Publications by Year: 2026

OBJECTIVES: Chronic pain affects one in five people and persists because protective nociception is converted into maladaptive neural, immune and psychological states. This review aimed to consolidate mechanistic and clinical evidence to clarify that transformation and identify leverage points for durable relief.

METHODS: Following the Scale for the Assessment of Narrative Review Articles (SANRA) guidance, we conducted a narrative review of articles published 1 January 2000-30 June 2025 across PubMed, Embase, Web of Science, Scopus, CINAHL, PsycINFO and the Cochrane Library, supplemented by grey literature. Eligible studies explored biological, immunological, genetic, epigenetic or psychosocial mechanisms or tested mechanism-targeted interventions. Data were thematically synthesised and appraised for methodological quality.

RESULTS: Convergent findings reveal a multistage cascade: peripheral sensitisation driven by aberrant ion channels and inflammatory mediators; spinal and supraspinal sensitisation sustained by glial activation and loss of inhibition; large-scale cortical and limbic reorganisation that embeds pain within memory and emotion circuits. Neuro-immune dialogue, microbiome dysbiosis, sex-specific responses and environment-induced epigenetic changes amplify these processes, while psychological stress and social adversity modulate their expression. Mapping these mechanisms to neuropathic, nociceptive and nociplastic syndromes highlights therapeutic windows exploited by emerging agents such as calcitonin-gene-related-peptide antibodies, chemogenetic nociceptor silencing, closed-loop neuromodulation, targeted cytokine blockade and microbiota modulation. Biomarker-informed precision approaches promise to replace empirical prescribing.

DISCUSSION: Synthesising cross-disciplinary evidence positions chronic pain as a systems disease requiring integrated, mechanism-based and person-centred care. Defining the shared biological scaffold clarifies why traditional symptom-focused treatments fail and outlines research priorities for disease-modifying analgesics and equitable delivery models.

There have been notable improvements in patient safety in recent years; however, significant challenges remain in reducing the incidence of preventable patient harm. Supporting patient safety efforts is increasingly important given increasing complexity of care and changing health needs, especially with aging populations. Emerging technologies and capabilities open new possibilities to address longstanding patient safety problems. For example, predictive analytics to support provider decision-making, increased patient interest in engagement in their care, and artificial intelligence provide opportunities to further reduce harm. Many of these examples support a more proactive approach to patient safety by focusing on anticipating, predicting, and preventing patient harm; however, implementation is essential to avoid unintended consequences. Additionally, health care organizations oftentimes cannot accomplish this work on their own and strategic partnerships are crucial for continued improvement. This paper proposes a strategic focus for health care leaders as they build comprehensive plans to prevent harm from adverse events. Drawing on international case examples from the Future of Health Community, it outlines actionable approaches to partnerships that can be adapted and implemented across diverse health care organizations.

Although the safety of retroviral vector (RV) gene therapy has been improved over the last years, insertional mutagenesis is still a risk factor, as seen in some of the clinical trials targeting hematopoietic stem cells. This highlights the necessity of appropriate preclinical genotoxicity assays. Our group previously developed the In Vitro Immortalization Assay (IVIM) and Surrogate Assay for Genotoxicity Assessment (SAGA) to evaluate the risk of side effects by integrating vectors. In this study, murine hematopoietic stem and progenitor cells are transduced with RVs, and genotoxicity can be detected by a proliferation advantage under limiting dilution conditions (IVIM) or the activation of genes associated with oncogenesis and stem cell-like properties (SAGA). A limitation of SAGA is the costly microarray technology. In this study, we present the digital droplet-based SAGA-Quantification (SAGA-Q) as a cost-efficient and faster alternative. Murine samples transduced with known mutagenic vector designs consistently showed upregulation of genotoxicity predictor genes. Based on a training set of 140 IVIM samples (including untransduced controls and samples transduced with long terminal repeat-driven γRV, SIN-LV.SF, SIN-LV.EFS, SIN-LV.PGK.RAG2, SIN-LV.MND.RAG1, and SIN-LV.MND.RAG2), we used random forest prediction for reliable and fast identification of genotoxic vector designs. The relevance of the predictor genes for the immortalization process was further highlighted by an elevated expression in immortalized clones. By simplifying SAGA to SAGA-Q, we aim to increase the accessibility of genotoxicity assessment and, thus, support the safer translation of gene therapy products to clinical trials.

INTRODUCTION: Routine screening for health-related social needs (HRSNs) is inconsistent, creating disparities in who gets identified and supported. Transgender patients, already facing structural stigma, may be especially affected.

METHODS: We analyzed electronic health records from a large urban safety-net system (2018-2023). We identified 2639 transgender patients with at least one outpatient visit and created a ∼11:1 comparison cohort of 23 944 cisgender patients. Overall, 7.5% (n = 1997) completed a Social Needs Questionnaire (SNQ), including 1840 cisgender and 157 transgender patients. We compared screening rates using chi-square tests and assessed adjusted odds for HRSN with logistic regression.

RESULTS: Transgender patients were screened less often than cisgender patients (5.9% vs 7.7%, P = 0.001). Among those screened, they had more than twice the odds of housing instability, poor-quality housing, and healthcare costs. Odds for interpersonal violence were th3ree times higher. Findings were consistent in sensitivity analyses adjusting for age, insurance, and neighborhood.

CONCLUSION: Transgender patients were underscreened yet faced greater HRSNs. Standardized screening and expanded supports are critical to support transgender communities.

BACKGROUND: Antiphospholipid syndrome (APS) is associated with venous thromboembolism, which can lead to chronic thromboembolic pulmonary hypertension (CTEPH). Despite treatment with pulmonary endarterectomy (PEA), some patients continue to experience pulmonary hypertension (PH), which is potentially caused by APS-related distal vasculopathy. The aim of this study was to assess persistent PH after surgery and to investigate post PEA outcomes, including immediate postoperative complications, hospitalizations within 1 year of surgery, and mortality.

METHODS: We performed a retrospective analysis of adult patients with CTEPH who underwent PEA. We included patients with and without APS. Data were obtained from the Saudi Pulmonary Hypertension Registry (2011-2022). We assessed immediate postoperative complications, rehospitalizations within 1 year, and mortality. Additionally, we evaluated patients with right heart catheterization 1 year before and after PEA for persistent PH.

RESULTS: The study included 37 patients with APS-CTEPH and 41 patients without APS. Persistent PH was observed in 43% of patients, with no significant difference between the groups. Notably, patients in the APS-CTEPH group who received pulmonary vasodilator therapy before PEA had a reduced risk of developing persistent PH. Postoperative complications were significantly higher in the APS-CTEPH group (p = 0.002). Despite these risks, the 5-year survival rate was 98.3%, with no significant difference between the groups.

CONCLUSION: APS is associated with a higher incidence of immediate postoperative complications and rehospitalizations within the 1st year after surgery. However, APS does not appear to increase the risk of persistent PH or affect long-term mortality in this cohort.

Latent factor models are valuable in bioinformatics for accounting for unmeasured variation alongside observed covariates. Yet many methods struggle to separate known effects from latent structure and to handle losses beyond standard regression. We present a unified framework that augments row and column predictors with a low-rank latent component, jointly modeling measured effects and residual variation. To remove ambiguity in estimating observed and latent effects, we impose a carefully designed set of orthogonality constraints on the coefficient and latent factor matrices, relative to the spans of the predictor matrices. These constraints ensure identifiability, yield a decomposition in which the latent term captures only variation unexplained by the covariates, and improve interpretability. An efficient algorithm handles general non-quadratic losses via surrogates with monotone descent. Each iteration updates the latent term by truncated singular value decomposition of a doubly projected residual and refines coefficients by projections. The number of latent factors is selected by applying an elbow rule to a degrees-of-freedom-adjusted information criterion. A parametric bootstrap provides valid inference on feature-outcome associations under the regularized low-rank structure. Applied to real pharmacogenomic data, the method recovers biologically coherent gene-drug associations missed by standard factor models, such as the EGFR-inhibitor link, highlights novel candidates with plausible mechanisms, and reveals gene programs aligned with compound modes of action, including a latent unfolded-protein-response module affecting drug sensitivity. These results support the framework's utility for precision oncology, yielding stronger biomarkers for patient stratification and deeper insight into drug resistance mechanisms.

OBJECTIVES: The coronavirus disease 2019 (COVID-19) pandemic had direct effects on population health through infection and morbidity, as well as indirect effects on population mental health. We estimated the network structure of post-traumatic stress symptoms (PTSS) and depressive symptoms throughout the pandemic in Korea and aimed to identify the most central and bridging symptoms.

METHODS: Participants aged 30-64 years completed mental health surveys across 3 phases of the COVID-19 pandemic: March 2020 (n=1,925), February-March 2021 (n=1,754), and December 2021-January 2022 (n=1,595). Using PTSS and depressive symptom data, we conducted network analyses, and the primary measures of symptom importance (centrality) were expected influence and bridge expected influence.

RESULTS: In the comorbidity network, although the most central symptoms fluctuated over the course of the pandemic, sleep problems were consistently identified as the most influential bridge symptoms throughout. The symptom network structure differed between the subacute and chronic phases of the pandemic.

CONCLUSIONS: We found evidence of changes in the network structure of PTSS and depressive symptoms, even as sleep problems retained a consistent role as a bridging symptom. Although overall network structures varied across phases of the pandemic, the bridging role of sleep-related symptoms remained consistently strong, suggesting that sleep problems may represent a general and enduring mechanism underlying PTSS-depression comorbidity. During future pandemics, prompt screening for sleep problems may help prevent the development of comorbidity between PTSS and depressive symptoms.

BACKGROUND: Hindfoot nail placement, whether for tibiotalocalcaneal (TTC) arthrodesis or as the index procedure for geriatric ankle fractures or comminuted pilon fractures, is challenging because of anatomical constraints. Although it may be assumed that a straight hindfoot nail should align parallel with the tibial axis, this can lead to either medial calcaneal cortical perforation, varus hindfoot malalignment, or iatrogenic medialization of the foot. This simulation study aims to quantify the angulation required for a straight hindfoot nail to achieve both intraosseous calcaneal placement and preserve native hindfoot alignment in patients without significant coronal plane malalignment.

METHODS: We retrospectively analyzed 61 weightbearing computed tomography (WBCT) scans from patients (mean age 43.6 years) with radiographically physiologic hindfoot alignment (mean hindfoot alignment angle: 1.3 degrees, Meary angle: 4.9 degrees). Using multiplanar reconstruction of CT images, 10-mm and 12-mm virtual hindfoot nails were superimposed on each coronal scan. First, the virtual nail was positioned to ensure calcaneal intraosseous placement, defined as ≥2 mm of bone between the nail and the medial calcaneal cortex. The angle between the virtual nail and the tibial anatomic axis was recorded. Second, the virtual nail was repositioned to be parallel to the tibial axis and centered within the tibial canal; medial cortical breach and distance to the medial cortex of the calcaneus were then assessed.

RESULTS: To maintain proper intraosseous calcaneal placement and alignment, a mean valgus angulation of 4.0 degrees (95% CI, 3.5-4.4) for 10-mm nails and 4.9 degrees (95% CI, 4.4-5.4) for 12-mm nails relative to the tibial axis was required. When the nail was aligned strictly parallel to the tibial axis, 60 of 61 scans demonstrated medial calcaneal breach. To avoid this breach, an average medial foot translation of 9.2 mm or iatrogenic hindfoot varus ≥5.8 degrees would be necessary.

CONCLUSION: This WBCT-based simulation suggests that a valgus orientation of approximately 4 degrees is needed for a straight hindfoot nail to (1) maintain proper calcaneal intraosseous placement and (2) preserve physiologic hindfoot alignment.

LEVEL OF EVIDENCE: Level III, retrospective cohort study.

BACKGROUND: Women with a history of gestational diabetes (GDM) have an increased risk of cardiovascular disease (CVD) throughout their lifetime. It is still unclear whether adhering to a healthy lifestyle can modify the association of GDM with the risk of CVD and mortality.

METHODS: This study included 125,435 parous women from the UK Biobank prospective cohort. The history of GDM was determined by self-reported diagnosis or hospital admission records. A healthy lifestyle score was defined by incorporating self-reported information on five modifiable risk factors, including smoking, alcohol intake, physical activity, diet, and sleep duration. The primary outcome was a composite of major CVD and all-cause mortality.

RESULTS: The mean age was 56.4 ± 7.9 yrs, and 668 participants had a history of GDM. After a median follow-up of 13.6 years, 9371 had major CVD events, and 6750 died. The association between GDM history with the composite of major CVD and all-cause mortality was stronger among women with the least healthy lifestyles (HR, 2.35 [95% CI, 1.72-3.22]) compared to those with moderately healthy (1.31 [0.84-2.06]) or the healthiest lifestyles (1.24 [0.75-2.06]; P = 0.001 for interaction). The relative excess risk due to interaction between GDM history and the least healthy lifestyles was 0.52 (0.27-0.77; P = 0.02). Compared to women with no GDM history and the healthiest lifestyle, those with GDM history and the least healthy lifestyle had a threefold increased risk of the composite outcome (3.00 [2.20-4.10]), while women with GDM history and the healthiest lifestyle did not experience a significantly higher risk (1.19 [0.71-1.97]).

CONCLUSIONS: Women with a history of GDM did not experience a higher risk of all-cause mortality and major CVD when adhering to a healthy lifestyle in midlife.

Hypertrophic cardiomyopathy (HCM) is a common, often genetic, cardiomyopathy that is characterized by substantial heterogeneity. Cardiovascular magnetic resonance (CMR), with its high spatial resolution and tomographic imaging capability, has emerged as an imaging modality particularly well suited to characterize the diverse phenotypic expression in this disease. CMR allows for accurate diagnosis of HCM and differentiating HCM from other causes of left ventricular (LV) hypertrophy. CMR plays a critical role in risk stratification and prevention of sudden death in HCM, identifying important risk markers including massive LV hypertrophy, LV apical aneurysms, end-stage HCM, and extensive late gadolinium enhancement, with one or more of these risk markers is associated with a higher risk of sudden death and deserving consideration for primary prevention implanted cardioverter defibrillators. CMR also aids in management of LV outflow obstruction by defining outflow tract anatomy and guiding pre-procedural surgical planning for surgical septal myectomy. The 20-year experience of CMR in HCM has helped transform HCM into a contemporary treatable disease associated with low mortality rates for the vast majority of patients.