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Scleromyxedema is a rare, chronic cutaneous mucinosis defined histopathologically by a triad of dermal mucin deposition, fibroblast proliferation, and dermal fibrosis. However, additional underrecognized histopathologic patterns or findings may complicate diagnosis and lead to misclassification. A retrospective review of 22 biopsy-confirmed cases of scleromyxedema was performed to characterize both classic and uncommon histopathologic variants of scleromyxedema, with emphasis on patterns that may obscure or mimic other dermatologic entities. All cases were evaluated for mucin, fibrosis, fibroblast proliferation, inflammatory infiltrates, granulomas, eosinophilic infiltration, and eccrine gland hyperplasia using hematoxylin and eosin and special stains, with immunohistochemistry as it was needed. Sixteen cases (72.7%) demonstrated the classic histologic triad. In contrast, 6 cases (27.3%) showed a granulomatous pattern characterized by interstitial collections of CD68+ histiocytes, multinucleated giant cells, sparse lymphocytes, and mucin, but lacked the full classical triad-posing a risk of misdiagnosis as granuloma annulare or other granulomatous dermatoses. Eosinophilic infiltrates were identified in 4 cases (18.2%), and eccrine gland hyperplasia in 2 cases (9.1%). Both findings coexisted with the classical triad and may mimic inflammatory or adnexal conditions. Scleromyxedema presents with broader histopathologic variability than classically recognized. The granulomatous pattern, which may lack the defining triad, can obscure diagnosis without clinical correlation. In contrast, eosinophilic infiltration and eccrine gland hyperplasia, though infrequent, typically coexist with classic features and should be recognized as part of the histologic spectrum. Awareness of these variants is essential to avoid misdiagnosis and ensure accurate clinicopathologic interpretation.

Acetaminophen (APAP) overdose is the leading cause of acute liver failure in Western countries. However, the inflammatory mechanisms underlying APAP-induced liver injury (AILI) remain obscure. Interleukin (IL)-19 exerts its function via binding to the IL-20 receptor complex (IL-20R1/IL-20R2). This study aims to investigate the role of IL-19 in AILI. Il19 deficient mice and myeloid cell-specific Il20r2 knockout mice were generated and subjected to AILI. Single-cell RNA sequencing (ScRNA-seq) was performed to analyze liver macrophage subsets. Il19 deficient mice displayed heightened susceptibility to AILI, which was accompanied by a distinct transcriptional profile with a pronounced increase in proinflammatory macrophage infiltration. Treatment with recombinant IL-19 markedly suppressed proinflammatory macrophage infiltration, mitigating AILI. ScRNA-Seq analysis revealed that Il20r2 deficiency in myeloid cells exacerbated AILI due to increased infiltration of S100A8/A9+ proinflammatory macrophages. Mechanistically, IL-19 downregulated CCAAT/ enhancer binding protein β (C/EBPβ) protein expression in macrophages by promoting its post-translational SUMOylation, which diminished the transcriptional control of proinflammatory genes that regulated S100A8/A9 expression, ultimately ameliorating AILI. IL-19 is a key determinant of limiting proinflammatory macrophage infiltration, thus ameliorating AILI in the early stage. Our study suggests that IL-19 may represent a potential target for treating AILI. IL-19, a member of the IL-10 family, exerts its function via binding to the IL-20 receptor complex (IL-20R1/IL-20R2); however, its exact functions and in-depth mechanisms in liver diseases remain poorly understood. In this study, we concluded that IL-19 protects against APAP-induced liver injury by limiting S100A8/A9+ proinflammatory macrophage infiltration as evidenced that Il19 knockout and myeloid cell-specific Il20r2 deficient mice were more susceptible to APAP hepatotoxicity, exhibiting a distinct transcriptional landscape characterized by an obviously elevated S100A8/A9+ proinflammatory macrophage infiltration. IL-19 may be a novel therapeutic anti-inflammatory cytokine via SUMOylating of C/EBPβ, playing a key role in limiting proinflammatory cell infiltration during acute liver injury.

Digital transformation in healthcare frequently underperforms because organizations treat it as technical installation rather than sociotechnical redesign, underinvesting in the human-centered psychological dimensions of change leadership among nursing managers. Prior research has predominantly employed linear, variable-centered models that obscure conditional interdependencies among leadership, commitment, and innovation constructs, leaving the network architecture through which these factors jointly configure transformation readiness largely unmapped. To examine the network structure linking digital leadership, commitment to change, and creative self-efficacy among Chinese nursing managers and identify intervention leverage points for human-centered digital transformation. Hospitals across multiple Chinese provinces. Cross-sectional network analysis of 2764 nursing managers using validated instruments. Network analysis was selected over conventional regression-based approaches for its capacity to model simultaneous conditional dependencies without imposing a priori directional assumptions. Gaussian graphical models with regularized partial correlations identified conditional dependencies. Centrality metrics and bridge analysis determined node importance and cross-domain connections. Bootstrap procedures assessed stability and parameter accuracy. Affective commitment exhibited highest expected influence and was identified as the principal psychological bridge linking leadership to innovation. Continuance commitment showed negative expected influence, suggesting an association with inhibitory network patterns. Positive attitude and track record demonstrated strongest bridge connections from leadership to commitment domains, surpassing technical competencies. Network stability analyses confirmed robust interpretability. Human-centered digital transformation effectiveness appears associated with cultivating authentic affective commitment rather than compliance-driven engagement. Organizations should prioritize emotion-focused leadership development, eliminate coercive change strategies, and select champions based on optimistic orientation and credible success records as approaches that may support innovation capacity.

Mate selection has important fitness implications and thus has been a prominent focus across the evolutionary social sciences. However, despite ample evidence that human mate selection is uniquely shaped by others, existing research allocates outsized attention to individual preferences. Here, we take stock of the implications of arranged marriage, highlighting measurement issues that obscure continua of parental influence and likely drive inconsistency in the downstream literature. Focusing on parent-offspring conflict over spouse selection, we find (i) culturally widespread evidence of conflicting preferences, but limited evidence that conflict impacts realized spouse selection, (ii) parental approval predicts marriage outcomes more so than parental control, and (iii) that key predictions about socioecological variation in the form and consequences of conflict remain largely untested. We conclude that a more satisfying account of human mating will require refined measurement of its social embeddedness, greater focus on conflict negotiation, and continued cross-cultural research.

Diagnosing necrotizing soft tissue infection (NSTI) in the emergency department remains challenging and is primarily a clinical diagnosis despite the availability of decision tools and advanced imaging. In patients with Hidradenitis Suppurativa (HS), baseline skin changes, prior surgical interventions and disrupted tissue planes may obscure early findings, while presentations can mimic less severe conditions such as cellulitis, abscess, or an HS flare. We present the case of a 28-year-old man with HS on adalimumab who presented with left axillary pain and swelling at a prior HS site. He was tachycardic but afebrile with localized erythema on initial examination. On repeat evaluation 50  minutes later, the erythema had rapidly extended along the lateral thoracoabdominal wall, raising concern for NSTI. The patient underwent emergent operative exploration, which revealed copious purulent fluid with disruption of fascial plans and nonviable tissue, consistent with NSTI. His postoperative course was prolonged, requiring surgical intensive care, and he was discharged to subacute rehabilitation on hospital day 25. NSTI in patients with HS may present with subtle or nonspecific findings, and underlying disease-related changes may obscure early diagnosis. These cases require a high index of suspicion, frequent reassessment, and early surgical intervention to optimize outcomes.

Internationally educated nurses are increasingly central to healthcare systems facing persistent workforce shortages, ageing populations, and rising care demands. Yet research continues to show that migration and workforce entry are often accompanied by significant disruption to professional practice. Although these experiences are commonly described through the language of deskilling, post-migration skill change is still often framed as a linear process of adaptation and eventual professional equivalence. In this discursive paper, I argue that linear accounts of post-migration skill adjustment are analytically limited because they obscure how host healthcare systems shape what counts as legitimate nursing competence. I propose instead that deskilling, upskilling, unskilling, and mis-skilling should be understood as overlapping and sometimes contradictory outcomes of how these systems regulate, recognize, and reorganize nursing labor. Drawing on nursing workforce scholarship, professional regulation literature, migration studies, and the sociology of work, I reframe skill disruption as a structural effect of skill governance, shaped by risk management, selective recognition, and the preservation of professional hierarchies. A conceptual model of skill governance is presented to show how prior expertise is filtered through regulatory and organizational processes, producing uneven forms of professional incorporation. This reframing has implications for workforce policy, regulatory practice, and nursing leadership by shifting attention from individual adaptation to system accountability and more equitable forms of workforce integration.

Despite extensive research on adherence in first-episode psychosis (FEP), reliance on self-report or clinician judgment has limited accuracy and obscured nuanced clinical associations. This longitudinal study examined the predictive value of psychopathology, insight, and functioning for objectively measured treatment adherence across a one-year follow-up using therapeutic drug monitoring (TDM). Seventy-eight FEP patients were assessed at baseline, 2 months, and 12 months. Clinical measures included the Brief Psychiatric Rating Scale (BPRS), Scale for the Assessment of Negative Symptoms (SANS), Social and Occupational Functioning Assessment Scale (SOFAS), and the Schedule for the Assessment of Insight-Expanded version (SAI-E). Adherence was defined by comparing plasma antipsychotic concentrations to prescribed doses according to international consensus guidelines. Generalized linear mixed models (GLMMs) were used to model time-dependent associations. While overall adherence declined, time alone was not a significant predictor. Instead, current positive symptom severity (approximately 4-5% lower odds of adherence per BPRS point) was associated with lower odds of adherence, while prior non-adherence predicted subsequent adherence. In contrast, insight, negative symptoms, and functioning showed no consistent association with adherence. A marginal association between improved functioning and better adherence was observed at 12 months. Adherence in FEP appears to fluctuate in relation to current clinical state rather than follow a stable linear pattern. These findings highlight the value of objective TDM monitoring and early intervention, supporting predictive models that incorporate evolving symptom patterns rather than static baseline measures. Clinical trial number: not applicable.

Ultrasound beamforming plays a crucial role in the formation of an ultrasound image. The conventional delay-and-sum (DAS) method is efficient but susceptible to acoustic clutter which obscures imaging. While many clutter reduction techniques have emerged, recent efforts increasingly use deep neural network (DNN) beamformers trained on simulated data, which offers convenient access to ground truth. However, the domain gap between simulated training data and in vivo test data undermines model performance. Recent domain-adaptive work proposed to bridge the gap with a CycleGAN style-transfer map, but the limitation of the map and the source of domain mismatch remains poorly understood. This work seeks to identify the contribution of reverberation and phase aberration to the domain mismatch by selectively introducing them in simulation. We used KL divergence and Wasserstein-2 distance to quantify domain shift and validated their use with the downstream beamformer performance. Using the Wasserstein-2 distance between simulation data with no reverberation and phase aberration and in vivo data as reference, we showed that including aberration and reverberation in simulation reduced the domain gap by 7.4% and 45%, respectively. The domain gap was reduced by 53% when both sources of image degradation were included in simulation, and reduced by 64% with the use of CycleGAN maps. We further demonstrated that CycleGAN efficacy is dependent on source distribution and revealed that best beamformer results were achieved when reverberation and phase aberration were both present in simulation.

Plant organs are shed through a tightly regulated process called abscission, which involves coordinated changes that enable cell separation and formation of a new protective barrier. However, the cellular processes within the abscission zone, where plant organs detach, are largely understudied. This gap is mainly due to difficulties in visualizing this region, due to its small size and location often being obscured by other plant tissues. Here, we present a simple and accessible method to visualize changes in cell shape and lignification in the abscission zone of Arabidopsis thaliana floral organs. Cell walls are stained with calcofluor white and lignin is simultaneously detected using its intrinsic autofluorescence. This inexpensive approach allows clear imaging of cellular changes during abscission zone development and can be applied to mutants with abscission-related defects.

We introduce a framework for analysing topological tipping in time evolutionary point clouds by extending the recently proposed topological optimal transport (TpOT) distance. While TpOT unifies geometrical, homological and higher-order relations into one metric, its global scalar distance can obscure transient, localized structural reorganizations during dynamic phase transitions. To overcome this limitation, we present a hierarchical dynamic evaluation framework driven by a novel topological and hypergraph reconstruction strategy. Instead of directly interpolating abstract network parameters, our method interpolates the underlying spatial geometry and rigorously re-computes the valid topological structures, ensuring physical fidelity. Along this geodesic, we introduce a set of multi-scale indicators: macroscopic metrics (topological distortion and persistence entropy) to capture global shifts, and a novel mesoscopic dual-perspective hypergraph entropy (node-perspective and edge-perspective) to detect highly sensitive, asynchronous local rewirings. We further propagate the cycle-level entropy change onto individual vertices to form a point-level topological field. Extensive evaluations of physical dynamical systems (Rayleigh-van der Pol limit cycles, double-well cluster fusion), high-dimensional biological aggregation (D'Orsogna model) and longitudinal stroke fMRI data demonstrate the utility of combining transport-based alignment with multi-scale entropy diagnostics for dynamic topological analysis. This article is part of the theme issue 'Critical transitions and intelligent control in complex systems'.

Zoonotic tuberculosis (zTB) remains a blind spot in TB control, sustained less by biological rarity than by diagnostic and surveillance design. Brazil illustrates this gap: despite endemic bovine TB and sustained zoonotic transmission risks, zTB is rarely identified because it is not actively targeted. We show that only two human zTB cases were notified between 2013 and 2024 following introduction of reporting, and six cases are described in the literature. Further detection of mono-pyrazinamide resistance may represent undiagnosed zTB, but diagnostic gaps prevent estimation. By outlining current diagnostic paths, we argue that the human-centric diagnostics obscures occupational, foodborne, and animal-linked infection. Emerging subnational One Health initiatives demonstrate that integrated animal-human surveillance is feasible. Therefore, we propose a risk-based, One Health diagnostic protocol for zTB within the Brazilian public health system, and argue that without structural and policy adaptation, human-TB elimination strategies will continue to exclude zTB by design, not only in Brazil.

Health technology assessment (HTA) bodies are increasingly asked to consider the personal utility of genomic testing: the informational, practical and psychosocial value of results beyond direct changes in clinical management. Yet treating all non-clinical benefits as normatively equivalent risks obscures the distributive task of publicly funded HTA, while refusing to consider them at all ignores forms of value that may bear on rights, equity and system design. This article offers a decision-structuring framework that distinguishes between discretionary personal utility and justice-based personal utility. The framework is expressly residual: where a benefit can already be captured through conventional HTA domains, such as health-related quality of life, avoided downstream costs, caregiver effects or standard clinical utility, it should be counted there rather than relabelled as personal utility. I then identify a third category, derivative value, for constructs such as hope value and option value whose realisation depends on future scientific, institutional or policy contingencies external to the patient. The framework does not supply an algorithm for reimbursement. Instead, it clarifies burden of justification, guards against double-counting and helps HTA bodies separate patient-indexed claims from broader public-value arguments. Applied to diagnostic genomic testing for childhood hearing impairment, the framework shows how some commonly invoked benefits are better treated as discretionary, others as justice-relevant and others as requiring separate policy justification. I conclude with practical steps that analysts and policy leaders can adopt now: residual-domain mapping, non-duplication checks, structured scenario analyses and deliberative documentation of contested classifications.

Macrophages dynamically reprogram their metabolic states in response to environmental stimuli, thereby exerting distinct immune functions. In our preliminary study, a gut microbiota-derived metabolite, 3-hydroxypropionic acid (3-HPA), is increased in chronic inflammation and generates cysteine carboxyethylated neoantigens. However, the role of such metabolite-induced modification in regulating the function of macrophages remains obscure. Here, we show that 3-HPA alleviates inflammation in a mouse model of sepsis and inhibits the macrophage inflammatory response. Mechanistically, 3-HPA induces glyceraldehyde-3-phosphate dehydrogenase (GAPDH) carboxyethylation, which promotes GAPDH degradation via the ubiquitin-proteasome pathway, thereby suppressing its enzymatic activity and expression to inhibit glycolysis. Concomitantly, reduced GAPDH activity elevates the NAD+/NADH ratio, which enhances mitochondrial oxidation by upregulating arginine biosynthesis and the TCA cycle pathway. Overall, our research reveals the mechanism by which GAPDH carboxyethylation mediates metabolic reprogramming and regulates inflammation during inflammatory macrophage activation.

A subaortic anomalous left brachiocephalic (innominate) vein is a rare systemic venous anomaly. Although usually asymptomatic, when it traverses the aortopulmonary window it may obscure the operative field and increase the risk of vascular injury during left upper mediastinal procedures, including station 4 L lymph node dissection and exposure or control of the left pulmonary artery. A man in his seventies presented with a 4.2-cm solid mass in the left upper lobe (S3b) and an enlarged station 4L lymph node. Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) of station 4L demonstrated carcinoma consistent with non-small cell lung cancer (NSCLC). Given resectable single-station N2 disease and pre-existing interstitial lung disease with a usual interstitial pneumonia (UIP) pattern, a surgery-first strategy was selected. Preoperative contrast-enhanced computed tomography (CT) with three-dimensional reconstruction demonstrated an anomalous left brachiocephalic vein coursing along the left lateral side of the aortic arch and then beneath the aortic arch, superior to the left pulmonary artery, and crossing the aortopulmonary window before draining into the superior vena cava (Takada pattern b/c). Video-assisted thoracoscopic left upper lobectomy with systematic mediastinal lymph node dissection was performed. Early identification of the left vagus nerve enabled safe proximal tracing to the left recurrent laryngeal nerve. En bloc dissection of the station 4L and station 5 lymph node regions and left pulmonary artery management were completed without neural or vascular injury. The ductus arteriosus ligament (DL) could not be identified intraoperatively, suggesting a retroductal course (Takada pattern c). Preoperative identification of a subaortic anomalous left brachiocephalic vein on contrast-enhanced computed tomography (CT) with three-dimensional (3D) reconstruction, together with early identification of the vagus and recurrent laryngeal nerves and careful pulmonary artery management after establishing a safe dissection plane, may facilitate safe dissection in the aortopulmonary window and help prevent neural or vascular injury.

Viruses such as coronaviruses or filoviruses use their surface glycoproteins (GPs) to attach to the host cell, triggering the fusion of the viral membrane with the endosome membrane. Epitopes on the viral GP are major targets for antibody-mediated recognition and neutralization. During the fusion process, the GP undergoes conformational changes triggered by fluctuations in environmental pH. Structural states are typically classified into three distinct conformations: prefusion, intermediate, and postfusion. These conformations serve as essential templates for prediction of conformational epitopes and structure-based vaccine design. Despite their importance, many viral GP structures remain absent from the Protein Data Bank (PDB). Fortunately, recent breakthroughs in computational structure prediction have greatly enhanced the accuracy and accessibility of protein modeling. In this study, we utilized AlphaFold2-Multimer (AF2-M), version 2.3, to predict various GP structural conformations and observed that the overall frequency of predictions in the postfusion conformation is low. Therefore, we hypothesized that adapting the AF2-M protocol is necessary to enrich for specific conformations, thereby enabling the prediction of both pre- and postfusion conformations. AF2-M requires only the input sequence and internally generates multiple sequence alignments (MSAs) and optional templates before applying its pretrained model weights. We tested the use of template data to enrich pre- or postfusion conformations and demonstrated that our approach significantly increases the prediction frequency of class I fusion protein structures in both conformations, with the template dataset playing a crucial role in guiding modeling towards the intended state. Furthermore, we showed that the lack of correlation between pLDDT and TM-scores suggests that low pLDDT values may obscure the presence of valid alternative conformations.

This study investigates the determinants of vulnerable road user (VRU) crash severity by accounting for unobserved heterogeneity both across and within crash subpopulations. Conventional single-model approaches assume homogeneous effects across all crashes, potentially masking context-dependent severity mechanisms. Crash data for 15,578 pedestrian and 11,433 bicyclist collisions occurring at or near intersections in 20 California cities (2016-2025) were extracted from the Statewide Integrated Traffic Records System (SWITRS). A two-stage analytical framework was employed. First, latent class analysis identified three distinct crash typologies for each VRU mode based on movement patterns, lighting, weather, and collision factors. Second, mixed logit (MXL) models were estimated for each latent class to capture within-cluster heterogeneity through random parameters. Pseudo-elasticity analysis quantified the practical magnitude of variable effects. Temporal stability was assessed by estimating separate models across pre-COVID, during-COVID, and post-COVID periods. Truck involvement, dark conditions without streetlights, and state highway location consistently elevated severe outcome odds across all clusters for both VRU types, while VRU age 65+ shifted injury distributions toward moderate rather than the most severe outcomes. Critically, several factors exhibited context-dependent effects. VRU fault increased severity when drivers traveled straight, but decreased severity in turning-driver crashes for bicyclists, indicating fundamentally different causal mechanisms. State highway effects ranged from the strongest fatal predictor in straight-driver pedestrian crashes to non-significant in other configurations. Different random parameters were identified across clusters, confirming that unobserved heterogeneity operates through distinct mechanisms in different crash contexts. Crash severity determinants are both universally important and context-dependent, with the same variable capable of opposing effects across crash configurations. These findings demonstrate that aggregate models pooling heterogeneous crash types obscure critical variation and support the adoption of context-sensitive approaches to crash modeling.

Visualization of mineralized tissues such as tooth and bone in ground sections is widely used for histological studies. However, unstained ground sections often provide limited contrast and obscure microscopic details. Natural plant-based stains have been explored as cost-effective and safer alternatives to synthetic dyes. Terminalia chebula, rich in tannins and polyphenolic compounds, has shown potential staining affinity for hard tissues. The aim of this study is to evaluate the staining efficacy of T. chebula on ground sections of tooth and bone by comparing stained and unstained sections, and to assess contrast, structural detail, and observer acceptance under stereomicroscope and compound microscope. Forty extracted normal teeth and 40 bone samples from human skulls were prepared into thin ground sections (~50&#x2009;&#x3bc;m). Each section was initially observed unstained (Group 2) and then stained with T. chebula extract for 4&#x2009;h (Group 1). Photomicrographs were taken under both microscopes and evaluated by blinded oral pathologists and students for contrast, structural detail, and acceptance using standardized grading and scoring systems. T. chebula staining significantly improved contrast in tooth sections under both stereomicroscope and compound microscope (p < 0.001). Enhanced visualization of enamel rods, dentinal tubules, and cementum was observed. Bone sections demonstrated improvement in contrast under stereomicroscopy; however, under compound microscopy, unstained bone sections showed relatively higher Grade 1 contrast. Improvements in structural detail were more pronounced in tooth sections than bone sections. Observer acceptance was significantly higher for stained tooth sections (p < 0.001), whereas moderate but significant improvement was noted for bone sections. T. chebula stain enhances contrast and improves visualization of microstructural features in tooth ground sections, supporting its potential as an effective and economical adjunct for teaching and research in dental histology. Further studies are required to optimize staining protocols and to evaluate its broader applicability, particularly in bone specimens.

Many clinical trials of metastatic non-small cell lung cancer (mNSCLC) include a composite endpoint of cough, chest pain and dyspnea to assess patient-reported symptomatic deterioration using time-to-confirmed deterioration (TTCD) analyses. We sought to determine the robustness of this composite, and whether composites involving other patient-relevant symptoms of mNSCLC are more sensitive to progression. Data from nine mNSCLC trials with the EORTC QLQ-C30 and QLQ-LC13 were pooled. Spearman's correlation coefficients were used to assess associations between symptoms. Composites were evaluated based on the number of confirmed deterioration (CD) events, median TTCD, and positive predictive value (PPV) against progression-free survival (PFS). 5,157 patients with mNSCLC with at least one PRO assessment were included. Cough and dyspnea were frequently reported at baseline (79.8% and 67.8%, respectively) and moderately correlated (0.37), while chest pain was less common (41.5%) and showed weaker associations. The composite of cough, chest pain, and dyspnea had a median TTCD of 8 three-week treatment cycles and PPV of 78.3%. Composites including symptoms such as fatigue and general pain reached median TTCD earlier while maintaining high PPVs (78.3-81.3%). The median TTCD for single-item dyspnea was 50 cycles but was not reached for cough and chest pain. The composite of cough, chest pain, and dyspnea displayed strong properties; however, composites obscure the time course of included symptoms. Although median TTCD is reached earlier with a composite endpoint, greater clarity is obtained when symptoms are studied individually.

Antipsychotic medications are recommended for schizophrenia spectrum disorders, yet their long-term effects on functional recovery remain unclear, with conflicting evidence often derived from between-subject comparisons vulnerable to confounding by indication. We conducted a nationwide register-based cohort study of 65,630 individuals with incident schizophrenia spectrum disorders in Denmark (1998-2023). We modeled antipsychotic exposure against 'productive engagement' (employment or education). We used two analytical approaches: (1) within-subject stratified Cox models with time-varying covariates to eliminate time-invariant confounding; and (2) Fine-Gray competing risks models with baseline exposure, accounting for mortality and emigration. Over 26.9 million person-weeks, the overall productive engagement rate was 48.2%. Integration of hospital pharmacy data revealed 6.1% exposure misclassification in studies relying solely on community records. The primary within-subject analysis revealed significant temporal heterogeneity: medication use was associated with reduced engagement rates in the acute (0-2&#xa0;years; HR = 0.908) and consolidation phases (2-5&#xa0;years; HR = 0.946), but reversed to a small positive association in the maintenance phase (5+ years; HR = 1.019). The between-subject Fine-Gray model, which estimates cumulative engagement probabilities, yielded an SHR of 1.002 (95% CI = 0.988-1.015), a population-level average that obscured these phase-specific dynamics. Antipsychotic pharmacotherapy exerts a time-dependent, biphasic impact on vocational recovery. We identified a window of vulnerability during the post-acute 'consolidation' phase (years 2-5) where treatment is associated with a transient reduction in productive engagement, before becoming protective after 5 years. These findings challenge the assumption that symptomatic stability automatically facilitates functional reintegration.