Cesarean delivery is the most commonly performed surgery worldwide. Most obstetricians and gynecologists have become facile in performing cesarean delivery. However, the sequelae of multiple previous cesarean deliveries, such as postoperative uterine scar remodeling, and uterine dehiscence or rupture increase the complexity of cesarean delivery substantially. Adhesions, uterine dehiscence, uterine rupture, hysterotomy extensions, fibroids, and bleeding are common causes of increased surgical complexity, which varies depending on the degree of abnormal anatomy encountered and clinical acuity. Adhesions alter the texture, elasticity, and tensile strength of tissues. Adhesions distort anatomic planes and relationships and require careful dissection to avoid injuring other organs, such as the bladder or bowel, and to ensure hemostasis. Fibroids not only distort anatomic relationships but also may obscure the operative field, obstruct myometrial closure, or require removal for successful fetal delivery. Uterine dehiscence and rupture distort the bladder reflection, lower the uterine segment, and lead to fetal and maternal compromise, bleeding, and risk of hysterotomy extensions. Extensions commonly occur laterally, affecting uterine artery branches, or deeply toward the cervix and vagina. Rare cases of anatomic distortion include uterine sacculation secondary to an incarcerated retroverted uterus, whereby what appears to be the uterine fundus is actually the stretched lower uterine segment and bladder. Finally, cesarean delivery during cardiopulmonary resuscitation is arguably the most technically and psychologically challenging surgical scenario, with an estimated occurrence of 1 in 9000 deliveries in 2017 according to United States National Inpatient Sample estimates. Complex cesarean delivery requires technical expertise and advanced surgical skills. Recognition of normal anatomy and pathologic anatomic changes, continued surgical education, and a strategic approach to complex obstetrical surgery are key. This review aimed to illustrate the surgical approaches for selected complex scenarios using descriptions, images, and videos to help frontline surgeons who will face increasingly challenging cases over time.

Colorectal cancer often develops from adenomas over years, necessitating early intervention. Myeloid-derived suppressor cells (MDSCs) are major immune suppressive cell types in colon cancer development from adenomas through early inflammation-induced emergency myelopoiesis. Cannabidiol (CBD) is reported to function in psychosis, coronavirus infection and some cancers through immune regulation. However, its target and underlying mechanisms in colorectal adenomas are unknown.

The antitumor effect of CBD was validated in two classical colorectal adenomas models including azoxymethane (AOM)/dextran sulfate sodium salt (DSS) induced mice model and high-fat fed Apc^min/+ mice model. Single-cell RNA sequencing was used to identified the immune environment change after CBD treatment in mice colorectal adenomas. Target responsive accessibility profiling was used to find the target of CBD in MDSCs. Subsequently, multiple immunology assays and molecular biology experiment were employed to explore the adenomas prevention mechanisms of CBD.

Here, we found that CBD prevented the incidence of colorectal adenomas in AOM/DSS model and high-fat diet fed Apc^min/+ mice model. Our single-cell RNA sequencing data and the results of immunofluorescence revealed that CBD treatment significantly decreased the number of MDSCs in both two colon adenomas models. Mechanistically, CBD bound to the guanine nucleotide exchange factor domain of EEF1B2, inhibiting its function in translational elongation and subsequent C/EBPβ synthesis. This disruption suppressed the differentiation and generation of MDSCs, leading to enhanced T-cell activation and prevention of colorectal adenoma progression.

Our findings reveal EEF1B2-mediated C/EBPβ protein synthesis as a crucial pathway in MDSC generation and highlight the potential of CBD as an early intervention strategy for colorectal adenomas.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive lymphoproliferative disorder that accounts for approximately 10–15% of pediatric and 25% of adult cases of acute lymphoblastic leukemia (ALL) and is associated with a poor prognosis, particularly in adults. In T-ALL, research has predominantly focused on the oncogenic role of NOTCH1. However, a growing body of evidence indicates that NOTCH3 also contributes to leukemogenesis and plays a non-redundant role in the disease. Furthermore, overexpression of NOTCH3 was reported in several solid tumors, including breast, ovarian, and non-small cell lung cancers (NSCLC), with functional studies supporting its oncogenic role in these malignancies. A few years ago, we identified HDAC6 as a key regulator of NOTCH3 degradation in cancer cells and demonstrated that tubacin, a compound which inhibits HDAC6, impairs NOTCH3 stability and signaling in T-ALL cells. In the present study, we demonstrate that ACY-1215, an HDAC6 inhibitor currently in clinical trials, effectively reduces NOTCH3 levels in T-ALL cells and exhibits synergistic effects with the proteasome inhibitor bortezomib. Importantly, in vivo experiments using TALL-1 cells—a NOTCH3-addicted T-ALL model—showed that the combination of ACY-1215 and bortezomib significantly suppresses leukemia progression. Given that both drugs have acceptable safety profiles in patients, we propose that this combination warrants further clinical evaluation in tumors characterized by NOTCH3 overexpression.

The online version contains supplementary material available at 10.1186/s40364-025-00878-9.

Pharmacology role-play is a participatory learning exercise in which students take on the roles of healthcare providers and patients or family members, explaining diseases and pharmacological treatments based on presented case scenarios, and actively learning through mutual communication. Traditionally conducted face-to-face within a single university, this exercise has shifted to online formats during the COVID-19 pandemic, and more recently, attempts have been made to implement inter-university online sessions that utilize remote collaborative learning. In this study, we compared the educational outcomes of online role-play conducted independently at Kochi University and Ehime University in 2020 with those of an inter-university online role-play jointly conducted by both universities in 2021. Participants were third-year medical students at Kochi University and second-year medical students at Ehime University. After completing all assignments, students were asked to complete a post-session questionnaire. Five-point Likert scale responses were analyzed, and free-text comments were further examined using text mining with co-occurrence network analysis. The results indicated that inter-university role-play, compared with single-university sessions, facilitated the recognition of diverse perspectives and promoted deeper reflection through discussion. This experience contributed to enhanced understanding of patients' perspectives, increased motivation for becoming physicians, and improved learning attitudes. These findings suggest that inter-university online role-play is an effective educational approach for enhancing learning outcomes in pharmacology education.

Inhalation delivery of protein therapeutics has emerged as a promising non-invasive alternative to traditional injectable formulations that offers potential for both localized and systemic treatment of pulmonary diseases. This review comprehensively summarizes the current advances in inhalable protein formulations, with emphasis on design strategies, formulation technologies, barriers to effective delivery, and disease-specific applications. Key aspects include the role of particle size, surface charge, and protein engineering in optimizing lung deposition and cellular uptake, as well as techniques such as spray freeze drying and PEGylation to enhance protein stability. The review also explores novel therapeutic approaches that target cystic fibrosis, asthma, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, lung infections, and cancer, including the use of antibodies, nanobodies, exosomes, and albumin-based carriers. Clinical translation remains limited, but ongoing innovation in delivery systems and molecular design is thought to hold significant promise for expanding the therapeutic landscape of inhaled protein drugs.

Our objective was to estimate the effect of initiating an inhaled corticosteroids-containing single-inhaler triple agent (ICS-LABA-LAMA) compared with a single-inhaler LABA-LAMA dual bronchodilator in patients with COPD on the risk of severe COVID-19 prior to the roll-out of vaccines.

We conducted a cohort study emulating a randomized trial, among patients with COPD aged 40 years or more in the UK, comparing those who initiated a triple inhaler with those who initiated a dual bronchodilator inhaler between March 1 and December 31, 2020. Weighting by fine stratification of the propensity score was used to account for confounders. The risk of hospitalized COVID-19 was compared with a Cox proportional hazards model in an as-treated analysis with a 30-day grace period.

The study cohort included 876 patients initiating a triple inhaler and 5010 initiating a dual LABA-LAMA inhaler. The adjusted incidence rate of hospitalized COVID-19 was 5.6 per 100 person-years in the triple inhaler group and 2.9 per 100 person-years in the dual inhaler group, with a corresponding hazard ratio (HR) of 1.96 (95% confidence interval 1.01-3.77). Sensitivity analyses on the duration of the grace period, using an intent-to-treat exposure classification, or starting follow-up 14 days after treatment initiation (accounting for treatment initiation for an undocumented SARS-CoV-2 infection) were generally consistent with the main analysis.

Patients with COPD prescribed an ICS-containing triple inhaler were potentially exposed to an increased risk of severe COVID-19 prior to the vaccine era. As SARS-CoV-2 continues to cause significant burden, these findings should be considered when determining initiation of inhaled treatment in COPD.

Venous thromboembolism (VTE) is labeled as an adverse effect of the adeno-vector-based vaccines AstraZeneca and Johnson & Johnson. We aimed to study whether there was an increase in general practitioner (GP) consultations for VTE after COVID-19 vaccination.

An exposure-anchored self-controlled cohort study was performed among COVID-19 vaccinated persons aged ≥ 12 years who were registered in the PHARMO Data Network and Nivel Primary Care Database in the Netherlands. The focal window was set at 28 days after each COVID-19 vaccination and the referent window at all time outside the focal window. Adjusted incidence rate ratios (aIRR), adjusting for SARS-CoV-2 infection, were calculated using Poisson regression.

In total, 2 133 853 persons were included. The highest increase in GP consultations for VTE was observed after Johnson & Johnson vaccination (aIRR: 3.14, 95% CI: 1.50-6.57), and a slight increase after Pfizer/BioNTech dose 1 (aIRR: 1.24, 95% CI: 1.09-1.40). Risk groups were 12-60 year-olds with increased GP consultations for VTE after Johnson & Johnson (aIRR: 2.30, 95% CI: 1.44-3.69) and Pfizer/BioNTech (aIRR: 1.29, 95% CI: 1.11-1.50), and in specific groups of males aged 12-60 years. Also, females using hormone-containing contraceptives or hormone replacement therapy (HRT) showed increased GP consultations for VTE after AstraZeneca (aIRR: 2.87, 95% CI: 1.13-7.33) and Pfizer/BioNTech (aIRR: 1.48, 95% CI: 1.10-2.01).

Increased GP consultations for VTE were observed after both vector and mRNA vaccination, in particular among males, 12-60 year olds, and females using hormone-containing contraceptives or HRT.

Natural plant-derived flavonoids hold considerable promise for the treatment of ulcerative colitis (UC) due to their intrinsic anti-inflammatory and antioxidant activities as well as their favorable biocompatibility. Nevertheless, clinical translation remains hindered by multiple barriers, including poor structural stability in the harsh gastric environment, low bioavailability, limited intestinal retention and non-specific distribution throughout the gastrointestinal tract. To overcome these limitations, we developed a pH-responsive, colon-localized nanodelivery system composed of chitosan-encapsulated, flavonoid-loaded gold nanoparticles derived from Radix Puerariae thomsonii (CRPT-NPs). CRPT-NPs exhibit pH-dependent degradability, conferring gastric protection and site-preferential release in the inflamed colon. In a dextran sulfate sodium-induced murine colitis model, CRPT-NPs markedly alleviated colonic inflammation, reduced pro-inflammatory cytokine levels, and promoted restoration of epithelial integrity. Proteomic profiling further revealed that the therapeutic effects of CRPT-NPs are associated with modulation of inflammation- and mucosal barrier-related proteins. Further mechanistic studies revealed the involvement of a DSG2-mediated ERK/p38 MAPK signaling axis in the protective effects of CRPT-NPs. Importantly, CRPT-NPs demonstrated favorable biosafety profiles in both in vitro and in vivo. Collectively, these findings support CRPT-NPs as a robust nanotherapeutic platform with translational potential for UC treatment, and provide mechanistic insight into the passive, pH-driven delivery of botanical agents to inflamed intestinal tissues.

Respiratory syncytial virus (RSV) infection is a global health concern that poses a significant threat to children under the age of five. Yet vaccine development has been hindered by historical safety concerns, including vaccine-associated enhanced respiratory disease (VAERD). To address these challenges, we rationally engineered a soluble, stable, and deimmunized flagellin-derived adjuvant (FIC) to activated mucosal immunity, which plays a critical role in protecting against respiratory diseases and is considered safe for children. In mouse models, FIC adjuvanted RSV prefusion F (preF) vaccines elicited a Th1-biased immune response, characterized by elevated expression levels of IFN-γ, IL-2, and TNF-α and robust pre-F-specific humoral, cellular, and mucosal immunity, while minimizing flagellin-associated immunogenicity. Further, a sequential immunization regimen incorporating FIC significantly enhanced protection against both upper and lower respiratory tract RSV challenges. Notably, intranasal sequential immunization enhanced antigen-specific cytokine production from splenocytes, thereby optimizing the vaccine's efficacy against RSV. These findings indicated that structure-guided adjuvant optimization combined with mucosal prime-boost strategies can overcome historical barriers in RSV vaccinology, offering a promising pathway for respiratory pathogen vaccine development.

This study analyzed the role of vaccination in preventing COVID-19-related mortality in patients with schizophrenia.

This retrospective cohort study analyzed data from the Influenza Epidemiological Surveillance Information System (Sistema de Informação da Vigilância Epidemiológica da Gripe [SIVEP-Gripe]) database, focusing on patients aged = 18 years with laboratory-confirmed COVID-19 between February 2020 and February 2023. The primary exposure was schizophrenia. The primary outcome of interest was the role of vaccines in preventing COVID-19-associated mortality. Statistical analysis included multiple binary logistic regressions to determine the impact of schizophrenia on mortality and to compare vaccine protection between cohorts.

The cohort included 2,131,089 patients, 3,516 (0.2%) of whom had schizophrenia. After adjusting for potential confounders, patients with schizophrenia presented a significantly higher risk of severe disease (OR = 1.59, 95%CI 1.39-1.81) and mortality (OR = 1.65, 95%CI 1.45-1.87). After the booster dose, protection against mortality was estimated at 67.7% (95%CI 66.5-68.7) in the non-schizophrenia cohort and 62.4% (95%CI 44.1-74.6) in the schizophrenia cohort. Mortality rate differences of approximately 20% and 10% were observed between boosted and non-vaccinated individuals among the schizophrenia and non-schizophrenia cohorts, respectively. Consequently, five patients (95%CI 4-8) with schizophrenia and 10 patients (95%CI 9-11) in the general population would need to receive a booster dose to prevent one fatality.

Our results suggest that vaccination provided similar protection against COVID-19-related mortality in individuals with and without schizophrenia. However, the magnitude of the intervention effect was double for individuals with schizophrenia due to their higher baseline risk.