Citations

Cellular and molecular heterogeneity in the liver has been increasingly recognized to drive liver fibrosis progression, but the particular events that occur initially in response to liver injury and trigger immune cell recruitment remain unclear. Here, we identify epigenetically aberrant liver sinusoidal endothelial cells (LSECs) as key players in this process. Mechanistically, the epigenetic readers like bromodomain-containing protein 4–dependent (BRD4-dependent) super enhancers (SEs) activate proinflammatory genes, including promyelocytic leukemia (PML). The PML protein, in turn, binds BRD4 and amplifies proinflammatory angiocrine signaling through phase separation–dependent SE activation via PML/BRD4 condensate formation. In mouse models, LSEC-specific depletion of the PML/BRD4 complex mitigates liver inflammation and fibrosis. Single-cell RNA-seq reveals that epigenetically aberrant LSECs exhibit a reprogrammed proinflammatory angiocrine landscape in mouse fibrotic livers. TIMP1 + LSECs promote the recruitment of CD63 + monocyte–derived macrophages (MoMFs) during liver fibrosis progression. Thereby, PML/BRD4 in LSECs governs inflammatory immune cell recruitment in liver fibrosis. Pharmacological BRD4 inhibition or epigenetic PML-SE repression alleviates liver inflammation and fibrosis. In conclusion, PML/BRD4-mediated SE activation via phase separation drives proinflammatory angiocrine signaling in LSECs, initiating the inflammatory cascade and subsequent immune cell recruitment during liver fibrosis.

Background: Primary spine/pelvic tumors are aggressive, and en bloc resection is often essential. While stereotactic navigation is increasingly used for instrumentation in spine surgery, its specific role in tumor resection remains incompletely defined. Purpose: We sought to describe (1) reported rates of achieving negative margins, (2) local recurrence, (3) complications attributed to navigation, and (4) comparative outcomes from studies involving nonnavigated controls. Methods: We conducted a systematic review according to preferred reporting items for systematic reviews and meta-analysis guidelines. Databases were queried for studies investigating the use of stereotactic navigation in primary spine/pelvic tumor surgery. Outcomes including surgical margin status, local recurrence, and complications were extracted and qualitatively synthesized using a best-evidence approach. Results: Twenty-one studies with 240 patients were included. The mean patient age was 46 years with follow-up of 33.4 months. Tumors were most often located in the sacrum/pelvis (81.3%), followed by the thoracic (8.3%), cervical (5.8%), and lumbar spine (4.6%). Chordoma (31.7%) and chondrosarcoma (27.1%) were the most frequently reported types. Negative surgical margins were achieved in 88.3% of cases. Local recurrence was reported in 16% of patients, with the highest observed in chondrosarcoma (32.4%). Complications occurred in 30.3% of patients; however, only 1% (2 cases) were attributed to navigation use. Two comparative studies examining navigated versus nonnavigated cohorts suggested improved bony margins and lower recurrence risk with navigation. Conclusion: Early studies suggest that stereotactic navigation may be a feasible and safe adjunct for the resection of primary spine/pelvic tumors, particularly in achieving adequate bony margins. However, the current evidence is limited to small retrospective studies with heterogeneity in methodology, tumor type, and follow-up. Level of Evidence: Level IV: Systematic review of level-III and level-IV studies.

Failed pediatric endotracheal intubation, prompting surgical airway management via emergency front of neck access (eFONA), is an intrinsically challenging topic. While rare, all emergency airway providers must be equipped to handle these complex clinical scenarios, both through initial training and maintenance of competency. Needle cricothyrotomy is a commonly taught method in cannot intubate cannot oxygenate (CICO) scenarios for children under age eight. However, needle cricothyrotomy is technically difficult, profoundly rare, and maintaining competency is a challenge. From a multidisciplinary perspective, we examine the utility of continuing to teach needle cricothyrotomy and explore alternatives. This project group suggests that pediatric eFONA training across disciplines should focus on surgical tracheotomy rather than needle cricothyrotomy, with consideration given to specialty-specific human performance factors.

Triple-negative breast cancer (TNBC) remains highly aggressive and refractory to conventional treatments, underscoring the need for novel combination strategies. Here, we employed 2D and 3D in vitro models, transcriptomic profiling, and in vivo xenograft studies to evaluate the anticancer efficacy of cannabinoids combined with the terpene β-caryophyllene (BC) in resistant TNBC models. Among the tested cannabinoids, cannabichromene (CBC) exhibited the greatest potency, and its combination with BC at sub-toxic concentrations significantly reduced IC50 values, enhanced cytotoxicity in spheroids, and suppressed colony formation and migration. The combination treatment induced pronounced G1 cell cycle arrest and increased apoptotic cell death. Western blot analyses revealed downregulation of PARP, Survivin, mTOR, Vimentin, Glypican-5, and PD-L1, while RNA sequencing demonstrated suppression of proliferative and migratory signaling pathways alongside activation of apoptosis, autophagy, and ferroptosis-related pathways. In vivo, CBC + BC significantly inhibited tumor growth in MDA-MB-231 xenografts, outperforming single-agent treatments. Collectively, these findings demonstrate that BC synergistically enhances cannabinoid activity, yielding superior antiproliferative and anti-migratory effects, and highlight this combination as a promising therapeutic strategy for resistant TNBC.

Summary This nutshell review discusses the pathophysiology, diagnostic features, treatment strategies and avenues for future research in a recently identified thrombotic entity, monoclonal gammopathy of thrombotic significance (MGTS). MGTS is an anti‐platelet factor 4 (PF4) antibody‐mediated disorder distinct from heparin‐induced thrombocytopenia (HIT) and vaccine‐induced thrombotic thrombocytopenia (VITT), as it involves the production of persistent, monoclonal anti‐PF4 antibodies. Several subtypes of MGTS, including ‘HIT‐like’, ‘VITT‐like’ and ‘non‐HIT/VITT‐like’, exhibit unique serological profiles that can complicate diagnosis. Recognition of ‘HIT‐like’ MGTS is critical to avoid heparin exposure in these patients, which can result in adverse effects like those seen in heparin‐exposed HIT patients. ‘Non‐HIT/VITT‐like’ MGTS antibodies have only been detected in PF4‐enhanced functional testing; therefore, we recommend using these platelet‐based tests as the front‐line assay for detecting MGTS antibodies. Mass profiling using mass spectrometry is critical for the ‘fingerprinting’ of monoclonal antibodies to establish a diagnosis of MGTS. Treatments used in HIT and VITT, such as non‐heparin anticoagulants and intravenous immunoglobulin G, are typically insufficient for managing MGTS. Emerging MGTS therapies, such as plasma cell‐directed drugs and Bruton tyrosine kinase inhibitors, are discussed. The review concludes with an emphasis on areas of future research in MGTS.

Most palliative care (PC) physicians will change jobs over the course of their career, yet few supports exist to guide them through this often unfamiliar process. Job transitions frequently elicit stress and uncertainty, as individuals balance personal and professional priorities, navigate complex negotiations, and assume the inherent risks of pursuing new opportunities. Yet, when approached intentionally, a job transition can also be a transformative process that allows for self-discovery, cultivation of new skills and connections, and reshaping of one’s professional identity. This article, written by a team of PC physicians who have made job transitions themselves, offers 10 tips for navigating this professional step successfully. With emphases on authentic communication, skilled mentorship, relationship building, and exploration of local culture—the article offers practical advice to help PC physicians navigate a job transition confidently, while staying grounded in their personal values and the work they find most meaningful.

Background and objectives India’s rapid urbanisation, economic liberalisation, and rising fast food consumption are driving a nutritional transition that parallels the growing epidemic of non communicable diseases, particularly type 2 diabetes mellitus. This study examines the association between fast food expenditure and diabetes prevalence across 18 Indian States, stratified by gender and urban-rural residence. Methods The fast-food attributed diabetes index study (FADIS) utilised publicly available State-level data to evaluate correlations between fast food spending and diabetes prevalence. A novel framework, DIAGRAM (diabetes and intake gradient analysis model), was applied to parse these associations across urban and rural men and women. The WEIGHT (women’s elevated intake and glucose-health evaluation tracker) model assessed the prevalence of overweight as a predictor of diabetes in women. Results We found a strong positive correlation between fast food expenditure and diabetes prevalence among urban populations, specifically urban men (r=0.653, P =0.003) and urban women (r=0.619, P =0.0062). Rural patterns were less consistent and weaker. The WEIGHT model identified the prevalence of overweight as a significant contributor to diabetes risk among women. Interpretation and conclusions In this ecological analysis, we found that fast-food expenditure had a strong correlation with diabetes prevalence, particularly among urban men and women. In women, overweight prevalence rather than fast-food expenditure emerged as the significant predictor in multivariable analyses. These findings highlight the need for gender-sensitive and region-specific public health strategies to address India’s evolving nutritional transitions and diabetes burden.