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Current understanding of how multiple stressors shape freshwater biodiversity at continental scales relies heavily on evidence from postindustrial temperate regions, potentially misrepresenting the dynamics of ecosystems facing rapid development and extreme environmental heterogeneity. Here, we present a standardized, continental-scale field survey of benthic macroinvertebrates across 502 sites in China to test the universality of established macroecological patterns. Contrary to the expectation that physical habitat and climatic gradients primarily drive community structure, we found that organic pollution, with a focus on oxygen-demand assays (COD and BOD), emerged as the single most influential variable, explaining the largest proportion of variation in taxonomic, functional, and phylogenetic diversity. Together with total nitrogen and total phosphorus loading, this chemical pressure largely overrode the explanatory contribution of land-use and climatic drivers, with stressor interactions characterized by asymmetric dominance rather than the synergistic amplification commonly predicted. Furthermore, despite steep environmental gradients that theoretically favor deterministic sorting, community assembly was overwhelmingly dominated by stochastic processes ( ∼ $$ \sim $$ 86%, based on overall pairwise comparisons across all sites). We suggest this pattern is consistent with a "stochastic trap" hypothesis, potentially arising from high-frequency anthropogenic disturbances that weaken trait-environment matching. These findings indicate that biodiversity frameworks derived from stabilized, temperate systems may not generalize to the compressed modernity of developing regions. We propose that global conservation strategies should consider prioritizing the reduction of chemical bottlenecks, which may act as critical physiological constraints on freshwater resilience in the Anthropocene.
Savoring has been identified as a promising strategy to foster emotional and psychological well-being and to reduce depression in elders. However, research on online savoring interventions for this population remains limited. This registered RCT aimed to examine the effectiveness of a 3-week online intervention (six activities), Savor-Aging, in promoting subjective and psychological well-being and reducing depressive symptoms. Seventy-six healthy older adults (M = 69.9, SD = 4.8) were randomly assigned to a savoring group or a positive emotion (PE) group. Life satisfaction, positive and negative affect, flourishing, and depression were assessed at baseline (T0), post-intervention (T1), and 1-month follow-up (T2) to test psychological changes. Longitudinal quantitative data were analyzed using linear mixed-effects models, whereas qualitative feedback was thematically analyzed. Significant overall time effects emerged for negative affect and depressive symptoms. Although most time × group interactions were not significant, the savoring condition showed more consistent improvements over time, including reductions in negative affect and depressive symptoms that were maintained at follow-up. Significant time effects emerged for flourishing only in the savoring group immediately after the intervention. Participants described the savoring intervention as pleasant, engaging, and meaningful. Overall, Savor-Aging appears to be a feasible and effective self-help intervention to support emotional well-being and reduce depression in older adults, offering an accessible approach to positive aging.
The central catecholamine systems, norepinephrine and dopamine, play a critical role in encoding the valence of environmental stimuli to promote engagement in behaviors that potentiate an organism's survival. Furthermore, both neurochemicals in limbic brain areas such as the nucleus accumbens (NAc) and bed nucleus of the stria terminalis (BNST) are major targets of stimulant drugs. Canonically, limbic norepinephrine signaling is enhanced in the presence of aversive or noxious stimuli whereas dopamine transmission is generally considered to increase in response to appetitive or rewarding stimuli. However, it remains to be elucidated whether sex differences, especially at different stages of the estrous cycle, distinctly regulate catecholamine transmission in vivo. In this study we (i) identified estrous cycle-dependent changes in catecholamine regulation via their transporters and autoreceptors in the BNST and NAc of anesthetized rats and (ii) determined how the psychostimulant methamphetamine (METH) impacts norepinephrine and dopamine transmission in the BNST and NAc, respectively, in male and freely cycling female rats using in vivo fast-scan cyclic voltammetry. Our results demonstrate electrically evoked BNST norepinephrine levels are increased by METH the greatest during the non-estrus (diestrus/proestrus) stages while NAc dopamine release evoked by electrical stimulation and METH is heightened in estrus. This limbic norepinephrine and dopamine regulation suggests a critical role of estrous cycle stage on catecholamine dynamics. These findings offer new insights into the role of estrous cycle stage on how the brain encodes environmental stimuli and provide a new framework for sex-specific therapies for targeting the central catecholamine systems in health and disease ranging from drug use disorders to obesity.
The Locus of Control short scale (IE-4) is a screening instrument for locus of control (LOC). Assessment of LOC is highly relevant within psychological research and social sciences. The aim of the current study was to evaluate the screening tool in a large representative sample, with special focus on its dimensionality and the presence of acquiescence bias. The current sample (N = 2522; Age: M = 48.50 years (SD = 17.75); 50.1% female) was representative for the German adult population with respect to gender, age, and education. After conducting a CFA including an uncorrelated method factor, model fit indices generally indicated a good fit. Additionally, we found evidence of good reliability. Results from this study suggest that the IE-4 is best considered as a unifactorial measure when accounting for acquiescence bias.
A positive benefit - risk profile is a prerequisite for the market approval of medical devices. However, regulations are often criticized for providing limited information on benefit‒risk assessment (BRA) despite growing expectations for quantitative methods. A clearer understanding of regulatory requirements, existing methodologies, and unresolved issues is needed. Relevant regulatory documents referencing BRA for medical devices were systematically identified, with a primary focus on the European regulation followed by screening to extract BRA‑related requirements and any explicitly or implicitly described methods. The findings were analyzed and consolidated by BRA context, type, objective, methodological description, and implementation, thereby establishing a basis for the BRA methodological landscape. BRA is not a single concept, but a set of context‑dependent assessments across lifecycle of a medical device. BRA within clinical evaluation framed into BRAs of risk management holds a pivotal role and is supported by the most detailed methodological guidance, although BRAs in other contexts are important. A structured overview of existing BRA requirements clarifies their treatment across regulatory documents. By differentiating BRA contexts, types, objectives, and required methodological detail, the analysis supports a more transparent understanding of BRA and helps identify priorities for methodological refinement and interface clarification. This review examines how the benefits and risks of medical devices are assessed through, a process called benefit – risk assessment (BRA). A positive benefit – risk profile is essential for regulatory approval of medical devices, but current guidances are often unclear, inconsistent, or generic. BRA is applied at many stages of a device’s lifecycle, including design and manufacture, risk management, clinical evaluation, and post-market monitoring; however, the methods used can vary depending on the context, assessment objectives, device type, and available evidence. Moreover, the methods are interrelated in various ways.The review finds that BRA is primarily placed in the context of clinical evaluation, within the framework of risk management BRAs. This complext of BRAs represents core BRA according to ISO 14971:2020. Outside of this context, BRA approaches are often poorly described, leaving manufacturers and regulators uncertain about when and how to assess different types of devices, especially those with indirect benefits.However, several regulatory guidance documents, such as the SCHEER and FDA documents or the AFNOR XP S99-223 standard, provide useful examples of context-specific BRA approaches with substantial levels of detail supporting practical implementation. The AFNOR XP S99-223 standard offers the most structured approach to BRA in the context of clinical evaluation, including life-cycle management; however, it primarily addresses devices with direct clinical benefits and does not cover all relevant device types or data sources.Overall, the review highlights the need for clearer, harmonized, and context-specific BRA methodologies that consider assessment objectives, device type, available evidence, and life-cycle stage. Implementing such approaches will improve transparency, consistency, and decision-making, helping manufacturers and regulators ensure that medical devices are safe, effective, and beneficial for patients.
Hydroxyurea (HU) is the most widely prescribed disease-modifying treatment in sickle cell disease (SCD), though treatment responses vary due to metabolism and adherence. We examined HU blood levels and treatment response in patients with homozygous sickle cell disease (HbSS). We measured HU in whole blood of 955 SCD patients enrolled in GenoMed4All using mass spectrometry. HU detection was defined as Z-score > 2.5 relative to untreated healthy controls. Among HbSS patients not receiving recent transfusion therapy (n = 539), HU was detected in 39% (143/369) of HU-prescribed patients ≥ 10 years (median age 31.8 [10.0-69.9]). In only 24% (23/109) of young patients (< 10 years, median age 5.9 [1.2-9.9]), HU was detected, despite comparable HU dosing (18.8 vs. 20.3 mg/kg/day). Detectable HU was associated with increased MCV (p < 0.001), and in patients ≥ 10 years also with increased HbF, despite low HbF (< 10%) in 25%. Neutropenia occurred in 8.0% of patients with detectable HU, 4.5% with undetected HU. Only one patient had severe neutropenia (< 0.5 × 10e9/l). In young patients, neutropenia occurred in 1.4% with undetected HU, and in 8.7% with detected HU. This is the largest study to date that reports data on HU levels in HbSS patients. Most HU-prescribed patients, particularly young patients, had undetectable HU levels. Low MCV, HbF, and absent toxicity in children and limited toxicity in adults suggest that treatment for patients with undetectable HU is suboptimal. These findings warrant the need to optimize dosing and adherence to improve treatment in SCD, especially in young patients.
A force field interpolation method for generating initial guesses for transition state optimizations is presented. The user supplies reactants and products as SMILES strings (or XYZ coordinates), after which automatically constructed force fields are interpolated to approximate the potential energy surface (PES) along the reaction coordinate. The transition state guess is obtained by sampling along this approximate PES. Reliance on force fields ensures the method is transparent in its workings and computationally inexpensive. The workflow is implemented in VeloxChem, enabling Jupyter notebook execution with a few lines of Python code. An interactive widget makes visualization and inspection of results easy and intuitive, and a flexible Python API facilitates integration into complex automated workflows. The method is demonstrated on ten chemically diverse systems, including a transition-metal catalytic cycle. Benchmarking across 121 reactions resulted in convergence for 115 transition states, with an average cost of 107 gradient evaluations per reaction-comparable to more demanding double-ended methods.
Non-geniculate coralline genus Harveylithon includes 12 species worldwide. In this study, we propose three new species, Ha. koreanum sp. nov., Ha. longiforme sp. nov., and Ha. planiforme sp. nov., based on integrative molecular and morphological analyses. These three new species share the diagnostic morphological characters of Harveylithon, including a monomerous, non-coaxial thallus construction with perithallial cells oriented perpendicularly to the surface; a hypothallial layer composed of rectangular cells aligned parallel to the substratum; and the presence of trichocytes occurring singly, in pairs, or in clusters. Our phylogenetic analyses of a concatenated four-gene data set (COI + rbcL + psbA + SSU rRNA) clearly resolved the three new species within Harveylithon, each forming a well-supported and distinct lineage. The topologies of the individual-gene phylogenies based on the psbA and the SSU rRNA genes were largely congruent and supported these relationships, whereas phylogenetic trees based on the rbcL and COI genes did not recover Harveylithon as monophyletic, with Dawsoniolithon species nested within the Harveylithon clade. Interspecific sequence divergences between new species and their congeners were 6.3%-13.7% for the COI gene, 0.8%-9.8% for the psbA gene, and 1.8%-14.6% for the rbcL gene. Harveylithon koreanum sp. nov. and Ha. planiforme sp. nov. are currently known from only Jeju Island in Korea, whereas Ha. longiforme sp. nov. was identified from both Jeju Island, Korea, and India, indicating that it may have a broad Indo-Pacific distribution. In addition, we newly generated the psbA gene sequence from the generitype, Ha. rupestre (TRH A3-149) and incorporated it into our molecular data set to stabilize the phylogenetic circumscription of the genus.
The YouthViolence surveys were conducted to retrospectively map young Norwegians' (age 16-19 years) exposure to violence and abuse, both within their families and in their peer relations. The aim was to provide high-quality data for victimisation research and policy development and for monitoring and evaluating prevention work. This study design article outlines the relevance of the YouthViolence study and its characteristics. Data were obtained from three repeated cross-sectional surveys conducted in 2007 (N = 7,103), 2015 (N = 4,530) and 2023 (N = 16,081) with national samples of Norwegian senior high school students. The first two surveys included students in their final year of senior high school, while the 2023 survey sampled students from all three senior high school levels. A subsample of the 2007 participants (n = 3,319) was followed longitudinally until 2021 (age 32-33 years) based on linked survey-administrative data. The YouthViolence survey findings provide important knowledge on topics such as direct and indirect parental violence, physical and digital sexual violence, and polyvictimisation, as well as on procedures for mapping violence and abuse among youth and have led to the publication of over 25 scientific papers. The study also provides extensive knowledge inputs for governmental whitepapers and strategies on the prevention and handling of violence and abuse and to non-governmental organisations that offer victim support. The YouthViolence survey findings and their wide applicability in knowledge and policy development highlight the importance of continuously and systematically mapping young people's exposure to violence and abuse.
The aim of this study was to compare cardiorespiratory responses during high-intensity land-based exercise between free-breathing and breath-holding conditions in swimmers. Twenty varsity swimmers (20 ± 2 years, 10 females) performed 20 s bouts of simultaneous arm and leg ergometry exercise at high intensity (total power output = 606 ± 76 W). Heart rate (HR), muscle deoxygenation ([HHb]) and total hemoglobin ([THb]) at the triceps and vastus lateralis, and gas exchange and ventilatory variables were recorded continuously. Blood pressure and lactate were measured pre- and post-exercise. Exercise HR was higher under the breath-holding condition (free-breathing [FB] = 118 ± 14 bpm, breath-holding [BH] = 131 ± 17 bpm; p = 0.001) as were post-exercise blood pressures (systolic: FB = 141 ± 14 mmHg, BH = 156 ± 16 mmHg, p = 0.002; diastolic: FB = 71 ± 14 mmHg, BH = 79 ± 9 mmHg; p = 0.01, respectively). During exercise, muscle [THb] was higher under the breath-holding condition (FB = -1.6 ± 2.7 μM, BH = -0.3 ± 1.6 μM; p = 0.01). No between-condition differences in post-exercise blood lactate (FB = 8.8 ± 1.8 mmol.L-1, BH = 9.2 ± 3.9 mmol.L-1; p = 0.63) or [HHb] (FB = 2.9 ± 2.6 μM, BH = 3.4 ± 2.2 μM; p = 0.39) were observed. These data suggest that the exercise response prevailed over the breath-holding response during high-intensity land-based exercise in swimmers and that intrinsic oxygen stores may have been sufficient to sustain the aerobic energy contribution during 20 s high-intensity exercise while breath holding.
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Sesame (Sesamum indicum L., 2n = 26) is one of the oldest oilseed crops and is often called the 'queen of oilseeds' due to its high content of unsaturated fatty acids and natural antioxidants. Despite its long history, the origin and global spread of cultivated sesame remain unresolved. We assembled a telomere-to-telomere (T2T), high-quality reference genome of sesame (cv. Yuzhi11) to investigate sequence differences between genomes and its origin and the local adaptation evolution of flowering time (DF). We generated a 305 Mb T2T sesame reference genome (cv. Yuzhi11) with > 99.99% base-level accuracy, identifying 31 063 protein-coding genes. Repetitive elements accounted for 52.03% of the genome. Population genomic analysis of 927 accessions from 14 regions identified four major groups. Integrative analyses of linkage disequilibrium decay (LD), nucleotide diversity (π), and fixation index (FST) support East Africa as the center of origin, with subsequent migration through the Middle East, to South Asia, South-East Asia, East Asia and ultimately to other parts of the world. Genome-wide association studies (GWAS) and selection scans identified 30 genes associated with flowering time. SiUBP16 is a candidate associated with 7.6% of DF variation. Early-flowering accessions carried up to 225 favourable alleles. A flowering time prediction model for high-latitude regions achieved 96% accuracy. We present a high-quality T2T reference genome for cultivated sesame, shedding light on its origin, evolutionary history, and regional flowering time adaptation. This genome insights valuable tools for breeding programs aimed at improving yield and environmental adaptation in sesame and related crops.
This study aimed to develop and externally validate machine learning-based models for predicting macrosomia and spontaneous preterm birth (sPTB) using multidimensional clinical data. This retrospective cohort study included 14 238 pregnant women who received prenatal care between 2018 and 2023. Demographic characteristics, laboratory parameters, and delivery outcomes were integrated, with Least Absolute Shrinkage and Selection Operator regression used for feature selection. Predictive models were developed using logistic regression and machine learning algorithms (Light Gradient Boosting Machine, Adaptive Boosting, and gradient boosting decision tree), and performance was evaluated using the area under the curve (AUC), Brier score, decision curve analysis, and external validation results. Key predictors of macrosomia included pre-pregnancy body mass index, 1-h postprandial glucose, maternal education level, and comorbidities. The logistic regression model for macrosomia achieved an AUC of 0.742 (95% CI: 0.617-0.866) in external validation. For sPTB, significant predictors were comorbidities, aspartate aminotransferase, and uric acid, with the logistic regression model yielding an AUC of 0.706 (95% CI: 0.587-0.824) in external validation. Both models showed good calibration, with Brier scores of 0.182 (macrosomia) and 0.192 (sPTB). The predictive models effectively identify pregnancies at high risk of macrosomia and sPTB, facilitating early identification and targeted intervention. External validation highlights the need for prospective, multicenter studies in diverse populations to enhance generalizability.
Traditional anatomical resources like cadaveric dissection and professional atlases are the gold standard, but face constraints in cost and accessibility. The rapid integration of generative artificial intelligence (AI) in medical education offers new possibilities for custom anatomical illustration. Text-to-image AI generators provide an inexpensive and swift alternative for medical illustration. However, the anatomical fidelity and educational reliability of these models remain insufficiently validated. This study aimed to evaluate the accuracy of four prominent AI image generators in producing anatomically correct illustrations of the human heart, kidney, and brain. Four AI platforms-Copilot, Microsoft Designer, Gemini, and Freepik-were prompted to generate high-resolution, textbook-style illustrations of the heart (sternocostal view), kidney (coronal cross-section), and brain (lateral view). A total of 12 selected images were evaluated by a radiologist and two anatomists utilizing a structured 5-point Likert scale across five domains: textural realism, topological validity, morphometric accuracy, perspective and depth perception, and educational utility. Significant variability in performance was observed across platforms. Gemini consistently demonstrated superior performance, achieving perfect intraclass correlation coefficients (ICCs) and the highest ratings on complex topological tasks, including the representation of coronary vasculature and cortical sulci/gyri. Copilot showed high spatial accuracy in renal hilum organization. While all platforms showed high reliability and accuracy across broad morphological shapes (aortic arch, cerebral poles), accuracy declined sharply as anatomical complexity increased. AI-generated anatomical illustrations currently vary from medically indistinguishable to biologically impossible. While Gemini and Copilot show promise for supplemental educational use, the high frequency of hallucinated anatomical details in other platforms poses a risk for medical misinformation. The study underscores the necessity for expert supervision and for developing AI models trained on curated, peer-reviewed medical datasets.
This study aimed to explore psychological distress (PD) patterns in pregnant women with recurrent pregnancy loss (RPL) during early pregnancy and to examine the association between sleep characteristics and these patterns. A total of 203 pregnant women with RPL were recruited between October 2022 and April 2023 at the study hospital. The patients' PD was assessed using the Patient Health Questionnaire-9 and the Generalized Anxiety Disorder 7-Item Questionnaire. The Pittsburgh Sleep Quality Index (PSQI) was employed to measure the sleep conditions. Latent profile analysis and multivariable logistic regression were used to identify the patterns of PD in RPL women and connections between their sleep characteristics and these identified patterns. Three PD patterns were identified in participants, including "mild PD" (57.15%), "moderate PD" (36.45%), and "severe PD" (6.40%). Subjective sleep quality, sleep disturbance, sleep efficiency, diurnal dysfunction, and PSQI score in patients varied significantly among the different PD patterns (p < 0.05). Compared with "mild PD," poor subjective sleep quality (Moderate: aOR= 2.76, 95%CI 1.37-5.56; Severe: aOR= 7.19, 95%CI 1.99-25.98) and diurnal dysfunction (Moderate: aOR= 3.1, 95%CI 1.62-5.97; Severe: aOR= 25.16, 95%CI 5.57-113.61) were significantly associated with "moderate" or "severe" PD. Addtionally, low sleep efficiency markedly increased the risk of "severe PD" (aOR= 28.76, 95%CI 1.09-759.02). This study identified three distinct patterns of PD (mild, moderate, and severe) among women with RPL during early pregnancy. Specific sleep characteristics, including poor subjective sleep quality, diurnal dysfunction, and low sleep efficiency, were significantly associated with moderate/severe PD.
The Finnish Ayrshire cattle belong to the Nordic Red breeds. The basis of selection in Nordic Red breeds shifted from traditional pedigree-based breeding values to genomic breeding values between 2011 and 2014. Joint genetic evaluation and admixture among the Nordic Red breeds have led to the formation of a composite Nordic Red population; consequently, contemporary Finnish Ayrshire represents an admixed population. We identified recent selection signatures in the Finnish Ayrshire genome using two complementary approaches: the Hudson estimator of Wright's fixation index (FST) and generation proxy selection mapping (GPSM). Hudson FST quantifies population-differentiation between groups, whereas GPSM detects selection signatures within a single population by regressing birth year on SNP genotypes. The aim of this study was to identify temporal allele frequency changes in SNPs consistent with selection during the genomic era and to evaluate their associations with milk production and fertility traits in Finnish Ayrshire. Genotypes were available for 64,160 cows across 46,914 SNPs, and phenotypic data on milk production and fertility traits were available for 49,417 genotyped individuals. Based on Hudson FST, 56 SNPs showed genetic differentiation between cows selected using pedigree-based and genomic information. In addition, 54 SNPs exhibited temporal allele frequency changes consistent with selection according to GPSM. Overall, 11 SNPs were identified by both methods. Of the 54 SNPs, thirteen were associated with the interval from first to last insemination in Finnish Ayrshire heifers. These results suggest that a substantial proportion of SNPs exhibiting temporal allele frequency changes during genomic selection are associated with heifer fertility.
Traumatic brain injury (TBI) is one of the leading causes of mortality and disability worldwide, with secondary injury recognized as a critical therapeutic target. Quercetin (QR), a natural flavonoid, exerts antioxidant and anti-inflammatory effects by modulating the Nrf2-Keap1 pathway and shows neuroprotective potential in various neurological disorders. In this study, network pharmacology analysis identified 496 overlapping targets of QR and TBI, further highlighting the pivotal role of the Nrf2-Keap1 pathway in TBI treatment. However, the poor blood-brain barrier (BBB) permeability and low bioavailability of QR hinder effective brain-targeted delivery and limit its clinical translation. To address these challenges, we developed CAQK peptide-modified, reactive oxygen species (ROS)-responsive nanoparticles (C-PPS/Q), using PPS120 as the core for targeted QR delivery. C-PPS/Q exhibited ROS-triggered QR release, significantly enhanced HT22 cell uptake in vitro, reduced ROS levels and apoptosis. In a TBI mouse model, C-PPS/Q specifically accumulated at the lesion site, prolonged the half-life of QR, demonstrated excellent biocompatibility, preserved BBB integrity, attenuated neuroinflammation, inhibited aberrant Nrf2-Keap1 pathway activation, and markedly improved neurological function. Collectively, C-PPS/Q nanoparticles effectively mitigate secondary brain injury after TBI and represent a promising brain-targeted therapeutic strategy for TBI management.
International statements suggest using the Global Leadership Initiative on Malnutrition (GLIM) criteria in intensive care units (ICUs); however, the economic impact of GLIM-defined malnutrition in sepsis remains unclear. This study investigated the association between GLIM-defined malnutrition and in-hospital costs in sepsis. We conducted a sub-analysis of the prospective cohort study, Investing Long-term Outcomes of Sepsis or Septic shock, among medically managed critically ill patients with sepsis in 15 Japanese ICUs. Associations between GLIM-defined malnutrition and cost categories (low, moderate, and high) were assessed using multinomial logistic regression (reference: low-cost group), adjusted for age, sex, Charlson Comorbidity Index, and Sequential Organ Failure Assessment score. Individual GLIM components were also examined. Total in-hospital costs and secondary outcomes were compared between malnutrition and non-malnutrition groups using inverse probability of treatment weighting. Among 259 patients, 111 had GLIM-defined malnutrition. GLIM-defined malnutrition was associated with both the moderate-cost (adjusted odds ratio [AOR]: 2.03, 95% confidence interval [CI]: 1.05-3.89) and high-cost classifications (AOR: 2.27, 95% CI: 1.20-4.29). Among GLIM components, reduced muscle mass (AOR: 1.95, 95% CI: 1.04-3.68) and reduced food intake (AOR: 2.61, 95% CI: 1.39-4.92) were associated with the high-cost classification. After weighting, the malnutrition group had significantly higher median in-hospital costs (24,959 vs. 18,651 USD), longer hospital stays, and longer ICU stays than the non-malnutrition group. GLIM-defined malnutrition-particularly reduced muscle mass and reduced food intake-was associated with higher in-hospital costs in sepsis and may be a potential indicator of high-cost hospitalization.
The complexity of the treatment of borderline personality disorder (BPD) is largely due to its heterogeneity. The aim of this study is to identify empirically derived patterns of co-occurring personality traits in individuals with primary BPD and to examine their clinical correlates. Millon's personality traits (MCMI-IV) of 97 BPD patients were assessed and a cluster analysis of these traits was performed. Patients were evaluated on different clinical dimensions of BPD and compared between the different clusters found. Three trait-pattern clusters were obtained. Pattern 1 showed higher scores for borderline, histrionic, narcissistic and antisocial traits. Pattern 2 had higher scores for borderline, dependent and avoidant traits. Pattern 3 had lower levels of all the traits. Patients in patterns 1 and 2 showed greater scores on anxious-depressive scales. Pattern 1 also showed greater scores for anger expression. Pattern 3 patients were characterized for receiving more pharmacological treatment. Findings provide evidence for three patterns of co-occurring traits within BPD, consistent with dimensional conceptualizations and longstanding categorical overlap. These patterns align with externalizing-leaning, internalizing-leaning, and attenuated configurations and may help generate hypotheses for early characterization and treatment personalization.
Drug discovery remains constrained by high attrition rates and the fragmented evaluation of exposure, efficacy, and safety. Mechanistic models offer a biologically grounded framework for connecting these determinants across multiple levels of biological organization. This may help improve translational decision-making by supporting earlier and more integrated assessment of candidate progression. This narrative review examines the conceptual basis and current role of next-generation mechanistic models in drug discovery, with emphasis on physiologically based pharmacokinetic models, virtual cell-based assays, quantitative systems pharmacology, artificial intelligence (AI)-augmented mechanistic models, and emerging virtual-cell frameworks. It highlights how these approaches may connect efficacy and safety across biological scales, support in vitro-to-in vivo extrapolation, incorporate in silico predictions, and improve candidate prioritization. The literature was surveyed through PubMed searches conducted up to 25 May 2026. Next-generation mechanistic models are unlikely to transform drug discovery simply by increasing biological detail or computational sophistication. Progress in this direction will depend on standardized data streams, robust validation, explicit model calibration, reproducibility, tighter integration between models, and careful alignment between model design and context of use. Under these conditions, mechanistic frameworks may become important components of a more predictive and less attrition-prone drug discovery pipeline.