Search Results (238)

Background: Infective endocarditis (IE) requires 4–6 weeks of intravenous antimicrobial therapy, and timely transition to outpatient parenteral antimicrobial therapy (OPAT) allows clinically stable patients to complete treatment outside the hospital. Because OPAT requires home infusion services or post-acute facility placement that typically depend on coverage, insurance status may strongly influence length of stay (LOS); national data on this association in IE remain limited. Methods: We performed a retrospective cross-sectional analysis of the 2016–2019 National Inpatient Sample (NIS) using ICD-10-CM codes I33 and I38 to identify adult IE hospitalizations. Patients were classified as insured (Medicare, Medicaid, or private insurance) or uninsured (self-pay or no charge). Outcomes included mean and prolonged LOS (>14 and >28 days), in-hospital mortality, discharge against medical advice (AMA), and hospitalization costs. Comparisons used chi-square and Student’s t-tests with appropriate NIS survey weighting. Multivariable Gamma regression (LOS, cost) and logistic regression (binary outcomes) were performed, adjusting for age, sex, race/ethnicity, income quartile, injection drug use (IDU), Elixhauser Comorbidity Index, and hospital characteristics, with an insurance × IDU interaction term. Results: Of 87,211 weighted IE hospitalizations, 81,667 (93.6%) were insured and 5544 (6.4%) were uninsured. Uninsured patients were younger (mean age 40.1 vs. 59.4 years) with lower comorbidity burden but higher injection drug use (IDU) prevalence (38.7% vs. 15.5%). Mean LOS was longer among the uninsured (15.5 vs. 12.4 days, p < 0.001); LOS > 14 days occurred in 35.8% vs. 26.6%, and LOS > 28 days in 18.5% vs. 9.2% (both p < 0.001). AMA discharge was four-fold higher among the uninsured (22.2% vs. 5.5%, p < 0.001), while unadjusted in-hospital mortality was similar (9.0% vs. 9.4%, p = 0.32). LOS and AMA disparities persisted in both IDU and non-IDU subgroups, with a six-fold AMA disparity among non-IDU patients (15.2% vs. 2.5%). Based on multivariable analysis, uninsured status remained independently associated with prolonged LOS > 28 days (adjusted odds ratio [aOR] 1.46, 95% CI 1.30–1.65), AMA discharge (aOR 3.51, 95% CI 3.10–3.97), and—after accounting for age and comorbidity differences—higher in-hospital mortality (aOR 1.25, 95% CI 1.10–1.43). Conclusions: Uninsured adults hospitalized with IE experienced longer stays, markedly higher AMA rates, and—after adjustment for age and comorbidity—higher in-hospital mortality than insured patients. These findings are consistent with nonclinical barriers to discharge—particularly limited OPAT and post-acute care access—and suggest that the younger, less comorbid profile of uninsured patients masks an underlying outcome disparity. The results identify uninsured IE patients as a population that may benefit from alternative care models and policy reforms expanding safe post-acute antimicrobial therapy. Full article

Objective: Online patient education materials (OPEMs) are important resources for patients seeking health information. While the National Institutes of Health (NIH) and American Medical Association (AMA) recommend a sixth-grade readability level for OPEMs, commonly available material often exceeds such criteria. Large language models (LLMs), such as ChatGPT and Gemini, have emerged as tools for health education with potential applications in simplification of health material. This study assesses the utility of ChatGPT and Gemini in enhancing the readability of OPEMs for peripheral nerve surgeries. Methods: Eleven common peripheral nerve surgeries were used as online search terms. The first 20 unique search results were assessed; results were excluded if they did not include patient-facing material. ChatGPT and Gemini were instructed to rewrite the text of the OPEM at or below a sixth-grade reading level. Readability metrics were calculated for original OPEMs, alongside ChatGPT and Gemini rewrites. LLM responses were reviewed for accuracy/quality (five-point scale) and comprehensiveness (three-point scale) using predefined criteria. Results: A total of 220 websites were assessed. In total, 155 OPEMs met the inclusion criteria; 65 websites were excluded because they were academic journal articles or other provider-facing materials. The average Flesch–Kincaid grade level (FKGL) of OPEMs was 11.3, significantly greater than the NIH/AMA-sixth grade recommendations (p < 0.001). The average FKGL of ChatGPT rewrites was significantly lower than that of OPEMs (11.3 vs. 7.5, p < 0.001), as was the average FKGL of Gemini rewrites (11.3 vs. 5.6, p < 0.001). ChatGPT rewrites were of higher accuracy/quality (4.5/5.0 vs. 4.0/5.0, p < 0.001) and comprehensiveness (2.0/3.0 vs. 1.0/3.0, p < 0.001) relative to Gemini rewrites. Conclusions: The readability of online patient education materials for peripheral nerve surgery significantly exceeded NIH/AMA recommendations. ChatGPT and Gemini were able to significantly simplify the reading level of these OPEMs. LLMs may serve as tools to improve the readability of peripheral nerve surgery OPEMs. Full article

Chromium (Cr) is one of the most toxic heavy metals in the environment. The tolerance to metal stress involves sophisticated regulation of gene expression networks, which involve microRNAs (miRNAs). However, the role of miRNAs in Cr stress response in Avicennia marina has not been resolved, and was addressed here. The analysis of response characteristics revealed that morpho-physiological traits such as root length, Cr accumulation level and antioxidant enzyme activity all exhibit significant changes under Cr stress. Via sRNA sequencing, a total of 27 known and 149 novel miRNAs were identified, 63 of which showed differential expression after Cr stress (q-value < 0.001). Further, 571 miRNA-target interaction pairs were identified for differentially expressed miRNAs, corresponding to 355 target genes. GO and KEGG analyses indicated that these target genes could participate in stress-related biological processes such as signal transduction, transcription regulation, protein synthesis and the MAPK signaling pathway. 54 miRNA target genes, corresponding to 37 miRNAs such as Ama-miR160, Ama-nmiR25-5p and Ama-nmiR118-5p, were enriched for “plant signal hormone transduction” (ko04075), “phenylpropanoid biosynthesis” (ko00940) and “MAPK signaling pathway” (ko04016), which indicated an important role of these miRNAs in regulating Cr stress response in A. marina. Based on the findings, a Cr stress-responsive regulatory model was developed, offering new insights into the molecular regulatory mechanisms of Cr response. In conclusion, this study shows the identity and potential role of miRNAs in the heavy metal stress response of A. marina, and provides the foundation for future research. Full article

Background: The distance and angle between the superior mesenteric artery (SMA) and abdominal aorta play a role in the etiology of SMA syndrome. Retroperitoneal fat has been reported to affect both the distance and angle. Very few studies have reported the normal range of these measurements. The present study aimed to evaluate the reference values of the aortomesenteric angle (AMA) and aortomesenteric distance (AMD) in asymptomatic patients, as well as to determine the influence of age, sex, and anthropometric variables on these values. Methods: A retrospective cross-sectional study was conducted at Sultan Qaboos University Hospital. Computed tomography angiography scans of the abdomen from 141 Omani adult patients (aged ≥18 years) were included in the study. The morphometric data of the AMA and AMD were measured at the third part of the duodenum using sagittal and axial multiplanar reconstruction of CTA images. Patient data, including age, sex, height, weight, and BMI, were collected from the medical records. Statistical analyses included the Mann–Whitney U, Kruskal–Wallis H and Jonckheere–Terpstra J-T tests with significance set at p < 0.05. Results: The mean AMA was 57.16 ± 22.06°, and the mean AMD was 21.35 ± 10.25 mm. The AMD varied significantly across age groups (H = 17.29, p < 0.001) and showed a positive trend with increasing age (p = 0.001). Both AMA (p = 0.001) and AMD (p < 0.001) differed significantly across BMI categories, with significant increasing trends (p = 0.033 and p ≤ 0.001, respectively). No statistically significant differences were observed between sexes and study parameters (p > 0.05). Conclusions: The present study demonstrates that the reference values of the AMA and AMD are within the range of those reported in other populations. The variations in these values with BMI and age underscore the importance of individualized imaging interpretation and preoperative planning. The reported baseline data may enhance diagnostic accuracy and assist with surgical planning and radiological evaluation of suspected SMA syndrome. Full article

Bovine babesiosis is a tick-borne disease that poses significant economic losses to global cattle production, and diverse vaccine platforms have been developed to combat it. This work critically evaluates global research on bovine babesiosis vaccines, integrating historical milestones with recent advances in antigen discovery and immunization approaches and assessing their protective efficacy through meta-analysis. Using comprehensive database searches, we identified 413 publications on bovine babesiosis vaccines, of which 168 met the inclusion criteria, spanning from 1960 to August 2025. Analysis revealed that B. bovis dominated the research output, followed by B. bigemina and B. divergens. Five key methodological approaches emerged: field trials, controlled experiments, immunogenicity assessments, in vitro assays, and in silico antigen analyses, with a notable shift toward immunogenicity and computational studies post-2000. Frequently studied antigens included RAP-1, MSA-2c, AMA-1, 11C5, and 12D3 (B. bovis); RAP-1 and GP45 (B. bigemina); and Bd37 (B. divergens). Geographically, research was concentrated in the United States, Australia, Argentina, Mexico, and France, which were identified as the top contributors in that order, primarily focusing on live and recombinant vaccines, with minimal African participation despite high cattle populations. Bibliometric analysis showed increasing publication output, with leading journals such as Veterinary Parasitology, Infection and Immunity, and Parasites & Vectors as the top three. Thematic evolution highlighted a transition from live vaccines to recombinant and multi-epitope strategies, with increasing emphasis on conserved antigens and novel platforms. However, more field evaluations are required to determine whether these new technologies can achieve protective efficacy comparable to that of live vaccines. This work underscores the need for sustained investment, intersectoral collaboration, and validation using standardized and comparable metrics in field trials to translate laboratory innovations into effective, safe, and globally accessible vaccines against bovine babesiosis. Full article

Background: Primary biliary cholangitis (PBC) is a rare autoimmune liver disease characterized by marked clinical and serological heterogeneity. Although diagnosis is mainly based on antimitochondrial antibodies (AMAs) and alkaline phosphatase (ALP), non-classical presentations remain a relevant cause of diagnostic delay. In this context, laboratory medicine plays a pivotal role in both diagnosis and long-term disease management. Methods: This manuscript represents a structured clinical review of laboratory biomarkers relevant to the diagnosis, monitoring, and prognostic stratification of PBC, integrated with a representative atypical case with long-term follow-up to illustrate the practical application of laboratory-driven diagnostic. Results: The analysis confirms the central role of immunological and biochemical markers in treatment monitoring and prognostic assessment, while highlighting their limitations in selected clinical scenarios. The reported case, characterized by persistent AMA negativity and consistently normal ALP levels, illustrates how expanded laboratory testing can support the identification of non-standard disease phenotypes. In this setting, parallel testing for AMA- and PBC-specific autoantibodies was essential to achieve a correct diagnosis. Moreover, alternative biomarkers, including gamma-glutamyl transferase (GGT) and selected immunological markers, provided clinically meaningful information when conventional markers were not informative. Conclusions: By integrating current evidence with a long-term clinical case, this work moves beyond a descriptive overview and proposes a practical, laboratory-driven diagnostic and follow-up framework for PBC. It highlights laboratory opportunities to facilitate timely diagnosis, appropriate prognostic stratification, and disease monitoring, including the assessment of associated comorbidities. Full article

Antibiotic residues in water buffalo milk are a food-safety concern, yet depletion data are scarce. The purpose of this study was to characterize the depletion profiles of amoxicillin (AMOX) and its two major metabolites, amoxicilloic acid (AMA) and amoxicillin diketopiperazine-2′,5′-dione (2,5-DKP), in Anatolian water buffalo milk after a single intramuscular administration and to estimate a milk withdrawal time relative to the EU MRL. We tested the hypothesis that AMOX concentrations would decrease below the EU MRL over successive milkings and that AMA and 2,5-DKP would exhibit depletion kinetics distinct from the parent compound. Five lactating Anatolian water buffaloes received a single intramuscular injection of amoxicillin (15 milligrams per kilogram). Milk was collected at each milking (twice daily) for seven days and analyzed by liquid chromatography–tandem mass spectrometry with quantification limits below the European Union maximum residue limit for amoxicillin in milk (4 micrograms per kilogram). Amoxicillin peaked at the second milking (mean 13.65 micrograms per kilogram), mean concentrations fell below the maximum residue limit from the sixth milking, and they became non-quantifiable from the tenth milking onward. Two major metabolites, amoxicillinic acid and amoxicillin diketopiperazine-2′,5′-dione, peaked earlier (2,5-DKP Tmax 12 h) or at higher concentrations (AMA Cmax 32.64 µg/kg vs. AMOX 13.65 µg/kg) and remained detectable up to the thirteenth milking, with longer apparent terminal half-lives (32.0 and 52.8 h) than amoxicillin (23.5 h); the mixed-effects model confirmed different depletion rates among analytes (milking × analyte interaction p = 4.63 × 10⁻⁵). A log-linear withdrawal model applying the EMA 95/95 tolerance limit indicated that the first time point at which the upper tolerance limit fell below the EU MRL was 84.7 h after dosing; rounded up to the next 12 h milking interval, this corresponds to a reported withdrawal period of 96 h (≈8 milkings). These results provide species-specific residue kinetics for amoxicillin in Anatolian buffalo milk and support considering metabolites in monitoring and withdrawal-time decisions. Full article

Background/Objectives: Accessory mandibular foramina (AMaFs) are small osseous openings of the mandible that are clinically relevant anatomical variations. This study aimed to characterize the morphology and spatial distribution of AMaFs in dry mandibles and to integrate the existing anatomical evidence through a systematic review and meta-analysis, with the goal of clarifying their potential clinical relevance. Methods: A series of dry mandibles from human adults of unknown age and sex from our laboratory collection was examined to document AMaFs using direct osteological inspection. Stainless steel wire threads and digimatic caliper measurements were utilized by two separate raters. Cluster analysis was employed for the classification of foramina into distinct spatial groups. Furthermore, in accordance with the PRISMA guidelines, an unrestricted literature search was conducted across PubMed, Scopus, SciELO, and Google Scholar using appropriate database-specific combinations of the terms “accessory mandibular” and “foramen/foramina” to search for studies on the prevalence and morphology of AMaFs in dry mandibles or cadaveric material. Radiological studies were excluded. The search was completed on 13 July 2025. Study quality was evaluated using the appropriate AQUA tool. Data synthesis was carried out using STATA 19. No external funding was received. Results: A total of 96 dry mandibles (50 dentate and 46 edentulous) were analyzed. AMaFs were detected in 8/96 mandibles (8.3%). In these mandibles, a total of 25 accessory mandibular foramina, all superior to the mandibular foramen, were identified (mean: 3.13 foramina/mandible), with a mean diameter (SD) of 0.56 ± 0.10 mm and a mean distance from the mandibular foramen of 11.34 ± 1.29 mm (mean vertical distance: 10.32 ± 1.35 mm; mean absolute horizontal distance: 3.78 ± 0.49 mm). Of these foramina, 21/25 (84%) had a diameter ≥0.5 mm; the number, diameters, and distances from the mandibular foramen were comparable between left and right hemimandibles. Based on their positioning relative to the mandibular foramen, the AMaFs were classified into two distinct groups (clusters). In the meta-analysis, a total of 36 studies were included. In most of the mandibles (65.1%; 95% CI: 57.7–72.2%; I²: 94.9%), no AMaFs were detected. The unilateral presence of one or more AMaFs was observed in 20.9% of the mandibles (95% CI: 16.3–25.9%; I²: 91.3%), while bilateral occurrence was identified in 10.6% (95% CI: 6.9–15.0%; I²: 93.0%). Additionally, 2.4% of the mandibles (95% CI: 1.0–4.2%; I²: 86.3%) exhibited multiple AMaFs (≥2) on at least one side. On average, each hemimandible contained 0.253 AMaFs (95% CI: 0.198–0.312; I²: 96.9%). The overall mean diameter of AMaFs was estimated to be 0.65 ± 0.33 mm. The substantial heterogeneity observed was not explained by geographic origin, sample size, publication period, or publication bias. Conclusions: AMaFs were detected in approximately one-third of the mandibles in the studies included in the meta-analysis. AMaFs are typically located superior to the mandibular foramen and may represent additional anatomical pathways associated with inferior alveolar nerve branching. Awareness of these features could help clinicians to anticipate anatomical variability during mandibular surgery and when applying local anesthesia. In addition, it should be acknowledged that inferior alveolar nerve block failure is multifactorial and not solely determined by the presence of AMaFs. Full article

In malaria-endemic regions, women remain vulnerable to Plasmodium falciparum infection at the time of delivery. However, the immunological mechanisms underlying infection-associated inflammation in primigravid women remain poorly characterized. This exploratory study investigated cytokine-based immune profiles reflecting malaria infection status at delivery. We assessed 33 primigravid women from Nanoro, Burkina Faso (mean age 19 years; range 18–20.5) at childbirth. Antibody responses to P. falciparum antigens (PfCSP, PfAMA-1, and EBA-175) and plasma levels of cytokines (IL-4, IL-10, IL-6, TNF-α, and IFN-γ) were quantified using enzyme immunoassays. Multivariate analyses, including principal component analysis (PCA) and hierarchical clustering, identified three distinct immune profiles: (1) a low-inflammatory cluster with reduced IL-6 and TNF-α, (2) a TNF-α–dominant cluster, and (3) a highly pro-inflammatory cluster with elevated IL-6 and TNF-α. Cluster stability was supported by bootstrap analysis (AU ≥ 92%). All women in the most inflammatory cluster were P. falciparum–positive at delivery (Fisher’s exact test, p = 0.04; exploratory association). These cytokine-driven profiles reflect biologically distinct inflammatory states associated with concurrent infection at delivery rather than predictive immune predispositions. The findings underscore the potential of cytokine profiling as a hypothesis-generating tool to guide future longitudinal studies on immune regulation and the postpartum period. Full article

Math anxiety, or a student’s lack of confidence in learning mathematics, is one of the emotional dimensions with the greatest impact on mathematics education. Sociological factors such as sex and age, demographic aspects like cultural characteristics, and emotional variables such as general anxiety have been identified as significantly influencing math anxiety. This study conducts quantitative, descriptive, correlational, and regression analyses of the influence of sex, age, and general anxiety on math anxiety in a sample of 185 Spanish elementary students. It also examines whether the effects of age and general anxiety on math anxiety differ by sex. For this purpose, students’ responses to a quantitative questionnaire are analyzed. The instrument combines two validated scales: (i) STAIC T-Anxiety, measuring general anxiety, and (ii) AMAS, measuring math anxiety. Results show that students exhibit moderate average math anxiety, which is not significantly affected by sex. However, significant correlations between math anxiety, age, and general anxiety were found, independent of sex. The study highlights the need to design corrective measures for math anxiety and suggests lines for future research. Full article

This work investigates the structural evolution and electrocatalytic activity of the amorphous metal alloy Al₈₇Y₄Gd₁Ni₄Fe₄ during short-term annealing and its effect on the kinetics of the hydrogen evolution reaction (HER) in 1 M KOH. It is shown that a 5 min heat treatment at 647 ± 2 K initiates controlled nanocrystallisation with the formation of AlFe₂Ni, GdFe₂ and Al(X) (X = Gd, Ni, Y, Fe) phases, which are uniformly dispersed in the amorphous matrix. According to XRD, DSC and HRTEM data, it was established that the formation of intermetallic nanodomains leads to a decrease in charge transfer energy barriers and the appearance of additional active centres of H* adsorption. Electrochemical studies have shown an increase in cathode current density, an increase in i₀ by 2–3 orders of magnitude, and a decrease in R_ct after annealing, confirming the improvement in HER kinetics. Potentiostatic tests showed an increase in the volumetric hydrogen evolution rate from 35.1 to 106.0 mL/(g·min) during the first immersion and up to 217.9 mL/(g·min) during reuse. SEM/EDS analysis revealed surface reconstruction and Ni enrichment after HER, which contributes to the acceleration of the H* recombination stage. The synergy of the amorphous matrix and nanophases ensures high electrocatalytic activity and stability of the system, making annealed AMA a promising low-cost catalyst for alkaline hydrogen evolution. Full article

Background/Objectives: This study aimed to develop an ultra-performance liquid chromatography–tandem mass spectrometry (UPLC-MS/MS) method for quantifying amantadine (AMA) in rat plasma and to investigate its pharmacokinetics under simulated high-altitude hypoxia, contrasting its behavior with that of its structural analog memantine (MEM). Methods: The method entailed using memantine (MEM) as an internal standard. Sample preparation involved protein precipitation, followed by gradient elution with detection via positive electrospray ionization and selective reaction monitoring (SRM). The method validation complied with the International Conference on Harmonization (ICH) M10 guidelines. Pharmacokinetic studies were conducted in rats exposed to either low altitude (1500 m) or simulated high altitude (6500 m) after a single oral dose of AMA (10 mg/kg). Results: The assay demonstrated linearity from 5 to 1000 µg/L, with accuracy, precision, recovery, and stability all meeting the respective acceptance criteria. Hypoxia did not significantly alter systemic exposure to AMA, as measured by parameters such as the area under the concentration–time curve (AUC), maximum concentration (Cmax), and apparent clearance (CLz/F). However, hypoxia prolonged the elimination half-life by 55% and increased the variance in the mean residence time. This finding contrasts sharply with our previous results on MEM under identical hypoxic conditions, which showed a 72.15% increase in AUC and a 41.99% decrease in CLz/F. Conclusions: A robust UPLC-MS/MS method for quantifying AMA was successfully established. AMA exhibits unique pharmacokinetic resilience to acute hypoxia, characterized by increased variability in elimination without changes in overall exposure. This profile starkly differs from the heightened exposure and reduced clearance observed for drugs like MEM, which are predominantly cleared by hepatic metabolism (under the studied conditions). These findings are consistent with the concept that a drug’s primary elimination pathway (renal excretion vs. hepatic metabolism) critically determines its pharmacokinetic susceptibility to hypoxic stress. Full article

Amorphous metal alloys (AMAs) are characterized by good mechanical and electrochemical properties. However, due to crystallization processes occurring at higher temperatures (Ta ˃ 600 K), these properties may deteriorate. The aim of this work was to investigate the effects of short-term annealing at T₃ = 611 ± 1 K and to determine the risks of such thermal modifications for the electrochemical properties of the material. A comprehensive analysis shows that short-term isothermal annealing (5 min) of the amorphous metal alloy Al₈₇Y₄Gd₁Ni₈ at a temperature of 611 ± 1 K improves the tribological properties of the material. However, it has been established that heat treatment for 5 min is optimal and leads to temporary thickening of the film and the formation of an almost ideal double layer, but annealing for 15–60 min negatively affects the electrochemical properties of this material, indicating a decrease in the protective properties of the passivating layers. Full article

Background/Objectives: The study evaluated whether the cumulative burden of multiple, modifiable risk factors worsened cardiovascular disease (CVD) mortality in West Virginia. Methods: This retrospective observational study looked at all CVD mortality rates per county of West Virginia between 2011 and 2020 and each county’s modifiable risks. Income, ratio of people per PCP (PCP Ratio), and Food Desert Status (FDS), and the death rate from the Census Bureau, AMA, US Department of Agriculture, and the West Virginia Department of Health and Human Services (WV HHS) were collected, respectively. Multiple linear regression and ANOVA analyses were performed for each combination of factors towards the death rate. Results: Multiple linear regression demonstrated that combined risk factors were more strongly associated with CVD mortality than any single factor alone. Over the 10-year period, West Virginia’s population aged overall. Each individual risk factor was significantly associated with CVD mortality (Income: F(1,537) = 53.39, p < 0.0001; PCP Ratio: F(1,537) = 21.49, p < 0.0001; FDS: F(1,537) = 5.13, p = 0.024). Two two-way interactions were significant (PCP Ratio:Income: F(1,537) = 22.03, p < 0.001; FDS:Income: F(1,537) = 5.23, p = 0.022), while the PCP Ratio:FDS interaction and the three-way interaction were not. Conclusions: Counties burdened by several modifiable risk factors experienced disproportionately elevated CVD mortality, exceeding what would be predicted by the additive effects of each risk factor individually. These findings highlighted the importance of addressing cumulative socioeconomic and healthcare access factors at the county level. Full article

Background and Objectives: Mechanical alignment (MA) has long been the gold standard in total knee arthroplasty (TKA), aiming for neutral hip–knee–ankle alignment with proven long-term survivorship. However, up to 20% of patients remain dissatisfied, often due to neglect of individual constitutional limb variation and subsequent soft tissue imbalance. This has driven the development of alternative alignment philosophies. This current concepts review aims to determine the various evolving alignment strategies, elucidate their underlying principles, and demonstrate the available clinical outcomes data. Materials and Methods: This review examines MA and the paradigm shift towards personalized alignment techniques, including Kinematic Alignment (KA), restricted Kinematic Alignment (rKA), inverse Kinematic Alignment (iKA), adjusted mechanical alignment (aMA), and the most recent evolution, Functional Alignment (FA). Results: Kinematic alignment and its derivatives (rKA, iKA) seek to better replicate native joint morphology and tension, often reducing the need for soft tissue releases and improving functional outcomes compared to MA. rKA and iKA introduce protective boundaries to avoid extreme phenotypes and possible instability. FA leverages robotic platforms and integrates these principles with real-time gap balancing, demonstrating promise for consistent, personalized outcomes. Some reports, however, advise caution with adjusted Mechanical Alignment (aMA), particularly those that result in phenotypes such as Coronal Plane Alignment of the Knee (CPAK) VII or VIII, which may increase the risk of revision. Conclusions: The philosophy of TKA has evolved from a uniform mechanical target (MA) to a more nuanced, patient-specific strategy. While promising mid- to long-term outcomes and comparable survival data support the viability of KA and its derivatives, critical needs remain, including standardizing nomenclature (especially for FA) and conducting high-quality comparative trials. Future directions involve leveraging high-volume intraoperative data and Artificial Intelligence (AI) to refine decision-making and further personalize alignment strategies, without compromising long-term implant survivorship. Full article