Journal of Personalized Medicine最新文献

Multiple sclerosis (MS) is a chronic, immune-mediated disorder of the central nervous system, increasingly recognized as a disease continuum that begins years before the first neurological event. Genetic susceptibility, environmental exposures, and silent neuroinflammation contribute to early disease activity. Recent studies have highlighted a preclinical phase that includes both a biological stage, characterized by elevated biomarkers such as serum neurofilament light chain up to 10 years before onset, and a prodromal phase, marked by subtle but measurable symptoms. Population-based cohorts consistently show increased healthcare use, higher prevalence of psychiatric and cognitive disturbances, fatigue, pain, and gastrointestinal disorders years before diagnosis, which may represent prodromal symptoms. Radiologically isolated syndrome (RIS), defined by incidental demyelinating lesions in asymptomatic individuals, represents the visible form of this phase and provides a unique opportunity to study the transition to clinical disease. Approximately half of RIS patients develop MS within a decade, with predictors including younger age, male sex, CSF oligoclonal bands, and spinal cord involvement. Recent randomized controlled trials demonstrated that early use of disease-modifying therapies in RIS significantly reduces conversion risk. Defining the preclinical and prodromal phases of MS offers a major opportunity to refine risk stratification, enable earlier intervention, and ultimately prevent or delay the onset of clinically definite MS.

Background/Objectives: Patients with chronic kidney disease (CKD) frequently experience upper gastrointestinal (GI) symptoms such as epigastric discomfort, nausea, vomiting, and early satiety. These symptoms can contribute to malabsorption and intermittent dehydration, ultimately accelerating the decline of residual renal function. However, they are often attributed to electrolyte imbalances or fluid overload, and the possibility of underlying gastroparesis is frequently overlooked by both patients and caregivers. This study aimed to provide new insights into the relationship between CKD and gastroparesis through a dual, population-based retrospective analysis that incorporated both inpatient and outpatient data. Methods: From the National Inpatient Sample (NIS) database, 3,579,372 patients diagnosed with gastroparesis, with or without CKD, were identified. From the TriNetX database, 6,263,251 patients presenting to ambulatory clinics with a chief complaint of nausea and vomiting were included. In both datasets, gastroparesis was defined using ICD-10-CM codes. Results: In the inpatient cohort, the prevalence of gastroparesis increased in proportion to CKD severity, with the highest likelihood observed in advanced stages compared to patients without CKD. An increased risk of gastroparesis was also observed in the outpatient CKD cohort from an independent TriNetX database, while the severity-dependent phenotype was not consistent. However, after rigorous propensity score matching, advanced CKD remained significantly associated with higher odds of gastroparesis, with the greatest risk observed in patients with end-stage renal disease (ESRD). Conclusions: These findings, validated across two large and independent datasets representing both inpatient and outpatient populations, demonstrate a consistent association between CKD severity and gastroparesis. They highlight the importance of routine screening and early management of gastroparesis in patients with advanced CKD to improve outcomes and reduce disease burden for CKD patients with sign of early satiety or dyspepsia.

Objectives: Prior research has found that social anxiety and intolerance of uncertainty (IU) are both related to problematic smartphone use (PSU) severity. However, research about the mediating effect of IU from social anxiety to PSU is limited. Methods: We conducted a cross-sectional analysis of self-report online data from 329 college students in the United States, evaluating IU, social anxiety, and PSU through structural equation modeling. Results: We found that confirmatory factor analytic models of social anxiety, IU and PSU each fit well. Our overall structural equation model also indicated good fit, and IU acted as a significant mediator of the link between social anxiety and PSU severity. To test model specificity, we compared it with an alternative model that added a direct path from social anxiety to PSU. Although the alternative model showed slightly better fit, the improvement was minimal, and theoretical grounds supported keeping the simpler initial model. Conclusions: These results indicate that IU may represent a critical cognitive-affective mechanism linking social anxiety to PSU. PSU might function as a coping mechanism for some individuals to alleviate the negative emotion associated with social anxiety and IU.

Background: Cell-in-cell (CIC) structure is a histological picture of a whole cell inside another cell. Homotypic CIC structures formed by cancer cells are consistently demonstrated to be a factor of poor prognosis and resistance to chemo- and immunotherapy in colorectal cancer (CRC). However, the absence of a standardized counting method limits the use of this factor in the applied research. Objective: To propose an adapted method for quantifying CIC structures in CRC surgical specimens and to evaluate their correlation with established adverse prognostic factors. Methods: A total of 250 histological slides of surgical specimens from 58 patients with pT1-pT4 colorectal adenocarcinoma were studied. Identification of tumor cells and visualization of CIC structures were performed by immunohistochemistry (CK20). Quantitative assessment was performed on digital scans of H&E stained slides. Quantitative assessment was performed on digital slide scans stained with H&E. CIC structures were counted in 5 fields of view corresponding to a ×40 objective (0.975 mm²). A correlation analysis of CIC structures with CRC poor prognosis factors was performed. Results: Immunohistochemical study (CK20) confirmed the formation and prevalence of homotypic structures (95%) over heterotypic ones (5%) (p < 0.001). This finding informed the evaluation of H&E-stained slides and the formulation of criteria for CIC structure identification. A significant predominance of CIC structures in the invasive front was established compared to the tumor central zone (16.7 ± 5.2 and 1.2 ± 1.3 per 5 fields of view, respectively, p < 0.0001). Correlation analysis revealed weak but statistically significant relationships with the tumor-stromal ratio, the tumor buds number and the density of tumor-infiltrating lymphocytes. No correlations were found with the right- or left-sided location, pTNM, grading, lymphovascular and perineural invasion. Conclusions: The paper presents the adapted CIC structures counting method for surgical specimens of CRC, defines the criteria of the CIC, and demonstrates a higher number of CIC structures in the tumor invasive front. Weak correlations between the CIC structures and established factors of CRC poor prognosis are obtained.

Background/Objectives: Diabetes mellitus (DM), especially insulin-dependent DM (IDDM), is strongly associated with adverse outcomes following percutaneous coronary intervention (PCI) failure. Polymer-free drug-eluting stents (PF-DESs) have emerged as a promising strategy to mitigate long-term coronary inflammation. This study aimed to evaluate the role of PF-DES, as compared to permanent-polymer DES (PP-DES) and biodegradable-polymer DES (BP-DES), in a real-world cohort of IDDM patients with obstructive coronary artery disease (CAD) undergoing PCI. Methods: IDDM patients with CAD who underwent PCI with DES at Parma University Hospital were divided into two study groups: PF-DES group vs. BP/PP-DES group. The primary endpoint was target vessel failure (TVF) at the 4-year follow-up. Survival analyses and propensity score matching (PSM) were performed to account for baseline differences. Results: A total of 170 IDDM patients with 215 treated lesions (31.6% PF-DES; 68.4% BP/PP-DES) were included. The PF-DES group experienced significantly lower rates of TVF (10.3% vs. 27.2%, p < 0.01, log rank p = 0.0072) compared with the BP/PP-DES group. PSM analysis confirmed the good clinical performance of PF-DES (HR 0.27, p < 0.01). Conclusions: In this PSM-based observational study, PF-DESs were associated with significantly lower rates of TVF compared with BP/PP-DESs in IDDM patients undergoing PCI for CAD. These suggest that PF-DES may represent a personalized PCI strategy for IDDM patients, with prognostic benefits that become increasingly pronounced as the clinical and anatomical risk profile worsens.

The introduction of immune checkpoint inhibitors (ICIs) as a part of immunotherapy represented a therapeutic breakthrough in the landscape of cancer treatment. The action of these inhibitors consists of blocking certain inhibitory receptors in the immune system. Blocking these inhibitory pathways, ICIs induce an enhanced T cell-mediated response necessary to neutralize tumor cells. Over the last 10 years, programmed death cell protein1 (PD-1), PD ligand 1 (PD-L1), and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) have been among the inhibitory receptors most targeted by ICIs. Currently, this innovative therapeutic approach faces two major challenges: early identification of cancer patients who are likely to get a significant therapeutic benefit through the use of these inhibitors, and the second challenge is the early prediction of likely immune-related adverse events (irAEs) associated with such therapy. The aim of the present text is to discuss the current research efforts to discover and develop much needed effective biomarkers, which may represent an important step towards more efficient and risk-free immunotherapy. We also highlight the increasing role in clinical analyses of liquid biopsy sampling combined with mass spectrometry-based proteomics and how such combination is contributing to current research efforts to enhance the role of immunotherapy.

Primary biliary cholangitis (PBC) is a heterogeneous autoimmune liver disease in which clinical presentation, disease progression, and response to therapy vary markedly from patient to patient. This heterogeneity reflects its complex, multifactorial, and not-completely elucidated pathogenesis. Currently, serological markers are available to non-invasively diagnose PBC, reserving liver biopsy for selected cases with atypical presentations or diagnostic uncertainty. Anyway, the accurate non-invasive prediction of liver-related and non-liver-related (i.e., extra-hepatic, including pruritus) outcomes remains an open challenge, as well as an urgent need, considering the great variability in clinical course and prognosis reported in PBC patients. Moreover, although ursodeoxycholic acid (UDCA) remains the standard first-line treatment, not all individuals respond equally, either in terms of therapeutic efficacy or timing of biochemical improvement. This further variability in treatment response underscores the inadequacy of uniform management approaches and reinforces the urgent need for personalized medicine, where treatment decisions are guided by patient-specific biological and clinical parameters. In this scenario, the identification and validation of non-invasive predictive biomarkers capable of detecting early therapeutic responsiveness are pivotal for optimizing care pathways. Finally, a growing portion of patients show an insufficient UDCA response or are UDCA intolerant, making the identification of novel strategies of care an urgent need. Concerning this, very recently, new therapeutic options beyond UDCA targeting, among the other pathways, bile acid metabolism (including the modern Peroxisome Proliferator-Activated Receptor agonists), immune regulation, and fibrogenesis, have expanded the treatment landscape. In the Era of Precision Medicine, these diagnostic, prognostic, and therapeutic innovations, by reflecting the complexity of PBC pathogenesis, underline the cruciality of a patient-tailored strategy to improve outcomes and mitigate disease progression. The present review reports recent advances, highlights ongoing challenges, and outlines future perspectives in the management of PBC.

Background: Biological sex differences are well-recognized as non-negligible factors in implementing precision medicine practice. Sex chromosomes influence protein expression and signaling, and thus cellular pathways are often regulated differently. Additionally, the importance of sex as a biological variable has gained significant traction in biomedical research, including transfusion medicine. Regarding transfusion medicine, several studies reveal the role of gender in blood transfusion, blood donors' behavior towards donation, blood products' composition and storage, transfusion therapy, and possibly post-transfusion patient outcomes. Methods: In this review, the role of sex and gender in the whole transfusion chain (from the blood donor to the blood product and the patient) is assessed and summarized using data from observational studies, registry analyses, and randomized trials. Results: Female donors face higher deferral rates due to biological factors (iron deficiency, low hemoglobin, pregnancy) and sociocultural factors (caregiving responsibilities, misinformation). However, women are more likely to donate based on empathy, moral duty, or community responsibility and are more consistent in sustaining voluntary donation during crises. Men donate more frequently, typically driven by external motivators, and provide red blood cell (RBC) products with higher hemoglobin content, whereas RBCs from female donors exhibit greater metabolic stability and reduced hemolysis during storage. Plasma from multiparous women possibly contains alloantibodies associated with adverse transfusion reactions, namely transfusion-related acute lung injury (TRALI). Platelet function also varies by sex, though its possible clinical impact is still unknown. Although observational studies suggest sex-mismatched transfusions are associated with increased morbidity and mortality-particularly in transfusions from female donors to male recipients-large registries and randomized controlled trials show inconsistent or negligible effect on survival. Conclusions: Donor and recipient sex are emerging variables of possible clinical importance in transfusion practice. Incorporating sex-informed insights into donor recruitment, blood product handling and transfusion policies may improve safety while advancing precision medicine. Further large-scale trials are needed to elucidate the impact of sex in transfusion, identify and eliminate possible risks, and bridge the gap between biological insights and clinical practice.

Background/Objectives: Headache after a traumatic brain injury (TBI) is one of the most common post-concussive symptoms and is associated with altered pain processing and elevated disability levels. Understanding physiologic correlates of nociception in individuals with persistent post-traumatic headache (pPTH) may help identify novel treatment targets for pain-related disability. The objective of this case-control study was to compare extra- and intracranial hemodynamic responses to a noxious cold pressor task (CPT) between individuals with pPTH and healthy controls (HC) using functional near-infrared spectroscopy (fNIRS). Methods: Ten individuals with pPTH were compared to ten HC with no history of TBI, persistent headache, or chronic pain. fNIRS optodes over the medial prefrontal cortex (PFC) measured extra- and intracranial peak-to-peak hemodynamic responses during tepid- (control) and cold-water (CPT) hand immersion. Evoked pain responses during the CPT were assessed with numeric pain ratings. Linear mixed effects modeling assessed the role of group and evoked pain on hemodynamic responses. Results: pPTH group membership (p = 0.031) predicted greater extracranial hemodynamic responses to the CPT, whereas intracranial PFC responses did not differ between groups. Regardless of group membership, greater increases in pain intensity during the CPT were associated with increased hemodynamic responses for the dorsomedial PFC (p = 0.031). Conclusions: Compared to controls, individuals with pPTH responded to a noxious cold stimulus with elevated systemic hemodynamic responses regulated by the autonomic nervous system. Irrespective of group, hemodynamic responses within the dmPFC were associated with evoked pain responses to the CPT and may provide a useful biomarker for individual variations in cortical pain processing for healthy and clinical populations.

Heart failure (HF) affects over 55 million individuals globally, with prevalence projected to exceed 11 million in the United States by 2050 and is increasingly recognized as a systemic disorder extending beyond hemodynamic dysfunction to encompass profound alterations in neural and gut physiology. Cognitive impairment affects nearly half of HF patients and represents a major determinant of morbidity, self-care capacity, and mortality. Recent advances suggest that the gut microbiome serves as a pivotal intermediary in the heart-brain crosstalk, influencing neurocognitive outcomes through inflammatory, metabolic, and neurohumoral pathways. Dysbiosis in HF disrupts intestinal barrier integrity, facilitating translocation of endotoxins and microbial metabolites such as trimethylamine-N-oxide (TMAO), short-chain fatty acids (SCFAs), and bile acids, which in turn modulate neuroinflammation, cerebral perfusion, and neuronal signaling. The gut-heart-brain axis provides an integrative framework linking HF and cognitive impairment pathophysiology through dysbiosis-driven systemic inflammation and metabolite dysregulation. Gut-derived biomarkers and microbiome-targeted interventions represent promising strategies for detection of early alterations and precision treatment, highlighting the urge for prospective, multi-omics studies to establish causality and therapeutic efficacy. This review synthesizes current evidence connecting gut microbiome dysbiosis and metabolite alterations to both HF and cognitive impairment pathophysiology and proposes translational strategies for integrating microbiome-targeted therapies in HF patients with cognitive dysfunction.