Parton distribution functions (PDFs) play a central role in describing experimental data at colliders and provide insight into the structure of nucleons. As the LHC enters an era of high-precision measurements, a robust PDF determination with a reliable uncertainty quantification has become mandatory in order to match the experimental precision. The NNPDF collaboration has pioneered the use of machine learning (ML) techniques for PDF determinations, using neural networks (NNs) to parametrise the unknown PDFs in a flexible and unbiased way. The NNs are then trained on experimental data by means of stochastic gradient descent algorithms. The statistical robustness of the results is validated by extensive closure tests using synthetic data. In this work, we develop a theoretical framework based on the neural tangent kernel (NTK) to analyse the training dynamics of neural networks. This approach allows us to derive, under precise assumptions, an analytical description of the neural network evolution during training, enabling a quantitative understanding of the training process. Having an analytical handle on the training dynamics allows us to clarify the role of the NN architecture and the impact of the experimental data in a transparent way. Similarly, we are able to describe the evolution of the covariance of the NN output during training, providing a quantitative description of how uncertainties are propagated from the data to the fitted function. Interestingly, the methodology developed in this work can be used to understand the minimization of a loss function for any kind of parametrization, thereby providing a unified framework to compare different PDF determinations, like, e.g., fits based on a particular functional form. While our results are not a substitute for PDF fitting, they do provide a powerful diagnostic tool to assess the robustness of current fitting methodologies. Beyond its relevance for particle physics phenomenology, our analysis of PDF determinations provides a testbed to apply theoretical ideas about the learning process developed in the ML community. As seen in applications from other domains, we find that our results deviate from the simple picture of the lazy training regime discussed in the ML literature.
The transport properties of single-molecule junctions are fundamentally governed by the energy alignment of molecular frontier orbitals relative to the electrode Fermi level. Although charging-induced reorganization is known to significantly shift this alignment, precisely how these shifts give rise to distinct transport behaviors remains elusive. Here, we use combined scanning tunneling microscopy (STM) and non-contact atomic force microscopy (AFM) at 5.5 K to investigate individual copper phthalocyanine (CuPc) molecules on a bilayer NaCl film supported by Cu(100) substrate. We identified three distinct transport phenotypes on the same substrate-characterized by behaviors ranging from elastic tunneling and dynamic charging to stable charge trapping. These phenotypes depend mainly on the reorganized orbital energy of the singly occupied molecular orbital (SOMO) relative to the substrate Fermi energy. We find that when the SOMO lies close to the substrate Fermi level, the molecule enters a sensitive charge-trapping regime in which an energy shift of only ~100 meV can change the charged-state lifetime by several orders of magnitude. This result is well captured by a theoretical model. Furthermore, we demonstrate that a pentacene molecule-functionalized tip can switch the transport behaviors. Our findings reveal how atomic-scale dielectric disorder within the moiré superlattice amplifies subtle electronic inhomogeneities into discrete transport regimes, underscoring the extreme sensitivity of molecular conductance to orbital-level alignment near the charge trapping regime and to local environmental engineering.
: Growth hormone deficiency (GHD) can lead to significant growth and developmental issues, necessitating long-term treatment. Once-weekly somatrogon is a long-acting recombinant human growth hormone analogue, approved for treatment of children with GHD. : Assess the long-term safety and efficacy of somatrogon in children with GHD. : Open-label extension (OLE) study following an initial 12-month open-label phase 2 study. : Conducted at 14 centers across Hungary, Bulgaria, Belarus, Ukraine, Russia, Greece, and the US. : Fifty-three children with GHD (67.9% male, mean age 6.0±2.1 years) completed the phase 2 study and 48 entered the OLE. : Participants received once-weekly somatrogon for up to 9 years. : Safety endpoints included adverse events (AEs), antidrug antibodies (ADAs), local site injection reactions, and insulin-like growth factor-I SDS. Efficacy endpoints included annual height velocity (HV), change in height SDS, and annual bone maturation. Treatment-emergent AEs (TEAEs) incidence was 52.1% at OLE year (Y) 1, decreasing to 23.8% by Y9. Serious AEs were rare with only isolated cases reported. ADA positivity was observed, but no neutralizing antibodies were found. No correlation between ADA presence and TEAE incidence or severity was noted, nor was there a difference in growth based on ADA presence. Mean annualized HV remained > 5 cm/year, and height SDS improved from -4.0 at baseline to -0.2 by Y8. No changes in the ratio of bone age/chronological age were observed. Once-weekly somatrogon is a well-tolerated and a viable long-term treatment for GHD in children. More real-world data are needed. Clinicaltrials.gov: NCT01592500.
A strong correlation has been found between ferroptosis and various diseases, with iron overload being prominently implicated. However, few studies have specifically focused on triggering ferroptosis by directly eliciting iron overload via forming lipophilic iron complexes. Here, we show that the natural compound hinokitiol (HK) forms a stable, lipophilic 3:1 complex with Fe(III) (HK-Fe(III)), which rapidly enters HT-1080 cells via passive diffusion and delivers iron preferentially to the endoplasmic reticulum (ER). Notably, 10 μM HK-Fe(III) induces potent ferroptosis within 5 hours-substantially faster than classical inducers such as erastin, RSL3, and FINO2. Mechanistically, HK-Fe(III) specifically triggers ER peroxidation without significant involvement of mitochondria or lysosomes, and the ER-targeted antioxidant stobadine completely inhibits cell death. Enrichment of polyunsaturated fatty acids (PUFAs) in the ER enhanced the efficiency of HK-Fe(III)-induced ferroptosis by strengthening ER peroxidation, suggesting that ER peroxidation is a key factor in lipophilic iron complex-induced ferroptosis. HK-Fe(III) could also induce cognitive deficits and ferroptosis in hippocampal cells in mice, indicating its potential to establish animal models for neurodegenerative diseases through iron overload. This study identifies a unique ferroptosis mechanism based on ER-targeted iron delivery and ER peroxidation, and provides a rapid and potent inducer for studying ferroptosis in vitro and in vivo, with potential applications in disease modeling and therapy.
Cadmium (Cd(II), hereafter Cd) is a toxic heavy metal that has detrimental effects on the gut microbiota. We investigated the effects of acute Cd exposure on human fecal microbiotas using 24-h in vitro cultures from 20 healthy adult donors. Regression analysis of butyrate production in the absence (-Cd) versus presence (+Cd) of Cd identified three categories of microbial responses: sensitive, intermediate, and resilient. Under Cd stress, sensitive microbiomes exhibited significant decreases in butyrate, coupled with elevated acetate and lactate production, while resilient microbiomes did not show significant changes in butyrate and exhibited attenuated increases in lactate compared with sensitive microbiomes. Several genera differed significantly between sensitive and resilient communities after exposure to Cd, but the most striking difference was in Anaerostipes. Network analysis revealed a significantly greater disruption of microbial interactions in sensitive communities compared with resilient communities. In resilient communities, butyrate production was primarily associated with Faecalibacterium in the absence of Cd and Anaerostipes in the presence of Cd. Furthermore, supplementation of sensitive microbiotas with Anaerostipes species restored butyrate production in the presence of Cd. These findings highlight distinct gut microbial responses to acute Cd exposure and provide a foundation to investigate microbiota features underlying Cd sensitivity or resilience.IMPORTANCECadmium (Cd) is a widespread environmental contaminant that enters the human intestine, where it can disrupt the gut microbial community and negatively impact digestive and systemic health. However, this study demonstrates that human gut microbiomes vary in their responses to cadmium exposure: sensitive communities exhibit losses of beneficial organisms, particularly butyrate-producing taxa that contribute to intestinal integrity and metabolic balance, whereas resilient communities retain microorganisms with this key functional capacity. Anaerostipes appeared to be involved, at least in part, with Cd resilience. This work advances our understanding of how gut microbial functions may mitigate the adverse effects of cadmium exposure by identifying the compositional features that distinguish sensitive from resilient microbiomes. These findings highlight the importance of elucidating microbiome-mediated mechanisms that sustain host health and lay the groundwork for deeper mechanistic studies to mitigate cadmium toxicity.
When nanoparticles (NPs) enter biological environments, they are rapidly coated by biomolecules, forming the protein corona (PC) that defines their biological identity and dictates how NPs are recognized, distributed, and processed by living systems. Capturing the authentic features of the PC demands experimental conditions that preserve its native state, which are difficult to achieve once NPs are removed from their biological milieu. Despite significant progress, current PC quantification methods still rely on separating the NP-PC complex from its native environment, thereby compromising the corona's integrity and preventing accurate evaluation of its physicochemical properties. Here, we introduce a fractionation-free approach based on synchrotron small-angle X-ray scattering (SAXS) to quantitatively determine the amount of protein adsorbed onto silica NPs under native conditions. By modeling the scattering contribution of free versus bound proteins, we directly extracted the adsorbed mass in both single-protein (serum albumin) and complex proteomic (human serum) systems. The resulting adsorption isotherms enabled the determination of thermodynamic parameters, distinguishing between simple monolayer-like and more complex adsorption regimes. Together, these findings establish SAXS as a non-invasive and quantitative technique for probing the PC in situ without perturbing equilibrium, advancing SAXS toward quantitative PC characterization.
Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) are among the most well-known and prevalent neurodegenerative disorders. These diseases result from an interaction between the environment and genetically predisposed individuals. This review examines the evidence available in the literature underlying this multifaceted interaction, focusing on various chemical substances such as metals, fertilizers, and herbicides, as well as toxic agents of microbiological origin, including cyanobacteria and their neurotoxins. In addition, the pathways through which toxic substances can enter the human body are discussed, such as air and water, which may lead to absorption through the lungs, the gastrointestinal tract, the skin, and mucosae. The routes by which neurotoxic substances gain access to the human body may help explain the increased risk of developing neurodegenerative diseases observed in sports played on soil and grass surfaces, such as soccer, American football, and golf.
Brown trout (Salmo trutta) has adapted to a wide range of habitats and displays a variety of life-history strategies. Being facultatively anadromous, populations without migration barriers to the sea consist of both resident and anadromous individuals in different proportions. This affects genetic drift and the level of gene flow between populations, and therefore shapes the metapopulation structure. Here, utilizing genetic variation at 95 SNP markers, we describe the genetic structure and effective size of a brown trout population inhabiting the Fremstad catchment that supports both anadromous and freshwater resident life histories. Compared to other sea trout populations in the region, the Fremstad population is genetically divergent with a unique genetic signal. A weak and significant genetic structure was observed in the Fremstad catchment, and anadromous individuals were not assigned to a specific lake or stream. The effective population size of brown trout in the Fremstad catchment is large compared to the average annual entry of sea trout into the catchment; hence, a large proportion of non-anadromous spawners likely contribute to the population. Approximately 2% of sea trout entering the catchment were strays from other populations. Because of a large proportion of non-anadromous spawners, the proportion of strays into the overall spawning population is likely to be lower than observed among the sea trout, and contribute to the genetic divergence of the Fremstad population from other populations. This study adds to our understanding of the evolutionary drivers that affect the genetic structure of anadromous brown trout populations and demonstrates how small spawning streams can be evolutionarily important in supporting a large and genetically unique population.
Bromodomain-containing proteins serve as epigenetic regulators, where bromodomains recognize acetylated proteins and histones to drive changes in gene expression. Due to their regulatory role in gene expression, bromodomain-containing proteins have served as important targets for drug-discovery efforts, in particular the bromodomain and extra-terminal (BET) family proteins. The selective targeting of these proteins through both inhibition and targeted protein degradation has revealed diverse biological mechanisms. For BET bromodomain-containing proteins, we discuss the unique biological effects of selective inhibition and degradation for efficacy and clinical safety concerns for both BET inhibitors that have entered Phase III clinical trials and recent BET degrader clinical candidates. We also describe the current inhibitory and targeted protein degradation approaches of non-BET bromodomain-containing proteins. This review summarizes current approaches of bromodomain-targeting inhibition and degradation to provide insight on molecular mechanisms and updates the clinical progress of these modalities as the field awaits the approval of the first bromodomain-targeted therapeutic.
Managing marine pollution from expanded polystyrene (EPS) is a critical environmental challenge, yet reliable empirical data on the actual recovery burden are often lacking. This investigation addresses this gap by using primary field data from three comprehensive sampling cycles. Through a combined life cycle assessment and cost analysis, the environmental and economic impacts of remediation versus industrial prevention were compared. The results quantify the cost of inaction, showing that collection from hard-to-reach shores accounts for 99.5% of the total cost and 83% of CO2 emissions, with geographic dispersion and labour intensity as the main limiting factors. In contrast, mechanical processing is technologically mature and has low operating costs. The investigation also redefines sustainability metrics based on the waste's end use, valorizing recycled EPS as a substitute for natural mineral aggregates (sand). This approach turns the disadvantage of low density into an advantage, achieving a greater than 99% reduction in carbon footprint per cubic metre compared to mineral aggregates. The present article clearly highlights that collecting waste before entering the marine environment is essential. At the same time, converting marine EPS into a resource is viable, as the environmental benefits of preserving natural deposits offset the high recovery costs, supporting a practical circular economy strategy.
In an increasingly connected world a global One Health approach to the management of human, animal and ecosystem health will be critical to effective infectious disease responses. The emergence and rapid global spread of several emerging and re-emerging pathogens in the past decade has highlighted the need for rapid, sensitive and accurate diagnostics. Metagenomics, while commonly used for research purposes for almost two decades, entered the global spotlight during the COVID-19 pandemic. In this review we discuss the impacts that metagenomic studies have had on our understanding of origins, aetiology and ecology of infectious diseases within a One Health context. We also discuss the role of metagenomics in the future of diagnostics and disease surveillance, and outline the challenges and limitations of current metagenomic methods.
Instrumentation failure (IF) is a major complication after lumbar spondylectomy for spinal tumors, yet risk factors remain poorly defined. The present study aimed to determine the prevalence of IF and identify variables associated with IF and revision surgery using pooled individual patient data. A systematic review and individual patient data analysis were performed per PRISMA guidelines. PubMed, CDSR, and Epistemonikos were searched through January 2025, and additional patient-level data were obtained from prior series. Studies were included if they reported outcomes after lumbar spondylectomy for primary or metastatic tumors. Demographic, tumor, surgical, and (neo)adjuvant therapy variables were extracted. Statistical analyses included chi-square tests, t-tests, and Firth's penalized logistic regression. Variables with p < 0.1 on univariable analysis and considered clinically relevant were entered into a penalized multivariable model, with a sensitivity analysis incorporating estimated blood loss as a surrogate of operative burden. A total of 169 patients (mean age 40.7 ± 17.6 years) were included after screening. IF occurred in 14% (23/169) of patients, with 96% of those requiring revision. On univariable regression, risk factors for IF included combined approach (OR 4.72, p = 0.01), staged procedures (OR 5.51, p < 0.001), pelvic fixation (OR 5.17, p < 0.001), multilevel spondylectomy (OR 2.74, p = 0.036), longer operative time (OR 1.17 per hour, p = 0.001), and greater blood loss (OR 1.16 per liter, p = 0.034). On primary multivariable analysis incorporating clinically relevant variables, no variable retained statistical significance, although pelvic fixation demonstrated the strongest trend (OR 2.19, p = 0.12). On sensitivity analysis adjusting for operative burden, pelvic fixation was significantly associated with IF (OR 4.95, p = 0.043). Median time to IF was 27 months. IF after lumbar spondylectomy occurs in roughly one in seven patients and is associated with multiple markers of procedural complexity. Although no single independent predictor was identified in the primary multivariable analysis, pelvic fixation demonstrated the strongest association across models, likely reflecting the increased biomechanical demands of lumbosacral constructs. Careful planning, reinforcement strategies, and long-term follow-up are critical to mitigate failure risk.
Environmental contaminants and non-native species introductions negatively affect aquatic ecosystem conservation. Mercury (Hg) accumulates within food webs where it can biomagnify to toxic concentrations, which can be affected by altered trophic relationships from non-native species. This study examined Hg concentrations (n samples = 655) and stable carbon and nitrogen isotope (n = 746) compositions in native (n = 313) and non-native (n = 342) species among four river subbasins (Gunnison, Lower Green, Colorado-Dolores, and White-Yampa), in the Upper Colorado River Basin (UCRB) during 2016 and 2017 to inform the potential combined effects of Hg exposure and non-native species interactions on native fishes of conservation concern. We assessed Hg biomagnification at the fish assemblage level, compared concentrations to risk thresholds for fish and human health, and evaluated niche overlap among trophic levels across subbasins. The generalist-invertivores feeding guild had the lowest Hg concentrations (0.001-0.191 μg g-1 wet weight), and no individuals exceeded the U.S. Environmental Protection Agency aquatic life criterion (0.225 μg g-1). Piscivores had the highest concentrations (0.008-1.840 μg g-1), and 74% of individuals exceeded the criterion. Biomagnification across trophic levels was observed throughout the UCRB, yet varied by subbasin, with higher magnification factors in the Lower Green and White-Yampa subbasins which also had the highest proportion of non-native species. Stable isotope compositions revealed niche overlap among native and non-native species. Additionally, trophic position varied within species among the subbasins. The proliferation of non-native species has likely reshaped food webs and may have intensified the potential threat Hg poses to native fish recovery and conservation. This study documented increased Hg concentrations relative to past assessments, suggesting that continued monitoring could assist in evaluating trends in Hg accumulation. Particularly studies that focus on sources entering the food web, vectors for accumulation, and competitive interactions among native and non-native species.
Stuttering can significantly influence individuals' career trajectories through mechanisms such as role entrapment, occupational segregation, job dissatisfaction, and stigma-based discrimination. In professional contexts where verbal fluency is narrowly defined and highly valued, people who stutter (PWS) may face systemic barriers. This study examines how PWS experience, interpret, and negotiate the role of stuttering in recruitment processes, career choices, job roles and opportunities for advancement. An online survey and Interpretative Phenomenological Analysis (IPA) were used to examine responses from 45 Finnish-speaking adults who stutter and have work experience. Participants described restrictive workplace speech norms and expectations of fluency as key constraints that generated cognitive and emotional load. Many reported that stuttering had influenced their career pathways, including not entering preferred fields, although its perceived influence on occupational choices had lessened over time. Speaking-intensive tasks-such as phone work, presentations, and spontaneous verbal interaction-were identified as the most challenging. Fluent speakers were often perceived as gatekeepers who informally determined which roles were considered suitable for PWS, though some participants also self-restricted their job tasks. Experiences were highly situational, and a minority reported positive or empowering aspects of stuttering at work. The study concludes that discrimination often stems not from actual ability but from biased expectations and rigid norms surrounding fluent speech. These norms delay access to preferred professions and constrain career development. Promoting inclusion requires challenging dominant communication standards and recognizing diverse communicative competencies. Enhancing awareness and visibility of PWS in professional environments is essential for systemic change.
Gynecologic malignancies - principally cervical cancer (CC), endometrial carcinoma (EC), and ovarian cancer (OC) - have been managed with conventional modalities including surgery, radiotherapy, chemotherapy, targeted therapy, and immunotherapy, yielding modest overall outcomes. The scarcity of effective later-line options has fueled rapid advances in antibody-drug conjugate (ADC) research. Precision-targeted, highly potent ADCs hold the promise of improving outcomes for patients with gynecologic tumors. To date, multiple ADCs directed against antigens such as tissue factor (TF), human epidermal growth factor receptor 2 (HER2), trophoblast cell-surface antigen 2 (Trop2), and folate receptor alpha (FRα) have entered clinical trials or received regulatory approval for CC, EC, and OC. These agents have demonstrated superiority over conventional chemotherapy in patients with recurrent or metastatic disease, with particularly pronounced efficacy in populations exhibiting high target expression. Nevertheless, clinical translation remains challenged by response heterogeneity attributable to tumor heterogeneity, the emergence of resistance mechanisms, and class-specific adverse events including ocular toxicity, interstitial lung disease (ILD), hepatotoxicity, and peripheral neuropathy. Continued refinement of next-generation ADC platforms - encompassing bispecific ADCs, dual-payload ADCs, peptide-drug conjugates (PDCs), and radionuclide-conjugated drugs - is anticipated to overcome current limitations and deliver superior oncologic outcomes.
Artificial intelligence (AI) is increasingly entering professional practice, raising questions about how professionals interpret algorithmic authority, protect judgment autonomy, and negotiate human-AI boundaries. This systematic review uses music teachers as an instrumental case to examine AI-related psychological responses, cognitive appraisals, and professional decisions in a judgment-intensive and emotionally involved educational context. Following PRISMA 2020, 20 studies published from 2023 onwards were synthesized through thematic synthesis, directed content analysis, and higher-order evidence-to-theme mapping. MMAT 2018 was used for quality appraisal, with evidence-tiering applied to classify evidence strength. The synthesis identified four interrelated psychological-cognitive-professional decision pathways: professional boundaries and retention of judgment authority, learning-process regulation and critical engagement, adaptive co-creation and professional capacity reconstruction, and risk perception with bounded adoption. Across these pathways, music teachers did not simply accept or reject AI; rather, they selectively integrated AI by weighing technological convenience, pedagogical value, professional responsibility, and risks to student agency or cultural interpretation. A further synthesis showed that the depth and mode of AI adoption were jointly shaped by individual capability, organizational environment, and technological characteristics. The review suggests that AI training for music teachers should move beyond tool operation toward judgment-oriented preparation, including task-suitability evaluation, output review, critical-use pedagogy, and ethical guidance. For psychology-related professions, the findings should be treated as hypothesis-generating propositions rather than direct clinical recommendations, because psychological service contexts involve higher ethical responsibility, decision-making risk, and professional accountability.
Many diverse bacteria can enter non- or slow-growing states where they are transiently tolerant to antibiotics. Despite its medical importance, the genetic mechanisms underlying this 'persistence' remain largely unknown, especially for spontaneous (type II) persistence that arises during exponential growth. To address this challenge, here we combine genomic, transcriptomic, and lipidomic analysis to explore the persistence mechanisms. We first analyzed the genome of the high-persistence mutant Escherichia coli DS1 (hipQ) to identify candidate genes for the high-persistence phenotype. We then compared the gene expression profile of these isolated persisters to that of normally growing cells with RNA-Seq and found that the activation of stress response mechanisms is likely not important in the entrance into hipQ-driven spontaneous persistence during exponential growth. Transcriptomic results also suggest that modifications in the cell membrane are closely linked to persistence, as further corroborated by lipidomic profiles showing a higher level of unsaturated fatty acids in persisters compared to normally growing cells. Taken together, our results indicate that changing membrane composition is associated with persistence, and further our understanding of spontaneous persister cells from the DS1 (hipQ) context.
Sport is frequently positioned as a context for positive development. However, athletes may face unique risks for interpersonal violence in coach-athlete and authority-athlete relationships alongside adverse experiences outside of sporting contexts. Given that little quantitative research considers both sources of trauma in relation to athlete mental health, the current study was designed to explore how coach violence, authority violence, and adverse childhood experiences (ACEs) contribute to mental health symptomology. Drawing on attachment theory, athlete mental health is recognized to be shaped by both prior developmental adversity and ongoing relational dynamics within sport. To examine these connections, participants (N = 341, Mage = 21.72 years, SDage = 4.56, 80.4% female) were a mixture of current and former athletes, with the majority identifying as White women from a Western region of the United States. Robust multiple regression analyses highlighted that coach violence, authority violence, and ACEs were associated with depression, post-traumatic stress disorder (PTSD), and dissociation. Interactions between coach violence and ACEs were associated with anxiety, depression, and dissociation, while a three-way interaction among coach violence, authority violence, and ACEs was associated with PTSD. These findings support the view that athletes are not blank slates upon entering sport; instead, pre-existing trauma and histories may shape their vulnerability to further harm and influence how they respond to relational dynamics within the sport environment. Rather than viewing sport participation as uniformly protective, results underscore the need to consider how developmental histories and interpersonal dynamics jointly shape athlete well-being. By integrating developmental theory and trauma-informed principles, this research provides insights into how practitioners can recognize signs of trauma, minimize re-traumatization, and create emotionally safe environments to promote mental health and relational safety in sport.
Adolescent females with ADHD exhibit heightened vulnerability to hormonal fluctuations, yet the specific clinical pathways associated with their acute suicide risk remain unclear. This study investigated whether ADHD diagnosis relates to premenstrual "Interpersonal Anger" and examined its sequential linkage to suicidal ideation (SI) alongside general depression. This retrospective chart review analyzed 392 female psychiatric outpatients (mean age 15.3 years). Premenstrual symptoms were quantified using a validated retrospective scale. Depressive severity was evaluated using a modified QIDS-SR-J (excluding the SI item). Hierarchical linear and logistic regression analyses were conducted to determine the dynamic predictors of premenstrual distress and SI. ADHD was associated with a significantly higher prevalence of suspected premenstrual dysphoric disorder (22.1% vs. 13.3%; p = .039). Hierarchical linear regression revealed that ADHD diagnosis was a significant independent predictor of the premenstrual "Interpersonal Anger" factor score (β = 0.148, p = .002), even after rigorously controlling for baseline depression. In hierarchical logistic regression predicting the presence of active SI, premenstrual Interpersonal Anger emerged as a robust predictor when entered individually in Step 2 (OR = 1.096, 95% CI [1.046, 1.149], p < .001). However, upon entering baseline depressive severity in Step 3, general depression demonstrated an overwhelming association with SI (OR = 1.281, 95% CI [1.209, 1.357], p < .001), while the direct effect of Interpersonal Anger was fully attenuated (OR = 0.997, 95% CI [0.941, 1.057], p = .923). Perimenstrual suicidal risk in adolescent females with ADHD does not follow a simple, independent direct pathway; rather, its effect is statistically subsumed by overall depressive severity. The acute premenstrual anger-potentially linked to neurodevelopmental impulsivity-appears to be closely integrated into the broader framework of general depression, which ultimately drives the proximal risk of suicidal distress. Suicide prevention for neurodivergent adolescents warrants phase-aware screening and targeted interventions addressing premenstrual conflict within an integrated care framework.
Over the last decade, there has been a global emphasis on prioritising disparities in surgical care in low- and middle-income countries. The Three Delays Model, originally developed for maternal mortality, has been increasingly applied to surgical and injury populations, yet few studies have quantified delay predictors for emergency abdominal surgery in sub-Saharan Africa. This study aims to identify where the longest delays in accessing emergency laparotomy are, determine factors associated with delays and identify delays associated with mortality. We conducted a prospective observational study of 240 consecutive emergency laparotomy patients at a tertiary referral centre in Lusaka, Zambia (April 2024 to April 2025). Data were collected from patients or caregivers and medical record review by the research team during the postoperative phase of care using a questionnaire. Using the Three Delays Model, variables were collected for each of the following delays: (1) seeking care, (2) reaching care and (3) receiving care. The primary outcome was time spent in each delay. Multivariable linear regression on log₁₀-transformed delay times was used to identify predictors of the first and second delays across the full analytic cohort. Logistic regression assessed delays associated with in-hospital mortality. Among 240 patients, the median total time from symptom onset to emergency laparotomy was 34 hours. The longest delay occurred in the seeking care phase, with a median of 18.5 hours (IQR: 2-72 hours), followed by reaching care with a median of 7.5 hours (IQR: 3-29.5 hours) and receiving care with a median of 8 hours (IQR: 6-11 hours). On multivariable log10 linear regression, believing symptoms would resolve and being referred from another facility predicted prolonged first delay. Predictors of prolonged second delay included less urgent surgical indication, education status and referral status. There were 28 in-hospital deaths (11.7%). Time in the first delay was associated with mortality (OR 1.01, 95% CI 1.001 to 1.008, p=0.006). The longest delays to emergency laparotomy in Zambia occurred before patients entered the health system. Symptom misperception and referral from other facilities were the strongest modifiable predictors of delay.