Search Results (582)

Postmenopausal ovarian hormone deficiency (OHD) contributes to overactive bladder (OAB) through oxidative stress, mitochondrial dysfunction, and dysregulated estrogen receptor (ER) signaling. This study investigated whether estradiol (E2) alleviates dysfunction by modulating the ER/Smad/miRNA-200/KLF4/mTOR signaling pathway to restore mitochondrial quality control. Thirty female Sprague-Dawley rats were initially allocated to Sham, Ovariectomy (OVX) and OVX + E2 group; after attrition during the 12-month protocol, six surviving animals per group were included in the principal analyses. The OVX + E2 group received daily intramuscular E2 (IM, 30 μg/kg/day) for one month. Bladder function was assessed via micturition volume and frequency by metabolic cages, cystometrograms, and contractility assays. Mechanisms were analyzed using immunofluorescence, Western blotting, transmission electron microscopy (TEM), and miRNA sequencing. OVX rats exhibited significant overactivity and compromised contractility, accompanied by upregulated ERα and downregulated ERβ/GPER. Molecularly, OHD was associated with the upregulation of the miRNA-200 family (miRNA-200a-3p, miRNA-200b-3p and miRNA-200b-5p), which was accompanied by reduced levels of KLF4 and autophagy proteins (ATG7, ATG12 and Beclin-1), as well as elevated p-mTOR expression. TEM revealed the accumulation of damaged mitochondria with ultrastructural features associated with impaired mitophagy. However, E2 treatment ameliorated these abnormalities. These improvements were associated with the restoration of TGF-β/Smad signaling, downregulation of selected miRNA-200 family members, recovery of KLF4 level, and increased expression of autophagy-related markers, accompanied by improved mitochondrial ultrastructural integrity. This cellular restoration might be correlated with improved urodynamic parameters. E2 might exert therapeutic effects by improving mitochondrial quality, potentially via the ER/Smad/miRNA-200/KLF4 signaling pathway. These findings provided mechanistic insights into estrogen-mediated protection and highlight this proposed signaling pathway as a therapeutic target for postmenopausal OAB. Full article

Background: Otolaryngology conditions significantly influence public health globally, often posing challenges in accessing specialized ear, nose, and throat (ENT) services. Digital referral systems can facilitate access to specialized care while supporting resource allocation. This study analyzed ENT digital referrals through the digital referral system of the Saudi Medical Referrals Centre to describe utilization patterns across different ENT subspecialties. Methods: This retrospective cross-sectional study analyzed 50,514 ENT digital referrals across Saudi Arabia from January 2023 to December 2024. Crude population-based rates per 10,000 were calculated using national census data. Cross-tabulation tables were utilized to compare patient demographics, regional variables, and referral characteristics with ENT subspecialties. Results: ENT digital referral utilization over two years reached 15.70 per 10,000 population (7.38 in 2023, and 8.32 in 2024). Patients over 60 years showed the highest rates (42.17), followed by children aged 1–7 years (29.90). Females demonstrated a higher crude population-based rate (17.07 vs. 14.83) despite males comprising 57.76% of total referrals. General ENT services represented 59.49% of referrals, audiology services 32.92%, while specialized services showed lower volumes. Routine outpatient referrals predominated at 91.14%, and only 1.3% of total requests required intensive care beds. Most referrals were managed internally (93.75%) with overall acceptance rate reaching 89.41%. Conclusions: The findings demonstrate distinct age- and subspecialty-related utilization patterns within Saudi Arabia’s national ENT digital referral system, with the highest demand among older patients and young children. General ENT constituted the majority of referrals, while other specialized services appeared in smaller volumes. The predominantly outpatient, highly accepted, and internally managed referral patterns establish baseline metrics for national ENT subspecialty access. These findings outline nationwide coordination patterns of subspecialty care and support continued investment in digital health infrastructure for specialized care coordination. Full article

Conventional soybean lecithin has limited hydrophilicity, which may restrict its efficacy as a feed emulsifier. This study evaluated graded hydroxylated lecithin supplementation in Jiangnan White geese. Six hundred one-day-old females were allocated to five treatments, with six pens of 20 geese each: a basal diet, 50, 100, or 200 mg/kg hydroxylated lecithin, and 100 mg/kg conventional soybean lecithin. The pen served as the experimental unit (n = 6). After 64 days, all lecithin-supplemented groups had higher final body weight and average daily gain than the control (p < 0.05), whereas 100 and 200 mg/kg hydroxylated lecithin reduced feed conversion ratio (p < 0.05). After false-discovery-rate adjustment within prespecified outcome families, robust treatment effects remained for selected serum indices, leg-muscle shear force, muscle-fibre morphology, inosine monophosphate, several flavour-associated amino acids, selected fatty acid outcomes, and tissue-specific expression of the candidate genes (q < 0.05). Nominal differences in intramuscular fat, carcass traits, body measurements, and several individual fatty acids did not withstand adjustment and were treated as exploratory. The equal-dose comparison did not show a consistent advantage over conventional soybean lecithin. Overall, hydroxylated lecithin elicited endpoint- and dose-dependent responses, but their commercial relevance and underlying mechanisms require confirmation. Full article

Background: Physical exercise induces coordinated endocrine and metabolic adaptations that contribute to the regulation of glucose homeostasis, lipid metabolism, stress responses, and anabolic processes. However, the integrated effects of combined aerobic and resistance exercise on multiple endocrine and metabolic outcomes require further investigation. This study aimed to evaluate the effects of a 12-week combined aerobic and resistance exercise program on endocrine and metabolic parameters in normal-weight and mildly overweight adults. Methods: A total of 60 adults were randomly allocated to an exercise group (EX, n = 30) or a control group (CON, n = 30). The EX-group completed a supervised 12-week combined exercise program consisting of three 60 min sessions per week, including aerobic exercise and multi-joint resistance training, whereas the CON-group maintained their habitual physical activity levels. Endocrine parameters, including insulin, glucagon, cortisol, growth hormone (GH), thyroid hormones, and sex-specific hormones, as well as fasting glucose, lipid profile, and homeostasis model assessment of insulin resistance (HOMA-IR), were assessed at baseline and after 12 weeks. Results: Compared with the control condition, the exercise program was associated with favorable changes in endocrine and metabolic profiles. The EX-group showed reductions in fasting insulin, cortisol, fasting glucose, and HOMA-IR, together with increased GH levels. Favorable changes were also observed in the lipid profile, including reductions in total cholesterol, low-density lipoprotein cholesterol (LDL), and triglycerides and an increase in high-density lipoproteins cholesterol (HDL). In the male subgroup, total testosterone increased following the intervention, whereas estradiol changes in the female subgroup were more limited. Changes in insulin were associated with changes in glucose regulation and lipid parameters, while GH and cortisol changes showed additional associations with metabolic outcomes. Conclusions: These findings support the role of structured combined exercise as a non-pharmacological strategy for promoting endocrine and metabolic health and preventing metabolic dysfunction. Full article

Whether vocalisations during disbudding predict later outcomes in goat kids is unknown. In this preliminary study, we allocated 18 female Tianfu goat kids to disbudding (n = 9) or sham (n = 9). Disbudding used a hot iron without analgesia; sham kids received an unheated iron. Vocalisations, tail flicks, and struggles were recorded. Fundamental frequency (F0) and Mel-frequency cepstral coefficients (MFCCs) were extracted. Body weight and temperament were assessed at 90 days post-procedure; home-pen behaviour was scan-sampled at 60 and 90 days post-procedure. Two kids were excluded due to insufficient recordings, leaving 16 (9 disbudded, 7 sham). Disbudded kids vocalised more frequently (14.5 vs. 8.1 calls/min, p = 0.0007) and had lower minimum F0 (283.4 vs. 366.1 Hz, p = 0.020), with significant MFCC shifts. Several acoustic features correlated with body weight at 90 days post-procedure (mfcc_12_std: r = 0.903, p = 0.001) and temperament (mfcc_2_mean: r = −0.788, p = 0.012) after controlling for disbudding weight. The first principal component of acoustic features (PC1) correlated with lower body weight at 90 days post-procedure in disbudded kids (r = −0.786, p = 0.036), but not in shams (r = −0.257, p = 0.623). No subgroup differences were found in home-pen behaviours. These findings indicate that acute pain vocalisations may reflect individual stress reactivity—a possible ‘vocal phenotype’—and, with validation, could inform non-invasive screening for at-risk kids. Full article

Energy trade-offs underlying brain size evolution represent a central topic in evolutionary biology. The Expensive Brain Hypothesis (EBH) posits that the high energetic costs of large brains must be compensated for by increased energy intake or reduced allocation to other costly tissues and functions. We examined the Minshan toad (Bufo minshanicus) along an elevational gradient (2594–3441 m) on the eastern Tibetan Plateau, measuring relative sizes of the brain, five visceral organs, and two reproductive organs, as well as body condition (SMI). Body size and condition significantly decreased with elevation. Relative brain mass showed a non-significant increasing trend with elevation, whereas relative masses of the liver, heart, and alimentary tract significantly increased, and lung mass significantly decreased, with pronounced sexual dimorphism. Relative brain mass was positively correlated with most viscera and male reproductive organs, while a significant brain–ovary trade-off occurred only in females at mid elevation. Overall, elevational environmental conditions shape divergent organ mass covariation patterns. High-altitude habitats may relax energetic constraints to allow coordinated organ development, while moderate mid-altitude stress induces brain–ovary resource trade-offs in females. Our findings do not universally contradict the EBH and instead demonstrate that energetic trade-offs are strongly context-dependent rather than ubiquitous across elevational gradients. Full article

Early adult life represents a critical developmental window during which insects undergo profound physiological reorganization. Despite the economic importance of the yellow mealworm, Tenebrio molitor L., this transition remains poorly characterized/understood. This study provides an integrated characterization of the energetic, cuticular and immunological remodelling that occurs during the first week post-emergence, a critical developmental window with important implications for experimental standardization and mass-rearing optimization. Body mass, Scaled Mass Index (SMI), and cuticular tanning trajectories were monitored at 0, 1, 5, and 7 days, along with cellular (tsotal haemocyte count, THC) and humoral (phenoloxidase activity, PO) immunocompetence at 2 and 7 days in both sexes. Newly emerged adults underwent an energetically demanding early phase characterized by significant proportional mass loss, followed by stabilization and improved SMI by day 7. In parallel, THC increased more than twofold, while the humoral defences remained stable. Cuticle melanization followed a synchronized age-dependent trajectory in both sexes, reaching structural stabilization by the end of the first week. Correlation analysis revealed sex-specific patterns of resource allocation. Females showed a positive association between initial body condition and mature PO activity. Conversely, males exhibited a negative trend between cuticle tanning effort and PO activity, suggesting a clear competition for shared physiological resources. Overall, our findings identify early adulthood as a phase of coordinated physiological remodelling, during which energetic reorganization, cuticle maturation, and cellular immune expansion are synchronized to establish adult functional competence. Full article

This study investigated the effects of dietary inclusion of corn and peas on the fecal microbiota composition and functional potential in Sarda goats. Twelve female goats were allocated to two groups, a group grazing on a natural pasture (GP) and a group grazing on the same pasture with a diet enriched with corn and peas (GC), both grain supplements at 100 g/day. Fecal samples were collected, freeze-dried and subjected to 16S rRNA gene sequencing of the V4–V5 region, followed by bioinformatic and statistical analyses. Alpha diversity metrics indicated a significant reduction in microbial richness and phylogenetic diversity in the GC group, and beta diversity analysis revealed distinct community clustering. Taxonomic profiling showed Firmicutes and Bacteroidota as the dominant phyla, with a significantly altered Firmicutes/Bacteroidota (F/B) ratio in the GC group. LEfSe analysis identified 31 differentially abundant taxa between the groups. Functional profiling revealed 28 KEGG Level 3 pathways enriched in both groups. Pathways related to cell growth and motility were more abundant in the GP group, while the GC was enriched in amino acid metabolism and membrane-associated processes. These findings suggest that dietary supplementation with plant-based concentrates modulates both the taxonomic structure and functional potential of the fecal microbiota in goats. Full article

This study evaluated the effects of Fibrafid, a plant-based functional feed additive, on growth performance, carcass traits, meat quality, and intestinal histomorphometry of broilers fed standard or moderately nutrient-reduced diets. A total of 432 one-day-old Ross 308 chicks (initial body weight, 44.9 ± 0.30 g) were randomly allocated to a 2 × 3 factorial arrangement comprising two dietary nutrient densities (standard or diets with 1.5% lower metabolizable energy and 5% lower digestible amino acid density) and three Fibrafid inclusion levels (0, 1.5, or 2.5 kg/ton). Each treatment comprised six replicates of 12 birds (six males and six females) and was evaluated from day 1 to 24. Dietary nutrient reduction affected growth performance and breast meat quality pH and ultimate lightness values, whereas Fibrafid supplementation, particularly at 2.5 kg/ton, improved overall gain by 5.3%, grower-phase feed conversion ratio by 4.0%, EPEF by 8.08%, relative thymus weight by 64.8%, while reducing abdominal fat deposition by 27.1% relative to the unsupplemented control (p < 0.05). Several breast meat quality traits were also improved, including greater water-holding capacity and myofibril fragmentation index and lower drip and cooking losses (p < 0.05). Jejunal morphology was enhanced, as indicated by increased villus dimensions and goblet cell density (p < 0.05). Significant Diet × Fibrafid interactions were observed for grower performance, EPEF, overall feed intake, and several intestinal morphological variables (p < 0.05). In conclusion, Fibrafid supplementation, particularly at 2.5 kg/ton, was associated with improved growth performance, EPEF, selected carcass and breast meat quality traits, and jejunal morphology during the first 24 days of age. These findings suggest that Fibrafid may be a promising natural feed additive for broiler diets formulated at standard or moderately reduced nutrient densities. However, further studies extending to market age and evaluating nutrient digestibility, intestinal microbiota, blood biochemical indices, and economic returns are warranted to clarify its mechanisms and practical value under commercial production conditions. Full article

Background: Non-group 1 pulmonary hypertension, also known as secondary pulmonary hypertension (SPH), is predominantly observed among females. However, there is a significant lack of data concerning factors associated with hospitalization among patients diagnosed with SPH. This study aims to provide clinicians with vital insights for the identification of high-risk groups and for the more effective management of contributory risk factors within the female population affected by SPH. Methods: Using the 2019 National Inpatient Sample, we identified female admissions with SPH (n = 648,190), accounting for 3.8% of the total 17,236,228 female admissions. An Artificial Neural Network (ANN) analysis was conducted to evaluate predictive factors. We randomly allocated 3,319,543 patients into training and testing datasets at a ratio of 70:30, comprising 2,323,696 (70%) for training and 995,847 (30%) for testing, to calibrate and validate the performance of the ANN algorithm. Model performance was assessed by comparing misclassification rates between training and testing sets and by the area under the receiver operating characteristic curve (AUC); only internal validation was performed. Results: Females hospitalized with SPH were generally of older age, with a median of 75 years compared to 58 years, and more frequently identified as White (67.7% versus 65.5%) or Black (20.5% versus 15.5%) relative to those without SPH. They also demonstrated a higher prevalence of most atherosclerotic cardiovascular disease (ASCVD) risk factors or their equivalents, including complicated hypertension (50.6% versus 17.8%), diabetes with chronic complications (30.6% versus 13.7%), and hyperlipidemia (50.8% versus 29.2%), as well as other comorbidities such as COPD (43.4% versus 20.2%) and CKD (43.3% versus 14.0%), and exhibited increased all-cause mortality (4.5% versus 1.8%) (p < 0.001). Our ANN model achieved an AUC of 0.823, indicating good predictive capability. The rates of incorrect predictions were comparable in both the testing and training cohorts, at 3.8% each. The factors most strongly associated with a coded SPH diagnosis included age at admission, complicated hypertension, chronic kidney disease, chronic obstructive pulmonary disease, uncomplicated hypertension, prior VTE, race, arthropathies, and AIDS. Conclusions: Our ANN model identified demographic and comorbidity factors associated with a coded SPH diagnosis among hospitalized females, with good discrimination (AUC = 0.823). Because the model classifies the presence of an existing diagnosis rather than predicting future hospitalization, and was validated only internally, external and prospective validation is required before clinical application. Once validated, these factors could support individualized, sex-specific risk stratification for high-risk female populations, consistent with the goals of personalized medicine. Full article

Background/Objectives: Perinatal asphyxia (PA) is a major cause of neonatal mortality and morbidity both in the short and in the long term. The identification of novel reliable biomarkers is essential in order to improve early diagnosis and allow for accurate prognostication of short- and long-term outcomes. The aim of the current study was to identify serum metabolites substantially affected by PA and resuscitation, using an experimental model in neonate piglets. Methods: A prospective, randomized experimental pilot animal study was conducted in 33 neonate Landrace/Large White female piglets, 1–4 days old. Following initial preparation and stabilization, the animals were allocated to three groups. Group A served as the control group while Group B and Group C piglets underwent asphyxia until severe bradycardia or hypotension occurred. Group C animals were subsequently resuscitated, and after return of spontaneous circulation (ROSC), they were stabilized and remained under further monitoring for 30 min. Blood samples for metabolic profiling were obtained at predefined timepoints as defined below. “Baseline” samples were taken from all animals after the initial stabilization; “asphyxia” sampling was performed at the time of hemodynamic compromise, while “final” sampling was performed 1 h after baseline in Group A animals and 30 min post-ROSC in Group C animals. The serum samples obtained were further analyzed using nuclear magnetic resonance (NMR) spectroscopy. Results: Distinct metabolic phenotypes were observed between the “baseline” state and asphyxia. Post-resuscitation and post-ROSC, the metabolic phenotype appeared to partially shift back to the “baseline” cluster but remained distinct from both of the other groups. The results were further processed using a structured biomarker discovery pipeline. Key metabolites that were found to significantly differentiate “baseline” and “asphyxia” states were lactate, succinate, lysine, fumarate, hypoxanthine and isoleucine (decrease) (p < 0.001). As far as the “baseline” against stabilization post-ROSC comparison is concerned, lactate, lysine, fumarate, hypoxanthine, succinate, acetate, alanine, glutamine, glutamate and choline differed significantly (p < 0.001). No metabolite survived False Discovery Rate correction and reached statistical significance in the direct “Asphyxia” versus “Resuscitation” comparison. Conclusions: This pilot study demonstrates that severe asphyxia in neonatal piglets is associated with a distinct serum metabolic signature, and several abnormalities remain detectable 30 min after ROSC, suggesting incomplete early metabolic recovery. The findings support the candidacy of lactate, succinate, fumarate, hypoxanthine and related metabolites for further assessment and validation as markers of acute hypoxic injury. Further investigation focused on these metabolites could also contribute to the elucidation of the involved pathophysiological mechanisms of PA and the development of novel therapeutic approaches. Full article

Introduction: In polytrauma patients, effective triaging and resource allocation are critical in managing haemorrhage. This study aimed to analyse the association of haematocrit and haemoglobin with early death within 72 h in polytrauma patients stratified by sex. A sample of 3059 polytrauma patients was analysed using SPSS and the Watson Trauma Pathway Explorer up to 48 h after admission. Methods: A retrospective cohort of 3059 polytrauma patients (ISS ≥ 16) admitted 1996–2022 was analysed. Haemoglobin and haematocrit were measured at admission and serially through 48 h. Receiver operating characteristic (ROC) analysis assessed discriminatory performance for early death within 72 h. Multivariable logistic regression adjusted for injury severity, age, physiological status, and resuscitation volumes. Results: Significant sex-based differences in haemoglobin and haematocrit were observed at all time points (p < 0.05) in univariable analysis; haemoglobin and haematocrit showed significant associations with mortality in males at multiple time points (admission, 1 h, 3 h, 12 h, 24 h) and in females at admission and 1 h. After multivariable adjustment, haematocrit and haemoglobin for males at 2 h remained significant. Discriminatory performance was poor across all time points: in males, haemoglobin AUC ranged from 0.51 (95% CI 0.33–0.68) at admission to 0.59 (95% CI 0.43–0.75) at 48 h; in females, from 0.44 (95% CI 0.16–0.72) at 1 h to 0.68 (95% CI 0.44–0.93) at 3 h. Females exhibited a higher mortality in the early hours and at 8 h after admission. Mortality thresholds were lower in females than males at 1 h,3 h, 6 h, 24 h and 48 h for haematocrit and at 1 h, 2 h, 3 h and 8 h for haemoglobin, with the lowest value at 2 h for haemoglobin (females: 7.55 g/dL, males: 8.5 g/dL) and 1 h for haematocrit in females. Conclusions: While crude comparisons demonstrated sex-specific temporal patterns in haemoglobin and haematocrit between survivors and non-survivors, these associations did not remain statistically significant after multivariable adjustment and Benjamini-Hochberg correction for multiple testing (all FDR-adjusted p ≥ 0.200). Associations were substantially confounded by resuscitation practices. Discriminatory performance was poor across all time points (AUC 0.44–0.68). These findings should be considered hypothesis-generating and require prospective validation in cohorts with standardised resuscitation protocols before clinical implementation. Full article

Medication-related osteonecrosis of the jaws (MRONJ) remains a challenging complication associated with antiresorptive therapy, highlighting the need for effective adjunctive preventive strategies. This study evaluated the effects of systemic ozone therapy, alone or combined with topical 10% metronidazole paste or 2% chlorhexidine gel, on alveolar repair in a zoledronate-induced rat model of MRONJ. Forty-two ovariectomized female Wistar rats were allocated into seven experimental groups. Following mandibular first molar extraction, animals received systemic ozone therapy and/or topical antimicrobial treatment according to the experimental protocol. Clinical, histomorphometric, micro-computed tomography (micro-CT), Picrosirius Red, and immunohistochemical analyses were performed. Zoledronate treatment markedly impaired alveolar repair, resulting in reduced new bone formation, increased non-vital bone, epithelial disorganization, and unfavorable bone microarchitecture. Systemic ozone therapy significantly increased new bone formation and improved bone microstructural parameters compared with untreated zoledronate animals. Ozone-treated groups also exhibited more organized collagen fibers and increased VEGF and osteocalcin immunostaining. Topical metronidazole and chlorhexidine were associated with favorable tissue repair findings, while combined therapies showed more favorable outcomes than zoledronate treatment alone. These findings suggest that systemic ozone therapy, particularly when associated with topical antimicrobial treatments, improves alveolar repair and represents a promising adjunctive strategy for preventing MRONJ. Full article

The clinical use of doxorubicin (DOX), an effective chemotherapeutic drug for breast cancer, is limited by off-target nephrotoxicity, which is exacerbated in elderly patients. While excessive mitochondrial fission is known to contribute to DOX-induced cardiotoxicity, its role in DOX-induced nephrotoxicity, particularly in the context of renal aging, remains unclear. To explore this and investigate the therapeutic potential of the mitochondrial fission inhibitor Mdivi-1, female Wistar rats with D-galactose-induced accelerated renal aging were allocated into four groups: vehicle, DOX, DOX+Mdivi-1 co-treatment, and DOX+Mdivi-1 post-treatment. DOX administration resulted in significant renal dysfunction, oxidative stress, inflammation, and histopathological damage. Mitochondrial dysfunction along with the increased expression of fission protein, decreased fusion proteins, and activation of apoptotic markers and PINK1 expression were also evident. Remarkably, both co-treatment and post-treatment with Mdivi-1 comparably and significantly attenuated DOX-induced renal damage. This study suggests that Mdivi-1 mitigates DOX-induced nephrotoxicity in the aged kidney by modulating mitochondrial dynamics, suppressing oxidative stress and inflammation, and inhibiting apoptosis. These findings highlight mitochondrial fission as a promising therapeutic target for the treatment of doxorubicin toxicity and provide further support for the possible use of Mdivi-1 as a therapeutic strategy to protect the kidneys of elderly breast cancer patients undergoing chemotherapy. Full article

Attention-deficit/hyperactivity disorder (ADHD) is traditionally defined by symptoms of inattention, hyperactivity, and impulsivity. However, growing evidence suggests that this framework incompletely reflects the underlying neurobiology and clinical heterogeneity of the disorder, particularly in females. Current models of dopaminergic neurotransmission propose that ADHD is characterized not by simple dopamine deficiency but by dysregulation of tonic and phasic dopamine signaling. Theoretical models propose that reduced tonic dopamine activity may coexist with enhanced stimulus-dependent phasic responses in ADHD. Whether such signaling differences produce alternating states of underactivation and hyperactivation within the same individual has not been directly demonstrated and constitutes a central hypothesis of the present framework. In this narrative hypothesis paper, I examine evidence linking dopaminergic dysregulation to a broader ADHD phenotype encompassing four functional domains: energy regulation, attention allocation, behavioral activation, and emotional reactivity and awareness. Within these domains, hyperactivity and hypoactivity, inattention and hyperfocus, impulsive responding and difficulty initiating action, and emotional hyperreactivity and alexithymia are treated as potentially related manifestations rather than established psychometric opposites. Neuroimaging studies report alterations in dopamine transporter and receptor availability, while clinical and behavioral studies document associations between ADHD and different, sometimes contrasting manifestations within the proposed domains. Importantly, internally experienced manifestations such as emotional dysregulation, hypoactivity, procrastination, and hyperfocus appear particularly relevant to female presentations of ADHD. I propose that ADHD should be conceptualized as a multidimensional disorder of dopaminergic regulation. This framework may better explain phenotypic diversity, improve identification of underrecognized presentations, and guide future biomarker-driven and precision-medicine approaches to ADHD. Full article