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Immune checkpoint inhibitors (ICIs) are a standard treatment across cancers, yet most patients do not respond, and existing biomarkers generalize poorly across tumor types and therapies. Here we present COMPASS, a pan-cancer foundation model that predicts immunotherapy response from bulk tumor transcriptomes using a concept bottleneck transformer. COMPASS encodes gene expression through 44 biologically grounded immune concepts representing immune cell states, tumor-microenvironment interaction and signaling pathways. Trained on 10,184 tumors across 33 cancer types, COMPASS achieves better average performance than 22 methods across 16 clinical cohorts spanning seven cancers and six ICIs, improving accuracy by 8.5% and area under the precision-recall curve by 15.7% on average across cohorts. COMPASS generalizes to cancer types and treatments not represented during fine-tuning and may inform indication selection and patient stratification. In survival analyses, patients classified by COMPASS as responders had longer overall survival (hazard ratio&#x2009;=&#x2009;4.7, P&#x2009;<&#x2009;0.0001). Personalized response maps connect gene expression to immune concepts, identifying programs associated with response and resistance; in immune-inflamed non-responders, COMPASS highlights programs including TGF&#x3b2; signaling, endothelial exclusion, CD4+ T cell dysfunction and B cell deficiency. COMPASS predicts immunotherapy response and provides hypothesis-generating mechanistic insight for trial design and translational studies.

Background and ObjectiveAutonomic dysfunction may arise in chronic systemic diseases, including autoimmune connective tissue disorders. This study aimed to quantify autonomic symptom burden in patients with systemic lupus erythematosus (SLE) and systemic sclerosis (SSc), examine clinical correlates, and compare results with controls without autoimmune disease.MethodsThis cross-sectional study included 50 SLE patients, 50 SSc patients, and 35 controls. Clinical and demographic characteristics were collected during visits. Autonomic symptom burden was assessed using the Composite Autonomic Symptom Score-31 (COMPASS-31). COMPASS-31 total and subdomain scores were examined across groups and within disease groups according to clinical and serological variables. A post-hoc COMPASS-31 score >32.5 was used to define high autonomic symptom burden.ResultsMedian total COMPASS-31 scores differed across groups and were higher in both SLE and SSc than in controls (15.43 and 20.53 vs 9.03; p = 0.001). Compared with SLE, SSc had higher orthostatic and vasomotor symptom burden. Using COMPASS-31 > 32.5, high autonomic symptom burden was present in 7/50 (14%) SLE and 13/50 (26%) SSc patients, while none of the controls exceeded the cut-off. In multivariable models, serositis and joint involvement predicted high symptom burden in SLE, whereas clinically significant gastrointestinal involvement and musculoskeletal involvement were independent predictors in SSc. After adjustment for age, sex, and comorbidity, total COMPASS-31 remained higher than in controls in both SLE (&#x3b2; = 7.01; p = 0.013) and SSc (&#x3b2; = 11.24; p < 0.001).ConclusionAutonomic symptom burden appears to be higher in patients with SLE and SSc than in controls. The subgroup differences suggest that autonomic symptoms may cluster with specific organ involvement. COMPASS-31 may be a practical screening tool to identify patients who could benefit from further objective autonomic evaluation. Routine, structured assessment may support timely recognition and management of autonomic symptoms in clinical practice.

Hypermobile Ehlers-Danlos syndrome (hEDS), frequently presents with pain and autonomic symptoms suggestive of small fiber neuropathy (SFN). However, systematic comparisons between hEDS and idiopathic SFN (iSFN) using combined clinical, functional, and morphological approaches are lacking. We prospectively studied a population of SFN patients who also fulfilled the 2017 criteria for hEDS (hEDS/SFN) and compared them with a group of iSFN patients of similar age. All underwent SFN-Symptoms Inventory Questionnaire (SFN-SIQ), Douleur Neuropathique 4 (DN4), and the Composite Autonomic Symptom Score-31 (COMPASS-31) questionnaires, quantitative sensory testing (QST), autonomic testing (cardiovascular reflexes, sympathetic skin response, dynamic sweat test), and skin biopsy from leg, thigh, and fingertip. Clinical, morphological and functional data were compared with our normative dataset and between the two patient groups. 35 hEDS/SFN and 38 iSFN patients were included in the study. hEDS/SFN patients had earlier symptom onset (19.5&#x2009;&#xb1;&#x2009;5.9 years vs. 35.2&#x2009;&#xb1;&#x2009;8.7 years, p&#x2009;<&#x2009;0.001), more generalized distribution, and higher COMPASS-31 scores (54.3&#x2009;&#xb1;&#x2009;16.9 vs. 33.9&#x2009;&#xb1;&#x2009;19.4 p&#x2009;<&#x2009;0.01), particularly in orthostatic intolerance, gastrointestinal, and urinary domains. Postural Orthostatic Tachycardia Syndrome (POTS) was present in half of hEDS/SFN patients while it was not found in iSFN (51.5% vs. 0.0%). Skin biopsy revealed similar intraepidermal nerve fiber loss in both groups, but hEDS had greater autonomic fiber loss (p&#x2009;<&#x2009;0.05). Small fiber involvement in hEDS is characterized by earlier onset, more generalized pain and severe autonomic symptoms, and higher autonomic morpho-functional impairment compared with iSFN. Systematic autonomic assessment and targeted management should be considered in this population.

Neuronal synapses are eliminated during brain development and disease through pruning by glial cells. Individual synapses are marked for engulfment by 'eat-me' signals, which include externalized phosphatidylserine. In apoptotic cells, phosphatidylserine externalization is driven by caspase-dependent activation of Xkr scramblases 1 and inactivation of specific flippases 2 . Localized caspase activation at neuronal synapses can mediate spatially-restricted synaptic phosphatidylserine exposure leading to synapse pruning by glial cells during development and neurodegeneration 3-6 . It is unknown which caspase-regulated flippases and scramblases promote synaptic phosphatidylserine exposure and whether there are any caspase-independent mechanisms of phosphatidylserine exposure relevant for synapse elimination. To address this question, we here develop a scalable CRISPR screening approach, COMPASS-seq (compartment-anchored sgRNA screen sequencing), to uncover the genetic underpinnings of subcellular phenotypes. COMPASS-seq is compatible with in vitro and in vivo systems and a wide range of subcellular compartments; we here apply it to the neuronal synapse. We discover that inhibition of the caspase-independent, calcium-activated anoctamin ANO3 (TMEM16C) is sufficient to increase synapse numbers in vivo . ANO3 co-localizes with IP3 receptor 1 (ITPR1), a calcium channel in the endoplasmic reticulum, to form a postsynaptic signaling platform that drives spatially restricted phosphatidylserine exposure at synapses. Activation of the ITPR1 calcium channel activity is sufficient to drive synaptic phosphatidylserine exposure via an ANO3-dependent but caspase-independent mechanism. Our results suggest a mechanism for integrating synaptic activity information to control synaptic pruning. The role of ANO3 in regulating synapses could shed light on the mechanisms underlying its numerous associations with both dementia 7 and other neurological diseases 8,9 .

Urinary Autonomic Dysfunction (UAD) is a common complication of Type 2 Diabetes Mellitus (T2DM) that can substantially impair quality of life. It may manifest as loss of bladder control, difficulty initiating or maintaining urination, and incomplete bladder emptying. However, its prevalence and risk factors remain underexplored, particularly in low-resource settings like Zanzibar. This study aimed to determine the prevalence of UAD and its association with pharmacological, clinical, and lifestyle factors among T2DM patients in Zanzibar. A cross-sectional study was conducted among 364 patients with T2DM attending outpatient clinics in Zanzibar. Participants were recruited from local healthcare facilities, and data were collected using structured interviews. UAD symptoms were assessed using the urinary subdomain of the Composite Autonomic Symptom Score-31 (COMPASS-31). Descriptive and inferential statistical analyses were conducted to determine the prevalence and identify factors associated with UAD. The prevalence of urinary autonomic dysfunction (UAD) was 24.5% (89/364). Multivariable logistic regression analysis showed that a history of cigarette smoking was independently associated with higher odds of UAD (AOR&#x2009;=&#x2009;4.15, 95% CI: 1.73-9.94, p&#x2009;=&#x2009;0.001). Participants who reported rarely consuming vegetables or consuming only one portion per day had significantly higher odds of UAD than those consuming two or more portions daily (AOR&#x2009;=&#x2009;3.65, 95% CI: 1.67-7.96, p&#x2009;=&#x2009;0.001). Use of lipid-lowering medications was also independently associated with higher odds of UAD (AOR&#x2009;=&#x2009;3.81, 95% CI: 1.83-7.93, p&#x2009;<&#x2009;0.001). UAD affected nearly one-quarter of patients with type 2 diabetes mellitus in Zanzibar. Cigarette smoking, low vegetable intake, and the use of lipid-lowering medications were significantly associated with increased odds of UAD.&#xa0;These findings support the need for routine assessment of urinary symptoms in patients with T2DM and greater attention to potentially modifiable lifestyle factors. Further longitudinal studies are needed to clarify the temporal and clinical relationship between lipid-lowering medication use and UAD.

The interfacial interactions between energetic filler crystals, metallic fuels, and polymer binders govern the mechanical integrity, processing characteristics, and safety performance of polymer-bonded explosives (PBXs). Despite extensive prior investigations of individual binary interfaces, a systematic comparative dataset spanning all three interface classes under a unified computational protocol has not been available, and the effect of alloying additions to aluminum fuels on interfacial adhesion remains unexplored. To address these gaps, molecular dynamics simulations were performed to comprehensively characterize interfacial adhesion and mechanical properties across 23 binary material combinations involving &#x3b5; -hexanitrohexaazaisowurtzitane (CL-20), three metallic phases (Al, Al-2.5 at.% Li, Al-5.0 at.% B), and five polymer binders (fluororubber F2603, butadiene rubber BR, ethylene-vinyl acetate EVA, ethylene-propylene-diene monomer EPDM, and microcrystalline wax). The results reveal a three-tier hierarchy of interfacial interaction strength: metal/wax interfaces exhibit the strongest cohesion (cohesive energy density > 4.5 &#xd7; 10 9 kJ &#xb7; cm - 3 ), dominated by van der Waals forces; CL-20/metal interfaces show intermediate binding ( &#x223c; 1.8 &#xd7; 10 9 kJ &#xb7; cm - 3 ) with mixed van der Waals-electrostatic character; and CL-20/polymer interfaces represent the mechanically weakest links (< 6.2 &#xd7; 10 8 kJ &#xb7; cm - 3 ). Alloying aluminum with Li or B produced no significant enhancement in interfacial adhesion compared to pure Al. Among polymer binders, EVA exhibited the optimal balance of CL-20 interfacial adhesion and composite stiffness, while EPDM offered superior ductility. All molecular dynamics simulations employed the COMPASS III force field as implemented in the Forcite Plus module of Materials Studio 2023 (BIOVIA, Dassault Syst&#xe8;mes). Interface models were constructed using the Build Layers tool with a 6 &#xd7; 6 &#xd7; 3 Al supercell and a 2 &#xd7; 2 &#xd7; 3 &#x3b5; -CL-20 supercell. Each model was geometry-optimized (convergence threshold 1 &#xd7; 10 - 4 kcal &#xb7; mol - 1 &#xb7; &#xc5; - 1 ) and equilibrated under NVT ensemble conditions at 295 K for 500 ps. Cohesive energy density with van der Waals and electrostatic decomposition, binding energy, and mechanical properties-including elastic modulus, bulk modulus, shear modulus, Poisson's ratio, and the C 12 - C 44 anisotropy index calculated via the Voigt-Reuss-Hill approximation-were computed for all material combinations and averaged over 51 equilibrated trajectory frames.

Moral injury, and stakes-dependent invisibility commonly arise from system issues and can lead to profound emotional distress, including feelings of shame and betrayal, but both are often disregarded by institutions. Stakes-dependent invisibility highlights the lack of power, the lack of perceived recognition of one's contribution, and the lack of a voice, resulting in the failure to meet the individual's needs. The mechanism of harm behind moral injury, however, is distinctively different: moral injury goes much deeper, focusing on the internal psychological and ethical damage caused by powerlessness or by actions taken or experienced, which are in direct conflict with the person's own moral compass, violating their own conscience.

Nurses play a key role in person-centered psychiatric care by supporting patient recovery, fostering independence, and building trusting relationships. However, organizational rules may conflict with nurses' ethical values, leading to moral distress, burnout, and resignation. Drawing on the theory of positive deviance, previous research has identified how nurses may engage in positive rebel leadership, leading and practicing nursing in ways that diverge from prevailing norms, rules, codes of conduct, and workplace strategies. This study explores how such leadership in psychiatric care can support professional standards and improve patient outcomes. The aim was to describe nurses' experiences of rebel nurse leadership in psychiatric care. A qualitative descriptive design was employed, using semistructured individual interviews with 33 nurses experienced in psychiatric care. A qualitative content analysis and meta-synthesis were conducted, with the support of generative artificial intelligence in the synthesis process. The results describe nurses' experiences of rebel nurse leadership in psychiatric care as taking responsibility, guided by professional competence and an internal ethical compass; leading change and challenging hierarchies to enable holistic care that respects patients' rights and dignity; relying on the support of colleagues and management, while facing the risk of exclusion. The study shows how rebel nurse leadership, grounded in professional competence and ethical conviction, might support person-centered and high-quality psychiatric care. The findings illustrate how such leadership emerges in response to organizational norms that constrain nursing practice and frame acts of resistance as expressions of professional responsibility. The study emphasizes the importance of supporting nurses' autonomy to enable improvements in care quality and patient outcomes.

Retroperitoneal sarcoma (RPS) is a rare malignancy with poor long-term prognosis. Diagnosis often occurs at advanced stages, challenging complete resection. This study analyzes prognostic factors influencing patient survival with particular focus on the interaction between tumor differentiation and surgical radicality. A series of 223 patients surgically treated for RPS between 2009 and 2024 was analyzed. Histopathological findings, including tumor grading and resection margins, were correlated with overall survival (OS) and progression-free survival (PFS). Median follow-up was 32.6 months. Median OS was 67.4 months (95% CI: 45.3-89.5). Regarding histology, median OS was 123.5 months (95% CI: 111.2-135.9) for well-differentiated liposarcoma (WDLPS), 32.6 months (95% CI: 15.6-49.5) for dedifferentiated liposarcoma (DDLPS), 52.6 months (95% CI: 42.4-62.9) for leiomyosarcoma (LMS), and 67.5 months (95% CI: 38.6-96.3) for other RPS subtypes. Tumor grading significantly influenced patient survival: median OS was 121.2 months for G1 (95% CI: 101.3-141.2), 59.7 months for G2 (95% CI: 30.3-89.1), and 24.1 months for G3 tumors (95% CI: 4.3-44.0). As to resection margins, median OS was 89.9 months (95% CI: 16.2-163.7) for R0, 69.6 months (95% CI: 27.3-111.8) for R1 and 13.6 months (95% CI: 0.0-34.5) for R2 resections. Within the G2 subgroup, R2 resulted in significantly inferior outcomes compared to pooled R0/R1 resections (p&#x202f;<&#x202f;0.003), whereas no significant difference was observable in G1 or G3 RPS. Tumor biology drives the prognosis of RPS, attenuating the relative impact of resection margins in G1 and G3 RPS. Surgical radicality remains a decisive prognostic factor, particularly in G2 RPS. Consequently, tumor grading could serve as an additional compass within histology-driven treatment frameworks to individualize surgical decision-making.

The 2:1 CL-20/3,5-MDNP co-crystal explosive represents a novel energetic material with outstanding energy density and detonation characteristics, regarded as a promising candidate to replace RDX. Nevertheless, it still exhibits relatively high sensitivity As contrasted with insensitive high explosives such as TATB. To abate the sensitivity of the 2:1 CL-20/3,5-MDNP co-crystal explosive, a theoretical model of the 2:1 CL-20/3,5-MDNP co-crystal was constructed in this work. Five distinct polymers, including BR (polybutadiene rubber), EVA (ethylene-vinyl acetate copolymer), PEG (polyethylene glycol), F2603, and PVDF (polyvinylidene fluoride), were separately deposited onto five crystallographic surfaces: (0 -1 1), (0 -2 0), (0 0 1), (0 1 1), and (0 2 0), yielding a series of PBXs. The influences of these polymeric binders on the structural stability, trigger bond length, mechanical properties, and detonation performance of the associated PBX systems were anticipated by means of theoretical evaluations. Amidst the five PBX constructs, the CL-20/3,5-MDNP/EVA system possesses the highest binding energy, indicative of superior structural stability, interfacial compatibility, and reduced sensitivity. In contrast, while the CL-20/3,5-MDNP/PEG formulation exhibits superior initiation characteristics, it is noted to display relatively weak interfacial compatibility.In summary, the CL-20/3,5-MDNP/EVA system is recommended for applications prioritizing high stability and strong compatibility, whereas the CL-20/3,5-MDNP/PEG system is more suitable for scenarios demanding enhanced detonation performance. Within the Materials Studio software environment, the properties of 2:1 CL-20/3,5-MDNP co-crystal-based PBXs were predicted using molecular dynamics (MD) simulations. The MD simulation time step was set to 1&#xa0;fs, with a total simulation duration of 2&#xa0;ns. The isothermal-isobaric (NPT) ensemble was employed throughout the 2-ns MD run. The COMPASS force field was adopted, and the system temperature was maintained at 298&#xa0;K.

Despite decades of psychotherapy research yielding over 100 empirically supported treatment protocols, clinical practice continues to face persistent challenges, including high dropout rates averaging 15-20% in controlled settings and widespread treatment resistance. The central tension is the "research-practice gap": whereas research validates singular, manualized protocols, clinicians predominantly operate eclectically. Critically, the field lacks a standardized framework to guide how clinicians should select and sequence interventions-not merely which protocols exist. Emerging paradigms such as the Research Domain Criteria (RDoC) and modular treatment approaches point toward individualized, mechanism-driven intervention; however, a unifying clinical integration framework remains absent. This paper proposes the "Smart Therapy" model as a theoretical framework and perspective on the foundations of a potential Fourth Wave of psychotherapy-conceptualized not as a novel philosophical school, but as an Integrated Multimodal Biopsychosocial Assessment-to-Intervention model. Grounded in the neuroscience of psychotherapy, the model posits that intervention selection should be driven by a standardized, three-domain assessment: (1) biological prerequisites; (2) deep neurostructural pattern issues ("Hardware"), referring to maladaptive memory traces encoded via trauma and adversity; and (3) "active cognitive-process habits ("Software"), referring primarily to maladaptive metacognitive regulatory styles centered on the Cognitive Attentional Syndrome (CAS)". The Smart Therapy model proposes a five-level, sequenced intervention dosing framework. Level 1 establishes collaborative goal-setting and value alignment ("The Compass"). Level 2 screens and addresses biological prerequisites-including neuroinflammation, hypothalamic-pituitary-adrenal (HPA) axis dysregulation, and micronutrient deficiencies-that constitute primary barriers to psychotherapeutic efficacy. Level 3 delivers the core psychological intervention, matched to the Hardware/Software assessment: "process-focused approaches, primarily Metacognitive Therapy (MCT), and where appropriate Acceptance and Commitment Therapy (ACT), for Software presentations. Pattern-reprocessing approaches (Eye Movement Desensitization and Reprocessing [EMDR], Schema Therapy, Psychodynamic Therapy) for Hardware presentations-the latter explicitly leveraging neuroplasticity mechanisms to restructure maladaptive memory networks. Levels 4 and 5 add behavioral activation and systemic interventions as augmentation strategies. Smart Therapy offers a framework to bridge the research-practice gap by standardizing the assessment process rather than the treatment protocol. Its central, falsifiable hypothesis is whether Hardware/Software assessment-guided intervention matching-particularly the use of MCT for Software-dominant presentations-may improve remission, reduce dropout, and increase treatment efficiency-compared to treatment-as-usual and single manualized protocols. Future research should prioritize component-based dismantling studies over monolithic protocol comparisons.

Two decades after the patient safety movement reshaped how medicine understands harm, emergency care remains a complex and risk-laden environment. Despite major advances in measurement, reporting, and accountability, most safety frameworks still look backward - analyzing errors after they occur rather than anticipating and preventing them. The next frontier in safety is not more reporting; it is real-time learning. It demands systems that can detect and respond to risk as it unfolds, while learning and adapting in response to every signal. To meet that challenge, the authors developed and, in January 2023, implemented a systems-based model for quality and safety surveillance that turns the emergency department (ED) into a continuous learning environment. This model, Safety Evaluation and Networked Tracking for Real-Time Yield (SENTRY), combines Safety I (error prevention) and Safety II (adaptive resilience) principles to build a continuous surveillance and feedback ecosystem across three phases: prehospital care, emergency care including hospital-based transfers, and postdischarge care transitions and follow-up. Safety signals are captured through multiple inputs - including incident reports, key performance indicators, rapid-response activations, and 72-hour return audits - and reviewed through a standardized rubric grounded in national frameworks such as Agency for Healthcare Research and Quality Patient Safety Indicators and Reason's Swiss cheese model. Structured data from each case are integrated into a centralized Research Electronic Data Capture (REDCap) repository, enabling longitudinal analysis, recognition of recurring patterns, and prioritization of targeted interventions. Since implementation, automated pharmacist consults for prostacyclin medication have been associated with no observed delays in recognition and medication reconciliation. Comparing preintervention with postintervention, the mean and median time from ED arrival to prostacyclin reconciliation decreased by half. Automated aspiration precautions and nothing-by-mouth standing orders for high-risk patients were associated with the prevention of aspiration-related ED safety events, which decreased to zero events in 2024-2025, from an average of three identifiable events in 2023-2024. Use of an artificial intelligence-based triage tool was associated with improved throughput, alignment of acuity with clinical risk, and improved triage inequities. Same-day specialty pathways, including an outpatient diuresis clinic for heart failure patients, have been credited with averting more than 27 inpatient admissions over a 7-month period. Beyond these discrete outcomes, the framework has reshaped how safety is lived in daily practice - transforming surveillance from a retrospective exercise into a culture of continuous learning. Embedded feedback loops, charge nurse reporting, and nurse-driven safety rounds sustain engagement and momentum. Quantitative and qualitative insights now drive workflow redesign, policy, and education, allowing the ED to function as both a mirror reflecting vulnerability and a compass guiding improvement. While challenges such as alert fatigue, infrastructure demands, and sustainability remain, this model shows that continuous surveillance and adaptive learning can coexist within the realities of emergency care.

To address the gap between global sustainability commitments and action, piecemeal solutions targeting singular impacts fall short. Interventions remain fragmented across sectors and frequently prioritize downstream remediation over upstream prevention. Emphasizing the pressing importance of moving toward more systemic approaches, this paper introduces an integrated sustainability hierarchy framework. Reviewing existing hierarchies on waste, climate change, biodiversity, and more, we provide a cross-domain compass that transcends siloed debates and enables systematic development of policy agendas, impact-oriented financial portfolios, and assessment of interventions. Using the ongoing Global Plastics Treaty negotiations as an illustration, we demonstrate the value of the sustainability hierarchy for multi-dimensional sustainability challenges, going beyond existing domain-specific hierarchies. The framework contributes a practical and theoretically grounded tool for advancing systemic sustainability under conditions of accelerating socio-ecological risk and political backsliding.

Interest in psychedelic drugs has increased rapidly because of their potential therapeutic role in psychiatric disorders. Impairments in the sociocognitive skills needed to build and maintain social relationships are prominent features of many psychiatric and neurodevelopmental disorders. Emerging evidence suggests that compounds such as 3,4-methylenedioxymethamphetamine (MDMA), lysergic acid diethylamide (LSD), and psilocybin may influence these impairments. This review aimed to determine whether psychedelic drugs may modulate social cognition in individuals with psychiatric or neurodevelopmental disorders associated with cognitive impairment. A search of the MEDLINE, PsycINFO, EMBASE, and Scopus databases was conducted. Twenty studies were identified that evaluated the effects of ketamine, MDMA, psilocybin, LSD, and ayahuasca in depressive disorders, anxiety disorders, autism spectrum disorder (ASD), and post-traumatic stress disorder (PTSD). Findings included neural activation patterns suggesting that ketamine and psilocybin may modulate processes relevant to social perception, particularly facial emotion processing, in depressive disorders. Positive findings were also reported for MDMA in participants with PTSD, including improvements in self-reported psychosocial functioning, self-awareness, and self-compassion. Current evidence suggests that psychedelic drugs may modulate processes relevant to social cognition in psychiatric disorders, although direct evidence of improved social-cognitive functioning remains limited. Not applicable.