC has evolved from empiric treatment to mutation subtype–guided strategies, from advanced disease to earlier-stage interventions, and from monotherapy to rational combination regimens. Somatic EGFR mutations remain key predictive biomarkers guiding treatment selection, therapeutic intensification, resistance mechanism-directed treatment, and disease monitoring through plasma circulating tumor DNA burden. In parallel, germline EGFR alterations are increasingly recognized as contributors to inherited lung cancer susceptibility, particularly among never-smokers and familial clusters. Germline EGFR T790M is the best-characterized pathogenic variant, creating a permissive background for multifocal lung nodules and lung adenocarcinoma development, often following acquisition of a second somatic EGFR driver mutation. Recent familial, regional, and paired tumor–normal sequencing studies have reframed germline EGFR alterations from rare case reports into an emerging hereditary lung cancer syndrome. Clinically, germline EGFR should be suspected when EGFR T790M is detected prior to TKI exposure, particularly at variant allele fractions near 50%, or in patients with multifocal ground-glass nodules, multiple primary lung adenocarcinomas, early-onset disease, never/light smoking history, or family history of lung cancer. Confirmation requires germline testing and genetic counseling. This review highlights current knowledge, recent advances, and future directions in somatic and germline EGFR-mutant NSCLC, emphasizing translational relevance for clinicians and researchers.

Abstract: Metabolic syndrome (MetS) is a complex and multifactorial condition characterized by insulin resistance, visceral obesity, dyslipidemia, hypertension, and chronic low-grade inflammation, all of which contribute to increased cardiovascular risk. Central to its pathophysiology is metainflammation, a persistent inflammatory state closely linked to oxidative stress and mitochondrial dysfunction. This review aims to provide an inte-grated and updated overview of the interplay between metaflammation, oxidative stress, mitochondrial dysfunction, and organokine signaling in the development and progression of MetS and its cardiovascular complications. Current evidence indicates that mitochondrial dysfunction plays a pivotal role by promoting excessive production of reactive oxygen species (ROS), impairing ATP synthesis, and disrupting redox bal-ance, thereby exacerbating insulin resistance and endothelial dysfunction. In parallel, dysregulated secretion of organokines—including adipokines, myokines, hepatokines, cardiokines, osteokines, and renokines—alters interorgan communication and ampli-fies pro-inflammatory and atherogenic pathways. Additionally, gut microbiota con-tributes to metabolic homeostasis through the production of short-chain fatty acids, whereas dysbiosis is associated with worsening metabolic parameters. Collectively, these interconnected mechanisms establish a self-perpetuating cycle that drives meta-bolic dysfunction and cardiovascular disease progression. This review highlights the central role of the metainflammation–mitochondrial dysfunction axis and emphasizes the importance of organokine-mediated crosstalk as a key regulator of systemic me-tabolism. Targeting these pathways may represent a promising strategy for the pre-vention and management of MetS and its associated complications.

Abstract: Metabolic diseases, such as obesity, type 2 diabetes (T2DM), and metabolic dysfunction-associated steatotic liver disease (MASLD, formerly NAFLD), emerge from chronic nutrient overload that progressively disrupts cellular homeostasis and precipitates persistent inflammatory remodeling. Two stress-adaptive programs sit at the center of such pathological transition: autophagy, the homeostatic engine responsible for lysosomal recycling and organelle quality control, and cellular senescence, a tissue repair system that becomes deleterious when persistent, driving dysfunction through stable growth arrest and senescence-associated secretory phenotype (SASP)-associated inflammatory remodeling. Emerging evidence identifies lysine acetylation as a nutrient-sensitive molecular rheostat that orchestrates the reciprocal regulation of these two processes across metabolic tissues. Because acetylation dynamics are governed by the availability of acetyl-CoA and the NAD⁺-dependent deacetylation capacity of sirtuins, metabolic stress reshapes the enzymatic balance between acetyltransferases (KATs, e.g., p300/CBP) and deacetylases. This shift triggers a “double blow” to cellular health; the simultaneous suppression of autophagic flux and the epigenetic stabilization of senescent state. This review synthesizes mechanistic evidence showing how acetylation inhibits autophagy at multiple checkpoints, ranging from the activity of core autophagy proteins to lysosomal biogenesis, while concurrently reinforcing senescence through chromatin hyperacetylation and the activation of non-histone effectors such as NF-κB, p53 and FOXO proteins. We place particular emphasis on the mTORC1-p300-SIRT1 axis as the primary integration hub coupling nutrient status to this dual regulation. Finally, we discuss tissue-specific manifestations in the liver, adipose tissue, and other metabolic organs and highlight emerging therapeutic strategies, such as KAT inhibition/sirtuin activation, aimed at restoring the acetylation rheostat to improve autophagic competence while restraining senescence-driven metabolic decline.

Abstract: Background/Objectives: The supraclavicular foramen (SCF) is a rare anatomical variant formed when a branch of the supraclavicular nerve traverses the clavicle through a complete transclavicular canal. Published studies differ substantially in study material, denominators, and reporting of side-specific and bilateral data, so bilateral anatomy is often synthesized as if pairing were irrelevant. This study aimed to describe SCF in a Greek osteological sample and to apply a meta-analytic framework distinguishing per-clavicle prevalence, marginal laterality, paired laterality, and separately observed bilateral prevalence. Methods: We examined 115 dry clavicles of Greek origin for SCF frequency, size, and topography. Measurements were obtained independently by two observers using stainless-steel wires and digital calipers, with inter-rater agreement assessed by intraclass correlation coefficients. A systematic review and meta-analysis were then conducted according to PRISMA 2020. Quantitative synthesis included pooled per-clavicle prevalence, conventional marginal left-versus-right comparison, and feasibility-based paired laterality analysis under explicit dependence assumptions when bilateral information was incomplete. Observed bilateral prevalence was analyzed separately using only studies with directly reported body-level bilateral counts. Study quality was assessed using AQUA and CATAM. Results: Complete transclavicular canals, identified by paired supraclavicular foramina representing entrance and exit openings, were present in 3/115 clavicles (2.4%), with a mean patency diameter of 1.5 ± 0.8 mm and a mean relative acromial position of 0.44 ± 0.12. Inter-rater reliability was excellent. Pooled per-clavicle prevalence was 2.2% (95% CI: 1.4–3.0%; I² = 71%). Conventional marginal laterality showed significant left-sided predominance (OR = 1.76, 95% CI: 1.16–2.66; I² = 0%), while feasibility-based paired laterality yielded a stronger effect (paired OR = 2.26, 95% CI: 1.30–3.94). The main observed bilateral-prevalence model yielded 0.95% (95% CI: 0.33–2.70%). Minor small-study effects were suggested by the Doi/LFK framework. Conclusions: SCF is an uncommon developmental variant with consistent left-sided predominance. Bilateral anatomical variants should not be synthesized as if all observations were unpaired; separating per-clavicle prevalence, marginal laterality, paired laterality, and observed bilateral prevalence provides a more transparent and biologically meaningful synthesis.

Abstract: Lipedema affects an estimated 11 to 12% of women and is characterized by bilateral, symmetric, painful enlargement of the limb subcutaneous fat that resists dietary weight loss. Its primary substrate is increasingly understood to be adipo-vascular and connective: genome-wide association studies implicate adipose, vascular, and extracellular-matrix loci rather than immune genes, and the affected fat is metabolically healthier than its mass predicts. Inflammation is itself well documented in lipedema tissue, but its type 2, reparative character suggests that it amplifies this substrate rather than initiating the disease. Against this substrate, however, a focused neuroimmune cluster remains unexplained by purely structural models: a diagnostically accurate quantitative sensory testing pattern, elevated tissue histamine, frequent comorbid fibromyalgia, and disease that is more severe in limbs carrying an additional local vascular trigger. We hypothesize that altered tissue mechanics and adipo-vascular biology help trigger a localized immune cascade, so that these observations may define a clinically identifiable subgroup exhibiting a type 2 immune and mast cell-activation endotype, nested within the broader adipo-vascular disorder. The core framework is deliberately limited to this testable sequence: adipo-vascular susceptibility, per-cell mast cell/type 2 activation, histaminergic peripheral sensitization, the quantitative sensory testing signature, and pain generation in a clinically identifiable endotype. We argue that the endotype is best characterized by per-cell mast cell secretory activity rather than abundance, which is not consistently increased in lipedema tissue. It is defined a priori, before treatment exposure, by a composite of baseline features (affected-fat erythema or warmth, atopic or mast cell-activation features, and the characteristic quantitative sensory testing pattern), with response to mast cell-directed therapy reserved as its prospective test rather than a defining criterion. We present the framework as a graded synthesis, distinguishing evidence shown directly in lipedema from that inferred from related fields and from untested hypotheses. Broader adipogenic, gut-immune, HLA-associated, cancer-related, ADHD-related, and systemic immunomodulatory concepts are separated into a dedicated exploratory section; they are secondary hypotheses and are not required for the central mast cell-histamine-QST-pain claim. The framework identifies mast cell activation as a potential therapeutic target in this subgroup for future investigation, pending prospective validation.

Abstract: Background Bloodstream infection (BSI) complicates 20–50% of ICU sepsis cases and independently increases mortality. Conventional biomarkers — procalcitonin and C-reactive protein — lose discriminative power amid the high background inflammation of critical illness. Cell population data (CPD) from automated hematology analyzers offer morphological neutrophil metrics at no added cost. We evaluated NE-WY (neutrophil side scatter width) and NE-SFL (neutrophil fluorescence intensity) for confirmed BSI identification in ICU patients. Methods This STARD 2015-compliant prospective study enrolled 72 adult ICU patients at Dr. Soetomo General Academic Hospital, Surabaya. The primary analysis compared G1 (Sepsis-3 criteria, NHSN LCBI-confirmed BSI; n=26) against G2 (SOFA < 2, negative culture; n=21). NE-WY and NE-SFL were measured on Sysmex XN-3000; MDW on Beckman Coulter DxH 900. ROC analysis with DeLong AUC comparison assessed diagnostic accuracy. A pre-specified sensitivity analysis included G1 versus G2 plus 25 suspected-sepsis patients with non-diagnostic cultures (n=72). Results NE-WY was higher in G1 (median 789.5 [IQR 758.8–867.3]) than G2 (686.0 [IQR 650.0–747.0]; p=0.001, r=0.47). At cutoff 766, NE-WY AUC was 0.775 (95%CI 0.632–0.917): sensitivity 73.1% (95%CI 53.9–86.3%), specificity 85.7% (95%CI 65.3–95.0%), PPV 86.4%, NPV 72.0%, and accuracy 78.7%. NE-WY outperformed MDW (AUC 0.533; DeLong p=0.047). In the sensitivity analysis (n=72), NE-WY AUC fell to 0.620 (95%CI 0.485–0.756), indicating that performance depends on comparator composition. Conclusions NE-WY identifies confirmed BSI against non-septic ICU controls with AUC=0.775 and specificity 85.7%, outperforming MDW. Performance falls to AUC=0.620 against a mixed comparator that includes suspected-sepsis patients. Future studies should compare culture-confirmed BSI against culture-negative Sepsis-3 patients to isolate the bacteraemia-specific signal.