医学最新文献

Gestational diabetes mellitus (GDM) poses a significant threat to perinatal health. Diagnosis based solely on glycemic parameters shows limited accuracy. The Systemic Immune-Inflammation Index (SII), a quantitative marker of inflammation, may improve diagnostic precision. This study analyzed clinical data stratified by GDM and obesity status to evaluate the diagnostic utility of SII and its underlying mechanisms involving placental NF-κB and 5-hydroxytryptamine (5-HT) signaling. We observed elevated SII levels in GDM patients, which correlated positively with glucose levels and inflammatory indicators (white blood cell count, fasting blood glucose, postprandial blood glucose). Logistic regression and receiver operating characteristic analyses confirmed the diagnostic value of SII, which was further enhanced when combined with clinical covariates. Placental expression of tryptophan hydroxylase 1 (TPH1) and NF-κB was significantly increased in GDM and closely linked to SII levels. Dysregulation of placental 5-HT signaling, characterized by increased TPH1 and monoamine oxidase A (MAO-A) expression alongside reduced serotonin transporter (SERT), was associated with maternal overweight. Moreover, SII, BMI, TPH1, and NF-κB all correlated with insulin resistance (IR). These results support SII as a non-invasive diagnostic indicator for GDM and highlight the role of placental 5-HT/NF-κB signaling in its pathogenesis, providing insights for early diagnosis and targeted therapy.

Objective: The systemic inflammatory response index (SIRI), a novel and integrated hematological index calculated as (neutrophil count × monocyte count)/lymphocyte count, has been recognized as a reliable marker of systemic inflammation. This article undertakes an analysis of clinical data from preeclampsia (PE) patients, aiming to comprehensively assess the relationship between SIRI, PE, and the severity of PE.

Methods: A total of 783 pregnant women in their third trimester were divided into severe preeclampsia (SP) (n = 275), non-SP (n = 273), and control (n = 235) groups. Pearson correlation analysis was performed to investigate the relationship between SIRI and blood pressure. Receiver operating characteristic (ROC) curves were employed to evaluate the predictive ability of SIRI. Multivariate logistic regression analysis was used to assess the association between SIRI and the severity of PE.

Results: There was a significant relationship between SIRI and systolic blood pressure (r = 0.488, p < 0.001) as well as diastolic blood pressure (r = 0.462, p < 0.001). ROC curve revealed that pregnant women with SIRI ≥ 1.84 × 10⁹/L were more likely to experience non-SP (AUC: 0.662; 95% CI: 0.615-0.710; p < 0.001), and those with SIRI ≥ 2.45 × 10⁹/L were prone to SP (AUC: 0.879; 95% CI: 0.850-0.910; p < 0.001). Multivariate logistic regression analysis demonstrated that SIRI served as an independent risk factor for both non-SP and SP (p < 0.001).

Conclusion: There is a strong correlation between SIRI and the severity of PE, and SIRI shows potential in predicting the severity of PE.

Posterior reversible encephalopathy syndrome (PRES) is a neurological complication linked to preeclampsia and eclampsia. This study compared the clinical and radiological features of PRES in patients with these conditions. This retrospective single-center cohort study from 2010 to 2024 included patients diagnosed with preeclampsia and eclampsia who underwent MRI due to neurological symptoms. Two radiologists, blinded to the clinical data, re-evaluated the MRIs twice. PRES cases were assessed based on the sites and patterns of involvement. Maternal and perinatal outcomes, along with laboratory characteristics, were reviewed through medical records. The study included 157 patients with preeclampsia and eclampsia who underwent MRI for neurological symptoms. PRES was diagnosed in 55 patients (35.0%), with a higher incidence of eclampsia (64.71%) compared to preeclampsia (20.75%). Patients with PRES were younger, had lower gravidity and parity, and were at an earlier gestational age than those with normal MRI findings. The parietal and occipital regions were the most affected in both preeclampsia and eclampsia patients with PRES. Parietal lobe and bilateral involvement were more common in the eclampsia group. Atypical involvement, including brainstem and cerebellar lesions, was observed in both groups. These findings suggest that eclampsia may represent a neurological manifestation of PRES.

Objectives: We report a case of Persistent polyclonal B-cell lymphocytosis (PPBL), a rare and benign lymphoproliferative disorder, to highlight the importance of recognising its characteristic features in order to avoid unnecessary investigations and inappropriate treatment. We also underscore the potential reversibility of disease features with smoking cessation.

Results: The patient presented with a prolonged history of low-level abdominal discomfort and unintentional weight loss on a background of a significant smoking history. Physical examination revealed splenomegaly. The laboratory results revealed a persistent lymphocytosis, prompting a referral to a haematology specialist with a working diagnosis of a malignant lymphoproliferative disorder. Subsequent investigations revealed markedly elevated polyclonal IgM with no monoclonal paraprotein via serum electrophoresis. A peripheral blood smear demonstrated characteristic binucleate lymphocytes, and flow cytometry confirmed polyclonal B-cell expansion with a normal immunophenotype. Molecular and cytogenetic analysis excluded B-cell neoplasia and supported a final diagnosis of PPBL.

Discussion: PPBL can closely mimic malignant chronic lymphoproliferative disorders. Recognition of its characteristic laboratory and morphological features, namely polyclonal lymphocytosis, atypical binucleated lymphocytes, and elevated serum immunoglobulin M (IgM) without a monoclonal paraprotein, is essential to avoid unnecessary invasive investigations and inappropriate treatment. PPBL pathogenesis remains elusive but is likely to involve a genetic predisposition and chronic antigen stimulation. Cigarette smoking appears to be the dominant environmental trigger, with cessation often leading to stabilisation or resolution of lymphocytosis. The role of the Epstein‒Barr virus has been proposed given the binucleated lymphocytes and polyclonal B-cell expansion, but evidence remains inconclusive.

Conclusion: This case highlights the importance of recognising PPBL to avoid unnecessary invasive investigations and inappropriate treatment and underscores the potential reversibility of disease features with smoking cessation.

Background: Regulatory T cells (Tregs) may influence prognosis in leukemia. This study aimed to explore the effects and mechanisms of Treg subclusters on the prognosis in B-cell acute lymphoblastic leukemia (B-ALL) using single-cell RNA sequencing (scRNA-Seq).

Methods: scRNA-seq was performed on sorted T cells from adults with newly diagnosed (Dix) B-ALL and healthy donors (HD) to establish the training cohort. Treg phenotypes, functions, and prognostic relevance were evaluated. A scRNA-seq dataset from the GEO database, including Dix and relapsed B-ALL, served as the validation cohort. Key findings were confirmed by flow cytometry. Transcription factor and cell-cell interaction analyses were conducted to clarify the mechanisms linking Treg subsets to prognosis.

Results: Tregs were divided into CCR7^high and CCR7^low subclusters. The proportion of CCR7^low Tregs was higher in B-ALL than in HD and in Rel than in Dix. Patients with higher CCR7^low Treg signature scores had a poorer prognosis. Compared with CCR7^high Tregs, CCR7^low Tregs exhibited enhanced activation, proliferation, and immunosuppression. Trajectory analysis suggested differentiation from CCR7^high to CCR7^low Tregs. IKZF2 and JUNB showed consistently increased activity and expression in CCR7^low Tregs across cohorts. CCR7^low Tregs showed increased interactions with terminal effector and exhausted CD8⁺ T cells through the LGALS9-P4HB/HAVCR2/CD44 pathway.

Conclusion: An increased proportion of CCR7^low Tregs correlated with poor prognosis in B-ALL, potentially due to enhanced activation, proliferation, and immunosuppression. IKZF2 and JUNB upregulation may promote CCR7^low Treg differentiation and function. Moreover, CCR7^low Tregs may impair CD8⁺ T cell immunity through the LGALS9-P4HB/HAVCR2/CD44 signaling.

In May 2022, a global outbreak of mpox (formerly known as monkeypox) was declared an international public health emergency. During this time, healthcare workers scrambled to respond to the outbreak amidst a lack of resources, knowledge gaps and pressures related to COVID-19. This period posed a risk of heightened moral distress, defined as distress arising from a situation in which a healthcare worker knows the right thing to do but is externally constrained from doing so. An international survey of healthcare workers was developed to understand their experiences of responding to mpox, including open-text questions regarding moral distress. Drawing on thematic analysis of these open text responses, this paper conceptualises the forms of distress experienced by health workers as 'outbreak distress'-an emotional and psychological response to the synergistic effects that arise from stressed systems, uncertainty and stigma that characterise many, and especially new, infectious disease outbreaks. In the context of pandemic preparedness, outbreak distress represents a novel concept for understanding additional pressures on healthcare systems in future unknown and re-emerging outbreaks.

The COVID-19 pandemic intensified existing social and gender inequalities, disproportionately affecting Black women living in communities like Soweto, South Africa. This paper primarily draws on qualitative data from 25 in-depth interviews conducted in 2021, complemented by descriptive survey data from 204 women collected between 2020 and 2021. We employed inductive thematic analysis guided by the socio-ecological model to examine how intersecting individual, interpersonal, community and societal factors shaped women's experiences during the pandemic. Women played vital caregiving roles, supporting families and communities despite considerable personal stress linked to fears of infection, violence, isolation and economic hardship. On an interpersonal level, stigma related to COVID-19 severely disrupted social bonds, causing mistrust and exclusion within communities. At the societal level, pre-existing distrust in government institutions worsened, contributing to vaccine hesitancy. The widespread looting and unrest observed in Soweto during lockdowns are interpreted as collective resistance reflecting the community's perceived right to survival and fair treatment amid structural neglect. We argue that public health responses must adopt multi-level strategies that recognise women's crucial caregiving roles, address stigma through community engagement, rebuild institutional trust and promote economic justice.

We report the discovery and optimization of marstacimab, a novel monoclonal antibody targeting tissue factor pathway inhibitor (TFPI), for the treatment of hemophilia A and B. Hybridoma and phage display approaches identified antibodies that blocked the TFPI: coagulation factor Xa (FXa) interaction. Antibodies bound TFPI with nanomolar affinity to multiple epitopes, including one that covered the entire FXa binding surface and others that partially overlapped the interface from different sides of the TFPI-K2 domain. Several antibodies reduced bleeding in a hemophilia A mouse injury model for up to 96 h following a single dose. Rabbit pharmacokinetic studies indicated that antibodies with ≤~1 nM TFPI-binding affinity were cleared rapidly from circulation, whereas TFPI-23 (5.72 nM) had a longer plasma residence time. Pharmacokinetic-pharmacodynamic modeling indicated that this intermediate affinity allowed circulating concentrations of antibodies such as TFPI-23 to maintain concentrations required for 50% residual activity; in contrast, higher-affinity antibodies quickly decreased to concentrations that would not effectively neutralize TFPI. The end-to-end process leading to final candidate selection incorporated rigorous assessment of biophysical properties, including thermal stability, aggregation propensity, viscosity, predicted immunogenicity, stable cell line productivity, and nonspecific binding. An optimized derivative of TFPI-23, TFPI-106 (PF-06741086, known as marstacimab), had the functional and biophysical properties with other characteristics suitable for clinical development and was selected as the final candidate. TFPI-106 elicited enhanced hemostasis in hemophilic plasma, shortened clotting time, and enhanced thrombin generation velocity. Marstacimab is now approved for patients with hemophilia A or B with or without inhibitors.

Objective: This study aimed to investigate the antitumor activity and molecular mechanism of Parthenolide (Par) against intrahepatic cholangiocarcinoma (ICC), a highly malignant liver tumor with poor prognosis, to explore potential new treatment strategies.

Methods: Par was identified through screening an FDA compound library. In vitro assays were performed to assess its effects on ICC cell proliferation, colony formation, invasion, migration, cell cycle, and apoptosis. An in vivo nude mouse tumor model was used to evaluate tumor growth inhibition. Transcriptomic analysis, molecular docking, and cellular thermal shift assays were employed to identify key targets and pathways. Changes in ferroptosis-related markers, including iron ion levels, lipid peroxides, SOD activity, and GPX4 expression, were measured. Rescue experiments with the ferroptosis inhibitor ferrostatin-1 were conducted to validate the role of ferroptosis.

Results: Par significantly inhibited ICC cell proliferation, colony formation, invasion, and migration, induced G2/M phase arrest, and promoted apoptosis in vitro; and suppressed tumor growth in vivo. Transcriptomic analysis showed upregulation of HMOX-1 and downregulation of Ubiquitin D (UBD) after Par treatment. Par was confirmed to bind to the UBD protein. Enrichment analysis indicated ferroptosis as a key pathway, with Par treatment leading to increased iron ions, lipid peroxide accumulation, reduced SOD activity, and downregulated GPX4. Ferrostatin-1 partially reversed Par-induced inhibitory effects.

Conclusion: This study demonstrates for the first time that Par exerts anti-ICC effects related to inhibition of UBD, thereby activating the ferroptosis pathway. These findings provide a novel potential strategy and therapeutic target for ICC treatment.